[ CAS No. 274693-55-9 ] {[proInfo.proName]}

Name: 274693-55-9|2-(((3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol|95%
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SKU: A732186
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Quality Control of [ 274693-55-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 274693-55-9 ]

CAS No. :	274693-55-9	MDL No. :	MFCD19687251
Formula :	C₁₀H₁₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WNYYMPICYAOQAE-RYPBNFRJSA-N
M.W :	217.26	Pubchem ID :	9942596
Synonyms :

Calculated chemistry of [ 274693-55-9 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	53.12
TPSA :	73.94 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.31 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.2
Log Po/w (XLOGP3) :	-0.96
Log Po/w (WLOGP) :	-0.38
Log Po/w (MLOGP) :	-0.63
Log Po/w (SILICOS-IT) :	-0.03
Consensus Log Po/w :	0.04

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.38
Solubility :	89.7 mg/ml ; 0.413 mol/l
Class :	Very soluble
Log S (Ali) :	-0.11
Solubility :	170.0 mg/ml ; 0.78 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.49
Solubility :	71.0 mg/ml ; 0.327 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.36

Safety of [ 274693-55-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 274693-55-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 274693-55-9 ]
Downstream synthetic route of [ 274693-55-9 ]

[ 274693-55-9 ] Synthesis Path-Upstream 1~1

1
[ 274693-55-9 ]
[ 87-69-4 ]
[ 376608-65-0 ]

Yield	Reaction Conditions	Operation in experiment
302.6 g	at 20 - 40℃; for 21 h;	The temperature of the solution was raised to 40 ° C and 150 g of L-tartaric acid was added. The mixture was stirred at 40 ° C for 1h and then at 20 ° C 20h, precipitation of a large number of solid, filtration, filter cake with cold isopropyl alcohol (100ml) wash, 40 ° C vacuum drying 8h, you can get white powderL-tartaric acid salt of the compound X in the form of 302. 6g.

Reference： [1] Patent: CN106279095, 2017, A, . Location in patent: Paragraph 0050

[ 274693-55-9 ] Synthesis Path-Downstream 1~88

1
[ 145783-15-9 ]
[ 274693-55-9 ]
2-[((3aR,4S,6R,6aS)-6-[5-amino-6-chloro-2-(mercaptopropyl)pyrimidin-4-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxolan-4-yl)oxy]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		Adding four flasks intermediate I (20g, 84.03mmol), intermediate II (33.93g), DMF (80 ml), water (40 ml), stirring 20 minutes, cooling to 20 C, dropwise triethylamine (42.5g, 0 . 42mol), heating to reflux, HPLC tracking intermediate insulation reaction to I the reaction is complete, the reaction water quenching with ethyl acetate extraction, the organic phase dried with anhydrous sodium sulfate to decompression desolution of the intermediate III (33.4g, 95.0% yield).
93.5%	With N-ethyl-N,N-diisopropylamine; at 120 - 125℃; for 10h;Inert atmosphere;	ake a 500ml three-necked flask,Equipped with a condensing return tube and nitrogen ball protection.Add 2-[[(3AR,4S,6R,6AS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenten-1,3-dioxolan-4-yl ]oxy]ethanol (88.7 g, 408.3 mmol, 1.0 eq), 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (98.0 g, 408.3 mmol, 1.0 eq), N,N- Diisopropylethylamine (79.1 g, 612.5 mmol, 1.5 eq),Stir at 120-125 C for 10 hours (HPLC detection,The peak area percentage was 4,6-dichloro-2-(propylthio)-5-aminopyrimidine <1.0%), the heating was stopped and the temperature was lowered to <60 C, and ethyl acetate and water were added for washing and extraction. Concentrated to 200 ml of ethyl acetate under reduced pressure and recrystallized from petroleum ether.Made a white solid 160g,The yield is 93.5%.HPLC peak area percentage SM-C ? 98.5%.
88.3%	With sodium hydrogencarbonate; In water; at 100℃; for 20h;	(1) 570g compound II and 2500g water are mixed, then with stirring, add in batches 756g sodium bicarbonate. After completion of addition, while stirring add in batches 350g compound I. Then heat to 100 C. Stir the reaction for 20h, the reaction solution becomes dark red muddy shape, stop heating, cooling to 40 C the following, the reaction product is added to 1000 ml ethyl acetate, stirring 5 min later, the liquid, aqueous phase for the 500 ml ethyl acetate extraction a, combined organic phase, the organic phase by adding 100 ml normal heptane, stirring to wash-out when a large amount of white solid, continue to stir 1h, filtered, get white solid compound III, product after drying 554g, yield of 88.3%, purity of 99.8%;

