WO2012063115A2 - Process for the preparation of rosuvastatin calcium via novel amine intermediate - Google Patents

Process for the preparation of rosuvastatin calcium via novel amine intermediate Download PDF

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WO2012063115A2
WO2012063115A2 PCT/IB2011/002633 IB2011002633W WO2012063115A2 WO 2012063115 A2 WO2012063115 A2 WO 2012063115A2 IB 2011002633 W IB2011002633 W IB 2011002633W WO 2012063115 A2 WO2012063115 A2 WO 2012063115A2
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group
methyl
rosuvastatin
process according
formula
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PCT/IB2011/002633
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French (fr)
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WO2012063115A3 (en
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Khushwant Singh
Anand Kumar Singh
Rahul Srivastava
Pramod Kumar
Dharam Vir
Ashutosh Agarwal
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Jubilant Life Sciences Ltd.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the present invention relates to pyrimidine derivative and in particular to rosuvastatin calcium. More specifically, the present invention is directed to the novel amine salts of rosuvastatin and its process for the preparation. Moreover, the present invention also relates to improved process for the preparation of rosuvastatin calcium, employing novel amine salts as an intermediate.
  • (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3/?,5S)-3,5-dihydroxyhept-6-enoic acid (Rosuvastatin) calcium of Formula I is an inhibitor of HMG-CoA reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
  • Rosuvastatin calcium reduces cholesterol by increasing the number of low-density lipoprotein (LDL) receptors on the cell-surface to enhance uptake and catabolism of LDL. It also inhibits hepatic synthesis of very-low-density lipoprotein (VLDL), which reduces the total number of VLDL and LDL particles.
  • VLDL very-low-density lipoprotein
  • the treatment reduces triglycerides (TG) and leads to increase in the high-density lipoprotein cholesterol (HDLC.)
  • US RE37,314 describes a process for the preparation of Rosuvastatin calcium and its various alkali metal salts such as lithium, sodium, potassium and cesium and alkaline earth metal salts such as beryllium, magnesium and calcium.
  • US'314 patent in Example 7 discloses the preparation of rosuvastatin calcium in powdery form by dissolving the corresponding sodium salt in water under nitrogen atmosphere, adding calcium chloride and collecting the resulting precipitate by filtration.
  • the main drawback of the process is that the rosuvastatin calcium obtained from the said process contains diasteromeric impurity in more than 1%, which is difficult to remove even after multiple purifications.
  • the yield of the final rosuvastatin calcium decreases, which in turn increases the production cost, thus uneconomical for commercial scale production.
  • US 6,841,554 and US 7,129,352 disclose the preparation of crystalline amine salts of rosuvastatin and further conversion to rosuvastatin calcium.
  • US '554 patent specifically claims crystalline ammonium, methylammonium, ethylammonium, diethanolammonium, tris(hydroxymethyl)methyl ammonium, benzylammonium, 4-methoxybenzylammonium, lithium and magnesium salt of rosuvastatin. These patents do not mention the yield and diastereomeric impurity of the final rosuvastatin salt.
  • US 6,838,566 describes different salts of HMG-CoA reductase inhibitor with organic amines selected from the group ( ⁇ )-l,2-dimethylpropylamine, 3-(2- aminoethylamino)-propylamine, n-butylamine, secondary butylamine, tertiary butylamine, dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine, N-methylcyclohexylamine, N,N- diisopropylethylenediamine, NN-diethylenediamine, N-methyl-l,3-propanediamine, N- methylethylenediamine, ⁇ , ⁇ , ⁇ ', V-tetramethyl- 1 ,2-diaminoethane, N, ⁇ , ⁇ ', iV-tetramethyl- 1 ,4-diaminobutane
  • US'566 patent also mention that amines having a larger organic group and especially those having bulky groups, readily crystallize, and to a lower extent form salts with unwanted side products when compared with amines having small organic groups. US'566 patent does not specifically disclose the preparation of rosuvastatin calcium from the novel amine salt.
  • WO2005051921 discloses the crystalline isopropylammonium and cyclohexyl ammonium salts of rosuvastatin and using the said salt for the purification of rosuvastatin calcium. Further, WO'921 application is silent about the purity and diastereomeric impurity of the final rosuvastatin calcium.
  • WO2005077916 discloses diisopropylammonium, dicyclohexylammonium and (S)(+)-D-methylbenzyl ammonium salt of rosuvastatin and further conversion to rosuvastatin calcium.
  • WO2008067440 discloses the dehydroabietylamine salt of rosuvastatin and further conversion to rosuvastatin calcium.
  • the disadvantage of the process is the use of expensive amine, which not only increases the production cost, but also makes the process uneconomical.
  • WO2008038132 discloses the NN-dibenzylethylenediamine salt of rosuvastatin and further using the said crystalline amine salt for the preparation of amorphous rosuvastatin calcium.
  • WO2010035284 discloses the (S)-2-amino-3,3-dimethylbutane or (5 (-)- ⁇ - methyl benzylamine salt of rosuvastatin and further using the said crystalline amine salt for the preparation of amorphous rosuvastatin calcium.
  • novel amine salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino] pyrimidin-5-yl]-(3i?,5S)- dihydroxyhept-6-enoic acid Rosuvastatin selected from the group comprising of S-benzylisothiourea, L-lycine, L-arginine, aminoguanidine in crystalline or amorphous solid, anhydrous, solvate or hydrate form.
  • Fig. 1 shows the X-Ray powder diffraction pattern of crystalline S- benzylisothiourea salt of(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methy methylsulfony aminoJpyrimidin-S-ylHS ⁇ 55)- dihydroxyhept-6-enoic acid.
  • the present invention discloses in its aspect novel amine salts of rosuvastatin with organic amines, wherein the organic amine according to the present invention is selected from the group consisting of:
  • Ri and R 2 independently denote hydrogen, straight or branched chain alkyl having Ci -8 carbon atom;
  • Z is independently selected from the group comprising of -HN-(CH 2 )2-NH 2 , amino group, amino phenyl, or CH 3 -CH(NH 2 )-, Z' is independently selected from hydrogen, NH 2 or
  • R is selected from amino, alkyl amino, carboxy hydrazine (CO-NH-NH 2 ) or
  • Substituted thiazoles selected from the group comprising of 2-aminobenzothiazole, 6- aminobenzothiazole, 2-amino-4-methylthiazole and the like or
  • Substituted azoles such as 3-amino-l,2,4-triazole, substituted pyrazole such as 2-(2H- pyrazol-3-yl)ethanamine and the like or
  • Purine derivatives such as adenine, pyrimidine derivatives such as 2,4-diamino-6- hydroxypyrimidine, 4,5-diamino-6-hydroxy-2-mercaptopyrimidine or triazine derivative such as 2,4-diamino-6-phenyl-l ,3,5-triazine, 2-amino-4-ethoxy-6-(methylamino)- 1,3,5 - triazine and the like or
  • Heterocyclic amines such as 2-methylpiperazine, 2-methylpiperidine, tetrahydrofurfuryl amine and the like.
  • the preferred organic amine is S- benzylisothiourea represented by the following formula
  • novel amine salt of (E)-7- [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]- (3R,5S)- dihydroxyhept-6-enoic acid Rosuvastatin
  • Rosuvastatin preferably selected from the group consisting of S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine in the form of crystalline or amorphous solid, anhydrous, solvate or hydrate form.
  • the amine salts of S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine are selected from the group comprising of hydrochloride, hydrobromide, acetate and the like, preferably hydrochloride.
  • rosuvastatin sodium salt of Formula VI' to amine salt of rosuvastatin such as S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine, preferably S-benzylisothiourea salt of rosuvastatin is carried out in an organic solvent, wherein the organic solvent is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate and the like, ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like, nitriles such as acetonitrile propionitrile and the like, sulphoxides such as dimethyl sulphoxide, and the like, amides such as di
  • methyl ester of rosuvastatin to its corresponding rosuvastatin S-benzylisothiourea or its salt can optionally take place with or without isolation of corresponding rosuvastatin salt such as rosuvastatin sodium.
