WO2009157014A2 - A process for preparing hmg-coa reductase inhibitors and intermediates - Google Patents

A process for preparing hmg-coa reductase inhibitors and intermediates Download PDF

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WO2009157014A2
WO2009157014A2 PCT/IN2009/000065 IN2009000065W WO2009157014A2 WO 2009157014 A2 WO2009157014 A2 WO 2009157014A2 IN 2009000065 W IN2009000065 W IN 2009000065W WO 2009157014 A2 WO2009157014 A2 WO 2009157014A2
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formula
impurity
isopropyl
compound
depicted
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PCT/IN2009/000065
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French (fr)
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WO2009157014A3 (en
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Shriprakash Dhar Dwivedi
Anil Ganpat Holkar
Dhimant Jasubhai Patel
Mahesh L. Rupapara
Mayur R. Patel
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Cadila Healthcare Limited
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Publication of WO2009157014A3 publication Critical patent/WO2009157014A3/en

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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
    • C07D239/30—Halogen atoms or nitro radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the present invention relates to a process for preparing HMG-CoA reductase inhibitors and intermediates thereof. Particularly, the present invention relates to an improved process for synthesizing calcium salt of (E)-7-[4-(4-flurophenyl)-6- isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6- heptenoic acid (Rosuvastatin Calcium) in high purity.
  • Rosuvastatin that is chemically known as (E)-7-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid and its salts, which are HMG-CoA reductase inhibitors and useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
  • [methyl(methylsulfonyl)amino]- pyrimidm-5-yl](3R,5S)-3,5-dihydroxy-6-heplen ⁇ ie acid and its salts is a HMG-CoA reductase inhibitor, a superstatin developed by Shionogi for the treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996, Direct Communication, Shionogi 8 Feb. 1999 and 25 Feb. 2000). It can lower LDL- cholesterol and triglycerides more effectively than the first generation drugs.
  • Rosuvastatin calcium has the following structure being shown by formula (1)
  • Rosuvastatin calcium is marketed under the trade name of CRESTOR for treatment of a mammal such as a human. According to the maker of CRESTOR, it is administered in a daily dose of from about 5 mg to about 40 mg. For patients requiring less aggressive LDL-C reductions or who have pre-disposing factors for myopathy, the 5 mg dose is recommended, while 10 mg dose is recommended for the average patient, 20 mg dose for patients with marked hypercholesterolemia and aggressive lipid targets (>192 mg/dL), and the 40 mg dose for patients who have not been responsive to lower doses.
  • WO 03/032995 further discloses a method of preventing dementia by administering to a patient rosuvastatin.
  • U.S. Pat. No. 5,260,440 discloses the process to produce rosuvastatin salt.
  • the process of UlS.Pat.No.5,260,440 starts with the methyl ester of rosuvastatirrrknown an (methyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy -(E)-6-heptenate (methyl rosuvastatin)).
  • the process for preparation of the intermediates disclosed in the '440 patent is incorporated herein by reference.
  • rosuvastatin sodium is prepared from its methyl ester according to Example 1 (6) by adding sodium hydroxide to a solution of the methyl ester in ethanol, followed inter alia by distillation, followed by addition of ether to the residue obtained from distillation.
  • the present applicants found that diethyl ether may not be used in production; after distillation of the solvent, the present applicants obtained a viscous oil that hardly precipitates in diethyl ether.
  • EP 1417180 Bl discloses the preparation of aminopyrimidine compounds of formula (8) wherein R is a hydrocarbonyl group, and each of R 1 and R 2 independently is a hydrogen atom, an alkyl group, an alkylsulfonyl group, or an arylsulfonyl group, more particularly to the preparation of a 2-(N-methyl-N- methanesulfonylamnino)pyrimidine compound having the following formula (3)
  • EP ' 180 Bl also discloses the process for the preparation of (N-melhyl-N- methanesulfonylaninino) pyrimidine compound having the following formula (3) via novel intermediates of formula (1), formula (4), formula (9) and formula (10),
  • WO 2006/067456 A2 discloses the process for the preparation of various intermediates for "the preparation of (N-methyl-N-methanesulfonylamnino) pyrimidine compound having the following formula (3)
  • Reaction scheme-2 to scheme-6 provides various reaction sequences for the preparation of pyrimidine intermediates useful for the synthesis of rosuvastatin calcium.
  • the intermediates obtained are condensed with side chain to obtain rosuvastatin calcium via condensed product.
  • WO 2007/007119 Al discloses the process for the manufacture of rosuvastatin and intermediates as disclosed in scheme-7.
  • WO 2006/00126035 A2 discloses the process for the manufacture of rosuvastatin and intermediates as disclosed in scheme-8.
  • the acid of formula (III) is treated with suitable organic or inorganic base to form a salt, then eliminating acetonide group and reacting with calcium chloride in a base; or reacting rosuvastatin protected diol acid of formula (III) therein with suitable organic or inorganic base to form a salt, then eliminating acetonide group arid reacting with calcium chloride in a base; or reacting a salt of formula (III) therein formed with an organic or inorganic base then by eliminating acetonide group and reacting with calcium chloride in a base to obtain amorphous rosuvastatin calcium.
  • Suitable organic or inorganic bases used for the preparation of salt of rosuvastatin protected diol acid of formula (III) therein are selected from methylamine, diethanolamine, ethanolamine, magnesium sulfate, L-lysine, benzylamine, L-(-)- ⁇ -methyl-benzylamine or N-methyl-D-glucosamine.
  • US 6,844,437 Bl and US 6,784,171 B2 provides the process for the preparation of tert-butyl (E)-(6- ⁇ 2-[4-(4-fluorophenyl)-6-isopropyl-2-
  • US 6,841,554 B2 discloses a crystalline salt of the compound (E)-(6- ⁇ 2-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] ⁇ -(3R,5S)- 3,5-dihydroxyhept-6-enoic acid of formula (I), wherein the salt in an ammonium, methylammonium, ethylammonium, diethanolammonium, tris(hydroxymethyl)methyl ammonium, benzylammonium, 4-methoxybenzylammonium, lithium or magnesium salt.
  • the present invention provides an improved process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5),
  • the present invention an improved process for the preparation of rosuvastatin or its salts like calcium of formula (1)
  • step (b) reacting compound of formula (5) obtained in step (a) with monomethyl amine solution at an ambient temperature to obtain tert-butyr2 :: ((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidm-5-yl)vinyl)-2,2-dimethyl-l,3- dioxan-4-yl)acetate (4);
  • the present invention provides a novel intermediate, 2-chloro-[4-(4'-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) in crystalline form characterized by X-ray powder diffraction as depicted in Figure-3.
  • the present invention provides a novel intermediate, triphenyl[2-chloro- ⁇ 4-(4' -flourphenyl)-6-isopro ⁇ yl-pyrimidin-5- ylmethyl ⁇ -phosphonium]bromide of formula (10) in crystalline form characterized by X-ray powder diffraction as depicted in Figure-4.
  • the present invention provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4-fluorophenyl)-6- isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5) in crystalline form.
  • the present invention provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4 ' -fluorophenyl)-6-iso ⁇ ro ⁇ yl-2- (methylamino)pyrimidin-5-yl) vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate (4);
  • the present invention provides a novel intermediate, amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula (2') in crystalline form, preferably the amine salt is n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonaraido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetic acid in crystalline form.
  • process comprises; a) providing amorphous rosuvastatin calcium prepared as per any of the process herein above; b) preparing the slurry in hot water; c) maintaining the reaction mixture for sufficient amount of time at elevated temperature; and d) recovering stable amorphous rosuvastatin calcium.
  • FIG.l X-ray diffraction of amorphous rosuvastatin calcium prepared as per present invention.
  • FIG.2 X-ray diffraction of crystalline intermediate of formula (9).
  • FIG.3 Differential Scanning Calorimetric analysis of crystalline intermediate of formula (9).
  • FIG.4 1 H NMR spectra of crystalline intermediate of formula (9).
  • FIG.5 13 C NMR spectra of crystalline intermediate of formula (9).
  • FIG.6 IR spectra of crystalline intermediate of formula (9).
  • FIG.7 X-ray diffraction of crystalline intermediate of formula (10).
  • FIG.8 . Differential Scanning Calorimetric analysis of crystalline intermediate of formula (10).
  • FIG.9 1 H NMR spectra of crystalline intermediate of formula (10)
  • FIG.10 13 C NMR spectra of crystalline intermediate of formula (10).
  • FIG.ll IR spectra of crystalline intermediate of formula (10).
  • FIG.12 X-ray diffraction of crystalline intermediate of formula (5).
  • FIG.13 Differential Scanning Calorimetric analysis of crystalline intermediate of formula (5).
  • FIG.14 1 H NMR-spectra of crystalline intermediate of formula (5)
  • FIG.15 13 C NMR spectra of crystalline intermediate of formula (5).
  • FIG.16 IR spectra of crystalline intermediate of formula (5).
  • FIG.12 X-ray diffraction of crystalline intermediate of formula (5).
  • FIG.13 Differential Scanning Calorimetric analysis of crystalline intermediate of formula (5).
  • FIG.14 1 H NMR spectra of crystalline intermediate of formula (5)
  • FIG.15 13 C NMR spectra of crystalline intermediate of formula (5).
  • FIG.16 IR spectra of crystalline intermediate of formula (5).
  • FIG.17 X-ray diffraction of crystalline intermediate of formula (4).
  • FIG.18 Differential Scanning Calorimetric analysis of crystalline intermediate of formula (4).
  • FIG.19 1 H NMR spectra of crystalline intermediate of formula (4).
  • FIG.20 13 C NMR spectra of crystalline intermediate of formula (4).
  • FIG.21 IR spectra of crystalline intermediate of formula (4).
  • FIG.22 X-ray diffraction of crystalline intermediate of formula (2').
  • FIG.23 Differential Scanning Calorimetric analysis of crystalline intermediate of formula (2').
  • FIG.24 1 H NMR spectra of crystalline intermediate of formula (2').
  • FIG.25 13 C NMR spectra of crystalline intermediate of formula (T).
  • FIG.26 IR spectra of crystalline intermediate of formula (2').
  • FIG.27 X-ray diffraction of crystalline intermediate of formula (9a).
  • FIG.28 Differential Scanning Calorimetric analysis of crystalline intermediate of formula (9a).
  • FIG.29 1 H NMR spectra of crystalline intermediate of formula (9a).
  • FIG.30 13 C NMR spectra of crystalline intermediate of formula (9a).
  • FIG.31 IR spectra of crystalline intermediate of formula (9a).
  • FIG.32 1 H NMR spectra of an isolated impurity-B.
  • FIG.33 13 C NMR spectra of an isolated impurity-B.
  • FIG.34 1 H NMR spectra of an isolated impurity-C.
  • FIG.35 13 C NMR spectra of an isolated impurity-C.
  • FIG.36 X-ray diffraction of crystalline intermediate of formula (2").
  • FIG.37 Differential Scanning Calorimetric analysis of crystalline intermediate of formula (2").
  • FIG.38 IR spectra of crystalline intermediate -of formula (2").
  • the present invention an improved process for the preparation of rosuvastatin or its salts like calcium of formula (1)
  • the present invention provides a novel intermediate, 2-chloro-[4-(4'-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) in crystalline form characterized by X-ray powder diffraction as depicted in Figure-3.
  • the present invention provides a novel intermediate, triphenyl[2-chloro- ⁇ 4-(4'-flourphenyl)-6-isopropyl-pyrimidin-5- ylmethyl ⁇ - ⁇ hosphonium]bromide of formula (10) in crystalline form characterized by X-ray powder diffraction as depicted in Figure-4.
  • the present invention provides a novel intermediate, tert-butyl 2-((4Ij,6S)-6-((E)-2-(2-chloro-4-(4-fluorophenyl)-6- isopropylpyrimidin-5-yl)vinyl)-2,2-dimetnyl-l,3-dioxan-4-yl)acetate of formula (5) in crystalline form.
  • the present invention provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2- (methylamino)pyrimidm-5-yl)vinyl)-2,2-dimethyl-l 5 3-dioxan-4-yl)acetate (4);
  • the present invention provides a novel intermediate, amine salt of 2-((4R,6S)-6-j((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5 -yj.) vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetic acid of formula (2') in crystalline form, preferably the amine salt is n-propyl amine salt of 2-((4R,6S)-6j((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yi)vinyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetic acid in crystalline form.
  • process comprises; e) providing amorphous xosuvastatin calcium prepared as per any of the processJietein above; f) preparing the slurry in hot water; g) maintaining the reaction mixture for sufficient amount of time at elevated temperature; and h) recovering stable amorphous rosuvastatin calcium.
  • the present invention provides an improved process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)viiiyl)-2 5 2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5),
  • Halogenation as in step (a) can be done with suitable halogenating agent can be selected for the thionyl chloride, phosphorus oxylchloride, phosphorus pentachloride, phosphorus trichloride and the like, preferably thionyl chloride in suitable organic solvent selected from C1-C4 alcohols like methanol, ethanol, propanol, butanol, isopropanol and the like., halogenated aliphatic hydrocarbons- -like— methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride and the like, aromatic hydrocarbons like toluene, xylene, ethyl benzene and the like, preferably toluene.
  • suitable halogenating agent can be selected for the thionyl chloride, phosphorus oxylchloride, phosphorus pentachloride, phosphorus trichloride and the like, preferably thiony
  • the compound of formula (8) can be reduced to alcohol of formula (9) by using diisobutylaluminium hydride (DIBAL) in a suitable organic solvent selected from aromatic hydrocarbons like toluene, xylene, ethyl benzene., esters like ethyl acetate, methyl acetate, isopropyl acetate, t-butyl acetate etc., ethers like diisopropyl ether, diethyl ether., methyltertbutylether., halogenated aliphatic hydrocarbons like methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride etc., preferably toluene.
  • DIBAL diisobutylaluminium hydride
  • 6-isopropyl] pyrimidine prepared in-situ by reacting compound of formula (8) with phosphrous bromide can be further reacted with Wittig reagent like triphenyl phosphine, tributyl phosphine, preferably triphenyl phosphine in a suitable organic solvent like non-polar solvents selected from toluene, o-xylene, chlorobenzene preferably toluene at a temperature ranging from 80 to 14O 0 C, preferably at 100°-l 10°C to provide novel intermediate triphenyl[2-chloro- ⁇ 4-(4-flou ⁇ henyl)-6-isopropyl- pyrimidin-5-ylmethyl ⁇ -phosphonium]bromide compound of formula (10).
  • Wittig reagent like triphenyl phosphine, tributyl phosphine, preferably triphenyl phosphine in a suitable organic solvent like non-polar
  • the wittig reagent of formula (10) is reacted ' with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11) in presence of suitable base selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably potassium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidine or mixture thereof, preferably dimethylsulfoxide at a temperature ranging from 40° to 8O 0 C preferably 60° to 7O 0 C to provide novel intermediate tert-butyl-(E)-(6- ⁇ 2-[4-(4-fluorophenyl)-6- isopropyl-2-chloro]pyrimidin-5-yl
  • the present invention an improved process for the preparation of amorphous rosuvastatin calcium of formula (1)
  • step (b) reacting compound of formula (5) obtained in step (a) with monomethyl amine solution at an ambient temperature to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl- l,3-dioxan-4-yl)acetate (4);
  • step (f) treating residue of step (e) with organic base in a suitable organic solvent or mixture thereof with water to adjust the pH of about 8 to about 9 to obtain amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yi)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetic acid of formula (2');
  • the Wittig reagent of formula (10) is reacted with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate
  • suitable base selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbon
  • the compound of formula (5) can be converted to compound of formula (4) as in step (b) by reaction with monomethyl amine solution at an ambient temperature.
  • the monomethyl amine solution is 25% solution in methanol.
  • the ambient temperature of the reaction meaning room temperature i.e. at about 25 0 C to about 35 0 C.
  • reaction mixture is cooled to about O 0 C to about 5°C and filtered to isolate tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidin-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (4).