87.2%	With triethylamine; In butan-1-ol; at 100℃; under 760.051 Torr; for 55h;Sealed tube;	Example 6 Synthesis of 2-[((3aR,4S,6R,6aS)-6-[[5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl]amino]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy]ethanol (Compound I) Take 250mL reaction flask 4,6-dichloro-2-(propylthio)pyrimidin-5-amine (16.1g, 68mmol), <strong>[274693-55-9]2-[[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy]-1-ethanol</strong> (14.8g, 68mmol), triethylamine (68.7g, 680mmol) and n-butanol (100mL) were added at atmospheric pressure. The resulting reaction mixture was sealed and heated to 100C, reflux for 55h. Followed by cooling to 30C. The solvent was distilled off. Isopropyl acetate and water, the phases were separated. The aqueous phase was extracted with isopropyl acetate, the combined organic phases, washed. Dried over anhydrous magnesium sulfate. Filter. The solvent was distilled off, give a reddish brown oil. N-heptane was added after a beating, white solid 24.9g, yield 87.2%. HPLC purity was 99.4%.
86%	With N-ethyl-N,N-diisopropylamine; In 1,4 dimethylcyclohexane; at 90℃; for 20h;	A solution of 2 - [[(3R, 4S, 6R, 6S) -6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxolan-4-yl]oxy] - ethanol succinate (100.6g, 0.30mol) was added to a 500ml 1,4- dioxane, during stirring, was addedthe N, N- diisopropylethylamine (193.0g, 1.5mol) And 4,6-dichloro-5-amino-2-propylthiopyrimidine (71.4 g,0.30 mol) were added and heated to 90 C and the TLC was monitored until 4,6-dichloro-5-amino- The reaction of thiopyrimidine was complete and stirred for20 hours. The reaction was quenched by the addition of saturated ammonium chloride solution. Theorganic phase waswashedwithsaturated brineand dried over anhydrous sodium sulfate. The organic phase was subtracted Concentrated, and then recrystallized from ethyl acetate and petroleum ether,dried at40 Cto give 108.1 g of a white solid in 86% yield.
86%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 90℃; for 20h;	To a solution of (2) (1.06 g, 0.03 mol) in 1,4-dioxane, (3)(7.14 g, 0.03 mol) and DIEPA (19.3 g, 0.15 mol) were added;the resulting reaction mixture was heated to 90 C for 20 huntil complete conversion of the reactant (3) (monitored byTLC). Then the reaction was quenched with saturated ammoniumchloride solution (5 ml) and the solution was evaporatedunder vacuum to remove 1,4-dioxane. The resulting residue was dissolved in acetic ester and washed with water and brinefor twice. Combined the organic layers, dried with anhydrousNa2SO4, filtered, and evaporated under vacuum to afford thecrude product as a while solid, which was then recrystallizedin acetic ester and petroleum ether affording pure product (4)(1.08 g, 86%).
57.2%	With triethylamine; sodium iodide; In 1,4-dioxane; at 120℃; for 7h;	To a solution of 2 (80 mg, 0.37 mmol, 1.0 eq) in 1,4-dioxane were added 3 (78 mg, 0.33 mmol, 0.9 eq), sodium iodide (11 mg, 0.07 mmol, 0.2 eq) and triethylamine (186 mg, 1.84 mmol, 5.0 eq). The resulting reaction mixture was heated to 120 C over 7 h, then the solution was evaporated under vacuum to move 1,4-dioxane, the residue was dissolved in EtOAc, then washed with water and brine, the EtOAc layer was dried and evaporated under vacuum to give the title product as a brown oil (106 mg, 57.2%). EI-MS m/z 419.2 (M+H)+.
	With potassium tert-butylate;	It has been verified that using the salts according to the invention with the purity of at least 96 % ee makes it possible to obtain, in any of the further steps of the synthesis of ticagrelor, the final product containing less than 0.15 % of the isomeric impurity IV with a configuration derived from the undesired diastereoiso ier la, without the necessity to use chromatographic purification.The salts of compound I with D-(-)-mandelic and R-(-)-3-chloromandelic acid in the purities mentioned in Examples 1 and 2 were used for the preparation of ticagrelor, which is illustrated in Scheme 1. The salts of the compound I with the said acids are marked I * HA therein. ticagrelorSCHEME 1Abbreviations used:CBz = benzyloxycarbonyl,MIBK methyl isobutyl ketone,DIPEA diisopropylethylamine.The total yield of the method described in Scheme 1 was 16 %. The quality of the obtained product was determined using the liquid chromatography method and amounted to 99.5 % with the content of impurity IV lower than 0.1 %. The method of preparation of ticagrelor according to Scheme 1 did not require the use of chromatographic purification in any of the steps of its synthesis.
	With triethylamine; at 100℃; for 12h;	1 g (4 mmol) of 4,6-dichloro-2- (propylthio) -5-aminopyrimidine, 11.5 g (4 mmol) of NH2-R and 1.7 g (16 mmol) of triethylamine were added to a reaction flask,After stirring at 100 C for 12h under stirring, the mixture was cooled to room temperature and added with 30mL of water. Each was washed with ethyl acetate and saturated brine three times, and the solvent was removed by rotary evaporation to give Compound 5 as a pink powder.To 0.42 g (1 mmol) of compound 5, 10 mL of glacial acetic acid and 0.14 g (2 mmol) of sodium nitrite were added and refluxed for 3 hours at 100 C. After cooling to room temperature, ammonia water was added to neutrality, extracted with ethyl acetate and evaporated to dryness to give compound 6;To 0.45 g (1 mmol) of compound 6, 30 mL of toluene, 0.58 g (5 mmol) of potassium carbonate and 0.17 g (1 mmol) of NH2-R were added and refluxed at 210 C for 2 hours.Cooled to room temperature, filtered and the filtrate was evaporated to dryness to give compound 7; Compound 7 was refluxed in hydrochloric acid at 100 C for 2 hours to obtain the compound ticagrelor.

Reference： [1]Patent: CN105503876,2016,A .Location in patent: Paragraph 0015
[2]Patent: CN105198864,2018,B .Location in patent: Paragraph 0022-0031
[3]Patent: CN105669681,2016,A .Location in patent: Paragraph 0028
[4]Patent: CN103626745,2016,B .Location in patent: Paragraph 0080; 0081; 0082
[5]Patent: CN107033146,2017,A .Location in patent: Paragraph 0070-0074
[6]Structural Chemistry,2018,vol. 29,p. 1663 - 1670
[7]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6013 - 6018
[8]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[9]Patent: WO2012/142983,2012,A1 .Location in patent: Page/Page column 5-7
[10]Patent: CN107089984,2017,A .Location in patent: Paragraph 0041; 0051; 0060; 0069
[11]Structural Chemistry,2018,vol. 29,p. 871 - 879

2
[ 274693-54-8 ]
[ 274693-55-9 ]

Yield	Reaction Conditions	Operation in experiment
75.7%	With 5%-palladium/activated carbon; In methanol; at 20℃; for 1h;	Under an atmosphere of hydrogen, a suspension of 21 (53 mg, 0.15 mmol, eq) and 5% Pd/C (5 mg) in methanol (2 mL) was stirred at ambient temperature for about 60 min. After filtration, the resulting filtrate was evaporated under vacuum to give the title product as a colorless oil (25 mg, 75.7% yield). EI-MS m/z 218.2 (M+H)+.
	palladium on charcoal; In ethanol;	c) [3aR-(3aalpha,4alpha,6alpha,6aalpha)]-2-[[6-Amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol A slurry of 5% palladium on charcoal (4 g) in ethanol was added to a solution of the product from step b) (39.96 g) in ethanol (250 ml) and the mixture was hydrogenated at 1.2 bar for 20 hours. The catalyst was filtered off and the filtrate was concentrated to give the subtitle compound (23.65 g). MS (APCI) 160 (M+H+, 100%).
	With ammonium formate;palladium 10% on activated carbon; In ethanol; at 30 - 70℃;Product distribution / selectivity;	Compound V (70g) was dissolved in ethanol (5- 10V). Ammonium formate (12.56 g) and 10% Pd/C (7.0 g) were added. The reaction mixture was heated to 30-70C for 1-3 hours. The reaction mixture was filtered. The ethanol was distilled off and the resultmg residue was isolated as dense oil as the free base (39.0g, 90%).

