In this process, nitrilation is carried out using diethylcyanomethyl phosphate. The disadvantage of this process is that during conversion of cyano functionality into aldehyde, lots of impurities are formed along with unwanted cis-isomer, therefore the yield and purity of the product are poor.
WO 03/097614 A2 describes a modified procedure for the preparation of the starting material 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarboxaldehyde and further conversion to Rosuvastatin by condensing with methyl (3R)-3-[(tert-butyldimethylsilyl)oxy]-5-oxo-6-
triphenylphosphoranylidene hexanoate. The condensed product was deprotected using methanesulfonic acid and subsequently converted to Rosuvastatin calcium (2:1) salt.
WO 2004/052867 A1 describes a process to prepare Rosuvastatin by condensing 1- cyano-(2S)-2-[(tert-butyldimethylsilyl)oxy]-4-oxo-5-triphenylphosphoranylidene pentane with 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)- 5-pyrimidinecarbaldehyde and subsequent deprotection of silyl group, reduction and hydrolysis.
WO 2000/049014 A1 discloses a novel chemical process for the manufacture of tert- butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-methyl(methylsulfonyl)amino]- pyrimidin-5-yl]vinyl}-(4R,6S)-2,2-dimethyl[l,3]dioxan-4-yl)acetate, which
comprises reaction of diphenyl {4-(4-fluorophenyl)-6-isopropyl-2-[methyl- (methylsulfonyl)amino]pyrimidin-5-yl-methyl}phosphineoxide with tert-butyl 2- [(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate and its further conversion to Rosuvastatin.
WO 2004/014872 A1 describes a process for the manufacture of Rosuvastatin calcium (2:1) salt which comprises mixing a solution of calcium chloride with a solution of water soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-








optionally substituted by hydroxyl, R7 represents hydrogen, halogen, C1-C4 alkyl or Ci-C4alkoxy, Rg is an aliphatic residue selected from C1-C4 alkyl.
We have now found an improved process to prepare (+)-(3R,5S)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3,5- dihydroxy-6E-heptenoic acid calcium salt of Formula I that is cost effective and industrially feasible.
OBJECTIVE
The main objective of the present invention is to provide an improved process for preparing (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl- sulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6E-heptenoic acid calcium salt of Formula I.
Yet another objective of the present invention is to provide an improved process for preparing (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl- sulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6E-heptenoic acid calcium salt of Formula I, which is simple, industrially applicable and economically viable.
















The compound of Formula XI is esterified to get enantiomerically pure compound of Formula V.
The enantiomerically pure compound of Formula V is protected with a suitable hydroxy protecting group like tertiary butyl dimethylsilyl, dihydropyran etc. The protection is carried out in an organic solvent selected from toluene, N,N'- Dimethylformamide, tetrahydrofuran, dichloromethane etc., with or without an acid catalyst. The acid catalyst can be chosen from pyridinium p-toluene sulfonate, p- toluenesulfonic acid, acetic acid etc. The hydroxy protection is carried out at a temperature ranging from 0-50°C preferably at 0-30°C. The compound of Formula VI is isolated by washing the organic layer with water and evaporating the solvent.
The compound of Formula VI is treated with anion generated from acetates like ethyl acetate, phenyl acetate, methyl acetate, t-butyl acetate in an organic solvent. For anion generation several bases can be used like n-butyllithium, lithium diisopropylethylamine, lithium hexamethyldisilazane, sodium hexamethyldisilazane, or inorganic bases in combination with phase transfer catalyst, more preferably lithium diisopropylethylamine is used. The solvent employed is selected from tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, hexane, heptane or mixture thereof. The reaction is carried out at temperature -78°C to 0°C. The reaction mixture is quenched in IN HC1 and extracted with a suitable organic solvent to produce compound of Formula VII.
The compound of Formula VII is deprotected using acid catalysts like p- toluenesulfonic acid, acetic acid, hydrochloric acid, hydrofluoric acid etc., or salts such as sodium fluoride, potassium fluoride. The preferred acid catalyst employed is /j-toluenesulfonic acid to give hydroxy compound of Formula VIII.
The compound of Formula VIII is stereoselectively reduced with metal borohydrides in presence of chelating agent like trialkylboranes or boranates like dialkyl alkoxy







c) oxidizing the compound of Formula XV to give (2E)-3-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of Formula II.
