WO2012172564A1 - Process for preparation of rosuvastatin calcium - Google Patents

Process for preparation of rosuvastatin calcium Download PDF

Info

Publication number
WO2012172564A1
WO2012172564A1 PCT/IN2012/000366 IN2012000366W WO2012172564A1 WO 2012172564 A1 WO2012172564 A1 WO 2012172564A1 IN 2012000366 W IN2012000366 W IN 2012000366W WO 2012172564 A1 WO2012172564 A1 WO 2012172564A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
rosuvastatin
tert
compound
preparation
Prior art date
Application number
PCT/IN2012/000366
Other languages
French (fr)
Inventor
Vilas Hareshwar Dahanukar
Narendra Bhalchandra Ambhaikar
Ravi kumar VADALI
Suresh Babu Meruva
Swapna Manikonda
Raghavendra Rao Kamaraju
Upadhya TIMMANNA
Aaseef MOHAMMED
Ranga Prasad PULIPATI
Yakub Iqbal MOHAMMED
Original Assignee
Dr. Reddy's Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Limited filed Critical Dr. Reddy's Laboratories Limited
Publication of WO2012172564A1 publication Critical patent/WO2012172564A1/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic 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
    • C07D239/28Heterocyclic 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
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/42One nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic 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
    • C07D239/28Heterocyclic 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
    • C07D239/32One oxygen, sulfur or nitrogen atom
    • C07D239/34One oxygen atom
    • C07D239/36One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D407/00Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present application relates to a process for the preparation of 4- (fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I)
  • the present application also relates to a process for the preparation of substantially pure a statin (II)
  • Rosuvastatin calcium (XVII) is a well known HMG-CoA reductase inhibitor which is used for the treatment of hypercholesterolemia.
  • Hirai et al. U.S. Patent No. USRE 37, 314 E1 discloses rosuvastatin and its pharmaceutically acceptable salts.
  • the patent teaches a process for the preparation of pyrimidine aldehyde of formula (I) and also a process for preparing rosuvastatin using pyrimidine aldehyde of formula (I).
  • Huang et al. WO 2008/151510 A1 discloses a process for the preparation of pyrimid
  • Scheme 1 Preparation of pyrimidine aldehyde (XVII) as disclosed in WO 2008/151510 A1 Taylor et al.
  • U. S. Patent No. 6,844,437 B1 discloses a process for the preparation of rosuvastatin calcium as outlined in Scheme 2.
  • the diphenyl phosphine oxide is coupled with an aldehyde in presence of a base to provide the acetonide protected tert-butyl ester.
  • acetonide protecting group is then cleaved in an acidic medium and the tert-butyl group is cleaved in a basic medium and the resulting sodium salt is treated with methylamine to obtain a methyl ammonium salt of rosuvastatin.
  • Rosuvastatin calcium is prepared from the methyl ammonium salt via its sodium salt.
  • acetonide group of compound of formula (II) is hydrolyzed by acid and then the ester group is hydrolyzed with base to provide rosuvastatin acid which is then treated with tert-butylamine to provide tert-butylamine salt of rosuvastatin.
  • Tert- butyl amine salt of rosuvastatin is first treated with sodium hydroxide followed by calcium acetate to provide rosuvastatin calcium (XVII).
  • One aspect of the present application relates to a process for preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl- pyrimidine of formula (I) as shown in scheme 4.
  • Another aspect of the present application relates to use of 4-(fluorophenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I), for preparing rosuvastatin.
  • Yet another aspect of the present application relates to purification of acetonide protected tert-butyl ester of rosuvastatin (II).
  • Still another aspect of the present application relates to substantially pure compound of formula (II) free from any impurity, specifically free from the impurity at RRT 1.07 ⁇ 0.02 designated as Impurity A.
  • Still another aspect of the present application relates to a process for the preparation of substantially pure amorphous rosuvastatin calcium using substantially pure compound of formula (II) as an intermediate.
  • Yet another aspect of the present application relates to a process for the preparation of substantially pure amorphous rosuvastatin calcium comprising: a) removal of dihydroxy protecting group of pure acetonide protected tert- butyl, ester of rosuvastatin (II) prepared by a process of claim 11 in an acidic medium;
  • step b) converting the product of step b) to tert-butyl amine salt of rosuvastatin; e) optionally purifying tert-butyl amine salt of rosuvastatin;
  • step f) treating the product of step f) with an aqueous solution of calcium chloride.
  • Fig. 1 shows the PXRD of acetonide protected tert-butyl ester of rosuvastatin of formula (II).
  • a process is provided for preparing 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- formyl-pyrimidine of formula (I), which may be used as an intermediate for preparing rosuvastatin.
  • the present application provides a process comprising dehydration and halogenation, in any order or simultaneously, of the hydroxy pyrimidine compound of formula (VII) to give halogenated compound of formula (VIII):
  • X is halogen and selected from a group of chloro, bromo and iodo.
  • the present application provides a process further comprising preparation of hydroxy pyrimidine compound of formula (VII) by oxidation of dihydropyrimidine ketone of formula (VI) in a suitable solvent
  • the present application provides a process further comprising the preparation of dihydropyrimidine ketone of formula (VI) by amidation of the compound of formula (III) followed by condensation with 4- fluorobenzaldehyde in presence of urea and metal salt in suitable solvent
  • R is C1-C6 alkyl, C6-C14 aryl, or C6-C14 (aryl)alkyl.
  • the present application provides a process further comprising reaction of halogenated compound of formula (VIII) with N-methyl- methanesulfonamide in presence of a base and in a suitable solvent to give 2-(N- methyl-methanesulfonyl amino)pyridine compound of formula (IX)
  • the present application provides a process further comprising reduction of the 2-(N-methyl-methanesulfonyl amino)pyridine compound of formula (IX) by reaction with a reducing agent in a suitable solvent to give 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl- pyrimidine of formula (I)
  • the present application provides a process for the preparation of the compound of Formula (I) comprising:
  • R is Ci-C 6 alkyl, C 6 -Ci4aryl, or C6-C 14 (aryl)alkyl;
  • Suitable amidation agents which can be used in step a) for amidation include but are not limited to ammonia solution.
  • Suitable metal salts used for condensation of fluorobenzaldehyde (V) and the amidated compound (IV) include, but are not limited to cuprous chloride, aluminum chloride, or tin chloride.
  • Suitable organic solvents for condensation of step a) include alcohol solvents like methanol or isopropyl alcohol; ketone solvents such as acetone; aromatic hydrocarbon solvents like toluene or xylene; dimethyl sulphoxide; ethers like THF or 1 ,4-dioxane; chlorinated hydrocarbon solvents, such as chloroform, ethylene dichloride, carbon tetrachloride, or methylene chloride; or mixtures thereof.
  • the temperature at which the condensation reaction between compound of formula (IV) and fluorobenzaldehyde (V) is carried out in between about 30 °C and about 70 °C. In one embodiment, the temperature is between about 35 °C and about 65 °C.
  • Suitable oxidizing agents which can be used in step b) include, but are not limited to, organic peroxides like tert-butyl hydroperoxide, hydrogen peroxide, benzoyl peroxide, benzyl peroxide, m-chloro-perbenzoic acid, oxone®, and the like.