	With hydrogen;palladium on activated charcoal; In ethanol;	It has been verified that using the salts according to the invention with the purity of at least 96 % ee makes it possible to obtain, in any of the further steps of the synthesis of ticagrelor, the final product containing less than 0.15 % of the isomeric impurity IV with a configuration derived from the undesired diastereoiso ier la, without the necessity to use chromatographic purification.The salts of compound I with D-(-)-mandelic and R-(-)-3-chloromandelic acid in the purities mentioned in Examples 1 and 2 were used for the preparation of ticagrelor, which is illustrated in Scheme 1. The salts of the compound I with the said acids are marked I * HA therein. ticagrelorSCHEME 1Abbreviations used:CBz = benzyloxycarbonyl,MIBK methyl isobutyl ketone,DIPEA diisopropylethylamine.The total yield of the method described in Scheme 1 was 16 %. The quality of the obtained product was determined using the liquid chromatography method and amounted to 99.5 % with the content of impurity IV lower than 0.1 %. The method of preparation of ticagrelor according to Scheme 1 did not require the use of chromatographic purification in any of the steps of its synthesis.
	With palladium 10% on activated carbon; ammonium formate; In ethanol; at 40℃; for 1h;	To a 3000 ml three-necked flask was added 329.8 g of compound IX,117.5 g of ammonium formate,72.3 g of 10% bPd / C,1650ml ethanol, placed in the oil bath, the temperature control 40 stirring reaction 1h, suction filtration, the filtrate is the compound X ethanol solution,

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6013 - 6018
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[3]Patent: US6525060,2003,B1
[4]Patent: WO2012/138981,2012,A2 .Location in patent: Page/Page column 80
[5]Patent: WO2012/142983,2012,A1 .Location in patent: Page/Page column 5-7
[6]Patent: CN106279095,2017,A .Location in patent: Paragraph 0026; 0049

Yield	Reaction Conditions	Operation in experiment
65%	With lithium aluminium tetrahydride; In tetrahydrofuran; for 1h;Reflux;	Step 10[00116] 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][l,3]dioxol-4-yloxy)ethanol: A solution of ethyl 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)acetate (4.2 g, 16.2 mmol, 1.00 equiv.) in dry tetrahydrofuran (50 mL) was slowly added to a suspension of lithium aluminum hydride (1.23 g, 32.4 mmol, 2.00 equiv.) in tetrahydrofuran (50 mL). The mixture was heated at reflux for about 1 hour, and then water was added (2 mL). After the solids were collected by filtratration, the solids were washed with tetrahydrofuran (50 mL) and then dried in vacuo to give the title product as a yellow oil (2.3 g, 65 %). MS: m /z = 218(MH)+.
		Step c: Preparation of [3aR-(3aalpha,4alpha,6alpha,6aalpha)]-2-[[6-amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol (alternatively named: 2-[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy}-1-ethanol). A slurry of 5% palladium on charcoal (4 g) in ethanol was added to a solution of the product from Step (b) (39.96 g) in ethanol (250 ml) and the mixture was hydrogenated at 1.2 bar for 20 hours. The catalyst was filtered off and the filtrate was concentrated to give the subtitle compound (23.65 g). MS (APCI) 160 (M+H+, 100%).

4
[ 274693-55-9 ]
[ 144-62-7 ]
[ 1402150-30-4 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 65℃;	Examples Example 1. Preparation of (3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2- dimethyltetrahydro-3aH-cyclopenta[

Reference： [1]Patent: WO2010/30224,2010,A1 .Location in patent: Page/Page column 6

5
[ 274693-55-9 ]
[ 2743-38-6 ]
bis[(3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-aminium] 2,3-bis(benzoyloxy)succinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 10 - 50℃; for 4h;	Example 2. Preparation of Bis[(3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2- dimethyltetrahydro-3aH-cyclopenta[

Reference： [1]Patent: WO2010/30224,2010,A1 .Location in patent: Page/Page column 6-7

6
[ 274693-55-9 ]
[ 145783-14-8 ]
[ 1265919-25-2 ]

Yield	Reaction Conditions	Operation in experiment
93.5%	With triethylamine; In dichloromethane; at 10 - 20℃; for 2h;	Add 500 ml of dichloromethane to the reaction flask at room temperature.Compound a 26.7 g (0.1 mol), compound b 32.6 g (0.15 mol), Mechanically dissolved, Cool in an ice bath to below 10 C. And controlled temperature drop of 20.2g of triethylamine, drip,The reaction was stirred for 2 h while warming to room temperature. After the reaction, the organic phase is washed, Washing with 0.1 mol/L hydrochloric acid to remove excess compound b, Finally, it is washed to neutrality and dried over anhydrous sodium sulfate. Concentrating the dry solution to obtain the target product c, Drying gave 41.9 g of a white solid, yield 93.5%, HPLC purity 98.75%. Compound a is a commercial product, supplied by Nanjing Claisen Pharmaceutical Chemical Co., Ltd., and its chemical name is 4,6-dichloro-5-nitro-2-propylthiopyrimidine.Compound b is a commercial product supplied by Nanjing Claisen Pharmaceutical Chemical Co., Ltd., and its chemical name is 2-[[(3aR, 4S,6R, 6aS)-6-aminotetrahydro-2,2-dimethyl-4H- Cyclopentene-1,3-dioxolan-4-yl]oxy]ethanolCompound C: 2-[[(3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-propylthiopyrimidin-4-amino)tetrahydro-2,2-dimethyl -4H-cyclopenteno-1,3-dioxolan-4-yl]oxy]ethanol
45%	In tetrahydrofuran; at 0 - 10℃; for 2h;	[00120] 2-((3aR,4S,6R,6aS)-6-(6-chloro-5-nitro-2-(propylthio)pyrimidin-4-ylamino)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol: A solution of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (1.07 g, 3.99 mmol, 1.00 equiv.), and 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4- yloxy)ethanol (570 mg, 4.41 mmol, 1.20 equiv.) in tetrahydrofuran (20 mL) was stirred at 0- 10 0C for about 2 hours and then water (20 mL) was added. Standard extractive workup with ethyl acetate (3 x 20 mL) afforded the title product as a yellow oil (800 mg; yield = 45 %). 1H NMR (300 MHz, CDCl3) delta: 8.65 (b, 1 H), 4.66-4.76 (m, 2 H), 4.56 (m, 1 H), 3.99 (d, / = 7.5 Hz, 1 H), 3.70-3.87 (m, 3 H), 3.64-3.67 (m, 1 H), 3.07-3.20 (m, 2 H), 2.34 (m, 1 H), 1.97 (m, 1 H), 1.76-1.82 (m, 2 H), 1.46 (s, 3 H), 1.27 (s, 3 H), 1.07 (t, / = 7.5 Hz, 3 H).

