Name: 150322-43-3|5-(2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate|98%
Brand: Ambeed
SKU: A125835
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1
[ 150322-38-6 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
65%	With acetic anhydride In <i>N</i>-methyl-acetamide; mineral oil	R.1.c (c) (c) 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine To a solution of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (2.6 g) obtained in reference example 1(b) in a mixture of dimethylformamide (10 ml) and acetic anhydride (5 ml), cooled in an ice bath, was added sodium hydride (60% dispersion in mineral oil, 0.35 g), then the mixture was stirred at the same temperature for 30 minutes, and then at room temperature for 3 hours. After the reaction, the mixture was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification of the residue by chromatography on a silica gel column using toluene/ethyl acetate=3/1 as the eluant, the product was crystallized from diisopropyl ether to afford the title compound (1.88 g, yield 65%) as white crystals. mp: 120-122° C.; 1H NMR (CDCl3) δppm: 0.80-0.95 (2H, m), 0.99-1.16 (2H, m), 2.27 (3H, s), 2.21-2.34 (1H, m), 2.70-2.95 (4H, m), 3.47 (1H, d, J=15.0 Hz), 3.57 (1H, d, J=15.0 Hz), 4.83 (1H, s), 6.27 (1H, s), 7.10-7.55 (4H, m); IR (KBr) νmaxcm-1: 1758, 1704; Mass (CI, m/z): 374 (M++1), 304; Anal Calcd. for C20H20FNO3S: C, 64.32; H, 5.40; N, 3.75 Found: C, 64.46; H, 5.39; N, 3.73.
65%	With acetic anhydride; sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 3.5h;	1.B.c To a solution of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydro thieno[3,2-c]pyridine (2.6 g) obtained in reference part (b) in a mixture of dimethylformamide (10 ml) and acetic anhydride (5 ml), cooled in an ice bath, was added sodium hydride (60% dispersion in mineral oil, 0.35 g), then the mixture was stirred at the same temperature for 30 minutes, and then at room temperature for 3 hours. After the reaction, the mixture was extracted with ethyl acetate and the extract washed with saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After purification of the residue by chromatography on a silica gel column using toluene/ethyl acetate=3/1 as the eluant, the product was crystallized from diisopropyl ether to afford the title compound (1.88 g, yield 65%) as white crystals. Mp: 120-122° C.; 1H NMR (CDCl3) δ ppm: 0.80-0.95 (2H, m),0.99-1.16 (2H, m), 2.27 (3H, s), 2.21-2.34 (1H, m), 2.70-2.95 (4H, m), 3.47 (1H, d, J=15.0 Hz), 3.57 (1H, d, J=15.0 Hz), 4.83 (1H, s), 6.27 (1H, s), 7.10-7.55 (4H, m); Mass (Cl, m/z): 374 (M ++1), 304; Anal Calcd. for C20H20FNO3 S: C, 64.32; H, 5.40; N, 3.75. Found: C, 64.46; H, 5.39; N, 3.73.
	Multi-step reaction with 2 steps 1.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 2.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 2.2: 6 h / 0 - 5 °C

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - US2003/134872, 2003, A1
[2]Current Patent Assignee: KG ACQUISITION, LLC - US2007/243243, 2007, A1 Location in patent: Page/Page column 21
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2

2
[ 952340-38-4 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid In acetyl chloride; toluene	R.8 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) Reference Example 8 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) A mixture of 300 mg of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 3 ml of acetic acid was allowed to react under stirring at room temperature (20° C.) for 0.25 hour. To the obtained mixed solution was added 0.5 ml of an acetic acid solution in which 79 mg of acetyl chloride was dissolved, and the mixture was further stirred at room temperature (20° C.) for 4 hours. Thereafter, 552 mg of acetyl chloride was added to the mixture, and the resulting mixture was allowed to react under leaving to stand at room temperature (20° C.) overnight. To the obtained reaction mixture were added 20 ml of toluene and 80 ml of an aqueous saturated sodium hydrogen carbonate solution, and separation operation was carried out to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a concentrate. The obtained concentrate was purified by silica gel chromatography (eluent; ethyl acetate: hexane =1:3) to obtain 180 mg of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.
	With p-toluenesulfonic acid monohydrate; acetic anhydride; acetic acid In toluene	R.10 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) Reference Example 10 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) A mixture of 500 mg of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 5 ml of acetic acid and 230 mg of p-toluenesulfonic acid monohydrate was stirred at room temperature (20° C.) for 3 hours to obtain a mixed solution. To the obtained mixed solution was added 530 mg of acetic anhydride, and the mixture was allowed to react under stirring at room temperature (20° C.) for 88 hours. To the obtained reaction mixture were added 20 ml of toluene and 120 ml of an aqueous saturated sodium hydrogen carbonate solution, and separation operation was carried out to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a concentrate. The obtained concentrate was purified by silica gel chromatography (eluent; ethyl acetate: hexane =1:3) to obtain 360 mg of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. In the following, a process for preparing a salt of a 5-alkyl-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2-one is explained by Reference examples 11-1 and 11-2.
	With p-toluenesulfonic acid monohydrate; acetic anhydride In toluene	R.9 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) Reference Example 9 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) A mixture of 530 mg of acetic anhydride and 230 mg of p-toluenesulfonic acid monohydrate was stirred at room temperature (20° C.) for 0.5 hour to obtain a mixed solution. To the obtained mixed solution was added 500 mg of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, and the mixture was stirred at room temperature (20° C.) for 21 hours. Thereafter, 530 mg of acetic anhydride was added to the mixture, and the resulting mixture was allowed to react under further stirring for 50 hours. To the obtained reaction mixture were added 20 ml of toluene and 30 ml of an aqueous saturated sodium hydrogen carbonate solution, and separation operation was carried out to obtain an organic layer. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a concentrate. The obtained concentrate was purified by silica gel chromatography (eluent; ethyl acetate: hexane =1:3) to obtain 310 mg of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

Multi-step reaction with 2 steps 1: hydrogenchloride; water / ethyl acetate / 20 °C 2: acetic acid / toluene / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - US5874581, 1999, A
[2]Current Patent Assignee: UBE INDUSTRIES LIMITED - US5874581, 1999, A
[3]Current Patent Assignee: UBE INDUSTRIES LIMITED - US5874581, 1999, A
[4]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1

3
aqueous potassium dihydrogen phosphate [ No CAS ]
potassium dihydrogen phosphate [ No CAS ]
[ 952340-38-4 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine In tetrahydrofuran; ethanol; acetic anhydride	R.7 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) Reference Example 7 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) A mixture of 6.7 g of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 3.04 g of triethylamine, 0.2 g of 4-dimethylaminopyridine and 15 ml of tetrahydrofuran was stirred at room temperature (20° C.) for 0.25 hour. Thereafter, 7 ml of a tetrahydrofuran solution in which 4.7 g of acetic anhydride was dissolved was added dropwise to the mixture, and the resulting mixture was reacted under further stirring at room temperature (20° C.) for 4.5 hours. The obtained reaction mixture was cooled to -10° C., 1.1 ml of a 10 mM potassium dihydrogen phosphate aqueous solution was slowly added dropwise thereto, and the mixture was stirred at -10° C. for 1 hour. Thereafter, a solution of 9.9 ml of a 10 mm aqueous potassium dihydrogen phosphate solution and 11 ml of ethanol was further added dropwise to the mixture, and the resulting mixture was stirred at -10 ° C. for 0.5 hour to obtain precipitated crystals. The obtained precipitated crystals were filtered and dried to obtain 5.1 g of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - US5874581, 1999, A

4
aqueous potassium dihydrogen phosphate [ No CAS ]
[ 952340-38-4 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine In acetic anhydride; acetonitrile	R.4 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) Reference Example 4 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) A mixture of 1.0 g of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 0.46 g of triethylamine, 14 mg of 4-dimethylaminopyridine and 3 ml of acetonitrile was stirred at room temperature (20° C.) for 0.25 hour. Thereafter, 2 ml of an acetonitrile solution in which 0.46 g of acetic anhydride was dissolved was added dropwise to the mixture, and the resulting mixture was allowed to react under further stirring at room temperature (20° C.) for 1 hour. To the obtained reaction mixture was added 3.3 ml of a 10 mM aqueous potassium dihydrogen phosphate solution, and the mixture was stirred at room temperature (20° C.) for 1 hour to obtain precipitated crystals. The obtained precipitated crystals were filtered and dried to obtain 0.76 g of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. Melting point; 120° to 121° C.

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - US5874581, 1999, A

5
2-(tert-butyldiphenylsilyloxy)-5-(α-cyclopropyl-carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
		R.6 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) Reference Example 6 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) In the same manner as in Reference example 4 except for using 1.0 g of 2-(tert-butyldiphenylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine in place of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetra-hydrothieno[3,2-c]pyridine, a reaction and procedures were carried out to obtain 0.66 g of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine.

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - US5874581, 1999, A

6
2-triisopropylsilyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
		R.5 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) Reference Example 5 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (a compound of Compound No. 72) In the same manner as in Reference example 4 except for using 1.0 g of 2-triisopropylsilyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine in place of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine, a reaction and procedures were carried out to obtain 0.70 g of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine.

Reference： [1]Current Patent Assignee: UBE INDUSTRIES LIMITED - US5874581, 1999, A

7
[ 150322-43-3 ]
CS-747 hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride In di-isopropyl ether; water; ethyl acetate at 20℃; Inert atmosphere;	13.A Example 13Preparation of 2-(Acetoxy)-5-(a-cyclopropyl carbonyI-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c]-pyridine Hydrochloride (Prasugrel hydrochloride) Method AIn a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2- (Acetoxy)-5-(a-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]- pyridine Hydrochloride (100 g, 0.27 moles) was suspended in ethyl acetate (1500 ml) under nitrogen atmosphere at 20 +/-5 °C and stir for 10 to 20 min. Add active carbon in the reaction mass and stir for 5 to 10 min. Filter the reaction mass through hyflo supercell and washed with ethyl acetate. Cool the reaction at 5 +/-2 °C and slowly add 15% hydrochloric acid solution in Diisopropylether at 5 +/-2 °C and heat the reaction at 60 +/-2 °C stir for 1 to 2 hrs. Filter the product and slurry washed with ethyl acetate Dry the material under vacuum at 40-45 °C to obtain prasugrel hydrochloride (95 g, 99%).
98%	With hydrogenchloride In tetrahydrofuran at -5 - 20℃; for 16h;	8 Example 8 The Method for Preparing Crystalline Form A of Prasugrel Hydrochloride Prasugrel free base prepared by example 3 (2.3 g) disclosed herein was dissolved in tetrahydrofuran (30 ml) with stirring at room temperature until complete dissolution and the resulting mixture was further stirred for 10 minutes. A solution of hydrochloric acid in tetrahydrofuran (0.53 ml hydrochloric acid (37 wt. %) dissolved in 5 ml tetrahydrofuran) was added slowly to the resulting mixture over 1 hour at room temperature. The mixture was stirred at -5° C. for 15 hours followed by filtration. The obtained crystal was washed with tetrahydrofuran and dried under vacuum at 50° C. for 24 hours. The resulting product was prasugrel hydrochloride crystalline Form A. The yield was 98%.
98.2%	With acetyl chloride; <i>tert</i>-butyl alcohol In acetone at 20℃;	3 Example 3 The preparation method of high-purity prasugrel hydrochloride according to the present invention comprises the following steps: dissolving 10.0g (26.8mmol) Prasugrel in 100.0mL acetone in a 250mL round bottom flask, adding 3.8ml (40.2mmol) tert-butyl alcohol after stirring at room temperature, 2.3 mL (32.1 mmol) of acetyl chloride was slowly added dropwise and a white precipitate was quickly obtained upon completion of the addition. After 5h filtration, 20.0mL acetone washing, 40 vacuum drying 6h 10.8g Prasugrel Hydrochloride white solid, the yield of 98.2%, HPLC purity of 99.7%.

92.2%	With hydrogenchloride In acetone at 0℃; for 2h; Green chemistry;	3 Prasugrel (I) Preparation: 3 Example Connected to a stirrer, a thermometer and a 250 ml airway four-necked flask, 80 g of acetone was added, prepared in Example 1 of 18.6 g (0.05 mole) of 2-acetoxy-5-(1- cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c] pyridine access between (the VI), cooled to 0 ° C 4.5 -5 g of dry hydrogen chloride gas, thereafter 0 ° C the reaction was stirred for 2 hours, filtered, the filter cake was washed with 10 g of cold acetone, and dried to give a white solid prasugrel (I) 18.9 g, m.p. 194-196 ° C, yield 92.2%, HPLC purity.: 99.8%
91.72%	With chloro-trimethyl-silane; water In acetone at 45℃;	18 Example 18. Preparation of Prasugrel hydrochloride 30 g of prasugrel base pure were mixed with 300ml of acetone and 10.66 ml of TMS- Cl. The mixture was heated up to 45 °C and 0.16 ml of water were added. Afterwards, the mixture was cooled down to 0-5 °C and stirred for lh. The mixture was filtered. The solid obtained was dried at 60-65 °C for 4 hours to yield 30.2 g of prasugrel hydrochloride. Yield: 91.72%. Purity (HPLC): 99.80%.
89.3%	With hydrogenchloride In water; acetone at 20℃; for 3h;	5 5. Og (13.4 mmol) of Prager was added to a three-necked flask, 25 ml of acetone was added, and 1.18 ml (14.1 mmol) of 37% concentrated hydrochloric acid was added dropwise with stirring at room temperature for about 10 minutes. After 3 hours the precipitate was filtered, washed with 3 ml of acetone and dried in vacuo to give 4.93 g (0.012 11111) of white crystals in 89.3% yield
88.1%	With hydrogenchloride In ethanol; Isopropyl acetate at 20 - 45℃;	1 Prasugrel base (1.324 g; 3.545 mmol) is dissolved in isopropyl acetate (13 ml) at a temperature of up to 45 °C and cooled to the room temperature. To this solution a solution of HCl in ethanol (0.753 g containing 0.123 g of HCl) is added dropwise under stirring. The reaction mixture was stirred at the room temperature for 1 hour. The separated crystalline substance was aspirated and dried freely in air. 1.28 g of prasugrel hydrochloride of form B was obtained (88.1 %) with the melt, point = 165.8 to 168.2 °C. HPLC: purity 99.8%; content of the compound of formula III 0.1%.
88%	With isopropanolic hydrochloride In acetone at 50℃; for 1h; Large scale reaction;
88%	With hydrogenchloride In acetone at 0℃; Inert atmosphere;
80.7%	With hydrogenchloride In ethanol; butanone at 0 - 35℃; for 1h;	8 Example 8Preparation of prasugrel hydrochloride, form APrasugrel base (2.55 g; 6.82 mmol) is dissolved in ethyl methyl ketone (25 ml) at a temperature of up to 35 °C and cooled down to 0 °C in a water + ice bath. To this solution a solution of HCI in ethanol (1.45 ml containing 0.237 g of HCI) is added dropwise under stirring and at the temperature of 0 °C. The reaction mixture was stirred at the temperature of 0 °C for 1 hour. The separated crystalline substance was aspirated and dried freely in the air. 2.26 g of prasugrel hydrochloride of form A (80.7 %) were obtained with the melting point = 122 to 124 °C. HPLC: purity 99.3%; content of the compound of formula II 0.06%. X-ray analysisTable 6: Characteristic peaks of prasugrel hydrochloride, form AThe X-ray powder diffraction pattern is presented in the Annex in fig. 6a, DSC curve is in fig. 6b.
	Stage #1: prasugel In acetone at 32℃; Stage #2: With hydrogenchloride In water; acetone at 30 - 52℃; for 4h;	1 To 8.00 g of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 398 mg of activated clay was added 43 g of acetone, and the resulting mixture was then stirred at 32°C. The reaction solution was filtered, the residue was washed with 4.41 g of acetone, and then 1.12 g of 36% concentrated hydrochloric acid at 52°C was added dropwise to the solution over a period of one minute. Thereto was added as a seed crystal 238 mg of crystal B2 obtained by the method described in JP2002-145883, and the resultant mixture was then stirred at the same temperature for one hour. In addition, 1.07 g of 36% concentrated hydrochloric acid was added dropwise thereto over a period of one hour, and the resultant mixture was then stirred at 40°C for 2 hours and further at 30°C for 1 hour. The precipitated crystal was collected by filtration, washed with 15.8 g of acetone, and dried under reduced pressure at 50°C for 5 hours to provide 8.01 g of the title compound. Liquid chromatography of the resultant high-purity prasugrel hydrochloride is shown in Figure 5. Measurement conditions in Figure 5 are as follows. (Measurement Conditions) Detector: ultraviolet absorptiometer (measuring wavelength; 240 nm) Analytical Column: Cadenza CD-C 18, inner diameter; 4.6 mm, length; 15 cm, particle size; 3 µm Guard Column: none Column Temperature: 40°C Mobile Phase: 0.01 mol/L potassium dihydrogenphosphate aqueous solution:tetrahydrofuran:acetonitrile = 13:5:2 (V/V/V) Flow Rate: 1.0 mL/min.
	With hydrogenchloride In water; acetone at 40℃; for 1.01667h;	13.A.1 Concentrated hydrochloric acid (37%, d=1.19, 1.054 ml, 13.18 mmol) was added dropwise over 1 minute to a solution of pra- sugrel (5g 13.39 mmol) in acetone (50 ml) with stirring at 400C. The reaction mixture was stirred at the same temperature for 60 minutes. No crystallisation was observed. The volume of the mixture was then reduced to 10 ml and the solution was added dropwise to a suspension of 25g lactose (Lac- topress anhydrous 265) in 100 ml acetone and stirred for 15 minutes (homogeneous suspension) . Acetone was evaporated at 30°C for 1 hour and at 200C over night (rotary vane pump) . A free flowing powder was obtained. The prasugrel-HCl lactose premix had a water content of 0.85 % (Karl-Fischer titration) .
	With hydrogenchloride In water; acetone at 30 - 52℃; for 5h;	1.4; 2.3 To 8.00 g of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine obtained in (3) and 398 mg of activated clay was added 43 g of acetone, and the resultant mixture was then stirred at 32°C. The reaction solution was filtered, the residue was washed with 4.41 g of acetone, and then 1.12 g of 36% concentrated hydrochloric acid was added dropwise to the solution at 52°C over a period of one minute. Thereto was added as a seed crystal 238 mg of crystal B2 obtained by the method described in Japanese Patent Laid-Open No. 2002-145883, which was then stirred at the same temperature for one hour. In addition, 1.07 g of 36% concentrated hydrochloric acid was added dropwise thereto over a period of one hour, which was then stirred at 40°C for 2 hours and further at 30°C for 1 hour. The precipitated crystal was collected by filtration, washed with 15.8 g of acetone, and dried under reduced pressure at 50°C for 5 hours to provide 8.03 g of the title compound. Melting point: 194 to 197°C.
	In methanol; dichloromethane; water at 25 - 40℃;	11 EXAMPLE 11 : PREPARATION OF PRASUGREL HYDROCHLORIDE AMORPHOUS FORM.To a solution of prasugrel free base (500 mg) in methylene dichloride (10 mL) in a clean and dry round bottom flask, a mixture of methanol (2 mL) and aqueous hydrochloric acid (135 mg) is added at 25 0C. The reaction mixture is heated to 40 0C and then the solvent is distilled off. To the residue, isopropyl alcohol (10 mL) is added and then the solvent is distilled off completely. The obtained solid is dried for 4 hours at 40 0C to afford 510 mg of the title compound.
	With hydrogenchloride In ethyl acetate at 40℃; for 1.25h;	16 EXAMPLE 16: PREPARATION OF PRASUGREL HYDROCHLORIDE CRYSTALLINE FORM E.A solution of prasugrel free base (500 mg) and ethyl acetate (10 mL) in a round bottom flask are heated to 40 0C for 15 minutes. The pH of the reaction mass is adjusted to 2.0 using a solution of ethyl acetate hydrochloride (150 mg). The contents are stirred for 60 minutes and filtered. The wet cake is then dried at 60 0C for 2 hours to afford 400 mg of the title compound.
	With hydrogenchloride In isopropyl alcohol at 40℃; for 1.25h;	15 EXAMPLE 15: PREPARATION OF PRASUGREL HYDROCHLORIDE CRYSTALLINE FORM D.A mixture of prasugrel free base (500 mg) and isopropyl alcohol (10 mL) in a round bottom flask are heated to 40 0C for 15 minutes. The pH of the reaction mass is adjusted to 2 using a solution of isopropyl alcohol hydrochloride (150 mg). The contents are stirred for 60 minutes and then filtered. The wet cake is then dried at 60 0C for 2 hours to afford 400 mg of the title compound.
	With hydrogenchloride In acetone at 40℃; for 2h;	18 EXAMPLE 18: PREPARATION OF PRASUGREL HYDROCHLORIDE CRYSTALLINE FORM B1.To a solution of prasugrel free base (500 mg) and acetone (10 mL) in a round bottom flask at 40 0C, hydrogen chloride gas purged in acetone (1.95 g) is added and it is stirred at the same temperature for two hours. The precipitated solid is filtered and dried at 60 0C for 3 hours to afford 400 mg of the title compound.
	In water; iso-butanol at 28 - 40℃; for 1 - 1.25h;	13; 14 EXAMPLE 13: PREPARATION OF PRASUGREL HYDROCHLORIDE CRYSTALLINE FORM C.To a mixture of prasugrel free base (1000 mg) and 2-butanol (20 mL) in a round bottom flask at 40 0C, aqueous hydrochloric acid (271 mg) is added and the content is stirred for 60 minutes. The precipitated solid is filtered and dried at 60 0C for 2 hours to afford 800 mg of the title compound.EXAMPLE 14: ALTERNATE PROCESS FOR THE PREPARATION OF PRASUGREL HYDROCHLORIDE CRYSTALLINE FORM C.To a solution of prasugrel (500 mg) and 2-butanol (10 mL) in a round bottom flask at 28 0C, a mixture of 2-butanol (2.0 mL) and aqueous hydrochloric acid (135 mg) is added and it is stirred for 15 minutes. The reaction mixture is seeded with 2.0 mg of crystalline Form C crystal and stirred for 60 minutes. The separated solid is filtered, washed with 2-butanol (5 mL) and dried at 60 0C for 4 hours to afford 400 mg of the title compound.
	With hydrogenchloride In ethyl acetate; acetone at 25 - 55℃; for 0.75h; Inert atmosphere;	37 Example-37: Preparation of 5-[(lRS)-2-cyclopropyl-l-(2-fIuorophenyl)-2- oxoethyI]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride compound of formula-la:A mixture of 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate(100 -grams) prepared as per example-36 and acetone(900 ml) was heated to 30-40°C. Added 5 grams of activated carbon to the above reaction mixture at same temperature and stirred for 15 minutes. Filtered the reaction mixture and the filtrate was heated to 50-55°C under nitrogen atmosphere. Added slowly 500 ml of ethyl acetate hydrochloride solution to the reaction mixture at 50-55°C. Stirred the reaction mixture for 45 minutes at 25-30°C under nitrogen atmosphere. Filtered the precipitated solid and washed with acetone. Acetone(1000 ml) was added to the obtained compound and stirred for 45 minutes at 25-30°C under nitrogen atmosphere. Filtered the precipitated solid and washed with acetone. Dried the compound to get the highly pure title compound.Yield: 83 grams.Purity by HPLC: 99.78% ; PSD: D[4>3]=62.204 μ; D10 =2.330 μ, D50=50.777 μ; D90=l 17.203 μ.
	With hydrogenchloride In ethyl acetate; acetone at 0 - 5℃; for 0.75h;	9 Example-9: Preparation of Prasugrel hydrochloride crystalline form-B2: Dissolved the 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate (100 grams) in acetone (800 ml) and then heated to 35-40°C. Carbon (5 grams) was added to the reaction mixture and stirred for 15 minutes. Filtered the reaction mixture and filtrate was cooled to 0-5°C and then ethyl acetate hydrochloric acid (500 ml) was added to it. Then the reaction mixture was stirred for 45 minutes at 0- 5°C. The precipitated solid was filtered and washed with acetone. To the wet material added acetone (800 ml) and stirred for 45 minutes at 25-30°C. Filtered the reaction mixture, washed with acetone and dried the compound to get the title compound. The obtained prasugrel hydrochloride is packed using clear and block polyethylene bags under vacuum.Yield: 89 grams; Purity: 99.65 % by HPLC
	With hydrogenchloride In isopropyl alcohol; butanone at 35 - 40℃; for 1.33333h;	4 Example-4 Preparation of Prasugrel Hydrochloride 100 gm of Pure Prasugrel was charged in methyl ethyl ketone (800ml) in a clean & dry RBF. This reaction mass was stirred at room temperature for 30 min. and filtered through hyflow followed by washing hyflow bed with methyl ethyl ketone (200 ml) to obtain filtrate. The filtrate was heated up to 35-40°C to obtain reaction mixture. To this reaction mixture, IPA: HCl (33.5 ml) solution (solution prepared by purging HCl gas in isopropanol) was charged at 35-40°C in 20 min. The reaction mixture was maintained at 35-40°C for 60 min to obtain solid. The solid was filtered and washed with methyl ethyl ketone and dried in tray dryer at 50-55o C under vacuum to get prasugrel HCl (70-90 gm) polymorphic form B2. HPLC purity ~ above 99 % Desacetyl prasugrel impurity ~ less than 0.1 %
	With hydrogenchloride In isopropyl alcohol; acetone at 30 - 48℃; for 3.16667h;	4 Example 4: Preparation of prasugrel hydrochloride. Prasugrel (3 g) (obtained from example 3 and acetone (24 mL) are charged into a round bottom flask at 28°C and stirred until a clear solution is obtained. Activated carbon (0.06 g) is added to the reaction mass at 30°C and stirred for 30 minutes at the same temperature. The reaction mass is filtered under vacuum through Hyflow and washed with acetone (6 mL). The filtrate is charged into a round bottom flask at 28°C and heated to 48°C for 30 minutes. An isopropyl alcohol solution of hydrochloric acid (2.9 mL, 10%) is added by drops to the reaction mass at 48°C over 10 minutes. The reaction mass is seeded with prasugrel hydrochloride (0.006 g) at 48°C and stirred at the same temperature for 1 hour 30 minutes. The reaction mass is stirred for 1 hour 30 minutes at 30°C. The solid is collected by filtration, washed with acetone (3 mL), and then dried under vacuum at 65°C for 7 hours. Yield: 2.6 g; HPLC Purity: 99.87%; 3-fluoro impurity: 0.037%; any other impurity: less than 0.1%.
	With hydrogenchloride In ethyl acetate at 20 - 30℃; for 4h;	3 Preparation of prasugrel hydrochloride Prasugrel (50 gm) was dissolved in ethyl acetate (500 ml) and then added hydrochloric acid in ethyl acetate (72 ml) at room temperature. The reaction mass was maintained for 4 hours at room temperature and filtered. The solid obtained was dried to obtain 49.5 gm of prasugrel hydrochloride (HPLC Purity: 99.62%; Di0: 2.99 μιη, D50: 53.54 μτη and D90: 103.70 μϖι).
	With hydrogenchloride In ethyl acetate; acetone at 20 - 40℃; for 6.25h; Inert atmosphere;	38 Example 38 Preparation of 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride Compound of Formula-1a A mixture of 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate(100 grams) prepared as per example-36 and acetone(900 ml) was heated to 30-40° C. Added 5 grams of activated carbon to the above reaction mixture at same temperature and stirred for 15 minutes. Filtered the reaction mixture and the filtrate was heated to 30-40° C. under nitrogen atmosphere. Added slowly 500 ml of ethyl acetate hydrochloride solution to the reaction mixture at 20-30° C. Stirred the reaction mixture for 4 hrs. at 25-30° C. under nitrogen atmosphere. Filtered the precipitated solid and washed with acetone. Acetone(1000 ml) was added to the obtained compound and stirred for 6 hrs at 25-30° C. under nitrogen atmosphere. Filtered the precipitated solid and washed with acetone. Dried the compound to get the highly pure title compound. Yield: 83 grams. Purity by HPLC: 99.78%; PSD: D[4,3]=58.57882 ; D10=2.807μ, D50=44.266μ; D90=127.775μ.
	With hydrogenchloride In water; acetone at 40 - 45℃;
	With hydrogenchloride In water; acetone at 39.99℃;