  • (methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate of formula (4) can be converted to in-situ rosuvastatin protected diol ester compound of formula (3) as in step (c) by reaction compound of formula (4) with methane sulphonyl chloride in presence of suitable base selected from inorganic base like alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate or organic bases like triethylamine, diisopropylethylamine, diethylamine, pyridine, piperidine, morpholine etc, preferably triethylamine.
  • suitable base selected from inorganic base like alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate or organic bases like triethy
  • the reaction is carried out in a suitable organic solvent selected from the methylene dichloride, ethylene dichloride, toluene, polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidine or mixture thereof, preferably methylene dichloride at -3O 0 C to 10 0 C, preferably at about -2O 0 C to -25 0 C.
  • a suitable organic solvent selected from the methylene dichloride, ethylene dichloride, toluene, polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidine or mixture thereof, preferably methylene dichloride at -3O 0 C to 10 0 C, preferably at about -2O 0 C to -25 0 C.
  • the tert-butyl ester group of compound of formula (3) is hydrolyzed initially to obtain 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N-methylmethyl- sulfonamide)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4 r yl)acetic acid of formula (2).
  • the hydrolysis of compound of formula (3) is performed by in-situ reacting compound of formula (3) with a suitable base selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably sodium or potassium hydroxide at an elevated temperature.
  • a suitable base selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably sodium or potassium hydroxide at an elevated temperature.
  • the elevated temperature herein means, reaction is performed at about 5O 0 C to about 12O 0 C, more preferably at about 6O 0 C to about 90 0 C 5 most preferably at about 6O 0 C to about 7O 0 C.
  • reaction is performed in C 1 -C 4 alcoholic solvents like methanol, ethanol, butanol, isopropanol and the like preferably methanol.
  • the reaction mixture is concentrated as in step (e) to remove C 1 -C 4 alcoholic solvent like methanol under vacuum.
  • step (e) is treated with organic base like n-propyl amine, isopropylamine, tert-butyl amine, dicyclohexyl amine, ethyl amine etc., preferably n-propyl amine in suitable organic solvent selected from polar organic solvents like tetrahydrofuran, dimethylformamide, dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, acetone etc., or mixture thereof with water, preferably mixture of acetonitrile and water.
  • organic base like n-propyl amine, isopropylamine, tert-butyl amine, dicyclohexyl amine, ethyl amine etc.
  • suitable organic solvent selected from polar organic solvents like tetrahydrofuran, dimethylformamide, dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, acetone etc.,
  • the residue is treated with mixture of acetonitrile and water at 0 0 C to about 1O 0 C followed by treatment with acid like hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid preferably hydrochloric acid followed by treatment with n-propyl amine to adjust the pH of about 8 to about 9 to obtain n-propylamine salt of 2-((4R,6S)-6-((E)- 2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamide)pyrimidin-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula ⁇ (2')7 ""
  • the n-propylamine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamide)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula, (2') is treated strong acid like hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid preferably hydrochloric acid is a suitable organic solvent like polar organic solvent tetrahydrofuran, methanol, ethanol or non-polar solvent like ethyl acetate or toluene to eliminate acetonide protection group followed treatment with 10% sodium hydroxide to adjust the pH 7 to 7.5 to obtain in-situ rosuvastatin sodium salt.
  • the rosuvastatin sodium salt is further treated with mixture of toluene and ethyl acetate followed by treatment with suitable calcium source like calcium chloride, calcium acetate, calcium hydroxide etc., preferably calcium acetate to obtain amorphous rosuvastatin calcium salt.
  • suitable calcium source like calcium chloride, calcium acetate, calcium hydroxide etc., preferably calcium acetate to obtain amorphous rosuvastatin calcium salt.
  • the present invention provides stable amorphous rosuvastatin calcium having individual impurities like rosuvastaiin diastereomer less than about 0.1%, rosuvastatin lactone less than about 0.1%, rosuvastatin desflouro impurity less than 0.1%, rosuvastatin 5-oxo (B2) impurity less than 0.1%, rosuvastatin protected diol ester not in detectable amount, rosuvastatin 3- oxo impurity less than 0.1% by area percentage of HPLC when kept for 3 months at 25 0 C at 60% RH,
  • the present invention provides stable amorphous rosuvastatin calcium having individual impurities like rosuvastatin diastereomer less than about 0.1%, rosuvastatin lactone less than about 0.1%, rosuvastatin desflouro impurity less than 0.1%, rosuvastatin 5-oxo (B2) impurity less than 0.1%, rosuvastatin protected diol ester not in detectable amount, rosuvastatin 3- oxo impurity less than 0.1% by area percentage of HPLC when kept for 3 months at 4O 0 C at 75% RH.
  • the elevated lemperaturc for the reaction can be in the range of 35 0 C to about 6O 0 C, more preferably at about 40 0 C to about 45 0 C for sufficient time i.e. about 1 hour to obtain stable amorphous rosuvastatin calcium.
  • the present invention provides a novel intermediate, 2-chloro-[4-(4'-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) in crystalline form characterized by atleast one of the following properties,
  • the present invention provides a novel intermediate, triphenyl[2-chloro- ⁇ 4-(4-flourphenyl)-6-isopropyl-pyrimidin-5- ylmethyl ⁇ -phosphonium] bromide of formula (10) in crystalline form characterized by atleast one of the following properties,
  • the present invention provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4-fluorophenyl)-6- isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5) in crystalline form characterized by atleast one of the following properties,
  • the present invention provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluoro ⁇ henyl)-6-isopropyl-2- (methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (4) in crystalline form characterized by atleast one of the following properties,
  • the present invention provides a novel intermediate, amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido) pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula (2') in crystalline form, preferably the amine salt is n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid in crystalline form characterized by atleast one of the following properties,
  • n-propyl amine may be replaced by ethylamine to provide ethylamine salt of compound of formula (2") is also the scope of the present invention in its crystalline form characterized by characterized by atleast one of the following properties,
  • the process for preparing rosuvastatin calcium according Io present invention is simple, easy safe and yields rosuvastatin calcium with high degree of purity by HPLC greater than 99.0%.
  • undesired product (B) there results the formation of undesired product (B) and further reaction of condensed compound of formula (5) with monomethyl amine results in the formation of undesired product (C).
  • the present invention provides amorphous rosuvastatin calcium substantially free from undesired product (B) i.e. 2- chloro-4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidine and undesired product (C) i.e. 4-(4-fluorophenyl)-6-isopropyl-N,5-dimethylpyrimidin-2-amine.
  • substantially free herein above refers to the amorphous rosuvastatin calcium having undesired impurity (B) less than 0.1%, preferably less than 0.07%, more preferably less than 0.05% and most preferably not in detectable amount, i.e. 2- chloro-4-(4-fluorophenyl)-6-isopropyl-5-memylpyrimidine.
  • substantially free also refers to amorphous atorvastatin calcium having undesired impurity (C) less than 0.1%, preferably less than 0.08%, more preferably less than 0.04% and most preferably not in detectable amount, i.e.
  • the present invention provides isolated impurity-B characterized by 1 HNMR substantially as depicted in Figure-32 and 13 CNMR substantially as depicted in Figure-33. Further provides isolated impurity-C characterized by 1 HNMR substantially as depicted in Figure-34, 13 CNMR substantially as depicted in Figure-35.
  • triphenyl[2- chloro- ⁇ 4-(4'-flou ⁇ henyl)-6-isopropyl-pyrimidin-5-ylmethyl ⁇ -phosphonium]bromide compound of formula (10) involves bromination of compound (9) with triphenyl phosphonium bromide.
  • the reaction results in the undesired product (A) i.e. 2-bromo- 5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidine under' the drastic conditions.
  • the present invention provides amorphous rosuvastatin calcium substantially free from undesired product (A) i.e. 2- bromo-5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidine.
  • substantially free herein above refers to the amorphous rosuvastatin calcium having undesired impurity (A) less than 0.1%, preferably less than 0.07%, more preferably less than 0.05% and most preferably not in detectable amount when measured by area percentage of HPLC
  • amorphous rosuvastatin calcium substantially free from hemi-calcium salt of (3R,5S)-(E)-7-(2-chloro-4-(4-fluoro ⁇ henyl)-6-isopropylpyrimidin-5-yl)-3,5- dihydroxyhept-6-enoate) of formula (D)
  • substantially free herein above refers to the amorphous rosuvastatin calcium having undesired impurity (D) less than 0.15%, preferably less than 0.10%, more preferably less than 0.07%, and most preferably less than 0.05% when measured by area percentage of HPLC.
  • D undesired impurity
  • the Impurity Profile Determination of Rosuvastatin Ca comprised testing a sample using UPLC (Ultra performance liquid chromatography).
  • the UPLC testing parameters included a column of Aciqity Cl 8 1.7 ⁇ m 2.1*100 mm or equivalent column at a temperature of 40°C and eluted with a two solvent system.
  • a first reservoir, Reservoir A contained 6.8 g potassium dihydrogen orthophosphate and 2 ml of triethyl amine dissolved in 1000 ml water, adjusted to pH 2.0 with H 3 PO 4 , and a second reservoir, Reservoir B, contained acetonitrile.
  • the gradient was as follows: at the initial time, 74% Reservoir A and 26% Reservoir B; time 15.0 min 74% Reservoir A and 26% Reservoir B; and at time 35.0 min 40% Reservoir A and 60% Reservoir B, and at time 39.0 min 40% Reservoir A and 60% Reservoir B, and at lime 40.0 min 74% Reservoir A and 26% Reservoir B, and at time 45.0 min 74% Reservoir A and 26% Reservoir B.
  • the system equilibrated further for 10 min and a flow rate of 0.45 ml/min.
  • the detector was set for 240 nm.
  • the sample volume was 10 ⁇ L and the diluent was acetonitrile: water 80:20.
  • the mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
  • the sample was prepared by weighing accurately about 10 mg of Rosuvastatin Ca sample in a 20 ml amber volumetric flask. Dissolving the sample with 10 ml of acetonitrile and diluting to the desired volume with water. Thereafter, the freshly prepared sample was injected. The sample solutions were injected into the chromatograph and the chromatogram of sample was continued up to the end of the gradient. Thereafter, the areas for each peak in each solution was determined using a suitable integrator. The calculations were obtained using the following formula: Impurity Profile Determination
  • % impurity area impurity in sample X lOO
  • UPLC Ultra performance liquid chromatography
  • the UPLC testing parameters included a column of Aciqity Cl 8 1.7 ⁇ m 2.1*100 mm or equivalent column at a temperature of 40 0 C and eluted with a two solvent system.
  • a first reservoir, Reservoir A contained 6.8 g potassium dihydrogen orthophosphate and 2 ml of triethyl amine dissolved in 1000 ml water, adjusted to pH 2.0 with HsPO 4 , and a second reservoir, Reservoir B, contained acetonitrile.
  • the gradient was as follows: at the initial time, 65% Reservoir A and 35% Reservoir B; time 10.0 min 65% Reservoir A and 35% Reservoir B; and at time 35.0 min 40% Reservoir A and 60% Reservoir B, and at time 39.0 min 40% Reservoir A and 60% Reservoir B, and at time 40.0 min 65% Reservoir A and 35% Reservoir B 5 and at time 45.0 min 65% Reservoir A and 35% Reservoir B.
  • the system equilibrated further for 10 min and a flow rate of 0.40. ml/min.
  • the detector was set for 240 nm.
  • the sample volume was 10 ⁇ L and the diluent was acetonitrile: water 80:20..
  • the mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
  • the ethyl acetate portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure, to obtain 0.80 g o£2-chloro-4- (4-fluoro- phenyl) - ⁇ -isopropyl-S-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 76% (based on the amount of 4-(4'- fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
  • the reaction mixture was stirred for about 15 minutes at 0° to 5 0 C and raises the temperature to 25° to 3O 0 C.
  • the organic layer was treated with excess sodium thiosulphate solution.
  • the separated organic layer dried over sodium sulphate and concentrated at a temperature in the range of from about 60°-70°C. under reduced pressure to obtain oily residue (11 g).
  • the oily residue (1 Ig) was taken in toluene (40 mL).
  • Triphenyl phosphine (8 g) in toluene (40 ml) was added to the reaction mixture.
  • the reaction mixture was heated to a temperature of about HO 0 C. and maintained for about 3 to about 4 hours.
  • the reaction mixture was cooled to a temperature in the range of from about 20°C-25°C.
  • the precipitated product was filtered, washed with toluene (250 ml), and dried in a vacuum oven at a temperature of below about 6O 0 C. until the moisture content was about 1%.
  • the dried product appears as an off-white crystalline solid weighing about 11 g to about 12 g.
  • the yield was about 88% to about 94%.
  • the oily residue obtained after bromination followed by distillation of methylene dichloride can be also be isolated in the solid form by treatment with chilled methanol to obtain novel intermediate of formula (9a) i.e. 5-(bromomethyl)-2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidine.
  • reaction mixture was cooled to a temperature in the range of from about 25°-35°C.
  • Toluene 100 ml was added for dilution of the reaction mixture under stirring for about 30 minutes at a temperature in the range of from about 25°-35°C.
  • the reaction mixture was filtered, and the insoluble cake was separated.
  • the organic layer was added to water (100 ml) under stirring at a temperature in the range of from about 25°-35°C. and maintained for about 30 minutes. The organic layer was separated and washed twice with water (200 ml).
  • the organic layer was distilled in rotavapor bath at a temperature in the range of from about 50°C-70°C: under in a vacuum. After distillation, methanol (75 ml) was added to the residue at a temperature in the range of from about 55 0 C. to about 6O 0 C. and maintained for about 30 minutes. The reaction mixture was brought to a temperature in the range of from about 25°C-30°C. by slowly circulating water. During this, time, a product precipitated out. The precipitated mass was further cooled to a temperature of about 1O 0 C. for about 30 minutes and then filtered. The cake was washed with prechilled methanol (100 ml at a temperature of about 1O 0 C). The product was dried in an oven at a temperature of about 55 0 C. until the moisture content was about 1%. The dried product appeared as an off-white crystalline solid weighing about 7.8 g to about 8.2 g. (75% to about 8).
  • Example-4 Preparation of tert-butyl2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6- isopropyl-2-(methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate
  • Example-5 Preparation of n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2- dimethyl-l,3-dioxan-4-yl) acetic acid of formula (2'):
  • reaction mixture After maintaining for 1 hour under stirring, upon completion of reaction on TLC, the reaction mixture is quenched into 100 gm ice at 0 0 C to 5 0 C. Separated organic layer was washed with water and 80% methylene dichloride was distilled atmospherically at 4O 0 C to 50 0 C. The reaction mixture was treated with 21 mL 10% sodium hydroxide solution and 100 mL methanol. The remaining methylene dichloride was removed aze ⁇ lropically at 45 0 C to 5O 0 C. After MDC removal, the reaction mixture was treated with 200 mL methanol and temperature was raised upto reflux for about 60°C to 65 0 C for 6-8 hours. After the completion of the reaction on TLC, methanol was distilled under vacuum at 4O 0 C to 45°C.
  • reaction mixture was treated with 20 mL of water and 50 mL of acetonitrile and cooled to O 0 C to 1O 0 C.
  • the pH of the reaction mixture was adjusted using dil HCl at O 0 C to 1O 0 C.
  • the organic layer was separated and treated with n-propyl amine to adjust the pH to about 8 to 9 at O 0 C to 1O 0 C.
  • the reaction mixture was maintained at about 25°C to 35 0 C for 1 hour.
  • the product thus obtained was filtered and washed with chilled with acetonitrile.
  • Eiample-6 - Preparation of Ethyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'- fluOrophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2- dimethyl-l,3-dioxan-4-yl) acetic acid of formula (2")
  • Example-5 The process disclosed in Example-5 can be repeated in the similar manner by replacing n-propyl amine with ethyl amine to obtain Ethyl amine salt of 2-((4R,6S)-6- ((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid of formula (2").
  • ExampIe-7 Preparation of amorphous rosuvastatin calcium.