Reference： [1]Patent: CN104059069,2016,B .Location in patent: Paragraph 0033-0040
[2]Patent: WO2011/17108,2011,A2 .Location in patent: Page/Page column 41

7
[ 345898-95-5 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: EP2666771,2013,A1
[3]Patent: CN106279095,2017,A

8
[ 274693-55-9 ]
2-({(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-2,2-dimethyltetrahydro-3aH-cyclopentadiene[d][1,3]dioxolene-4-yl}oxy)ethanol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/142983,2012,A1
[3]Patent: CN105669681,2016,A
[4]Structural Chemistry,2018,vol. 29,p. 1663 - 1670

9
[ 274693-55-9 ]
[ 274693-27-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/85665,2012,A2
[3]Patent: WO2012/85665,2012,A2
[4]Patent: WO2012/85665,2012,A2
[5]Patent: WO2012/138981,2012,A2
[6]Patent: WO2013/37942,2013,A1
[7]Patent: WO2015/162630,2015,A1
[8]Patent: US2016/102101,2016,A1
[9]Patent: CN105669681,2016,A
[10]Patent: CN104059069,2016,B

10
[ 274693-55-9 ]
C₃₀H₃₈F₂N₆O₅S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602

11
[ 274693-55-9 ]
C₂₉H₃₆F₂N₆O₆S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602

12
[ 274693-55-9 ]
C₃₁H₄₀F₂N₆O₆S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602

13
[ 274693-55-9 ]
[ 1381841-44-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602

14
[ 274693-55-9 ]
[ 1381841-46-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602

15
[ 274693-55-9 ]
[ 274693-26-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/85665,2012,A2
[3]Patent: WO2012/142983,2012,A1
[4]Patent: WO2015/162630,2015,A1
[5]Patent: US2016/102101,2016,A1
[6]Patent: CN105669681,2016,A
[7]Patent: CN104059069,2016,B

16
[ 274693-55-9 ]
[ 1381841-39-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602

17
ethyl 2-(6-(benzyloxycarbonylamino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy) acetate [ No CAS ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/138981,2012,A2

18
[ 274693-53-7 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/138981,2012,A2
[3]Patent: WO2012/142983,2012,A1
[4]Patent: CN106279095,2017,A

19
[ 4099-85-8 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: EP2666771,2013,A1

20
[ 532-20-7 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602

21
[ 4137-56-8 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: EP2666771,2013,A1

22
[ 155934-55-7 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: EP2666771,2013,A1

23
[ 155899-66-4 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: WO2012/85665,2012,A2
[3]Patent: WO2012/138981,2012,A2
[4]Patent: WO2012/172426,2012,A1
[5]Patent: US2014/206867,2014,A1
[6]Patent: CN106279095,2017,A

24
[ 155855-51-9 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602
[2]Patent: EP2666771,2013,A1

25
[ 50600-40-3 ]
[ 274693-55-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3598 - 3602

26
[ 274693-55-9 ]
[ 1383715-60-3 ]

Reference： [1]Patent: WO2012/85665,2012,A2

27
[ 274693-55-9 ]
[ 1383715-61-4 ]

Reference： [1]Patent: WO2012/85665,2012,A2

28
[ 274693-55-9 ]
[ 1383715-62-5 ]

Reference： [1]Patent: WO2012/85665,2012,A2

29
[ 274693-55-9 ]
[ 1383715-63-6 ]

Reference： [1]Patent: WO2012/85665,2012,A2

30
[ 274693-55-9 ]
[ 1383715-64-7 ]

Reference： [1]Patent: WO2012/85665,2012,A2

31
[ 274693-55-9 ]
[ 1383715-58-9 ]
[ 1383715-59-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20 - 25℃; for 2h;	Step-3: Preparation of 2-[[(3aR,4S,6R,6aS)-6-[[4-[N-[(li?,2S)-2-(3,4-difluorophenyl) cyclopropan-l-yl]-N-tert-butoxycarbonyl]amino]-2-(propylthio)-5-nitropyrimidin-6-yl]-2,2- dimethyl-tetrahydro-3aH-cyclopenta[d] [ 1 ,3]dioxol-4-yl]oxy]ethanolTo a solution of 2-[[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]-dioxol-4-yl]oxy]-l-ethanol (0.60 g, prepared according to the example 8) in tetrahydrofuran (5 ml) was added Nu,Nu-diisopropylethyl amine (0.713 g) while maintaining the temperature at about 20-25C. A solution of 6-chloro-4-[[N-[(li?,2S)-2-(3,4- difluorophenyl)cyclopropan-l-yl]-N-tert-butoxycarbonyl]amino]-5-nitro-2-(propylthio) pyrimidine (1.38 g) in tetrahydrofuran (8 ml) was to the above solution while maintaining the temperature at about 20-25C over a period of 10-15 minutes, followed by stirring for 2 hours at the same temperature. After completion of the reaction, toluene (10 ml) and saturated sodium chloride solution (10 ml) were added to the reaction mass. The resulting mass was stirred for 5 minutes, followed by layer separation. The aqueous layer was extracted twice with toluene (2 x 10 ml). The combined organic layer was washed with saturated sodium chloride solution (10 ml) and then dried over sodium sulfate. The organic layer containing the product was evaporated to dryness under reduced pressure. The concentrated mass was further purified (silica gel, 25% ethyl acetate in hexane) to produce 0.67 g of 2- [[(3aR,4S,6R,6aS)-6-[[4-[N-[(li?,2S)-2-(3,4-difluorophenyl)cyclopropan-l-yl]-N-tert-butoxy carbonyl]amino]-2-(propylthio)-5-nitropyrimidin-6-yl]-2,2-dimethyl-tetrahydro-3aH- cyclopenta[d][ 1 ,3]dioxol-4-yl]oxy]ethanol.Mass [M-H]: 680.3.