Reference： [1]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1 Location in patent: Page/Page column 24
[2]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - US2014/155351, 2014, A1 Location in patent: Paragraph 0090
[3]Current Patent Assignee: SHANDONG LUKANG PHARMACEUTICAL CO., LTD. - CN105601643, 2016, A Location in patent: Paragraph 0038
[4]Current Patent Assignee: XINFA PHARMACEUTICAL CO LTD - CN104592250, 2016, B Location in patent: Paragraph 0023-0025; 0056-0057
[5]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2013/14295, 2013, A1 Location in patent: Page/Page column 26-27
[6]Current Patent Assignee: JIANGSU FANGSHENG PHARMACEUTICAL - CN103923101, 2017, B Location in patent: Paragraph 0028; 0029
[7]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/69473, 2011, A1 Location in patent: Page/Page column 8
[8]Location in patent: experimental part Aalla, Sampath; Gilla, Goverdhan; Metil, Dattatray Shamrao; Anumula, Raghupathi Reddy; Vummenthala, Prabhaker Reddy; Padi, Pratap Reddy [Organic Process Research and Development, 2012, vol. 16, # 2, p. 240 - 243]
[9]Ou, Wenhua; Yi, Weiyin; Liu, Feng; Pan, Xianhua; Peng, Xijiang [Journal of Chemical Research, 2013, vol. 37, # 6, p. 369 - 371]
[10]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57593, 2011, A2 Location in patent: Page/Page column 16-17
[11]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2003136, 2008, A1 Location in patent: Page/Page column 8-9
[12]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 21-22
[13]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2123656, 2009, A1 Location in patent: Page/Page column 2; 4; 12
[14]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2009/62044, 2009, A2 Location in patent: Page/Page column 44
[15]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2009/62044, 2009, A2 Location in patent: Page/Page column 45
[16]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2009/62044, 2009, A2 Location in patent: Page/Page column 45
[17]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2009/62044, 2009, A2 Location in patent: Page/Page column 46
[18]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2009/62044, 2009, A2 Location in patent: Page/Page column 45
[19]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2 Location in patent: Page/Page column 52
[20]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/92720, 2011, A2 Location in patent: Example 9
[21]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2011/117782, 2011, A1 Location in patent: Page/Page column 8
[22]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2012/18791, 2012, A2 Location in patent: Page/Page column 29
[23]Current Patent Assignee: HETERO DRUGS LIMITED - WO2012/23145, 2012, A2 Location in patent: Page/Page column 8-9
[24]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1 Location in patent: Page/Page column 24
[25]Umasankara Sastry; Nageswrara Rao; Appi Reddy; Gandhi [Asian Journal of Chemistry, 2013, vol. 25, # 14, p. 7783 - 7789]
[26]Du, Wei; Yin, Qiuxiang; Gong, Junbo; Bao, Ying; Zhang, Xia; Sun, Xiaowei; Ding, Suping; Xie, Chuang; Zhang, Meijing; Hao, Hongxun [Crystal Growth and Design, 2014, vol. 14, # 9, p. 4519 - 4525]

8
[ 952340-38-4 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine With dmap; triethylamine In acetone at 0℃; for 0.166667h; Stage #2: acetic anhydride In acetone	5 Example 5 The Method for Preparing Prasugrel The Method for Preparing Prasugrel -(Tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (1.0 eq.) prepared by example 4 was dissolved in acetone (10.0 mL) and the mixture was cooled to 0° C. Triethylamine (1.1 eq.) was added slowly followed by adding 4-dimethylaminopyridine (DMAP) (0.025 g) and the mixture was stirred for 10 minutes. Acetic anhydride (1.5 eq.) in acetone was then added. The reaction was monitored by Thin Layer Chromatography (TLC) (petroleum ether/ethyl acetate=10/1 or 5/1). After the reaction was completed, cold water (7.5 mL) was added to the reaction mixture and the mixture was stirred for 15 minutes. It was then cooled to -5° C. and further stirred for 3 hours. After filtration, solid precipitate was washed with a mixture of pre-cooled acetone/water (1:1 v/v) (10 ml). The obtained prasugrel free base was dried under vacuum at 50° C. for 24 hours. The yield was 90%.
	With triethylamine In acetonitrile at -15℃; for 1h;	1.3 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine A mixed solution of 6.20 g of acetic anhydride and 5.90 g of acetonitrile was added dropwise to the mixture of 22.5 g of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine obtained in (2), 7.65 g of triethylamine, 62.0 mg of 4-dimethylaminopyridine, and 113 g of acetonitrile, and the reaction was performed by stirring at -15°C for one hour. After the end of the reaction, 75.9 g of cold water was added to the resultant reaction solution, and the resultant mixture was then stirred at -10°C for 30 minutes. The precipitated crystal was collected by filtration, washed with a mixture of 22.7 g of precooled acetonitrile and 17.8 g of cold water, and dried under reduced pressure to provide 16.4 g of the title compound.
	Stage #1: 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine With dmap; triethylamine In acetonitrile at 20℃; for 0.25h; Stage #2: acetic anhydride In acetonitrile at 20℃;	1 Next, a mixture of 1.0 g of 2- (tert-butyldimethylsilyloxy) -5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4, 5, 6, 7-tetrahy-dro- thieno [3, 2-c] pyridine, 0.46 g of triethylamine, 14 mg of 4- dimethylaminopyridine and 3 ml of acetonitrile is stirred at room temperature (20 0C) for 0.25 hour. Thereafter, 2 ml of an acetonitrile solution in which 0.46 g of acetic anhydride is dis- solved is added dropwise to the mixture, and the resulting mixture is allowed to react under further stirring at room temperature (20 0C) for 1 hour.To the obtained reaction mixture is added 3.3 ml of a 10 mM aqueous potassium dihydrogen phosphate solution, and the mixture is stirred at room temperature (20 0C) for 1 hour to obtain precipitated crystals. The obtained precipitated crystals are filtered and dried to obtain 0.76 g of 2-acetoxy-5- (α- cyclopropylcarbonyl-2-fluorobenzyl) -4, 5, 6, 7-tetrahydrothieno- [3, 2-c] pyridine . The purity of the product as determined by HPLC was 99.5 %.1H-NMR (CDCl3; standard: tetramethylsilane ; equipment Bruker DTX 200, 200.1 MHz) : δ = 0.76-1.15 (m; 4H), 2.17-2.34 (m; IH), 2.26 (s; 3H), 2.58-3.05 (m; 4H), 3.57 (AB-system; 2H), 4,88 (s; IH), 6,27 (s; IH), 7,07-7,55 (m; 4H) ppm.13C NMR (CDCl3; standard: tetramethylsilane; equipment: Bruker DTX 200, 50,3 MHz) : δ = 11.98 (s), 12.58 (s), 18.79 (s) , 21.09 (s), 25.44 (s) , 48.91 (s) , 50.96 (s) , 72.04 (s) , 112.39 (s), 116.28 (d; 22,9 Hz), 122.43 (d; 14,1 Hz), 124.9 (d, 2.9 Hz), 126.14 (s), 129.79 (s), 130.43 (d; 8,1 Hz), 131.07 (d; 2.9 Hz), 149.98 (s), 161.75 (d; 247.3 Hz), 168.14 (s), 208.04 (s) ppm.

	With dmap; triethylamine In acetonitrile at 0℃;	1.3; 2.2 To a mixture of 15.0 g of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine obtained in (2), 5.10 g of triethylamine, 41.3 mg of 4-dimethylaminopyridine, and 75 g of acetonitrile was added dropwise 3.90 g of an acetonitrile solution in which 4.13 g of acetic anhydride was dissolved, and the resultant mixture was reacted by stirring at 0°C for one hour. After completion of the reaction, 50.6 g of cold water was added to the resultant reaction solution, which was then stirred at -15°C for 30 minutes. The precipitated crystal was collected by filtration, washed with a mixed solution of 15.1 g of acetonitrile and 11.9 g of water, and then dried under reduced pressure to provide 10.8 g of the title compound. Melting point: 122 to 124°C.
	With dmap; triethylamine In acetonitrile at -4 - -3℃; for 2.25h;	8 Example 8: Preparation of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2- oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate. Acetonitrile (625 mL) and 2-(2-((tert-butyldimethylsilyl)oxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)- yl)-1-cyclopropyl-2-(2-fluorophenyl)ethanone (100 g) are charged into a round bottom flask at 25°C. Triethylamine (37.63 g) and 4-dimethylaminopyridine (0.28 g) are added to the reaction mass at 15 °C. The reaction mass is cooled to -4°C. The solution of acetic anhydride (29.9 g) in acetonitrile (37 mL) is added dropwise to the reaction mass at -4°C in 1 hour 15 minutes. The reaction mass is maintained for 1 hour at -3°C. Water (368 mL) is added to the reaction mass at - 5°C in 45 minutes. The reaction mass is maintained for 45 minutes at -5°C. The solid is collected by filtration, washed with chilled acetonitrile and water mixture (100+100 ml), and then dried under vacuum at 62°C. Yield: 67.7 g; HPLC Purity: 99.63 %.

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - US2014/155351, 2014, A1 Location in patent: Paragraph 0085
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2003136, 2008, A1 Location in patent: Page/Page column 10
[3]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 15-16
[4]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2123656, 2009, A1 Location in patent: Page/Page column 12
[5]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2012/18791, 2012, A2 Location in patent: Page/Page column 31

9
[ 150322-38-6 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
92.58%	With triethylamine; sodium hydroxide In water; ethyl acetate at 7 - 50℃;	12 Preparation of 2-acetoxy-5-(α-cyclopropanocarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine 8 2-Oxo-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2,4,5,6,7-tetrahydrothieno[3,2] formed in Example 9 or Example 10. -c]pyridine 7(15g, 4.6mol) in acetic anhydride (30g)With triethylamine (30g)The reaction in the presence of a mixture,After the reaction, the ice water bath was cooled to 7 ° C.Quenched by adding pure water (60 ml).Add sodium hydroxide solution to adjust the pH to 2.8.30 ~ 50 under ethyl acetate (90ml) and extracted,Concentrated under normal pressure, dry,2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine 8 (12.87 g) was obtained.The yield was 92.58%, and the purity by HPLC was 99.8%.
90.2%	With triethylamine In dichloromethane for 3h; Reflux;	6 Example6. synthesis of prasugrel The 6g (0.018mol) compound 7 dissolved in 60 ml of methylene chloride, by adding 2.7g (0.027mol) triethylamine and 1.8g (0.018mol) acetic anhydride, heating to reflux, when the TLC tracking without raw material point (about reflux reaction 3 hours), cooling, adding 30 ml water washing, separating, drying with anhydrous sodium sulfate an organic phase, filtering, for 40 °C reduced pressure distillation, steams finishes, with 20 ml methanol stirring, filtering, for 40 °C blast drying to constant weight, to get the 6.1g pale yellow solid compound: prasugrel, purity 97.9%, yield 90.2%.
83.2%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 4h;	1-5 Example 1 At 0 ° C,Add 38.3 ga and 350 ml of dichloromethane to a 1 L three-neck round bottom flask, and add 77.6 g of DIPEA at a temperature control of 0 ° C. After the completion of the dropwise addition, stir for 0.5 h, continue to add 51.4 gb, and stir the reaction for 3 h after the end of the addition. 51.7 g of DIPEA was added dropwise, and then 20.4 g of acetic anhydride was added dropwise to the reaction system to control the temperature of the reaction system to 0 ° C. After the completion of the dropwise addition, the reaction was further stirred for 4 hours, the reaction was completed, and 350 ml of water was added for extraction, and the organic phase was dried over anhydrous sodium sulfate. After drying, filtration and concentration under reduced pressure gave 62.1 g of a yellow solid, which was determined to be d, yield was 83.2%, and HPLC purity was 99.3%.

76.8%	With triethylamine at 0 - 20℃; for 4h;	11 Synthesis of prasugrel The 5 - (α-cyclopropane carbonyl-2-fluorobenzyl) - 2-oxo -2, 4, 5, 6, 7, 7a-tetrahydro-thieno [3,2-c] pyridine 3.3g (10mmol), triethylamine 3g (30mmol) mixing, 0 °C instillment second grade anhydried 2.1g (20mmol), dropping the reaction stirring the mixture at room temperature for 4 hours, ethyl acetate extraction, anhydrous ammonium sulfate drying and filtering, concentrating ethyl acetate, anhydrous methanol is recrystallized to get prasugrel 2.87g, yield of 76.8%, purity 99.64%.
75%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃;
70%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere;	1.3 3. Under argon protection,The product D (0.226 mmol, 75 mg),Acetic anhydride (0.34 mmol, 34.7 mg) was dissolved in DMF (2.0 mL)Cooled to 0 ° C, triethylamine was slowly added,Room temperature reaction 1h,Ethyl acetate extraction,Combine organic phase with water Wash 2 times, saturated salt washed 2 times, anhydrous sodium sulfate drying,The solvent was distilled off under reduced pressure and purified by column chromatography to give Pregrel (white solid, 59.2 mg, yield 70%).
54%	With triethylamine In dichloromethane at 25℃; for 1h;	8 Example 8. Preparation of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydro thieno[3,2-c]pyridin-2-yl acetate (prasugel base). Example 8. Preparation of 5-(2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl)- 4,5,6,7-tetrahydro thieno[3,2-c]pyridin-2-yl acetate (prasugel base). 14.8 mL of triethylamine (100 mmol) and 10 mL of acetic anhydride (100 mmol) were added to a solution of 10 g of 5-(2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl)- 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one (30 mmol) in 50 mL of methylene chloride at 25°C. The resulting reaction mixture was stirred for 1 hour at 25°C. Afterwards, 100 mL of a 5 % (w/v) aqueous solution of sodium bicarbonate was charged to the reaction mixture and stirred for 15 minutes. The organic layer was washed with 100 mL of a 5 % (w/v) aqueous solution of sodium bicarbonate and the organic solvent removed under reduced pressure to obtain 10 g of the title compound, as a colourless oil. Finally, 30 mL of methanol were added to the colourless oily and stirred for 1 hour at 25 °C. The resulting suspension was cooled down to 0 °C and stirred for 1 hour. The solid was filtered and washed with 10 mL of cool methanol and dried at 40°C for 16 hours yielding 5.9 g of the title compound. Yield 54 %. Purity (HPLC) 99 %.
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 10 - 30℃; for 3.33333h;	9 Example-9: Preparation of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyI) -4,5,6,7-tetrahydrothieno[3, 2-c] pyridine.; To a solution of 5-(α.-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine (0.5 grams) dissolved in a mixture of acetonitrile (10 ml) and acetic anhydride(3 ml), added diisopropylethyl amine (3ml). The mixture was then stirred for 20 minutes at 10-150C temperature, after which it was stirred for further 3 hours at 25-300C temperature. Ethyl acetate (20 ml) was added to the mixture, which was then washed four times, each time with 10 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to give yellow oil. This oil was crystallized from diisopropyl ether, to obtain the title compound as white crystals, melting at 120-123° C. 1 H NMR (CDCl3) δppm: 0.81-0.94 (2H, m), 1.03-1.08 (2H, m), 2.21-2.34 (4H, m), 2.79-2.94 (4H, m), 3.52-3.56 (2H, m), 4.88 (IH, s), 6.26 (IH, s), 7.10-7.49 (4H, m) Mass (CI, m/z): 374 (M+ +1), 331, 206, 177; Yield: 0.31grams
	With triethylamine In acetonitrile at 0 - 30℃; for 3h;	22 Example-22: Preparation of Prasugrel:; Triethylamine (53.5 grams) was added to a mixture of 5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (50 grams) and acetonitrile (350 ml) at 0-50C. Acetic anhydride (50 ml) was added drop-wise to the reaction mixture at 0-50C and then stirred for 3 hours at 25-300C. The reaction mixture was quenched with water and then extracted it with ethyl acetate. The ethyl acetate layer washed with sodium chloride followed by water. The ethyl acetate layer dried over sodium sulphate and then distilled off the solvent completely. Cyclohexane and ethyl acetate was added to the obtained crude and cooled to 0-50C. The reaction mixture was stirred for 90 minutes at 0-50C. The solid was filtered, washed with cyclohexane and then dried to get the title compound. Yield: 28.7 grams: Purity: 96.5% HPLC
	With sodium hydride In N,N-dimethyl-formamide at 10 - 28℃; for 2.16667h;	7 EXAMPLE 7: PREPARATION OF 2-ACETOXY-5-(A-CYCLOPROPYL CARBONYL-2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2- C]PYRIDINE (FORMULA I).5-[2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]5,6,7,7a-tetrahydro- thieno[3,2-c]pyridin-2(4h)-one (20.0 g) and dimethylfornnannide (75 mL) are charged into a round bottom flask. The reaction mixture is cooled to 10 0C and then acetic anhydride (37.5 mL) is added to the obtained reaction solution. Sodium hydride (60% dispersion in mineral oil, 3.0 g) is added to the reaction mixture at 10 0C over a period of 25 minutes, and then the mixture is stirred at a temperature of 28 0C for 1 hour 45 minutes. Saturated ammonium chloride (100 mL) is added to the obtained reaction mixture. The mixture is extracted with ethyl acetate (2100 mL) and the separated organic layer is washed with saturated sodium chloride solution (2100 mL). The obtained organic layer is concentrated completely under reduced pressure at 50 0C. The crude product is dissolved in diisopropyl ether (50 mL) at 30 0C and it is kept overnight. The obtained suspension is filtered and the solid is washed with 10 mL of diisopropyl ether. The solid is dried at 50 0C for 2 hours to afford 6.2 g of the title compound.Purity: 95.46% by HPLC.
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 10 - 30℃; for 3.33333h;	11 Example-ll: Preparation of 2-Acetoxy-5-(a-cyclopropylcarbonyl-2- fluorobenzyl) -4,5,6,7-tetrahydrothieno[3, 2-c] pyridine.; To a solution of 5-(a-cyclopropylcarbonyl-2-fluoroberi2yl)-2-oxo-2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine (0.5 grams) dissolved in a mixture of acetonitrile (10 ml) and acetic anhydride(0.3 ml), added diisopropylethyl amine (0.55 ml). The mixture was then stirred for 20 minutes at 10-15°C temperature, after which it was stirred for further 3 hours at 25-30°C temperature. Ethyl acetate (20 ml) was added to the mixture, which was then washed four times, each time with 10 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to give yellow oil. This oil was crystallized from diisopropyl ether to get the title compound as white crystals.Yield: 0.31 grams; Melting point: 120-123° C.
	With sodium hydride In N,N-dimethyl-formamide; mineral oil Cooling with ice;	8 Example 8 2-acetoxv-5-(alpha-cvclopropvlcarbonvl-2-fluorobenzyl)-4,5,6J- tetrahydro-thieno-[3,2-c] pyridine To a solution of 2-oxo-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-2,4,5, 6,7,7a- hexahydrothieno[3,2-c]pyridine (477 mg) and acetic anhydride (1 ml) in DMF (5 ml), with cooling using an ice bath, sodium hydride (60% mineral oil) (102mg) was added in portions. The reaction was followed by HPLC. Ethyl acetate (10 ml) was added to the reaction mixture. The mixture was extracted with 1M HC1 (2x5 ml). The acid layers were combined and basified to pH 6, followed by an extraction with ethyl acetate (2x25 ml). The organic layer was washed with brine (25 ml), dried on Na2S04, filtered and evaporated under reduced pressure. The obtained crude oil was purified by column chromatography. Yield: 155 mg, white solid.
	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 5℃; for 3h;	12 Example 12 2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydro-thieno-[3,2-c] pyridine A mixture of 1.55g crude 2-oxo-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)- 2,4,5, 6,7,7a-hexahydrothieno[3,2-c]pyridine from Example 1 1 in 8 ml DMF and 3 ml AC2O was stirred at ~5°C. NaH (0.3 g, 60% in mineral oil) was added in portions. The mixture was stirred for 3 hours at ~5°C. Then 30 ml EtOAc was added followed by 1 ml water. The mixture was extracted with HC1 solution (1 M, 2x5 ml). Combined acidic layers were neutralized to pH 6 and extracted with EtOAc (50 ml). Separated EtOAc layer was washed with brine (10 ml), dried and concentrated in vacuo to give the desired product (900 mg).
	With 4-methyl-morpholine; dmap In acetonitrile at 4℃; for 3h;	3 Example 3: Preparation of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2- oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate. 2-Bromo-1 - cyclopropyl-2-(2-fluorophenyl)ethanone (7.5 g) (obtained from example 2 and acetonitrile (25 mL) are charged into a round bottom flask at 26°C. Sodium carbonate (6.06 g) is added to the reaction mass at 26°C. 5,6,7,7a-tetrahydro- thieno[3,2-c]pyridin-2(4H)-one (5.0 g) is added to the reaction mass at 26°C. The reaction mass is stirred for 28 hours at 26°C. The reaction mass is filtered and washed with acetonitrile (10 mL). The filtrate is charged into a round bottom flask at 27°C and cooled to 4°C. N-methylmorpholine (5.25 g) and 4- dimethylaminopyridine (0.0349 g) are added to the filtrate at 4°C. Acetic anhydride (3.981 g) is added by drops to the reaction mass at 4°C. The reaction mass is stirred for 3 hours at 4°C. Water (35 ml) is added by drops to the reaction mass at 4°C in 15 minutes. The reaction mass is stirred at 4°C for 1 hour 30 minutes. The solid is collected by filtration and washed with chilled acetonitrile and water mixture (5+5 ml). The wet solid material and acetonitrile (25 ml_) are charged into a round bottom flask at 28°C and heated to 48°C for 10 minutes to obtain clear solution. The solution is cooled to 5°C and stirred at the same temperature for 1 hour 30 minutes. The solid is collected by filtration, washed with chilled acetonitrile (5 mL), and then dried under vacuum at 70°C for 5 hours. Yield: 3.96 g; HPLC Purity: 99.57%; 3-fluoro impurity: 0.027%.
9 kg	With 4-methyl-morpholine; dmap In acetonitrile at 0℃; for 4h; Large scale reaction;
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 10 - 30℃; for 3h;	11 Example 11Preparation of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridineTo a solution of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (0.5 grams) dissolved in a mixture of acetonitrile (10 ml) and acetic anhydride(0.3 ml), added diisopropylethyl amine (0.55 ml). The mixture was then stirred for 20 minutes at 10-15° C. temperature, after which it was stirred for further 3 hours at 25-30° C. temperature. Ethyl acetate (20 ml) was added to the mixture, which was then washed four times, each time with 10 ml of a saturated aqueous solution of sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure to give yellow oil. This oil was crystallized from diisopropyl ether to get the title compound as white crystals.Yield: 0.31 grams; Melting point: 120-123° C
	Stage #1: 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one With triethylamine In dichloromethane at 25 - 30℃; for 0.25h; Stage #2: acetic anhydride at 0 - 5℃; for 6h;	36 Example 36Preparation of 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate Compound of Formula-1Triethylamine (98 grams) was added to a solution of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (100 grams) prepared as per example-35 in methylene chloride (1000 ml) and stirred for 15 minutes at 25-30° C. The reaction mixture was cooled to 0-5° C. and acetic anhydride (62 grams) was added to it and then stirred for 6 hrs at 0-5° C. Added water (300 ml) to the reaction mixture at 25-30° C. and stirred for 15 minutes. Separated the both aqueous and organic layers and the organic layer was washed with aq.sodium bicarbonate solution followed by washed with water. Distilled of the solvent from organic layer completely under reduced pressure. Added 75 ml of cyclohexane to the reaction mixture and distilled off the solvent completely under reduced pressure. To the obtained solid added acetonitrile (50 ml) at 25-30° C. and heated the reaction mixture to 40-50° C. Stirred the reaction mixture for 20 minutes at same temperature. Added isopropyl alcohol (75 ml) to the reaction mixture at 25-30° C. and then heated to 40-50° C. Stirred the reaction mixture for 30 minutes at same temperature. Cooled the reaction mixture to 10-15° C. and stirred for 1 hr at same temperature. Filtered the precipitated solid and washed with isopropyl alcohol. Dried the compound to get the highly pure title compound.Yield: 75 grams; Melting point: 120-125° C.Purity by HPLC: 99.55%; Methyl keto impurity: Not detected
	With potassium carbonate In N,N-dimethyl-formamide at 0 - 5℃; Inert atmosphere;
8.8 g	Stage #1: 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at -5℃; for 0.25h; Stage #2: acetic anhydride In acetonitrile at 0 - 5℃;	4 Example 4: Preparation of prasugrel Cyclopentylcarbonyl-2-fluorobenzyl bromide (9.4 g) and 2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine hydrochloride And water (94 mL) is added. Then, 4.2 g of potassium carbonate was added thereto, followed by stirring at room temperature for 1 hour. To this was added 4.2 g of potassium carbonate, and the mixture was stirred at room temperature for 1 hour. Then, 4.2 g of potassium carbonate was added again and stirred. After confirming that the reaction was completed, the byproduct was filtered and washed with ethyl acetate. 75.0 mL of ethyl acetate and 75.0 mL of water were added to the filtrate, and the organic layer was separated after stirring. The organic mixed solution was washed with an aqueous ammonium chloride solution, water and an aqueous sodium chloride solution, and concentrated under reduced pressure to obtain 2-oxoprazole glycolated oil. After 36.3 mL of acetonitrile was added to dissolve it, the solution was cooled to -5 ° C or lower, 17.8 mL of N-ethyldiisopropylamine and 0.04 g of dimethylaminopyridine were added, and the mixture was stirred for 15 minutes. 6.9 mL of acetic anhydride was added dropwise thereto, followed by stirring at 0 to 5 ° C. 96.7 mL of water and 96.7 mL of ethyl acetate were added to the reaction mixture, stirred, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and an aqueous solution of sodium chloride, followed by drying under reduced pressure. To this, 4.9 mL of acetonitrile and 14.6 mL of isopropyl alcohol were added to precipitate crystals. This was filtered to obtain 8.8 g of dried prasugrel. (Total yield of both processes 65.0%, purity 99.87%)
	With dmap; triethylamine at 0 - 5℃; for 2h; Large scale;	4 Example 4: Preparation of crude prasugrel base of Formula (Γ) To 52 1 methyl-isobutyl-ketone 17.8 kg anhydrous sodium-carbonate and 10.0 kg 96% 5,6,7,7a-tetrahydrothieno[3,2-c]pyridine-2(4H)-one hydrochloride of Formula (TV) are measured then 13.4 kg 96% 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)ethanone of Formula (III) is added. The mixture is stirred for 10 h at 40°C then cooled, and the inorganic compounds are filtered off. To the filtrate 300 g dimethylamino-pyridine and 22.4 1 triethyl- amine are added, cooled to 0-5°C then 11.0 1 acetic anhydride is added dropwise. After 2 h, to the mixture 40 1 ethyl acetate then 40 1 water are added dropwise. After separation the organic phase is dried then evaporated to dryness. 2x40 1 ethanol is poured onto the reminder then evaporated. The oily remainder is solved in 40 1 ethanol. The crystalline material is stirred first at 20-25°C for 1 h then at 0-5°C for further 1 h then filtered, washed with 8 1 cool ethanol and dried. (0082) Thus 11.4 kg crude prasugrel base is obtained. (Yield: 61 %.)