  • reaction mixture was stirred and treated with 25 SmL IN HCl and maintained for 2 hours at 2O 0 C to 25 0 C. After the completion of the reabtion on TLC, the reaction mixture was treated with 10% potassium hydroxide solkion at 10 0 C to 15 0 C and maintained for 2 hours at 2O 0 C to 25 0 C. After completion of ⁇ he reaction as monitored by TLC, the reaction mixture was treated with IN HCl to get pH of 8 to 8.5 and charcoalized. The reaction mixture was filtered and washed with acetonitrile. The filtrate was extracted with mixture of toluene and ethyl acetate in the ratio of 7:3. at 25 0 C to 35 0 C.
  • the 100 g wet-cake of rosuvastatin calcium as prepared in Example- 7 and 500 mL of water were taken into RBF.
  • the reaction mixture was heated at about 4O 0 C to 45 0 C for about 1 hour.
  • the product thus obtained was hot filtered and washed with hot water at about 40 0 C to about 45°C.
  • the product was air dried for 2 hours at 25°C to about 35 0 C followed by vacuum drying for 12 hours to obtain 75 g of stable amorphous rosuvastatin calcium.
  • Stable amorphous rosuvastatin calcium as prepared by above process is having individual impurities like rosuvastatin diastereomer less than about 0.1%, rosuvastatin lactone less than about 0.1%, rosuvastatin desflouro impurity less than 0.1%, rosuvastatin 5-oxo (B2) impurity less than 0.1%, rosuvastatin protected diol ester not in detectable amount, rosuvastatin 3-oxo impurity less than 0.1% by area percentage of HPLC when kept for 3 months at 25 0 C at 60% RH as well as at 4O 0 C at 75%RH. The below HPLC conditions were used to analyze the stable amorphous rosuvastatin calcium.
  • Mobile Phase A - Water:: Acetonitrile::l% Trifluoroacetic acid:::700::290::10
  • Mobile Phase B - Water: :Acetonitrile::l% Trifluoroacetic acid:::240::750::10
  • the gradient was as follows: at the initial time, 100% Mobile Phase-A and 0% Mobile Phase-B; time 30.0 min 100% Mobile Phase-A and 0% Mobile Phase-B; and at time 50.0 min 60% Mobile Phase-A and 40% Mobile Phase-B, and at time 80.0 min 0% Mobile Phase-A and 100% Mobile Phase-B, and at time 81.0 min 100% Mobile Phase- A and 0% Mobile Phase-B, and at time 90.0 min 100% Mobile Phase-A and 0%
  • the present invention provides an improved process for the synthesis of amorphous
  • Rosuvastatin Calcium 2) The present invention provides an improved process for preparing rosuvastatin calcium in amorphous form via novel intermediates.
  • the present invention provides an improved process for preparing rosuvastatin calcium via novel crystalline intermediates characterized by X-ray powder diffraction. 4)
  • the main advantage of the present invention is to provide rosuvastatin calcium with high yield and high purity by HPLC greater than 99% with single individual impurity ⁇ 0.1%.
  • the present invention also provides the process for the stabilization of amorphous atorvastatin calcium at 25 0 C in 60% RH and at 40 0 C in 75% RH. 6)
  • the process is simple, safe, cost effective and can be employed for commercial production.

Abstract

The present invention relates to an improved process for synthesizing calcium salt of (E)-7-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid (Rosuvastatin Calcium) in high purity.

Description

A PROCESS FOR PREPARING HMG-COA REDUCTASE INHIBITORS AND
INTERMEDIATES
FIELD OF THE INVENTION
The present invention relates to a process for preparing HMG-CoA reductase inhibitors and intermediates thereof. Particularly, the present invention relates to an improved process for synthesizing calcium salt of (E)-7-[4-(4-flurophenyl)-6- isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6- heptenoic acid (Rosuvastatin Calcium) in high purity. BACKGROUND OF THE INVENTION:
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
US patent no. RE 37314 (Reissue of US 5260440) discloses Rosuvastatin that is chemically known as (E)-7-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methyl sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxy-6-heptenoic acid and its salts, which are HMG-CoA reductase inhibitors and useful in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
Rosuvastatin calcium, (E)-7-[4-(4-flurophenyl)-6-isopropyl-2-
[methyl(methylsulfonyl)amino]- pyrimidm-5-yl](3R,5S)-3,5-dihydroxy-6-heplenυie acid and its salts is a HMG-CoA reductase inhibitor, a superstatin developed by Shionogi for the treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996, Direct Communication, Shionogi 8 Feb. 1999 and 25 Feb. 2000). It can lower LDL- cholesterol and triglycerides more effectively than the first generation drugs.
Figure imgf000002_0001
Rosuvastatin calcium has the following structure being shown by formula (1) Rosuvastatin calcium is marketed under the trade name of CRESTOR for treatment of a mammal such as a human. According to the maker of CRESTOR, it is administered in a daily dose of from about 5 mg to about 40 mg. For patients requiring less aggressive LDL-C reductions or who have pre-disposing factors for myopathy, the 5 mg dose is recommended, while 10 mg dose is recommended for the average patient, 20 mg dose for patients with marked hypercholesterolemia and aggressive lipid targets (>192 mg/dL), and the 40 mg dose for patients who have not been responsive to lower doses. WO 03/032995 further discloses a method of preventing dementia by administering to a patient rosuvastatin. U.S. Pat. No. 5,260,440 discloses the process to produce rosuvastatin salt. The process of UlS.Pat.No.5,260,440 starts with the methyl ester of rosuvastatirrrknown an (methyl-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy -(E)-6-heptenate (methyl rosuvastatin)). The process for preparation of the intermediates disclosed in the '440 patent is incorporated herein by reference.
In the '440 patent, rosuvastatin sodium is prepared from its methyl ester according to Example 1 (6) by adding sodium hydroxide to a solution of the methyl ester in ethanol, followed inter alia by distillation, followed by addition of ether to the residue obtained from distillation. When preparing a salt of rosuvastatin, the present applicants found that diethyl ether may not be used in production; after distillation of the solvent, the present applicants obtained a viscous oil that hardly precipitates in diethyl ether.
EP 1417180 Bl discloses the preparation of aminopyrimidine compounds of formula (8) wherein R is a hydrocarbonyl group, and each of R1 and R2 independently is a hydrogen atom, an alkyl group, an alkylsulfonyl group, or an arylsulfonyl group, more particularly to the preparation of a 2-(N-methyl-N- methanesulfonylamnino)pyrimidine compound having the following formula (3)
Figure imgf000003_0001
wherein R represents a hydrocarbyl group. EP ' 180 Bl also discloses the process for the preparation of (N-melhyl-N- methanesulfonylaninino) pyrimidine compound having the following formula (3) via novel intermediates of formula (1), formula (4), formula (9) and formula (10),
Figure imgf000004_0001
(1) (4) O) (10) respectively.
General reaction sequence for the preparation of novel intermediates as above is described in scheme- 1 as below.
Scheme-1
WO 2006/067456 A2 discloses the process for the preparation of various intermediates for "the preparation of (N-methyl-N-methanesulfonylamnino) pyrimidine compound having the following formula (3)
Figure imgf000004_0002
(4) (1)
Figure imgf000004_0003
Figure imgf000005_0001
Reaction scheme-2 to scheme-6 provides various reaction sequences for the preparation of pyrimidine intermediates useful for the synthesis of rosuvastatin calcium. The intermediates obtained are condensed with side chain to obtain rosuvastatin calcium via condensed product.
Figure imgf000005_0002
Scheme-2
Figure imgf000006_0001
Scheme-3
Figure imgf000006_0002
Scheme-4
Figure imgf000007_0001
Scheme-5
Figure imgf000008_0001
Scheme-6
WO 2007/007119 Al discloses the process for the manufacture of rosuvastatin and intermediates as disclosed in scheme-7.
Figure imgf000008_0002
WO 2006/00126035 A2 discloses the process for the manufacture of rosuvastatin and intermediates as disclosed in scheme-8.
Figure imgf000009_0001
Rosuvastatin Calcium (Amorphous) Scheme-8
According to the above reaction sequence, the rosuvastatin calcium prepared as per the process disclosed in WO '035 A2 involves the alkaline hydrolysis of rosuvastatin protected diol ester (II) (R = C1-4 alkyl ester except tert-butyl) therein initially with strong base like sodium hydroxide and obtaining rosuvastatin protected diol acid of formula (III) therein. The acid of formula (III) is treated with suitable organic or inorganic base to form a salt, then eliminating acetonide group and reacting with calcium chloride in a base; or reacting rosuvastatin protected diol acid of formula (III) therein with suitable organic or inorganic base to form a salt, then eliminating acetonide group arid reacting with calcium chloride in a base; or reacting a salt of formula (III) therein formed with an organic or inorganic base then by eliminating acetonide group and reacting with calcium chloride in a base to obtain amorphous rosuvastatin calcium. Suitable organic or inorganic bases used for the preparation of salt of rosuvastatin protected diol acid of formula (III) therein are selected from methylamine, diethanolamine, ethanolamine, magnesium sulfate, L-lysine, benzylamine, L-(-)-α-methyl-benzylamine or N-methyl-D-glucosamine. US 6,844,437 Bl and US 6,784,171 B2 provides the process for the preparation 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- flourophenyl)-6-isopiOpyl-2-[methyl)methylsulfonyl)amino [pyrimid-in-5-
Figure imgf000010_0001
ylmethyl]phosphine oxide with tert-butyl 2-[(4R,6S)-6-formyl-2,2~dimethyl-l,3- dioxan-4-yl] acetate in the presence of a strong base.
US 6,841,554 B2 discloses a crystalline salt of the compound (E)-(6-{2-[4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]}-(3R,5S)- 3,5-dihydroxyhept-6-enoic acid of formula (I), wherein the salt in an ammonium, methylammonium, ethylammonium, diethanolammonium, tris(hydroxymethyl)methyl ammonium, benzylammonium, 4-methoxybenzylammonium, lithium or magnesium salt.
Figure imgf000010_0002
US 4,977,279., US 5,278,313 and US 6,472,544 Bl discloses the aldehyde side chain of formula (XII) useful for the synthesis of various HMG-CoA reductase inhibitors are taken herein as reference.
Figure imgf000010_0003
(XII) Thus, there is still a need for providing a process for the preparation of rosuvastatin calcium that is industrially applicable and cost-viable providing rosuvastatin calcium in high yields.
The inventors of the present invention has found that the use of novel intermediates in synthesis of pyrimidine derivative and its condensation with aldehyde side chain would alleviates the hitherto problems associated with prior art for preparing rosuvastatin salts as described above. Objects of Invention:
It is an object of the present invention to overcome or substantially ameliorate one or more of the disadvantages of the prior art or at least to provide a useful alternative.
It is an object of the present invention to provide an improved process for the synthesis of HMG-CoA reductase inhibitors, particularly an improved process for preparing rosuvastatin calcium in high yield and purity.
It is an object of the present invention to provide crystalline intermediates for the preparation of HMG-CoA reductase inhibitors.
It is further object of the present invention to provide an improved process for the synthesis of novel intermediates for the synthesis of reductase inhibitors. Summary of Invention:
According to first embodiment, the present invention provides an improved process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5),
Figure imgf000011_0001
which comprises of:
(a) reacting compound of formula (7) by halogenating agent in a suitable organic solvent, wherein R is a alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an arylalkyl group having an alkyl moiety of 1-3 carbon atoms or an aryl group to obtain 2-chloro-4-(4'-flourophenyl)-6-isopropyl-5- substitutedpyrimidine compound of formula (8);
Figure imgf000012_0001
(b) reducing 2-chloro-4-(4'-flourophenyl)-6-isopropyl-5-substitutedpyrimidine compound of formula (8) with diisobutylaluminium hydride (DIBAL) in suitable organic solvent to give 2-chloro-[4-(4-flourophenyl)-6-isopropyl-pyrimidin-5-
Figure imgf000012_0002
yl]methanol compound of formula (9);
(c) reacting 2-chloro-[4-(4'-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) with phosphorus tribromide for in-situ preparation of 2- chloro-[4-(4-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methyl bromide;
(d) reacting in-situ 2-chloro-4-(4'-flourophenyl)-5-(bromomethyl)-6- isopropyljpyrimidine with triphenly phosphine in a suitable organic solvent at an elevated temperature to obtain triphenyl[2-chloro-{4-(4'-flourphenyl)-6-isopropyl- pyrimidin-5-ylmethyl}-phosphonium]bromide compound of formula (10); and
Figure imgf000012_0003
(e) reacting compound of formula (10) with tert-butyl-2-[(4R,6S)-6-formyl-2,2- dimethyl-1, 3 -dioxan-4-yl] acetate (BFA) of formula (11) in presence of base to obtain compound of formula (5).
Figure imgf000013_0001
According to second embodiment, the present invention an improved process for the preparation of rosuvastatin or its salts like calcium of formula (1)
Figure imgf000013_0002
which comprises of: (a) reacting triphenyl[2-chloro-{4-(4-flouφhenyl)-6-isopropyl-pyrimidin-5-ylmethyl}- phosphonium]bromide of formula (10)
Figure imgf000013_0003
with tert-butyl-2-[(4R,6S)-6-formyl-252-dimethyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11)
Figure imgf000013_0004
in presence of base to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate of formula (5);
Figure imgf000014_0001
(b) reacting compound of formula (5) obtained in step (a) with monomethyl amine solution at an ambient temperature to obtain tert-butyr2::((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidm-5-yl)vinyl)-2,2-dimethyl-l,3- dioxan-4-yl)acetate (4);
Figure imgf000014_0002
(c) reacting compound of formula (4) with methane sulphonyl chloride in presence of base in a suitable organic solvent at -30°C to +1O0C temperature to obtain in-situ tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4t-fluorophenyl)-6-isopropyl-2-(N- nietliylmethylsulfonamido)pj'rimidin-5-yl)vinyl)-2,2-dimethyl-l53-dioxan-4- yl)acelale of formula (3);
Figure imgf000014_0003
(d) reacting compound of formula (3) with a base in C1-C4 alcohol at an elevated temperature to obtain solution of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6- isopropyl-2-(N-methylmetliyl- sulfonamido)pyrimidm-5-yl)vinyl)-2,2-dimethyl- l,3-dioxan-4-yl)acetic acid of formula (2);
Figure imgf000015_0001
(e) optionally concentrating the solution and removing Cj-C4 alcoholic solvent;
(f) treating compound of formula with organic base in a suitable organic solvent or mixture thereof with water to adjust the pH of about 8 to about 9 to obtain amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isoprdpyl-2-(N- methylmethylsulfonamido)pyrimidiή-5-yl)vinyl)-2,2-dimethyl-13::dioxan-4- yl)acetic acid of formula (2');
Figure imgf000015_0002
(g) eliminating acetonide protection group in amine salt of formula (2') and reacting with source of calcium to the solution to precipitate rosuvastatin calcium; and
(h) recovering the rosuvastatin calcium salt.
According to third embodiment, the present invention provides a novel intermediate, 2-chloro-[4-(4'-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) in crystalline form characterized by X-ray powder diffraction as depicted in Figure-3.
Figure imgf000015_0003
According to fourth embodiment, the present invention provides a novel intermediate, triphenyl[2-chloro- {4-(4' -flourphenyl)-6-isoproρyl-pyrimidin-5- ylmethyl}-phosphonium]bromide of formula (10) in crystalline form characterized by X-ray powder diffraction as depicted in Figure-4.
Figure imgf000016_0001
According to fifth embodiment, the present invention, provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4-fluorophenyl)-6- isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5) in crystalline form.
Figure imgf000016_0002
According to sixth embodiment, the present invention provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4 ' -fluorophenyl)-6-isoρroρyl-2- (methylamino)pyrimidin-5-yl) vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate (4);
Figure imgf000016_0003
According to seventh embodiment, the present invention provides a novel intermediate, amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula (2') in crystalline form, preferably the amine salt is n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonaraido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetic acid in crystalline form.
Figure imgf000017_0001
According to further aspect to the present invention, there is provided a process for the preparation of stable amorphous rosuvastatin calcium of formula (1),
Figure imgf000017_0002
which process comprises; a) providing amorphous rosuvastatin calcium prepared as per any of the process herein above; b) preparing the slurry in hot water; c) maintaining the reaction mixture for sufficient amount of time at elevated temperature; and d) recovering stable amorphous rosuvastatin calcium.