  • Suitable solvents which can be used for the reaction step b) include, but are not limited to halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane or the like; alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, or 2-butanol; nitrile solvents such as acetonitrile or propionitrile; ketone solvents like acetone; aromatic hydrocarbon solvents like toluene or xylene; dimethyl sulfone; dimethyl sulphoxide; or mixtures thereof.
  • Suitable temperature at which step b) can be carried out is in the range from about 0 °C to about 30 °C.
  • Suitable dehydrating agents which can be used in step c) include but not limited to phosphorous pentoxide, sulfuric acid, calcium chloride, calcium carbonate and phosphorous oxychloride.
  • Suitable halogenating agent which can be used in step c) include but not limited to phosphorous oxychloride, phosphorous trichloride, phosphorous bromide, hydrobromic acid, iodine and sodium iodide.
  • dehydration is performed first and then the dehydrated compound is subjected to halogenation.
  • halogenation is performed first and then the halogenated product is subjected to dehydration.
  • dehydration and halogenation is performed by using a single reagent like phosphorous oxychloride.
  • Suitable bases which can be used in step d) include but not limited to alkali carbonates like sodium carbonate, potassium carbonate, or lithium carbonate; alkali metal bicarbonate like sodium bicarbonate, potassium bicarbonate, or lithium bicarbonate; alkali hydroxide like sodium hydroxide, lithium hydroxide, or potassium hydroxide; alkali metal alkoxides like sodium methoxide, potassium tert- butoxide, or lithium methoxide; and amines like triethyl amine.
  • Suitable solvents which can be used for the reaction step d) include, but are not limited to halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane or the like; alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, or 2-butanol; nitrile solvents such as acetonitrile or propionitrile; ketone solvents like acetone; aromatic hydrocarbon solvents like toluene or xylene; dimethyl sulfone; dimethyl sulphoxide; ester solvents like ethyl acetate; amide solvents like dimethyl formamide; or mixtures thereof.
  • Suitable temperature at which step d) can be carried out is in the range from about 25 °C to about 120 °C.
  • Suitable reducing agents which can be used in step e) include, but not limited to, diisobutyl aluminum hydride, Vitride® solution, or lithium aluminum hydride.
  • Suitable solvents which can be used for the reaction step e) include, but are not limited to halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane or the like; aromatic hydrocarbon solvents like toluene, xylene or benzene; or mixtures thereof.
  • Suitable temperature at which step e) can be carried out is in the range of about 0 °C to about 70 °C.
  • Isolation and purification of the intermediate of formula (I) described above can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase- transfer chromatography, column chromatography, or by a combination of these procedures.
  • suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase- transfer chromatography, column chromatography, or by a combination of these procedures.
  • Another aspect of the present application provides use of 4-(fluorophenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I) prepared according to the disclosure for preparing rosuvastatin.
  • Yet another aspect of the present application provides a process for the preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- formyl-pyrimidine of formula (I) from amide intermediates of formula (VI) and (VII), thus providing a process which affords cost effective route which can be practiced on an industrial scale.
  • Still another. aspect of the present application relates to purification of tert- butyl (E) (6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-
  • Acetonide protected tert-butyl ester of rosuvastatin (II) may be prepared by following the process disclosed in the prior art references.
  • compound of formula (I) obtained by the process of the present application may be subjected to appropriate reactions as disclosed in the prior art to obtain suitable intermediates for the preparation of acetonide protected tert-butyl ester of rosuvastatin (II).
  • Impurity A at RRT 1.07 ⁇ 0.2 upto a level of 1.0 %. Removal of the Impurity A from the compound of formula (II) has become very difficult, and thus fails to prepare pure rosuvastatin calcium as the said impurity is carried forward to rosuvastatin calcium. Crystallization of acetonide protected tert-butyl ester (II) from methanol as reported in US6,844,437 B1 and WO05/54207A1or from a mixture of toluene-hexane as reported in WO07/125547A2 or isopropanol as reported in WO05/54207A1 does not result substantially pure compound of formula (II). Hence, there is a need in the art to develop an effective purification method to produce substantially pure compound of formula (II).
  • the solution was again cooled to 30 °C to about 40 °C and maintained for about 45 minutes to about 75 minutes.
  • the solution was cooled to about -5 °C to about 0 °C and the precipitated crystalline material is collected by filtration and washed with cold n-butanol and cold n-heptane to provide substantially pure compound of formula (II).
  • the compound of formula (II) is recrystallized in n-butanol using 1-2 times over input to achieve the desired purity.
  • substantially pure compound of formula (II) refers to substantially pure compound of formula (II).
  • substantially pure acetonide protected tert-butyl ester of rosuvastatin (II) means that the compound is free from any impurity and specifically free from the Impurity A.
  • substantially pure acetonide protected tert- butyl ester of rosuvastatin (II) means that the compound is having at least about 95 % purity by HPLC.
  • the compound of formula (II) is having at least 98 % purity by HPLC and more specifically the compound of formula (II) is having more than about 99 % purity by HPLC.
  • Substantially pure acetonide protected tert- butyl ester of rosuvastatin (II) does not contain more than about 5 % of total impurities by HPLC, specifically less than about 2 % of total impurities and more specifically less than about 1 % of total impurities.
  • Substantially pure acetonide protected tert-butyl ester of rosuvastatin (II) does not contain more than about 0.15 % of the Impurity A and specifically less than about 0.05 % of the Impurity A.
  • acetonide protected tert-butyl ester of rosuvastatin (II) is known in the prior art from methanol, isopropanol and a mixture of toluene-hexane, the XRPD of the crystalline compound has not been reported.
  • One embodiment of the present application relates to crystalline acetonide protected tert-butyl ester of rosuvastatin (II) obtained by crystallization from n- butanol.
  • Another embodiment of the present application relates to the crystalline acetonide protected tert-butyl ester of rosuvastatin (II) having an X-Ray powder diffraction (XRPD) pattern substantially as shown in Fig.
  • Yet another embodiment of the present application relates to crystalline acetonide protected tert-butyl ester of rosuvastatin (II) having an XRPD pattern with one or more peaks present at 2-theta 6.80, 7.60, 11.24, 15.24, 19.14 and 21.42 ⁇ 0.2 °.
  • acetonide protected tert-butyl ester of rosuvastatin (II) is treated in an acidic medium to remove the dihydroxy protecting acetonide group by following the process as disclosed in prior art references.
  • Rosuvastatin has two diastereomers, namely (R, R)-isomer of rosuvastatin of formula (XIII) and (S, S)- isomer of rosuvastatin of formula (XIV). It was observed that diastereomeric impurity of rosuvastatin, specifically the (R, R)-isomer of rosuvastatin of formula (XIII) is generated during the deprotection of the acetonide group in acidic medium.
  • the inventors of the present application have tried different acids and different reaction conditions to restrict the generation of the diastereomeric impurity during the reaction since the removal of the diastereomeric impurity is found to be very difficult in final compound after the isolation. They have surprisingly found that when trifluoroacetic acid (TFA) is employed for the removal of the dihydroxy protecting acetonide group, the generation of diastereomeric impurity of rosuvastatin, specifically the (R, R)-isomer of rosuvastatin of formula (XIII) i
  • TFA trifluoroacetic acid
  • acetonide protected tert-butyl ester of rosuvastatin (II) is treated with TFA in an organic solvent at a temperature of from about 10 °C to about 60 °C for 30 minutes to 5 hours to obtain dihydroxy rosuvastatin ester of formula (XV) which may be subjected to ne
  • the organic solvent used for deprotection reaction is selected from a group of acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and mixtures thereof. More specifically, the organic solvent is acetonitrile.
