[ CAS No. 147118-40-9 ] {[proInfo.proName]}

Name: 147118-40-9|Methyl (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate|95%
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Product Details of [ 147118-40-9 ]

CAS No. :	147118-40-9	MDL No. :	MFCD12756002
Formula :	C₂₃H₃₀FN₃O₆S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SUTPUCLJAVPJRS-NDZBKKTDSA-N
M.W :	495.56	Pubchem ID :	25183331
Synonyms :

Safety of [ 147118-40-9 ]

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
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Application In Synthesis of [ 147118-40-9 ]

* 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.

Downstream synthetic route of [ 147118-40-9 ]

[ 147118-40-9 ] Synthesis Path-Downstream 1~55

1
[ 147118-39-6 ]
[ 147118-40-9 ]

Yield	Reaction Conditions	Operation in experiment
85.2%		To a solution of 13g of the compound of Formula V in 350 ml of anhydrous tetrahydrofuran and 90ml of methanol, was added a solution of 13 ml of 1M diethylmethoxyborane in tetrahydrufuran at-78 C, and the mixture was stirred at the same temperature for 30 minutes. To the mixture, was added 1.3g of a sodium borohydride and the mixture was stirred for another 3 hours. Acetic acid (16ml) was added thereto, and the mixture was adjusted to pH 8 with saturated sodium bicarbonate and extracted with ether. The organic layer was washed with water, dried and evaporated ether under reduced pressure. To the resulting residue, methanol was added and the mixture was evaporated under reduced pressure. The resulting residue was subjected to column chromatography of silica gel eluting with methylene chloride/ether (3: 1) to give 11. 4g of dihydroxy compound, methyl 7- [4-fluorophenyl)-6-isopropyl-2- (N-methyl-N- methylsulphonylamino) pyrimidin-5-yl]- (3R, 5S)-dihydroxy- (E)-6-heptenate (VI) as syrup. Yield: 85. 2percent
85.2%		(5); To a solution of 13 g of compound iii in 350 mL of anhydrous THF and 90 mL of methanol, a solution of 29.7 mL of 1 M diethylmethoxyborane-THF is added at -78°C. The mixture is stirred at the same temperature for 30 minutes. NaBIL; (1.3 g) is added and the mixture is stirred for 3 hours. Acetic acid (16 mL) is added thereto, and the mixture is adjusted to pH 8 with saturated sodium bicarbonate and extracted with ether. The organic layer is washed with water, dried, and the ether is evaporated under reduced pressure. Methanol is added to the resulting residue and the mixture is evaporated three times under reduced pressure. The resulting residue is subjected to column chromatography on silica gel, eluting with methylene chloride/ether (3/1) to give 11.4 g (Yield: 85.2percent) of methyl 7-[4-(4-fluorophenyl)-6-iso-propyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (compound iv) as a syrup.
		Example-4Preparation of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)-pyrimidin-5-yl1-(3R,5S)-dihvdroxy -(E)-6-heptenate (Compound-Q Coinpound-CTetrahydrofuran (1800 ml) was taken in a flask and cooled to -90 °C. To this sodiumborohydride (10 g) and diethyl methoxyborane (1.0 M solution in THF) was added and maintained for 30 minutes. To this reaction mixture, solution of methyl 7-[4- (4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R) -3-hydroxy-5-oxo-(E)-6-heptenate (Compound A) (100.0 g Compound A dissolved in 700 ml THF and 700 ml methanol) was slowly added and maintained at a temperature - 90 0C for 2-3 hours. Acetic acid was added to the reaction mass and the temperature was raised to room temperature. To this reaction mass, a mixture of ethyl acetate and water was added. Organic layer was washed with brine solution and dried over sodium sulfate. Methanol was added to the residue and evaporated to yield methyl 7-[4-(4-flourophenyl)- 6-isopropyl:2-(N-methyl-N-methylsuIfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy- (E)--heptenate