The compound of Formula XII is reacted with a phosphorous compound of Formula XIII optionally in the presence of a base such as organic or inorganic base and a solvent selected from acetonitrile, dichloromethane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol and mixtures thereof, at temperature ranging from 20 to 90°C, preferably 40-80°C for 8 h to yield a compound of Formula XIV. The organic base is selected from sodium methoxide, lithium diisopropylamide, n-butyllithium, lithium hexamethyldisilazane, sodium hexamethyldisilazane. The inorganic base is selected from sodium hydride, potassium hydride, sodium hydroxide, potassium carbonate. The obtained compound of Formula XIV is reduced using a reducing agent such as DIBAL, Vitride, LAH etc., in an organic solvent such as toluene, tetrahydrofuran at -70° to -80°C, preferably at -78°C to yield a compound of Formula XV. The compound of Formula XV is oxidized using an oxidizing agent such as pyridiniumdichromate (PDC), pyridinium chlorochromate (PCC), manganese dioxide (MnC^), 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO), and tetrapropylammoniumperrutheniate (TPAP), sodium hypochlorite (NaOCl) / TEMPO, N-methylmorpholine N-oxide (NMO) and the like at the temperature ranging from 0 to 100°C preferably at 0 to 20°C to yield compound of Formula II.
The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.
PREPARATION OF 3-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N-
METHYL-N-METHYLSULFONYLAMINO)PYRIMIDIN-5-YL]-(2E)-
PROPENAL
Step I:
Preparation of Methyl (2E)-3-[4-(4-fluorophenyI)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]propenoate
4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidine-5- ylcarboxaldehyde (5 g) was dissolved in acetonitrile (25 ml) and to the resulting solution Methyl (triphenylphosphoranylidene)acetate (5.23 g) was added at room temperature. The reaction mixture was stirred at 80-81°C for 8 h for completion. Thereafter, acetonitrile was distilled off under reduced pressure to give crude mass, which was crystallized from isopropyl alcohol to yield pure methyl (2E)-3-[4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5- yl]propenoate. Yield: 5.4 g (96.0 %)
'H NMR (300 MHz) in CDC13; 5(ppm): 1.32 (d, J=6Hz, 6H), 3.34-3.43 (m, 1H), 3.52 (s, 3H), 3.59 (s, 3H), 3.77 (s, 3H), 5.86 (d, J=15Hz, 1H), 7.10-7.27 (n, 2H), 7.58- 7.63 (m, 2H), 7.74 (d, J=15Hz, 1H)
Step II:
Preparation of (2E)-3-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N- methyIsulfonylamino)pyrimidin-5-yl]-propen-l-ol
Methyl (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl- amino)pyrimidin-5-yl]-l-propenoate (5.4 g) obtained in step I above was dissolved in toluene (30 ml) and the resulting solution was cooled to -78°C. To this solution, diisobutylaluminium hydride (20% solution in toluene, 45.2 ml) was added and the reaction mass was stirred at -70°C for 15 min. Thereafter, reaction
mass was poured into aqueous hydrochloric acid (IN, 30 ml). The organic layer was separated and washed with water (20 ml). The solvent was distilled under reduced pressure to yield pure (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-propen-l-ol. Yield: 5.1 g (98.0%)
JH NMR (300 MHz) in CDC13; 8(ppm): 1.28 (d, J=6.9 Hz, 6H), 3.38-3.42 (m, 1H), 3.53 (s, 3H), 3.59 (s, 3H), 4.22 (brs, 2H), 5.67 (dt, J=16.0 & 5Hz), 6.6 (d, J=16.0Hz, 1H), 7.08-7.14 (m, 2H), 7.64-7.69 (m, 2H)
Step III:
Preparation of (2E)-3-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-propenaI