Reference： [1]Patent: WO2012/85665,2012,A2 .Location in patent: Page/Page column 55-56

32
[ 1383715-55-6 ]
[ 274693-55-9 ]

Reference： [1]Patent: WO2012/85665,2012,A2
[2]Patent: WO2012/172426,2012,A1
[3]Patent: US2014/206867,2014,A1

33
[ 1383715-56-7 ]
[ 274693-55-9 ]

Reference： [1]Patent: WO2012/85665,2012,A2
[2]Patent: WO2012/172426,2012,A1
[3]Patent: US2014/206867,2014,A1

34
[ 1383715-57-8 ]
[ 274693-55-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;20% palladium hydroxide-activated charcoal; In methanol; at 20 - 25℃; under 2327.23 Torr; for 10h;Autoclave; Inert atmosphere;	Example 8Preparation of 2-[[(3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d] [ 1 ,3]-dioxol-4-yl]oxy]- 1 -ethanolA mixture of 2-[[(3ai?,45',6i?,6a5)-6-(N,N-Dibenzylamino)-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]dioxol-4-yl]oxy]ethanol (1.25 g), palladium hydroxide (20% on carbon, 0.3 g) and methanol (150 ml) was taken into an autoclave, followed by nitrogen flushing. The mixture was hydrogenated under hydrogen pressure of 45 psi for 10 hours at 20-25C. After completion of the reaction, the reaction mass was filtered through a celite bed and the celite bed was washed with methanol (15 ml). The filtrate was concentrated under reduced pressure to obtain 0.7 g of 2-[[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l, 3 ]-dioxol-4-yl]oxy]-l -ethanol.Mass [M+H]: 218.0

Reference： [1]Patent: WO2012/85665,2012,A2 .Location in patent: Page/Page column 53

35
[ 274693-55-9 ]
[ 1402150-32-6 ]

Reference： [1]Patent: WO2012/138981,2012,A2

36
[ 274693-55-9 ]
[ 1354945-69-9 ]

Reference： [1]Patent: WO2012/138981,2012,A2
[2]Patent: CN107033146,2017,A
[3]Structural Chemistry,2018,vol. 29,p. 871 - 879

37
[ 274693-55-9 ]
[ 1402150-28-0 ]
[ 1402150-31-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 40 - 80℃;Inert atmosphere;Product distribution / selectivity;	To a mixture of compound VI free base (20.0 g), compound GammaChi (24.49g) and ethanol (240 mL) was added triethylamine (9.31 g) under an inert atmosphere. The resulting reaction mixture was heated to 40-80 C for 3-6hrs. The reaction was monitored by TLC and HPLC. After completion of reaction, ethanol was distilled off under reduced pressure. Water (280 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic layer was distilled off at 40 "C under reduced pressure. The thus obtained residue was crystallized from a mixture of methyl-iert-butyl ether and diisopropyl ether to give compound X (35.0g).

Reference： [1]Patent: WO2012/138981,2012,A2 .Location in patent: Page/Page column 82

38
[ 88756-83-6 ]
[ 274693-55-9 ]

Reference： [1]Patent: WO2012/142983,2012,A1
[2]Patent: WO2012/142983,2012,A1

39
[ 1392909-30-6 ]
[ 274693-55-9 ]

Reference： [1]Patent: WO2012/142983,2012,A1

40
[ 1392909-34-0 ]
[ 274693-55-9 ]

Reference： [1]Patent: WO2012/142983,2012,A1

41
[ 1416158-39-8 ]
[ 274693-55-9 ]

Yield	Reaction Conditions	Operation in experiment
		tert-Butyl [[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [<i][l,3]dioxol-4-yl]oxy]acetate free base (1 g, obtained above) was dissolved in dichloromethane (10 ml), followed by the addition of lithium borohydride (0.17 g) under nitrogen atmosphere. The resulting mixture was stirred for 24 hours at 20 to 25C. After completion of the reaction, acetic acid (1 ml) was added to the reaction mass, followed by stirring for 15 minutes. To the resulting solution was added solid potassium carbonate (1 g), followed by stirring for 30 minutes. The suspension was filtered and the solid cake was washed with dichloromethane (10 ml), followed by the evaporation of combined dichloromethane filtrate and washing under reduced pressure while maintaining the temperature at about 40C to obtain yellow oil which was further purified by column chromatography (silica gel 60-120 mesh, 10% methanol in dichloromethane) to obtain 0.7 g of pure 2-[[(3aR,45,,6R,6a5,)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][l,3]- dioxol-4-yl] oxy] - 1 -ethanol.
0.7 g	With lithium borohydride; In dichloromethane; at 20 - 25℃; for 24h;pH 10 - 10.5;Inert atmosphere;	tert-Butyl [[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta [d][1,3]dioxol-4-yl]oxy]acetate free base (1 g, obtained above) was dissolved in dichloromethane (10 ml), followed by the addition of lithium borohydride (0.17 g) under nitrogen atmosphere. The resulting mixture was stirred for 24 hours at 20 to 25 C. After completion of the reaction, acetic acid (1 ml) was added to the reaction mass, followed by stiffing for 15 minutes. To the resulting solution was added solid potassium carbonate (1 g), followed by stirring for 30 minutes. The suspension was filtered and the solid cake was washed with dichloromethane (10 ml), followed by the evaporation of combined dichloromethane filtrate and washing under reduced pressure while maintaining the temperature at about 40 C. to obtain yellow oil which was further purified by column chromatography (silica gel 60-120 mesh, 10% methanol in dichloromethane) to obtain 0.7 g of pure 2-[[(3aR,4S,6R,6aS)-6-Amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl]oxy]-1-ethanol.

Reference： [1]Patent: WO2012/172426,2012,A1 .Location in patent: Page/Page column 20
[2]Patent: US2014/206867,2014,A1 .Location in patent: Paragraph 0089

42
[ 274693-55-9 ]
[ 1444301-60-3 ]

Yield	Reaction Conditions	Operation in experiment
80%		AMALA was prepared according to the process described in WO01 /92263.A solution of AMALA (1 .0 g, 4.60 mmol) and 3 M HCI (5 m L) in MeOH (15 m L) was stirred at room temperature for 24 hours. Solvents were then evaporated to dryness. 2-Propanol (20 m L) and Na2C03 (2.0 g) was added to the residue. The resulting mixture was stirred at room temperature for 24 h. Insoluble salts were then filtered off and filtrate was concentrated to afford title compound as a colorless oil (0.57 g, 80% yield) : 1 H NMR (DMSO- ¾) 6 = 1 .07 (m, 1 H), 2.19 (m , 1 H), 2.87 (dd, J = 14.7, 7.8 Hz, 1 H), 3.00-3.60 (m , 10H), 3.53 (m , 1 H), 3.74 (dd, J = 5.4, 3.4, 1 H) ; 13C NMR (DMSO-d6) delta = 36.4, 55.0, 60.4, 70.7, 75.1 , 78.7, 83.3; MS (ESI) m/z: 178 [MH]+.
4.0 g	With hydrogenchloride; In methanol; water; at 10℃; for 11h;	Example 4 Preparation of (1 S,2S,3R,5S)-3-amino-5-(2-hydroxyethoxy)cyclopentane-l ,2-diol, Concentrated hydrochloric acid (3.3 ml) was dissolved in methanol (10 ml), then the mixture was added dropwise to a solution of 2-(((3aR,4S,6R,6aS) -6-amino- 2,2-dimethyltetrahydro-3aH-cyclopenta[d][l ,3]dioxol-4-yl)oxy)ethanol (prepared according to WO 01 /192263) (5.0 g) in methanol (10 ml), after the mixture was stirred for 11 hours at 10 C. the aqueous layer was separated, the organic layer was adjusted to pH 8.0 and extracted with Ethyl acetate three times, then combined the organic layers, concentrated under reduced pressure to obtain the title compound 4.0 g.