	With methanol; sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; at -90 - -80℃;Inert atmosphere;Product distribution / selectivity;	In a round bottom flask 2000 ml Tetrahydrofuran (THF) was added under the nitrogen atmosphere and cooled to -90°C then 1Og sodium borohydride was added followed by 230ml diethylmethoxyborane (1 M solution in THF) in 90-120mins. In this reaction mass, mixture of lOOg of Methyl -7-[4-(4-fiourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylaniino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate5 700 ml THF and 700 ml methanol was added for a duration of 90-120min then stirred for 2 hrs at -90 to -80°C. After the completion of reaction, 124 ml acetic acid was added and stirred for 30-60 min at same temperature. Above reaction mass was diluted with 1500ml ethyl acetate and washed with brine solution. To the organic layer, 500 ml DM water was added and pH was adjusted to neutral by ~ 500 ml 6 percent sodium bicarbonate solution. Both the layers were separated Sc the organic layer was dried over sodium sulphate. The organic layer was concentrated at 40-450C. Above concentrated mass was diluted with 900ml ethyl alcohol and then cooled to 0°C. Sodium hydroxide solution was added in 60- 90 min. The reaction mass was stirred for 30 min at room temperature and the pH was adjusted to 11.5-12.0 by using ~ 4 percent sodium hydroxide solution. In this reaction mass, 1Og activated carbon was added and stirred for 20 min. The reaction mass was filtered and washed with ethanol/DM water mixture. The reaction mass was concentrated up to thick residue at 40-45°C. To this concentrated mass, 500 ml DM water was added followed by 1000ml ethyl acetate and the pH was adjusted to 3.5- 4.0 with 1:4 aqueous hydrochloric acid. Both the layers were separated and the organic layer was washed with brine solution.The organic layer was dried over sodium sulphate and concentrated till dryness at 40-45°C. To the above concentrated mass, 1000 ml acetonitrile was added stirred at room temperature for half an hour. Slowly 20.5 g (S)-2-amino-3, 3 -dimethyl butane was added and stirred for almost 2 hrs. The solid was filtered and washed with acetonitrile and diisopropyl ether. Finally the solid was dried for 6-9 hrs at 40-45°C.Above obtained (S)-2-amino-3, 3 -dimethyl butane salt of rosuvastatin was suspended in 1000 ml isopropanol followed by 100 ml methanol. This reaction mass was heated for half an hour at 60-80°C then stirred for 3-4 hrs at 5-1O0C. The solid was filtered washed with isopropanol and diisopropyl ether. 95 gms of (S)-2-amino-3, 3 -dimethyl butane salt of rosuvastatin was obtained.
		The synthetic route is shown in flow diagram 3:The detailed preparing process is as follows:300mL anhydrous THF, 85mL anhydrous methanol and 6.3g (3R,6E)-7-[4-(4-flurophenyl)-6-(1-methylethyl)-2-[methyl (methyl sulfonyl) amino]-5-pyrimidyl]-3-hydroxy-5-oxo-6-methyl heptenoate were added to a 500mL reaction flask.Subsequently, the reaction system was flushed with N2, and the mixture was stirred until the solid was dissolved.The reaction mixture was cooled to -85°C by using liquid nitrogen, and 12.8mL THF solution containing 1M diethyl methoxyl borane was added at constant speed at -85°C within 30 minutes.The mixture was stirred for 60 minutes at -85°C, subsequently, 0.7g sodium borohydride was uniformly added in several portions.The addition process took about 90 minutes, and then the mixture was allowed to stand at -85°C for 6 hours.The temperature of the mixture was increased to 30°C within 2 hours and the reaction lasted for 3 hours at 30°C.Subsequently, 1.2g glacial acetic acid was added, and the obtained solution was vacuum distilled to remove mixed solvent containing methanol-THF at 50°C. As a result, oily product was obtained.50mL methanol was added to dissolve the oily product.The obtained solution was vacuum distilled to remove methanol at 50°C.Then 50mL methanol was added to dissolve the oily product, the obtained solution was vacuum distilled to remove methanol at 50°C, and the obtained oily product remained in the reaction flask.Afterwards, 50mL ethyl acetate and 50mL water were added to the reaction flask and stirred for 15 minutes, subsequently, the mixture was allowed to stand for layering.The obtained water phase was extracted twice with ethyl acetate (30mL each time), where the water phase was stirred for 15 minutes during each extraction, and the obtained mixture was allowed to stand for layering.Then the organic phases were combined and washed with saturated sodium bicarbonate solution (40mL).Subsequently, the obtained mixture was washed twice with saturated sodium chloride solution (40mL each time), where the solution was stirred for 15 minutes during each washing.It was then allowed to stand for layering.The water phase was removed, while 2g anhydrous sodium sulfate was added to the organic phase and stirred for 30 minutes.Then anhydrous sodium sulfate was removed by pumping filtration.The filtrate was vacuum distilled to remove ethyl acetate at 50°C.As a result, 6.0g oily (3R,5S,6E)-7-[4-(4-flurophenyl)-6-(1-methyl ethyl)-2-[methyl (methyl sulfonyl) amino]-5-pyrimidyl]-3,5-dihydroxy-6-methyl heptenoate was obtained, and could directly be used in the next step.; Example 8. Preparation of crystalline (3R, 5S, 6E)-7-[4-(4-flurophenyl)-6-(1-methyl ethyl)-2-[methyl (methyl sulfonyl) amino]-5-pyrimidyl]-3, 5-dihydroxy-6-heptenoic-3-methyl butyrate (crystal form I)After 80mL ethyl ether and 1.5mL acetonitrile was added to 10g (3R,5S,6E)-7-[4-(4-flurophenyl)-6-(1-methyl ethyl)-2-[methyl (methyl sulfonyl) amino]-5-pyrimidyl]-3,5-dihydroxy-6-heptenoic-3-methyl butyrate. The mixture was heated until the mixture was fully dissolved, then it was cooled to 0-5°C and devitrified for 24 hours. As a result, 7.7g crystalline solid was obtained with a yield of 77percent. The XRD spectrum is shown in Figure 5.
	With methanol; sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; at -90 - -80℃; for 6h;Inert atmosphere;	Example 3Preparation of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-iV- methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(.pound.)-6-heptenate (VI)A mixture of tetrahydrofuran (800 ml) and methanol (200 ml) was cooled to -90 ° to - 75°C under nitrogen atmosphere. Sodium borohydride (7.7g) was added and the reaction mass was stirred for 30 minutes at the same temperature under nitrogen atmosphere. Diethylmethoxyborane (100 ml) was added to the resulting reaction mixture and was stirred for few minutes at same temperature. Methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3 ?)-3-hydroxy-5-oxo-(E)-6- heptenate (lOOg) taken in a mixture of tetrahydrofuran (800 ml) and methanol (200 ml), was added to the reaction mixture over a period of 4.0 hour at -90° to -80°C under nitrogen atmosphere. The reaction mass was stirred for 2.0 hours at -90° to -80°C. After the reaction completion, the temperature of reaction mass was raised to 0°C and then to room temperature. The pH of the resulting mixture was adjusted to 9.0-9.5 using 5percent aqueous acetic acid solution. To the resulting mixture, water (200 ml) and methyl tertiary butyl ether (500 ml) were added and was stirred for few minutes. The organic layer was separated, and concentrated under vacuum at 45-50°C to obtain the title compound as thick oily mass.