  • the hydrolysis of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3-3 ⁇ 4,5S)-dihydroxy (E)-6-heptenate is carried out in presence of a base, wherein the base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of lithium, sodium, potassium, calcium, magnesium, barium and the like, preferably sodium hydroxide.
  • the solvent used for hydrolysis is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like, ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, sulphoxides such as dimethyl sulphoxide, and the like, amides such as dimethylacetamide, dimethylformamide and the like, water or mixtures thereof.
  • the reaction is carried out at a temperature between -5-50°C, preferably 0-20°C for 1-4 hours, preferably 2-3 hours.
  • S-benzylisothiourea salt of rosuvastatin is in crystalline form characterized by its XRD pattern having significant peak at about 15.5, 17.6, 18.5, 19.7, 20.8, 22.2, 23.9, 27.2, 31.6 ⁇ 0.2 degree two theta as given in Fig 1.
  • the XRPD data reported herein was obtained using Cu Ka radiation, having the wavelength 1.54A and using a PANalytical powder X-ray Diffractometer.
  • the present invention provides, a process for the preparation of crystalline S-benzylisothiourea salt of (E)-7-[4-(4-fluorophenyl)-6- isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3/?, 5S)- dihydroxyhept-6- enoic acid (Rosuvastatin), by crystallizing the S-benzylisothiourea salt of rosuvastatin in an organic solvent and isolating the resulting amine salt of rosuvastatin.
  • the organic solvent used herein is selected from the group comprising of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate and the like, nitriles such as acetonitrile, propionitrile and the like, alcohols such as methanol, ethanol, propanol, butanol and the like, water or mixture thereof, preferably acetone.
  • ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like
  • esters such as ethyl acetate, propyl acetate and the like
  • nitriles such as acetonitrile, propionitrile and the like
  • alcohols such as methanol, ethanol, propanol, butanol and the like, water or mixture thereof, preferably acetone.
  • step (a) the condensation of 4-(4-fluorophenyl)-6-isopropyl-2-(jV-methyl-N- methylsulfonylamino)-5-pyrimidinecarbaldehyde of Formula II is carried out with less than 1.2 mole equivalent of methyl (3i?)-3-(tert-butyldimethylsilyloxy)-5-oxo-6- triphenylphosphoranylidene hexanoate of Formula III in an organic solvent, wherein the organic solvent is selected from the group comprising of Cs-Cg linear, branched or cyclic hydrocarbon such as pentane, hexane, heptane, octane, cyclohexane and the like, aromatic hydrocarbon such as toluene, benzene, chlorobenzene and the like, alcohols such as methanol, ethanol, propanol, butanol and the like, esters such as ethyl acetate, prop
  • the resulting compound of Formula IV prepared according to present invention is in high purity and is prepared in environment friendly manner because the reaction condition used are simple and avoid the use of stringent reaction condition such as use of low temperature and inert atmosphere.
  • step (b) the resulting compound of Formula IV undergoes deprotection of tert- butyldimethylsilyl group using an acid, wherein the acid is selected from organic acid such as methanesulphonic acid, /?-toluenesulphonic acid, acetic acid and the like, inorganic acid such as hydrochloric acid, sulphuric acid or mixture thereof, preferably methanesulphonic acid.
  • organic acid such as methanesulphonic acid, /?-toluenesulphonic acid, acetic acid and the like
  • inorganic acid such as hydrochloric acid, sulphuric acid or mixture thereof, preferably methanesulphonic acid.
  • the solvent used herein is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like, esters such as ethyl acetate, propyl acetate and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, nitriles such as acetonitrile, propionitrile and the like or mixture thereof, preferably acetonitrile or their combination with water in various proportions.
  • the reaction is carried out at temperature between 20-50°C, preferably between 25-40°C for 4-10 hours, preferably for 6-8 hours.
  • the resulting compound of Formula V is used as such for the stereoselective reduction or is purified using organic solvent selected from the group comprising of alcohol such as methanol, ethanol, propanol, butanol and the like, chlorinated hydrocarbon such as dichloromethane and the like, ethers such as tetrahydrofuran and the like, nitriles such as acetonitrile and the like or in combination with anti-solvent selected from the group comprising of hydrocarbons such as hexane, cyclohexane and the like, ethers such as methyl tertiary butyl ether, diisopropyl ether and the like or water.
  • organic solvent selected from the group comprising of alcohol such as methanol, ethanol, propanol, butanol and the like, chlorinated hydrocarbon such as dichloromethane and the like, ethers such as tetrahydrofuran and the like, nitriles such as acetonitrile
  • step (c) the resulting keto ester compound of Formula V is steroselectively reduced using diethylmethoxyborane and metal borohydride in a solvent, wherein the metal borohydride is selected from the group comprising of lithium borohydride, sodium borohydride and the like, preferably sodium borohydride.
  • the solvent is selected from the group comprising of hydrocarbons such as toluene, xylene and the like, alcohols such as methanol, ethanol, propanol, butanol and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate and the like, ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, sulphoxides such as dimethyl sulphoxide, and the like, amides such as dimethylacetamide, dimethylformamide and the like, or mixtures thereof, preferably mixture of tetrahydrofuran and methanol, with optimized quantity of reducing agent and in the appropriate sequence of solvent(s), reagent(s) and substrate.
  • the reduction reaction is
  • step (d) the resulting methyl ester compound of Formula VI is hydrolyzed in presence of a base in solvent selected from organic solvent, water or mixture thereof to obtain rosuvastatin salt, preferably rosuvastatin sodium of Formula VI'.
  • the base used for hydrolysis is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonates, bicarbonates and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of lithium, sodium, potassium, calcium, magnesium, barium and the like, preferably sodium hydroxide.
  • the solvent used for hydrolysis is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like, ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, sulphoxides such as dimethyl sulphoxide, and the like, amides such as dimethylacetamide, dimethylformamide and the like, water or mixtures thereof.
  • alcohols such as methanol, ethanol, propanol, butanol and the like
  • ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like
  • nitriles such as acetonitrile, propionitrile and the like
  • sulphoxides such as dimethyl sulphoxide
  • amides such as dimethylacetamide, dimethylformamide and the like, water or
  • step (e) the resulting rosuvastatin salt is treated with an appropriate amine such as S-benzylisothiourea or its salt in an organic solvent and isolating the S- benzylisothiourea salt of rosuvastatin.
  • an appropriate amine such as S-benzylisothiourea or its salt in an organic solvent and isolating the S- benzylisothiourea salt of rosuvastatin.
  • the salt of S-benzylisothiourea used herein is selected from the group comprising of hydrochloride, hydrobromide, acetate and the like.
  • the organic solvent used for the conversion of rosuvastatin sodium of Formula VI' to S-benzylisothiourea salt of rosuvastatin is selected from the group comprising of chlorinated or non chlorinated hydrocarbons such as dichloromethane, chloroform and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate and the like, nitriles such as acetonitrile, propionitrile and the like, alcohols such as methanol, ethanol, propanol, butanol and the like, water or mixture thereof, preferably acetone.
  • chlorinated or non chlorinated hydrocarbons such as dichloromethane, chloroform and the like
  • ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like
  • esters such as
  • the resulting S-benzylisothiourea salt of rosuvastatin is then converted to rosuvastatin calcium, preferably in amorphous form having purity more than 99% and having low content of diasteromeric impurity by treating the rosuvastatin S- benzylisothiourea of Formula VII with a base followed by addition of calcium salt in an solvent to obtain rosuvastatin calcium of Formula I.
  • the calcium salt used herein is selected from the group comprising of calcium chloride, calcium acetate, calcium nitrate, calcium hydroxide, calcium palmitate, calcium pivalate, calcium carbonate, calcium bicarbonate and the like, preferably calcium acetate.