Reference： [1]Current Patent Assignee: Dong Dandan - CN108218889, 2018, A Location in patent: Paragraph 0033; 0034
[2]Current Patent Assignee: CHONGQING ANGE LONGXIANG PHARMACEUTICAL - CN105272993, 2016, A Location in patent: Paragraph 0066; 0067; 0068; 0069; 0070
[3]Current Patent Assignee: SHANGDONG NEW TIME PHARMACEUTICAL CO LTD - CN104725396, 2019, B Location in patent: Paragraph 0032-0041
[4]Current Patent Assignee: QINGDAO CHENDA BIOLOGICAL TECHNOLOGY CO LTD - CN105884793, 2016, A Location in patent: Paragraph 0053; 0054; 0055
[5]Tang, Shi-Zhong; Zhao, Wenshuang; Chen, Tao; Liu, Yang; Zhang, Xiao-Ming; Zhang, Fu-Min [Advanced Synthesis and Catalysis, 2017, vol. 359, # 23, p. 4177 - 4183]
[6]Current Patent Assignee: LANZHOU UNIVERSITY - CN107056803, 2017, A Location in patent: Paragraph 0039; 0040; 0041; 0042
[7]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2013/14295, 2013, A1 Location in patent: Page/Page column 23
[8]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2009/66326, 2009, A2 Location in patent: Page/Page column 17
[9]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2009/66326, 2009, A2 Location in patent: Page/Page column 20-21
[10]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2009/62044, 2009, A2 Location in patent: Page/Page column 42
[11]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2 Location in patent: Page/Page column 42
[12]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1 Location in patent: Page/Page column 18
[13]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1 Location in patent: Page/Page column 19; 20
[14]Current Patent Assignee: DR REDDY&apos;S LABORATORIES LIMITED - WO2012/18791, 2012, A2 Location in patent: Page/Page column 28-29
[15]Location in patent: experimental part Aalla, Sampath; Gilla, Goverdhan; Metil, Dattatray Shamrao; Anumula, Raghupathi Reddy; Vummenthala, Prabhaker Reddy; Padi, Pratap Reddy [Organic Process Research and Development, 2012, vol. 16, # 2, p. 240 - 243]
[16]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1 Location in patent: Page/Page column 20
[17]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1 Location in patent: Page/Page column 24
[18]Umasankara Sastry; Nageswrara Rao; Appi Reddy; Gandhi [Asian Journal of Chemistry, 2013, vol. 25, # 14, p. 7783 - 7789]
[19]Current Patent Assignee: Ildong Pharmaceutical Co., Ltd.; Lee, Young-young; Lee, Kun-hee - KR2017/47686, 2017, A Location in patent: Paragraph 0073; 0074
[20]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2017/221187, 2017, A1 Location in patent: Page/Page column 13; 14

10
[ 204205-33-4 ]
[ 1151904-84-5 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
36.6%	With triethylamine; In dichloromethane; at -15 - 20℃;Product distribution / selectivity;	Example 3Synthesis of prasugrel by coupling thiophene acetate Al hydrochloride with the bromide CI2.00 g Thiophene acetate Al hydrochloride (Example 2) and 2.75 g bromide compound CI, were suspended in25 ml dichloromethane (dried over CaCl2). The suspension was cooled to -15/-10C,1.73 g triethylamine was added dropwise over 5 minutes. The yellow suspension was kept at -10C for 1 hour and was then allowed to slowly warm to 0-5C. Reaction progress was monitored with HPLC. After 4 hours 20 minutes, the reaction mixture was allowed to warm to ambient temperature. After 5.5 hours, the obtained dark brown suspension was washed with2x25 ml water, dried (Na2S04) and concentrated in vacuo.[0051] The obtained oil was filtered over silica 60 (63-200 mueta , 10 g) using toluene/ethyl acetate 20/1 (v/v) as eluens. The filtrate was concentrated in vacuo. To the obtained oil,20 ml isopropyl ether was added. The suspension was stirred over night at ambient temperature. The solid was isolated by filtration and dried at air.Isolated yield: 1.17 g (36.6%), off-white/bit yellowish solidHPLC: 98.4% purity
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25 - 30℃; for 2 - 3h;Product distribution / selectivity;	EXAMPLE 10: PREPARATION OF 2-ACETOXY-5-(A-CYCLOPROPYL CARBONYL-2-FLUOROBENZYL)-4,5,6,7-TETRAHYDROTHIENO[3,2- C]PYRIDINE (FORMULA I).Acetic acid 4,5,6,7-tetrahydro-thieno[3,2-c]pyhdin-2-yl ester hydrochloride (54.0 g), dichloromethane (750 mL) and diisopropylethylamine (94.6 mL) are charged into a round bottom flask. A solution of 2-fluoro-alpha-cyclopropylcarbonyl bromide (68.0 g of 2-fluoro-alpha-cyclopropylcarbonyl bromide in 250 mL of dichloromethane) is added to the reaction mixture dropwise at a temperature of 25 0C to 30 0C and maintained at that temperature for 2 to 3 hours. Water (500 mL) is added to the reaction mixture and layers are separated. Organic layer is washed with water (3*100 mL) and then dried over sodium sulfate followed by <n="45"/>evaporation under reduced pressure at a temperature of 35 0C to 45 0C. The resulting residue is subjected to silica gel column chromatography, using a 20:80 mixture of ethyl acetate and hexane by volume as the eluent, to give a yellow oil. Diisopropyl ether (200 ml_) is added to the obtained oil and stirred for 10 minutes at a temperature of 25 0C to 35 0C. The obtained suspension is filtered and the solid is dried at a temperature of 50 0C to 55 0C for 1 to 2 hours to afford the title compound (9.0 g).Purity: 74% by HPLC.

Reference： [1]Patent: WO2011/29456,2011,A1 .Location in patent: Page/Page column 17
[2]Patent: WO2009/62044,2009,A2 .Location in patent: Page/Page column 43-44

11
[ 110-17-8 ]
[ 150322-43-3 ]
2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol at 25 - 65℃; for 2h;	10 Example-10: Preparation of 2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluoro benzyl)-4,5,6,7-tetrahydrothieno[3, 2-c] pyridine fumarate.; To a solution of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3, 2-c] pyridine (5 grams) in isopropyl alcohol(50ml) added drop wise a solution of fumaric acid (1.5 grams) in isopropyl alcohol (20ml) with constant stirring at 25° C. The reaction mixture was heated to 60-650C and stirred for 2 hours. The reaction mixture was cooled to 20-250C. The crystals obtained were filtered, washed with isopropyl alcohol (10 ml) and dried to obtain the title compound as crystalline solid. M. R: 218-220° C. Yield: 5.5 grams

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2009/66326, 2009, A2 Location in patent: Page/Page column 17

12
2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine fumarate [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate In water; ethyl acetate for 0.5h;	27 Example-27: Purification of Prasugrel:; A mixture of 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno[3,2-c] pyridine fumarate (5 grams) and ethyl acetate and aqueous sodium carbonate was stirred for 30 minutes. The aqueous and organic layers were separated. The combined organic layer was washed with water and distilled the organic layer completely under reduced pressure and isolated pure prasugrel as a solid prasugrel.Yield: 2 grams; Purity: 99.89% by HPLC

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2009/66326, 2009, A2 Location in patent: Page/Page column 22-23

13
[ 75-75-2 ]
[ 150322-43-3 ]
[ 1060616-84-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	In acetone at 20 - 26℃; Cooling;	To a stirred solution of 6.0 g Prasugrel in 35 ml. dry acetone a solution of 1.6 g methane sulfonic acid in 6 rnL acetone was added at 20 °C under cooling. The addition was completed within approx. 70 min. After the cooling bath was removed the temperature was allowed to reach 26 0C and was stirred at this temperature for 2 hours. The reaction mass was filtered off and the wet cake was suck dried under vacuum and was subsequently washed with 36 ml_ of dry diethylether and 36 mL dry acetone. The wet cake was dried at 400C for 2 hours and for 6 hours at 500C under vacuum (0 mbar). Yield: 70%; DSC: 109.60C.
	In methanol	10 250 mg prasugrel (free base) were dissolved in 5 ml of methanol and the solution was stirred at room temperature. An equimolar amount of methane-sulfonic acid dissolved in 2 ml methanol was added. The solvent was evaporated in a rotatory evaporator and dried over night in vacuum.13C NMR (CDCl3, standard: tetramethylsilane; equipment: Bruker DTX 200, 50.3 MHz) : δ = 13.62 (s), 13.87 (s), 20.12 (s), 21.05(s), 22.07 (broad) , 39.41 (s) , 48.74 (broad), 50.87 (broad), 111.34 (s) , 115.01 (d; 12.72 Hz), 117.31 (d ; 21.2Hz), 123.08 (s), 123.87 (s), 126.59 (s), 133.38 (broad), 134.65 (d; 9.9Hz), 151.47 (s), 161.78 (d; 252.9Hz), 167.6 (s), 201.55 (s) ppm.The 13C-NMR spectrum of prasugrel mesylate is shown in Fig. 5.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/129983, 2009, A1 Location in patent: Page/Page column 17
[2]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 20

14
[ 594-45-6 ]
[ 150322-43-3 ]
[ 1178975-70-6 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol	9 250 mg prasugrel (free base) were dissolved in 5 ml of metha- nol and the solution was stirred at room temperature. An equimolar amount of ethane sulfonic acid dissolved in 2 ml methanol was added. The solvent was evaporated in a rotatory evaporator and dried over night in vacuum.13C NMR ([D6]DMSO; standard: tetramethylsilane; equipment:Bruker DTX 200, 50.3 MHz) : δ = 10.34 (s) , 13.41 (s) , 13.87(s), 20.53 (s), 21.28 (s) , 22.47(s), 46.09(s), 50.42 (broad),69.91 (s), 112.78 (s) , 116.20 (d; 14.1 Hz), 117.73 (d; 21.2Hz), 124.48 (s ), 125.05 (s), 126.76 (s), 133.3 (s) , 134.65 (d; 8.5Hz), 150.74 (s) , 161.87 (d; 250.1Hz), 168.51 (s) , 202.65 (s) ppm.The 13C-NMR spectrum of prasugrel ethanesulfonate is shown in Fig. 3, the 1H-NMR spectrum in Fig. 4.

Reference： [1]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 19

15
[ 120-18-3 ]
[ 150322-43-3 ]
[ 1178975-69-3 ]

Yield	Reaction Conditions	Operation in experiment
69%	In acetone at 20℃; for 0.75h;	3 30 ml dry acetone was added to 3.0 g Prasugrel and stirred for 15 min to get a clear solution. A solution of 1.635 g of 2-naphtahlene sulfonic acid in 12 ml acetone (dried over 3A Molecular sieve) was added slowly to the clear solution of Prasugrel in acetone at room temperature in 30 min. The reaction mixture was stirred at room temperature for 15 min. The acetone was completely evaporated resulting in an oily layer in the flask. 90 ml toluene was added to the oil and stirred slowly for 2 hours at ambient temperature. The reaction mass was kept in a freezer overnight, was filtered under nitrogen atmosphere at room temperature and dried under high vaccum for approximately two days. Yield: 69%; DSC: 1570C; Melting range = 152-156°C; IR: 1755, 1711 , 1617, 1593, 1496, 1376 cm"1; HPLC: Prasugrel = 99.17%
	In methanol	8 250 mg prasugrel (free base) were dissolved in 5 ml of methanol and the solution was stirred at room temperature. An equimolar amount of 2-naphthalene sulfonic acid dissolved in 2 ml methanol was added. The solvent was evaporated in a rotatory evaporator and dried over night in vacuum.13C NMR ([D6]DMSO; standard: tetramethylsilane; equipment: Bruker DTX 200, 50.3 MHz) : δ = 13.44 (s) , 13.89 (s) , 20.55(s), 21.33 (s), 22.63 (s) , 50.5 (broad), 70.1 (s) , 112.78(s), 116.01 (d; 14.1 Hz), 117.73 (d; 21.2 Hz), 124.63 (s),124.79 (s), 124.99 (s), 125.07 (s), 126.73 (s) , 127.18 (s),127.35 (s), 128.25, 128.36, 129.29 (s) , 133.01 (s) , 133.16 (s), 133.64 (s), 134.59 (d; 8.5 Hz), 146.27 (s) , 150.74 (s) ,161.87 (d; 250.1Hz), 168.51 (s) , 202.84 (s) ppm.The 13C-NMR spectrum of prasugrel-2-napsylate is shown in Fig. 1, the 1H-NMR spectrum in Fig. 2.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/129983, 2009, A1 Location in patent: Page/Page column 15-16
[2]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 18-19

16
[ 81-04-9 ]
[ 150322-43-3 ]
prasugrel 1,5-naphthalenedisulfonic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In isopropyl alcohol at 20 - 50℃;	To a clear solution of 7 g Prasugrel in approx. 120 mL isopropanol a solution of 1 ,5- naphthalene disulfonic acid (1 ,5-NDS) was added in 20 mL isopropanol at ambient temperature. The reaction mixture was warmed up to approx. 5O0C and stirred for approx. 20 min. The product started to precipitate at this temperature. The reaction was cooled to room temperature stirred for some additional time (appr. 1 h) in order to complete precipitation. The product was collected by the usage of vacuum in a Bchner funnel. The product was dried under vacuum. The obtained cake was washed with isopropanol and dried under vacuum at 50 0C - 60 0C for 24 hours. Yield: 75%
	In acetone at 20℃;	14 0.5 g Prasugrel base were suspended in 1.5 ml acetone at room temperature. To the solution 386 mg naphthalene-1, 5- disulfonic acid were added under stirring. The solution was sonicated in an ultrasonic bath at room temperature. A few milligrams of Prasugrel-HCl crystals (prepared according to WO2008/000418) were added to the clear solution. A white precipitate was obtained after storing for one night at -200C. The salt was filtered off and dried at room temperature under vacuum for 6 hours to yield 640 mg. White crystals, melting point 1800C.1-H NMR (DMSO-d6, standard: tetramethylsilane, equipment:Bruker DTX 200, 200.1 MHz) : δ = 0.77-1.22 (m, 4H), 1.76-2.00 (m, IH), 2.27 (s, 3H), 2.89 - 4.7 (broad, 6H), 5.97-6.18(broad, IH), 6.50-6.65 (broad, IH), 7.25-7.73 (m, 6H), 7.91(d ,6.4 Hz, 2H), 8.85(d ,8.6 Hz, 2H), 10.12-11.6 (broad, NH+) ppmX-Ray (CuKα-radiation, powder diffractometer X' PERT PRO Bragg Brentano flat sample reflection instrument, start position: 3.0 degree 2Th, end position 65.0 degree 2Th, step size 0.017 degree 2Th, PSD length 2.12 degree 2Th, temperature 25 degree C) : Degree 2Th ReI. Int.)(+/- 0.2) (> 8 %)8.7 9.09.6 100.010.6 8.814.3 21.416.1 10.217.5 9.817.9 8.922.5 8.123.8 11.7) relative intensity may change depending on the crystal size and morphology.The X-ray diffraction pattern of prasugrel-dinapsylate is shown in Figure 7.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/129983, 2009, A1 Location in patent: Page/Page column 13
[2]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 24-25

17
[ 110-04-3 ]
[ 150322-43-3 ]
prasugrel 1,2-diesylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetone at 20℃;	17 0.5 g Prasugrel base was suspended in 1.5 ml acetone at room temperature. To the solution 254.7 mg 1,2 -ethane di- sulfonic acid were added under stirring. A few milligrams of Prasugrel-HCl crystals (prepared according to WO2008/000418) were added to the clear solution. The solution was sonicated in an ultrasonic bath at room temperature. No precipitate was obtained after storage for one night at -200C. The amount of acetone was reduced (vacuum) and water was added carefully until a white precipitate was noticed, a few crystals of Prasugrel-HCl were additionally added. After storage for one week at -200C white crystals were obtained. The salt was filtered off and dried at room temperature under vacuum for 6 hours to yield 80 mg. White crystals, melting point 137°C.1-H NMR (DMSO-d6, standard: tetramethylsilane, equipment:Bruker DTX 200, 200.1 MHz) : δ = 0.78-1.23 (m, 4H), 1.80- 2.00 (m, IH), 2.26 (s, 3H), 2.62 (s, 4H), 2.89-4.48(broad, 6H), 5.98-6.20 (broad, IH), 6.5-6.65 (broad, IH),7.29-7.76 (m, 4H), 10.27-11.59 (broad, NH+ ) ppmX-Ray (CuKα-radiation, powder diffractometer X' PERT PRO Bragg Brentano flat sample reflection instrument, start position: 3.0 degree 2Th, end position 65.0 degree 2Th, step size 0,017 degree 2Th, PSD length 2.12 degree 2Th, temperature 25 degree C) :Degree 2Th ReI. Int.)(+/- 0^2) (> 20 %)9.8 26.514.0 25.814.8 100.015.1 53, 516.6 28.218.6 24.722.2 50.222.7 25.425.8 32.0) relative intensity may change depending on the crystal size and morphologyThe X-ray diffraction pattern of prasugrel-diesylate is shown in Figure 10.

Reference： [1]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 27-28

18
[ 98-11-3 ]
[ 150322-43-3 ]
[ 952340-40-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	In diethyl ether; acetone at -10 - 35℃; for 12h;	6 Example 6Preparation of prasugrel benzene sulfonatePrasugrel base (1.554 g; 4.16 mmol) is dissolved in acetone (15 ml) at a temperature of up to 35 °C and cooled down to the room temperature. Benzene sulfonic acid (0.625 g; 3.95 mmol) is dissolved in diethyl ether (6.2 ml) and the solution is added to the prasugrel solution. Another 8 ml of diethyl ether are added to the mixture, the solution is cooled down to -10 °C, inoculated and stirred at the temperature of -10 °C for 12 h. The separated crystals are aspirated, washed with diethyl ether and dried freely. 1.96 g (93%) of white crystals with the melting point of 162.5 to 163.5 °C are obtained. HPLC: purity 99.9%; content of the compound of formula II 0.02%. X-ray analysisTable 4: Characteristic peaks of prasugrel benzene sulfonate:The X-ray powder diffraction pattern is presented in the Annex in fig. 4a, DSC curve is in fig. 4b.
93%	In diethyl ether; acetone at 20℃;	19 Prasugrel base (1 .554 g; 4.16 mmol) is dissolved in acetone (15 ml) at a temperature of up to 35 °C and cooled down to the room temperature. Benzene sulfonic acid (0.625 g; 3.95 mmol) is dissolved in diethyl ether (6.2 ml) and the solution is added to the prasugrel solution. Another 8 ml of diethyl ether are added to the solution, the solution is cooled down to -10 °C, inoculated, and stirred at the temperature of -10 °C for 12 h. The precipitated crystals are aspirated, washed with diethyl ether and dried freely. 1 .96 g (93%) of white crystals with the melt, point of 162.5-163.5 °C are obtained.
79%	In acetone at 30℃; for 6h;	1 To a clear solution of 6 g Prasugrel in approx. 35 ml. acetone (dry) a solution of 2.6 g benzene sulfonic acid in 6 ml. acetone (dry) was added at a temperature of approx. 30 0C. The reaction mixture was kept at this temperature for additional 6 hours. The formed precipitate was filtered off and the resulting wet cake was suck dried and washed with 6 mL dry acetone. The solid was dried at 400C for 1 hour and at 5O0C for 13 hours under vacuum (5 mbar).Yield 79%. DSC : 162.4 0C; MP = 160-164°C

In methanol

11 250 mg prasugrel (free base) were dissolved in 5 ml of methanol and the solution was stirred at room temperature. An equimolar amount of benzene sulfonic acid dissolved in 2 ml methanol was added. The solvent was evaporated in a rotatory evaporator and dried over night in vacuum.13C NMR (CDCl3; standard: tetramethylsilane, equipment: Bruker DTX 200, 50.3 MHz) : δ = 13.59 (s), 13.84 (s), 20.04 (s), 21.05 (s), 21.76 (broad), 48.17 (broad), 50.53 (s) , 51.0 (broad), 68.83 (broad), 111.26 (s) , 114.85 (d; 14.1Hz), 117.28 (d; 21.2Hz), 123.05 (s), 123.87 (s), 126.31 (s), 126.48 (s), 128.29 (s) , 130.07 (s) , 133.69 (s ) , 134.28 (d; 8.5Hz), 145.59 (s) , 151.46 (s) , 159.30 (d; 250.1Hz), 167.63 (s), 201.32 (s) ppm.The 13C-NMR spectrum of prasugrel besylate i s shown in Fig . 6 .

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57593, 2011, A2 Location in patent: Page/Page column 14-15
[2]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57592, 2011, A1 Location in patent: Page/Page column 18
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/129983, 2009, A1 Location in patent: Page/Page column 14
[4]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 20

19
[ 85-47-2 ]
[ 150322-43-3 ]
[ 1178975-73-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	In acetone at 20℃; for 0.333333h;	1.2 ml dry acetone was added to 200 mg Prasugrel and stirred for 15 min to get a clear solution. 109 mg 1-naphtalene sulfonic acid was added and stirred for 5 min at room temperature resulting in a clear solution. The product crystallizes out after 15 min and a thick slurry was observed. 2.4 ml dry acetone was added to make it stirrable. The suspension was stirred for 2 hours and filtered. The solid was washed with 0.6 ml acetone and dried at elevated temperature for 2 hours. Yield: 66%; DSC: 1080C; Melting range = 106-1140C; IR = 1750, 1712, 1227 cnV1.
	In acetone at 20℃;	16 1 g Prasugrel base was suspended in 3 ml acetone at room temperature. To the solution 702 mg naphthalene-1- sulfonicacid were added under stirring. The solution was sonicated in an ultrasonic bath at room temperature. A few milligrams of Prasugrel-HCl crystals (prepared according to WO2008/000418) were added to the clear solution. A white precipitate was obtained after storage for one night at - 200C. The salt was filtered off and dried at room temperature under vacuum for 6 hours to yield 1330 mg. White crystals, melting point 116°C.1-H NMR (DMSO-d6, standard: tetramethylsilane, equipment:Bruker DTX 200, 200.1 MHz) : δ= 0.78-1.2 (m, 2H), 1.78-2.00(m, IH), 2.27 (s, 3H), 2.87-4.54 (broad, 6H), 5.91-6.23 (broad, IH) , 6.47-6.65 (broad, IH) , 7.31-7.77 (m, 6H) , 7.79- 7.98 (m, 3H) , 8.76-8.87 (m, IH) , 10.15-11.72 (broad, NH+) ppm.X-Ray (CuKα-radiation, powder diffractometer X' PERT PRO Bragg Brentano flat sample reflection instrument, start position: 3.0 degree 2Th, end position 65.0 degree 2Th, step size 0,017 degree 2Th, PSD length 2.12 degree 2Th, temperature 25 degree C) :Degree 2Th ReI. Int.)(+/- 0.2) (> 8 %)7.3 oo.o9.1 11.214.6 8.614.8 9.615.7 8.616.0 8.319.0 18.220.6 9.621.2 10.621.6 9.923.6 14.9) relative intensity may change depending on the crystal size and morphologyThe X-ray diffraction pattern of prasugrel-1-napsylate is shown in Figure 9.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/129983, 2009, A1 Location in patent: Page/Page column 16
[2]Current Patent Assignee: HELM AG - WO2009/98142, 2009, A1 Location in patent: Page/Page column 26-27

20
[ 204205-33-4 ]
[ 1190589-93-5 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
32.85%		Example-6; Preparation of 2-Acetoxy-5-(alpha-cycloprpylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydrothieno [3,2-c] pyridine (I); To a solution of 2-acetoxy- -4,5,6,7-tetrahydrothieno[3,2-c]rhoyridine-p-toluenesulfonate (7.0 gm) in dimethylformamide (35 ml) was cooled to 5 -100C and was added with sodium bicarbonate (2.38 gm). The reaction mass was stirred for 15 minutes and added with 2- bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone (5.1 gm) in dimethylformamide (15 ml) and stirred for 5 hours at room temperature and followed by addition of acetic anhydride (3.8 ml) and stirred for 3 hrs at RT. After then reaction mass was cooled to 5 -10C and added with water (700 ml) and tert-butyl methyl ether (105 ml). Stirred the mixture at room temperature and filtered through celite bed. The celite bed was washed with TBME. The obtained TBME layer was washed with water and brine solution, dried the organic layer, and distilled solvent under reduced pressure to get the oily mass. The oily product was crystallized from ethanol to afford the good crystal of prasugrel free base, which was dried under vacuum at 50C for 24 hours (2.3 g, yield = 32.85%).