	With sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; methanol; at -105 - 95℃;Product distribution / selectivity;	Sodium borohydride (3.2g) was added to a cold solution of tetrahydrofuran (130 ml) and methanol (30 ml) at -105°C to -95°C, followed by addition of diethylmethoxyborane (28ml, 1M in THF). Thereafter, a solution of 7-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl- methyl-amino)-pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoic acid methyl ester (20 g) in tetrahydrofuran (30 ml) and methanol (10 ml) was added to above reaction mass at -105°C to -95°C. After completion of reaction, acetic acid (15.4 ml) was added to the reaction mass and temperature of reaction mass was raised to 20-25 °C. Solvents were distilled off completely under vacuum from the reaction mixture. Methanol (40 ml) was added to resulting residue and distilled out. Water (100 ml) was added to resulting residue followed by extraction of product with ethyl acetate (100 ml). Organic layer was washed with saturated solution of sodium bicarbonate and then with saturated sodium chloride solution. Resulting organic layer was concentrated under vacuum to give 22 g of title compound having purity 94.93 percent; and anti-isomer- 0.96 percent by HPLC.
10.7 g	With sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; methanol; at -78 - -75℃; for 1.5h;	at -78°C internal reactor temperature, tetrahydrofuran (THF) and 80 mL in a mixed solution of 20 mL of methanol was added NaBH4 (sodium borohydride) 1 g (1.3 eq) was added thereto. After 15 minutes, 50percent Et2BOMe in THF solution (diethyl-methoxy-borane, DEMB) was added dropwise 2.53 mL (0.5 eq). Dissolving the compound of formula g 10 (0.02 mol, 99.1percent purity) in 20 mL THF, was slowly added dropwise thereto for about one hour while maintaining the reactor internal temperature of -78 ~ -75°C. After the dropwise addition the internal temperature was stirred for 30 minutes at -78 ~ -75°C. After the slow dropwise addition of 10 mL 35percent aqueous hydrogen peroxide solution to the reaction solution was heated to an internal temperature of 0 .150 mL of ethyl acetate and 100 mL of purified water was added to the reaction solution and extraction. To remove the water layer and 10percent NaHCO3aqueous solution 100 mL, 10percent Na2SO3was washed with 100 mL aqueous solution and the organic layer was washed in turn with 10percent NaCl solution 100 mL. and concentrated in vacuo at 45 ~ 50°C the organic layer to give the compound formula III (R= Me ) and 10.7 g was obtained yellow oil with an HPLC purity of 98.5percent.
6 g		rous methanol 85 ml, 6.3 g TP-13 was added and the reaction was purged with nitrogen and stirred until all the TP-13 was dissolved.Cooled to -80 ° C to -85 ° C with liquid nitrogen and 12.8 ml of a tetrahydrofuran solution of 1 M diethylmethoxyborane was added dropwise to control the rate of dropping to keep the temperature from -80 ° C to -85 ° C And the dropping time is about 30 min.Maintain the temperature between -80 ~ -85 , continue stirring 55 ~ 60min.And then evenly add 0.7 g sodium borohydride, about 80 ~ 90min after adding, to maintain the temperature between -80 ~ -85 , this process requires 5.5 ~ 6h, the end of the reaction.And then heated to 20 ° C to 30 ° C in 2 hours. After 2 to 3 hours of continuous incubation, 1.2 g of glacial acetic acid was added, followed by distillation under reduced pressure at 45 ° C to 55 ° C to remove the organic solvent mixed with methanol and tetrahydrofuran to give an oil Things.After adding 50 ml of methanol to dissolve the oil, it was distilled under reduced pressure at 45 ° C to 55 ° C to remove methanol to obtain an oil.The mixture was further added with 50 ml of methanol to dissolve the oil and distilled under reduced pressure at 45 ° C to 55 ° C to remove methanol to give the final oil.Then, 50 ml of ethyl acetate and 50 ml of water were added to the final oil, and the mixture was stirred for 10 to 15 minutes. The mixture was allowed to stand and the aqueous layer was repeatedly extracted twice with ethyl acetate. Each time, 30 ml of acetic acid Ethyl ester, each time for 10 to 15 minutes, static liquid separation, and finally the organic layer.The resulting organic layer was washed successively with 40 ml of a saturated aqueous solution of sodium bicarbonate and twice with a saturated aqueous solution of sodium chloride, each time with an amount of 40 ml of a desaturated sodium chloride aqueous solution, and the mixture was stirred for 10 to 15 minutes Set the liquid, discard the water layer.The organic layer was added with 2 g of anhydrous sodium sulfate, stirred for 30 min, and the anhydrous sodium sulfate was removed by suction filtration. The filtrate was distilled at a temperature of 40 ° C to 50 ° C under reduced pressure to remove the ethyl acetate organic solvent to obtain 6.0 g of RSM oil
15.8 g	With methanol; sodium tetrahydroborate; diethyl methoxy borane; In tetrahydrofuran; at -80 - 25℃; for 8.5h;Inert atmosphere;	S3: Under nitrogen protection, 110 g of tetrahydrofuran and 27.5 g of methanol were added to the reaction flask, the temperature was lowered to -80 ± 5 ° C, 3.19 g of sodium borohydride was added, and the mixture was stirred for 15 minutes, and the temperature was controlled to -80 ± 5 ° C, and 49.5 g was added dropwise. The solution of percentEt2BOMe in tetrahydrofuran was diluted for 1 h. After the end of the incubation, 15.84 g of the S2 product in tetrahydrofuran solution was added dropwise, and the dropping temperature was controlled to -80 ± 5 ° C. After 4 h, the temperature was raised to 4.5 h and the temperature was raised to 20-25 ° C, then adjusted with glacial acetic acid PH = 6.0-7.0, stirred for 30 minutes, re-test PH = 6.0-7.0 qualified, concentrated to dryness under reduced pressure, the end of concentration, then add ethyl acetate and water to stir and dissolve The mixture was allowed to stand for stratification, and the water layer was discarded. The organic layer was washed once with saturated brine, and the organic layer was collected. The organic layer was concentrated at 45 ° C to give an oil (3R, 5S)-7-[4-(4-fluorobenzene) Methyl-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid methyl ester 15.8 g ;