  • the reaction mixture is treated with an aqueous solution of an alkali metal hydroxide selected from a group of sodium hydroxide, potassium hydroxide and lithium hydroxide to hydrolyze the tert-butyl ester group.
  • the alkali metal hydroxide is sodium hydroxide.
  • the aqueous solution of the reaction mixture containing rosuvastatin sodium is washed with an organic solvent, preferably for about 2-3 times.
  • the organic solvent is selected from a group of esters, alcohols, hydrocarbons, ethers and a mixture thereof.
  • the organic solvent is a hydrocarbon solvent. More specifically, the hydrocarbon solvent is an aromatic hydrocarbon solvent and most specifically the aromatic hydrocarbon solvent is toluene.
  • the aqueous solution containing rosuvastatin sodium is mixed with an organic solvent.
  • the organic solvent is selected from a group of esters, alcohols, hydrocarbons, ethers and a mixture thereof.
  • the organic solvent is ether solvent.
  • the ether solvent is selected from a group of diethyl ether, diisopropyl ether and methyl tert-butyl ether.
  • the organic solvent is methyl tert-butyl ether (MTBE).
  • sodium chloride is added and the reaction mass is cooled from a temperature of about 15 °C to about 30 °C. Specifically, the reaction mass is cooled to 20 °C.
  • the pH of the mixture is adjusted from about pH 1 to about pH 5 by the addition of aqueous sodium bisulphate solution.
  • the pH of the reaction mass is adjusted from about pH 2 to about pH 4.
  • the organic layer is separated from the reaction mass.
  • a solution of tert-butyl amine in an organic solvent selected from a group of esters, alcohols, hydrocarbons, ethers and a mixture thereof is added to the above organic solvent containing rosuvastatin acid at a temperature of about 5 °C to about 40 °C, specifically at a temperature of about 25 °C to about 35 °C.
  • the reaction mixture is then stirred for a period of about 1 hour to 10 hours, specifically the reaction mixture is stirred for a period of about 2 hours to about 8 hours and more specifically the reaction mixture is stirred for a period of about 4 hours to about 6 hours.
  • the reaction mixture is then cooled to a temperature of about 5 °C to about 25 °C, specifically to a temperature of about 15 °C to about 25 °C.
  • the resulting solid is filtered and the wet cake is washed with an organic solvent.
  • the resulted tert-butyl amine salt of rosuvastatin (XVI) is purified by leaching in an organic solvent or from a mixture of organic solvents.
  • the organic solvent is selected from a group of an ester solvent, an alcohol solvent, a hydrocarbon solvent, an ether solvent, a nitrile solvent and a mixture thereof.
  • (XVI) is a mixture of a nitrile solvent and an alcohol solvent. More specifically, the solvent for crystallization is a mixture of acetonitrile and I PA.
  • the tert-butyl amine salt of rosuvastatin (XVI) is suspended in water and an aqueous solution of an alkali metal hydroxide selected from a group of sodium hydroxide, lithium hydroxide and potassium hydroxide is added at a temperature of about 15 °C to about 40 °C, specifically from about 25 °C to about 35 °C and stirred for 30 minutes to 5 hours.
  • the alkali metal hydroxide is sodium hydroxide.
  • the reaction mass is heated to a temperature from about 40 °C to about 90 °C for 30 minutes to 3 hours under vacuum. Specifically, the reaction mass heated from about 40 °C to about 50 °C for 1 to 2 hours under vacuum.
  • reaction mass is diluted with water and filtered through a 0.2-0.4 micron filter.
  • the reaction mass is cooled from about 15 °C to about 20 °C.
  • An aqueous solution of calcium chloride is added slowly to the reaction mass maintaining the temperature from about 15 °C to about 20 °C for a period of about 5 to about 25 minutes.
  • the isolated solid was filtered and the wet cake containing rosuvastatin calcium is stirred with water for a period of about 5 minutes to 30 minutes to ensure the removal of all inorganic salts.
  • the solid is then filtered and dried under vacuum to provide substantially pure amorphous rosuvastatin calcium (XVII).
  • Substantially pure amorphous rosuvastatin calcium means that the compound is having at least about 95 % purity by HPLC. Specifically, amorphous rosuvastatin calcium (XVII) is having at least about 98 % purity by HPLC and more specifically amorphous rosuvastatin calcium (XVII) is more than about 99 % pure by HPLC. Substantially pure amorphous rosuvastatin calcium
  • XVII does not contain more than about 0.15 % of Impurity A and specifically less than about 0.05 % of Impurity A.
  • Substantially pure amorphous rosuvastatin calcium (XVII) does not contain more than about 0.15 % of diastereomeric impurity and specifically less than about 0.05 % of diastereomeric impurity.
  • the substantially pure amorphous rosuvastatin calcium (XVII) of the present application may be subjected to micronization, milling to result the required particle size which is suitable for formulation.
  • Still another aspect of the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising rosuvastatin prepared according to the process of the present disclosure along with one or more pharmaceutically acceptable carriers, excipient, or diluents.
  • compositions comprising rosuvastatin or its salts and its combination with a pharmaceutically acceptable carrier of this disclosure may further formulated as solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions.
  • Formulations may be in the form of immediate release, delayed release or modified release.
  • immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems.
  • the compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization.
  • Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.
  • Compositions of the present disclosure may further comprise one or more pharmaceutically acceptable excipients.
  • compositions that find use in the present disclosure include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants
  • reaction mass was then cooled to 0- 5 °C and sodium thiosulfate solution (10 % w/v) was slowly added.
  • Ammonium chloride solution (25 % w/v) was slowly added to reaction mass at 0-5 °C and stirred for one hour.
  • the precipitated solid was collected by filtration, washed with water (50 mL), and dried to the title compound.
  • a mixture of acetonide protected tert-butyl ester of rosuvastatin (II) and n- Butanol (200 mL) was heated to 70-80 °C and maintained for a period of 45 minutes to 1 hour.
  • the reaction mixture was then cooled to 60-65 °C and seeding material was added.
  • the reaction mass was stirred at 60-65 °C for 1 hr and further cooled to 50-55 °C.
  • the reaction mass is stirred 1 hr at 50-55 °C, and further cooled to 30-35 °C.
  • the reaction mass was maintained for 1 hour at this temperature and then cooled to -5 to 0 °C.
  • the crystalline precipitate was collected by filtration and washed with chilled n-Butanol (100 mL), heptane (150 mL) and dried to provide pure acetonide protected tert-butyl ester of rosuvastatin (II).
  • MTBE 250 mL was further added to the aqueous layer. Then sodium chloride (6.25 g) was added to the reaction mixture. An aqueous solution of sodium bisulphate (15 g in 100 mL of water) was added to the reaction mass and the pH was adjusted to 2.4. The organic layer was separated. The aqueous layer was again extracted with MTBE (200 mL) and the combined organic layer was washed with sodium chloride solution (125 mL). A solution of tert-butyl amine (7.91 g) in MTBE (250 mL) was added to the reaction mixture and stirred for 2-6 hours. The reaction mixture was cooled to 15-20 °C and stirred at this temperature for 1 hour. The precipitated solid was isolated and dried.