Brief description of figures: -
A preferred embodiment of the invention will now be described, by way of example only, with reference to the accompaying figures in which:
FIG.l: X-ray diffraction of amorphous rosuvastatin calcium prepared as per present invention.
FIG.2: X-ray diffraction of crystalline intermediate of formula (9). FIG.3: Differential Scanning Calorimetric analysis of crystalline intermediate of formula (9).
FIG.4: 1H NMR spectra of crystalline intermediate of formula (9). FIG.5: 13C NMR spectra of crystalline intermediate of formula (9). FIG.6: IR spectra of crystalline intermediate of formula (9).
FIG.7: X-ray diffraction of crystalline intermediate of formula (10). FIG.8: . Differential Scanning Calorimetric analysis of crystalline intermediate of formula (10).
FIG.9: 1H NMR spectra of crystalline intermediate of formula (10) FIG.10: 13C NMR spectra of crystalline intermediate of formula (10). FIG.ll: IR spectra of crystalline intermediate of formula (10). FIG.12: X-ray diffraction of crystalline intermediate of formula (5). FIG.13: Differential Scanning Calorimetric analysis of crystalline intermediate of formula (5). FIG.14: 1H NMR-spectra of crystalline intermediate of formula (5) FIG.15: 13C NMR spectra of crystalline intermediate of formula (5). FIG.16: IR spectra of crystalline intermediate of formula (5). FIG.12: X-ray diffraction of crystalline intermediate of formula (5). FIG.13: Differential Scanning Calorimetric analysis of crystalline intermediate of formula (5).
FIG.14: 1H NMR spectra of crystalline intermediate of formula (5) FIG.15: 13C NMR spectra of crystalline intermediate of formula (5). FIG.16: IR spectra of crystalline intermediate of formula (5). FIG.17: X-ray diffraction of crystalline intermediate of formula (4). FIG.18: Differential Scanning Calorimetric analysis of crystalline intermediate of formula (4).
FIG.19: 1H NMR spectra of crystalline intermediate of formula (4). FIG.20: 13C NMR spectra of crystalline intermediate of formula (4). FIG.21: IR spectra of crystalline intermediate of formula (4). FIG.22: X-ray diffraction of crystalline intermediate of formula (2').
FIG.23: Differential Scanning Calorimetric analysis of crystalline intermediate of formula (2').
FIG.24: 1H NMR spectra of crystalline intermediate of formula (2').
FIG.25: 13C NMR spectra of crystalline intermediate of formula (T). FIG.26: IR spectra of crystalline intermediate of formula (2').
FIG.27: X-ray diffraction of crystalline intermediate of formula (9a).
FIG.28: Differential Scanning Calorimetric analysis of crystalline intermediate of formula (9a).
FIG.29: 1H NMR spectra of crystalline intermediate of formula (9a).
FIG.30: 13C NMR spectra of crystalline intermediate of formula (9a).
FIG.31: IR spectra of crystalline intermediate of formula (9a).
FIG.32: 1H NMR spectra of an isolated impurity-B.
FIG.33: 13C NMR spectra of an isolated impurity-B.
FIG.34: 1H NMR spectra of an isolated impurity-C.
FIG.35: 13C NMR spectra of an isolated impurity-C.
FIG.36: X-ray diffraction of crystalline intermediate of formula (2").
FIG.37: Differential Scanning Calorimetric analysis of crystalline intermediate of formula (2").
FIG.38: IR spectra of crystalline intermediate -of formula (2").
Detailed description on Invention:
According to the present invention provides an improved process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4-fluorophenyl)-6- isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5),
Figure imgf000019_0001
which comprises of:
(a) reacting compound of formula (7) by halogenating agent in a suitable organic solvent, wherein R is a alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an arylalkyl group having an alkyl moiety of 1-3 carbon atoms or an aryl group to obtain 2-chloro-4-(4'-flourophenyl)-6-isopropyl-5- substitutedpyrimidine compound of formula (8);
Figure imgf000020_0001
(b) reducing 2-chloro-4-(4' -flourophenyl)-64sopropyl-5-substitutedpyrimidme compound of formula (8) with suitable reducing agent in suitable organic solvent to give 2-chloro-[4-(4-flourophenyl)-6-isopropyl-pyrimidin-5--yL]methanol compound of formula (9);
Figure imgf000020_0002
(c) reacting 2-chloro-[4-(4'-flouroph.enyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) with phosphrous tribromide for preparation of 2-chloro- [4-(4-fiourophenyl)-6-isopropyl-pyrimidin-5-yl]methyl bromide;
(d) reacting 2-chloro-4-(4' -flourophenyl)-5-(bromomethyl)-6-isopropyl]pyrimidine bromide with triphenly phosphine in a suitable organic solvent at an elevated temperature to obtain triphenyl[2-chloro-{4-(4'-flourphenyl)-6-isopropyl- pyrimidin-5-ylmethyl}-ρhosphonium]bromide compound of formula (10); and
Figure imgf000020_0003
(e) reacting wittig reagent of formula (10) with tert-butyl-2-[(4R,6S)-6-formyl-2,2- dimethyl-1 ,3 -dioxan-4-yl] acetate (BFA) of formula (11) in presence of base to obtain compound of formula (5)
Figure imgf000021_0001
According to second embodiment, the present invention an improved process for the preparation of rosuvastatin or its salts like calcium of formula (1)
Figure imgf000021_0002
which comprises of:
(a) reacting triphenyl[2-chloro-{4-(4-flourphenyl)-6-isopropyl-pyrimidin-5-ylmethyl}- phosphoniumjbromide of formula (10)
Figure imgf000021_0003
with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11)
Figure imgf000021_0004
in presence of base to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylρyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate of formula (5);
Figure imgf000022_0001
(b) reacting compound of formula (5) with monomethyl amine to obtain tert-butyl 2- ((4R,6S)-6-((E)-2-(4-(4'-fluoroplienyl)-6-isopropyl-2-(methylammo)pyrimidin-5- yl)vinyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate (4);
Figure imgf000022_0002
(c) reacting compound of formula (4) with methane sulphonyl chloride in presence of base to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate of formula (3);
Figure imgf000022_0003
(d) reacting compound of formula (3) with a base to obtain 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(N-methylmethyl- sulfonamido)pyrimidin-5-yl)vinyl)- 2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula (2);
Figure imgf000022_0004
(e) treating compound of formula (2) with organic base to obtain amine salt of 2- ((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l ,3-dioxan-4- yl)acetic acid of formula (T);
Figure imgf000023_0001
(f) eliminating acetonide protection group in amine salt of formula (2') and reacting with source of calcium to the solution to precipitate rosuvastatin calcium; and
(g) recovering the rosuvastatin calcium salt.
According to third embodiment, the present invention provides a novel intermediate, 2-chloro-[4-(4'-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) in crystalline form characterized by X-ray powder diffraction as depicted in Figure-3.
Figure imgf000023_0002
According to fourth embodiment, the present invention provides a novel intermediate, triphenyl[2-chloro-{4-(4'-flourphenyl)-6-isopropyl-pyrimidin-5- ylmethyl}-ρhosphonium]bromide of formula (10) in crystalline form characterized by X-ray powder diffraction as depicted in Figure-4.
Figure imgf000023_0003
According to fifth embodiment the present invention provides a novel intermediate, tert-butyl 2-((4Ij,6S)-6-((E)-2-(2-chloro-4-(4-fluorophenyl)-6- isopropylpyrimidin-5-yl)vinyl)-2,2-dimetnyl-l,3-dioxan-4-yl)acetate of formula (5) in crystalline form.
Figure imgf000024_0001
According to sixth embodiment, the present invention " provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2- (methylamino)pyrimidm-5-yl)vinyl)-2,2-dimethyl-l53-dioxan-4-yl)acetate (4);
Figure imgf000024_0002
According to seventh embodiment, the present invention provides a novel intermediate, amine salt of 2-((4R,6S)-6-j((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5 -yj.) vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetic acid of formula (2') in crystalline form, preferably the amine salt is n-propyl amine salt of 2-((4R,6S)-6j((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yi)vinyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetic acid in crystalline form.
Figure imgf000024_0003
According to further aspect to the present invention, there is provided a process for the preparation of stable amorphous rosuvastatin calcium of formula (1),
Figure imgf000025_0001
which process comprises; e) providing amorphous xosuvastatin calcium prepared as per any of the processJietein above; f) preparing the slurry in hot water; g) maintaining the reaction mixture for sufficient amount of time at elevated temperature; and h) recovering stable amorphous rosuvastatin calcium.
According preferred embodiment, the present invention provides an improved process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)viiiyl)-252-dimethyl-l,3-dioxan-4-yl)acetate of formula (5),
Figure imgf000025_0002
which comprises of:
(a) reacting compound of formula (7) by halogenating agent in a suitable organic solvent, wherein R is a alkyl group having 1 to 0 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an arylalkyl group having an alkyl moiety of 1-3 carbon atoms or an aryl group to obtain 2-chloro-4-(4'-flourophenyl)-6-isopropyl-5- substitutedpyrimidine compound of formula (8);
Figure imgf000026_0001
(b) reducing 2-chloro-4-(4-flourophenyl)-6-isopropyl-5-substitutedpyrimidine compound of formula (8) with diisobutylaluminium hydride (DIBAL) in suitable organic solvent to give 2-chloro-[4-(4-flourophenyi)-6-isopropyl-pyrimidin-5- yl]methanol compound of formula (9);
(c) reacting 2-chloro-[4-(4'-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) with phosphorus bromide for in-situ preparation of 2- chloro- [4-(4-flourophenyl)-6-isopropyl-pyrimidin- 5 -yl] methyl btom i de ;
Figure imgf000026_0002
(d) reacting in-situ 2-chloro-4-(4'-flourophenyl)-5-(bromomethyl)-6- isopropyl]pyrimidine with triphenly phosphine in a suitable, organic solvent at an elevated temperature to obtain triphenyl[2-chloro-{4-(4'-fiourphenyl)-6-isopropyl- pyrimidin-5-ylmethyl}-phosphonium]bromide compound of formula (10); and
Figure imgf000026_0003
(e) reacting compound of formula (10) with tert-butyl-2-[(4R,6S)-6-formyl-2,2- dimethyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11) in presence of base in a polar aprotic solvent; and
Figure imgf000027_0001
(f) isolating tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4-fiuorophenyl)-6- isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate of formula (5).
Halogenation as in step (a) can be done with suitable halogenating agent can be selected for the thionyl chloride, phosphorus oxylchloride, phosphorus pentachloride, phosphorus trichloride and the like, preferably thionyl chloride in suitable organic solvent selected from C1-C4 alcohols like methanol, ethanol, propanol, butanol, isopropanol and the like., halogenated aliphatic hydrocarbons- -like— methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride and the like, aromatic hydrocarbons like toluene, xylene, ethyl benzene and the like, preferably toluene.
According to one of the aspect of the present invention, the compound of formula (8) can be reduced to alcohol of formula (9) by using diisobutylaluminium hydride (DIBAL) in a suitable organic solvent selected from aromatic hydrocarbons like toluene, xylene, ethyl benzene., esters like ethyl acetate, methyl acetate, isopropyl acetate, t-butyl acetate etc., ethers like diisopropyl ether, diethyl ether., methyltertbutylether., halogenated aliphatic hydrocarbons like methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride etc., preferably toluene.
According to further embodiment, 2-chlorυ-4-(41-flυuioρhenyl)-5-(bromomethyl)-
6-isopropyl] pyrimidine prepared in-situ by reacting compound of formula (8) with phosphrous bromide can be further reacted with Wittig reagent like triphenyl phosphine, tributyl phosphine, preferably triphenyl phosphine in a suitable organic solvent like non-polar solvents selected from toluene, o-xylene, chlorobenzene preferably toluene at a temperature ranging from 80 to 14O0C, preferably at 100°-l 10°C to provide novel intermediate triphenyl[2-chloro-{4-(4-flouφhenyl)-6-isopropyl- pyrimidin-5-ylmethyl}-phosphonium]bromide compound of formula (10).
According to most preferred embodiment, the wittig reagent of formula (10) is reacted ' with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11) in presence of suitable base selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably potassium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidine or mixture thereof, preferably dimethylsulfoxide at a temperature ranging from 40° to 8O0C preferably 60° to 7O0C to provide novel intermediate tert-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6- isopropyl-2-chloro]pyrimidin-5-yl}-vinyl}-(4R,6S)-2,2-dimethyl[l,3]dioxan-4- yl)acetate of formula (5).
According to preferred embodiment, the present invention an improved process for the preparation of amorphous rosuvastatin calcium of formula (1)
Figure imgf000028_0001
comprises of: (a) reacting triphenyl[2-chloro-{4-(4-fiourphenyl)-6-isopropyl-pyrimidin-5- ylmethyl}-phosphonium]bromide of formula (10)
Figure imgf000028_0002
with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11)
Figure imgf000028_0003
in presence of base in a polar aprotic solvent to obtain tert-butyl 2-((4R,6S)-6-((E)- 2-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3- dioxan-4-yl)acetate of formula (5);
Figure imgf000029_0001
(b) reacting compound of formula (5) obtained in step (a) with monomethyl amine solution at an ambient temperature to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl- l,3-dioxan-4-yl)acetate (4);
Figure imgf000029_0002
(c) reacting compound of formula (4) with methane sulphonyl chloride in presence of base in a suitable organic solvent at -3O0C to +1O0C temperature to obtain in-situ tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate of formula (3 ) ;
Figure imgf000029_0003
(d) hydrolyzing in-situ compound of formula (3) with a base in C1-C4 alcohol at an elevated temperature to obtain solution of 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)- 2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula (2)
Figure imgf000030_0001
(e) concentrating the solution and removing Ci-C4 alcoholic solvent;
(f) treating residue of step (e) with organic base in a suitable organic solvent or mixture thereof with water to adjust the pH of about 8 to about 9 to obtain amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yi)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetic acid of formula (2');
Figure imgf000030_0002
(g) eliminating acetonide protection group in amine salt of formula (T) and reacting with source of calcium to the solution to obtain rosuvastatin calcium.
According to most preferred embodiment, the Wittig reagent of formula (10) is reacted with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate
(BFA) of formula (11) in presence of suitable base selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably potassium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixture thereof, preferably dimethylsulfoxide at a temperature ranging from 40° to 8O0C preferably 60° to 7O0C to provide novel intermediate tert-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-chloro]pyrimidin- 5-yl}-vinyl}-(4R,6S)-252-dimethyl[l,3]dioxan-4-yl)acetate of formula (5).
According to still further aspect of the present invention, the compound of formula (5) can be converted to compound of formula (4) as in step (b) by reaction with monomethyl amine solution at an ambient temperature. The monomethyl amine solution is 25% solution in methanol. The ambient temperature of the reaction meaning room temperature i.e. at about 250C to about 350C. After the completion of the reaction, the reaction mixture is cooled to about O0C to about 5°C and filtered to isolate tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidin-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (4).
The tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-
(methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate of formula (4) can be converted to in-situ rosuvastatin protected diol ester compound of formula (3) as in step (c) by reaction compound of formula (4) with methane sulphonyl chloride in presence of suitable base selected from inorganic base like alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate or organic bases like triethylamine, diisopropylethylamine, diethylamine, pyridine, piperidine, morpholine etc, preferably triethylamine. The reaction is carried out in a suitable organic solvent selected from the methylene dichloride, ethylene dichloride, toluene, polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidine or mixture thereof, preferably methylene dichloride at -3O0C to 100C, preferably at about -2O0C to -250C. The tert-butyl ester group of compound of formula (3) is hydrolyzed initially to obtain 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N-methylmethyl- sulfonamide)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4ryl)acetic acid of formula (2). The hydrolysis of compound of formula (3) is performed by in-situ reacting compound of formula (3) with a suitable base selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably sodium or potassium hydroxide at an elevated temperature.