  • the solvent is selected from the group comprising of alcohol such as methanol, ethanol, propanol and the like or water or mixture thereof.
  • the conversion of the S-benzylisothiourea salt of rosuvastatin to rosuvastatin calcium can optionally take place with or without isolation of rosuvatstatin salt such as rosuvastatin sodium of Formula VI'.
  • the 5-benzylisothiourea salt of rosuvastatin prepared according to the present invention has purity greater than 99% and contains diastereomeric content less than 0.5%. Further the rosuvastatin calcium prepared using the S-benzylisothiourea salt of rosuvastatin has purity greater than 99.5% and contains diastereomeric content less than 0.5%.
  • Methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3i?)-3-(ter/-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate obtained from example 1 was taken in acetonitrile 800 ml) at 25-30°C. To the resulting solution, methane sulphonic acid (19.1 g in 85 ml water) was added. The reaction mixture was then stirred for 6-8 hours. After the reaction completion, saturated sodium bicarbonate solution was added.
  • the pH of the resulting mixture was adjusted to 9.0-9.5 using 5% aqueous acetic acid solution.
  • 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.
  • Methyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3i?,5S)-dihydroxy-(E)-6-heptenate thus obtained was taken in isopropanol (1000 ml) and water (1000 ml) and was stirred at room temperature.
  • the reaction mixture was cooled to 0-10°C and aqueous sodium hydroxide solution was added to the reaction mixture.
  • the pH was adjusted to 9-10 using 10% aqueous acetic acid.
  • the resulting reaction mixture was concentrated and was cooled to room temperature.
  • Methyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(iV-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3/?,5S)-dihydroxy-(E)-6-heptenate (lOOg) was taken in isopropanol (1000 ml) and stirred.
  • the reaction mixture was cooled to 5-10°C and sodium hydroxide solution (8.9g in 200 ml water) was added to the reaction mixture over a period of 0.5 hours at 5-10°C.
  • the reaction mixture was stirred for few minutes and warmed to 25- 30°C.
  • the resulting mixture was further stirred for 2 hours.
  • reaction mass was concentrated at 45-50°C to obtain a thick oily mass.
  • the reaction mass was then chased off with methyl ethyl ketone to obtain a solid residue.
  • the pH was adjusted to 8.5-9.0 using 10% aqueous acetic acid followed by addition of S- benzylisothiourea hydrochloride.
  • the resulting reaction mixture was stirred for 15-16 hours to obtain solid, which was washed with methyl ethyl ketone and dried to obtain the title compound as solid.
  • S-Benzylisothiourea rosuvastatin (lOOg) was taken in water (500ml) and methyl tertiary butyl ether (500 ml) at room temperature. The pH was adjusted between 1-2 by using 2N HC1 solution. The organic layer was separated and washed with water. To the organic layer, aqueous NaOH solution was added and the layers were separated. The pH of the aqueous layer was adjusted to 8-8.5 using 0.5% aqueous acetic acid. The resulting solution was filtered through micron filter and aqueous solution of calcium acetate (13.14 g, dissolved in 200ml water) was added at 25-30°C. The resulting mixture was stirred for 1 - 2 hrs. The resulting solid was filtered, washed with water and dried under vacuum to obtain title compound.

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Abstract

The present invention, relates to novel amine salts of rosuvastatin and its process for the preparation. Moreover, the present invention also relates to improved process for the preparation of rosuvastatin calcium, employing novel amine salts as an intermediate.

Description

PROCESS FOR THE PREPARATION OF ROSUVASTATIN CALCIUM VIA
NOVEL AMINE INTERMEDIATE
FIELD OF THE INVENTION
The present invention, relates to pyrimidine derivative and in particular to rosuvastatin calcium. More specifically, the present invention is directed to the novel amine salts of rosuvastatin and its process for the preparation. Moreover, the present invention also relates to improved process for the preparation of rosuvastatin calcium, employing novel amine salts as an intermediate.
BACKGROUND OF THE INVENTION
(E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3/?,5S)-3,5-dihydroxyhept-6-enoic acid (Rosuvastatin) calcium of Formula I is an inhibitor of HMG-CoA reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Figure imgf000002_0001
Formula I
Rosuvastatin calcium reduces cholesterol by increasing the number of low-density lipoprotein (LDL) receptors on the cell-surface to enhance uptake and catabolism of LDL. It also inhibits hepatic synthesis of very-low-density lipoprotein (VLDL), which reduces the total number of VLDL and LDL particles. The treatment reduces triglycerides (TG) and leads to increase in the high-density lipoprotein cholesterol (HDLC.)
US RE37,314 describes a process for the preparation of Rosuvastatin calcium and its various alkali metal salts such as lithium, sodium, potassium and cesium and alkaline earth metal salts such as beryllium, magnesium and calcium. However, US'314 patent in Example 7 discloses the preparation of rosuvastatin calcium in powdery form by dissolving the corresponding sodium salt in water under nitrogen atmosphere, adding calcium chloride and collecting the resulting precipitate by filtration. The main drawback of the process is that the rosuvastatin calcium obtained from the said process contains diasteromeric impurity in more than 1%, which is difficult to remove even after multiple purifications. Furthermore, due to the multiple purifications, the yield of the final rosuvastatin calcium decreases, which in turn increases the production cost, thus uneconomical for commercial scale production.
US 6,841,554 and US 7,129,352 disclose the preparation of crystalline amine salts of rosuvastatin and further conversion to rosuvastatin calcium. US '554 patent specifically claims crystalline ammonium, methylammonium, ethylammonium, diethanolammonium, tris(hydroxymethyl)methyl ammonium, benzylammonium, 4-methoxybenzylammonium, lithium and magnesium salt of rosuvastatin. These patents do not mention the yield and diastereomeric impurity of the final rosuvastatin salt.
US 6,838,566 describes different salts of HMG-CoA reductase inhibitor with organic amines selected from the group (±)-l,2-dimethylpropylamine, 3-(2- aminoethylamino)-propylamine, n-butylamine, secondary butylamine, tertiary butylamine, dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, dicyclohexylamine, N-methylcyclohexylamine, N,N- diisopropylethylenediamine, NN-diethylenediamine, N-methyl-l,3-propanediamine, N- methylethylenediamine, Ν,Ν,Ν', V-tetramethyl- 1 ,2-diaminoethane, N, Ν,Ν', iV-tetramethyl- 1 ,4-diaminobutane, Ν,Ν,Ν', N-tetramethyl- 1 ,6-diaminohexane, 1 ,2-dipiperidinethane, dipiperidinemethane, 2-amino-3,3-dimethylbutane, N,N-dimethylcyclohexylamine, neopentylamine, adamantylamine, N,N-diethyl cyclohexylamine, N- isopropylcyclohexylamine, N-methylcyclohexylamine, cyclobutylamine and norborylamine. However, US'566 patent also mention that amines having a larger organic group and especially those having bulky groups, readily crystallize, and to a lower extent form salts with unwanted side products when compared with amines having small organic groups. US'566 patent does not specifically disclose the preparation of rosuvastatin calcium from the novel amine salt.
WO2005051921 discloses the crystalline isopropylammonium and cyclohexyl ammonium salts of rosuvastatin and using the said salt for the purification of rosuvastatin calcium. Further, WO'921 application is silent about the purity and diastereomeric impurity of the final rosuvastatin calcium. WO2005077916 discloses diisopropylammonium, dicyclohexylammonium and (S)(+)-D-methylbenzyl ammonium salt of rosuvastatin and further conversion to rosuvastatin calcium.
WO2008067440 discloses the dehydroabietylamine salt of rosuvastatin and further conversion to rosuvastatin calcium. The disadvantage of the process is the use of expensive amine, which not only increases the production cost, but also makes the process uneconomical.