  • the solid was suspended in a mixture of acetonitrile (62.5 mL) and IPA (62.5 mL) and heated to a temperature of 50-55 °C for 1-3 hours. The reaction mixture was then cooled to 25-35 °C and stirred at this temperature for 2-6 hours. The reaction mixture was further cooled to 10-15 °C and stirred for 1 hour. The precipitated solid was filtered, washed with a mixture of acetonitrile and IPA and dried to provide the title compound.

Abstract

Disclosed is the process for the preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I), which is the intermediate of rosuvastatin calcium. Purification of substantially pure acetonide protected tert-butyl ester of rosuvastatin (II) and its use for the preparation of substantially pure amorphous rosuvastatin calcium are also disclosed.

Description

PROCESS FOR PREPARATION OF ROSUVASTATIN
CALCIUM FIELD OF INVENTION
The present application relates to a process for the preparation of 4- (fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I)
Figure imgf000002_0001
(I)
which is an intermediate in the synthesis of rosuvastatin.
The present application also relates to a process for the preparation of substantially pure a statin (II)
Figure imgf000002_0002
and its use for the preparation of substantially pure amorphous rosuvastatin calcium.
INTRODUCTION
Rosuvastatin calcium (XVII) is a well known HMG-CoA reductase inhibitor which is used for the treatment of hypercholesterolemia.
Figure imgf000003_0001
(XVII)
Hirai et al. U.S. Patent No. USRE 37, 314 E1 discloses rosuvastatin and its pharmaceutically acceptable salts. The patent teaches a process for the preparation of pyrimidine aldehyde of formula (I) and also a process for preparing rosuvastatin using pyrimidine aldehyde of formula (I).
Huang et al. WO 2008/151510 A1 discloses a process for the preparation of pyrimid
Figure imgf000003_0002
Scheme 1: Preparation of pyrimidine aldehyde (XVII) as disclosed in WO 2008/151510 A1 Taylor et al. U. S. Patent No. 6,844,437 B1 discloses a process for the preparation of rosuvastatin calcium as outlined in Scheme 2. In this method, the diphenyl phosphine oxide is coupled with an aldehyde in presence of a base to provide the acetonide protected tert-butyl ester. The acetonide protecting group is then cleaved in an acidic medium and the tert-butyl group is cleaved in a basic medium and the resulting sodium salt is treated with methylamine to obtain a methyl ammonium salt of rosuvastatin. Rosuvastatin calcium is prepared from the methyl ammonium salt via its sodium salt.
Figure imgf000004_0001
(XVII)
Scheme 2: Preparation of rosuvastatin calcium (XVII) as disclosed in U.S. Patent No.
6,844,437 B1 Marine et al. PCT Publication No. WO07/125547A2 discloses a process for the preparation of rosuvastatin as shown in Scheme 3. The process involves Julia- Kocienski olefination reaction between a pyrimidine sulfone and a chiral aldehyde to provide acetonide protected tert-butyl ester of rosuvastatin of formula (II). First the acetonide group of compound of formula (II) is hydrolyzed by acid and then the ester group is hydrolyzed with base to provide rosuvastatin acid which is then treated with tert-butylamine to provide tert-butylamine salt of rosuvastatin. Tert- butyl amine salt of rosuvastatin is first treated with sodium hydroxide followed by calcium acetate to provide rosuvastatin calcium (XVII).
Figure imgf000005_0001
(XVII)
Scheme 3: Preparation of rosuvastatin calcium (XVII) as disclosed in PCT Application No.
WO07/125547 A2 SUMMARY
One aspect of the present application relates to a process for preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl- pyrimidine of formula (I) as shown in scheme 4.
Another aspect of the present application relates to use of 4-(fluorophenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I), for preparing rosuvastatin.
Figure imgf000006_0001
Scheme 4
Yet another aspect of the present application relates to purification of acetonide protected tert-butyl ester of rosuvastatin (II).
Still another aspect of the present application relates to substantially pure compound of formula (II) free from any impurity, specifically free from the impurity at RRT 1.07 ± 0.02 designated as Impurity A.
Another aspect of the present application relates to crystalline acetOnide protected tert-butyl ester of rosuvastatin (II) having an XRPD pattern with peaks at 29 = 6.80, 7.60, 11.24, 15.24, 19.14 and 21.42 ±0.2 °.
Still another aspect of the present application relates to a process for the preparation of substantially pure amorphous rosuvastatin calcium using substantially pure compound of formula (II) as an intermediate. Yet another aspect of the present application relates to a process for the preparation of substantially pure amorphous rosuvastatin calcium comprising: a) removal of dihydroxy protecting group of pure acetonide protected tert- butyl, ester of rosuvastatin (II) prepared by a process of claim 11 in an acidic medium;
b) hydrolyzing the tert-butyl ester group of the product of step a) in a basic medium;
c) converting the product of step b) to tert-butyl amine salt of rosuvastatin; e) optionally purifying tert-butyl amine salt of rosuvastatin;
f) treating tert-butyl amine salt of rosuvastatin with alkali metal hydroxide and
g) treating the product of step f) with an aqueous solution of calcium chloride.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows the PXRD of acetonide protected tert-butyl ester of rosuvastatin of formula (II).
DETAILED DESCRIPTION
In accordance with the present application, a process is provided for preparing 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- formyl-pyrimidine of formula (I), which may be used as an intermediate for preparing rosuvastatin.
In one aspect, the present application provides a process comprising dehydration and halogenation, in any order or simultaneously, of the hydroxy pyrimidine compound of formula (VII) to give halogenated compound of formula (VIII):
Figure imgf000007_0001
wherein X is halogen and selected from a group of chloro, bromo and iodo.
In another aspect, the present application provides a process further comprising preparation of hydroxy pyrimidine compound of formula (VII) by oxidation of dihydropyrimidine ketone of formula (VI) in a suitable solvent
Figure imgf000008_0001
(VI) (VII)
In yet another aspect, the present application provides a process further comprising the preparation of dihydropyrimidine ketone of formula (VI) by amidation of the compound of formula (III) followed by condensation with 4- fluorobenzaldehyde in presence of urea and metal salt in suitable solvent
Figure imgf000008_0002
wherein R is C1-C6 alkyl, C6-C14 aryl, or C6-C14 (aryl)alkyl.