The elevated temperature herein means, reaction is performed at about 5O0C to about 12O0C, more preferably at about 6O0C to about 900C5 most preferably at about 6O0C to about 7O0C.
The reaction is performed in C1-C4 alcoholic solvents like methanol, ethanol, butanol, isopropanol and the like preferably methanol. After completion of the reaction on TLC, the reaction mixture is concentrated as in step (e) to remove C1-C4 alcoholic solvent like methanol under vacuum. The residue of step (e) is treated with organic base like n-propyl amine, isopropylamine, tert-butyl amine, dicyclohexyl amine, ethyl amine etc., preferably n-propyl amine in suitable organic solvent selected from polar organic solvents like tetrahydrofuran, dimethylformamide, dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, acetone etc., or mixture thereof with water, preferably mixture of acetonitrile and water.
The residue is treated with mixture of acetonitrile and water at 00C to about 1O0C followed by treatment with acid like hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid preferably hydrochloric acid followed by treatment with n-propyl amine to adjust the pH of about 8 to about 9 to obtain n-propylamine salt of 2-((4R,6S)-6-((E)- 2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamide)pyrimidin-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula~(2')7 ""
According to still further aspect of the present invention, the n-propylamine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamide)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula,, (2') is treated strong acid like hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid preferably hydrochloric acid is a suitable organic solvent like polar organic solvent tetrahydrofuran, methanol, ethanol or non-polar solvent like ethyl acetate or toluene to eliminate acetonide protection group followed treatment with 10% sodium hydroxide to adjust the pH 7 to 7.5 to obtain in-situ rosuvastatin sodium salt.
The rosuvastatin sodium salt is further treated with mixture of toluene and ethyl acetate followed by treatment with suitable calcium source like calcium chloride, calcium acetate, calcium hydroxide etc., preferably calcium acetate to obtain amorphous rosuvastatin calcium salt. According to further aspect to the present invention, there is provided a process for the preparation of stable amorphous rosuvastatin calcium of formula (1),
Figure imgf000032_0001
which process comprises; (a) providing amorphous rosuvastatin calcium prepared as per any of the process herein above;
(b) preparing the slurry in hot water;
(c) maintaining the reaction mixture for sufficient amount of time at elevated temperature; and
(d) recovering stable amorphous rosuvastatin calcium.
According to most important embodiment, the present invention provides stable amorphous rosuvastatin calcium having individual impurities like rosuvastaiin diastereomer less than about 0.1%, rosuvastatin lactone less than about 0.1%, rosuvastatin desflouro impurity less than 0.1%, rosuvastatin 5-oxo (B2) impurity less than 0.1%, rosuvastatin protected diol ester not in detectable amount, rosuvastatin 3- oxo impurity less than 0.1% by area percentage of HPLC when kept for 3 months at 250C at 60% RH,
According to most important embodiment, the present invention provides stable amorphous rosuvastatin calcium having individual impurities like rosuvastatin diastereomer less than about 0.1%, rosuvastatin lactone less than about 0.1%, rosuvastatin desflouro impurity less than 0.1%, rosuvastatin 5-oxo (B2) impurity less than 0.1%, rosuvastatin protected diol ester not in detectable amount, rosuvastatin 3- oxo impurity less than 0.1% by area percentage of HPLC when kept for 3 months at 4O0C at 75% RH.
The elevated lemperaturc for the reaction can be in the range of 350C to about 6O0C, more preferably at about 400C to about 450C for sufficient time i.e. about 1 hour to obtain stable amorphous rosuvastatin calcium.
According to third embodiment, the present invention provides a novel intermediate, 2-chloro-[4-(4'-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) in crystalline form characterized by atleast one of the following properties,
Figure imgf000033_0001
(i) X-ray powder diffraction pattern substantially as depicted in Figure-2; or (ii) having characteristics peaks at about 12.7, 19.5, 23.0, 25.7 and 26.0±0.2 2Θ; or (iii) having endothermic peak at about 1820C in differential scanning calorimetry; or (iv) differential scanning calorimetry substantially as depicted in Figure-3; or (v) having peaks at about 3390, 2980, 2931, 1607, 1548, 1511, 1390, 1231, 1165,
1148, 1026, 916,
849, 740, 668 and 568 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure-6.
According to fourth embodiment, the present invention provides a novel intermediate, triphenyl[2-chloro- {4-(4-flourphenyl)-6-isopropyl-pyrimidin-5- ylmethyl}-phosphonium] bromide of formula (10) in crystalline form characterized by atleast one of the following properties,
Figure imgf000034_0001
(i) X-ray powder diffraction pattern substantially as depicted in Figure-7; or (ii) having characteristics peaks at about 9.6, 11.2, 17.0, 20.5, 22.4, 23.8, 29.6 and
31.7 ±0.2 2θ; or (iii) having two endothermic peak at about 930C and 2450C in differential scanning calorimetry; or
(iv) differential scanning calorimetry substantially as depicted in Figure-8; or (v) having peaks at about 3448, 3371, 2988, 1602, 1537, 1509, 1436, 1384, 1323,
1293, 1229, 1157, 1102, 921, 853, 752, 694, 569, and 521 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure- 11. •
According to fifth embodiment, the present invention provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4-fluorophenyl)-6- isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5) in crystalline form characterized by atleast one of the following properties,
Figure imgf000035_0001
(i) X-ray powder diffraction pattern substantially as depicted in Figure- 12; or (ii) having characteristics peaks at about 8.1, 10.6, 12.2, 14.0, 18.6, 20.1, 22.2, 27.8 and 28.4 ±0.2 2Θ; or (iii) having two endothermic peak at about 87°C and 2380C in differential scanning calorimetry; or
(iv) differential scanning calorimetry substantially as depicted in Figure- 13; or (v) having peaks at about 2996, 2978, 2894, 1716, 1518, 1508, 1380, 1324, 1290, 1224, 1157,
1073, 984, 845, 813 and 573 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure- 16.
According to sixth embodiment, the present invention provides a novel intermediate, tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluoroρhenyl)-6-isopropyl-2- (methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (4) in crystalline form characterized by atleast one of the following properties,
Figure imgf000035_0002
(i) X-ray powder diffraction pattern substantially as depicted in Figure- 17; or (ii) having characteristics peaks at about 7.2, 11.9, 17.3, 18.1, 20.0, 24.1 and 3.0.7
±0.2 2Θ; or
(iii) having endothermic peak at about 1640C in differential scanning calorimetry; or (iv) differential scanning calorimetry substantially as depicted in Figure- 18; or (v) having peaks at about 3266, 3117, 2970, 2940, 1732, 1551, 1445, 1401, 1315,
1228, 1153, 1084, 851 and 515 crn'On'1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure-21.
According to seventh embodiment, the present invention provides a novel intermediate, amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido) pyrimidin-5-yl) vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula (2') in crystalline form, preferably the amine salt is n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid in crystalline form characterized by atleast one of the following properties,
Figure imgf000036_0001
(0 X-ray powder diffraction pattern substantially as depicted in Figure-22; or
(μ) having characteristics peaks at about 9.5, 15.6, 17.8, 20.3 and 25.0±0.2 2θ; or
(iii) having endothermic peak at about 148°C in differential scanning calorimetry; or
(iv) differential scanning calorimetry substantially us depicted in Figure-23; or
(V) having peaks at about 2976, 2889, 2816, 2704, 2577, 2217, 1633, 1543, 1428, 1341, 1268, 1138, 845, 765 and 568 cm"1 in Infrared spectral analysis;
(vi) Infrared spectral analysis substantially as depicted in Figure-26.
The n-propyl amine may be replaced by ethylamine to provide ethylamine salt of compound of formula (2") is also the scope of the present invention in its crystalline form characterized by characterized by atleast one of the following properties,
Figure imgf000036_0002
(i) X-ray powder diffraction pattern substantially as depicted in Figure-38; or
(ϋ) having characteristics peaks at about 12.7, 19.5, 23.0, 25.7 and 26.0±0.2 2Θ; or
(iii) having endothermic peak at about 1880C in differential scanning calorimetry; or
(iv) differential scanning calorimetry substantially as depicted in Figure-39; or
(V) having peaks at about 2971, 2356, 2228, 2218, 1605, 1597, 1 1544, 1511, 1396, 1382, 1267, 1197, 1150, 1031 and 855 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure-40.
According to the most preferred embodiment of present invention, the process for the preparation of HMG-CoA reductase inhibitors like rosuvastatin calcium of formula (1) can be illustrated by below mentioned scheme- 8 and scheme-9, which should not be considered as limiting the scope of the invention.
Figure imgf000037_0001
(6) (7)
Halogenation
Figure imgf000037_0002
Figure imgf000038_0001
Scheme-10
According to the present invention there is provided a calcium salt of the compound (E)-7-[4-(4-flurophenyl)-6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl](3R, 5S)-3, 5-dihydroxy-6-heptenoic acid with high purity level (individual known/unknown impurity less than 0.1%). The process for preparing rosuvastatin calcium according Io present invention is simple, easy safe and yields rosuvastatin calcium with high degree of purity by HPLC greater than 99.0%.
According to the most important embodiment of the present invention, the process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5)
Figure imgf000039_0001
the condensation of compound of formula (10) i.e. triphenyl[2-chloro-{4-(4- flourphenyl)-6risopropyl-pyrimidin-5-ylmethyl}-phosphonium]bromide with tert-butyl- 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11)
Figure imgf000039_0002
there results the formation of undesired product (B) and further reaction of condensed compound of formula (5) with monomethyl amine results in the formation of undesired product (C).
Figure imgf000040_0001
According to the most preferred embodiment, the present invention provides amorphous rosuvastatin calcium substantially free from undesired product (B) i.e. 2- chloro-4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidine and undesired product (C) i.e. 4-(4-fluorophenyl)-6-isopropyl-N,5-dimethylpyrimidin-2-amine.
The term "substantially free" herein above refers to the amorphous rosuvastatin calcium having undesired impurity (B) less than 0.1%, preferably less than 0.07%, more preferably less than 0.05% and most preferably not in detectable amount, i.e. 2- chloro-4-(4-fluorophenyl)-6-isopropyl-5-memylpyrimidine. Furthermore, "substantially free" also refers to amorphous atorvastatin calcium having undesired impurity (C) less than 0.1%, preferably less than 0.08%, more preferably less than 0.04% and most preferably not in detectable amount, i.e. 4-(4-fluorophenyl)-6-isopropyl-N,5- dimethylpyrimidin-2-amine when measured by area percentage of HPLC. According to the another most preferred embodiments, the present invention provides isolated impurity-B characterized by 1HNMR substantially as depicted in Figure-32 and 13CNMR substantially as depicted in Figure-33. Further provides isolated impurity-C characterized by 1HNMR substantially as depicted in Figure-34, 13CNMR substantially as depicted in Figure-35. According to another preferred embodiment, the formation of triphenyl[2- chloro-{4-(4'-flouφhenyl)-6-isopropyl-pyrimidin-5-ylmethyl}-phosphonium]bromide compound of formula (10) involves bromination of compound (9) with triphenyl phosphonium bromide. The reaction results in the undesired product (A) i.e. 2-bromo- 5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidine under' the drastic conditions.
According to the most preferred embodiment, the present invention provides amorphous rosuvastatin calcium substantially free from undesired product (A) i.e. 2- bromo-5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidine.
Figure imgf000041_0001
The term "substantially free" herein above refers to the amorphous rosuvastatin calcium having undesired impurity (A) less than 0.1%, preferably less than 0.07%, more preferably less than 0.05% and most preferably not in detectable amount when measured by area percentage of HPLC
According to another embodiment of the present invention, there is also provided amorphous rosuvastatin calcium substantially free from hemi-calcium salt of (3R,5S)-(E)-7-(2-chloro-4-(4-fluoroρhenyl)-6-isopropylpyrimidin-5-yl)-3,5- dihydroxyhept-6-enoate) of formula (D)
Figure imgf000041_0002
The term "substantially free" herein above refers to the amorphous rosuvastatin calcium having undesired impurity (D) less than 0.15%, preferably less than 0.10%, more preferably less than 0.07%, and most preferably less than 0.05% when measured by area percentage of HPLC.
The Impurity Profile Determination of Rosuvastatin Ca comprised testing a sample using UPLC (Ultra performance liquid chromatography). Typically, the UPLC testing parameters included a column of Aciqity Cl 8 1.7 μm 2.1*100 mm or equivalent column at a temperature of 40°C and eluted with a two solvent system. A first reservoir, Reservoir A, contained 6.8 g potassium dihydrogen orthophosphate and 2 ml of triethyl amine dissolved in 1000 ml water, adjusted to pH 2.0 with H3PO4, and a second reservoir, Reservoir B, contained acetonitrile. The gradient was as follows: at the initial time, 74% Reservoir A and 26% Reservoir B; time 15.0 min 74% Reservoir A and 26% Reservoir B; and at time 35.0 min 40% Reservoir A and 60% Reservoir B, and at time 39.0 min 40% Reservoir A and 60% Reservoir B, and at lime 40.0 min 74% Reservoir A and 26% Reservoir B, and at time 45.0 min 74% Reservoir A and 26% Reservoir B. The system equilibrated further for 10 min and a flow rate of 0.45 ml/min. The detector was set for 240 nm. The sample volume was 10 μL and the diluent was acetonitrile: water 80:20. As commonly known by the skilled artisan, the mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
The sample was prepared by weighing accurately about 10 mg of Rosuvastatin Ca sample in a 20 ml amber volumetric flask. Dissolving the sample with 10 ml of acetonitrile and diluting to the desired volume with water. Thereafter, the freshly prepared sample was injected. The sample solutions were injected into the chromatograph and the chromatogram of sample was continued up to the end of the gradient. Thereafter, the areas for each peak in each solution was determined using a suitable integrator. The calculations were obtained using the following formula: Impurity Profile Determination
% impurity = area impurity in sample X lOO
Total area
The Impurity Profile Determination of tert-butyl2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(methylaminό)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3- dioxan-4-yl)acetate (4) to check the impurity level of Impurity-A, Impurity-B and Impurity-C comprised testing a sample using UPLC (Ultra performance liquid chromatography). Typically, the UPLC testing parameters included a column of Aciqity Cl 8 1.7 μm 2.1*100 mm or equivalent column at a temperature of 400C and eluted with a two solvent system. A first reservoir, Reservoir A, contained 6.8 g potassium dihydrogen orthophosphate and 2 ml of triethyl amine dissolved in 1000 ml water, adjusted to pH 2.0 with HsPO4, and a second reservoir, Reservoir B, contained acetonitrile. The gradient was as follows: at the initial time, 65% Reservoir A and 35% Reservoir B; time 10.0 min 65% Reservoir A and 35% Reservoir B; and at time 35.0 min 40% Reservoir A and 60% Reservoir B, and at time 39.0 min 40% Reservoir A and 60% Reservoir B, and at time 40.0 min 65% Reservoir A and 35% Reservoir B5 and at time 45.0 min 65% Reservoir A and 35% Reservoir B. The system equilibrated further for 10 min and a flow rate of 0.40. ml/min. The detector was set for 240 nm. The sample volume was 10 μL and the diluent was acetonitrile: water 80:20.. As commonly known by the skilled artisan, the mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The Examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. Reference examples:
Reference Example 1: Preparation of 4-(4-fluorophenyl)-6-isopropyl-5- methoxycarbonyl-3,4-2(lH)-dihydro pyrimidinone (6)
Figure imgf000043_0001
(6)
In a 500mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 28.8 g (0.2 mol.) of methyl isobutyrylacetate, 24.8 g (0.2 mol. ) of 4-fruorobenzaldehyde, 21.O g (0.35 mol. ) of urea, 200 mg (2 mmol. ) of copper (I) chloride, 2 mL of sulfuric acid, and 200 mL of methanol. The content of the flask was heated to64-65 C for 24 hours under reflux with stirring, to carry out the reaction. There was precipitated crystalline product. The crystalline product was collected on a filter paper and washed with methanol to obtain 49.7 g of4- (4- fluorophenyl)-6-isopropyl-5- methoxycarbonyl-3,4-2(lH)-dihydropyrimidinone as a colorless crystalline product having the below-mentioned characteristics. The yield was 85% (based on the amount of methyl isobutyrylacetate). m.p.: 223-2250C UV (CH3CN, urn): 194.3, 278.6 IR (KBr,cm~l) : 3296,3229, 3137,2963, 1685,1629, 1504, 1225, 1097.