WO2008038132 discloses the NN-dibenzylethylenediamine salt of rosuvastatin and further using the said crystalline amine salt for the preparation of amorphous rosuvastatin calcium.
WO2010035284 discloses the (S)-2-amino-3,3-dimethylbutane or (5 (-)-α- methyl benzylamine salt of rosuvastatin and further using the said crystalline amine salt for the preparation of amorphous rosuvastatin calcium.
It is well known that alkali metal salts of organic acids are often hygroscopic in nature, which may cause problem during the isolation step. Isolation of rosuvastatin sodium, which is a common intermediate, used for the preparation of rosuvastatin calcium salt might be unrepeatable with respect to yield and physical state, in other words reaction condition and evaporation of solvent is difficult to control. The processes disclosed in the prior art have tried to solve the problem by preparing rosuvastatin sodium in situ but result in the contamination of final rosuvastatin calcium with various impurities, which are difficult to remove even after multiple purification steps, thus decrease the yield of the final rosuvastatin calcium and increase the production cost. Besides this, the processes disclosed in the prior arts utilize expensive chiral amine, which not only increases the production cost, but also makes the process uneconomical.
Therefore, there is a need in the art to develop a new amine salt of rosuvastatin, which is easy to prepare on industrial scale in highly pure form and in cost effective manner. Subsequently, its conversion to rosuvastatin calcium should be simple and in high yield and high purity.
OBJECT AND SUMMARY OF THE INVENTION
It is the principal object of the present invention to provide novel amine salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]- (3R, 5S)- dihydroxyhept-6-enoic acid (Rosuvastatin). According to yet another object of the present invention, there is provided novel amine salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino] pyrimidin-5-yl]-(3i?,5S)- dihydroxyhept-6-enoic acid (Rosuvastatin) selected from the group comprising of S-benzylisothiourea, L-lycine, L-arginine, aminoguanidine in crystalline or amorphous solid, anhydrous, solvate or hydrate form.
According to another object of the present invention, there is provided a process for the preparation of novel amine salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3 ?, 55)- dihydroxyhept-6-enoic acid (Rosuvastatin), selected from the group comprising of S-benzylisothiourea, L-lycine, L- arginine and aminoguanidine, preferably S-benzylisothiourea salt of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]-(37?,5S)- dihydroxyhept-6-enoic acid (Rosuvastatin).
According to yet another object of the present invention, there is provided a process for the preparation of crystalline S-benzylisothiourea salt of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3 ?, 5S)- dihydroxyhept-6-enoic acid (Rosuvastatin).
According to yet another object of the present invention there is provided an improved process for the preparation of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methylimethylsulfony aminolpyrimidin-S-ylj-Q/-, 55)- dihydroxyhept-6-enoic acid (Rosuvastatin) calcium of Formula I in high yield and low diastereomeric impurity employing novel amine salt, preferably S-benzylisothiourea salt of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]-(3i?,5S)- dihydroxyhept-6-enoic acid (Rosuvastatin).
According to yet another aspect of the present invention there is provided an improved process for the preparation of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino] pyrimidin-5-yl]-(3/?,5S)- dihydroxyhept-6-enoic acid (Rosuvastatin) calcium of Formula I, employing S-benzylisothiourea salt of rosuvastatin, the process comprising the steps of:
Figure imgf000006_0001
Formula I
(a) condensing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbaldehyde of Formula II;
Figure imgf000006_0002
Formula II
with methyl (3/?)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanoate of Formula HI, with or without azeotropic reflux; o OTBDMS
Ph3R COOCH3
Formula III
to obtain methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3i?)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6- heptenate of Formula IV;
Figure imgf000006_0003
Formula IV (b) deprotecting the tert-butyldimethylsilyl group of the condensed product of Formula IV to obtain methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3 ?)-3-hydroxy-5-oxo-(E)-6-heptenate of Formula
V;
Figure imgf000007_0001
Formula V
(c) stereoselectively reducing the keto group of the compound of the Formula V to obtain methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3i?,5S)- I;
Figure imgf000007_0002
Formula VI
(d) hydrolyzing the resulting compound of Formula VI in presence of a base to form rosuvastatin sodium of Formula VI';
Figure imgf000007_0003
Formula VI'
(e) treating the resulting compound of Formula VI' with S-benzylisothiourea or its salt to obtain rosuvastatin S-benzylisothiourea of Formula VII;
Figure imgf000008_0001
Formula VII
(e) reacting rosuvastatin S-benzylisothiourea of Formula VII with calcium salt to obtain rosuvastatin calcium of Formula I.
DESCRIPTION OF THE DRAWING
Fig. 1 shows the X-Ray powder diffraction pattern of crystalline S- benzylisothiourea salt of(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methy methylsulfony aminoJpyrimidin-S-ylHS^ 55)- dihydroxyhept-6-enoic acid.
DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The present invention discloses in its aspect novel amine salts of rosuvastatin with organic amines, wherein the organic amine according to the present invention is selected from the group consisting of:
(a)
Figure imgf000008_0002
wherein
Ri and R2 independently denote hydrogen, straight or branched chain alkyl having Ci-8 carbon atom; X denotes straight or branched chain alkyl having C1-8 carbon, amino alkyl group having 4 to 12 carbon, -NH-NH2, -NH-C(=NH)-NH2, -NH- (C=NH)(CH2)3-CH3, -NH-CH2-CH=C(CH3)2, -NH-(CH2)4-NH2, -NH-(C=NH)-N- morpholine, -NH-(C=NH)-piperidine, -S-CH3, -S-Ph, -S-CH2-Ph or (b)
Figure imgf000009_0001
Y denotes alkyl substituted or unsubstituted imidazole, amino group, -CH(OH)-CH2NH2, -NH-C(=NH)NH2, n is an integer from 1 to 8 or
(c)
Figure imgf000009_0002
wherein R' denotes H, -NH2, 4-aminophenyl and R" denotes 4-aminophenyl, 4,4- diaminophenyl, Br, CI, or
(d)
Figure imgf000009_0003
wherein Z is independently selected from the group comprising of -HN-(CH2)2-NH2, amino group, amino phenyl, or CH3-CH(NH2)-, Z' is independently selected from hydrogen, NH2 or
(e)
Figure imgf000009_0004
wherein R is selected from amino, alkyl amino, carboxy hydrazine (CO-NH-NH2) or
(f) Substituted thiazoles selected from the group comprising of 2-aminobenzothiazole, 6- aminobenzothiazole, 2-amino-4-methylthiazole and the like or
(g) Substituted azoles such as 3-amino-l,2,4-triazole, substituted pyrazole such as 2-(2H- pyrazol-3-yl)ethanamine and the like or
(h) Purine derivatives such as adenine, pyrimidine derivatives such as 2,4-diamino-6- hydroxypyrimidine, 4,5-diamino-6-hydroxy-2-mercaptopyrimidine or triazine derivative such as 2,4-diamino-6-phenyl-l ,3,5-triazine, 2-amino-4-ethoxy-6-(methylamino)- 1,3,5 - triazine and the like or
(i) Heterocyclic amines such as 2-methylpiperazine, 2-methylpiperidine, tetrahydrofurfuryl amine and the like. According to the present invention the preferred organic amine is S- benzylisothiourea represented by the following formula
Figure imgf000010_0001
Formula X
According to the present invention, there is provided novel amine salt of (E)-7- [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]- (3R,5S)- dihydroxyhept-6-enoic acid (Rosuvastatin), preferably selected from the group consisting of S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine in the form of crystalline or amorphous solid, anhydrous, solvate or hydrate form.
According to the present invention, there is provided a process for the preparation of novel amine salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]-(3/?, 5S)- dihydroxyhept-6-enoic acid (Rosuvastatin), preferably selected from the group consisting of S-benzylisothiourea, L- lycine, L-arginine and aminoguanidine by treating (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3i?, 55)- dihydroxyhept-6-enoic acid sodium salt of Formula VI' with S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine or their salts in an organic solvent and isolating the resulting amine salt of rosuvastatin.