In still another aspect, the present application provides a process further comprising reaction of halogenated compound of formula (VIII) with N-methyl- methanesulfonamide in presence of a base and in a suitable solvent to give 2-(N- methyl-methanesulfonyl amino)pyridine compound of formula (IX)
Figure imgf000008_0003
(IX) In another aspect, the present application provides a process further comprising reduction of the 2-(N-methyl-methanesulfonyl amino)pyridine compound of formula (IX) by reaction with a reducing agent in a suitable solvent to give 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl- pyrimidine of formula (I)
Figure imgf000009_0001
(IX) (I)
In still another aspect, the present application provides a process for the preparation of the compound of Formula (I) comprising:
a) amidation of compound of formula (III)
Figure imgf000009_0002
followed by condensation with 4-flurobenzaldehyde in presence of urea and metal salt in suitable solvent to give dihydropyrimidine ketone of formula (VI)
Figure imgf000009_0003
wherein R is Ci-C6alkyl, C6-Ci4aryl, or C6-C14(aryl)alkyl;
b) oxidation of dihydropyrimidine ketone of formula (VI) in a suitable solvent to give hydroxy pyrimidine compound of formula (VII)
Figure imgf000010_0001
(VI) (VII)
c) dehydration and halogenation, in any order or simultaneously, of the hydroxy pyrimidine compound of formula (VII) to give halogenated compound of for
Figure imgf000010_0002
(VII) (vni) wherein X is halogen and selected from a group of chloro, bromo and iodo;
d) reaction of halogenated compound of formula (VIII) with N-methyl- methanesulfonamide in presence of a base and in a suitable solvent to give 2-(N- methyl-methanesulfon (IX)
Figure imgf000010_0003
and
e) reduction of the 2-( N-methyl-methanesulfonyl amino)pyridine compound of formula (IX) by reacting with a reducing agent in a suitable solvent to give 4- (fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I)
Figure imgf000011_0001
(IX) (I)
Suitable amidation agents which can be used in step a) for amidation include but are not limited to ammonia solution. The temperature at which the amidation of step a) is carried out in between about 5 °C and about 40 °C. In one embodiment, the temperature is between about 10 °C and about 30 °C. Suitable metal salts used for condensation of fluorobenzaldehyde (V) and the amidated compound (IV) include, but are not limited to cuprous chloride, aluminum chloride, or tin chloride.
Suitable organic solvents for condensation of step a) include alcohol solvents like methanol or isopropyl alcohol; ketone solvents such as acetone; aromatic hydrocarbon solvents like toluene or xylene; dimethyl sulphoxide; ethers like THF or 1 ,4-dioxane; chlorinated hydrocarbon solvents, such as chloroform, ethylene dichloride, carbon tetrachloride, or methylene chloride; or mixtures thereof. The temperature at which the condensation reaction between compound of formula (IV) and fluorobenzaldehyde (V) is carried out in between about 30 °C and about 70 °C. In one embodiment, the temperature is between about 35 °C and about 65 °C.
Suitable oxidizing agents which can be used in step b) include, but are not limited to, organic peroxides like tert-butyl hydroperoxide, hydrogen peroxide, benzoyl peroxide, benzyl peroxide, m-chloro-perbenzoic acid, oxone®, and the like. Suitable solvents which can be used for the reaction step b) include, but are not limited to halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane or the like; alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, or 2-butanol; nitrile solvents such as acetonitrile or propionitrile; ketone solvents like acetone; aromatic hydrocarbon solvents like toluene or xylene; dimethyl sulfone; dimethyl sulphoxide; or mixtures thereof. Suitable temperature at which step b) can be carried out is in the range from about 0 °C to about 30 °C.
Suitable dehydrating agents which can be used in step c) include but not limited to phosphorous pentoxide, sulfuric acid, calcium chloride, calcium carbonate and phosphorous oxychloride. Suitable halogenating agent which can be used in step c) include but not limited to phosphorous oxychloride, phosphorous trichloride, phosphorous bromide, hydrobromic acid, iodine and sodium iodide. In one embodiment, dehydration is performed first and then the dehydrated compound is subjected to halogenation. In another embodiment, halogenation is performed first and then the halogenated product is subjected to dehydration. In yet another embodiment, dehydration and halogenation is performed by using a single reagent like phosphorous oxychloride.
Suitable bases which can be used in step d) include but not limited to alkali carbonates like sodium carbonate, potassium carbonate, or lithium carbonate; alkali metal bicarbonate like sodium bicarbonate, potassium bicarbonate, or lithium bicarbonate; alkali hydroxide like sodium hydroxide, lithium hydroxide, or potassium hydroxide; alkali metal alkoxides like sodium methoxide, potassium tert- butoxide, or lithium methoxide; and amines like triethyl amine. Suitable solvents which can be used for the reaction step d) include, but are not limited to halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane or the like; alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, or 2-butanol; nitrile solvents such as acetonitrile or propionitrile; ketone solvents like acetone; aromatic hydrocarbon solvents like toluene or xylene; dimethyl sulfone; dimethyl sulphoxide; ester solvents like ethyl acetate; amide solvents like dimethyl formamide; or mixtures thereof. Suitable temperature at which step d) can be carried out is in the range from about 25 °C to about 120 °C.
Suitable reducing agents which can be used in step e) include, but not limited to, diisobutyl aluminum hydride, Vitride® solution, or lithium aluminum hydride. Suitable solvents which can be used for the reaction step e) include, but are not limited to halogenated solvents such as chloroform, ethylene dichloride, carbon tetrachloride, dichloromethane or the like; aromatic hydrocarbon solvents like toluene, xylene or benzene; or mixtures thereof. Suitable temperature at which step e) can be carried out is in the range of about 0 °C to about 70 °C. Isolation and purification of the intermediate of formula (I) described above can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase- transfer chromatography, column chromatography, or by a combination of these procedures.
Another aspect of the present application provides use of 4-(fluorophenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I) prepared according to the disclosure for preparing rosuvastatin.
Yet another aspect of the present application provides a process for the preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- formyl-pyrimidine of formula (I) from amide intermediates of formula (VI) and (VII), thus providing a process which affords cost effective route which can be practiced on an industrial scale.
Still another. aspect of the present application relates to purification of tert- butyl (E) (6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-
[methyl(methylsulphonyl)amino]pyrimidin-5-yl]vinyl]-(4R,6S)-2,2- dimethyl[1 ,3]dioxin-4-yl)acetate (II) (hereinafter referred as acetonide protected tert-butyl ester of rosuvastatin).
Acetonide protected tert-butyl ester of rosuvastatin (II) may be prepared by following the process disclosed in the prior art references. Alternatively, compound of formula (I) obtained by the process of the present application may be subjected to appropriate reactions as disclosed in the prior art to obtain suitable intermediates for the preparation of acetonide protected tert-butyl ester of rosuvastatin (II).
It has been observed that compound of formula (II) contains an impurity
(hereinafter Impurity A) at RRT 1.07±0.2 upto a level of 1.0 %. Removal of the Impurity A from the compound of formula (II) has become very difficult, and thus fails to prepare pure rosuvastatin calcium as the said impurity is carried forward to rosuvastatin calcium. Crystallization of acetonide protected tert-butyl ester (II) from methanol as reported in US6,844,437 B1 and WO05/54207A1or from a mixture of toluene-hexane as reported in WO07/125547A2 or isopropanol as reported in WO05/54207A1 does not result substantially pure compound of formula (II). Hence, there is a need in the art to develop an effective purification method to produce substantially pure compound of formula (II).