Reference： [1]Patent: WO2003/97614,2003,A2 .Location in patent: Page/Page column 8; 13
[2]Patent: WO2006/17357,2006,A1 .Location in patent: Page/Page column 16
[3]Bioorganic and Medicinal Chemistry,1997,vol. 5,p. 437 - 444
[4]Patent: WO2009/128091,2009,A2 .Location in patent: Page/Page column 9
[5]Patent: WO2010/35284,2010,A2 .Location in patent: Page/Page column 8-9
[6]Patent: EP2298745,2011,A1 .Location in patent: Page/Page column 16; 19
[7]Patent: WO2012/63115,2012,A2 .Location in patent: Page/Page column 17-18
[8]Patent: WO2012/176218,2012,A1 .Location in patent: Page/Page column 20-21
[9]Patent: KR2016/8026,2016,A .Location in patent: Paragraph 0038; 0039
[10]Patent: CN104230817,2016,B .Location in patent: Paragraph 0047 - 0050
[11]Patent: CN108586358,2018,A .Location in patent: Paragraph 0034; 0042; 0046; 0050

2
[ 147118-40-9 ]
rosuvastatin sodium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.0%	With sodium hydroxide; ethanol; water; at 0 - 20℃; for 1h;	(6) To a solution of 11.4 g of compound iv in 160 mL of ethanol, sodium hydroxide (0.1 N, 223 mL) is added under ice-cooling. The reaction mixture is warmed to room temperature and stirred for 1 hour. The solvent is distilled off under reduced pressure, and ether is added to the resulting residue. The mixture is stirred to give 11.0 g (Yield: 95.0percent) of compound v as powdery crystals.
	With sodium hydroxide; In ethanol; at 20℃; for 1h;	To a solution of 11.4g of the compound of Formula VI in 160ml of ethanol, was added 1 OOml of 0.25 N sodium hydroxide under ice-cooling. The reaction mixture was warmed to room temperature and stirred for 1 hour. The solution was concentrated to remove the organic solvent under vacuum at 35 C-40 C. The aqueous layer was washed with methyl tertiary butyl ether (MTBE) (500x2ml) twice and filtered through a hyflo bed. The aqueous layer was used as such in the next step.
	With water; sodium hydroxide; In ethanol; at 0 - 20℃;	Example-5Preparation of Rosuvastatin Sodium <n="11"/> Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)- pyrimidin-5-yl]-(3R,5S)-dihydroxy -(E)--heptenate (100 g ) was added to ethyl alcohol (900 ml). To this aqueous sodium hydroxide (8.0 g sodium hydroxide dissolved in 500 ml of water) was added at a temperature of 0-5 °C. The reaction mixture was heated to room temperature and maintained for 1-2 hours. After completion of the reaction, the reaction mass was concentrated and ethyl alcohol was added and the reaction mass was distilled off azeotropically. To the obtained residue diisopropyl ether was added and stirred for lhour and filtered. The filtered solid was dried to yield Rosuvastatin sodium.