Reference： [1]Patent: WO2013/37942,2013,A1 .Location in patent: Page/Page column 37
[2]Patent: WO2013/163892,2013,A1 .Location in patent: Page/Page column 17

43
[ 274693-55-9 ]
[ 1451196-00-1 ]

Reference： [1]Patent: WO2013/37942,2013,A1

44
[ 274693-55-9 ]
[ 1451195-45-1 ]

Reference： [1]Patent: WO2013/37942,2013,A1

45
[ 274693-55-9 ]
[ 1427524-43-3 ]

Reference： [1]Patent: WO2013/37942,2013,A1

46
[ 274693-55-9 ]
2-(((3aS,4S,6R,6aS)-6-amino-2-methyltetrahydro-3aH-cyclopenta[d][1,3,2]dioxaborol-4-yl)oxy)ethanol [ No CAS ]

Reference： [1]Patent: WO2013/163892,2013,A1

47
[ 1444301-50-1 ]
[ 274693-55-9 ]

Yield	Reaction Conditions	Operation in experiment
63%	With palladium 10% on activated carbon; hydrogen; In methanol; at 40℃; under 7500.75 Torr; for 168h;	A mixture of (3aS,4R,6S,6aR)-N-benzyl-6-(2-(benzyloxy)ethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (XI', 56 g), methanol (2.2 L) and 10 % Pd/C (15 g) under 10 bar of hydrogen is stirred at 40 C for 7 days, the Pd/C is removed by filtration and methanol is removed under reduced pressure to give 19.32 g (63 %) of 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (XIV).

Reference： [1]Patent: EP2666771,2013,A1 .Location in patent: Paragraph 0088; 0089

48
[ 78341-96-5 ]
[ 274693-55-9 ]

Reference： [1]Patent: EP2666771,2013,A1

49
[ 155855-53-1 ]
[ 274693-55-9 ]

Reference： [1]Patent: EP2666771,2013,A1

50
[ 10257-32-6 ]
[ 274693-55-9 ]

Reference： [1]Patent: EP2666771,2013,A1
[2]Patent: EP2666771,2013,A1

51
(3aS,4R,6S,6aR)-N-benzyl-6-(2-(benzyloxy)ethoxy)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine fumarate salt [ No CAS ]
[ 274693-55-9 ]

Reference： [1]Patent: EP2666771,2013,A1

52
[ 1416158-40-1 ]
[ 274693-55-9 ]

Reference： [1]Patent: US2014/206867,2014,A1

53
[ 274693-55-9 ]
[ 4359-87-9 ]
2-(((3aR,4S,6R,6aS)-6-((2,6-dichloro-5-nitropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With sodium carbonate; In tetrahydrofuran; at 20℃; for 4h;	To a cooled and stirring solution of 4.5gm of <strong>[4359-87-9]2,4,6-trichloro-5-nitropyrimidine</strong> 31 in 40ml of THF and sodium carbonate, another solution of 4.3gm of 2- (((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopenta[d][l,3]dioxol-4-yl)oxyl)ethanol 11 in 25ml THF was added slowly, drop wise. The reaction mixture was slowly brought to room temperature and stirred for 3-4 hrs. The progress of reaction was monitored by TLC. The work-up involved removal of THF under reduced pressure, water addition to the residue and extracting in ethyl acetate. Concentration of ethyl acetate layer and usual purification gave 4.8gm of oily liquid 32 (59%), which gave a satisfactory mass of 408 in MS. Some of the selective and characteristic peak in NMR were 8.5delta (1H, d for N-H), 4.75 (1H, m), 4.6 (d, 1H), 4.47 (d, 1), 4.07 (m, 1 H), 3.75 - 3.9 (m, 4H), 2.28 (m, 1H), 1.85 (m, 1H), 1.4 (s, 3H), 1.2 (s, 3H).

Reference： [1]Patent: WO2015/162630,2015,A1 .Location in patent: Page/Page column 32-33

54
[ 274693-55-9 ]
2-(((3aR,4S,6R,6aS)-6-(5,7-dichloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol [ No CAS ]

Reference： [1]Patent: WO2015/162630,2015,A1
[2]Patent: US2016/102101,2016,A1

55
[ 274693-55-9 ]
2-(((3aR,4S,6R,6aS)-6-(5-chloro-7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol [ No CAS ]

Reference： [1]Patent: WO2015/162630,2015,A1
[2]Patent: US2016/102101,2016,A1

56
[ 274693-55-9 ]
2-(((3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol [ No CAS ]

Reference： [1]Patent: WO2015/162630,2015,A1

57
[ 274693-55-9 ]
C₁₄H₁₉N₅O₆ [ No CAS ]

Reference： [1]Patent: US2016/102101,2016,A1

58
[ 274693-55-9 ]
[3aR-(3aα, 4α,6α,6aα)]-[6-azido-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxane-4-oxy]ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.6%	With triflic azide; potassium carbonate; copper(II) sulfate; In acetonitrile; at 0 - 20℃; for 3h;Inert atmosphere;	2.17 g of [3aR-(3aalpha,4alpha,6alpha,6aalpha)]-6-amino-2,2-dimethyl-1,3-tetrahydro-cyclopenta-4H-dioxa cyclopentyl-4-ol (XI) (10 mmol), 2.76 g of potassium carbonate (20 mmol), 32 mg of copper sulfate (2% eq) and 25 mL of acetonitrile were added to a reaction flask, and added the solution of trifluoromethanesulfonyl azide (XII) (2.1 g, 12 mmol) in acetonitrile under 0 C. and nitrogen atmosphere, stirred at room temperature to react 3 hours, and the reaction ended with the TLC detection. The solution was concentrated under reduced pressure and the residue was recrystallized from n-hexane and ethyl acetate to get 2.25 g of [3aR-(3aalpha, 4alpha,6alpha,6aalpha)]-[6-azido-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxane-4-oxy]ethanol (IX), with a yield of 92.6%.