Methyl (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl- amino)pyrimidin-5-yl]propen-l-ol (5.1 g) was added to molecular sieves (1 g) in dichloromethane (50 ml) and stirred for 15 min at room temperature. A solution of pyridinium dichromate (6.07 g) in dichloromethane (20 ml) was added to the above reaction mixture and continued stirring for 5 h at room temperature. After completion of the reaction, the reaction mass was filtered through a column of silica gel (230-400 mesh) and the eluate was distilled under reduced pressure to yield a semi-solid compound, which was crystallized from Hexane : Ethyl acetate (95 : 5 v/v) to yield (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-propenal. Yield: 5.0 g (98.5 %)
JH NMR (300 MHz) in CDC13; 8(ppm): 1.36 (d, J=5 Hz, 6H), 3.38-3.42 (m, 1H), 3.56 (s, 3H), 3.59 (s, 3H), 6.19-6.27 (dd, J=16.5 & 7.5Hz), 7.13-7.18 (m, 2H), 7.55 (d, J=16.5Hz, 1H), 7.60-7.63 (m, 2H), 9.63 (d, J=7.5Hz, 1H)
PREPARATION OF (3S)-5-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULFONYLAMINO)PYRIMIDIN-5-YL]-3- HYDROXY-4-PENTENOIC ACID (lS)-2-HYDROXY-l,2,2-
TRIPHENYLETHYL ESTER
A mixture of hexamethyldisilazane (33.5 ml, 0.15 mol) and tetrahydrofuran (50 ml) was cooled to -10°C under nitrogen atmosphere. n-Butyllithium (3.92 ml, 14% in Hexanes) was added over a period of 20 min (Exothermic), keeping the temperature below 0°C. The reaction mixture was stirred at 0 to -5°C for 15 min and then cooled to -35°C before adding 2-(S)-acetoxy-l,l,2-triphenylethanol (4.84 g, 0.014 mol) over a period of 5 min. The temperature of the reaction mixture was allowed to go up to - 15°C and stirred for 45 min. The resulting homogeneous yellow solution was cooled to -78°C and a solution of (2E)-3-[4-(4-fluorophenyl-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-propenal (5 g, 0.013 mol) in tetrahydrofuran (20 ml) was added over a period of 30 min maintaining the temperature at -75 to - 78°C. The reaction mixture was stirred for 40 min at -78°C and then slowly raised the temperature to 0°C over a period of 20 min. The reaction mass was quenched by adding aqueous hydrochloric acid (5N, 30 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic extracts were washed with saturated sodium chloride solution (50 ml) and evaporated to get a solid mass. The product obtained from the above process was crystallized from hexane : ethyl acetate (9:1 v/v, 50 ml). Yield: 9.0 g
'H NMR (300 MHz, CDCh): 1.26 (d, J = 6Hz, 6H), 2.37 (d, J = 6Hz, 2H), 2.70 (6r5,lH), 2.84 (s, 1H), 3.30-3.35 (m, 1H), 3.53 (s, 3H),3.59 (s, 3H), 4.44 (brs, 1H), 5.37 (dd, J - 16, 5Hz, 1H), 6.6 (d, J = 16Hz, 1H), 6.7 (s, 1H), 7.05-7.19 (m, 15H), 7.28-7.38(/m,2H), 7.58-7.59 (m, 2H).
PREPARATION OF (3S)-5-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULFONYLAMINO)PYRIMIDIN-5-YL]-3- HYDROXY-(4E)PENTENOIC ACID METHYL ESTER
The product obtained in example 2 was dissolved in methanol and added anhydrous potassium carbonate (4 g). The mixture was stirred at room temperature for 3 h and methanol was distilled out from the reaction below 40°C under reduced pressure. Water (50 ml) was added to the resulting residue and extracted with methylene chloride (50 ml). The methylene chloride layer was separated, washed with water (50 ml), dried over sodium sulfate and evaporated to dryness to obtain a viscous liquid. The product was purified by column chromatography using silica gel and hexane: ethyl acetate (80:20 v/v) Yield: 5.5 g.
'H NMR (300 MHz, CDCh): 1.26 (d, J = 6Hz, 6H), 2.41-2.47 (m, 2H), 3.10 (brs, OH), 3.31-3.36 (m, 1H), 3.52 (s, 3H), 3.57 (s, 3H), 3.70 (s, 3H), 4.52 (brs, 1H), 5.44- 5.51 (dd, J = 15, 6Hz, 1H), 5.66 (d, J = 15Hz, 1H), 7.0-7.1 (m, 2H), 7.6-7.65 (m, 2H).