Reference： [1]Patent: WO2009/122440,2009,A1 .Location in patent: Page/Page column 33

21
[ 1190589-94-6 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 1.25h;	11 Example-11; Preparation of 2-Acetoxy-5-(α-cycloprpylcarbonyl-2-fluorobenzy.)-4,5,6,7- tetrahydrothieno [3 ,2-c] pyridine (I); To a cooled (0+/-3°C ) solution of Hydrobromide salt of 5-(α-cycloprpylcarbonyl-2- fluorobenzyl)-2-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (II) (20 gm) in a dimethylformamide (140 ml) and acetic anhydride (9.9 gm) was added with potassium carbonate (15.05 in dimethylformamide (20 ml), then mixture was stirred at the same temperature for 45 minutes. The reaction mixture further added with 4.95 gm of acetic anhydride at the same temperature and was stirred at the same temperature for 30 minutes. After the acetylation, the mixture was added to the pre-cooled (5+/-3°C) water at 5+/-3°C over a period of 30-45 minutes and stirred for 1 hrs. at the same temperature, filtered the obtained solid and washed with 3x20 ml of pre-chilled water and suck dried well. The obtained wet mass was charged in methanol (100 ml) at 25°C-30°C and stirred for 1 hour, filtered and washed with 2x20 ml of methanol. Dried the obtained title compound under reduced pressure at 35°C-40°C for 12 hrs. (Weight = 14.5 gm, Purity = 99%).

Reference： [1]Current Patent Assignee: TORRENT INVESTMENTS PRIVATE LIMITED - WO2009/122440, 2009, A1 Location in patent: Page/Page column 35

22
[ 150322-43-3 ]
[ 1191933-01-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sulfuric acid In acetone at -5℃; for 1.25h;	To a cooled solution (-5 0C) of 7 g Prasugrel in approx. 112 mL dry acetone a solution of 1.9 g H2SO4 (98%) in approx. 30 mL acetone was slowly added at approx. -5°C within 15 min. The temperature was maintained at this temperature for 30 min. Precipitation of the product was initiated by adding 1 mg seed crystals of Prasugrel-H2SO4. Within 30 min the precipitation was completed and the product was filtered off under a nitrogen atmosphere. The wet material was suck dried under vacuum and was washed with approx. 30 mL of dry acetone under nitrogen. Finally the product was washed with 14 mL of n-hexane under nitrogen. The product was dried at 45°C for 15 hours and then for 6 hours at 500C under vacuum (0 mbar). Yield 86%.
84%	With sulfuric acid In isopropyl alcohol at 20℃; for 6h;	5 To a suspension of prasugrel (20 g, 53.6 mmol) in isopropanol (200 ml) sulfuric acid (5.24 g, 53.4 mmol) was added slowly and stirred at room temperature for 6 hrs. The solid formed was filtered, washed with isopropanol (30 ml), and dried at 40 °C , to obtain the title compound as a white colored crystal (21.2 g, 84 %).Melting point : 104 °C to 107 °C (melting)Water content : 0.32 %Chemical purity : 98.7 %The results of 1H-NMR, IR, XRD and DSC are identical to those of Example 2.
78%	With sulfuric acid In acetone at -32 - -28℃; for 5.5h;	1 Example 1 Preparation of compound (II): 2-acetyloxy-5-(α-cycloproylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine bisulfate 8 g of refined 2-acetyloxy-5-(α-cycloproylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine is dissolved in 50 ml of acetone, and cooled to -32∼-28°C. The same temperature is maintained while adding dropwise 2.5 ml of concentrated sulfuric acid under stirring over 1.5 h. After the addition is completed, the mixture is stirred under the same temperature for further 4 h, while a large amount of crystals precipitate. The reaction is stopped when no more crystals are precipitated. The mixture is filtered, and the filter cake is washed with ice-cold acetone and then dried in vacuum under 60°C to obtain 8.2 g of white crystals. Yield: 78%. Melting point of the crystals: mp: 145-148°C

63%	With sulfuric acid In acetone at 20 - 40℃;	2 Example 2 Preparation of form I of Prasugrel hydrogensulfate 250.0 mg Prasugrel and 1.2 eq. (44 μl) concentrated sulfuric acid (95 - 97 %) were dissolved in 2 ml acetone at 40 °C. The solution was slowly cooled down to room temperature and Prasugrel hydrogensulfate seed crystals obtained in Example 1 were added. After 17.5 hours stirring at room temperature, the precipitate was filtered off, washed with acetone and dried at room temperature under vacuum to obtain 199.1 mg (63 % yield) of crystalline form I of Prasugrel hydrogensulfate.
	With sulfuric acid In methanol; acetic acid methyl ester; water at -20 - 5℃; for 69h;	47 Example 48: Preparation of crystalline Form SI of prasugrel hydrogen sulfate[00129] To a solution of prasugrel base (0.204 g) in 2.34 ml of methyl acetate /1.5% ethanol at 0-5°C, a dropwise solution of 29.3 μ of cone, sulfuric acid was added. The resulting oily reaction mixture was warmed to 20-25°C for about 30 minutes, then cooled again to 0-5 °C, seeded with small amount of prasugrel hydrogen sulfate Form SI and stirred for about 3 hours. The thus-obtained crystals were filtered and dried at 40 °C/ vacuum for about 17 hours. Prasugrel hydrogen sulfate (63 mg) was obtained. The flask was washed with 2 ml of methyl acetate, left crystals were filtered separately, and dried at 40 °C/vacuum for about 17 hours. Prasugrel hydrogen sulfate (84 mg) was obtained.
4.34 g	With sulfuric acid In iso-butanol at 0 - 50℃;	2 Example 1 5 g of prasugrel was dissolved in 15 ml of sec-butyl alcohol solvent, the temperature was raised to 50 °C and stirred to completely dissolve, and 1.35 g of concentrated sulfuric acid was added dropwise under continuous stirring, and the temperature was lowered to 0 °C at 10 °C/min under continuous stirring, stirring was then continued, the precipitated crystals were filtered, the filter cake was washed with ice-cold acetone, and the cake was dried under vacuum at 60°C to obtain 4.34 g of white prasugrel hydrogensulfate crystals.
7.68 g	With sulfuric acid at 55℃; for 2h;	4 Example 4 10 g prasugrel dissolved in 40 ml ethyl formate solvent,2.68g of concentrated sulfuric acid was added dropwise with stirring.Warm up to 55°C and stir for 2 hours to completely dissolve it.Heat filtration removes insoluble impurities and starts cooling under continuous stirring.Cool down to 5-10°C, keep warm for 1-2h, then cool down to 0°C.After a large amount of crystals have precipitated, the filter cake is washed with 50 ml of frozen ethanol.The cake was vacuum dried at 40 °C,7.68 g Prasugrel hydrogensulfate IV crystal form was obtained.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/129983, 2009, A1 Location in patent: Page/Page column 17
[2]Current Patent Assignee: HANMI SCIENCE CO LTD - WO2011/27988, 2011, A2 Location in patent: Page/Page column 14
[3]Current Patent Assignee: LUNAN PHARM GROUP - EP2325187, 2011, A1 Location in patent: Page/Page column 7-8
[4]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2112155, 2009, A1 Location in patent: Page/Page column 6
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/127300, 2011, A1 Location in patent: Page/Page column 24-25
[6]Current Patent Assignee: TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN107814810, 2018, A Location in patent: Paragraph 0032-0056
[7]Current Patent Assignee: TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN107915743, 2018, A Location in patent: Paragraph 0030; 0033; 0036; 0038; 0039; 0042; 0045

23
[ 104-15-4 ]
[ 150322-43-3 ]
[ 1155404-76-4 ]

Yield	Reaction Conditions	Operation in experiment
33%	In diethyl ether at 26℃; for 1h;	To a stirred solution of 500 mg Prasugrel in 10 mL dry diethyl ether a solution of 250 mg para-toluene sulfonic acid in 10 mL diethyl ether was added at 26 0C. During the addition the product started to precipitate. The reaction mixture was stirred for 1 hour. The solvent layer was decanted and the residual product was dried at 45 °C under vacuum (5 mbar) for 4 hours. Yield: 33%; DSC: no distinct peak. The product was obtained in amorphous form.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2009/129983, 2009, A1 Location in patent: Page/Page column 17

24
[ 951380-42-0 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 22 - 25℃;	1 Into a 250-ml three-neck flask equipped with a magnetic stirrer and a thermometer, which is closed with a calcium chloride tube, 12.22 g of p-toluenesulfonate of the compound of formula III and 40 ml of acetonitrile are charged. Under stirring, 13.6 ml of diisopropylethylamine are poured to the thick suspension and the mixture is stirred at the room temperature until a solution is obtained (5-10 minutes). Then, 3- cyclopropyl-1-(2-fluorophenyl)-3-oxopropyl methanesulfonate (compound of formula IV) (9.68 g) and 7.84 g of Et4N+Br are added to the flask. After that, the resulting mixture is stirred at a temperature of +22 to +25°C for 4 to 5 hours. The reaction is monitored with TLC. After disappearance of the starting substance 10 ml Of Ac2O and 50 mg of dimethylaminopyridine are added to the reaction mixture. The reaction mixture is further stirred at a temperature of +22 to +25 0C for another 1.5 to 2 hours. The reaction is monitored with TLC in the same system. After the conversion of the intermediate (II) the reaction mixture is cooled down to a temperature of -12 to -15 0C, 25 ml of a 2OmM aqueous solution of KH2PO4 are added. The mixture is inoculated and the product is left to crystallize under stirring at a temperature of -12 to -15 0C for 1.5 hours. The separated product is aspirated through a frit and on the frit it is washed with 20 ml of cooled ethanol. The product is freely dried at the room temperature. 4.06 g of the crude product are obtained with the purity of 96.11 % (HPLC).1H NMR (250 MHz, CDCI3) δ(ppm): 7.47 (ddd, J = 14.7, 7.4, 1.7 Hz, 1 H)1 7.31 (m, 1 H), 7.14 (m, 2H), 6.26 (s, 1 H), 4.82 (s, 1 H), 3.51 (m, 2H), 2.89 (m, 1 H), 2.79 (m, 3H), 4.30 (m, 1 H), 2.25 (s, 3H), 1.03 (m, 2H), 0.85 (m, 2H); 13C NMR (250 MHz, CDCI3) δ(ppm): 207.7, 167.7, 161.3 (d, J0F = 247,6 Hz), 149.5, 130.6 (d, JCF = 3.5 Hz), 129.9 (d, JCF = 8.4 Hz), 129.4, 125.8, 124.4 (d, JCF = 3.5 Hz), 122.1 (d, J0F = 14.1 Hz), 115.8 (d, JCF = 22.9 Hz), 112.0, 71.6, 50.5, 48.4, 25.0, 20.6,18.3,12.0, 11.4.
	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 4h; Inert atmosphere;	6 Preparation of 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno-[3,2-c]pyridin-2-yl acetate (Compound of Formula I) Example 6 364 mg of the compound of formula II were dissolved in 1.27 ml of dimethylformamide and 0.75 ml of acetanhydride in an inert atmosphere. The solution was cooled in a water+ice bath to the temperature of 0 to +5° C. and 156 ml of a 60% dispersion of NaH in mineral oil were added to the solution in parts. The reaction mixture was first stirred being cooled to 0 to +5° C. for 30 minutes and then at the room temperature for 3.5 hours. After this period the reaction mixture was diluted with 10 ml of ethyl acetate and carefully decomposed by addition of 3 ml of water. The organic layer was separated, washed with 5 ml of a saturated solution of NaCl, dried with anhydrous sodium sulfate. After concentrating in a rotational vacuum evaporator the crude product was chromatographed on silica gel with the toluene:ethyl acetate 3:1 solvent mixture. 324 mg of an oily product was obtained, which was crystallized from 2 ml of diethylether. 120 mg of the compound of formula I with the melting temperature of 120.5-124.6° C. were obtained. 1H NMR (250 MHz, CDCl3)(ppm): 7.47 (ddd, J=14.7, 7.4, 1.7 Hz, 1H), 7.31 (m, 1H), 7.14 (m, 2H), 6.26 (s, 1H), 4.82 (s, 1H), 3.51 (m, 2H), 2.89 (m, 1H), 2.79 (m, 3H), 4.30 (m, 1H), 2.25 (s, 3H), 1.03 (m, 2H), 0.85 (m, 2H); 13C NMR (250 MHz, CDCl3) (ppm): 207.7, 167.7, 161.3 (d, JCF=247.6 Hz), 149.5, 130.6 (d, JCF=3.5 Hz), 129.9 (d, JCF=8.4 Hz), 129.4, 125.8, 124.4 (d, JCF=3.5 Hz), 122.1 (d, JCF=14.1 Hz), 115.8 (d, JCF=22.9 Hz), 112.0, 71.6, 50.5, 48.4, 25.0, 20.6,18.3,12.0, 11.4;
	With triethylamine In N,N-dimethyl-formamide at -10 - 20℃; for 2.5h; Inert atmosphere;	6 18.76g 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo -4,5,6,7-tetrahydrothieno[3,2-c]pyridine (compound 4) prepared in Example 3, 4 or 5 and 60ml DMF were added to a 500ml four-neck flask equipped with a mechanical stirring device, a thermometer and a constant-pressure dropping funnel. The flask was placed in a water-ice bath and 17.17g triethylamine was injected under nitrogen atmosphere. The temperature was controlled at -10°C to 5°C and 17.34g acetic anhydride was added slowly in dropwise over 30 minutes. After the completion of addition, the mixture was kept for 10 minutes at this temperature and then stirred for 2 hours at room temperature. 100ml ethyl acetate and 150ml water were added thereto, and the system was allowed to seperation. The organic layer was washed with 150ml water, 50ml saturated NaHCO3 and 50ml saturated brine successively, and then dried over anhydrous magnesium sulfate. The resulting mixture was decolored with silica gel bed and filtered. The filtrate was distillated under reduced pressure and concentrated to give 26.10g brown gum.

With triethylamine In N,N-dimethyl-formamide at -10 - 20℃; for 2.5h; Inert atmosphere;

6 18.76 g 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (compound 4) prepared in Example 3, 4 or 5 and 60 ml DMF were added to a 500 ml four-neck flask equipped with a mechanical stirring device, a thermometer and a constant-pressure dropping funnel. The flask was placed in a water-ice bath and 17.17 g triethylamine was injected under nitrogen atmosphere. The temperature was controlled at -10° C. to 5° C. and 17.34 g acetic anhydride was added slowly in dropwise over 30 minutes. After the completion of addition, the mixture was kept for 10 minutes at this temperature and then stirred for 2 hours at room temperature. 100 ml ethyl acetate and 150 ml water were added thereto, and the system was allowed to seperation. The organic layer was washed with 150 ml water, 50 ml saturated NaHCO3 and 50 ml saturated brine successively, and then dried over anhydrous magnesium sulfate. The resulting mixture was decolored with silica gel bed and filtered. The filtrate was distillated under reduced pressure and concentrated to give 26.10 g brown gum.

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2010/60389, 2010, A1 Location in patent: Page/Page column 8-9
[2]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - US2010/228033, 2010, A1 Location in patent: Page/Page column 6
[3]Current Patent Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - EP2471795, 2012, A1 Location in patent: Page/Page column 5-6
[4]Current Patent Assignee: ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD. - US2012/142927, 2012, A1 Location in patent: Page/Page column 3

25
[ 150322-43-3 ]
[ 1060616-79-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogen bromide In acetone at 5 - 10℃; for 1h;	1 Example 1Preparation of prasugrel hydrobromide, form APrasugrel base (3.15 g, 8.43 mmol) is dissolved in acetone (46 ml) and the solution is, cooled down to 5 to 10 °C. A 48% solution of hydrobromic acid (0.90 ml; 8.01 mmol) is added to the solution dropwise, the solution is inoculated and stirred at a temperature of 5-10 °C for 1 hour. The separated crystals are aspirated. 3.60 g (99%) of prasugrel hydrobromide of form A with the melting point of 137-141°C are obtained. HPLC: purity 98.9%; content of the compound of formula II 0.67%.X-ray analysisTable 1 : Characteristic peaks of prasugrel hydrobromide of form A:The X-ray powder diffraction pattern is presented in the Annex in fig. 1 a, DSC curve is in fig. 1 b.
99%	With hydrogen bromide In water; acetone at 5 - 10℃; for 1h;	15 Prasugrel base (3.15 g, 8.43 mmol) is dissolved in acetone (46 ml) and the solution is cooled down to 5-10 °C. A 48% solution of hydrobromic acid (0.90 ml; 8.01 mmol) is added dropwise to the solution; the solution is inoculated and stirred at a temperature of 5-10 °C for 1 hour. The precipitated crystals are aspirated. 3.60 g (99%) of prasugrel hydrobromide, form A with the melt, point of 137-141 °C are obtained.
89%	With Acetyl bromide; acetic acid In ethyl acetate at 20 - 60℃; for 5.33333h;	3 Prasugrel base (7.5 g; 20.08 mmol) is dissolved in ethyl acetate at 60 °C. At this temperature, acetic acid (0.95 eq.) and acetylbromide (0.95 eq.) are added dropwise at the same time and the mixture is stirred at 60°C for another 20 min. The mixture will start to crystallize spontaneously. Subsequently, the heating is stopped and the stirring continues at the room temperature for another 5 h. The separated crystals are aspirated, washed with ethyl acetate and dried at 50°C in a vacuum drier for 24 h. 8.1 5 g (89 %) of prasugrel hydrobromide are obtained with the purity of >99 % (HPLC). M. p. 178-180°C. Water content 0.25 %; residual solvents: ethyl acetate < 5000 ppm The X-ray spectrum is the same as the spectrum presented in Example 1 .

86.4%	With hydrogen bromide; acetic acid In water at 25℃; for 2h;	5 Example 5: Preparion of acetic acid solvated crystal of 2-acetoxy-5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrobromate (crystal A) 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine (4 g) was dissolved in acetic acid (60 ml), and hydrogen bromide (40%) aqueous solution (2.16 g) was added dropwise with stirring at room temperature of 25°C. The mixture was stirred for 2 hours at the same temperature. The resulting crystals were separated by filtration and washed with a small amount of acetone and then dried at 60°C under reduced pressure for 4 hours to give the title compound as white crystals (4.77 g, yield 86.4%).
86.4%	With hydrogen bromide In water; acetic acid at 25℃; for 2h;	5 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (4 g) was dissolved in acetic acid (60 ml), and hydrogen bromide (40%) aqueous solution (2.16 g) was added dropwise with stirring at room temperature of 25° C. The mixture was stirred for 2 hours at the same temperature. The resulting crystals were separated by filtration and washed with a small amount of acetone and then dried at 60° C. under reduced pressure for 4 hours to give the title compound as white crystals (4.77 g, yield 86.4%).
	With hydrogen bromide In acetone at 25 - 30℃; for 3.16667h;	1 EXAMPLE 1: PREPARATIONOF CRYSTALLINE FORMOF PRASUGREL HYDROBROMIDE75.0 ml of acetone and 5.0 g prasugrel base were charged in a clean and dry 4 neck round-bottom-flask (RBF) followed by stirring for about 15 minutes. 2.7 g of Hydrobromic acid (48%v/v) was added dropwise at about 25°C to about 300C over about 10 minutes. The resultant reaction solution was stirred at about 25°C to about 3O0C for about 3 hours. The separated solid was filtered and the solid obtained was washed with 2x20 ml of acetone. The solid obtained was dried at about 500C to about 600C under vacuum for about 48 hours to afford 4.7 g of the title compound.Purity by HPLC: 99.5%All known and Unknown impurities = 0.5%.MASS (M/S): 374.15 a.m.uContent of HBr (%w/w by titrimetry): 17%w/w.Target compound has an X- ray powder diffraction (XRD) pattern with characteristic peaks at about 7.06, 8.31, 10.08, 1 1.46, 12.19, 12.82, 13.73, 14.17, 15.8, 16.7, 16.98,17.23, 17.73, 18.36, 18.70, 21.60, 23.42, 23.69, 24.21, 24.39, 24.9, 25.14, 25.82, 26.50,27.0, 29.89, 30.31 and 37.2 +/- 0.2 degrees two-theta, which is substantially in accordance with Figl .Differential scanning calorimetry (DSC) endotherm curve at about 138.25°C with an onset at about 128.29°C and an endset at about 146.34°C, which is substantially in accordance with Fig. 2.And Fourier Transform Infrared (FTIR) frequencies by infrared absorption which is substantially in accordance with Figure 3.
	With hydrogen bromide In water; acetone at 0 - 25℃; for 2.08333h;	20 Example 21 : Preparation of crystalline form II of prasugrel hydrobromide[00100] Prasugrel base (1.00 g) was dissolved in acetone (15.5 ml) at 20-25°C. Solution of 0.34 ml 47% HBr in 4.8 ml of acetone was added in solution of base. Clear solution was cooled down to 5-0°C. After 5 minutes crystallization took place. Suspension was stirred at 5-0°C for 2 hours, filtered, crystals were washed with acetone and dried at 40°C/ vacuum, yielding form II of prasugrel hydrobromide (1.26g). HPLC purity: 99.94%.[00101] The sample was left in an open Petri dish at room conditions (20-25°C, relative humidity 20-30%) for 1 month and then reanalyzed on HPLC giving purity of 99.84%.
12 g	With Acetyl bromide In isopropyl alcohol; acetone at 20℃; for 0.5h;	1 Preparation of pravicola hydrobromide: 250 mL round bottom flask10.0 g (26.8 mmol)Pragre was suspended in 100.0 mL of acetone,After stirring at 20 ° C, 3.1 ml (40.2 mmol) of isopropanol was added,Then 2.6 mL (32.1 mmol) of acetyl bromide was slowly added dropwise,After dripping for 30 min,Stop heating,Natural cooling,crystallization.3h after filtering,20.0 mL of acetone,Dried at 40 ° C under vacuum16h get it12.0gHydrobromide prasugrelWhite solid,HPLC purity 99.1%; 1H NMR (400 MHz, CDCl3)? 13.38 (d,J = 109.9 Hz, 1H), 7.97 (d, J = 71.5 Hz, 1H), 7.55 (d, J = 6.0 Hz, 1H), 7.38 (t, J = 7.0 Hz,(M, 2H), 6.38 (s, 1H), 5.67 (s, 1H), 4.63 (s, 1H), 4.01 (d, J = 179.2 Hz, 2H), 3.55(S, 1H), 3.27 (s, 1H), 2.89 (s, 1H), 2.30 (s, 3H), 1.81 (s, 1H), 1.28 (d, J = 23.0 Hz, 1H)(S, 1H), 1.04 (s, 1H), 0.89 (s, 1H)

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57593, 2011, A2 Location in patent: Page/Page column 11-12
[2]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57592, 2011, A1 Location in patent: Page/Page column 17
[3]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2012/89180, 2012, A1 Location in patent: Page/Page column 7-8
[4]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - EP2415774, 2012, A1 Location in patent: Page/Page column 8
[5]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - US2012/95035, 2012, A1 Location in patent: Page/Page column 5
[6]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2011/4392, 2011, A1 Location in patent: Page/Page column 12
[7]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/127300, 2011, A1 Location in patent: Page/Page column 18
[8]Current Patent Assignee: SHANDONG LUKANG PHARMACEUTICAL CO., LTD. - CN106083885, 2016, A Location in patent: Paragraph 0031; 0032; 0033; 0034; 0035; 0036; 0037-0048

26
[ 81-04-9 ]
[ 150322-43-3 ]
prasugrel 1,5-naphthalene disulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	In acetone at 20℃; for 6h;	6 Example 6: Preparation of prasugrel 1,5-naphthalene disulfonate2.0 g of prasugrel (5.35 mmol) was dissolved in 20 ml of acetone, 1.0 g of 1,5-naphthalane disulfonic acid tetrahydrate (2.78 mmol) was added thereto, and the mixture was stirred at room temperature for 6 hrs. The solid formed was filtered, washed with 5 ml of acetone, and dried at 40 °C to obtain 2.65 g of the title compound as a white-colored crystal (96%).Melting point: 218 "C to 220 °C (melting)Water content: 0.25%Chemical purity: 99.0%Combination ratio of naphthalane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR). 1H-NMR (DMSO-d6, ppm): δ 8.9(d, IH), 7.9(d, IH), 7.6(m, IH), 7.4~7.5(m, 4H), 6.6(s, IH), 6.0(s, IH), 4.0(m, 2H), 3.0(m, 2H), 2.4(m, IH), 2.2(s, 3H), 2.1(m, IH), 1.9(m, IH), l.l(m, 2H), 0.9(m, 2H).IR (KBr, cm"1): 3458, 2011, 2917, 2556, 2363, 1770, 1711, 1615, 1587, 1496, 1451, 1370, 1248, 1222, 1171, 1131, 1026, 766, 612.An XRD spectrum of the above was obtained using CuKa radiation and determined 2 theta (2Θ) major peaks having relative peak intensity of at least 30% (1/I0; I: the peak intensity; and I0: the peak intensity of the maximum peak), and the distances between crystal facets (d) are shown in Table 2. Said major peaks are shown in Fig. 4.A DSC (10 °C/min) scan showed endothermic peak with an onset point at206.33 °C and a minimum point at 223.38 "C which corresponds to the melting point of said compound as shown in Fig. 5.The difference of the water content by DVS of less than 1.0% was determined at a relative humidity ranging from 0 to 90%, as shown in Fig. 6.

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD - WO2011/16686, 2011, A2 Location in patent: Page/Page column 13-14

27
[ 110-04-3 ]
[ 150322-43-3 ]
prasugrel 1,2-ethane disulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	In isopropyl alcohol at 20 - 50℃;	3 Example 3: Preparation of prasugrel 1,2-ethane disulfonate2.0 g of prasugrel (5.35 mmol) was dissolved in 20 ml of isopropanol, 0.6 g of 1,2-ethane disulfonic acid (3.15 mmol) was added thereto, and the mixture was heated to 50 °C . The resulting mixture was slowly cooled to room temperature and stirred for 12 hrs. The solid formed was filtered, washed with 5 ml of isopropanol, and dried at 40 °C to obtain 2.23 g of the title compound as a white-colored crystal (89%).Melting point: 186°C to 1880C (melting)Water content (KF): 0.20%Chemical purity: 98.9%Combination ratio of ethane disulfonic acid: 0.5 molecules to one molecule of prasugrel (1H-NMR).The results of 1H-NMR, IR, XRD, DSC and DVS are identical to those of Example 1.