The amine salts of S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine are selected from the group comprising of hydrochloride, hydrobromide, acetate and the like, preferably hydrochloride.
The conversion of rosuvastatin sodium salt of Formula VI' to amine salt of rosuvastatin such as S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine, preferably S-benzylisothiourea salt of rosuvastatin is carried out in an organic solvent, wherein the organic solvent is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate and the like, ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like, nitriles such as acetonitrile propionitrile and the like, sulphoxides such as dimethyl sulphoxide, and the like, amides such as dimethylacetamide, dimethylformamide and the like or mixtures thereof, preferably acetone. The reaction is carried out at a temperature between 10-100°C, preferably 20-80°C for 10-20 hours, preferably 14-16 hours.
According to the present invention, there is provided a process for the preparation of S-benzylisothiourea salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]-(3/?, 5S)- dihydroxyhept-6-enoic acid (Rosuvastatin) by hydrolysis of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3i?,55)-dihydroxy (E)-6-heptenate in presence of a base in an organic solvent to obtain the rosuvastatin salt, preferably rosuvastatin sodium salt of Formula VP treating the resulting rosuvastatin salt with S-benzylisothiourea or its salt in an organic solvent and isolating the resulting 5-benzylisothiourea salt of rosuvastatin. Further, the conversion of methyl ester of rosuvastatin to its corresponding rosuvastatin S-benzylisothiourea or its salt can optionally take place with or without isolation of corresponding rosuvastatin salt such as rosuvastatin sodium.
The hydrolysis of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3-¾,5S)-dihydroxy (E)-6-heptenate is carried out in presence of a base, wherein the base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate, bicarbonate and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of lithium, sodium, potassium, calcium, magnesium, barium and the like, preferably sodium hydroxide. The solvent used for hydrolysis is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like, ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, sulphoxides such as dimethyl sulphoxide, and the like, amides such as dimethylacetamide, dimethylformamide and the like, water or mixtures thereof. The reaction is carried out at a temperature between -5-50°C, preferably 0-20°C for 1-4 hours, preferably 2-3 hours.
According to the present invention, there is provided S-benzylisothiourea salt of rosuvastatin is in crystalline form characterized by its XRD pattern having significant peak at about 15.5, 17.6, 18.5, 19.7, 20.8, 22.2, 23.9, 27.2, 31.6 ±0.2 degree two theta as given in Fig 1. The XRPD data reported herein was obtained using Cu Ka radiation, having the wavelength 1.54A and using a PANalytical powder X-ray Diffractometer. According to another aspect, the present invention provides, a process for the preparation of crystalline S-benzylisothiourea salt of (E)-7-[4-(4-fluorophenyl)-6- isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3/?, 5S)- dihydroxyhept-6- enoic acid (Rosuvastatin), by crystallizing the S-benzylisothiourea salt of rosuvastatin in an organic solvent and isolating the resulting amine salt of rosuvastatin. The organic solvent used herein is selected from the group comprising of ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate and the like, nitriles such as acetonitrile, propionitrile and the like, alcohols such as methanol, ethanol, propanol, butanol and the like, water or mixture thereof, preferably acetone.
According to the present invention, there is provided an improved process for the preparation of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl]-(3i?,5S)- dihydroxyhept-6-enoic acid (Rosuvastatin) calcium of Formula I in high yield and low diasteromeric impurity employing S-benzylisothiourea salt of rosuvastatin, the process comprising the steps of:
Figure imgf000012_0001
Formula I
(a) condensing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-iV-methylsulfonyl pyrimidinecarbaldehyde of Formu
Figure imgf000012_0002
Formula II
with methyl (3 ?)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanoate of Formula III with or without azeotropic reflux; O OTBDMS
Ph3P ^ COOCH3
Formula III
in an organic solvent to obtain methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3/?)-3-(ter/-butyldimethylsilyloxy)-5-oxo-(E)-6- heptenate of Formula IV;
Figure imgf000013_0001
Formula IV
(b) deprotecting the rt-butyldimethylsilyl group of the condensed product of Formula IV with an acid in a solvent to obtain methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3/?)-3-hydroxy-5-oxo-(E)-6-heptenate of Formula V;
Figure imgf000013_0002
Formula V
(c) stereoselectively reducing the resulting keto ester of Formula V with diethylmethoxyborane and metal borohydride in a solvent to obtain methyl 7-[4-(4- fluorophenyl)-6-isopropyl-2-methyl-(N-methylsulfonylamino)pyrimidin-5-yl]-(3/?,55)- dihydroxy-(E)-6-heptenate of Formula VI; COOCH3
CH3
Formula VI
(d) hydrolyzing the resulting 3,5-dihydroxy ester compound of Formula VI in presence of a base to form rosuvastatin sodium of Formula VI';
Figure imgf000014_0001
Formula VI'
(e) reacting the rosuvastatin sodium of Formula VI' with S-benzylisothiourea or its salt in an organic solvent to obtain rosuvastatin S-benzylisothiourea of Formula VII;
Figure imgf000014_0002
Formula VII
(f) treating the resulting rosuvastatin S-benzylisothiourea of Formula VII with calcium salt to obtain rosuvastatin calcium of Formula I.
In step (a) the condensation of 4-(4-fluorophenyl)-6-isopropyl-2-(jV-methyl-N- methylsulfonylamino)-5-pyrimidinecarbaldehyde of Formula II is carried out with less than 1.2 mole equivalent of methyl (3i?)-3-(tert-butyldimethylsilyloxy)-5-oxo-6- triphenylphosphoranylidene hexanoate of Formula III in an organic solvent, wherein the organic solvent is selected from the group comprising of Cs-Cg linear, branched or cyclic hydrocarbon such as pentane, hexane, heptane, octane, cyclohexane and the like, aromatic hydrocarbon such as toluene, benzene, chlorobenzene and the like, alcohols such as methanol, ethanol, propanol, butanol and the like, esters such as ethyl acetate, propyl acetate and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, nitriles such as acetonitrile, propionitrile and the like or mixture thereof, preferably cyclohexane. The reaction is carried out at temperature between 50-100°C, preferably between 60-90°C for 30-70 hours, preferably for 40-60 hours.
The resulting compound of Formula IV prepared according to present invention is in high purity and is prepared in environment friendly manner because the reaction condition used are simple and avoid the use of stringent reaction condition such as use of low temperature and inert atmosphere.
In step (b) the resulting compound of Formula IV undergoes deprotection of tert- butyldimethylsilyl group using an acid, wherein the acid is selected from organic acid such as methanesulphonic acid, /?-toluenesulphonic acid, acetic acid and the like, inorganic acid such as hydrochloric acid, sulphuric acid or mixture thereof, preferably methanesulphonic acid. The solvent used herein is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like, esters such as ethyl acetate, propyl acetate and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, nitriles such as acetonitrile, propionitrile and the like or mixture thereof, preferably acetonitrile or their combination with water in various proportions. The reaction is carried out at temperature between 20-50°C, preferably between 25-40°C for 4-10 hours, preferably for 6-8 hours.
The resulting compound of Formula V is used as such for the stereoselective reduction or is purified using organic solvent selected from the group comprising of alcohol such as methanol, ethanol, propanol, butanol and the like, chlorinated hydrocarbon such as dichloromethane and the like, ethers such as tetrahydrofuran and the like, nitriles such as acetonitrile and the like or in combination with anti-solvent selected from the group comprising of hydrocarbons such as hexane, cyclohexane and the like, ethers such as methyl tertiary butyl ether, diisopropyl ether and the like or water.