19 g

With sodium hydroxide; In water; acetonitrile; at 35 - 40℃;

Add 150 ml of acetonitrile to the 500 ml reaction flask and add 18.0 g of RSM. After completely dissolving, 40 ml of purified water was added and heated to 35 ° C to 40 ° C. 42 ml of 1N sodium hydroxide solution was added dropwise to control the dropping rate Keep the temperature between 35 ~ 40 , the entire drop process takes about 10 ~ 15min, continue to react and then need 2 to 2.5 hours.The reaction was completed at 40 ° C to 50 ° C under reduced pressure to remove the acetonitrile organic solvent and then 30 ml of purified water was added to open the jacketed cooling water to lower the temperature of the contents to 25 ° C to 30 ° C and washed with ether 3 times, each with ether 50 ml, each stirring 10 ~ 15min, static liquid separation, collecting water layer.Then add 3 g of activated carbon in the water layer, heating to maintain the temperature 35 ~ 40 , stirring 50 ~ 60min, filter, filter with 10 ml of purified water filter cake, combined filtrate and lotion, the filtrate was vacuum distillation RSA 19.0 g

Reference： [1]Bioorganic and Medicinal Chemistry,1997,vol. 5,p. 437 - 444
[2]Patent: WO2006/17357,2006,A1 .Location in patent: Page/Page column 16
[3]Patent: WO2003/97614,2003,A2 .Location in patent: Page/Page column 8; 14
[4]Patent: WO2009/128091,2009,A2 .Location in patent: Page/Page column 9-10
[5]Patent: CN104230817,2016,B .Location in patent: Paragraph 0051 - 0053

3
[ 67-64-1 ]
[ 147118-40-9 ]
[ 851440-19-2 ]