H-NMR (DMSO-ds, 6 (ppm)): 1.14 (6H, dd, J=6.8, 6.9Hz), 3.52 (3H, s), 4.0-4. 2(1 H, m), 5.15(1H, d, J=3.4Hz), 7.1-7. 2 (2H, m), 7.2-7.3 (2H, m), 7.76(1H, d, J=3.2Hz), 8.91(1H5 S).
Reference Example 2: Preparation of 4-(4'-fluorophenyl)-2-hydroxy-6-isopropyl-5- methoxycarbonyl pyrimidine (7)
Figure imgf000044_0001
(6) (7)
5 In a 5 OmL- volume glass flask equipped with a stirrer and a thermometer was placed 11 mL (144 mmol.) of nitric acid (60-61%, sp. gr.: 1.38). To the nitric acid was slowly added at room temperature 4.00 g (13.7 mmol.) of 4-(4-fluorophenyl)-6- isopropyl-5-methoxycarbonyl-3,4-2(lH)-dihydropyrimidinone prepared in the same manner as in Example 1, and the mixture was subjected to reaction for 30 minutes at
10 room temperature. After the reaction was complete, placing the mixture in 140 mL of saturated aqueous sodium hydrogen carbonate solution neutralized the reaction mixture. The reaction mixture was then extracted with ethyl acetate. The organic liquid portion was separated and concentrated under reduced pressure. The residue was crystallized from toluene.
15 The crystalline product was collected on a filter and washed with toluene to obtain 3.64 g of4-. (4- fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonyl- pyrimidine as a colorless crystalline product having the below-mentioned characteristics. Tlie yield was92% (based on the amount of4- (4-fluorophenyl)-6- isopropyl-5- methoxycarbonyl-3,4-2(lH)-dihydropyrimidinone).
.0 m.p.: 193 C (decomposed) UV (CH3CN, am): 196.6, 243.2, 317.9 IR (KBr5 cm4): 2991,2887, 1717,1653, 1589,1433, 1280, 1223. IH-NMR (DMSO-ds, 8 (ppm)): 1.23 (6H, d, J=6.8Hz), 3.0-3. 2(1H, m), 3.56 (3H5 s), 7.3-7. 4 (2H5 m), 7.5-7. 6 (2H, m), 12.25 (IH, brs).
»5 Reference Example-3: Preparation of 4-(4'-fluorophenyl)-2-hydroxy-6-isopropyl-5-
Figure imgf000044_0002
(6) (7) In a 50mL-volume glass flask equipped with a stirrer and a thermometer were placed 2.92 g (10 mmol.) of 4 (4-fluorophenyl) -6-isopropyl-5-methoxycarbonyl-3,4-2
(IH)- dihydropyrimidinone prepared in the same manner as in example 2 and 5 mL of acetic acid. To the mixture was slowly added 3.74 mL (50 mmol. ) of nitric acid (60- 61%, sp.gr. : 1.38). To the mixture was further added 0.07 g(l mmol. ) of sodium nitrite, and the reaction was carried out for one hour at room temperature. After the reaction was complete, placing the mixture in 50 mL of saturated aqueous sodium hydrogen carbonate solution neutralized the reaction mixture. The reaction mixture was then extracted with ethyl acetate. The organic liquid portion was separated and concentrated under reduced pressure. The residue was crystallized from toluene.
The crystalline product was collected on a filter and washed with toluene to obtain 2.61 g of 4-(4- fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonyl-
Figure imgf000045_0001
pyrimidine as a colorless crystalline product. The yield was 90% (based on the amount of 4-(4-fluorophenyl)-6-iso-propyl-5-methoxycarbonyl-3,4-2(lH)- dihydropyrimidinone).
Reference Example 4: Preparation of 2-chloro-4- (4-fluorophenyl6-isopropyl-5- methoxycarbonyl pyrimidine (8)
In a 25mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placedl.OO g (3.43 mmol.) of 4- (4-fluorophenyl)-2-hydroxy-6- isopropyl-5-methoxycarbonyl pyrimidine, 0. 5 mL (3.9 mmol.) of thionyl chloride, 3.44 mL of toluene, and 0.11 mL of N, N-dimethylformamide. The mixture was heated to80 C for 3 hours, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and poured into an ice/water mixture. The resulting aqueous mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The neutralized aqueous mixture was extracted with ethyl acetate.
The ethyl acetate portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure, to obtain 0.80 g o£2-chloro-4- (4-fluoro- phenyl) -β-isopropyl-S-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 76% (based on the amount of 4-(4'- fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Example-1: Preparation of [{4-(4'-Fluorophenyl)-6-isopropyl-2-chloro} pyrimidin-5- yl]methanol (9)
Figure imgf000046_0001
To a solution of the above obtained compound (8) (10.0 g, 0.0324 mole) in toluene (100 ml), was added drop wise diisobutylaluminium hydride DIBAL (20% solution in toluene; 82 ml) at -5° to O0C and stirred the solution or few hours. After the reaction was over, it was quenched with saturated ice cold hydrochloric acid solution followed by extraction with toluene and washing with brine solution. The product was isolated by distillation of toluene under reduced pressure to give 7.5 g titled compound, pyrimidine alcohol (9). Yield 83%; HPLC purity >99°/o. ExampIe-2: Preparation of Triphenyl [2-chloro-{4-(4-flourphenyl)-6-isopropyl-
Figure imgf000046_0002
pyrimidin-5-ylmethyl}-phosphonium]bromide (10)
Into a 2 L 4-necked round bottom flask [{4-(4'-Fluorbphenyl)-6-isopropyl-2- chloro} pyrimidin-5-yl] methanol (10 g), methylene dichloride (50 mL) were added at a temperature in the range of from about 0°-5°C. under stirring. Phosphorous tribromide (35 g) was slowly added over about 30 minutes at about 0°-5°C. After about 120 minutes, the reaction mixture was treated with 10% solution of sodium bicarbonate.
The reaction mixture was stirred for about 15 minutes at 0° to 50C and raises the temperature to 25° to 3O0C. The organic layer was treated with excess sodium thiosulphate solution. The separated organic layer dried over sodium sulphate and concentrated at a temperature in the range of from about 60°-70°C. under reduced pressure to obtain oily residue (11 g). The oily residue (1 Ig) was taken in toluene (40 mL). Triphenyl phosphine (8 g) in toluene (40 ml) was added to the reaction mixture. The reaction mixture was heated to a temperature of about HO0C. and maintained for about 3 to about 4 hours. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature in the range of from about 20°C-25°C. The precipitated product was filtered, washed with toluene (250 ml), and dried in a vacuum oven at a temperature of below about 6O0C. until the moisture content was about 1%. The dried product appears as an off-white crystalline solid weighing about 11 g to about 12 g. The yield was about 88% to about 94%. The oily residue obtained after bromination followed by distillation of methylene dichloride can be also be isolated in the solid form by treatment with chilled methanol to obtain novel intermediate of formula (9a) i.e. 5-(bromomethyl)-2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidine.
ExampIe-3: Preparation of tert-butyl-(E)-(6-{2-chloro-[4-(4'-fluorophenyl)-6- isopropyl]-pyrimidin-5-yl}-vinyl)-(4R,6S)-2,2-dimethyl[l,3]dioxan-4-yl)acetate of
Figure imgf000047_0001
formula (5)
Into a 2 L 4-necked round bottom flask, DMSO (41 ml), potassium carbonate (10.6 g), Triphenyl [2-chloro-{4-(4-flouφhenyl)-6-isopropyl-pyrimidin-5-ylmethyl}- phosphoniurn]bromide (13.5 g) of Example 2 and tert-butyl-2-[(4R,6S)-6-formyl-2,2- dimethyl-1, 3 -dioxan-4-yl] acetate (BFA) (8.5 g) were added at a temperature in the range of from about 25°C-35°C. under stirring. The reaction mixture was heated to a temperature in the range of from about 7O0C. to about 750C. for about 2 hours. After completion of the reaction as determined by TLC, the reaction mixture was cooled to a temperature in the range of from about 25°-35°C. Toluene (100 ml) was added for dilution of the reaction mixture under stirring for about 30 minutes at a temperature in the range of from about 25°-35°C. The reaction mixture was filtered, and the insoluble cake was separated. The organic layer was added to water (100 ml) under stirring at a temperature in the range of from about 25°-35°C. and maintained for about 30 minutes. The organic layer was separated and washed twice with water (200 ml). The organic layer was distilled in rotavapor bath at a temperature in the range of from about 50°C-70°C: under in a vacuum. After distillation, methanol (75 ml) was added to the residue at a temperature in the range of from about 550C. to about 6O0C. and maintained for about 30 minutes. The reaction mixture was brought to a temperature in the range of from about 25°C-30°C. by slowly circulating water. During this, time, a product precipitated out. The precipitated mass was further cooled to a temperature of about 1O0C. for about 30 minutes and then filtered. The cake was washed with prechilled methanol (100 ml at a temperature of about 1O0C). The product was dried in an oven at a temperature of about 550C. until the moisture content was about 1%. The dried product appeared as an off-white crystalline solid weighing about 7.8 g to about 8.2 g. (75% to about 8).
Example-4: Preparation of tert-butyl2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6- isopropyl-2-(methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate
Figure imgf000048_0001
of formula (4)
Into a 1 L 4-necked round bottom flask, tert-butyl-(E)-(6-{2-chloro-[4-(4'- fluorophenyl)-6-isopropyl]-pyrimidin-5-yl}-vinyl)-(4R,6S)-2,2-dimethyl[l,3]dioxan-4- yl)acetate of formula (5) (50 g) as prepared in Example 3 and 25% solution of monomethylamine (500 ml) were added and stirred under an inert atmosphere at about 25°C to 350C for about 24 hours. After the completion of the reaction on TLC, the reaction mixture was cooled to about O0C to 50C and maintained for about 1 hour. The reaction mixture was filtered and washed with chilled methanol. The product was dried at 5O0C to 550C to obtain tert-butyl2-((4R,6S)-6-((E)-2-(4-(4'-fmorophenyl)-6- isopropyl-2-(methyl- amino)pyrimidin-5-yl)vinyl)-2,2-dimelhyl- 1 ,3-dioxan-4- yl)acetate of formula (4).
Example-5: Preparation of n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2- dimethyl-l,3-dioxan-4-yl) acetic acid of formula (2'):
Figure imgf000049_0001
10 g of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isoρrόpyl-2- (methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate of formula (4) and 100 mL of methylene dichloride was taken into 500 mL RBF. 25 g of triethylamine was added into the reaction mixture at 250C to 35°C. The reaction mixture was cooled to get -2O0C to -250C and treated with methane sulphonyl chloride. After maintaining for 1 hour under stirring, upon completion of reaction on TLC, the reaction mixture is quenched into 100 gm ice at 00C to 50C. Separated organic layer was washed with water and 80% methylene dichloride was distilled atmospherically at 4O0C to 500C. The reaction mixture was treated with 21 mL 10% sodium hydroxide solution and 100 mL methanol. The remaining methylene dichloride was removed azeυlropically at 450C to 5O0C. After MDC removal, the reaction mixture was treated with 200 mL methanol and temperature was raised upto reflux for about 60°C to 650C for 6-8 hours. After the completion of the reaction on TLC, methanol was distilled under vacuum at 4O0C to 45°C.
Further, the reaction mixture was treated with 20 mL of water and 50 mL of acetonitrile and cooled to O0C to 1O0C. The pH of the reaction mixture was adjusted using dil HCl at O0C to 1O0C. The organic layer was separated and treated with n-propyl amine to adjust the pH to about 8 to 9 at O0C to 1O0C. The reaction mixture was maintained at about 25°C to 350C for 1 hour. The product thus obtained was filtered and washed with chilled with acetonitrile. The solid was dried at 5O0C to 550C to obtain n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluoroρhenyl)-6-isoρroρyl-2-(N- mέthylmethylsulfonamido)pyriniidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid of formula (2').
Eiample-6: - Preparation of Ethyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'- fluOrophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2- dimethyl-l,3-dioxan-4-yl) acetic acid of formula (2")
Figure imgf000050_0001
; The process disclosed in Example-5 can be repeated in the similar manner by replacing n-propyl amine with ethyl amine to obtain Ethyl amine salt of 2-((4R,6S)-6- ((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid of formula (2"). ExampIe-7: Preparation of amorphous rosuvastatin calcium.
Figure imgf000050_0002
1O g of n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluoroρhcnyl)-6-isoproρyl-2- (N->methyl- methylsulfonamido)pyrimidin-5-yl)viiiyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid of formula (2') and 90 mL acetonitrile in RBF at 250C to 350C. The reaction mixture was cooled to O0C to 1O0C. The reaction mixture was stirred and treated with 25 SmL IN HCl and maintained for 2 hours at 2O0C to 250C. After the completion of the reabtion on TLC, the reaction mixture was treated with 10% potassium hydroxide solkion at 100C to 150C and maintained for 2 hours at 2O0C to 250C. After completion of {he reaction as monitored by TLC, the reaction mixture was treated with IN HCl to get pH of 8 to 8.5 and charcoalized. The reaction mixture was filtered and washed with acetonitrile. The filtrate was extracted with mixture of toluene and ethyl acetate in the ratio of 7:3. at 250C to 350C. The solvents were distilled under vacuum at 35°C to 4O0C to remove the traces of solvents and further treated with water to make up the volume upto 80 mL. The aqueous solution was treated with 3.2 g of calcium acetate solution in 15 mL of water and maintained for 1 hour at 2O0C to 3O0C. The solid thus obtained was filtered and washed with water. The solid was dried at 4O0C under vacuum for 10 to 12 hours to obtain amorphous rosuvastatin calcium. Purity by HPLC > 99.0%. Example-8: Stability of Rosuvastatin Calcium
The 100 g wet-cake of rosuvastatin calcium as prepared in Example- 7 and 500 mL of water were taken into RBF. The reaction mixture was heated at about 4O0C to 450C for about 1 hour. The product thus obtained was hot filtered and washed with hot water at about 400C to about 45°C. The product was air dried for 2 hours at 25°C to about 350C followed by vacuum drying for 12 hours to obtain 75 g of stable amorphous rosuvastatin calcium.
Stable amorphous rosuvastatin calcium as prepared by above process is having individual impurities like rosuvastatin diastereomer less than about 0.1%, rosuvastatin lactone less than about 0.1%, rosuvastatin desflouro impurity less than 0.1%, rosuvastatin 5-oxo (B2) impurity less than 0.1%, rosuvastatin protected diol ester not in detectable amount, rosuvastatin 3-oxo impurity less than 0.1% by area percentage of HPLC when kept for 3 months at 250C at 60% RH as well as at 4O0C at 75%RH. The below HPLC conditions were used to analyze the stable amorphous rosuvastatin calcium.
Column: - Intersil ODS-3 (150 x 4.6 mm, 3 μ) or equivalent column. Oven Temperature: - 4O0C Flow rate: - 0.75 mL/min Wavelength: - 242 nm
Mobile Phase A: - Water:: Acetonitrile::l% Trifluoroacetic acid:::700::290::10 Mobile Phase B: - Water: :Acetonitrile::l% Trifluoroacetic acid:::240::750::10 Diluent: - Water: : Acetonitrile: :4 : 1
The gradient was as follows: at the initial time, 100% Mobile Phase-A and 0% Mobile Phase-B; time 30.0 min 100% Mobile Phase-A and 0% Mobile Phase-B; and at time 50.0 min 60% Mobile Phase-A and 40% Mobile Phase-B, and at time 80.0 min 0% Mobile Phase-A and 100% Mobile Phase-B, and at time 81.0 min 100% Mobile Phase- A and 0% Mobile Phase-B, and at time 90.0 min 100% Mobile Phase-A and 0%
Mobile Phase-B. Advantages of the Invention
1) The present invention provides an improved process for the synthesis of amorphous
Rosuvastatin Calcium. 2) The present invention provides an improved process for preparing rosuvastatin calcium in amorphous form via novel intermediates.