In step (c) the resulting keto ester compound of Formula V is steroselectively reduced using diethylmethoxyborane and metal borohydride in a solvent, wherein the metal borohydride is selected from the group comprising of lithium borohydride, sodium borohydride and the like, preferably sodium borohydride. The solvent is selected from the group comprising of hydrocarbons such as toluene, xylene and the like, alcohols such as methanol, ethanol, propanol, butanol and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate and the like, ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, sulphoxides such as dimethyl sulphoxide, and the like, amides such as dimethylacetamide, dimethylformamide and the like, or mixtures thereof, preferably mixture of tetrahydrofuran and methanol, with optimized quantity of reducing agent and in the appropriate sequence of solvent(s), reagent(s) and substrate. The reduction reaction is carried out at temperature lower than - 70°C to -90°C under inert atmosphere which reduces the formation of diastereomeric content during the reaction.
In step (d) the resulting methyl ester compound of Formula VI is hydrolyzed in presence of a base in solvent selected from organic solvent, water or mixture thereof to obtain rosuvastatin salt, preferably rosuvastatin sodium of Formula VI'.
The base used for hydrolysis is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonates, bicarbonates and the like, wherein the alkali and alkaline earth metal is selected from the group comprising of lithium, sodium, potassium, calcium, magnesium, barium and the like, preferably sodium hydroxide. The solvent used for hydrolysis is selected from the group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like, ethers such as methyl tertiary butyl ether, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, sulphoxides such as dimethyl sulphoxide, and the like, amides such as dimethylacetamide, dimethylformamide and the like, water or mixtures thereof.
In step (e) the resulting rosuvastatin salt is treated with an appropriate amine such as S-benzylisothiourea or its salt in an organic solvent and isolating the S- benzylisothiourea salt of rosuvastatin.
The salt of S-benzylisothiourea used herein is selected from the group comprising of hydrochloride, hydrobromide, acetate and the like.
In step (e), the organic solvent used for the conversion of rosuvastatin sodium of Formula VI' to S-benzylisothiourea salt of rosuvastatin is selected from the group comprising of chlorinated or non chlorinated hydrocarbons such as dichloromethane, chloroform and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters such as ethyl acetate, propyl acetate and the like, nitriles such as acetonitrile, propionitrile and the like, alcohols such as methanol, ethanol, propanol, butanol and the like, water or mixture thereof, preferably acetone.
The resulting S-benzylisothiourea salt of rosuvastatin is then converted to rosuvastatin calcium, preferably in amorphous form having purity more than 99% and having low content of diasteromeric impurity by treating the rosuvastatin S- benzylisothiourea of Formula VII with a base followed by addition of calcium salt in an solvent to obtain rosuvastatin calcium of Formula I. The calcium salt used herein is selected from the group comprising of calcium chloride, calcium acetate, calcium nitrate, calcium hydroxide, calcium palmitate, calcium pivalate, calcium carbonate, calcium bicarbonate and the like, preferably calcium acetate. The solvent is selected from the group comprising of alcohol such as methanol, ethanol, propanol and the like or water or mixture thereof.
Further, the conversion of the S-benzylisothiourea salt of rosuvastatin to rosuvastatin calcium can optionally take place with or without isolation of rosuvatstatin salt such as rosuvastatin sodium of Formula VI'.
The 5-benzylisothiourea salt of rosuvastatin prepared according to the present invention has purity greater than 99% and contains diastereomeric content less than 0.5%. Further the rosuvastatin calcium prepared using the S-benzylisothiourea salt of rosuvastatin has purity greater than 99.5% and contains diastereomeric content less than 0.5%.
The present invention is described in detail as illustrated in the non-limiting examples. It should be understood that variation and modification of the process are possible within the ambit of the invention broadly disclosed herein.
Example 1
Preparation of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonyIamino)pyrimidin-5-yI]-(3R)-3-(ter^butyldimethylsilyloxy)-5-oxo-( - 6-heptenate (IV)
4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbaldehyde (lOOg) was taken in cyclohexane (500 ml) and to this methyl (3 ?)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanoate (160g) was added at 25-30°C. The reaction mixture was refluxed under azeotropic condition at 80-85 °C for 48-60 hours under stirring. After completion of reaction, the reaction mixture was cooled and stirred for 2.0 hours. The reaction mass was filtered and washed with cyclohexane. The organic layer was concentrated under reduced pressure to obtain the title compound as thick oily mass.
Example 2
Preparation of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(£)-6-heptenate (V)
Methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3i?)-3-(ter/-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate obtained from example 1 was taken in acetonitrile 800 ml) at 25-30°C. To the resulting solution, methane sulphonic acid (19.1 g in 85 ml water) was added. The reaction mixture was then stirred for 6-8 hours. After the reaction completion, saturated sodium bicarbonate solution was added. Subsequently, water (850 ml) and methyl tertiary butyl ether (525 ml) was added and stirred. The organic layer was separated and the aqueous layer was extracted with methyl tertiary butyl ether. The organic layers were combined, washed first with water and then with saturated sodium bicarbonate solution and brine solution. The organic layers were concentrated under reduced pressure to obtain thick oily mass. The resulting oily mass was chased with methyl tertiary butyl ether to obtain solid. The resulting solid was taken in methyl tertiary butyl ether and was stirred for 1 hour. The reaction mass was cooled to 0-5 °C, stirred for 1 hour. The resulting solid was filtered, washed with methyl tertiary butyl ether and dried under vacuum to obtain the title compound.
Example 3
Preparation of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-iV- methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(£)-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 5% 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.
Example 4
Preparation of S-benzylisothiourea salt of Rosuvastatin (VII)
Methyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3i?,5S)-dihydroxy-(E)-6-heptenate thus obtained was taken in isopropanol (1000 ml) and water (1000 ml) and was stirred at room temperature. The reaction mixture was cooled to 0-10°C and aqueous sodium hydroxide solution was added to the reaction mixture. The pH was adjusted to 9-10 using 10% aqueous acetic acid. The resulting reaction mixture was concentrated and was cooled to room temperature. To it, methyl tertiary butyl ether was added and the pH was adjusted between 1 - 2 using 2N HC1 solution. The organic layer was separated and washed with water and concentrated. To the resulting oily mass, acetone (200 ml) was added and pH was adjusted between 10 - 1 1 using 30% aqueous sodium hydroxide solution. The resulting reaction mass was concentrated and the residue was dissolved in acetone (150 ml). A solution of S- benzylisothiourea hydrochloride (41 g) in acetone (250 ml) was added and was stirred for 15-16 hours, filtered the resulting solid and dried under vacuum to obtain the title compound.
Yield: 84-85% Diastereomeric content: 0.20%
Example 5
Preparation of L-lycine salt of rosuvastatin
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]- (3R,5S)- dihydroxyhept-6-enoic acid sodium salt (l .Og) was taken in ethyl acetate (10 ml) at 25-30°C. To the resulting mixture, L-lysine hydrochloride (0.4g) was added and was stirred for 5 hr at 25-30°C. The resulting solid was filtered off, washed with the ethyl acetate and dried under vacuum at 45-50°C to obtain the title compound.
Example 6
Preparation of L-arginine salt of rosuvastatin
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyI)amino]pyrimidin-5-yl]- (3R,5S)- dihydroxyhept-6-enoic acid sodium salt (l .Og) was taken in ethyl acetate (20 ml) at 25-30°C. To the resulting mixture, of L-arginine (0.4g) was added and stirred for 5 hr at room temperature. The resulting solid was filtered off, washed with the ethyl acetate and dried under vacuum at 45-50°C to obtain the title compound.
Example 7
Preparation of L-arginine salt of rosuvastatin
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]- (3R,5S)- dihydroxyhept-6-enoic acid sodium salt (l .Og) was taken in acetonitrile (20 ml) at 25-30°C. To the resulting mixture, L-arginine (0.4g) was added and stirred for 5 hr at room temperature. The resulting solid was filtered off, washed with the acetonitrile and dried under vacuum at 45-50°C to obtain the title compound.