Reference： [1]Patent: US2016/102101,2016,A1 .Location in patent: Paragraph 0057

59
[ 274693-55-9 ]
ticagrelor [ No CAS ]

Reference： [1]Patent: CN105503876,2016,A

60
[ 274693-55-9 ]
2-(((3aR,4S,6R,6aS)-6-((5-amino-6-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-2-(propylmercapto)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-1-ethanol [ No CAS ]

Reference： [1]Patent: CN105503876,2016,A
[2]Patent: CN104059069,2016,B

61
[ 274693-55-9 ]
2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropane)amino)-5-(propylthio)-3H-[1,2,3]triazole[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)-1-ethanol [ No CAS ]

Reference： [1]Patent: CN105503876,2016,A

62
C₁₅H₁₉NO₃ [ No CAS ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106279095,2017,A

63
[ 36468-53-8 ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106279095,2017,A

64
[ 274693-55-9 ]
[ 87-69-4 ]
[ 376608-65-0 ]

Yield	Reaction Conditions	Operation in experiment
302.6 g	at 20 - 40℃; for 21h;	The temperature of the solution was raised to 40 C and 150 g of L-tartaric acid was added. The mixture was stirred at 40 C for 1h and then at 20 C 20h, precipitation of a large number of solid, filtration, filter cake with cold isopropyl alcohol (100ml) wash, 40 C vacuum drying 8h, you can get white powderL-tartaric acid salt of the compound X in the form of 302. 6g.

Reference： [1]Patent: CN106279095,2017,A .Location in patent: Paragraph 0050

65
[ 4099-85-8 ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106279095,2017,A

66
[ 4137-56-8 ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106279095,2017,A

67
[ 38838-06-1 ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106279095,2017,A

68
[ 274693-55-9 ]
9-[(1′R,2′S,3′S,4′S)-2′,3′-dihydroxy-4′-hydroxyethoxycyclopentane-1'-yl]-9H-2-propylthio-6-(3,4-difluorobenzaldehyde hydrazone)-8-azapurine [ No CAS ]

Reference： [1]Patent: CN107033146,2017,A
[2]Structural Chemistry,2018,vol. 29,p. 871 - 879

69
(1R,2S)-2-(3,4-difluorophenyl)cyclopropanamine [ No CAS ]
[ 274693-55-9 ]
C₈H₁₀ClN₅S [ No CAS ]
[ 274693-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In toluene; at 210℃; for 2h;	1 g (4 mmol) of 4,6-dichloro-2- (propylthio) -5-aminopyrimidine, 11.5 g (4 mmol) of NH2-R and 1.7 g (16 mmol) of triethylamine were added to a reaction flask,After stirring at 100 C for 12h under stirring, the mixture was cooled to room temperature and added with 30mL of water. Each was washed with ethyl acetate and saturated brine three times, and the solvent was removed by rotary evaporation to give Compound 5 as a pink powder.To 0.42 g (1 mmol) of compound 5, 10 mL of glacial acetic acid and 0.14 g (2 mmol) of sodium nitrite were added and refluxed for 3 hours at 100 C. After cooling to room temperature, ammonia water was added to neutrality, extracted with ethyl acetate and evaporated to dryness to give compound 6;To 0.45 g (1 mmol) of compound 6, 30 mL of toluene, 0.58 g (5 mmol) of potassium carbonate and 0.17 g (1 mmol) of NH2-R1 were added and refluxed at 210 C for 2 hours.Cooled to room temperature, filtered and the filtrate was evaporated to dryness to give compound 7; Compound 7 was refluxed in hydrochloric acid at 100 C for 2 hours to obtain the compound ticagrelor.

Reference： [1]Patent: CN107089984,2017,A .Location in patent: Paragraph 0041; 0051; 0060; 0069

70
C₁₇H₂₄N₂O₆ [ No CAS ]
[ 274693-55-9 ]

Yield	Reaction Conditions	Operation in experiment
91.5%	With palladium on activated charcoal; hydrogen; acetic acid; In methanol; at 20℃; for 14h;	The compound shown in Formula IV is 17.62 g (50 mmol), 2 g of Pd/C,Acetic acid (1ml) and methanol were added to the reactor.7 bar of hydrogen gas is introduced and the reaction is stirred at room temperature for 14 hours, filtered and concentrated.The petroleum ether is then recrystallized to form ticagrelor intermediate2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-Dimethyl-4H-cyclopenta-1,3-dioxa-4-yl]oxyethanol, 8.11 g,Yield 91.5%, HPLC purity 99.55% (area normalization method).

Reference： [1]Patent: CN106496180,2017,A .Location in patent: Paragraph 0054; 0055; 0056

71
[ 542-92-7 ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106496180,2017,A
[2]Patent: CN106496179,2017,A

72
C₁₂H₁₂N₂O₃ [ No CAS ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106496180,2017,A

73
C₁₂H₁₆N₂O₅ [ No CAS ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106496180,2017,A

74
C₁₇H₂₅NO₄ [ No CAS ]
[ 274693-55-9 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With palladium on activated charcoal; hydrogen; acetic acid; In methanol; at 20℃; under 3750.38 - 6000.6 Torr; for 10h;	Compound 30.74g (100 mmol), 2g Pd/C, acetic acid (1ml), shown in Formula IVMethanol is added into the reaction vessel, and hydrogen is fed at 5-8 bar, and the reaction is stirred at room temperature for 10 hours.Filtration, concentration, and then recrystallization of petroleum ether to intermediate ticagrelor2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxa-4-yl]oxyethanol 16.44 g,Yield 92.8%, HPLC purity 99.42% (area normalization method).