Reference： [1]Current Patent Assignee: HANMI SCIENCE CO LTD - WO2011/16686, 2011, A2 Location in patent: Page/Page column 12

28
[ 109904-26-9 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydride / N,N-dimethyl-formamide / 3 h / 20 °C / Cooling with ice-water bath 2: hydrogenchloride / diethyl ether 3: triethylamine / dichloromethane / -15 - 20 °C
	Multi-step reaction with 3 steps 1.1: acetone / 0.42 h / 25 - 30 °C 2.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 2.2: 7 h / 25 - 30 °C 2.3: 8 h / 0 - 25 °C 3.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 3.2: 6 h / 0 - 5 °C
	Multi-step reaction with 2 steps 1.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 2.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 2.2: 6 h / 25 - 30 °C 2.3: 6.5 h / 0 - 30 °C

	Multi-step reaction with 3 steps 1.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 2.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 2.2: 7 h / 25 - 30 °C 3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 3 steps 1.1: acetone / 0.42 h / 25 - 30 °C 2.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 2.2: 7 h / 25 - 30 °C 3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 4 steps 1.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 2.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 2.2: 7 h / 25 - 30 °C 3.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: acetone / 0.42 h / 25 - 30 °C 2.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 2.2: 7 h / 25 - 30 °C 2.3: 8 h / 0 - 25 °C 3.1: sodium hydrogencarbonate / water / 0.5 h / 10 - 15 °C 4.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 4 steps 1.1: acetone / 0.42 h / 25 - 30 °C 2.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 2.2: 7 h / 25 - 30 °C 3.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1: tetrahydrofuran / 0 - 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C / Cooling with ice 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C
	Multi-step reaction with 3 steps 1: tetrahydrofuran / 0 - 20 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Cooling with ice 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 15 - 25 °C
	Multi-step reaction with 3 steps 1.1: hydrogenchloride / acetone 2.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 2.2: 6 h / 25 - 30 °C 2.3: 0 - 30 °C 3.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 3.2: 6 h / 0 - 5 °C
	Multi-step reaction with 2 steps 1.1: hydrogenchloride / water; acetone / 3 h / 55 - 60 °C 2.1: sodium hydrogencarbonate / N,N-dimethyl-formamide / 2 h / 50 - 55 °C 2.2: 10 - 45 °C
	Multi-step reaction with 5 steps 1: tetrahydrofuran / 25 °C 2: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 20 °C / Inert atmosphere 4: hydrogenchloride; water / ethyl acetate / 20 °C 5: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 2: ammonium bicarbonate / dichloromethane / 5 - 20 °C 3: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 2: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 20 °C / Inert atmosphere 4: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: tetrahydrofuran / 25 °C 2: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 20 °C / Inert atmosphere 4: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 2: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 20 °C / Inert atmosphere 4: hydrogenchloride; water / ethyl acetate / 20 °C 5: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 6 h / 0 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C 2.2: 1 h / 15 - 20 °C
	Multi-step reaction with 2 steps 1.1: hydrogenchloride / acetone / 4.5 h / 25 - 30 °C / Reflux 2.1: potassium carbonate / acetonitrile / 6.5 h / 25 - 30 °C 2.2: 6.5 h / 0 - 30 °C
	Multi-step reaction with 3 steps 1.1: hydrogenchloride / acetone / 4.5 h / 25 - 30 °C / Reflux 2.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 3.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 3.2: 6 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1.1: acetone / 0.92 h / 25 - 30 °C / Reflux 2.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 3.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 3.2: 6 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1.1: acetone / 0.92 h / 25 - 30 °C / Reflux 2.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 2.2: 8 h / 0 - 25 °C 3.1: acetic anhydride; triethylamine / dichloromethane / 6.25 h / 0 - 30 °C
	Multi-step reaction with 2 steps 1.1: tetrahydrofuran / 2 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C / Cooling with ice 2.2: 1 h / 20 °C
	Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide / 0 - 20 °C 1.2: 0 - 20 °C 2.1: tetrahydrofuran / 3 h / 20 °C 3.1: sodium hydrogencarbonate / N,N-dimethyl-formamide / 5 - 10 °C 3.2: 5 h / 20 °C 3.3: 3 h / 20 °C

Reference： [1]Current Patent Assignee: BC PARTNERS LLP - WO2011/29456, 2011, A1
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[5]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[6]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[7]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[8]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[9]Current Patent Assignee: SERVIER MONDE - WO2011/77173, 2011, A1
[10]Current Patent Assignee: SERVIER MONDE - WO2011/77174, 2011, A1
[11]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/92720, 2011, A2
[12]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2011/117782, 2011, A1
[13]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[14]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[15]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[16]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[17]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[18]Current Patent Assignee: SERVIER MONDE - WO2012/52788, 2012, A1
[19]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[20]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[21]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[22]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[23]Current Patent Assignee: SERVIER MONDE - US2013/30183, 2013, A1
[24]Current Patent Assignee: TORRENT INVESTMENTS PRIVATE LIMITED - WO2009/122440, 2009, A1

29
5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 1.2: 1 h / -78 °C 1.3: 1 h / -60 - 0 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 3 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 1.2: 1 h / -78 °C 1.3: 1 h / -60 - 0 °C 2.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 3.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 3.2: 6 h / 0 - 5 °C
	Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / 0 °C / Inert atmosphere 1.2: 1 h / -10 - 0 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[3]Current Patent Assignee: JIANGSU FANGSHENG PHARMACEUTICAL - CN103923101, 2017, B

30
[ 28783-41-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / 5 h / 25 - 35 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 2.2: 1 h / -78 °C 2.3: 1 h / -60 - 0 °C 3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 5 h / 25 - 35 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 2.2: 1 h / -78 °C 2.3: 1 h / -60 - 0 °C 3.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C / Inert atmosphere 2.3: 2 h / 0 - 30 °C 3.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 6 h / 25 - 30 °C 4.3: 6.5 h / 0 - 30 °C

	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C / Inert atmosphere 2.3: 2 h / 0 - 30 °C 3.1: acetone / 0.42 h / 25 - 30 °C 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 4.3: 8 h / 0 - 25 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C / Inert atmosphere 2.3: 2 h / 0 - 30 °C 3.1: acetone / 0.42 h / 25 - 30 °C 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C / Inert atmosphere 2.3: 2 h / 0 - 30 °C 3.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C / Inert atmosphere 2.3: 2 h / 0 - 30 °C 3.1: acetone / 0.42 h / 25 - 30 °C 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 5.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 6.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 6.2: 6 h / 0 - 5 °C
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C / Inert atmosphere 2.3: 2 h / 0 - 30 °C 3.1: acetone / 0.42 h / 25 - 30 °C 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 4.3: 8 h / 0 - 25 °C 5.1: sodium hydrogencarbonate / water / 0.5 h / 10 - 15 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C / Inert atmosphere 2.3: 2 h / 0 - 30 °C 3.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 5.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 6.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 6.2: 6 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3 h 2.1: n-butyllithium / hexane; tetrahydrofuran / -40 - 10 °C / Inert atmosphere 2.2: -40 - 10 °C / Inert atmosphere 2.3: -40 - 20 °C / Inert atmosphere 3.1: tetrahydrofuran / 0 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C / Cooling with ice 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C
	Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3 h 2.1: n-butyllithium / hexane; tetrahydrofuran / -40 - 10 °C / Inert atmosphere 2.2: -40 - 10 °C / Inert atmosphere 2.3: -40 - 20 °C / Inert atmosphere 3.1: tetrahydrofuran / 0 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Cooling with ice 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 15 - 25 °C
	Multi-step reaction with 7 steps 1.1: bromine / dichloromethane; water / 20 °C / pH 8.5 1.2: pH 8.5 / Alkaline conditions 2.1: triethylamine / dichloromethane / 0.75 h / Cooling with ice 3.1: potassium phosphate; copper; copper(l) iodide / 2-(N,N-dimethylamino)ethanol / 24 h / 80 °C 4.1: hydrogenchloride / diethyl ether / Cooling with ice 5.1: triethylamine / acetonitrile / Cooling with ice 6.1: hydrogenchloride; water / 5 h / 70 °C 6.2: pH 10 / Alkaline conditions 7.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C
	Multi-step reaction with 5 steps 1.1: bromine / dichloromethane; water / 20 °C / pH 8.5 1.2: pH 8.5 / Alkaline conditions 2.1: potassium phosphate; copper; copper(l) iodide / 18 h / 80 °C 3.1: triethylamine / dichloromethane / 5 h / 20 °C 4.1: hydrogenchloride; water / 4 h / 90 °C 4.2: pH 10 / Alkaline conditions 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C
	Multi-step reaction with 5 steps 1.1: bromine / dichloromethane; water / 20 °C / pH 8.5 1.2: pH 8.5 / Alkaline conditions 2.1: potassium phosphate; copper; copper(l) iodide / 2-(N,N-dimethylamino)ethanol / 72 h / 80 °C 3.1: triethylamine / acetonitrile / Cooling with ice 4.1: hydrogenchloride; water / 5 h / 70 °C 4.2: pH 10 / Alkaline conditions 5.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C
	Multi-step reaction with 7 steps 1.1: triethylamine / dichloromethane / 12 - 28 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 2.2: -5 - 10 °C 3.1: tetrahydrofuran / 25 °C 4.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 6.1: hydrogenchloride; water / ethyl acetate / 20 °C 7.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 12 - 28 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 2.2: -5 - 10 °C 3.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 4.1: ammonium bicarbonate / dichloromethane / 5 - 20 °C 5.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 12 - 28 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 2.2: -5 - 10 °C 3.1: tetrahydrofuran / 25 °C 4.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 6.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 12 - 28 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 2.2: -5 - 10 °C 3.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 4.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 6.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1.1: triethylamine / dichloromethane / 12 - 28 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 2.2: -5 - 10 °C 3.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 4.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 5.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 6.1: hydrogenchloride; water / ethyl acetate / 20 °C 7.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3 h 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / -40 - 10 °C / Inert atmosphere 2.2: 1 h / -40 - 10 °C 2.3: 1 h / -40 - 20 °C 3.1: tetrahydrofuran / 6 h / 0 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C 4.2: 1 h / 15 - 20 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C 2.3: 1.75 h / 0 - 30 °C / Reflux 3.1: hydrogenchloride / acetone / 4.5 h / 25 - 30 °C / Reflux 4.1: potassium carbonate / acetonitrile / 6.5 h / 25 - 30 °C 4.2: 6.5 h / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C 2.3: 1.75 h / 0 - 30 °C / Reflux 3.1: acetone / 0.92 h / 25 - 30 °C / Reflux 4.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C 2.3: 1.75 h / 0 - 30 °C / Reflux 3.1: hydrogenchloride / acetone / 4.5 h / 25 - 30 °C / Reflux 4.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 9 h / 0 - 5 °C 2.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 2.2: 1 h / 0 - 15 °C 2.3: 1.75 h / 0 - 30 °C / Reflux 3.1: acetone / 0.92 h / 25 - 30 °C / Reflux 4.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 4.2: 8 h / 0 - 25 °C 5.1: acetic anhydride; triethylamine / dichloromethane / 6.25 h / 0 - 30 °C
	Multi-step reaction with 8 steps 1: tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate / acetonitrile / 70 °C 2: hydrogen bromide; dihydrogen peroxide; acetic acid / methanol / 0 - 5 °C 3: copper(l) iodide; sodium iodide; sodium methylate / Reflux 4: methyl chloroformate 5: potassium carbonate / ethanol / 0 °C 6: tetrahydrofuran / 0 - 20 °C 7: hydrogenchloride / water / 12 h / 40 °C 8: sodium hydride / N,N-dimethyl-formamide / 0 °C
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3 h 2.1: n-butyllithium / tetrahydrofuran; hexane / -40 - 10 °C / Inert atmosphere 2.2: -40 - 10 °C 2.3: -40 - 20 °C 3.1: tetrahydrofuran / 2 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C / Cooling with ice 4.2: 1 h / 20 °C
	Multi-step reaction with 6 steps 1.1: sodium hydroxide / dichloromethane / 0.25 h / 20 °C 1.2: 8 h / 20 °C 2.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -10 - 0 °C / Inert atmosphere 2.2: 1.5 h / -10 °C 3.1: tetrahydrofuran / 0 - 20 °C 4.1: triethylamine / ethanol / 50 °C / Inert atmosphere 4.2: 8 h / 50 °C 5.1: acetic acid / ethanol / 4 °C / Inert atmosphere 5.2: 4 h / 4 - 20 °C 6.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 1 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[5]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[6]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[7]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[8]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[9]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[10]Current Patent Assignee: SERVIER MONDE - WO2011/77173, 2011, A1
[11]Current Patent Assignee: SERVIER MONDE - WO2011/77174, 2011, A1
[12]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1
[13]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1
[14]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1
[15]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[16]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[17]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[18]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[19]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[20]Current Patent Assignee: SERVIER MONDE - WO2012/52788, 2012, A1
[21]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[22]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[23]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[24]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[25]Pan, Xianhua; Huang, Rui; Zhang, Jianshui; Ding, Liping; Li, Weijin; Zhang, Qunhui; Liu, Feng [Tetrahedron Letters, 2012, vol. 53, # 40, p. 5364 - 5366]
[26]Current Patent Assignee: SERVIER MONDE - US2013/30183, 2013, A1
[27]Ou, Wenhua; Yi, Weiyin; Liu, Feng; Pan, Xianhua; Peng, Xijiang [Journal of Chemical Research, 2013, vol. 37, # 6, p. 369 - 371]

31
[ 150322-73-9 ]
[ 150322-43-3 ]

Reference： [1]Patent: WO2011/42918,2011,A2
[2]Patent: WO2011/42918,2011,A2
[3]Patent: WO2011/42918,2011,A2
[4]Patent: WO2011/42918,2011,A2
[5]Patent: WO2011/42918,2011,A2
[6]Patent: WO2011/42918,2011,A2
[7]Patent: WO2011/42918,2011,A2
[8]Patent: WO2011/42918,2011,A2
[9]Patent: WO2011/42918,2011,A2
[10]Patent: WO2011/92720,2011,A2
[11]Patent: WO2012/1486,2012,A1
[12]Patent: WO2012/1486,2012,A1
[13]Patent: WO2012/1486,2012,A1
[14]Patent: WO2012/23145,2012,A2
[15]Patent: WO2012/52788,2012,A1
[16]Patent: EP2471795,2012,A1
[17]Patent: EP2471795,2012,A1
[18]Patent: US2012/142927,2012,A1
[19]Patent: US2012/202066,2012,A1
[20]Patent: US2012/202066,2012,A1
[21]Patent: US2012/202066,2012,A1
[22]Patent: US2012/202066,2012,A1
[23]Patent: WO2013/14295,2013,A1
[24]Patent: WO2013/14295,2013,A1
[25]Patent: WO2014/114964,2014,A2
[26]Patent: CN105884793,2016,A
[27]Patent: CN107056803,2017,A
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[29]Patent: WO2017/221187,2017,A1
[30]Patent: WO2009/122440,2009,A1
[31]Patent: WO2009/122440,2009,A1

32
[ 451-82-1 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 5 h / 25 - 35 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 5.2: 1 h / -78 °C 5.3: 1 h / -60 - 0 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 6 h / 25 - 30 °C 4.3: 6.5 h / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C

	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 4.3: 8 h / 0 - 25 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 5.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 6.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 6.2: 6 h / 0 - 5 °C
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 5.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 6.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 6.2: 6 h / 0 - 5 °C
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 4.2: 7 h / 25 - 30 °C 4.3: 8 h / 0 - 25 °C 5.1: sodium hydrogencarbonate / water / 0.5 h / 10 - 15 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 7 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 2.2: 40 - 50 °C 2.3: 0.25 h / 0 - 30 °C 3.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 4.1: potassium carbonate / acetonitrile / 5 h / 25 - 35 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 5.2: 1 h / -78 °C 5.3: 1 h / -60 - 0 °C 6.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 7.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 7.2: 6 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 1.2: 5 - 65 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 3.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 4.1: hydrogenchloride; water / ethyl acetate / 20 °C 5.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 1.2: 5 - 65 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 3.1: ammonium bicarbonate / dichloromethane / 5 - 20 °C 4.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 1.2: 5 - 65 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 3.1: ammonium bicarbonate / dichloromethane / 5 - 20 °C 4.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 1.2: 5 - 65 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 3.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 4.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 1.2: 5 - 65 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 3.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 4.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 1.2: 5 - 65 °C 2.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 3.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 4.1: hydrogenchloride; water / ethyl acetate / 20 °C 5.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: sodium hydride / toluene; dimethyl sulfoxide / 1.5 h / 95 - 110 °C / Large scale 2: bromine / methanol / Large scale 3: sodium carbonate / 10 h / 40 °C / Large scale 4: dmap; triethylamine / 2 h / 0 - 5 °C / Large scale

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[5]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[6]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[7]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[8]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[9]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[10]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[11]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[12]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[13]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[14]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[15]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[16]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2017/221187, 2017, A1

33
[ 204205-33-4 ]
[ 115473-15-9 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example-29: One pot process for the preparation of Prasugrel:A mixture of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one hydrochloride (100 grams), potassium carbonate (215 grams) and acetonitrile (500 ml) was stirred for 30 minutes at 25-30C. 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)ethanone (89.5 grams) in acetonitrile (50 ml) was added to the reaction mixture and stirred for 6 hours at 25-30C. The reaction mixture was filtered and removed the precipitated solid. Triethylamine (98.2 grams) was added to the filtrate and then cooled to 0-5C. Acetic anhydride (1 19 grams) was added to the reaction mixture and stirred for 30 minutes at 0-5C. The reaction mixture was stirred for 6 hours at 25-30C. Then the reaction mixture was quenched with water and extracted the reaction mixture into toluene. The solvent from the toluene layer was distilled off under reduced pressure and methanol (100 ml) was added to the obtained residue and stirred for 45 min at reflux temperature. The reaction mixture was cooled to 0-5C and stirred for 45 minutes. The obtained solid was filtered, washed with methanol and then dried to get the title compound.Yield: 60 grams; Purity by HPLC: 98.97%
		Example-2 Preparation of 2-Acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (crude Prasugrel) 100 gm of 2-Oxo-2,4,5,6,7,7a-hexahydro thieno [3,2-c] pyridine hydrochloride was charged in 800 ml of dimethylformamide to obtain reaction mixture. To this sodium bicarbonate (175 gm) and alpha-Cyclopropyl carbonyl-2-fluorobenzylbromide (175 gm) was added at room temperature and allowed to heat at 50-55C for 2 hrs. The reaction mixture was cooled up to 10-15C. Acetic anhydride (118.67 gm) was added drop by drop at same temperature. The reaction mixture was heated to 40-45C for 3 hrs & cooled the reaction mixture to room temperature. Ethyl acetate and water was added to reaction mixture. The organic layer was separated and aqueous layer was discarded. The organic ethyl acetate layer was washed by aq. Na2CO3 followed by aq. NaCl solution. The ethyl layer was distilled of completely to obtain product mass. Methanol was charged in the obtained mass and stirred it at room temperature & cooled up to 0-5Cto obtain solid which was filtered and washed with methanol and dried at 50-55o C under vacuum to obtain crude prasugrel (85-95 gm).

Reference： [1]Patent: WO2011/42918,2011,A2 .Location in patent: Page/Page column 48-49
[2]Patent: WO2011/117782,2011,A1 .Location in patent: Page/Page column 7

34
[ 1243654-57-0 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrobromide With triethylamine In dichloromethane at 0 - 5℃; for 0.5h; Stage #2: acetic anhydride In dichloromethane	4 24.3 mmol) of 5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -2-oxo-2,4,5,6,7,7a-hexahydrothieno [3,2-c] pyridine bromate was added to a 250 ml three-necked flask, then 100 ml of methylene chloride was added, cooled to 0-5 ° C, and then 9.8 g (96.8 mmol) of triethylamine was added and stirred at the same temperature for 30 minutes. 6.18 g (60.5 mmol) of acetic anhydride was added dropwise and the mixture was finished in about 45 minutes.The reaction was continued for 5-6 hours. TLC monitoring reaction. To the reaction mixture was added 50 ml of water, and the organic layer was separated. The organic layer was washed successively with 25 ml of 5% NaHC03, 25 ml of water and dried over anhydrous Na2S04. The solvent was removed under reduced pressure at 50 ° C and the isopropanol was recrystallized and dried in vacuo to give 6.27 g of white crystals in 73%
	Stage #1: 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrobromide With triethylamine In dichloromethane at 25 - 30℃; for 0.25h; Stage #2: acetic anhydride In dichloromethane at 0 - 5℃; for 6h;	24 Example-24: Preparation of prasugrel compound of formula- 1 :Triethylamine (32 grams) was added to the solution of 5-(a-cyclo propylcarbonyl-2- fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine hydrobromide (60 grams) in methylene chloride (600 ml) and stirred for 15 minutes at 25-30°C and then cooled to 0-5°C. Acetic anhydride (64.5 ml) was added to the reaction mixture and stirred for 6 hrs at 0-5°C. Water was added to the reaction mixture and raised the temperature to 20-25°C. Separated both the aqueous and organic layers. Organic layer washed with aqueous sodium bicarbonate followed by water and then the solvent from the organic layer was distilled off under reduced pressure, isopropyl alcohol (48 ml) and acetonitrile (16 ml) was added to the obtained residue and stirred for 45 min at reflux temperature. The reaction mixture was cooled to 10-15°C and stirred for 60 minutes. The obtained solid was filtered, washed with isopropyl alcohol and then dried to get the title compound.Yield: 45 grams; Purity by HPLC: 99.20%
	Stage #1: 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine hydrobromide With triethylamine In dichloromethane at 25 - 30℃; for 0.25h; Stage #2: acetic anhydride In dichloromethane at 0 - 5℃; for 6h;	8 Example-8: Preparation of prasugrel compound of formula-1: Triethylamine (98 grams) was added to the solution of 5-(2-cyclopropyl-l-(2-fluoro phenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one hydrobromide (100 grams) in dichloromethane (1000 ml) and stirred for 15 minutes at 25-30°C and then cooled to 0-5 °C. Acetic anhydride (62 grams) was added to the reaction mixture and stirred for 6 hours at 0-5°C. The reaction mixture was quenched with water at 20-25°C and separated both the aqueous and organic layers. Organic layer was washed with aqueous sodium bicarbonate followed by water and then the solvent from the organic layer was distilled off under reduced pressure and isopropyl alcohol (125 ml) was added to the obtained residue and stirred for 45 min at 40-50°C. The reaction mixture was cooled to 10-15°C and stirred for 60 minutes. The solid obtained was filtered, washed with isopropyl alcohol and then dried to get the title compound.Yield: 84 grams.