3) The present invention provides an improved process for preparing rosuvastatin calcium via novel crystalline intermediates characterized by X-ray powder diffraction. 4) The main advantage of the present invention is to provide rosuvastatin calcium with high yield and high purity by HPLC greater than 99% with single individual impurity < 0.1%. 5) The present invention also provides the process for the stabilization of amorphous atorvastatin calcium at 250C in 60% RH and at 400C in 75% RH. 6) The process is simple, safe, cost effective and can be employed for commercial production.

Claims

Claims: -
1. A novel process the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of formula (5),
Figure imgf000053_0001
which comprises of:
(a) reacting compound of formula (7) by halogenating agent in a suitable organic solvent, wherein R is a alkyl group having 1 to 10 carbon atoms, a cycioalkyl group having 3 to 6 carbon atoms, an arylalkyl group having an alkyl moiety of 1-3 carbon atoms or an aryl group to obtain 2-chloro-4-(4'-flourophenyl)-6-isopropyl-5- substitutedpyrimidine compound of formula (8);
Figure imgf000053_0002
(b) reducing 2-chloro-4-(4'-flourophenyl)-6-isopropyl-5-substitutedpyrimidine compound of formula (8) with diisobutylaluminium hydride (DIBAL) in suitable organic solvent to give 2-chloro-[4-(4-flourophenyl)-6-isopropyl-pyrimidin-5- yl]methanol compound of formula (9);
Figure imgf000053_0003
(c) reacting 2-chloro-[4-(4'-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) with phosphorus tribromide for in-situ preparation of 2- chloro-[4-(4-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methyl bromide;
(d) reacting in-situ 2-chloro-4-(4'-flourophenyl)-5-(bromomethyl)-6- isopropyl]pyrimidine with triphenly phosphine in a suitable organic solvent at an elevated temperature to obtain triphenyl[2-chloro-{4-(4'-flourphenyl)-6-isopropyl- pyrimidin-5-ylmethyl}-phosphonium]bromide compound of formula (10); and
Figure imgf000054_0001
(e) reacting compound of formula (10) with tert-butyl-2-[(4R,6S)-6-formyl-2,2- dimethyl- r,3-dioxan-4-yl]acetate (BFA) of formula (11) in presence of base to obtain compound of formula (5).
Figure imgf000054_0002
2. A process as claimed in claim 1 (a), wherein suitable halogenating agent isselected from thionyl chloride, phosphorus oxylchloride, phosphorus pentachloride, phosphorus trichloride and the like, preferably thionyl chloride.
3. A process as claimed in claim 1 (a), wherein said suitable organic solvent is selected from C1-C4 alcohols like methanol, ethanol, propanol, butanbl, isopropanol and the like, halogenated aliphatic hydrocarbons like methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride and the like, aromatic hydrocarbons like toluene, xylene, ethyl benzene and the like, preferably toluene.
4. A process as claimed in claim 1 (b), wherein suitable organic solvent for reduction is selected from aromatic hydrocarbons like toluene, xylene, ethyl benzene, esters like ethyl acetate, methyl acetate, isopropyl acetate, t-butyl acetate etc, ethers like diisopropyl ether, diethyl ether, methyltertbutylether, halogenated aliphatic hydrocarbons like methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride etc., preferably toluene.
5. A process as claimed in claim 1 (d), wherein suitable wittig reagent is selected from triphenyl phosphine or tributyl phosphine, preferably triphenyl phosphine.
6. A process as claimed in claim 1 (d), wherein suitable organic solvent is selected from non-polar solvents like toluene, o-xylene, methylene dichloride, ethyl acetate, chlorobenzene etc. preferably, toluene.
7. A process as claimed in claim 1 (d), wherein said elevated temperature is in the range from 80 to 14O0C, preferably at 100°-l 1O0C.
8. A process as claimed in claim 1 (e), wherein said suitable base is selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably potassium carbonate.
9. A process as claimed in claim 1 (e), wherein said polar aprotic solvent is selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidine or mixture thereof, preferably dimethylsulfoxide.
10. A process as claimed in claim 1 (e), wherein the reaction is carried out at a temperature ranging from about 4O0C to about 8O0C5 preferably at about 600C to
7O0C to isolate tert-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isoρropyl-2- chloro]pyrimidin-5-yl}-vinyl}-(4R,6S)-2,2-dimethyl[l,3]dioxan-4-yl)acetate of formula (5).
11. A process for the preparation of rosuvastatin or its salts like calcium of formula (1)
Figure imgf000056_0001
which comprises of:
(a) reacting triphenyl[2-chloro-{4-(4-flouφhenyl)-6-isopropyl-pyrimidin-5-ylmethyl}- phosphoniumjbromide of formula (10)
Figure imgf000056_0002
with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11)
Figure imgf000056_0003
in presence of base to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate of formula (5);
Figure imgf000056_0004
(b) reacting compound of formula (5) obtained in step (a) with monomethyl amine solution at an ambient temperature to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(niethylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3- dioxan-4-yl)acetate (4);
Figure imgf000057_0001
(c) reacting compound of formula (4) with methane sulphonyl chloride in presence of base in a suitable organic solvent at -3O0C to +1O0C temperature to obtain in-situ tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isoproρyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 β -dioxan-4- yl)acetate of formula (3);
Figure imgf000057_0002
(d) reacting compound of formula (3) with a base in C1-C4 alcohol at an elevated temperature to obtain solution of 2-((4R,6S)-6-((E)~2-(4-(4'-fluorophenyl)-6- isopropyl-2-(N -methylmethyl- sulfonamido)pyrimidin-5 -yl)vinyl)-2,2-dimethyl- l,3-dioxan-4-yl)acetic acid of formula (2);
Figure imgf000057_0003
(e) optionally concentrating the solution and removing C1-C4 alcoholic solvent;
(f) treating compound of formula with organic base in a suitable organic solvent or mixture thereof with water to adjust the pH of about 8 to about 9 to obtain amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l ,3-dioxan-4- yl)acetic acid of formula (T);
Figure imgf000058_0001
(g) eliminating acetonide protection group in amine salt of formula (2') and reacting with source of calcium to the solution to precipitate rosuvastatin calcium; and
(h) recovering the rosuvastatin calcium salt.
12. A process as claimed in claim 11 (a), wherein suitable base is selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium, carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably potassium carbonate.
13. A process as claimed in claim 11 (a), wherein polar aprotic solvent can be selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide, N- methylpyrrolidine or mixture thereof, preferably dimethylsulfoxide.
14. A process as claimed in claim 11 (a), wherein the reaction is carried out at a temperature ranging from about. 4O0C to about 800C, preferably at about 6O0C to
7O0C.
15. A process as claimed in claim 14 (b), wherein said monomethyl amine solution is of
75% in methanol,
16. A process as claimed in claim 11 (b), wherein said ambient temperature is room temperature of about 250C to 35°C.
17. A process as claimed in claim 11 (c), wherein said base is selected from inorganic base like alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate or organic bases like triethylamine, diisopropylethylamine, diethylamine, pyridine, piperidine, morpholine etc, preferably triethylamine.
18. A process as claimed in claim 11 (c), wherein said suitable organic solvent is selected from methylene dichloride, ethylene dichloride, toluene or polar aprotic solvents like dimethylformamide, dimethylsulfoxide, dimethylacetamide, N- methylpyrrolidine or mixture thereof, preferably methylene dichloiϊde.
19. A process as claimed in claim 11 (c), wherein the reaction is carried out at temperature in the range of -3O0C to 10°C, preferably at -2O0C to -250C.
20. A process as claimed in claim 11 (d), wherein in-situ hydrolysis is done with suitable base selected from alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and cesium carbonate, preferably sodium or potassium hydroxide.
21. A process as claimed in claim 11 (d), wherein said hydrolysis is carried out at an elevated temperature in the range of 5O0C to 12O0C, more preferably at 600C to
9O0C and most preferably at 60°c to 7O0C.
22. A process as claimed in claim 11 (d), wherein said C1-C4 alcohols are selected from methanol, ethanol, butanol, isopropanol and the like preferably methanol.
23. A process as claimed in claim 11 (e), wherein reaction mixture is concentrated under vacuum to remove C1-C4 alcoholic solvents like methanol.
24. A process as claimed in claim 11 (f), wherein organic base is selected from n- propyl amine, isopropylamine, tert-butyl amine, dicyclohexyl amine, ethyl amine etc., preferably n-propyl amine or ethyl amine to obtain n-propyl amine or ethyl amine salt of formula (2') or (2") respectively.
25. A process as claimed in claim 11 (f), wherein suitable organic solvent is selected from polar organic solvents like tetrahydrofuran, dimethylformamide, dimethylacetamide, acetonitrile, methanol, ethanol, isopropanol, acetone etc., or mixture thereof with water, preferably mixture of acetonitrile and water.
26. A process as claimed in claim 11 (g), wherein elimination of acetonide protecting group is done by using acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, or acetic acid preferably hydrochloric acid.
27. A process as claimed in claim 11 (g) and 26, wherein elimination of acetonide protecting group is carried out in a suitable organic solvent like polar solvent tetrahydrofuran, methanol, ethanol or non-polar solvents like ethyl acetate or toluene followed by treatment with 10% sodium hydroxide solution to adjust the pH of 7 to 7.5 to obtain rosuvastatin sodium in-situ.
28. A process as claimed in claim 11 (g), wherein suitable calcium source is selected from calcium chloride, calcium acetate, calcium hydroxide etc., preferably calcium acetate to obtain amorphous rosuvastatin calcium salt.
29. A process for the preparation of stable amorphous rosuvastatin calcium of formula
(1), which process comprises;
Figure imgf000060_0001
(a) providing amorphous rosuvastatin calcium prepared as per the process of jny of the preceding claims;
(b) preparing the slurry in hot water;
(c) maintaining the reaction mixture for sufficient amount of time at elevated temperature; and (d) recovering stable amorphous rosuvastatin calcium.
30. A process according to claim 29, wherein stable amorphous rosuvastatin calcium is having individual impurities like rosuvastatin diastereomer less than about 0.1%, rosuvastatin lactone less than about 0.1%, rosuvastatin desflouro impurity less than 0.1%, rosuvastatin 5-oxo (B2) impurity less than 0.1%, rosuvastatin protected diol ester not in detectable amount, rosuvastatin 3-oxo impurity less than 0.1% by area percentage of HPLC when kept for 3 months at 250C at 60% RH.
31. A process as claimed in claim 29, wherein stable amorphous rosuvastatin calcium having individual impurities like rosuvastatin diastereomer less than about 0.1%, rosuvastatin lactone less than about 0.1%, rosuvastatin desflouro impurity less than 0.1%, rosuvastatin 5-oxo (B2) impurity less than 0.1%, rosuvastatin protected diol ester not in detectable amount, rosuvastatin 3-oxo impurity less than 0.1% by area percentage of HPLC when kept for 3 months at 4O0C at 75% RH.
32. A process as claimed in claim 29. Wherein elevated temperature is of about 350C to about 6O0C, preferably at about 4O0C to about 450C.
33. The compound of formula (9), i.e. 2-chloro-[4-(4'-flourophenyl)-6-isopropyl- pyrimidin-5-yl]methanol,
Figure imgf000061_0001
characterized by having 1HNMR substantially as depicted in Figure-4 and 13CNMR substantially as depicted in Figure-5.
34. The compound of formula (9) in crystalline form characterized by atleast one of the following properties,
(a) X-ray powder diffraction pattern substantially as depicted in Figure-2; or
(ii) having characteristics peaks at about 12.7, 19.5, 23.0, 25.7 and 26.0±0.2 2Θ; or
(iii) having endothermic peak at about 1820C in differential scanning calorimetry; or
(iv) differential scanning calorimetry substantially as depicted in Figure-3; or
(v) having peaks at about 3390, 2980, 2931, 1607, 1548, 1511, 1390, 1231, 1165,
1148,1026,916,
849, 740, 668 and 568 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure-6.
35. The compound of formula (10), • i.e. triphenyl[2-chloro-{4-(4-flourphenyl)-6- isopropyl-pyrimidin-5-ylmethyl}-phosphonium]bromide,
Figure imgf000061_0002
characterized by having 1HNMR substantially as depicted in Figure-9 and 13CNMR substantially as depicted in Figure- 10.
36. The compound of formula (10) in crystalline form characterized by atleast one of the following properties,
(i) X-ray powder diffraction pattern substantially as depicted in Figure-7; or (ii) having characteristics peaks at about 9.6, 11.2, 17.0, 20.5, 22.4, 23.8, 29.6 and 31.7 ±0.2 20; or (iii) having two endothermic peak at about 930C and 2450C in differential scanning calorimetry; or
(iv) differential scanning calorimetry substantially as depicted in Figure-8; or (v) having peaks at about 3448, 3371, 2988, 1602, 1537, 1509, 1436, 1384, 1323,
1293, 1229, 1157, 1102, 921, 853, 752, 694, 569, and 521 cm"1 in Infrared spectral analysis;
(vi) Infrared spectral analysis substantially as depicted in Figure- 11.
37. The compound of formula (5), i.e. tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopiOpylpyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4-
Figure imgf000062_0001
yl)acetate, characterized by having 1HNMR substantially as depicted in Figure- 14 and 13CNMR substantially as depicted in Figure-15.
38. The compound of formula (5) in crystalline form characterized by atleast one of the following properties, (i) X-ray powder diffraction pattern substantially as depicted in Figure-12; or
(ii) having characteristics peaks at about 8.1, 10.6, 12.2, 14.0, 18.6, 20.1, 22.2, 27.8 and 28.4 ±0.2 2Θ; or (iii) having two endothermic peak at about 870C and 2380C in differential scanning calorimetry; or
(iv) differential scanning calorimetry substantially as depicted in Figure-13; or (v) having peaks at about 2996, 2978, 2894, 1716, 1518, 1508, 1380, 1324, 1290, 1224, 1157,
1073, 984, 845, 813 and 573 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure- 16.
39. The compound of formula (4), i.e. tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidin-5-yl)vinyl)-2,2-dimethyl- 1,3- dioxan-4-yl)acetate,
Figure imgf000063_0001
characterized by having HNMR substantially as depicted in Figure- 19 and
13CNMR substantially as depicted in Figure-20.
40. The compound of formula (4) in crystalline form characterized by atleast one of the following properties,
(i) X-ray powder diffraction pattern substantially as depicted in Figure- 17; or Cii) having characteristics peaks at about 7.2, 11.9, 17.3. 18.1. 20.0, 24.1 and 30.7
±0.2 20; or (iii) having endothermic peak at about 1640C in differential scanning calorimetry; or (iv) differential scanning calorimetry substantially as depicted in Figure- 18; or (v) having peaks at about 3266, 3117, 2970, 2940, 1732, 1551, 1445, 1401, 1315,
1228, 1153, 1084, 851 and 515 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure-21.
41. The compound of formula (2'), i.e. n-propyl amine salt of 2-((4R,6S)-6-((E)-2-(4- (4'-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetic acid,
Figure imgf000063_0002
characterized by having 1HNMR substantially as depicted in Figure-24 and
13CNMR substantially as depicted in Figure-25.
42. The compound of formula (2') in crystalline form characterized by atleast one of the following properties, (i) X-ray powder diffraction pattern substantially as depicted in Figure-22; or (ii) having characteristics peaks at about 9.5, 15.6, 17.8, 20.3 and 25.0±0.2 2Θ; or (iii) having endothermic peak at about 1480C in differential scanning calorimetry; or (iv) differential scanning calorimetry substantially as depicted in Figure-23; or (v) having peaks at about 2976, 2889, 2816, 2704, 2577, 2217, 1633, 1543, 1428,
1341, 1268, 1138, 845, 765 and 568 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure-26.