Example 8
Preparation of aminoguanidine salt of rosuvastatin
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]- (3R,5S)- dihydroxyhept-6-enoic acid sodium salt (l .Og) was taken in ethyl acetate (10 ml) at 25-30°C. To the resulting mixture, aminoguanidine hydrochloride (0.26g) was added and stirred for 5 hour at room temperature. The resulting solid was filtered off, washed with the ethyl acetate and dried under vacuum at 45-50°C to obtain the title compound.
Example 9
Preparation of S-benzylisothiourea salt of Rosuvastatin (VII)
Methyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(iV-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3/?,5S)-dihydroxy-(E)-6-heptenate (lOOg) was taken in isopropanol (1000 ml) and stirred. The reaction mixture was cooled to 5-10°C and sodium hydroxide solution (8.9g in 200 ml water) was added to the reaction mixture over a period of 0.5 hours at 5-10°C. The reaction mixture was stirred for few minutes and warmed to 25- 30°C. The resulting mixture was further stirred for 2 hours. After reaction completion, the reaction mass was concentrated at 45-50°C to obtain a thick oily mass. The reaction mass was then chased off with methyl ethyl ketone to obtain a solid residue. The pH was adjusted to 8.5-9.0 using 10% aqueous acetic acid followed by addition of S- benzylisothiourea hydrochloride. The resulting reaction mixture was stirred for 15-16 hours to obtain solid, which was washed with methyl ethyl ketone and dried to obtain the title compound as solid.
Yield: 84 % Diastereomeric content: 0.22% Example 10
Preparation of Rosuvastatin calcium (I)
S-Benzylisothiourea rosuvastatin (50g) was taken in water (400ml) at room temperature. To the resulting mixture, sodium hydroxide (4.6g) was added and stirred for 8-10 hr. The resulting mixture was filtered to remove any solid, if present. To the resulting filtrate, methyl tertiary butyl ether was added. The reaction mass was stirred for 30 minutes. The layers were separated and to the resulting aqueous layer, 0.5% aqueous acetic acid was added to adjust the pH 9-10 using 0.5% aqueous acetic acid. The resulting solution was filtered through micron filter and aqueous solution of calcium acetate (6.7g dissolved in 100ml water) was added at 25-30°C. The resulting mixture was stirred for 2 hrs. The resulting solid was filtered, washed with water and dried under vacuum at 45-50°C to obtain title compound.
Purity: 99.7%; Diastereomeric content: 0.17%
Example 1 1
Preparation of Rosuvastatin calcium (I)
S-Benzylisothiourea rosuvastatin (lOOg) was taken in water (500ml) and methyl tertiary butyl ether (500 ml) at room temperature. The pH was adjusted between 1-2 by using 2N HC1 solution. The organic layer was separated and washed with water. To the organic layer, aqueous NaOH solution was added and the layers were separated. The pH of the aqueous layer was adjusted to 8-8.5 using 0.5% aqueous acetic acid. The resulting solution was filtered through micron filter and aqueous solution of calcium acetate (13.14 g, dissolved in 200ml water) was added at 25-30°C. The resulting mixture was stirred for 1 - 2 hrs. The resulting solid was filtered, washed with water and dried under vacuum to obtain title compound.
Purity: 99.7%; Diastereomeric content: 0.18%

Claims

We claim:
1. Novel amine salts of rosuvastatin with organic amine, wherein the organic selected from the group consisting of:
(a)
Figure imgf000022_0001
wherein
Ri and R2 independently denote hydrogen, straight or branched chain alkyl having Ci.g carbon atom; X denotes straight or branched chain alkyl having Ci-8 carbon, amino alkyl group having 4 to 12 carbon, -NH-NH2, -NH-C(=NH)-NH2, -NH- (C=NH)(CH2)3-CH3, -NH-CH2-CH=C(CH3)2, -NH-(CH2)4-NH2, -NH-(C=NH)-N- morpholine, -NH-(C=NH)-piperidine, -S-CH3, -S-Ph, -S-CH2-Ph or
(b)
Figure imgf000022_0002
Y denotes alkyl substituted or unsubstituted imidazole, amino group, -CH(OH)- CH2NH2,
-NH-C(=NH)NH2, n is an integer from 1 to 8 or
(c)
Figure imgf000022_0003
wherein R' denotes H, -NH2, 4-aminophenyl and R" denotes 4-aminophenyl, 4,4- diaminophenyl, Br, CI, or
(d)
Figure imgf000022_0004
wherein Z is independently selected from the group comprising of -HN-(CH2)2-NH2, amino group, amino phenyl, or CH3-CH(NH2)-, Z' is independently selected from hydrogen, NH2 or
(e)
Figure imgf000023_0001
wherein R is selected from amino, alkyl amino, carboxy hydrazine (CO-NH-NH2) or
(f) substituted thiazoles selected from the group comprising of 2-aminobenzothiazole, 6-aminobenzothiazole, 2-amino-4-methylthiazole or
(g) substituted azoles such as 3-amino-l ,2,4-triazole, substituted pyrazole such as 2- (2H-pyrazol-3-yl)ethanamine or
(h) purine derivatives such as adenine, pyrimidine derivatives such as 2,4-diamino-6- hydroxypyrimidine, 4,5-diamino-6-hydroxy-2-mercaptopyrimidine or triazine derivative such as 2,4-diamino-6-phenyl-l,3,5-triazine, 2-amino-4-ethoxy-6- (methylamino)-l,3,5-triazine or
(i) heterocyclic amines such as 2-methylpiperazine, 2-methylpiperidine, tetrahydrofurfuryl amine.
2. Novel amine salt of rosuvastatin according to claim 1 , wherein the amine is selected from the group consisting of S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine.
3. 5-Benzylisothiourea salt of fi)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl)amino]pyrimidin-5-yl]-(3 ?,5S)-dihydroxyhept-6-enoic
(Rosuvastatin) of following formula:
Figure imgf000023_0002
Formula VII
4. A compound according to claim 3, which is in solid form.
5. A compound according to claim 4, which is in crystalline form.
6. A compound according to claim 5, which is characterized by an X-ray powder diffraction pattern having characteristic peaks at 15.5, 17.6, 18.5,19.7, 20.8, 22.2, 23.9, 27.2, 31.6 ± 0.2 degrees 2 theta.
7. A process for the preparation of novel amine salt of (E)-7-[4-(4-fluorophenyl)-6- isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl]-(3 ?, 5S)- dihydroxyhept-6-enoic acid (Rosuvastatin) selected from the group consisting of S-benzylisothiourea, L-lycine, L-arginine and aminoguanidine by treating (E)-7- [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5- yl]-(3 ?, 5S)-dihydroxyhept-6-enoic acid sodium salt with S-benzylisothiourea, L- lycine, L-arginine and aminoguanidine or their salts in an organic solvent and isolating the resulting amine salt of rosuvastatin.
8. The process according to claim 7, wherein the salt of S-benzylisothiourea, L- lycine, L-arginine and aminoguanidine is selected from the group comprising of hydrochloride, hydrobromide and acetate.
9. The process according to claim 7, wherein the organic solvent is selected from the group comprising of alcohols, ketones, esters, ethers, nitriles, sulphoxides, amides and mixtures thereof.
10. The process according to claim 9, wherein the organic solvent is selected from the group comprising of methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate, methyl tertiary butyl ether, tetrahydrofuran, acetonitrile, propionitrile, dimethyl sulphoxide, dimethylacetamide and dimethylformamide.
1 1. A process for the preparation of S-benzylisothiourea salt of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]- (3 ?, 5S)-dihydroxyhept-6-enoic acid (Rosuvastatin) by hydrolysis of methyl 7-[4- (4-fluorophenyl)-6-isopropyl-2-methyl-N-methylsulfonylamino)pyrimidin-5-yl]- (3R, 5S)-dihydroxy (E)-6-heptenate in presence of a base in an organic solvent to obtain the rosuvastatin sodium, treating the resulting rosuvastatin sodium with S- benzylisothiourea or its salt in an .organic solvent and isolating the resulting S- benzylisothiourea salt of rosuvastatin.