Yield	Reaction Conditions	Operation in experiment
		Example 3 Methyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)ainino]- rhoyrimidin-5-yl]vmyl](4i?,65)-2,2-dimethyl-[l,3]dioxan-4-yl)-acetate IX; Methyl ester IX (1.07 g) was dissolved in acetone (5.5 ml) and dimethoxypropane (5.5 ml). P- toluenesulfonic acid (0.1 g) was then added, and the mixture was stirred at room temperature for 1.5 hours. Then, alkalization with triethylamine (0.12 ml) was carried out, and the solution was evaporated. After adding ethyl acetate (60 ml), the mixture was shaken with water (2 x 8 ml). The organic layer was dried with Na2SO4 and evaporated. The crude product was crystallized from isopropyl alcohol. 0.88 g of white crystals of acetonide IX was obtained, which were recrystallized from isopropyl alcohol.1H NMR (CDCl3) delta: 7.62 (m, 2H); 7.08 (m, 2H); 6.52 (dd, IH, //=16.21, /2=1.30); 5.45 (dd, IH, //=16.23, J2=5.36); 4.45 (m, IH); 4.35 (m, IH); 3.70 (s, 3H); 3.56 (s, 3H); 3.51 (s, 3H); 3.37 (sept, IH, /=6.68); 2.56 (dd, IH, //=15.68, J2=6.71); 2.38 (dd, IH, //=15.69, /2=6.39); 1.49 (s, 3H); 1.40 (s, 3H); 1.68 (m, IH); 1.27 (d, 3H, J=6.69); 1.23 (d, 3H, J=6.66).

Reference： [1]Patent: WO2007/121,2007,A1 .Location in patent: Page/Page column 10

4
[ 1310-73-2 ]
[ 147118-40-9 ]
rosuvastatin sodium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ethanol; water; at 25 - 30℃; for 1h;Product distribution / selectivity;	PREPARATION OF ROSUVASTATIN CALCIUM FOLLOWING THE PROCEDURE REPORTED IN THE US PATENT No RE 37,314Ethanolic solution of <strong>[147118-40-9]rosuvastatin methyl ester</strong> (5.53 g in ethanol (78 ml) was treated with aqueous solution of sodium hydroxide (0.1N, 100 ml) at cold temperature and the resulting solution was warmed to 25-30 0C and stirred at this temperature for lhr. Ethanol was evaporated under vacuum at 40-45 0C and the resulting aqueous layer <n="11"/>was washed twice with a mixture of 30percent v/v ethyl acetate/toluene (50 ml). The resulting rosuvastatin sodium solution was concentrated and treated with aqueous solution of calcium chloride (1 N, 10 ml). The resulting mass was stirred for 2 hrs, filtered, washed with DM water and dried under vacuum at 35-40 0C. Dry Wt. 3.2 g, Chromatographic purity (HPLC): 97.05 percent

Reference： [1]Patent: WO2008/38132,2008,A1 .Location in patent: Page/Page column 9-10

5
[ 147118-40-9 ]
[ 287714-41-4 ]