With triethylamine In dichloromethane at 0℃; for 3.5h;

1.III 5-(a-Cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno- [3,2-c]pyridine hydrobromide (60 gm) was dissolved in methylene chloride (524 ml) and then added triethylamine (60 gm) at room temperature. The solution was cooled to 0°C and then added acetic anhydride (60 gm) for 1 hour 30 minutes at 0°C. The reaction mass was maintained for 2 hours at 0°C and then added water (500 ml). The temperature of the reaction mass was raised to room temperature and then the layers were separated. The methylene chloride layer was dried with sodium sulfate and concentrated at below 45°C to obtain residual mass. The residual mass was dissolved in methanol (240 ml) and stirred for 2 hour 30 minutes at room temperature. The separated solid was filtered and dried to obtain 38.5 gm of prasugrel

Reference： [1]Current Patent Assignee: JIANGSU FANGSHENG PHARMACEUTICAL - CN103923101, 2017, B Location in patent: Paragraph 0025-0026
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2 Location in patent: Page/Page column 47
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/92720, 2011, A2 Location in patent: Example 8
[4]Current Patent Assignee: HETERO DRUGS LIMITED - WO2012/23145, 2012, A2 Location in patent: Page/Page column 8

35
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[ 150322-43-3 ]

Reference： [1]Patent: WO2011/42918,2011,A2
[2]Patent: WO2011/42918,2011,A2
[3]Patent: WO2011/42918,2011,A2
[4]Patent: WO2011/42918,2011,A2
[5]Patent: WO2011/42918,2011,A2
[6]Patent: WO2011/42918,2011,A2
[7]Patent: WO2011/42918,2011,A2
[8]Patent: WO2011/42918,2011,A2
[9]Patent: WO2011/92720,2011,A2
[10]Patent: WO2012/1486,2012,A1
[11]Patent: WO2012/1486,2012,A1
[12]Patent: WO2012/1486,2012,A1
[13]Patent: WO2012/23145,2012,A2
[14]Organic Process Research and Development,2012,vol. 16,p. 240 - 243
[15]Patent: EP2471795,2012,A1
[16]Patent: US2012/142927,2012,A1
[17]Patent: US2012/202066,2012,A1
[18]Patent: US2012/202066,2012,A1
[19]Patent: WO2013/14295,2013,A1
[20]Patent: WO2013/14295,2013,A1
[21]Journal of Chemical Research,2013,vol. 37,p. 369 - 371
[22]Asian Journal of Chemistry,2013,vol. 25,p. 7783 - 7789
[23]Patent: WO2009/122440,2009,A1

36
[ 109904-25-8 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C / Inert atmosphere 1.3: 2 h / 0 - 30 °C 2.1: acetone / 0.42 h / 25 - 30 °C 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 3.3: 8 h / 0 - 25 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C / Inert atmosphere 1.3: 2 h / 0 - 30 °C 2.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 6 h / 25 - 30 °C 3.3: 6.5 h / 0 - 30 °C
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C / Inert atmosphere 1.3: 2 h / 0 - 30 °C 2.1: acetone / 0.42 h / 25 - 30 °C 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 4.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C

	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C / Inert atmosphere 1.3: 2 h / 0 - 30 °C 2.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 4.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C / Inert atmosphere 1.3: 2 h / 0 - 30 °C 2.1: acetone / 0.42 h / 25 - 30 °C 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 3.3: 8 h / 0 - 25 °C 4.1: sodium hydrogencarbonate / water / 0.5 h / 10 - 15 °C 5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C / Inert atmosphere 1.3: 2 h / 0 - 30 °C 2.1: acetone / 0.42 h / 25 - 30 °C 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 4.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C / Inert atmosphere 1.3: 2 h / 0 - 30 °C 2.1: hydrogenchloride; water / acetone / 3 h / 25 - 30 °C 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 4.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -40 - 10 °C / Inert atmosphere 1.2: -40 - 10 °C / Inert atmosphere 1.3: -40 - 20 °C / Inert atmosphere 2.1: tetrahydrofuran / 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C / Cooling with ice 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C
	Multi-step reaction with 4 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / -40 - 10 °C / Inert atmosphere 1.2: -40 - 10 °C / Inert atmosphere 1.3: -40 - 20 °C / Inert atmosphere 2.1: tetrahydrofuran / 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Cooling with ice 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 15 - 25 °C
	Multi-step reaction with 6 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 1.2: -5 - 10 °C 2.1: tetrahydrofuran / 25 °C 3.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 5.1: hydrogenchloride; water / ethyl acetate / 20 °C 6.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 1.2: -5 - 10 °C 2.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 3.1: ammonium bicarbonate / dichloromethane / 5 - 20 °C 4.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 1.2: -5 - 10 °C 2.1: tetrahydrofuran / 25 °C 3.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 5.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 1.2: -5 - 10 °C 2.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 3.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 5.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 1.2: -5 - 10 °C 2.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 3.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 4.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 5.1: hydrogenchloride; water / ethyl acetate / 20 °C 6.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / -40 - 10 °C / Inert atmosphere 1.2: 1 h / -40 - 10 °C 1.3: 1 h / -40 - 20 °C 2.1: tetrahydrofuran / 6 h / 0 - 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C 3.2: 1 h / 15 - 20 °C
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C 1.3: 1.75 h / 0 - 30 °C / Reflux 2.1: hydrogenchloride / acetone / 4.5 h / 25 - 30 °C / Reflux 3.1: potassium carbonate / acetonitrile / 6.5 h / 25 - 30 °C 3.2: 6.5 h / 0 - 30 °C
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C 1.3: 1.75 h / 0 - 30 °C / Reflux 2.1: acetone / 0.92 h / 25 - 30 °C / Reflux 3.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C 1.3: 1.75 h / 0 - 30 °C / Reflux 2.1: hydrogenchloride / acetone / 4.5 h / 25 - 30 °C / Reflux 3.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 15 °C / Inert atmosphere 1.2: 1 h / 0 - 15 °C 1.3: 1.75 h / 0 - 30 °C / Reflux 2.1: acetone / 0.92 h / 25 - 30 °C / Reflux 3.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 3.2: 8 h / 0 - 25 °C 4.1: acetic anhydride; triethylamine / dichloromethane / 6.25 h / 0 - 30 °C
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / -40 - 10 °C / Inert atmosphere 1.2: -40 - 10 °C 1.3: -40 - 20 °C 2.1: tetrahydrofuran / 2 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C / Cooling with ice 3.2: 1 h / 20 °C
	Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2 h / -10 - 0 °C / Inert atmosphere 1.2: 1.5 h / -10 °C 2.1: tetrahydrofuran / 0 - 20 °C 3.1: triethylamine / ethanol / 50 °C / Inert atmosphere 3.2: 8 h / 50 °C 4.1: acetic acid / ethanol / 4 °C / Inert atmosphere 4.2: 4 h / 4 - 20 °C 5.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 1 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: n-hexyllithium; N,N,N,N,-tetramethylethylenediamine / toluene / 0 °C / Large scale 1.2: 1 h / 0 °C / Large scale 2.1: sodium carbonate / 10 h / 40 °C / Large scale 3.1: dmap; triethylamine / 2 h / 0 - 5 °C / Large scale

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[5]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[6]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[7]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[8]Current Patent Assignee: SERVIER MONDE - WO2011/77173, 2011, A1
[9]Current Patent Assignee: SERVIER MONDE - WO2011/77174, 2011, A1
[10]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[11]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[12]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[13]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[14]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[15]Current Patent Assignee: SERVIER MONDE - WO2012/52788, 2012, A1
[16]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[17]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[18]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[19]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[20]Current Patent Assignee: SERVIER MONDE - US2013/30183, 2013, A1
[21]Ou, Wenhua; Yi, Weiyin; Liu, Feng; Pan, Xianhua; Peng, Xijiang [Journal of Chemical Research, 2013, vol. 37, # 6, p. 369 - 371]
[22]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2017/221187, 2017, A1

37
[ 952340-39-5 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 1.2: 7 h / 25 - 30 °C 1.3: 8 h / 0 - 25 °C 2.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 2.2: 6 h / 0 - 5 °C
	Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 1.2: 7 h / 25 - 30 °C 2.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 1.2: 7 h / 25 - 30 °C 1.3: 8 h / 0 - 25 °C 2.1: sodium hydrogencarbonate / water / 0.5 h / 10 - 15 °C 3.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C

	Multi-step reaction with 3 steps 1.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 1.2: 7 h / 25 - 30 °C 2.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 3.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 3.2: 6 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: triethylamine / dichloromethane / 20 °C / Inert atmosphere 3: hydrogenchloride; water / ethyl acetate / 20 °C 4: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 2: triethylamine / dichloromethane / 20 °C / Inert atmosphere 3: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 2.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 2.2: 6 h / 0 - 5 °C
	Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 1.2: 8 h / 0 - 25 °C 2.1: acetic anhydride; triethylamine / dichloromethane / 6.25 h / 0 - 30 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[5]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[6]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[7]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[8]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1

38
[ 946402-23-9 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 5 h / 25 - 35 °C 4.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 4.2: 1 h / -78 °C 4.3: 1 h / -60 - 0 °C 5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 3 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 6 h / 25 - 30 °C 3.3: 6.5 h / 0 - 30 °C
	Multi-step reaction with 4 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 4.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C

	Multi-step reaction with 4 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 4.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 4 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 3.3: 8 h / 0 - 25 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 3.3: 8 h / 0 - 25 °C 4.1: sodium hydrogencarbonate / water / 0.5 h / 10 - 15 °C 5.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	Multi-step reaction with 5 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 4.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C
	Multi-step reaction with 5 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 0.5 h / 25 - 30 °C 3.2: 7 h / 25 - 30 °C 4.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C
	Multi-step reaction with 6 steps 1.1: iodine; magnesium / tetrahydrofuran / 25 - 50 °C 1.2: 40 - 50 °C 1.3: 0.25 h / 0 - 30 °C 2.1: toluene-4-sulfonic acid; 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / chloroform / 4 h / Reflux 3.1: potassium carbonate / acetonitrile / 5 h / 25 - 35 °C 4.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 4.2: 1 h / -78 °C 4.3: 1 h / -60 - 0 °C 5.1: hydrogen bromide / water; acetone / 1 h / 0 - 5 °C 6.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 6.2: 6 h / 0 - 5 °C
	Multi-step reaction with 3 steps 1.1: iodine; magnesium / tetrahydrofuran / 40 - 50 °C 1.2: 0.25 h / 0 - 30 °C 2.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 2.2: 8 h / 0 - 25 °C 3.1: acetic anhydride; triethylamine / dichloromethane / 6.25 h / 0 - 30 °C
	Multi-step reaction with 3 steps 1.1: iodine; magnesium / tetrahydrofuran / 40 - 50 °C 1.2: 0.25 h / 0 - 30 °C 2.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / toluene-4-sulfonic acid / dichloromethane / 4.75 h / 0 - 5 °C / Reflux 3.1: potassium carbonate / acetonitrile / 6.5 h / 25 - 30 °C 3.2: 6.5 h / 0 - 30 °C
	Multi-step reaction with 4 steps 1.1: iodine; magnesium / tetrahydrofuran / 40 - 50 °C 1.2: 0.25 h / 0 - 30 °C 2.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / toluene-4-sulfonic acid / dichloromethane / 4.75 h / 0 - 5 °C / Reflux 3.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1.1: iodine; magnesium / tetrahydrofuran / 40 - 50 °C 1.2: 0.25 h / 0 - 30 °C 2.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / toluene-4-sulfonic acid / dichloromethane / 4.75 h / 0 - 5 °C / Reflux 3.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 4.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 4.2: 6 h / 0 - 5 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[5]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[6]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[7]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[8]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[9]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[10]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[11]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[12]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[13]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1

39
[ 1243654-57-0 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water / 0.5 h / 10 - 15 °C 2: N-ethyl-N,N-diisopropylamine / acetonitrile / 3.33 h / 10 - 30 °C
	With acetic anhydride; triethylamine In dichloromethane at 0 - 30℃; for 6.25h;	24 Example 24Preparation of prasugrel Compound of Formula-1Triethylamine (32 grams) was added to the solution of 5-(α-cyclo propylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c] pyridine hydrobromide (60 grams) in methylene chloride (600 ml) and stirred for 15 minutes at 25-30° C. and then cooled to 0-5° C. Acetic anhydride (64.5 ml) was added to the reaction mixture and stirred for 6 hrs at 0-5° C. Water was added to the reaction mixture and raised the temperature to 20-25° C. Separated both the aqueous and organic layers. Organic layer washed with aqueous sodium bicarbonate followed by water and then the solvent from the organic layer was distilled off under reduced pressure, isopropyl alcohol (48 ml) and acetonitrile (16 ml) was added to the obtained residue and stirred for 45 min at reflux temperature. The reaction mixture was cooled to 10-15° C. and stirred for 60 minutes. The obtained solid was filtered, washed with isopropyl alcohol and then dried to get the title compound.Yield: 45 grams; Purity by HPLC: 99.20%

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/42918, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1 Location in patent: Page/Page column 22

40
[ 115473-15-9 ]
[ 150322-43-3 ]

Reference： [1]Patent: WO2011/42918,2011,A2
[2]Patent: WO2011/42918,2011,A2
[3]Patent: WO2011/92720,2011,A2
[4]Patent: WO2012/1486,2012,A1
[5]Patent: WO2012/1486,2012,A1
[6]Organic Process Research and Development,2012,vol. 16,p. 240 - 243
[7]Patent: US2012/202066,2012,A1
[8]Asian Journal of Chemistry,2013,vol. 25,p. 7783 - 7789

41
[ 150322-43-3 ]
[ 1060616-82-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With hydrogen iodide In water; acetone at 5 - 10℃; for 1.5h;	5 Example 5Preparation of prasugrel hydroiodidePrasugrel base (3.028 g; 8.11 mmol) is dissolved in acetone (16 ml) and cooled down in an ice bath to 5 to 10 °C. To the solution a 57% solution of hydrogen iodide in water (0.95 eq.) is added dropwise, the solution is inoculated and stirred at the temperature of ca. 5 °C for 1.5 h. 2.99 g of yellowish crystals (74%) are obtained; melting point: 123 to 125 °C. HPLC: purity 99.5%; content of the compound of formula II 0.22%. X-ray analysisTable 3: Characteristic peaks of prasugrel hydroiodide:The X-ray powder diffraction pattern is presented in the Annex in fig. 3a, DSC curve is in fig. 3b.
74%	With hydrogen iodide In water; acetone at 5 - 10℃; for 1.5h;	18 Prasugrel base (3.028 g; 8.1 1 mmol) is dissolved in acetone (16 ml) and cooled in an ice bath to 5-10 °C. A 57% solution of hydrogen iodide in water (0.95 eq.) is added dropwise to the solution, the solution is inoculated and stirred at the temperature of ca. 5 °C for 1 .5 h. 2.99 g of yellowish crystals (74%) are obtained, melting point: 123- 125 °C.

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57593, 2011, A2 Location in patent: Page/Page column 13-14
[2]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57592, 2011, A1 Location in patent: Page/Page column 18

42
[ 100-88-9 ]
[ 150322-43-3 ]
[ 1306607-31-7 ]

Yield	Reaction Conditions	Operation in experiment
45%	In acetone at -10℃; for 12h;	7 Example 7Preparation of prasugrel cyclamatePrasugrel base (2.2 g; 5.41 mmol) is dissolved in acetone (20 ml). Cyclamic acid (0.970 g; 5.41 mmol) is dissolved in acetone (9 ml) and the solution is added to the prasugrel solution, cooled down to -10 °C, inoculated and stirred at the temperature of -10 °C for 12 h. The separated crystals are aspirated, washed with acetone and dried freely. 0.730 g (45%) of white crystals with the melting point of 162.5 to 163.5 °C are obtained. HPLC: purity 99.7%; content of the compound of formula II 0.08%. X-ray analysisTable 5: Characteristic peaks of prasugrel cyclamate:The X-ray powder diffraction pattern is presented in the Annex in fig. 5a, DSC curve is in fig. 5b.
45%	In acetone	20 Prasugrel base (2.2 g; 5.41 mmol) is dissolved in acetone (20 ml). Cyclamic acid (0.970 g; 5.41 mmol) is dissolved in acetone (9 ml) and the solution is added to the prasugrel solution, cooled down to -10 °C, inoculated and stirred at the temperature of -10 °C for 12 h. The precipitated crystals are aspirated, washed with acetone and dried freely. 0.730 g (45%) of white crystals with the melt, point of 162.5-163.5 °C are obtained.

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57593, 2011, A2 Location in patent: Page/Page column 15-16
[2]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57592, 2011, A1 Location in patent: Page/Page column 18; 19

43
[ 150322-43-3 ]
2-acetyloxy-5-(α-cycloproylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine bisulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With sulfuric acid In water; acetone at -32 - -28℃; for 5.5h;	1 Example 1 Preparation of compound (II): 2-acetyloxy-5-(α-cycloproylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine bisulfate 8 g of refined 2-acetyloxy-5-(α-cycloproylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine is dissolved in 50 ml of acetone, and cooled to -32~-28° C. The same temperature is maintained while adding dropwise 2.5 ml of concentrated sulfuric acid under stirring over 1.5 h. After the addition is completed, the mixture is stirred under the same temperature for further 4 h, while a large amount of crystals precipitate. The reaction is stopped when no more crystals are precipitated. The mixture is filtered, and the filter cake is washed with ice-cold acetone and then dried in vacuum under 60° C. to obtain 8.2 g of white crystals. Yield: 78%. Melting point of the crystals: mp: 145-148° C.

Reference： [1]Current Patent Assignee: LUNAN PHARMACEUTICAL GROUP CO LTD - US2011/124675, 2011, A1 Location in patent: Page/Page column 4

44
[ 204205-33-4 ]
[ 178688-49-8 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
60.3%		68 ml of /V-ethyl-/V,/V-diisopropylamine (389 mmol; 2 eq.) are added to a suspension of 2-oxo-2,4, 5, 6,7a-hexahydrothieno[3,2-c]pyridine p-toluene sulfonate (66.86 g; 204.2 mmol; 1 .05 eq.) in 160 ml of acetonitrile. Thus prepared solution is added dropwise to a solution of 50 g of 1-cyclopropyl-2-bromo-2(2-fluorophenyl)ethanone (194.5 mmol) and 50 ml of acetonitrile, charged in a 1 L three-neck flask with a magnetic stirrer, thermometer and a dripping funnel closed with a calcium-chloride tube, such that the temperature does not exceed 30 C, and the mixture is stirred for 30 min, being monitored with TLC (silica gel on glass, toluene : ethyl acetate 3:1 ). After disappearance of the starting 1 -cyclopropyl-2-bromo-2(2-fluorophenyl)ethanone acetanhydride (60 ml; 3 eq.), A/-ethyl-A/,A/-diisopropylamine and a catalytic amount of /V,A/-dimethylaminopyridine are added to the mixture and reacted for 1 .5-2 h. The reaction is monitored with TLC in the same system. After this period the mixture is cooled down to -15 to -20 C and 150 ml of water are added in portions. The mixture is left to crystallize under thorough stirring at -15 to -6 C for 1 .5 to 2 hours. The separated product - prasugrel base - is aspirated and washed with 2 chi 25 ml of cooled ethanol on fritted glass and dried freely in air. 43.79 g (60.3 %) of crude prasugrel base with the purity of 99.44% (HPLC) is obtained; the content of the compound of formula II lower than 0.05%.The crude product obtained in this manner (43 g) is dissolved in acetonitrile (480 ml), acetanhydride (8 ml) is added and, after stirring for 1 hour, cooled down to -15 C, 200 ml of water are added in portions and the product is left to crystallize at -12 to -6 C for two hours. By aspiration on fritted glass, washing with 2x25 ml of cooled ethanol and drying in air, 34.81 g of white crystals with the purity of 99.4% (HPLC) are obtained; the content of the compound of formula II lower than 0.05%.

Reference： [1]Patent: WO2011/57592,2011,A1 .Location in patent: Page/Page column 12

45
[ 204205-33-4 ]
[ 951380-43-1 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
29%		V-Ethyldiisopropylamine (1.7 ml; 9.7 mmol) is added to a suspension of 2-oxo- 2,4,5,6,7a-hexahydrothieno[3,2-c]pyridine hydrochloride (0.89 g; 4.6 mmol) in acetonitrile (4 ml). Thus prepared solution is added dropwise to a solution of 1- cyclopropyl-2-bromo-2(2-fluorophenyl)ethanone (1.13 g; 4.4 mmol) in acetonitrile (2 ml) and the reaction is stirred at the room temperature for 1 .5 hours. Subsequently, acetanhydride (1 .2 ml; 13.2 mmol), /V-ethyldiisopropylamine (0.6 ml; 3.5 mmol) and a catalytic amount of N,A/-dimethylaminopyridine are added to the solution. The reaction is stirred at the room temperature for 2 hours. Then, the reaction mixture is cooled down to -15 C, 2.5 ml of water are added and the reaction is stirred at -12 to -8 C for 2 hours. The resulting white crystals are aspirated, washed with ethanol and dried in air. 0.48 g of prasugrel base (29%) is obtained. Melting point: 1 17.5-1 19.5 C, HPLC: purity 98.5%; content of the compound of formula II 0.09%.The crude product obtained in this manner (0.45 g) is dissolved in acetonitrile (10.5 ml) and, after addition of 0.2 ml of acetanhydride, the mixture is stirred at the room temperature for 1 h. Then, the mixture is cooled down to -15 C, water (4 ml) is added and white crystals precipitate under stirring at the temperature of -2 to -8 C. After two hours they are aspirated, washed with ethanol and dried. 0,31 g of white crystals of prasugrel are obtained. Melting point: 120 -121 C. HPLC: purity 99.4%; content of the compound of formula II 0.07%.

Reference： [1]Patent: WO2011/57592,2011,A1 .Location in patent: Page/Page column 10; 11

46
[ 178688-49-8 ]
[ 1100905-46-1 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one p-toluenesulfonate; 3-cyclopropyl-1-(2-fluorophenyl)-3-oxopropyl methanesulfonate With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1.5h; Stage #2: acetic anhydride With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 2h;	6 /V-Ethyldiisopropylamine (1.7 ml; 9.7 mmol) is added to a suspension of 2-oxo- 2,4,5,6,7a-hexahydrothieno[3,2-c]pyridine p-toluene sulfonate (1.52 g; 4.6 mmol) in acetonitrile (6 ml). 2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethylmethanesulfonate (1 .18 g; 4.4 mmol) is added to the resulting solution and the reaction is stirred at the room temperature for 1 .5 hours. Subsequently, acetanhydride (1 .2 ml; 13.2 mmol), N- ethyl-A/,A/-diisopropylamine (0.6 ml; 3.5 mmol) and a catalytic amount of N,N- dimethylaminopyridine are added to the solution. The reaction is stirred at the room temperature for 2 hours. Then, the reaction mixture is cooled down to -15 °C, 2.5 ml of water are added and the reaction is stirred at -12 to -8 °C for 2 h. The resulting white crystals are aspirated, washed with ethanol and air-dried. 0.52 g of prasugrel base are obtained (32%). Melting point: 1 16.5-1 19.5 °C, HPLC: purity 94%; content of the compound of formula II 0.20%. The crude product obtained in this manner (0.47 g) is dissolved in acetonitrile (6 ml) and, after addition of 0.2 ml of acetanhydride, the mixture is stirred at the room temperature for 1 h. Then, the mixture is cooled down to -15 °C, water (2 ml) is added and white crystals precipitate under stirring at a temperature of -12 to -8 °C. After two hours they are aspirated, washed with ethanol and dried. 0.34 g of white prasugrel crystals are obtained. Melting point: 120 -121 °C. The X-ray powder diffraction patterns is equal to that presented in Example 1.

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57592, 2011, A1 Location in patent: Page/Page column 13; 14

47
[ 1100905-46-1 ]
[ 951380-43-1 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
12%	Stage #1: 3-cyclopropyl-1-(2-fluorophenyl)-3-oxopropyl methanesulfonate; 2-oxo-2,4,5,6,7a-hexahydrothieno[3,2-c]pyridine hydrochloride With tetraethylammonium bromide; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1.5h; Stage #2: acetic anhydride With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 2h;	5 A/-Ethyl-/V,A/-diisopropylamine (1.7 ml; 9.7 mmol) is added to a suspension of 2-oxo- 2,4,5,6,7a-hexahydrothieno[3,2-c]pyridine hydrochloride (0.89 g; 4.6 mmol) in acetonitrile (6 ml). 2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethylmethanesulfonate (1 .18 g; 4.4 mmol) and 0.972 g (4.62 mmol) of tetraethylammonium bromide are added to the resulting solution and the reaction is stirred at the room temperature for 1.5 hours. Subsequently, acetanhydride (1.2 ml; 13.2 mmol), /V-ethyl-A/./V- diisopropylamine (0.6 ml; 3.5 mmol) and a catalytic quantity of N,N- dimethylaminopyridine are added to the reaction mixture. The reaction is stirred at the room temperature for 2 hours. The reaction mixture is cooled down to -15 °C, 2.5 ml of water are added and the reaction is stirred at -12 to -8 °C for 2 h. The resulting white crystals are aspirated, washed with ethanol and air-dried. 0.190 g of prasugrel base (12%) are obtained. Melting point: 1 18-120 °C, HPLC: purity 96.9%, content of the compound of formula II 0.22%.The crude product obtained in this manner (0.150 g) is dissolved in acetonitrile (2 ml) and, after addition of 0.1 ml of acetanhydride, the mixture is stirred at the room temperature for 1 h. Then, the mixture is cooled down to -15 °C, water (2 ml) is added and white crystals precipitate under stirring at a temperature of -12 to -8 °C. After two hours they are aspirated, washed with ethanol and dried. 0.100 g of white crystals of prasugrel are obtained. Melting point: 120 -121 °C. HPLC: purity 99.6%; content of the compound of formula II 0.05%.The X-ray powder diffraction pattern is equal to that presented in Example 1.

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2011/57592, 2011, A1 Location in patent: Page/Page column 12; 13

48
1-cyclopropyl-2-(2-fluorophenyl)-2-(2-hydroxy-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethan-1-one [ No CAS ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydride In N,N-dimethyl-formamide at 0℃;
85%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; Inert atmosphere;
46%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 15 - 25℃;	5.2 2 step: 28,4 cm (30,6 g; 0,30 mole) of acetic anhydride are added dropwise to the mixture of 70 ml of DMF and 37,65 cm3 (28,43 g; 0,22 mole) of DIPEA at 15- 20 °C under intensive stirring. The solution of the residual product of the step 1 and 120 ml of DMF are added dropwise to the reaction mixture under intensive stirring at 20-25 °C. The mixture is stirred for 1 hour at room temperature. The reaction mixture is poured onto the mixture of ice water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The collected organic phases are dried on MgS04. The solvent is removed in vacuo and ethanol is added to the residual product. After cooling to 0-5 °C the precipitated crystals are filtered, washed with ethanol. The yield is 38,1 g (51 %) crude prasugrel base. The crude product is recrystalized form acetonitrile.Yield: 34,4 g (46,0 %) colorless, crystalline product Yield for the whole synthetic process, calculated on the 4,5,6,7-tetrahydro- tieno[3,2-c]pyridine hydrochloride of the formula (VII) is 38,2 %.Mp.: 120-121 °CIR (KBr, cm"1): 3388, 2920, 2767, 1758, 1704, 1586, 1488, 1369, 1217, 1194, 1127, 1011.1H-NMR (CDCI3, 500 MHz): 7,47 (1H, td, J=7,5; 1,8 Hz); 7,30 (1H, m); 7,16 (1H, td, J=7,5; 1,1 Hz); 7,10 (1H, td, J=8,2; 1,1 Hz); 6,26 (1H, s); 4,82 (1H, s); 3,56 (1H, d, J=14,3 Hz); 3,48 (1H, d, J=14,3 Hz); 2,90 (1H, m); 2,78 (3H, m); 2,28 (1H, m); 2,23 (3H, s); 1,05 (1H, m); 1,00 (1H, m); 0,84 (2H, m).13C-NMR (CDCI3, 125 MHz): 207,4; 167,5; 161,1; 149,4; 130,4; 129,7; 129,3; 125,6; 124,2; 122,0; 115,6; 112,8; 71,5; 50,3; 48,3, 24,9; 20,4; 18,1, 11,8, 11,3.Elementary analysis [calculated on the basis of the formula of C20H2oFNC>3S (M: 373,45)]Calculated: C 64,33; H 5,40; N 3,75; S 8,59.Measured: C 64,18; H 5,50; N 3,69; S 8,75.