43. The isolated compound of formula (9a), i.e. 5-(bromomethyl)~2-chloro-4-(4- fiuorophenyl)-6-isopropylpyrimidine,
Figure imgf000064_0001
characterized by having 1HNMR substantially as depicted in Figure-29 and 13CNMR substantially as depicted in Figure-30.
44. The compound of formula (9a) in crystalline form characterized by atleast on of the following properties,
(i) X-ray powder diffraction pattern substantially as depicted in Figure-27; or (ii) having characteristics peaks at about 7.9, 13.8, 17.5, 17.9, 23.5 and 27.1±0.2 20; or
(iii) having endothermic peak at about 970C in differential scanning calorimetry; or (iv) differential scanning calorimetry substantially as depicted in Figure-28; or having peaks at about 3389, 3379, 2979, 2971, 2931, 1606, 1548, 1511, 1389, 1293, 1230, 1147, 1026 and 916 cm'1 in Infrared spectral analysis;
(v) Infrared spectral analysis substantially as depicted in Figure-31.
45. An amorphous rosuvastatin calcium substantially free from impurity-B i.e. 2- chloro-4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidine.
Figure imgf000064_0002
46. An amorphous rosuvastatin calcium as claimed in claim 45, wherein impuϊity-B is less than 0.1%, preferably less than 0.07%, more preferably less than 0.05% and most preferably not in detectable amount when measured by area percentage of HPLC.
47. An amorphous rosuvastatin calcium substantially free from impurity-C i.e. 4-(4- fluorophenyl)-6-isopropyl-N,5-dimethylpyrimidin-2-amine.
Figure imgf000065_0001
48. An amorphous rosuvastatin calcium as claimed in claim-47, wherein impurity-C is less than 0.1%, preferably less than 0.08%, more preferably less than 0.04% and most preferably not in detectable amount when measured by area percentage of HPLC.
49. An amorphous rosuvastatin calcium substantially free from impurity-A i.e. 2- bromo-5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidine.
Figure imgf000065_0002
50. An amorphous rosuvastatin calcium as claimed in claim 49, wherein impurity-A is less than 0.1%, preferably less than 0.07%, more preferably less than 0.05% and most preferably not in detectable amount when measured by area percentage of HPLC.
51. An amorphous rosuvastatin calcium substantially free from impurity-D i.e. hemi- calcium salt of (3R,5S)-(E)-7-(2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-
Figure imgf000065_0003
yl)-3,5-dihydroxyhept-6-enoate).
52. An amorphous rosuvastatin calcium as claimed in claim 51, wherein impurity-D is less than 0.15%, preferably less than 0.10%, more preferably less than 0.07%, and most preferably less than 0.05% when measured by area percentage of HPLC.
53. An isolated impurity-A i.e. 2-bromo-5-(bromomethyl)-4-(4-fluorophenyl)-6- isopropylpyrimidine
54. An isolated impurity-B i.e. 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5- methylpyrimidine.
55. An isolated impurity-B as claimed in claim-54, wherein impurity-B is characterized by 1H NMR substantially as depicted in Figure - 32 and 13C NMR substantially as depicted in Figure-33. "" " "
56. An isolated impurity-C i.e. 4-(4-fluorophenyl)-6-isopropyl-N,5-dimethylpyrimidin- 2-amine.
57. An isolated impurity-C as claimed in claim 56, wherein impurity-C is characterized by 1H NMR substantially as depicted in Figure - 34 and 13C NMR substantially as depicted in Figure-35.
58. An isolated impurity-D i.e. hemi-calcium salt of (3R,5S)-(E)-7-(2-chloro-4-(4- fluorophenyl)-6-isopropylpyrimidin-5-yl)-3,5-dihydroxyliept-6-enoate).
59. The compound of formula (2"), i.e. Ethyl amine salt of 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(N-methylmethylsu1fonamido)pyrimidin-5-yl)vinyl)-
2,2-dimethyl-l,3-dioxan-4-yl)acetic acid in crystalline form characterized by atleast
Figure imgf000066_0001
on of the following properties,
(i) X-ray powder diffraction pattern substantially as depicted in Figure-38; or (ii) having characteristics peaks at about 12.7, 19.5, 23.0, 25.7 and 26.0±0.2 2Θ; or (iii) having endothermic peak at about 1880C in differential scanning caloiϊmetry; or (iv) differential scanning calorimetry substantially as depicted in Figure-39; or (v) having peaks at about 2971, 2356, 2228, 2218, 1605, 1597, 11544, 1511, 1396, 1382, 1267, 1197, 1150, 1031 and 855 cm"1 in Infrared spectral analysis; (vi) Infrared spectral analysis substantially as depicted in Figure-40.
60. A process for determining the presence of a compound in a sample comprising carrying out UPLC or HPLC or TLC with 2-bromo-5-(bromomethyl)-4-(4- fluorophenyl)-6-isopropyl- pyrimidine i.e. impurity-A as a reference marker.
61. A process for determining the presence of a compound in a sample comprising carrying out UPLC or HPLC or TLC with 2-chloro-4-(4-fluorophenyl)-6-isopropyl-
5-methylpyrimidine i.e. impurity-B as a reference marker.
62. A process for determining the presence of a compound in a sample comprising carrying out UPLC or HPLC or TLC with 4-(4-fluorophenyl)-6-isopropyl-N,5- dimethylpyrimidin-2-amine i.e. impurity-C as a reference marker.
63. A process for determining the presence of a comp"δϋncTin a sample comprising carrying out UPLC or HPLC or TLC with hemi-calcium salt of (3R,5S)-(E)-7-(2- chloro-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-yl)-3,5-dihydroxyhept-6- enoate).i.e. impurity-D as a reference marker.
64. A method of determining the relative retention time (RRT) of an impurity in a sample of Impurity-A or Impurity-B or Impurity-C or Impurity-D comprising: (a) measuring by UPLC or HPLC or TLC the relative retention time (RRT) corresponding to Impurity-A or Impurity-B or Impurity-C or Impurity-D in a reference marker sample; (b) determining by UPLC or HPLC or TLC the relative retention time (RRT) corresponding to Impurity-A or Impurity-B or Impurity-C or Impurity-D in a sample rosuvastatin calcium; and (c) determining the relative retention time (RRT) of Impurity-A or Impurity-B or
Impurity-C or Impurity-D in the sample by comparing the relative retention time (RRT) of step (a) to the relative retention time (RRT) of step (b).
65. A process for determining the amount of a compound in a sample comprising carrying out UPLC or HPLC or TLC with Impurity-A or Impurity-B or Impurity-C or Impurity-D as a reference standard.
66. A UPLC method used to determine the presence of Impurity-A or Impurity-B or Impurity-C or Impurity-D in amorphous rosuvastatin calcium comprising:
(a) combining an amorphous rosuvastatin calcium sample with a buffer to obtain a solution;
(b) injecting the obtained solution into a 2.1x100 mm Aciqity Cl 8 (or similar) column; (c) gradient eluting the sample from the column at about 45 min using a mixture of Buffer (referred to as eluent A) and acetonitrile (referred to as eluent B); and
(d) measuring the content of Impurity-A or Impurity-B or Impurity-C or Impurily-D in the relevant sample with a UV detector (preferably at a 240 ran wavelength).
67. The method as claimed in claim 66, wherein the buffer contains H3PO4 and an aqueous solution Of K2HPO4 in a concentration of about 6.8 g in presence of 2.0 ml triethylamine in 1000 ml of water having a pH of about 2.0.
68. The method as claimed in claim 66, wherein the eluent used is a mixture of eluent
A and eluent B.
69. The method as claimed in claim 68, wherein the ratio between eluent A and eluent B varies over the time.
70. The method as claimed in claim 66, wherein the at the initial time the eluent contains 74% reservoir A and 26% reservoir B; time 15.0 min 74% reservoir A and 26% reservoir B; and at time 35.0 min 40% reservoir A and 60% reservoir B, and at time 39.0 min 40% reservoir A and 60% reservoir B, and at time 40.0 min 74% reservoir A and 26% reservoir B, and at time 45.0 min 74% reservoir A and 26% reservoir B.
71. A novel process for the preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4- (4-fluorophenyl)-6-isopropylpyrimidin-5-yl)vinyl)-2,2-dimethyl- 1 ,3 -dioxan-4- yl)acetate of formula (5),
Figure imgf000068_0001
which comprises of:
(a) reacting compound of formula (7) by halogenating agent in a suitable organic solvent, wherein R is a alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an arylalkyl group having an alkyl moiety of 1-3 carbon atoms or an aryl group to obtain 2-chloro-4-(4'-flourophenyl)-6-isopropyl-5- substitutedpyrimidine compound of formula (8);
Figure imgf000069_0001
(b) reducing 2-chloro-4-(4'-flourophenyl)-6-isopropyl-5-substitutedpyriraidine compound of formula (8) with suitable reducing agent in suitable organic solvent to give 2-chloro-[4-(4-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9);
Figure imgf000069_0002
(c) reacting 2-chloro-[4-(4'-flourophenyl)-6-isopropyl-pyrimidin-5-yl]methanol compound of formula (9) with phosphrous tribromide for preparation of 2-chloro- [4-(4-floυrophcnyl)-6-isopropyl-pyrimidin-5-yllmethyl bromide;
(d) reacting 2-chloro-4-(4'-flourophenyl)-5-(bromomethyl)-6-isopropyl]pyrimidine bromide with triphenly phosphine in a suitable organic solvent at an elevated temperature to obtain triphenyl[2-chloro-{4-(4'-flourphen3^1)-6-isopropyl- pyrimidin-5-yhnethyi}-phosphomumJ bromide compound of formula (10); and
Figure imgf000069_0003
(e) reacting wittig reagent of formula (10) with tert-butyl-2-[(4R,6S)-6-formyl-2,2- dimetliyl-l,3-dioxan-4-yl]acetate (BFA) of formula (11) in presence of base to obtain compound of formula (5)
Figure imgf000070_0001
72. A process for the preparation of rosuvastatin or its salts like calcium of formula (1)
Figure imgf000070_0002
comprises of:
(a) reacting triphenyl[2-chloro- {4-(4-flourphenyl)-6-isopropyl-pyrimidin-5-ylmethyl} - phosphonium-]bromide of formula (10)
Figure imgf000070_0003
with tert-butyl-2-[(4R,6S)-6-formyl-2,2-dimelhyl-l,3-dioxan-4-yl]acetatc (BFA) of formula (11)
Figure imgf000070_0004
in presence of base to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(2-chloro-4-(4- fluorophenyl)-6-isopropylρyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate of formula (5);
Figure imgf000071_0001
(b) reacting compound of formula (5) with monomethyl amine to obtain lert-butyl 2- ((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(methylamino)pyrimidin-5- yl)vinyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate (4);
Figure imgf000071_0002
(c) reacting compound of formula (4) with methane sulphonyl chloride in presence of base to obtain tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetate of formula (3);
Figure imgf000071_0003
(d) reacting compound of formula (3) with a base to obtain 2-((4R,6S)-6-((E)-2-(4-(4'- fluorophenyl)-6-isopropyl-2-(N-methylmethyl- sulfonamido)pyrirnidin-5-yl)vinyl)- 2,2-dimethyl-l,3-dioxan-4-yl)acetic acid of formula (2);
Figure imgf000071_0004
(e) treating compound of formula (2) with organic base to obtain amine salt of 2- ((4R,6S)-6-((E)-2-(4-(4'-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4- yl)acetic acid of formula (T);
Figure imgf000072_0001
(f) eliminating acetonide protection group in amine salt of formula (2') and reacting with source of calcium to obtain rosuvastatin calcium.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102219749A (en) * 2010-04-14 2011-10-19 上海京新生物医药有限公司 Method for preparing rosuvastatin calcium
WO2012038785A1 (en) * 2010-09-21 2012-03-29 Biocon Limited Polymorphs of rosuvastatin acetonide calcium ((3r,5s,6e)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimn)in-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt
WO2013181828A1 (en) * 2012-06-07 2013-12-12 上海迪赛诺药业有限公司 Preparation method of rosuvastatin calcium and intermediates thereof
CN104557885A (en) * 2014-12-23 2015-04-29 广东东阳光药业有限公司 Preparation method of rosuvastatin impurity A
CN104788387A (en) * 2015-04-17 2015-07-22 浙江海森药业有限公司 Preparation method for high-purity rosuvastatin calcium
CN104817505A (en) * 2015-04-23 2015-08-05 南京博优康远生物医药科技有限公司 Method of preparing N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidine-2-yl]-N-methylmethanesulfonamide
US9174945B2 (en) 2006-04-13 2015-11-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Rosuvastatin zinc salt
CN105669561A (en) * 2014-11-19 2016-06-15 南京博优康远生物医药科技有限公司 Preparation method of 4-(4-fluorophenyl)-5-alkoxycarbonyl-6-isopropyl-3,4-dihydropyridin-2(1H)-one
CN103467458B (en) * 2012-06-07 2016-08-03 上海迪赛诺药业有限公司 Rosuvastain calcium and the preparation method of intermediate thereof
CN111718334A (en) * 2019-03-20 2020-09-29 鲁南制药集团股份有限公司 Rosuvastatin calcium intermediate compound
CN114280181A (en) * 2021-12-23 2022-04-05 浙江海翔川南药业有限公司 Detection method of rosuvastatin intermediate and related substances thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103977A2 (en) * 2003-05-21 2004-12-02 Ciba Specialty Chemicals Holding Inc. Process for the preparation of pyrimidine derivatives
US20050124639A1 (en) * 2003-12-04 2005-06-09 Narendra Joshi Process for the preparation of pyrimidine derivatives
WO2006126035A2 (en) * 2005-05-26 2006-11-30 Richter Gedeon Vegyészeti Gyár Rt. Process for the preparation of rosuvastatin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103977A2 (en) * 2003-05-21 2004-12-02 Ciba Specialty Chemicals Holding Inc. Process for the preparation of pyrimidine derivatives
US20050124639A1 (en) * 2003-12-04 2005-06-09 Narendra Joshi Process for the preparation of pyrimidine derivatives
WO2006126035A2 (en) * 2005-05-26 2006-11-30 Richter Gedeon Vegyészeti Gyár Rt. Process for the preparation of rosuvastatin

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN102219749B (en) * 2010-04-14 2013-07-17 上海京新生物医药有限公司 Method for preparing rosuvastatin calcium
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WO2012038785A1 (en) * 2010-09-21 2012-03-29 Biocon Limited Polymorphs of rosuvastatin acetonide calcium ((3r,5s,6e)-7-[4-(4- fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimn)in-5- yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl) acetic acid calcium salt
CN103467458B (en) * 2012-06-07 2016-08-03 上海迪赛诺药业有限公司 Rosuvastain calcium and the preparation method of intermediate thereof
WO2013181828A1 (en) * 2012-06-07 2013-12-12 上海迪赛诺药业有限公司 Preparation method of rosuvastatin calcium and intermediates thereof
CN105669561A (en) * 2014-11-19 2016-06-15 南京博优康远生物医药科技有限公司 Preparation method of 4-(4-fluorophenyl)-5-alkoxycarbonyl-6-isopropyl-3,4-dihydropyridin-2(1H)-one
CN105669561B (en) * 2014-11-19 2018-11-27 南京博优康远生物医药科技有限公司 A kind of preparation method of -2 (1H) -one of 4- (4- fluorophenyl) -5- alkoxy carbonyl -6- isopropyl -3,4- dihydro-pyrimidin
CN104557885A (en) * 2014-12-23 2015-04-29 广东东阳光药业有限公司 Preparation method of rosuvastatin impurity A
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CN104817505A (en) * 2015-04-23 2015-08-05 南京博优康远生物医药科技有限公司 Method of preparing N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidine-2-yl]-N-methylmethanesulfonamide
CN111718334A (en) * 2019-03-20 2020-09-29 鲁南制药集团股份有限公司 Rosuvastatin calcium intermediate compound
CN111718334B (en) * 2019-03-20 2022-09-30 鲁南制药集团股份有限公司 Rosuvastatin calcium intermediate compound
CN114280181A (en) * 2021-12-23 2022-04-05 浙江海翔川南药业有限公司 Detection method of rosuvastatin intermediate and related substances thereof

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