Yield	Reaction Conditions	Operation in experiment
		In a round bottom flask 2000 ml Tetrahydrofuran (THF) was added under the nitrogen atmosphere and cooled to -90°C then 1Og sodium borohydride was added followed by 230ml diethylmethoxyborane (1 M solution in THF) in 90-120mins. In this reaction mass, mixture of lOOg of Methyl -7-[4-(4-fiourophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylaniino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate5 700 ml THF and 700 ml methanol was added for a duration of 90-120min then stirred for 2 hrs at -90 to -80°C. After the completion of reaction, 124 ml acetic acid was added and stirred for 30-60 min at same temperature. Above reaction mass was diluted with 1500ml ethyl acetate and washed with brine solution. To the organic layer, 500 ml DM water was added and pH was adjusted to neutral by ~ 500 ml 6 percent sodium bicarbonate solution. Both the layers were separated Sc the organic layer was dried over sodium sulphate. The organic layer was concentrated at 40-450C. Above concentrated mass was diluted with 900ml ethyl alcohol and then cooled to 0°C. Sodium hydroxide solution was added in 60- 90 min. The reaction mass was stirred for 30 min at room temperature and the pH was adjusted to 11.5-12.0 by using ~ 4 percent sodium hydroxide solution. In this reaction mass, 1Og activated carbon was added and stirred for 20 min. The reaction mass was filtered and washed with ethanol/DM water mixture. The reaction mass was concentrated up to thick residue at 40-45°C. To this concentrated mass, 500 ml DM water was added followed by 1000ml ethyl acetate and the pH was adjusted to 3.5- 4.0 with 1:4 aqueous hydrochloric acid. Both the layers were separated and the organic layer was washed with brine solution.The organic layer was dried over sodium sulphate and concentrated till dryness at 40-45°C. To the above concentrated mass, 1000 ml acetonitrile was added stirred at room temperature for half an hour. Slowly 20.5 g (S)-2-amino-3, 3 -dimethyl butane was added and stirred for almost 2 hrs. The solid was filtered and washed with acetonitrile and diisopropyl ether. Finally the solid was dried for 6-9 hrs at 40-45°C.Above obtained (S)-2-amino-3, 3 -dimethyl butane salt of rosuvastatin was suspended in 1000 ml isopropanol followed by 100 ml methanol. This reaction mass was heated for half an hour at 60-80°C then stirred for 3-4 hrs at 5-1O0C. The solid was filtered washed with isopropanol and diisopropyl ether. 95 gms of (S)-2-amino-3, 3 -dimethyl butane salt of rosuvastatin was obtained.
		Example 1-4Rosuvastatin free acid solutionRosuvastatin methyl ester (100 g) was dissolved in ethanol (2000 mL) , and while stirring at 0 0C sodium hydroxide aqueous solution (0.1 M, 2000 mL) was added dropwise. After stirring at 0 0C for 30 min, stirring was continued at room temperature for 1 h. The mixture was concentrated to ~ 1000 mL . Isopropyl acetate (2000 mL) was added, and hydrochloric acid (1 M, 200 mL) was added under vigorous stirring. After stirring for 1 h, the phases were separated and the organic phase was dried with azeotropic distillation.
		EXAMPLE 1; PREPARATION OF N,N'-DIBENZYLETHYLENEDIAMINE ROSUVASTATIN SALT; Rosuvastatin methyl ester (1 g) was dissolved in acetonitrile (15 ml) at 25-300C, and cooled to 0-50C. To this cooled solution, aqueous sodium hydroxide (0. IN, 20 ml) was added at 0-50C for 15 min and the temperature of the resulting solution was raised to 25-300C in 1 hr. After completion of the reaction, acetonitrile was evaporated under reduced pressure at 40-450C. The resulting reaction mass was diluted with DM water (15 ml) and washed with 30percent v/v ethyl actetate/toluene (50 ml) at 25-300C. The aqueous layer was treated with an aqueous hydrochloric acid (0.1N, 20 ml) at 0-50C. The resulting solution containing rosuvastatin acid was treated with an aqueous solution of N,N'-dibenzylethylenediamine diacetate (0.9 g in 5 ml DM water) at 24-3O0C and stirred for 2 h for complete precipitation of N5N1- dibenzylethylenediamine rosuvastatin salt. The off-white N5N1- dibenzylethylenediamine rosuvastatin salt was filtered and washed with DM water. This wet salt was slurry washed with ethyl acetate (5 ml) at 25-300C and dried under vacuum at 40-450C. Dry Wt. 0.3 g, Chromatographic purity (HPLC): 99.79, Anti isomer: 0.21percent.1HNMR (DMSO-d6): 1.2 (d, 6H5 J=6.6 Hz, (CHjS)2CH)), 1.39-1.52(m, 2H, CH2CHOH)5 2.19-2.27(m, 2H5 CH2COOH)5 2.6(s, 2H5 CH2NH2+CH2Ar)5 3.46(s, 3H, NCH3), 3.55(s, 3H, CH3SO2N), 3.45(m, IH5 (CH3)2CH), 3.72(s, 2H5 CH2Ar)5 3.82(m, <n="12"/>IH, CHOH), 4.2(m,lH, CHOH), 5.50-5.57( dd, IH, J=16.2 Hz, 5.7Hz, =CHCHOH), 6.5(d, IH, J= 16.2Hz, CH=CHCHOH), 7.25(m, 7H, ArH), 7.72(m, 2H, ArH).