12. A process according to claim 1 1 , wherein the base is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate and bicarbonate.
13. The process according to claim 12, wherein the alkali and alkaline earth metal is selected from the group comprising of lithium, sodium, potassium, calcium, magnesium and barium.
14. The process according to claim 1 1 , wherein the solvent used for hydrolysis is selected from the group comprising of alcohols, ethers, nitriles, sulphoxides, amides, water and mixtures thereof.
15. The process according to claim 14, wherein the organic solvent is selected from the group comprising of methanol, ethanol, propanol, butanol, methyl tertiary butyl ether, tetrahydrofuran, acetonitrile, propionitrile, dimethyl sulphoxide, dimethylacetamide and dimethylformamide.
16. The process according to claim 1 1 , wherein the solvent used for the amine salt formation is selected from the group comprising of alcohols, ketones, esters, ethers, nitriles, sulphoxides, amides and mixtures thereof.
17. The process according to claim 16, wherein the organic solvent is selected from the group comprising of methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate, methyl tertiary butyl ether, tetrahydrofuran, acetonitrile, propionitrile, dimethyl sulphoxide, dimethylacetamide and dimethylformamide.
18. A process for the preparation of crystalline S-benzylisothiourea salt of (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]- (3^, 5S)-dihydroxyhept-6-enoic acid (Rosuvastatin), by crystallizing the S- benzylisothiourea salt of rosuvastatin in an organic solvent and isolating the resulting amine salt of rosuvastatin.
19. The process according to claim 18, wherein the organic solvent is selected from the group comprising of ketones, esters, nitriles, alcohols, water and mixture thereof.
20. The process according to claim 19, wherein the organic solvent is selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate acetonitrile, propionitrile, methanol, ethanol, propanol and butanol.
21. A process for the preparation of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3i?,5iS)-dihydroxyhept-6-enoic acid (Rosuvastatin) calcium of Formula I, employing S-benzylisothiourea salt of rosuvastatin the process comprising the steps of:
Figure imgf000026_0001
Formula I
(a) condensing 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl
5-pyrimidinecarbaldehyde of Formula II
Figure imgf000026_0002
Formula II
with methyl (3i?)-3-(/ert-butyldimethylsilyloxy)-5-oxo-6- triphenylphosphoranylidene hexanoate of Formula III, with or without azeotropic reflux:
O OTBDMS
Ph3P^^\^^/COOCH3
Formula III in an organic solvent to obtain methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methylsulfonylamino)pyrimidin-5 -yl] -(3 R)-3 - tert- butyldimethylsil IV;
Figure imgf000027_0001
Formula IV
(b) deprotecting the tert-butyldimethylsilyl group of the condensed product of Formula IV with an acid in a solvent to obtain methyl 7-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3i?)-3-hydroxy- 5-oxo-(E)-6-heptenate of Formula V;
Figure imgf000027_0002
Formula V
(c) stereoselectively reducing the resulting keto ester of Formula V with diethylmethoxyborane and metal borohydride in a solvent to obtain methyl 7-[4- (4-fluorophenyl)-6-isopropyl-2-methyl-(N-methylsulfonylamino)pyrimidin-5-yl]- (3/?,5S)-dihydroxy-(E)-6-heptenate of Formula VI;
Figure imgf000027_0003
Formula VI (d) hydrolyzing the resulting 3,5-dihydroxy ester compound of Formula VI in presence of a base to form rosuvastatin sodium of Formula VI';
Figure imgf000028_0001
Formula VI'
(e) reacting the rosuvastatin sodium of Formula VI' with 5-benzylisothiourea or its salt in an organic solvent to obtain rosuvastatin S-benzylisothiourea of Formula VII;
Figure imgf000028_0002
Formula VII
(f) treating the resulting rosuvastatin S-benzylisothiourea of Formula VII with calcium salt to obtain rosuvastatin calcium of Formula I.
22. The process according to claim 21, wherein the organic solvent used in step (a) is selected from the group comprising of C5-C8 linear, branched or cyclic hydrocarbons, aromatic hydrocarbons, alcohols, esters, ketones, nitriles and mixtures thereof.
23. The process according to claim 22, wherein the organic solvent is selected from the group comprising of pentane, hexane, heptane, octane, cyclohexane, toluene, benzene, chlorobenzene, methanol, ethanol, propanol, butanol, ethyl acetate, propyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile and propionitrile.
24. The process according to claim 21 , wherein the acid used in step (b) is selected from the group comprising of organic acid, inorganic acid and mixtures thereof.
25. The process according to claim 24, wherein the acid is selected from the group comprising of methanesulphonic acid, /?-toluenesulphonic acid, acetic acid, hydrochloric acid and sulphuric acid.
26. The process according to claim 21 , wherein the solvent used in step (b) is selected from the group comprising of alcohols, esters, ketones, nitriles, water and mixture thereof.
27. The process according to claim 26, wherein the solvent is selected from the group comprising of methanol, ethanol, propanol, butanol, ethyl acetate, propyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile and propionitrile.
28. The process according to claim 21 , wherein the metal borohydride used in step (c) is selected from the group comprising of lithium borohydride and sodium borohydride.
29. The process according to claim 21, wherein the solvent used in step (c) for stereoselective reduction is selected from the group comprising of hydrocarbons, alcohols, esters, ethers, ketones, nitriles, sulphoxides, amides and mixtures thereof.
30. The process according to claim 29, wherein the solvent is selected from the group comprising of toluene, xylene, methanol, ethanol, propanol, butanol, ethyl acetate, propyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tertiary butyl ether, tetrahydrofuran, acetonitrile, propionitrile, dimethyl sulphoxide, dimethylacetamide and dimethylformamide.
31. The process according to claim 21 , wherein the base used in step (d) is selected from the group comprising of alkali or alkaline earth metal hydroxide, carbonate and bicarbonate.
32. The process according to claim 31, wherein the alkali and alkaline earth metal is selected from the group comprising of lithium, sodium, potassium, calcium, magnesium and barium.
33. The process according to claim 21, wherein the solvent used for hydrolysis in step (d) is selected from the group comprising of alcohols, ethers, nitriles, sulphoxides, amides, water and mixtures thereof.
34. The process according to claim 33, wherein the organic solvent is selected from the group comprising of methanol, ethanol, propanol, butanol, methyl tertiary butyl ether, tetrahydrofuran, acetonitrile, propionitrile, dimethyl sulphoxide, dimethylacetamide and dimethylformamide.
35. The process according to claim 21, wherein the salt of S-benzylisothiourea used in step (e) is selected from the group comprising of hydrochloride, hydrobromide and acetate.
36. The process according to claim 21, wherein the organic solvent used in step (e) is selected from the group comprising of chlorinated or nonchlorinated hydrocarbons, alcohols, ketones, esters, ethers, nitriles, water and mixtures thereof.
37. The process according to claim 21, wherein the organic solvent is selected from the group comprising of dichloromethane, chloroform, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate, methyl tertiary butyl ether, tetrahydrofuran, acetonitrile and propionitrile.
38. The process according to claim 21 , wherein the calcium salt used in step (f) is selected from the group comprising of calcium chloride, calcium acetate, calcium nitrate, calcium hydroxide, calcium palmitate, calcium pivalate, calcium carbonate and calcium bicarbonate.
39. The process according to claim 21, wherein the solvent used in step (f) is selected from the group comprising of alcohol, water and mixture thereof.
40. The process according to claim 39, wherein the alcohol is selected from the group comprising of methanol, ethanol and propanol.
41. Rosuvastatin calcium having purity greater than 99.5% and contains diasteromeric content less than 0.5%.
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