EXAMPLE 4
PREPARATION OF (3RS)-5-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULFONYLAMINO)PYRIMIDIN-5-YL]-3- (TETRAHYDROPYRANYLOXY]-(4E)-PENTENOIC ACID METHYLESTER
The product of example 3 (5.5 g, 0.012 mol) was dissolved in methylene chloride (55 ml) and pyridinium-p-toluenesulfonate was added (0.55 g) at 25°C followed by 3,4- dihydro-2H-pyran (1.34 ml, 0.014 mol). The reaction mass was stirred at room temperature for 24 h and added water (20 ml). The methylene chloride layer was separated, washed with water (20 ml), dried over sodium sulfate and evaporated under reduced pressure at below 40°C to obtain the product as an oily mass, which was used in the subsequent reaction without further purification. Yield: 6.5 g
PREPARATION OF (5S)-7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULFONYLAMINO)PYRIMIDIN-5-YL]-5- (TETRAHYDROPYRANYLOXY)-3- OXO-(6E)-HEPTENOIC ACID TERT- BUTYL ESTER
A mixture of diisopropylamine (8.5 ml, 0.06 mol) and tetrahydrofuran (35 ml) was cooled to -10°C and added n-butyllithium (18.8 ml, 14% solution in hexanes) slowly over a period of 15 min, keeping the temperature below 0°C. The mixture was stirred for 30 min, keeping the temperature between 0 to -5°C. Thereafter, the mixture was cooled to -78°C and added tert-butyl acetate (1.8 ml, 0.013 mol) slowly over a period of 30 min, maintaining the temperature below -75°C. The reaction mass was stirred for 30 min, keeping the temperature between -75 to -78°C. The product of example 4 (6.5 g, 0.012 mol) was dissolved in tetrahydrofuran (20 ml) and added to the reaction mass slowly over a period of 20 min at -78°C. The reaction mass was stirred at -78°C for 1 h and quenched by slow addition of IN aqueous hydrochloric acid (10 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (20 ml), dried over anhydrous sodium sulfate and evaporated to get the product as an oily mass and used as such in the next step. Yield: 7 g
EXAMPLE 6
PREPARATION OF (5S)-7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULFONYLAMINO)PYRIMIDIN-5-YL]-5- (HYDROXY)-3-OXO-(6E)-HEPTENOIC ACID TERT.BUTYL ESTER
The product obtained as per the procedure of example 4 (7.0 g, 0.01 mol) was dissolved in isopropyl alcohol (28 ml) and p-toluenesulfonic acid monohydrate (0.28
g, 0.0014 mol) was added to it. The mixture was stirred at room temperature for 24
h. After completion of the reaction, solvent was evaporated under reduced pressure at
below 40°C and water (20 ml) was added to it. The product was extracted using dichloromethane (35 ml) and washed the organic phase with water (20 ml). The organic layer was dried over sodium sulfate and evaporated the solvent to obtain the product
Yield: 4.8 g, 80%
*H NMR (300 MHz, CDCl3). 1.29 (s, 9H), 1.46 (d, J = 6Hz, 6H), 2.34-2.67 (m, 4H), 3.30-3.37 (m, 1H), 3.53 (s, 3H), 3.59 (s, 3H), 3.72 (s, 1H), 4.63 (brs, 1H), 5.44-5.53 (m, 1H), 6.69 (d, J = 15Hz, 1H), 7.09-7.28 (m, 2H), 7.63-7.65 (m, 2H)
EXAMPLE 7
PREPARATION OF t-BUTYL-(6E)-7-{4-(4-FLUOROPHENYL)-6- ISOPROP YL-2- [iV-METHYL-jV-METHYLSULFONYL AMINO] PYRIMIDIN- 5-YL}-(3R,5S)-3,5-DIHYDROXY HEPTENOATE
t-Butyl-(6E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[A^-methyl-7^-methylsulfonyl- amino]pyrimidin-5-yl}-(5S)-5-hydroxy-3-oxo heptenoate (2 g, 0.003 mol) was dissolved in tetrahydrofuran (54 ml) and methanol (14 ml) at 25-3 0°C under nitrogen atmosphere. The mixture was cooled to -78°C and diethylmethoxy borane (1 ml, 48 % solution in tetrahydrofuran, 0.004 mol) was added to it drop wise at -78°C over a period of 10 min. The mixture was stirred at -75°C to -78°C for one hour and sodium borohydride (0.14 gm, 0.003 mol) was added to it slowly over a period of 15 min. It was stirred for 2 h at -75°C to -78°C and quenched by adding acetic acid (2 ml) at - 78°C. Saturated aqueous sodium bicarbonate solution (50 ml) was added to it and stirred for 15 min. The organic layer was separated and aqueous layer was extracted with ethyl acetate (25 ml). The combined organic layer was washed with water (25 ml) and dried over sodium sulfate. The solvent was distilled out at 35-40°C under reduced pressure to obtain the title compound. Yield: 2 g 'H NMR: 1.27 (d, 6H), 1.47 (s, 9H), 1.50-1.58 (m, 1H), 2.38 (d, 2H), 3.37 (septet, 1H), 3.51 (s, 3H), 3.57 (s, 3H), 3.63 (bs, 1H), 3.80 (bs, 1H), 4.15-4.18 (m, 1H), 4.44- 4.48 (m, 1H), 5.46 (dd, 1H), 6.64 (d, 1H), 7.09 (t, 2H), 7.65 (dd, 2H).