With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;

4 Example 4Preparation of 2-Acetoxi-5-(2-fluor-a-cyclopropyl-carbonyl-benzyl)-4,5,6,7- tetrahydro-4i/-tieno[3,2-c] pyridine (prasugrel, I)160 cm3 of DMF are added to 65,5 g (0,2 mol) of 5,6,7,7a-tetrahydro-4H- tieno[3,2-c]-pyridine-2-on /? ra-toluenesulfonate (II, HA=PTSA). 75,3 cm3 (56,9 g; 0,44 mol) of NiV-diisopropyl-ethyl-amine (DIPEA) are added to the solution and 55,4 g of 2-bromo-l-cyclopropyl-2;(2-fluorophenyl)-ethanon (III) (containing 92,8 % of GC) dissolved is 94 cm3 (88,7 g) of dimethyl-formamide is added dropwise within app. 30 minutes under ice water cooling. The mixture is stirred for 1 hour at room temperature.37,65 cm3 (28,43 g; 0,22 mol) of DIPEA are added to the reaction mixture and under intensive stirring 28,4 cm (30,6 g; 0,30 mol) of acetic acid anhydride are added dropwise. The mixture is stirred for 1 hour at room temperature. The reaction mixture is poured onto the mixture of ice water and ethylacetate. The "phases are separated and the aqueous phase is extracted with ethylacetate. The collected organic phases are dried on MgS04. The solvent is removed in vacuo and ethanol is added to the remaining product. After cooling to 0-5 °C the precipitated crystals are filtered, washed with ethanol. The yield is 44,7 g (60,0 %) crude prasugrel base. The crude product is recrystallized from 5 fold volume ethanol.Yield: 41,1 g (55,0 %) colorless, crystalline product, HPLC purity > 99,80 %. Yield for the whole synthetic process, calculated on the 4,5,6,7-tetrahydro- tieno[3,2-c]pyridine hydrochloride of the formula (VII) is 45,7 %.Mp.: 120-121 °CIR (KBr, cm"1): 3388, 2920, 2767, 1758, 1704, 1586, 1488, , 1369, 1217, 1194, 1127, 1011.1H-NMR (CDC13, 500 MHz): 7,47 (IH, td, J=7,5; 1,8 Hz); 7,30 (IH, m); 7,16 (IH, td, J=7,5; 1,1 Hz); 7,10 (IH, td, J=8,2; 1,1 Hz); 6,26 (IH, s); 4,82 (IH, s); 3,56 (IH, d, J=14,3 Hz); 3,48 (IH, d, J=14,3 Hz); 2,90 (IH, m); 2,78 (3H, m); 2,28 (IH, m); 2,23 (3H, s); 1,05 (IH, m); 1,00 (IH, m); 0,84 (2H, m).13C-NMR (CDCI3, 125 MHz): 207,4; 167,5; 161,1; 149,4; 130,4; 129,7; 129,3; 125,6; 124,2; 122,0; 115,6; 112,8; 71,5; 50,3; 48,3, 24,9; 20,4; 18,1, 11,8, 11,3. Elementary analysis [calculated on the basis of the formula of C20H2oFN03S (M: 373,45)]Calculated: C 64,33; H 5,40; N 3,75; S 8,59.Measured: C 64,18; H 5,50; N 3,69; S 8,75.

Reference： [1]Pan, Xianhua; Huang, Rui; Zhang, Jianshui; Ding, Liping; Li, Weijin; Zhang, Qunhui; Liu, Feng [Tetrahedron Letters, 2012, vol. 53, # 40, p. 5364 - 5366]
[2]Ou, Wenhua; Yi, Weiyin; Liu, Feng; Pan, Xianhua; Peng, Xijiang [Journal of Chemical Research, 2013, vol. 37, # 6, p. 369 - 371]
[3]Current Patent Assignee: SERVIER MONDE - WO2011/77174, 2011, A1 Location in patent: Page/Page column 27-28
[4]Current Patent Assignee: SERVIER MONDE - WO2011/77173, 2011, A1 Location in patent: Page/Page column 18-19

49
[ 204205-33-4 ]
[ 952340-39-5 ]
[ 150322-43-3 ]

Reference： [1]Patent: WO2011/77174,2011,A1

50
[ 54903-50-3 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 20 °C 2.1: n-butyllithium / hexane; tetrahydrofuran / -40 - 10 °C / Inert atmosphere 2.2: -40 - 10 °C / Inert atmosphere 2.3: -40 - 20 °C / Inert atmosphere 3.1: tetrahydrofuran / 0 - 20 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C / Cooling with ice 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 15 - 25 °C
	Multi-step reaction with 5 steps 1.1: acetic acid / dichloromethane / 0.5 h / 0 °C 1.2: 5 h / 20 °C 2.1: acetic acid; hydrogen bromide; dihydrogen peroxide / methanol / 3 h / 20 °C / Cooling with ice 3.1: palladium diacetate; XPhos / N,N-dimethyl-formamide / 24 h / 100 °C / Inert atmosphere 4.1: 10 wt% Pd(OH)2 on carbon; hydrogen / ethanol / 20 °C / 2585.81 Torr 5.1: sodium hydride / dichloromethane; tetrahydrofuran / 3 h / 20 °C / Cooling with ice

Reference： [1]Current Patent Assignee: SERVIER MONDE - WO2011/77174, 2011, A1
[2]Current Patent Assignee: NANJING JIANCHENG MEDICINE SCIENCE TECHNOLOGY - CN103694251, 2018, B

51
2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 0.75 h / Cooling with ice 2.1: potassium phosphate; copper; copper(l) iodide / 2-(N,N-dimethylamino)ethanol / 24 h / 80 °C 3.1: hydrogenchloride / diethyl ether / Cooling with ice 4.1: triethylamine / acetonitrile / Cooling with ice 5.1: hydrogenchloride; water / 5 h / 70 °C 5.2: pH 10 / Alkaline conditions 6.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C
	Multi-step reaction with 4 steps 1.1: potassium phosphate; copper; copper(l) iodide / 2-(N,N-dimethylamino)ethanol / 72 h / 80 °C 2.1: triethylamine / acetonitrile / Cooling with ice 3.1: hydrogenchloride; water / 5 h / 70 °C 3.2: pH 10 / Alkaline conditions 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C
	Multi-step reaction with 4 steps 1.1: potassium phosphate; copper; copper(l) iodide / 18 h / 80 °C 2.1: triethylamine / dichloromethane / 5 h / 20 °C 3.1: hydrogenchloride; water / 4 h / 90 °C 3.2: pH 10 / Alkaline conditions 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C

Reference： [1]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1
[2]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1
[3]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1

52
[ 949922-62-7 ]
[ 150322-43-3 ]

Reference： [1]Patent: WO2011/110219,2011,A1

53
[ 1333429-05-2 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine / acetonitrile / Cooling with ice 2.1: hydrogenchloride; water / 5 h / 70 °C 2.2: pH 10 / Alkaline conditions 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C

Reference： [1]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1

54
[ 1333429-06-3 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: hydrogenchloride; water / 5 h / 70 °C 1.2: pH 10 / Alkaline conditions 2.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C

Reference： [1]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1

55
[ 1333429-08-5 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane / 5 h / 20 °C 2.1: hydrogenchloride; water / 4 h / 90 °C 2.2: pH 10 / Alkaline conditions 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C

Reference： [1]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1

56
[ 1333429-04-1 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: hydrogenchloride / diethyl ether / Cooling with ice 2.1: triethylamine / acetonitrile / Cooling with ice 3.1: hydrogenchloride; water / 5 h / 70 °C 3.2: pH 10 / Alkaline conditions 4.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 3 h / 5 °C

Reference： [1]Current Patent Assignee: BC PARTNERS LLP - WO2011/110219, 2011, A1

57
[ 150322-43-3 ]
[ 1338596-25-0 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid In water; acetone at 20 - 25℃; for 0.25h;	19 Example 19: Preparation of crystalline form of prasugrel nitrate[0098] To a solution of 251 mg of prasugrel base form I in 3.75 ml acetone at room temperature (20-25 °C), a solution of 50.6 μ (1.1 eq) 65% aqueous nitric acid in 1.25 ml acetone was added in portions and the resulting mixture was stirred at room temperature for about 15 minutes. After addition of 5 ml heptane at 0-5 °C (ice bath), the clear reaction mixture turned to an emulsion (clear oil drops on the bottom of the flask). A white precipitate was obtained after storage for 17 hours at about-25 °C. The mixture containing the precipitate was stirred for 1 hour at 0-5 °C (ice bath), filtered off, washed with 1 ml cold acetone/heptane (1 :1) and dried at 40°C/10 mbar for about 2.5 hours. White crystals (269 mg) of prasugrel nitrate were obtained.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/127300, 2011, A1 Location in patent: Page/Page column 17

58
[ 150322-43-3 ]
5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid In ethanol; acetic acid methyl ester; water at 0 - 25℃; for 5h;	45 Example 45: Preparation of crystalline Form PI of prasugrel phosphate[00126] To a solution of prasugrel base (1.006 g) in 21.67 ml of methyl acetate/7.7% ethanol at 20-25° C, a dropwise solution of 99% phosphoric acid (329.9 mg) in 2 ml of methyl acetate was added. Crystallization occurred within 30 minutes. After 3 hours at 20-25° C, the suspension was cooled to 0-5 °C and stirred for about 2 hours at that temperature. The obtained crystals were filtered, washed with 4 ml of methyl acetate and dried at 40° C/vacuum for about 1.5 hours. Prasugrel phosphate Form PI (0.883 g) was obtained.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/127300, 2011, A1 Location in patent: Page/Page column 24

59
[ 150322-38-6 ]
[ 75-36-5 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one; acetyl chloride With acetic acid In toluene at 20℃; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In water; toluene	12.B Method BIn a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 5-(a- cyclopropyIcarbonyl-2-fluoro-benzyl)-4,5,6,7-tetrahydrothieno -[3,2-c]-pyridine (100 g, 0.30 moles) was suspended in a mixture of toluene (400ml) and acetic acid (100 ml) under nitrogen atmosphere at 20 +/-5 °C and stir for 10 to 20 min. Slowly add acetyl chloride (180 g, 2.29 moles) in reaction mass at 20 +/-2 °C and stir for 12 to 16 hrs at 20 +/-2 °C. Quench the reaction mass into 30% sodium bicarbonate solution. Product extract with ethyl acetate (2 x 500 ml), organic layer washed with sodium chloride solution then water and dried over sodium sulfate. Recover the solvent under vacuum and crystalise the product in methanol, ethyl acetate, hexane or mixture thereof. Filter the product and slurry wash with methanol or ethyl acetate or hexane or mixture thereof. Dry the material at atmospheric pressure at 40-45 °C to obtain prasugrel (70 g, 99%). Method AIn a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-(tert- Butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7- tetrahydrothieno -[3,2-c]-pyridine (100 g, 0.22 moles) was suspended in a mixture of toluene (400ml) and acetic acid (100 ml) under nitrogen atmosphere at 20 +/-5 °C and stir for 10 to 20 min. Slowly add a solution of acetyl chloride (30 g, 0.38 moles) in acetic acid (140 ml) at 20 +/-2 °C. Stir the reaction mass for 4 to 6 hrs at 20 +/-2 °C. Slowly add acetyl chloride (180 g, 2.29 moles) in reaction mass at at 20 +/-2 °C and stir for 12 to 16 hrs at 20 +/-2 °C. Quench the reaction mass into 30% sodium bicarbonate solution. Product extract with ethyl acetate (2 x 500 ml), organic layer washed with sodium chloride solution then water and dried over sodium sulfate. Recover the solvent under vacuum and crystalise the product in methanol, ethyl acetate, hexane or mixture thereof. Filter the product and slurry wash with methanol or ethyl acetate or hexane or mixture thereof. Dry the material at atmospheric pressure at 40-45 °C to obtain prasugrel (80 g, 99%).
87.1%	With D₂₀₁ macroporous strong basic styrene anion exchange resin, average particle diameter: 1.0 mm In tetrahydrofuran at 45℃; for 1.5h;	9 Example 9Preparation of prasugrel A solution of 5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -2-oxo-2,4,5,6,7,7a-tetrahydrothieno [3,2-c] pyridine6.6 g (20 mmol) of 1.32 g of an anion exchange resin in THF(D201 macroporous strong basic styrene anion exchange resin, average particle diameter: 1.0 mm) were mixed, followed by addition of acetyl chloride (3.1 g, 40 mmol), and the mixture was stirred at 45C for 1.5 hours. The ethyl acetateExtracted, dried over anhydrous ammonium sulfate and filtered, concentrated ethyl acetate, anhydrous methanol recrystallized to prasugrel 6.5g, the yield was87.1%, purity 99.64%.

Reference： [1]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1 Location in patent: Page/Page column 23
[2]Current Patent Assignee: QINGDAO CHENDA BIOLOGICAL TECHNOLOGY CO LTD - CN106117240, 2016, A Location in patent: Paragraph 0048-0062; 0069; 0070

60
[ 952340-38-4 ]
[ 75-36-5 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine; acetyl chloride With acetic acid In toluene at 20℃; Inert atmosphere; Stage #2: With sodium hydrogencarbonate In water; toluene	12.A Method AIn a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-(tert- Butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7- tetrahydrothieno -[3,2-c]-pyridine (100 g, 0.22 moles) was suspended in a mixture of toluene (400ml) and acetic acid (100 ml) under nitrogen atmosphere at 20 +/-5 °C and stir for 10 to 20 min. Slowly add a solution of acetyl chloride (30 g, 0.38 moles) in acetic acid (140 ml) at 20 +/-2 °C. Stir the reaction mass for 4 to 6 hrs at 20 +/-2 °C. Slowly add acetyl chloride (180 g, 2.29 moles) in reaction mass at at 20 +/-2 °C and stir for 12 to 16 hrs at 20 +/-2 °C. Quench the reaction mass into 30% sodium bicarbonate solution. Product extract with ethyl acetate (2 x 500 ml), organic layer washed with sodium chloride solution then water and dried over sodium sulfate. Recover the solvent under vacuum and crystalise the product in methanol, ethyl acetate, hexane or mixture thereof. Filter the product and slurry wash with methanol or ethyl acetate or hexane or mixture thereof. Dry the material at atmospheric pressure at 40-45 °C to obtain prasugrel (80 g, 99%).

Reference： [1]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1 Location in patent: Page/Page column 23

61
[ 30433-91-1 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: dichloromethane / 40 - 45 °C 1.2: 20 - 70 °C 2.1: triethylamine / dichloromethane / 12 - 28 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 3.2: -5 - 10 °C 4.1: tetrahydrofuran / 25 °C 5.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 6.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 7.1: hydrogenchloride; water / ethyl acetate / 20 °C 8.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: dichloromethane / 40 - 45 °C 1.2: 20 - 70 °C 2.1: triethylamine / dichloromethane / 12 - 28 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 3.2: -5 - 10 °C 4.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 5.1: ammonium bicarbonate / dichloromethane / 5 - 20 °C 6.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1.1: dichloromethane / 40 - 45 °C 1.2: 20 - 70 °C 2.1: triethylamine / dichloromethane / 12 - 28 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 3.2: -5 - 10 °C 4.1: tetrahydrofuran / 25 °C 5.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 6.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 7.1: acetic acid / toluene / 20 °C / Inert atmosphere

	Multi-step reaction with 7 steps 1.1: dichloromethane / 40 - 45 °C 1.2: 20 - 70 °C 2.1: triethylamine / dichloromethane / 12 - 28 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 3.2: -5 - 10 °C 4.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 5.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 6.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 7.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 8 steps 1.1: dichloromethane / 40 - 45 °C 1.2: 20 - 70 °C 2.1: triethylamine / dichloromethane / 12 - 28 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -5 - 10 °C 3.2: -5 - 10 °C 4.1: hydrogenchloride / water; acetone / 1 h / 25 - 50 °C 5.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere 6.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 7.1: hydrogenchloride; water / ethyl acetate / 20 °C 8.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: sodium carbonate / tetrahydrofuran / 2 h / 20 °C 2.1: hydrogenchloride / methanol / 5 h / 20 °C 3.1: triethylamine; bromine / methanol / 2 h / 0 - 20 °C 4.1: magnesium / tetrahydrofuran / 1.5 h / Reflux 4.2: Reflux 5.1: copper(II) sulfate; sulfuric acid; dihydrogen peroxide / methanol / 16 h / 20 °C 6.1: triethylamine / dichloromethane / 3 h / Reflux

Reference： [1]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[2]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[3]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[4]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[5]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[6]Current Patent Assignee: CHONGQING ANGE LONGXIANG PHARMACEUTICAL - CN105272993, 2016, A

62
[ 345-35-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: tetrabutylammomium bromide / dichloromethane; water / 25 °C 2.1: sodium hydroxide; water / 5 - 95 °C 2.2: pH 2 - 3 3.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 3.2: 5 - 65 °C 4.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 5.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 6.1: hydrogenchloride; water / ethyl acetate / 20 °C 7.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: tetrabutylammomium bromide / dichloromethane; water / 25 °C 2.1: sodium hydroxide; water / 5 - 95 °C 2.2: pH 2 - 3 3.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 3.2: 5 - 65 °C 4.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 5.1: ammonium bicarbonate / dichloromethane / 5 - 20 °C 6.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: tetrabutylammomium bromide / dichloromethane; water / 25 °C 2.1: sodium hydroxide; water / 5 - 95 °C 2.2: pH 2 - 3 3.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 3.2: 5 - 65 °C 4.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 5.1: ammonium bicarbonate / dichloromethane / 5 - 20 °C 6.1: acetic acid / toluene / 20 °C / Inert atmosphere

	Multi-step reaction with 6 steps 1.1: tetrabutylammomium bromide / dichloromethane; water / 25 °C 2.1: sodium hydroxide; water / 5 - 95 °C 2.2: pH 2 - 3 3.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 3.2: 5 - 65 °C 4.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 5.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 6.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: tetrabutylammomium bromide / dichloromethane; water / 25 °C 2.1: sodium hydroxide; water / 5 - 95 °C 2.2: pH 2 - 3 3.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 3.2: 5 - 65 °C 4.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 5.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 6.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 7 steps 1.1: tetrabutylammomium bromide / dichloromethane; water / 25 °C 2.1: sodium hydroxide; water / 5 - 95 °C 2.2: pH 2 - 3 3.1: magnesium; isopropyl bromide / toluene; tetrahydrofuran / 15 - 65 °C 3.2: 5 - 65 °C 4.1: dibenzoyl peroxide; N-Bromosuccinimide / ethyl acetate / 25 - 60 °C 5.1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 6.1: hydrogenchloride; water / ethyl acetate / 20 °C 7.1: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: magnesium; iodine / tetrahydrofuran; 2-methyltetrahydrofuran / 1.5 h / 40 - 45 °C / Inert atmosphere 2.1: N-Bromosuccinimide; toluene-4-sulfonic acid / acetonitrile / 24 h / 40 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C / Cooling 3.2: 1 h / 15 - 20 °C
	Multi-step reaction with 3 steps 1.1: magnesium; iodine / tetrahydrofuran; toluene / 1.5 h / 40 - 45 °C / Inert atmosphere 2.1: N-Bromosuccinimide; toluene-4-sulfonic acid / acetonitrile / 24 h / 40 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1.5 h / 20 °C / Cooling 3.2: 1 h / 15 - 20 °C

Reference： [1]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[2]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[3]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[4]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[5]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[6]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[7]Current Patent Assignee: SERVIER MONDE - WO2014/114964, 2014, A2
[8]Current Patent Assignee: SERVIER MONDE - WO2014/114964, 2014, A2

63
[ 326-62-5 ]
[ 150322-43-3 ]

Reference： [1]Patent: WO2012/1486,2012,A1
[2]Patent: WO2012/1486,2012,A1
[3]Patent: WO2012/1486,2012,A1
[4]Patent: WO2012/1486,2012,A1
[5]Patent: WO2012/1486,2012,A1
[6]Patent: WO2012/1486,2012,A1
[7]Tetrahedron Letters,2012,vol. 53,p. 5364 - 5366

64
2-(tert-butyldimethylsilyloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 2: hydrogenchloride; water / ethyl acetate / 20 °C 3: acetic acid / toluene / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 20 °C / Inert atmosphere 2: acetic acid / toluene / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1
[2]Current Patent Assignee: MAYUKA LABS PVT - WO2012/1486, 2012, A1

65
CS-747 hydrochloride [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In water; acetonitrile at 0 - 5℃; for 2h;	9 Example 9: Conversion of prasugrel hydrochloride to prasugrel. Prasugrel hydrochloride (150 g), acetonitrile (600 mL) and water (600 mL) are charged into a round bottom flask at 28°C. The reaction mass is stirred to obtain a clear solution at 28°C. The solution is cooled to 0 to 5°C.The pH of the solution is adjusted to 8.2 with aqueous sodium bicarbonate (5% w/v) at 0 to 5°C. The reaction mass is stirred for 2 hours at 0 to 5°C. The solid is collected by filtration, washed with acetonitrile and water (150mL+150 mL), and then dried under vacuum at 60°C for 5 hours. Yield: 132.5 g

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2012/18791, 2012, A2 Location in patent: Page/Page column 31

66
[ 204205-33-4 ]
[ 952340-39-5 ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
55%		Example 82-Acetoxy-5-(2-fluoro-a-cyclopropyl-carbonyI-benzyl)-4,5,6,7- tetrahydro-4H-thieno[3,2-c] pyridine (prasugrel, compound of theFormula (I))65.5 g (0.2 mol) of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridine-2- one joara-toluenesulfonate (compound of the Formul (II), HA=PTSA) and 160 ml of N,N-dimethylformamide are combined. To this mixture are added 75.3 cm (56.9 g; 0.44 mol) NN-diisopropylethylamine (DIPEA). Subsequently while cooling the reaction mixture on an ice/water bath, 53.8 g of 2-bromo-l-cyclopropyl-2-(2-fmorophenyl)- ethanone of the Formula (III) having 95.5% content according to gas chromatographic assay, dissolved in 94 ml (88.7 g) of Nu,Nu- dimethylformamide are added dropwise in 30 minutes and the thus obtained mixture is stirred for one hour at room temperature. Thereafter 37.65 cm3 (28.43 g; 0.22 mol) of DIPEA are added to the reaction mixture and while stirring intensively and maintaining the temperature between 15 and 20 C, 28.4 ml (30.6 g; 0.30 mol) of acetic anhydride are added dropwise. Addition of acetic anhydride is followed by stirring for one hour at room temperature. The reaction mixture is poured into a mixture of ice, water and ethylacetate. The layers are separated, the aqueous layer is washed with ethylacetate.The organic layer and the washings are combined and dried over magnesium sulfate. The solution is evaporated in vacuo, and ethanol is added to the residue. The mixture is cooled to a temperature between 0 and 5 C, the crystals are filtered and washed with ethanol.Thus 44.7 g (60.0 %) of raw prasugrel are obtained, which are recrystallized from ethanol.Yield, 41.1 g (55.0 %) colourless, crystalline solid.Assay (measured by high-performance liquid chromatography), better than 99.80 %.The individual concentration of the impurities of the Formulae(XXIV) and (XXIVa) is less than 25 ppm each.Total yield (calculated for 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride of the Formula (IX)), 45.7 %.Melting point, 120-121 CIR (KBr, cm-1): 3388, 2920, 2767, 1758, 1704, 1586, 1488, 1369, 1217, 1194, 1127, 1011.1H-NMR (CDC13, 500 MHz): 7,47 (1H, td, J=7,5; 1,8 Hz); 7,30 (1H, m); 7,16 (1H, td, J=7,5; 1,1 Hz); 7,10 (1H, td, J=8,2; 1,1 Hz); 6,26 (1H, s); 4,82 (1H, s); 3,56 (1H, d, J=14,3 Hz); 3,48 (1H, d, J-14,3 Hz); 2,90 (1H, m); 2,78 (3H, m); 2,28 (1H, m); 2,23 (3H, s); 1,05 (1H, m); 1,00 (1H, m); 0,84 (2H, m).13C-NMR (CDCI3, 125 MHz): 207,4; 167,5; 161,1; 149,4; 130,4; 129,7; 129,3; 125,6; 124,2; 122,0; 115,6; 112,8; 71,5; 50,3; 48,3, 24,9; 20,4; 18,1, 11,8, 1 1,3. Elemental analysis calculated for the Formula C20H20FNO3S (M: 373,45)Calculated: C 64.33; H 5.40; N 3.75; S 8.59 %.Measured: C 64.18; H 5.50; N 3.69; S 8.75 %.
55%		Example 4 Preparation of 2-Acetoxi-5-(2-fluor-alpha-cyclopropyl-carbonyl-benzyl)-4,5,6,7-tetrahydro-4H-tieno[3,2-c]pyridine (prasugrel, I) 160 cm3 of DMF are added to 65.5 g (0.2 mol) of 5,6,7,7a-tetrahydro-4H-tieno[3,2-c]-pyridine-2-on para-toluenesulfonate (II, HA=PTSA). 75.3 cm3 (56.9 g; 0.44 mol) of N,N-diisopropyl-ethyl-amine (DIPEA) are added to the solution and 55.4 g of 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)-ethanon (III) (containing 92.8% of GC) dissolved is 94 cm3 (88.7 g) of dimethyl-formamide is added dropwise within app. 30 minutes under ice water cooling. The mixture is stirred for 1 hour at room temperature. 37.65 cm3 (28.43 g; 0.22 mol) of DIPEA are added to the reaction mixture and under intensive stirring 28.4 cm3 (30.6 g; 0.30 mol) of acetic acid anhydride are added dropwise. The mixture is stirred for 1 hour at room temperature. The reaction mixture is poured onto the mixture of ice water and ethylacetate. The phases are separated and the aqueous phase is extracted with ethylacetate. The collected organic phases are dried on MgSO4. The solvent is removed in vacuo and ethanol is added to the remaining product. After cooling to 0-5 C. the precipitated crystals are filtered, washed with ethanol. The yield is 44.7 g (60.0%) crude prasugrel base.Yield: 41.1 g (55.0%) colorless, crystalline product, HPLC purity >99.80%.[0068]Yield for the whole synthetic process, calculated on the 4,5,6,7-tetrahydro-tieno[3,2-c]pyridine hydrochloride of the formula (VII) is 45.7%.[0069]Mp.: 120-121 C.[0070]IR (KBr, cm-1): 3388, 2920, 2767, 1758, 1704, 1586, 1488, 1369, 1217, 1194, 1127, 1011.[0071]1H-NMR (CDCl3, 500 MHz): 7.47 (1H, td, J=7.5; 1.8 Hz); 7.30 (1H, m); 7.16 (1H, td, J=7.5; 1.1 Hz); 7.10 (1H, td, J=8.2; 1.1 Hz); 6.26 (1H, s); 4.82 (1H, s); 3.56 (1H, d, J=14.3 Hz); 3.48 (1H, d, J=14.3 Hz); 2.90 (1H, m); 2.78 (3H, m); 2.28 (1H, m); 2.23 (3H, s); 1.05 (1H, m); 1.00 (1H, m); 0.84 (2H, m).[0072]13C-NMR (CDCl3, 125 MHz): 207.4; 167.5; 161.1; 149.4; 130.4; 129.7; 129.3; 125.6; 124.2; 122.0; 115.6; 112.8; 71.5; 50.3; 48.3, 24.9; 20.4; 18.1, 11.8, 11.3.[0073]Elementary analysis [calculated on the basis of the formula of C20H20FNO3S (M: 373.45)][0074]Calculated: C 64.33; H 5.40; N 3.75; S 8.59.[0075]Measured: C 64.18; H 5.50; N 3.69; S 8.75.
55%		A mixture is prepared from 65.5 g (0.2 mole) of 5,6,7,7a-tetrahydro-4H-thieno-[3,2-c]pyridine- 2-one (compound of the Formula (8)) p-toluenesulfonate and 160 ml of dimethyl formamide. 75.3 ml (56.9 g, 0.44 mole) of Nu,Nu-diisopropyl-ethylamine /DIPEA/ are added, whereupon 53.8 g of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone (GC content 95.5 %), compound of the Formula (7, X = Br) dissolved in 94 ml (88.7 g) of dimethyl formamide are added under cooling with ice-cold water within about 30 minutes. The reaction mixture is stirred at room temperature for an hour, whereupon 37.65 ml (28.43 g, 0.22 mole) of DIPEA are added and thereafter 28.4 ml (30.6 g, 0.30 mole) of acetic anhydride are added drop wise at 15-20C under intensive stirring. The reaction mixture is stirred at room temperature for a further hour, whereupon the reaction mixture is poured on a mixture of ice-cold water and ethyl acetate. The phases are separated and the aqueous layer is extracted with ethyl acetate. The united organic layers are dried over magnesium sulphate. The solvent is removed in vacuo. To the evaporation residue ethanol is added, the mixture is cooled to 0-5C, the crystals obtained are filtered and washed with ethanol. The crude prasugrel is recrystallized from ethanol. Thus 41.1 g /55.0 %/ of a colourless crystalline product are obtained. HPLC purity larger than 99.80 %. Mp: 120-121C.