It was observed that crystallization of the compound of formula (II) from a solvent selected from a group of n-butanol, sec-butanol, tert-butanol, ethanol and mixture thereof produces substantially pure compound of formula (II). A mixture of compound of formula (II) and n-butanol was heated from about 50 °C to about 90 °C for about 30 minutes to about 90 minutes. The solution was then cooled to about 60 °C to about 70 °C. Optionally, a seeding material was added and the temperature is maintained for about 45 minutes to about 75 minutes. The solution was again cooled from about 50 °C to about 60 °C and maintained for about 45 minutes to about 75 minutes. The solution was again cooled to 30 °C to about 40 °C and maintained for about 45 minutes to about 75 minutes. Next, the solution was cooled to about -5 °C to about 0 °C and the precipitated crystalline material is collected by filtration and washed with cold n-butanol and cold n-heptane to provide substantially pure compound of formula (II). Optionally, the compound of formula (II) is recrystallized in n-butanol using 1-2 times over input to achieve the desired purity.
Another embodiment of the present application relates to substantially pure compound of formula (II). Substantially pure acetonide protected tert-butyl ester of rosuvastatin (II) means that the compound is free from any impurity and specifically free from the Impurity A. Substantially pure acetonide protected tert- butyl ester of rosuvastatin (II) means that the compound is having at least about 95 % purity by HPLC. Specifically, the compound of formula (II) is having at least 98 % purity by HPLC and more specifically the compound of formula (II) is having more than about 99 % purity by HPLC. Substantially pure acetonide protected tert- butyl ester of rosuvastatin (II) does not contain more than about 5 % of total impurities by HPLC, specifically less than about 2 % of total impurities and more specifically less than about 1 % of total impurities. Substantially pure acetonide protected tert-butyl ester of rosuvastatin (II) does not contain more than about 0.15 % of the Impurity A and specifically less than about 0.05 % of the Impurity A.
Although crystallization of acetonide protected tert-butyl ester of rosuvastatin (II) is known in the prior art from methanol, isopropanol and a mixture of toluene-hexane, the XRPD of the crystalline compound has not been reported. One embodiment of the present application relates to crystalline acetonide protected tert-butyl ester of rosuvastatin (II) obtained by crystallization from n- butanol. Another embodiment of the present application relates to the crystalline acetonide protected tert-butyl ester of rosuvastatin (II) having an X-Ray powder diffraction (XRPD) pattern substantially as shown in Fig. 1. Yet another embodiment of the present application relates to crystalline acetonide protected tert-butyl ester of rosuvastatin (II) having an XRPD pattern with one or more peaks present at 2-theta 6.80, 7.60, 11.24, 15.24, 19.14 and 21.42 ±0.2 °. The crystalline acetonide protected tert-butyl ester of rosuvastatin (II) of the present application having an XRPD pattern with peaks at 2Θ = 5.76, 6.80, 7.60, 8.52, 11.24, 14.40, 15.24, 16.16, 17.66, 18.10, 19.14, 19.82, 20.16, 21.42 and 24.88 ±0.2 °.
The acetonide protected tert-butyl ester of rosuvastatin (II) is treated in an acidic medium to remove the dihydroxy protecting acetonide group by following the process as disclosed in prior art references. Rosuvastatin has two diastereomers, namely (R, R)-isomer of rosuvastatin of formula (XIII) and (S, S)- isomer of rosuvastatin of formula (XIV). It was observed that diastereomeric impurity of rosuvastatin, specifically the (R, R)-isomer of rosuvastatin of formula (XIII) is generated during the deprotection of the acetonide group in acidic medium.
The inventors of the present application have tried different acids and different reaction conditions to restrict the generation of the diastereomeric impurity during the reaction since the removal of the diastereomeric impurity is found to be very difficult in final compound after the isolation. They have surprisingly found that when trifluoroacetic acid (TFA) is employed for the removal of the dihydroxy protecting acetonide group, the generation of diastereomeric impurity of rosuvastatin, specifically the (R, R)-isomer of rosuvastatin of formula (XIII) i
Figure imgf000016_0001
The acetonide protected tert-butyl ester of rosuvastatin (II) is treated with TFA in an organic solvent at a temperature of from about 10 °C to about 60 °C for 30 minutes to 5 hours to obtain dihydroxy rosuvastatin ester of formula (XV) which may be subjected to ne
Figure imgf000016_0002
Specifically, the organic solvent used for deprotection reaction is selected from a group of acetonitrile, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and mixtures thereof. More specifically, the organic solvent is acetonitrile. After the deprotection reaction is completed, the reaction mixture is treated with an aqueous solution of an alkali metal hydroxide selected from a group of sodium hydroxide, potassium hydroxide and lithium hydroxide to hydrolyze the tert-butyl ester group. Specifically, the alkali metal hydroxide is sodium hydroxide. The aqueous solution of the reaction mixture containing rosuvastatin sodium is washed with an organic solvent, preferably for about 2-3 times. The organic solvent is selected from a group of esters, alcohols, hydrocarbons, ethers and a mixture thereof. Specifically, the organic solvent is a hydrocarbon solvent. More specifically, the hydrocarbon solvent is an aromatic hydrocarbon solvent and most specifically the aromatic hydrocarbon solvent is toluene.
The aqueous solution containing rosuvastatin sodium is mixed with an organic solvent. The organic solvent is selected from a group of esters, alcohols, hydrocarbons, ethers and a mixture thereof. Specifically, the organic solvent is ether solvent. More specifically, the ether solvent is selected from a group of diethyl ether, diisopropyl ether and methyl tert-butyl ether. Most specifically, the organic solvent is methyl tert-butyl ether (MTBE). To the above solution of water and organic solvent, sodium chloride is added and the reaction mass is cooled from a temperature of about 15 °C to about 30 °C. Specifically, the reaction mass is cooled to 20 °C. The pH of the mixture is adjusted from about pH 1 to about pH 5 by the addition of aqueous sodium bisulphate solution. Specifically, the pH of the reaction mass is adjusted from about pH 2 to about pH 4. The organic layer is separated from the reaction mass.
A solution of tert-butyl amine in an organic solvent selected from a group of esters, alcohols, hydrocarbons, ethers and a mixture thereof is added to the above organic solvent containing rosuvastatin acid at a temperature of about 5 °C to about 40 °C, specifically at a temperature of about 25 °C to about 35 °C. The reaction mixture is then stirred for a period of about 1 hour to 10 hours, specifically the reaction mixture is stirred for a period of about 2 hours to about 8 hours and more specifically the reaction mixture is stirred for a period of about 4 hours to about 6 hours. The reaction mixture is then cooled to a temperature of about 5 °C to about 25 °C, specifically to a temperature of about 15 °C to about 25 °C. The resulting solid is filtered and the wet cake is washed with an organic solvent. Optionally, the resulted tert-butyl amine salt of rosuvastatin (XVI) is purified by leaching in an organic solvent or from a mixture of organic solvents. The organic solvent is selected from a group of an ester solvent, an alcohol solvent, a hydrocarbon solvent, an ether solvent, a nitrile solvent and a mixture thereof. Specifically, the solvent for the purification of tert-butyl amine salt of rosuvastatin
(XVI) is a mixture of a nitrile solvent and an alcohol solvent. More specifically, the solvent for crystallization is a mixture of acetonitrile and I PA.