EXAMPLE 8
PREPARATION OF N,N'-DIBENZYLETHYLENEDIAMINE
ROSUVASTATIN
Rosuvastatin t-butyl ester (1 g) was dissolved in ethanol (15 ml). The resulting solution was treated with 1 N aqueous sodium hydroxide (1.96 ml) at 25-30°C. The mixture was stirred for 1 h at 25-30°C for completion of hydrolysis. Ethanol was rotoevaporated and the residue is diluted with DM water (25 ml) and extracted with a mixture of ethyl acetate - toluene (4:6, 2 x 20 ml).
To the above aqueous layer, a solution of N,N'-dibenzylethylenediamine diacetate (0.34 g dissolved in 2 ml of water) was added and stirred for 2 h. The precipitated product was filtered, washed with water and dried under vacuum at 40-45°C. Dry Wt. 0.75 g
EXAMPLE 9
PURIFICATION OF N,N'-DIBENZYLETHYLENEDIAMINE
ROSUVASTATIN
N,N'-dibenzylethylenediamine rosuvastatin (0.5 g) was dissolved in methanol (1 ml) and treated with ethyl acetate (5 ml) at 25-30°C. The resulting mixture was cooled to 0-5°C and stirred for 1 h. The precipitated product was filtered and dried under vacuum.
Dry. Wt. 0.2 g, Chromatographic purity: 99.91%, Anti isomer: 0.19%.
Input Chromatographic purity: 99.33, Anti isomer: 0.66%.
PXRD (°2G) 5.6, 10.1, 11.3, 13.0, 14.7, 15.1, 16.0, 16.3, 17.0, 17.3, 17.8, 18.6, 19.0,
21.3, 21.9, 22.5, 23.5, 25.4, 30.9, 32.7 ± 0.2
EXAMPLE 10
PREPARATION OF ROSUVASTATIN CALCIUM
N,N'-dibenzylethylenediamine rosuvastatin salt (2 g) was dissolved in a mixture of ethyl acetate (30 ml) and DM water (30 ml) and cooled to 0-5°C. The above cold mixture was treated with aqueous hydrochloric acid (3 ml) at 0-5°C. The resulting clear solution was stirred for 10 min. The organic layer was separated, washed with water and cooled to 0-5°C. Aqueous sodium hydroxide (1 N, 30 ml) was added to the above organic layer and stirred at room temperature for 30 min for conversion of rosuvasatin acid to it sodium salt. Toluene (70 ml) was added to the above mixture and stirred for 10 min. The aqueous layer was separated and traces of solvent were removed at 40-45°C under vacuum. The resulting clear aqueous layer was treated with an aqueous solution of calcium chloride (IN, 3 ml) and resulting rosuvastatin calcium was filtered and dried. Dry Wt. 0.6 g; Chromatographic purity: 99.3%.