Reference： [1]Patent: CN106496179,2017,A .Location in patent: Paragraph 0056; 0057; 0058

75
C₁₂H₁₃NO [ No CAS ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106496179,2017,A

76
C₁₂H₁₇NO₃ [ No CAS ]
[ 274693-55-9 ]

Reference： [1]Patent: CN106496179,2017,A

77
[ 274693-55-9 ]
9-[(1′R,2′S,3′S,4′S)-2′,3′-dihydroxy-4′-hydroxyethoxycyclopentane-1'-yl]-9H-2-propylthio-6-(3-hydroxylbenzaldehyde hydrazone)-8-azapurine [ No CAS ]

Reference： [1]Structural Chemistry,2018,vol. 29,p. 871 - 879

78
[ 274693-55-9 ]
9-[(1′R,2′S,3′S,4′S)-2′,3′-dihydroxy-4′-hydroxyethoxycyclopentane-1'-yl]-9H-2-propylthio-6-(4-nitrobenzaldehyde hydrazone)-8-azapurine [ No CAS ]

Reference： [1]Structural Chemistry,2018,vol. 29,p. 871 - 879

79
[ 274693-55-9 ]
9-[(1′R,2′S,3′S,4′S)-2′,3′-dihydroxyl4′-hydroxyethoxycyclopentane-1'-yl]-9H-2-propylthio-6-(4-chlorobenzaldehyde hydrazone)-8-azapurine [ No CAS ]

Reference： [1]Structural Chemistry,2018,vol. 29,p. 871 - 879

80
[ 274693-55-9 ]
9-[(1’R,2’S,3’S,4’S)-2’,3’-dihydroxyl-4'-hydroxyethoxycyclopenta-1'-yl]-9H-2-thiopropyl-6-(3-nitrobenzaldehydehydrazone)-8-azepine [ No CAS ]

Reference： [1]Structural Chemistry,2018,vol. 29,p. 871 - 879

81
[ 274693-55-9 ]
[1S-[1a,2a,3β(1S*,2R*),5B]]-3-[7-[2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol [ No CAS ]

Reference： [1]Structural Chemistry,2018,vol. 29,p. 1663 - 1670

82
[ 274693-55-9 ]
2-({(3aR,4S,6R,6aS)-6-[7-[2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopentadiene[d][1,3]dioxolene-4-yl}oxy)ethanol [ No CAS ]

Reference： [1]Structural Chemistry,2018,vol. 29,p. 1663 - 1670

83
[ 59995-47-0 ]
[ 274693-55-9 ]

Reference： [1]Patent: CN108689984,2018,A

84
C₅H₈O₄ [ No CAS ]
[ 274693-55-9 ]

Reference： [1]Patent: CN108689984,2018,A

85
C₁₀H₁₆O₅ [ No CAS ]
[ 274693-55-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With hydrogenchloride; pyridoxal 5'-phosphate; isopropylamine; triethylamine; In water; at 25℃; for 16h;pH 8;Large scale; Enzymatic reaction;	At 25 C, the reaction solvent was added to the reaction vessel, and then the ammonia source was added.Adjust the pH to 8.0 with hydrochloric acid, then add PLP (pyridoxal phosphate,) and bioconversion enzymes (T68V, N76L, L213E, V302M, 4 positions of amino acids togetherReplace), slowly stir until all dissolved,Subsequently, the compound (5) was added and reacted for 16 hours. After the reaction was completed, the pH was adjusted to 2.0 with hydrochloric acid, and extracted with isopropyl acetate to leave an aqueous phase.The pH was adjusted to 12.0 with an aqueous sodium hydroxide solution, extracted with isopropyl acetate, and isopropyl acetate was concentrated under reduced pressure to give compound (1). The reaction solvent is water and dimethyl sulfoxide, and the volume ratio of the two is 1:1. The ammonia source was isopropylamine and triethylamine at a concentration of 0.5 M, and the molar ratio of the two was 1:1. The compound (5) was added to have an initial mass concentration of 100 g/L. The mass concentration ratio of the compound (5) and the bioconversion enzyme (T68V, N76L, L213E, V302M) was 35:1, the PLP was 0.1 times equivalent of the compound (5), and the mass concentration was 10 g/L. The obtained intermediate was examined by the method described above, and the mass yield of the compound 1 was 97%, and the purity by HPLC was 99.92%.

Reference： [1]Patent: CN108689984,2018,A .Location in patent: Paragraph 0032; 0043; 0044; 0045; 0052; 0057; 0062

86
[ 274693-55-9 ]
2-[[(3aR,4S,6R,6aS)-[6-[(1R,2S)2-(3,4-difluorophenyl)cyclopropylamine]-5-nitro-2-propylthiopyrimidine-4-amino]tetrahydro-2,2-dimethyl-4H-cyclopenteno-1,3-dioxolan-4-yl]oxy]ethanol [ No CAS ]

Reference： [1]Patent: CN104059069,2016,B

87
[ 274693-55-9 ]
[ 924-44-7 ]
[ 121-69-7 ]
ethyl-2-(4-(dimethylamino)phenyl)-2-(((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)amino)acetate [ No CAS ]
ethyl-2-(4-(dimethylamino)phenyl)-2-(((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)amino)acetate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 16528 - 16532

88
[ 274693-55-9 ]
[ 91322-00-8 ]
2-(((3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With triethylamine at 110℃; Sealed tube;	4.14 2-(((3aR,4S,6R,6aS)-6-((5-amino-2,6-dichloropyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (13a.2) The mixture of 2,4,6-trichloropyrimidin-5-amine 12a (1.0g, 5.0mmol), 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethanol (1.4g, 6.4mmol) and triethylamine (0.7mL, 5.0mmol) in acetonitrile (10mL) was placed in a sealed vessel and heated overnight at 110°C. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using 100% ethyl acetate to give 13a.2 as an oily residue (1.59g, 83% yield). 1H NMR (DMSO-d6): δ 1.23 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.86 (d, J=14.0Hz, 1H, 5′-Ha), 2.22 (m, 1H, 5‘-Hb), 3.51 (m, 4H, OCH2CH2OH), 3.90 (s, 1H, 4’-H), 4.30 (s, 1H, 6′-H), 4.50 (s, 1H, 6a′-H), 4.54 (s, 1H, 3a′-H), 5.04 (s, 1H, OCH2CH2OH), 5.17 (s, 2H, NH2), 6.83 (d, J=6.7Hz, 1H, NH). 13C NMR (DMSO-d6): δ 24.1, 26.3, 32.9, 56.6, 60.3, 70.3, 83.2, 83.5, 83.9, 110.2, 112.8, 136.5, 144.6, 152.7.

Reference： [1]Goffin, Eric; Jacques, Nicolas; Lancellotti, Patrizio; Musumeci, Lucia; Nchimi, Alain; Pirotte, Bernard; Oury, Cécile [European Journal of Medicinal Chemistry, 2020, vol. 208]

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Precautionary Statements-General
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Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P222	Do not allow contact with air.
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P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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P285	In case of inadequate ventilation wear respiratory protection.
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Response
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P321
P322
P330	Rinse mouth.
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P337	If eye irritation persists:
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P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
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P378
P380	Evacuate area.
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P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
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P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
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P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
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P337 + P313	IF eye irritation persists: Get medical advice/attention.
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Disposal
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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
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H221	Flammable gas
H222	Extremely flammable aerosol
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H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
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H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
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H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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[ 274693-55-9 ] Synthesis Path-Upstream 1~1

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