Reference： [1]Patent: WO2012/52788,2012,A1 .Location in patent: Page/Page column 37-39
[2]Patent: US2013/30183,2013,A1 .Location in patent: Paragraph 0065-0075
[3]Patent: WO2014/114964,2014,A2 .Location in patent: Page/Page column 17

67
[ 204205-33-4 ]
[ 115473-15-9 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
		Example 29One Pot Process for the Preparation of PrasugrelA mixture of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one hydrochloride (100 grams), potassium carbonate (215 grams) and acetonitrile (500 ml) was stirred for 30 minutes at 25-30 C. <strong>[204205-33-4]2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone</strong> (89.5 grams) in acetonitrile (50 ml) was added to the reaction mixture and stirred for 6 hours at 25-30 C. The reaction mixture was filtered and removed the precipitated solid. Triethylamine (98.2 grams) was added to the filtrate and then cooled to 0-5 C. Acetic anhydride (119 grams) was added to the reaction mixture and stirred for 30 minutes at 0-5 C. The reaction mixture was stirred for 6 hours at 25-30 C. Then the reaction mixture was quenched with water and extracted the reaction mixture into toluene. The solvent from the toluene layer was distilled off under reduced pressure and methanol (100 ml) was added to the obtained residue and stirred for 45 min at reflux temperature. The reaction mixture was cooled to 0-5 C. and stirred for 45 minutes. The obtained solid was filtered, washed with methanol and then dried to get the title compound.Yield: 60 grams; Purity by HPLC: 98.97%

Reference： [1]Patent: US2012/202066,2012,A1 .Location in patent: Page/Page column 22-23

68
C₁₈H₂₀FLiNOS^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: dihydrogen peroxide; boric acid tributyl ester / 1 h / -60 - 0 °C 2.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 2.2: 6 h / 0 - 5 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1

69
C₁₈H₁₉FNOS^(1-)*Li⁽¹⁺⁾ [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium; tetramethylurea / 1 h / -78 °C 2.1: dihydrogen peroxide; boric acid tributyl ester / 1 h / -60 - 0 °C 3.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 3.2: 6 h / 0 - 5 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1

70
2-(2-fluorophenyl acetic acid) [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: triethylamine / dicyclohexyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 40 - 50 °C 2.2: 0.25 h / 0 - 30 °C 3.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / toluene-4-sulfonic acid / dichloromethane / 4.75 h / 0 - 5 °C / Reflux 4.1: potassium carbonate / acetonitrile / 6.5 h / 25 - 30 °C 4.2: 6.5 h / 0 - 30 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / dicyclohexyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 40 - 50 °C 2.2: 0.25 h / 0 - 30 °C 3.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 3.2: 8 h / 0 - 25 °C 4.1: acetic anhydride; triethylamine / dichloromethane / 6.25 h / 0 - 30 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / dicyclohexyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 40 - 50 °C 2.2: 0.25 h / 0 - 30 °C 3.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / toluene-4-sulfonic acid / dichloromethane / 4.75 h / 0 - 5 °C / Reflux 4.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C

Multi-step reaction with 5 steps 1.1: triethylamine / dicyclohexyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 6 h / 0 - 5 °C 2.1: iodine; magnesium / tetrahydrofuran / 40 - 50 °C 2.2: 0.25 h / 0 - 30 °C 3.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / toluene-4-sulfonic acid / dichloromethane / 4.75 h / 0 - 5 °C / Reflux 4.1: potassium carbonate / acetonitrile / 7.5 h / 25 - 30 °C 5.1: triethylamine / dichloromethane / 0.25 h / 25 - 30 °C 5.2: 6 h / 0 - 5 °C

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[3]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1
[4]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - US2012/202066, 2012, A1

71
[ 1400867-30-2 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: tetrahydrofuran / 0 - 20 °C 2: hydrogenchloride / water / 12 h / 40 °C 3: sodium hydride / N,N-dimethyl-formamide / 0 °C

Reference： [1]Pan, Xianhua; Huang, Rui; Zhang, Jianshui; Ding, Liping; Li, Weijin; Zhang, Qunhui; Liu, Feng [Tetrahedron Letters, 2012, vol. 53, # 40, p. 5364 - 5366]

72
[ 55142-78-4 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: hydrogen bromide; dihydrogen peroxide; acetic acid / methanol / 0 - 5 °C 2: copper(l) iodide; sodium iodide; sodium methylate / Reflux 3: methyl chloroformate 4: potassium carbonate / ethanol / 0 °C 5: tetrahydrofuran / 0 - 20 °C 6: hydrogenchloride / water / 12 h / 40 °C 7: sodium hydride / N,N-dimethyl-formamide / 0 °C
	Multi-step reaction with 4 steps 1: acetic acid; hydrogen bromide; dihydrogen peroxide / methanol / 3 h / 20 °C / Cooling with ice 2: palladium diacetate; XPhos / N,N-dimethyl-formamide / 24 h / 100 °C / Inert atmosphere 3: 10 wt% Pd(OH)2 on carbon; hydrogen / ethanol / 20 °C / 2585.81 Torr 4: sodium hydride / dichloromethane; tetrahydrofuran / 3 h / 20 °C / Cooling with ice

Reference： [1]Pan, Xianhua; Huang, Rui; Zhang, Jianshui; Ding, Liping; Li, Weijin; Zhang, Qunhui; Liu, Feng [Tetrahedron Letters, 2012, vol. 53, # 40, p. 5364 - 5366]
[2]Current Patent Assignee: NANJING JIANCHENG MEDICINE SCIENCE TECHNOLOGY - CN103694251, 2018, B

73
[ 1056464-85-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: copper(l) iodide; sodium iodide; sodium methylate / Reflux 2: methyl chloroformate 3: potassium carbonate / ethanol / 0 °C 4: tetrahydrofuran / 0 - 20 °C 5: hydrogenchloride / water / 12 h / 40 °C 6: sodium hydride / N,N-dimethyl-formamide / 0 °C
	Multi-step reaction with 3 steps 1: palladium diacetate; XPhos / N,N-dimethyl-formamide / 24 h / 100 °C / Inert atmosphere 2: 10 wt% Pd(OH)2 on carbon; hydrogen / ethanol / 20 °C / 2585.81 Torr 3: sodium hydride / dichloromethane; tetrahydrofuran / 3 h / 20 °C / Cooling with ice

Reference： [1]Pan, Xianhua; Huang, Rui; Zhang, Jianshui; Ding, Liping; Li, Weijin; Zhang, Qunhui; Liu, Feng [Tetrahedron Letters, 2012, vol. 53, # 40, p. 5364 - 5366]
[2]Current Patent Assignee: NANJING JIANCHENG MEDICINE SCIENCE TECHNOLOGY - CN103694251, 2018, B

74
[ 1056464-86-8 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: methyl chloroformate 2: potassium carbonate / ethanol / 0 °C 3: tetrahydrofuran / 0 - 20 °C 4: hydrogenchloride / water / 12 h / 40 °C 5: sodium hydride / N,N-dimethyl-formamide / 0 °C

Reference： [1]Pan, Xianhua; Huang, Rui; Zhang, Jianshui; Ding, Liping; Li, Weijin; Zhang, Qunhui; Liu, Feng [Tetrahedron Letters, 2012, vol. 53, # 40, p. 5364 - 5366]

75
[ 1056549-88-2 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium carbonate / ethanol / 0 °C 2: tetrahydrofuran / 0 - 20 °C 3: hydrogenchloride / water / 12 h / 40 °C 4: sodium hydride / N,N-dimethyl-formamide / 0 °C

Reference： [1]Pan, Xianhua; Huang, Rui; Zhang, Jianshui; Ding, Liping; Li, Weijin; Zhang, Qunhui; Liu, Feng [Tetrahedron Letters, 2012, vol. 53, # 40, p. 5364 - 5366]

76
[ 446-48-0 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: tetrabutylammomium bromide / toluene; water / 55 °C 2: bromine / dichloromethane / 0 °C 3: potassium carbonate / ethanol / 0 °C 4: tetrahydrofuran / 0 - 20 °C 5: hydrogenchloride / water / 12 h / 40 °C 6: sodium hydride / N,N-dimethyl-formamide / 0 °C
	Multi-step reaction with 6 steps 1.1: sodium carbonate / tetrahydrofuran / 2 h / 20 °C 2.1: hydrogenchloride / methanol / 5 h / 20 °C 3.1: triethylamine; bromine / methanol / 2 h / 0 - 20 °C 4.1: magnesium / tetrahydrofuran / 1.5 h / Reflux 4.2: Reflux 5.1: copper(II) sulfate; sulfuric acid; dihydrogen peroxide / methanol / 16 h / 20 °C 6.1: triethylamine / dichloromethane / 3 h / Reflux
	Multi-step reaction with 3 steps 1.1: magnesium / methyl iodide / diethyl ether / 20 °C 1.2: 20 °C 1.3: 0 °C 2.1: 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile) / cyclohexane / 10 °C / Reflux 3.1: sodium hydrogencarbonate / N,N-dimethyl-formamide / 5 - 10 °C 3.2: 5 h / 20 °C 3.3: 3 h / 20 °C

Multi-step reaction with 5 steps 1.1: magnesium / methyl iodide / diethyl ether / 20 °C 1.2: 20 °C 1.3: 0 °C 2.1: 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile) / cyclohexane / 10 °C / Reflux 3.1: potassium hydrogencarbonate / acetonitrile / 10 - 15 °C 4.1: hydrogen bromide / acetic acid; acetone / 1 h / 0 - 5 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 1.25 h / 0 °C

Reference： [1]Pan, Xianhua; Huang, Rui; Zhang, Jianshui; Ding, Liping; Li, Weijin; Zhang, Qunhui; Liu, Feng [Tetrahedron Letters, 2012, vol. 53, # 40, p. 5364 - 5366]
[2]Current Patent Assignee: CHONGQING ANGE LONGXIANG PHARMACEUTICAL - CN105272993, 2016, A
[3]Current Patent Assignee: TORRENT INVESTMENTS PRIVATE LIMITED - WO2009/122440, 2009, A1
[4]Current Patent Assignee: TORRENT INVESTMENTS PRIVATE LIMITED - WO2009/122440, 2009, A1

77
[ 150322-38-6 ]
[ 108-22-5 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
59.72%	With toluene-4-sulfonic acid at 65 - 70℃; for 3.5h;	10 Example 10. Preparation of 2-acetoxy-5-(alpha-cyclopropyl carbonyl-2- fluorobenzyl)-4,5,6,7 tetrahydrothieno [3,2-c] pyridine (Prasugrel base) Example 10. Preparation of 2-acetoxy-5-(alpha-cyclopropyl carbonyl-2- fluorobenzyl)-4,5,6,7 tetrahydrothieno [3,2-c] pyridine (Prasugrel base) 349 ml of isopropenyl acetate, 119,4 g of PTSA and 208 g of 5-[2-Cyclopropyl-l-(2- fluoro-phenyl)-2-oxo-ethyl]-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one were mixed in a 2 liter round bottom flask fitted with a condenser, The mixture was heated up to 65-70 °C and stirred at this temperature for 3 and a half hours. Afterwards, the reaction mass was cooled down to 25-30 °C and quenched with 2.1 1 of chilled water. In addition, 160 g of sodium carbonate dissolved in 500 ml of water were added to adjust the pH of the reaction mass to 6.5 - 7. The mixture was extracted with 2 1 of ethyl acetate and the layers were separated. The aqueous layer was further extracted with 1 1 of ethyl acetate and the layers were separated. Subsequently, both organic layers obtained from the extractions were mixed and washed with 1 1 of brine solution. The layers were separated and the organic layer was subsequently dried with 100 g of sodium sulphate. The ethyl acetate was distilled out under vacuum at 45-50 °C and 416ml of methanol were added to the mixture followed by stirring for 30 minutes. The obtained solid was filtered and dried at 60-65 °C for 30 minutes to yield 140 g of the title compound, as a cream coloured solid. Yield: 59.72%. Purity (HPLC): 98.73%

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2013/14295, 2013, A1 Location in patent: Page/Page column 23-24

78
[ 389574-20-3 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
68.5%	With sodium carbonate In water; ethyl acetate for 0.25h;	14 Example 14. Preparation of Prasugrel base pure 180 g of prasugrel maleate, 1.8 1 of water and 1.8 1 of ethyl acetate were charged in a 10 litre round bottom flask. The pH of the mixture was adjusted to 6.8 by adding a solution of 38.92 g of sodium carbonate dissolved in 389 ml of water. The mixture was further stirred during 15 minutes. The two different layers formed were separated. Afterwards, the aqueous layer was extracted with 360 ml of ethyl acetate and the layers were separated. Subsequently, both ethyl acetate layers were combined and washed with 370 ml of a 20% w/v aqueous solution of sodium chloride. The ethyl acetate layer was next dried over 50 g of sodium sulphate and the solvent was distilled out under vacuum at 50-55 °C. After the distillation, 540 ml of methyl cyclohexane were added to the residue and it was further stirred for 30 minutes. The obtained solid was filtered and mixed with 1.54 1 of methanol heated up to 60-65 °C and stirred for 15 minutes. Afterwards, the reaction mass was cooled down to 25-30 °C and was maintained at the same temperature for 1 hour. The solid was filtered and washed with 255 ml of methanol. Lastly, the mixture was dried at 60-65 °C for 5-6 hours under vacuum to yield 94.0 g of prasugrel base pure. Yield: 68.5%. Purity (HPLC): 99.6%.

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2013/14295, 2013, A1 Location in patent: Page/Page column 25

79
[ 110-16-7 ]
[ 150322-43-3 ]
[ 389574-20-3 ]

Yield	Reaction Conditions	Operation in experiment
89.84%	In acetone at 25 - 30℃; for 3h;	13 Example 13. Preparation of prasugrel maleate salt 50.3g of maleic acid and 620 ml of acetone were mixed in a 1 liter round bottom flask. The mixture was stirred for 5 minutes. Next, 155 g of 2-acetoxy-5-(alpha-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7 tetrahydrothieno [3,2-c] pyridine were added to the reactor and the solution was further stirred for 3h at 25-30 °C. A precipitate was formed after the stirring. Afterwards, the mixture was cooled down to 0-5 °C and further stirred for lh. The mixture was filtered, washed with 310ml of acetone and the obtained solid dried at 60-65 °C to yield 182.56 g of prasugrel maleate salt. Yield: 89.84%. Purity(HPLC): 99.20%.

Reference： [1]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2013/14295, 2013, A1 Location in patent: Page/Page column 25

80
[ 150322-43-3 ]
[ 150322-38-6 ]

Yield	Reaction Conditions	Operation in experiment
	With cytosolic esterases Enzymatic reaction;

Reference： [1]Dansette, Patrick M.; Levent, Dan; Hessani, Assia; Mansuy, Daniel [Chemical Research in Toxicology, 2015, vol. 28, # 6, p. 1338 - 1345]

81
C₂₀H₂₄FNO₄ [ No CAS ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
68.5%	With zinc sulfide; acetic acid; triethylamine In tetrahydrofuran at -10 - 55℃; for 8h; Green chemistry;	1.d Place the above steps gave 1-cyclopropyl-2-o-fluorophenyl-N, N-di-t-butoxycarbonylethylaminoethanone (m), was added dropwise to a solution containing 12.0 g of tert-butanol potassium, and 50 g of dry tetrahydrofuran 500 ml four-necked flask (the flask connected with a stirrer, a thermometer and a dropping funnel), was added dropwise to the process is maintained between -10 -5 ° c, for about 4 hours dropping was completed, thereafter, 0 ° C for 3 hours to give 2-acetoxy-5-(α- cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydro-thieno [3,2-c] pyridine ( IV of); then, at between 5 and 10 ° C was added dropwise 18.5 g (0.11 mol) of ethyl bromoacetate 2Bi dropwise for about 1 hour, thereafter, 20 ° C after stirring for 5 hours, 20 g of 20% chlorine aqueous ammonium, 20 ° C for 3 hours. Was added 100 g of water, 200 g of ethyl acetate, 20 ° C for 30 minutes; separated and the aqueous layer was extracted with ethyl acetate three times, each time 50 g, ethyl acetate phase was combined, washed with saturated sodium chloride aqueous solution of 50 g , 10 g of anhydrous sodium sulfate for 4 hours and filtered, the filtrate recovered ethyl acetate, to give a residue (the V), after dissolved in 100 g of tetrahydrofuran, then transferred to a stirring, a thermometer and a 500 ml alkali absorption means four neck flask was added 30 g of acetic acid was heated at between 40 and 50 ° C was added portionwise 15 g (0.15 mol) of zinc sulfide powder, for about 1 hour addition was completed, the reaction was stirred for 3 hours between 55 ° C in the past 50 Zhi . Was cooled to -10 ° C, was added 15 g of acetic anhydride, and thereafter at 0 to 5 ° C was added dropwise 20 g of triethylamine, a dropping was completed, the reaction was stirred for 4 hours between 20 and 25 ° C. Was added 50 g of water, 100 g of ethyl acetate, 20 ° C for 30 minutes; separated and the aqueous layer was extracted 3 times with ethyl acetate, 50 g each, combined ethyl acetate phase was washed twice with saturated aqueous sodium chloride solution , each 10 g, 10 g of anhydrous sodium sulfate for 4 hours and filtered, the filtrate recovered ethyl acetate, the residue was treated with 100 g of methyl tert-butyl ether and recrystallized to give 25.6 g of white solid 2-acetoxy -5 - (α- cyclopropylcarbonyl-2-fluorobenzyl) _4,5,6,7- tetrahydro-thieno [3,2 (:] pyridine (¥ 1), m.p. 120-122 ° (3,1 ^ (purity: 99.3%, yield 68.5% (2-amino-o-fluorophenyl acetonitrile meter).

Reference： [1]Current Patent Assignee: XINFA PHARMACEUTICAL CO LTD - CN104592250, 2016, B Location in patent: Paragraph 0023-0024; 0052

82
[ 204205-33-4 ]
2-trimethylsilyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ No CAS ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
		The product obtained in Example 3 was added to 5000 ml of methylene chloride, 1400 ml of TEA and 80 g of tetrabutylammonium bromide,A-bromo-o-fluorobenzyl cyclopropyl ketone (1100-1200 g) was added dropwise. After completion of the dropwise addition, the mixture was heated under reflux and stirring was continued for 3 hours,TLC detection reaction was complete, add 4-dimethylaminopyridine (DMAP) 25g,Triethylamine (1000 ml) was dropwise added, and acetic anhydride (750 ml) was added thereto. The mixture was reacted at room temperature and the reaction was complete by TLC, add water and extracted with dichloromethane, washed with saturated sodium bicarbonate, and concentrated to give an oil, the crystallization to obtain prasugrel as a white solid.

Reference： [1]Patent: CN102558216,2016,B .Location in patent: Paragraph 0090-0091

83
[ 204205-33-4 ]
2-tri-tert-butylsilyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine [ No CAS ]
[ 108-24-7 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
		The product obtained in Example 1 was added to 5000 ml of methylene chloride, 1400 ml of TEA and 80 g of tetrabutylammonium bromide(Sinopharm Group Chemical Reagent Co., Ltd.) was added dropwise to a solution of alpha-bromo-o-fluorobenzyl cyclopropyl ketone (1100-1200 g)(Shanghai Zhiwei Chemical Technology Co., Ltd.). After completion of the dropwise addition, the mixture was heated under reflux and stirring was continued for 3 hours,TLC detection reaction was complete, 25 g of 4-dimethylaminopyridine (DMAP) (Sinopharm Group Chemical Reagent Co., Ltd.) was added, triethylamine (1000 ml) was added dropwise, acetic anhydride (Sinopharm Chemical Reagent Co., Ltd.) (750 ml) stirred at room temperature. TLC detection reaction completely, add water and extracted with dichloromethane, washed with saturated sodium bicarbonate, and concentrated to give an oil, the crystallization to obtain prasugrel as a white solid.

Reference： [1]Patent: CN102558216,2016,B .Location in patent: Paragraph 0086-0087

84
[ 64-19-7 ]
[ 150322-43-3 ]
5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxyethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl acetate acetic acid hydrobromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.2%	With hydrogen bromide In water at 40℃; for 0.166667h;	2 Example 2 Preparation of Prasugrel Hydrobromide Acetate (1) To the reaction flask was added 121.6 g of hydrobromide bromide and 1824 g of water, mixed and stirred to give a suspension;(2) To the suspension of the hydrobromide prasugrel suspension, 1033.6 ml of a solution of acetic acid was added dropwise, stirred and the temperature was raised to40 ° C, start the time, react for 10 minutes and then concentrate at 35 ° C to dryness under reduced pressure;(3) To the concentrate was added 608 ml of acetone, stirred and dissolved, placed overnight, precipitated solid, 60 ° C vacuum drying 4 small, The final product of the total product of hydrobromide prasugrel acetate 127.0g, the yield was 92.2%, purity 99.9%.

Reference： [1]Current Patent Assignee: HAINAN LINGKANG PHARMACEUTICAL CO., LTD - CN103450219, 2016, B Location in patent: Paragraph 0048-0051

85
[ 150322-43-3 ]
[ 130-85-8 ]
prasugrel pamoic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.85 g	In acetone; at 5 - 20℃; for 25h;	5.0 g of prasugrel free base was dissolved in 50 ml of acetone, and 600 ml of an acetone solution containing 5.20 g of pamoic acid was added dropwise. After completion of the dropwise addition, the reaction was completed by stirring at room temperature for 1 hour. The reaction solution was allowed to stand at 5° C. for 24 hours, suction filtered, and vacuum dried at 50° C. for 2 hours to obtain 7.85 g of a pale yellow solid.

Reference： [1]Patent: CN104370934,2018,B .Location in patent: Paragraph 0050-0051; 0053-0060

86
[ 204205-33-4 ]
[ 1151904-85-6 ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
29.5 g	With sodium hydride; In tetrahydrofuran; dichloromethane; at 20℃; for 3h;Cooling with ice;	A clean 500 mL flask was taken, and 7.0 g (0.18 mol) of sodium hydride was added thereto under ice-cooling, and 30 ml of dry tetrahydrofuran was stirred and dissolved.Another clean flask was taken, followed by 2-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine 17 · 4 g (0 · 08 mol), alpha-bromo-ortho-fluorobenzylcyclopropylmethanone 20,6 g (0.08 mol), 150 ml of dichloromethane was dissolved, and the solution was slowly added dropwise to a 500 ml flask, and the mixture was added dropwise, and stirred at room temperature for 3 hours.TLC showed no raw material remaining, glacial acetic acid was quenched to neutral, 150 ml of water was added, the organic phase was separated, the aqueous phase was extracted twice with dichloromethane, the organic phase was combined, dried, solvent was evaporated under reduced pressure, ether was redissolved, and then added dropwise. The ether solution of hydrogen chloride was adjusted to pH 3, stirred in an ice-water bath for 1 h, filtered and washed with diethyl ether and dried to give a white solid (29.5 g).

Reference： [1]Patent: CN103694251,2018,B .Location in patent: Paragraph 0017; 0027; 0028

87
[ 462-06-6 ]
2-chloro-2-(2-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-1-cyclopropylethanone [ No CAS ]
[ 150322-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With aluminum (III) chloride In diethyl ether; acetone at 15 - 25℃;	3.1; 3.2; 3.3 Example 3The preparation method of crude prasugrel includes the following process steps: (1) Adding diethyl ether (50 ml) and acetone to a reaction vessel containing prasugrel II intermediate (20.7 g, 7.8 mol)(50ml), under magnetic stirring until completely dissolved for use;(2) Add fluorobenzene (25.6 g, 9.4 mol) and aluminum trichloride (15.3 g, 2.34 mol) to another reaction vessel, and thoroughly stirAfter mixing, slowly add dropwise to the reaction vessel of the step (1), and after the completion of the dropwise addition, the mixture is stirred at 15 to 25 ° C until the reaction is completed;(3) Step (2) After the reaction is completed, pure water (60 ml) is added thereto, and the mixture is stirred until it is turbid and suspended, and then allowed to stand for stratification.After leaving the organic phase, the solvent was added to the aqueous layer to extract hexyl acetate (80 ml), and the separated organic phase and extracted organic phase were separated.After combining, wash with saturated sodium carbonate solution at least twice, then wash with saturated brine for at least twice, then add activated carbonDecolorize by stirring, filtered by conventional filtration and concentrated under reduced pressure.Obtained as a white solid 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (III) (38.2 g, 8.5 mol), that is, crude prasugrel, the yield is 88.34%,The purity is 99.78%.

Reference： [1]Current Patent Assignee: Dong Dandan - CN108383855, 2018, A Location in patent: Paragraph 0030; 0033

88
[ 150322-43-3 ]
C₂₀H₁₈⁽²⁾H₂FNO₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With [⁽²⁾H₆]acetone; tris(pentafluorophenyl)borate In toluene at 150℃; for 6h; Inert atmosphere;

Reference： [1]Chang, Yejin; Yesilcimen, Ahmet; Cao, Min; Zhang, Yuyang; Zhang, Bochao; Chan, Jessica Z.; Wasa, Masayuki [Journal of the American Chemical Society, 2019, vol. 141, # 37, p. 14570 - 14575]

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	150322-43-3	MDL No. :	MFCD09954140
Formula :	C₂₀H₂₀FNO₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DTGLZDAWLRGWQN-UHFFFAOYSA-N
M.W :	373.44	Pubchem ID :	6918456
Synonyms :	PCR 4099;CS 747;LY640315	Chemical Name :	5-(2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate

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Hazard Statements:	H302-H315-H319-H335	Packing Group:
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