The tert-butyl amine salt of rosuvastatin (XVI) is suspended in water and an aqueous solution of an alkali metal hydroxide selected from a group of sodium hydroxide, lithium hydroxide and potassium hydroxide is added at a temperature of about 15 °C to about 40 °C, specifically from about 25 °C to about 35 °C and stirred for 30 minutes to 5 hours. Specifically, the alkali metal hydroxide is sodium hydroxide. After the reaction is completed, the reaction mass is heated to a temperature from about 40 °C to about 90 °C for 30 minutes to 3 hours under vacuum. Specifically, the reaction mass heated from about 40 °C to about 50 °C for 1 to 2 hours under vacuum. Then the reaction mass is diluted with water and filtered through a 0.2-0.4 micron filter. The reaction mass is cooled from about 15 °C to about 20 °C. An aqueous solution of calcium chloride is added slowly to the reaction mass maintaining the temperature from about 15 °C to about 20 °C for a period of about 5 to about 25 minutes. The isolated solid was filtered and the wet cake containing rosuvastatin calcium is stirred with water for a period of about 5 minutes to 30 minutes to ensure the removal of all inorganic salts. The solid is then filtered and dried under vacuum to provide substantially pure amorphous rosuvastatin calcium (XVII).
Substantially pure amorphous rosuvastatin calcium (XVII) means that the compound is having at least about 95 % purity by HPLC. Specifically, amorphous rosuvastatin calcium (XVII) is having at least about 98 % purity by HPLC and more specifically amorphous rosuvastatin calcium (XVII) is more than about 99 % pure by HPLC. Substantially pure amorphous rosuvastatin calcium
(XVII) does not contain more than about 0.15 % of Impurity A and specifically less than about 0.05 % of Impurity A. Substantially pure amorphous rosuvastatin calcium (XVII) does not contain more than about 0.15 % of diastereomeric impurity and specifically less than about 0.05 % of diastereomeric impurity. The substantially pure amorphous rosuvastatin calcium (XVII) of the present application may be subjected to micronization, milling to result the required particle size which is suitable for formulation.
Still another aspect of the present disclosure provides a pharmaceutical composition comprising rosuvastatin prepared according to the process of the present disclosure along with one or more pharmaceutically acceptable carriers, excipient, or diluents.
The pharmaceutical composition comprising rosuvastatin or its salts and its combination with a pharmaceutically acceptable carrier of this disclosure may further formulated as solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present disclosure may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present disclosure include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Certain specific embodiments will be further explained in the following examples, which are being provided only for the purpose of illustration, and the scope of this application is not limited thereto.
EXAMPLES
EXAMPLE 1 : Preparation of 3-oxo pentanamide (IV)
To a solution of methyl isobutyl acetate (III) (100g) in toluene (50 mL) under nitrogen was added dimethylaminopyridine (7.56 g) and the solution cooled to 0-5 °C. Aqueous ammonia solution (500 mL) was added to the reaction mass over a period of 30 to 45 minutes maintaining the temperature below 10 °C. The reaction mixture was maintained at 30-35 °C for 1 hour and stirred at room temperature for 15-20 hours. Reaction mass was concentrated on a rotary evaporator at bath temperature 60-70 °C to furnish the crude product. The crude product was purified by column chromatography using n-hexane and ethyl acetate as solvent to give the title compound.
Yield: 65 g (72%).
EXAMPLE 2: Preparation of 4-(4-fluorophenyl)-6-isopropyl-2-oxo-1, 2,3,4- tetrahydro-pyrimidine-5-carboxamide (VI)
To a solution of 3-oxopentanamide (26 g), urea (21.17g), 4- fluorobenzaldehyde (V) (25g), and cuprous chloride (0.2 g) in methanol (150 mL) at 30-35 °C was added concentrated sulfuric acid (2 mL) under nitrogen atmosphere. The reaction mixture was refluxed at 65-70 °C for 15-18 hours. Reaction mass was cooled to 20- 25 °C, water (250 mL) was slowly added to the reaction mass and stirred for one hour. The precipitated solid was collected by filtration, washed with water (100 mL), and dried to yield the desired compound. Yield: 32 g (58%)
Purity by HPLC: 93.3%.
EXAMPLE 3: Preparation of 4-(4-fluorophenyl)-2-hydroxy-6- isopropylpyrimidine-5-carboxamide (VII)
To a solution of 4-(4-fluorophenyl)-6-isopropyl-2-oxo-1 ,2,3,4- tetrahydropyrimidine-5-carboxamide (VI) (5 g), potassium carbonate (0.24g), and cupric chloride dihydrate (0.03g) in dichloromethane (50 mL) at 25-30 °C was added 70% tert-butyl hydroperoxide (5 mL) under nitrogen atmosphere. The reaction mixture was maintained at 25-30 °C for 10-12 hours. Dichloromethane (50 mL) and methanol (10 mL) were added to the reaction mass and then maintained at 25-30 °C for 10-12 hours. The reaction mass was then cooled to 0- 5 °C and sodium thiosulfate solution (10 % w/v) was slowly added. Ammonium chloride solution (25 % w/v) was slowly added to reaction mass at 0-5 °C and stirred for one hour. The precipitated solid was collected by filtration, washed with water (50 mL), and dried to the title compound.
Yield: 3.8 g (76%).
EXAMPLE 4: Preparation of 2-chloro-4-(4-fluorophenyl)-6- isopropylpyrimidine-5-carbonitrile (VIII)
To a solution of 4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5- carboxamide (VII) (1 g) in dichloromethane (10 mL) at 0-5 °C was added phosphorous oxychloride (10 mL) under nitrogen atmosphere. The reaction mixture was heated to 35 °C and maintained at that temperature for 15-18 hours. The reaction mass cooled to 0-5 °C and phosphorous oxychloride (5 mL) was slowly added under nitrogen atmosphere. The reaction mixture was heated to 100-105 °C and maintained at same temperature for 15-18 hours. The reaction mass was then cooled to 25-30 °C and the excess phosphorous oxychloride was completely evaporated. To the residue, water (5 mL) and ethyl acetate (5 mL) was added at 0-5 °C. The organic layer was separated and washed twice with water (2 x 5 mL). The organic layer was washed with sodium chloride solution (10 % w/v), dried over sodium sulfate, and evaporated under vacuum to give 2-chloro-4-(4- fluorophenyl)-6-isopropyl pyrimidine-5-carbonitrile (VIII).
Yield: 0.4 g (40%)
Purity by HPLC: 88.4%.
EXAMPLE 5: Preparation of N-(5-cyano-4-(4-fluorophenyl)-6- isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (IX)
To a solution of 2-chloro-4-(4-fluorophenyl)-6-isopropylpyrimidine-5- carbonitrile (VIII) (1 g) and potassium carbonate (1.73g) in toluene (12 mL) at 25- 30°C was added N-methyl methane sulfonamide (0.47g) under nitrogen atmosphere and stirred for 5-10 minutes. The reaction mixture was heated to 110- 115 °C and refluxed azeotropically. The azeotropic distillation was maintained at same temperature for 6-8 hours. The reaction mass was cooled to 25-30 °C, filtered, and collected the wet cake, washed with ethyl acetate (5 mL). Water (10 mL) was added to the filtrate and stirred for 30 minutes. Organic layer was separated and washed the aqueous layer with ethyl acetate (2 x 0 mL). The combined ethyl acetate layers were washed with water (10 mL), dried over sodium sulfate, and evaporated under vacuum. The mixture of ethyl acetate and n- hexane was added to residue which was then stirred for 30 minutes. The solid was collected by filtration, washed with 30 % ethyl acetate in n-hexane (2mL), and dried under vacuum for 14-16 hours at 60-65°C to afford the title compound.