		Tentative Example 3 Preparation of 2-((4/?,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropmethylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimet^^ 4-methylpentan-2-yl ester from N-(4-(4-fluorophenyl)-5-formyl-6- isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (D) and 2-((4 ?,6S)-6- ((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate 4- methylpentan-2-yl esterThe 4-methylpentan-2-yl ester of compound (5a) with is a radical of formula (D), R3 and R4 are both methyl and R5 is 4-methylpentan-2-yl can be prepared according to the same procedures as outlined in Example 3 starting from 2-((4f?,6S)-6-((benzo[d]thiazol- 2-ylsulfonyl)methyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate 4-methylpentan-2-yl ester instead of the corresponding sec-butyl ester using the same molar amount.For reference purposes 2-((4f?,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate 4- methylpentan-2-yl ester was prepared from rosuvastatin methyl ester (EP 521471). Thus, rosuvastatin methyl ester (30 g, 61 mmol) was added to 200 mL of acetonitrile and 2N aqueous NaOH was added until the pH was stable at 12.5. The reaction mixture was stirred for 2 h at 20°C. Then the pH was lowered to 5.0 with 2N aqueous HCI. To the reaction mixture was added 200 mL of ethyl acetate and the organic phase was separated and washed 2 times with 100 mL of water. The ethyl acetate phase was dried over Na2S04, filtered and evaporated to a sirup (" 30 g of rosuvastatin acid). Part of this sirup (20 g) was dissolved in toluene and heated to reflux under azeotropic water removal for 4 h. The reaction mixture was cooled to 20°C and stirred for 18h. The precipitated solid was filtered, washed with toluene (2 x 10 mL) and dried to give 16.1 g (35 m mol) of N-(4-(4-fluorophenyl)-5-((E)-2-((2S,4 )-4-hydroxy-6-oxotetrahydro-2H- pyran-2-yl)vinyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as a white solid. 1 H NMR (300 MHz, CDCI3) delta 7.62 (dd, 2H), 7.1 1 (dd, 2H), 6.72 (dd, 1 H), 5.48 (dd, 1 H), 5.28-5.20 (m, 1 H), 4.38-4.30 (m, 1 H), 3.58 (s, 3H), 3.52 (s, 3H), 3.38-3.30 (m, 1 H), 2.80-2.60 (m, 2H), 2.10-2.00 (m, 1 H), 1 .95-1 .85 (m, 1 H), 1 .73-1.68 (m, 1 H), 1 .28 (d, 3H), 1.26 (d, 3H). Of this compound, 2.3 g (5.0 mmol) was added to 25 mL of 2-(4-methyl)-pentanol. Then 2 drops of methanesulphonic acid were added and the reaction mixture was heated to 60°C and stirred for 1 h. The reaction mixture was cooled to 20°C and stirred for 18h. Next 2,2-dimethoxypropane (0.78 g, 7.5 mol) was added and the mixture was stirred for 2h. The reaction mixture was quenched with 20 mL of saturated aqueous NaHC03 followed by addition of 25 mL of ethyl acetate. The organic phase was separated and washed 2 times with 20 mL of saturated aqueous NaHC03 The organic phase was evaporated and the residue slowly solidified to give the title compound as a solid (2.9 g, 96percent yield). 1 H NMR (300 MHz, CDCI3) delta 7.58 (dd, 2H), 7.01 (t, 2H), 6.46 (dd, 1 H), 5.42 (dd, 1 H), 4.87 (m, 1 H), 4.43 - 4.20 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H), 3.35 - 3.25 (m, 1 H), 2.38 (ddd, 2H), 1.59 - 1.43 (m, 4H), 1.40 (s, 3H), 1.35 (s, 3H), 1.20, (dd, 4 H), 1.14 (d, 6H), 0.83 (t, 6H).
		For reference purposes 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 4-methylpentan-2-yl ester was prepared from rosuvastatin methyl ester (EP 521471). Thus, rosuvastatin methyl ester (30 g, 61 mmol) was added to 200 mL of acetonitrile and 2N aqueous NaOH was added until the pH was stable at 12.5. The reaction mixture was stirred for 2 h at 20° C. Then the pH was lowered to 5.0 with 2N aqueous HCl. To the reaction mixture was added 200 mL of ethyl acetate and the organic phase was separated and washed 2 times with 100 mL of water. The ethyl acetate phase was dried over Na2SO4, filtered and evaporated to a sirup (?30 g of rosuvastatin acid). Part of this sirup (20 g) was dissolved in toluene and heated to reflux under azeotropic water removal for 4 h. The reaction mixture was cooled to 20° C. and stirred for 18 h. The precipitated solid was filtered, washed with toluene (2×10 mL) and dried to give 16.1 g (35 m mol) of N-(4-(4-fluorophenyl)-5-((E)-2-((2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)vinyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide as a white solid. 1H NMR (300 MHz, CDCl3) delta 7.62 (dd, 2H), 7.11 (dd, 2H), 6.72 (dd, 1H), 5.48 (dd, 1H), 5.28-5.20 (m, 1H), 4.38-4.30 (m, 1H), 3.58 (s, 3H), 3.52 (s, 3H), 3.38-3.30 (m, 1H), 2.80-2.60 (m, 2H), 2.10-2.00 (m, 1H), 1.95-1.85 (m, 1H), 1.73-1.68 (m, 1H), 1.28 (d, 3H), 1.26 (d, 3H).

Reference： [1]Patent: WO2010/35284,2010,A2 .Location in patent: Page/Page column 9
[2]Patent: WO2010/81861,2010,A1 .Location in patent: Page/Page column 42
[3]Patent: WO2008/38132,2008,A1 .Location in patent: Page/Page column 10-11
[4]Patent: EP2298745,2011,A1
[5]Patent: WO2012/98049,2012,A1 .Location in patent: Page/Page column 16-17
[6]Patent: US2013/296561,2013,A1 .Location in patent: Paragraph 0041

6
[ 459-57-4 ]
PhCH₂CH₂MgHal [ No CAS ]
[ 147118-40-9 ]