EXAMPLE 11
PREPARATION OF ROSUVASTATIN CALCIUM
N,N'-dibenzylethylenediamine rosuvastatin salt (1 g) was suspended in DM water(20ml) and treated with aqueous sodium hydroxide solution (0.1N, 16.63 ml) at 25-30° C. The resulting suspension was stirred for 30 min and the undissolved matter was filtered off. The clear aqueous layer was washed twice with 30%v/v ethyl acetate/toluene (5 ml). Traces of organic solvent from aqueous layer was removed under vacuum at 40-45°C. The clear aqueous layer containing Rosuvastatin sodium was treated with aqueous solution of calcium chloride (1 N, 1.66 ml), precipitated rosuvastatin calcium was filtered, washed with water and dried. Dry Wt. 0.35; Chromatographic purity: 99.24%; Anti isomer: 0.71%
PREPARATION OF (4E)-5-{4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULFONYLAMINO)PYRIMIDIN-5-YL}-(3S)-3- HYDROXY-4-PENTENOIC ACID, (a)-METHYLBENZYLAMINE SALT
(4E)-5-{4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-
pyrimidin-5-yl}-3-hydroxy-4-pentenoic acid (100 gm, 0.228 ml) which contains
predominantly S-isomer was dissolved in acetonitrile (1 litre) and R-(+)-a-
methylbenzylamine (27.7 gm, 0.228 ml) was added to it dropwise over a period of 30
min during which salt precipitated out. The above suspension was heated to 70-75°C
and water (75 ml) was added to it to get a clear solution, which was subsequently
cooled to 25°C to reprecipitate the product. It was further cooled to 5-10°C, filtered
and washed with chilled acetonitrile (150 ml, 5-10°C). The product obtained was
dried at 40-45°C under vacuum to constant weight.
Yield: 95 gm, (74%)
Purity: >99.5%
Chiral Purity: >99.5% ee
SOR: [a]20, +5.24 (c=l% in methanol)
'HNMR (CDC13, 300 MHz): 1.20 (d, J=7Hz, 6H, (CH3)2), 1.36 (d, J=7Hz, 3H, CH3),
2.0- 2.12 (m, 2H, CH2), 3.38-3.42 (m, 1H, -CH), 3.45 (s, 3H, CH3), 3.55 (s, 3H, CH3),
4.1- 4.2 (m, 1H, CH), 4.29-4.45 (m, 1H, CH), 5.52 (dd, J=16; 6Hz, 1H, CH), 6.54 (d, J=16Hz, 1H, CH), 7.25-7.69 (m, 7H, ArH), 7.71-7.74 (m, 1H, ArH).
EXAMPLE 13
PREPARATION OF (4E)-5-{4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N- METHYL-N-METHYLSULFONYLAMINO]PYRIMIDIN-5-YL}-(3S)-3- HYDROXY-4-PENTENOIC ACID
(4E)-5-{4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin- 5-yl} -(3 S)-3-hydroxy-4-pentenoic acid, a-methylbenzylamine salt (75 gm, 0.134
mol) was suspended in a mixture of methylene chloride (125 ml) and water (125 ml) at 25°C. The above suspension was cooled to 2-5°C and pH was adjusted to 3-3.5 by slow addition of IN aqueous Hydrochloric acid. Thereafter the organic layer was separated, washed with water (125 ml) and evaporated to dryness to get the pure product.
Yield: 57 gm (97%).

1) An improved process for preparing Rosuvastatin calcium of Formula I v
which comprises :
a) reacting (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-
methanesulfonyl- amino)pyrimidine]-propenal of Formula II,

with a compound of Formula III a or III b

wherein R', R" and R'" represent alkyl, aralkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, napthyl, substituted napthyl and heterocyclic residue, in the presence of a base and an organic solvent to produce a diastereomeric mixture of compound of Formula IV a or IV b at a temperature in the range of-78 °C to +20 °C













9) The process according to claim 1, the protection in step (c) is carried out using a protecting agent selected from tertiary butyl dimethylsilyl, dihydropyran.
10) The process according to claim 1, the protection in step (c) is carried out in an organic solvent selected from toluene, N,N'-Dimethylformamide, tetrahydrofuran, dichloromethane.
11) The process according to claim 1, the protection in step (c) is carried out in the presence of acid catalyst chosen from pyridine /7-toluene sulfonate, p- toluenesulfonic acid, acetic acid or salts such as sodium fluoride, potassium fluoride.
12) The process according to claim 1, the base in step (d) is selected from n- butyllithium, lithium diisopropylethylamine, lithium hexamethyldisilazane, sodium hexamethyldisilazane, or inorganic bases.
13) The process according to claim 1, the deprotection in step (e) is carried out using acid catalysts selected from p-toluenesulfonic acid, acetic acid.
14) The process according to claim 1, the stereoselective reduction in step (f) is carried out using metal borohydrides in presence of chelating agent like trialkylboranes or boranates like dialkyl alkoxy boranes.
2007
15) The process according to claim 14, the stereoselective reduction in step (f) is carried out in one or more organic solvents with sodium borohydride, potassium borohydride, calcium borohydride.
Dated this the day of

Dr. M.SIVAKUMARAN


(DIRECTOR)