Yield: 0.65 g (51.5%)
Purity by HPLC: 98.96%.
EXAMPLE 6: Preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonyl-amino)-5-formyl-pyrimidine (I)
To a solution of N-(5-cyano-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N- methylmethanesulfonamide (IX) (60 g) in dichloromethane (480 mL) at 0-5 °C was added DIBAL-H (205.4 mL) under nitrogen atmosphere. The reaction mixture was maintained at same temperature for 2 hours. To the reaction mass cold dilute hydrochloric acid solution and stirred for 1-2 hours at 0-5 °C. Dichloromethane (480 mL) was added to reaction mass. Slowly the temperature of the reaction mass was raised to 25-30 °C and the reaction mass was stirred at the same temperature for 8-10 hours. The organic layer was separated from the reaction mass and further extracted 2-3 times with dichioromethane. The combined organic layer was washed with water (600 mL) and stirred at 25-30 °C for one hour. The organic phase was separated and evaporated under vacuum completely. Isopropyl alcohol (60 mL) was added to the resultant residual mass and heated to a temperature of 60-70 °C for 2 hours. The reaction mixture was cooled to 5-10 °C, filtered the precipitated solid, washed with isopropyl alcohol (60 mL), and dried under vacuum for 12-15 hours at 60-70 °C to afford the desired compound (I). Yield: 48.6 g (80.3%)
Purity by HPLC: 99.54%.
Example 7: Purification of tert-butyl (E) (6-[2-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl]vinyl](4R,6S)-2,2- dimethyl[1,3]dioxin-4-yl)acetate (II)
A mixture of acetonide protected tert-butyl ester of rosuvastatin (II) and n- Butanol (200 mL) was heated to 70-80 °C and maintained for a period of 45 minutes to 1 hour. The reaction mixture was then cooled to 60-65 °C and seeding material was added. The reaction mass was stirred at 60-65 °C for 1 hr and further cooled to 50-55 °C. The reaction mass is stirred 1 hr at 50-55 °C, and further cooled to 30-35 °C. The reaction mass was maintained for 1 hour at this temperature and then cooled to -5 to 0 °C. The crystalline precipitate was collected by filtration and washed with chilled n-Butanol (100 mL), heptane (150 mL) and dried to provide pure acetonide protected tert-butyl ester of rosuvastatin (II).
Purity by HPLC: 98.8 %
Example 8: Preparation of tert-butyl amine salt of rosuvastatin (XVI)
To a solution of acetonide protected tert-butyl ester of rosuvastatin (II) (25 g) a dilute solution of TFA in water (2.5 g in 25 mL water) was added at 30-40 °C. The reaction was stirred for 30 minutes to 1 hour and then water (25 mL) was added to it. The reaction mixture was again stirred for 3-4 hours at the same temperature. Then an aqueous solution of sodium hydroxide (3.46 g in 100 mL water) was added and the reaction mixture was stirred for 1 hour. The reaction mixture was further diluted with water (200 mL) and washed with toluene (2 x 250 mL) and MTBE (125 mL). MTBE (250 mL) was further added to the aqueous layer. Then sodium chloride (6.25 g) was added to the reaction mixture. An aqueous solution of sodium bisulphate (15 g in 100 mL of water) was added to the reaction mass and the pH was adjusted to 2.4. The organic layer was separated. The aqueous layer was again extracted with MTBE (200 mL) and the combined organic layer was washed with sodium chloride solution (125 mL). A solution of tert-butyl amine (7.91 g) in MTBE (250 mL) was added to the reaction mixture and stirred for 2-6 hours. The reaction mixture was cooled to 15-20 °C and stirred at this temperature for 1 hour. The precipitated solid was isolated and dried. The solid was suspended in a mixture of acetonitrile (62.5 mL) and IPA (62.5 mL) and heated to a temperature of 50-55 °C for 1-3 hours. The reaction mixture was then cooled to 25-35 °C and stirred at this temperature for 2-6 hours. The reaction mixture was further cooled to 10-15 °C and stirred for 1 hour. The precipitated solid was filtered, washed with a mixture of acetonitrile and IPA and dried to provide the title compound.
Yield: 20.5 g (86 %)
Purity by HPLC: 99.82 %
Example 9: Preparation of substantially pure amorphous rosuvastatin calcium (XVII)
To an aqueous solution of tert-butyl amine salt of rosuvastatin (XVI) (25 g in 125 mL of water), a solution of sodium hydroxide (1.98 g) in water (50 mL) was added under nitrogen atmosphere and the reaction mixture was stirred for 1 hour. The reaction mass was heated to 40-45 °C and nitrogen gas was bubbled through the reaction mass under vacuum for 1-2 hrs and water (50 mL)was added to the reaction mass. The reaction mixture was then filtered through 0.2-0.4 micron filter and cooled to 15-20 °C. An aqueous solution of calcium chloride (2.75 g in 75 mL water) was added slowly to the reaction mixture for a period of 15-25 minutes and the reaction mixture was stirred for 15-45 minutes. The precipitated solid was filtered and washed with water. The wet cake was dried in vacuum oven below 50 °C for 6-10 hours. The dried material was sieved and charged into a reaction vessel and water (300 mL) was added to it. The reaction mixture was stirred for 15-45 minutes at 25-35 °C under nitrogen atmosphere. The solid was filtered and dried to provide the title compound.
Yield: 17.4 g (38 %)
Purity by HPLC: 99.77 %.

Claims

We claim:
1. A process for the preparation of 4-(fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)-5-formyl-pyrimidine of formula (I)
Figure imgf000026_0001
(I)
comprising
a) amidation of compound of formula (III) followed by condensation with 4- flurobenzaldehyde in presence of urea and metal salt in suitable solvent to give dihydropyrimidine ketone of formula (VI)
Figure imgf000026_0002
wherein R is alkyl, aryl, arylalkyl;
b) oxidation of dihydropyrimidine ketone of formula (VI) in suitable solvent to give hydroxy py
Figure imgf000026_0003
(VI) (VII) c) dehydration followed by halogenation of hydroxyl pyrimidine compound of formula VII) to give halogenate compound of formula (VIII)
Figure imgf000027_0001
Wherein X is halogen and selected from a group of chloro, bromo and iodo; d) reaction of halogenated compound of formula (VIII) with N-methyl- methanesulfonamide in presence of a base and suitable solvent to give 2-( N- methyl-methanesulfonyl amino)pyridine compound of formula (IX)
Figure imgf000027_0002
e) reaction of 2-( N-methyl-methanesulfonyl amino)pyridine of formula (IX) with suitable reducing agents in suitable solvent to give 4-(fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-formyl-pyrimidine of formula (I)
Figure imgf000027_0003
2. A Process for preparation of compound of formula (VII) comprising
a) amidation of compound of formula (III) followed by condensation with 4- flurobenzaldehyde in presence of urea and metal salt in suitable solvent to give dihydropyrimidine ketone of formula (VI)
Figure imgf000028_0001
wherein R is alkyl, aryl, arylalkyl
b) oxidation of dihydropyrimidine ketone of formula (VI) in suitable solvent to give hydroxy pyrim
Figure imgf000028_0002
(VI) (VII)
3. The process of claim 1 or claim 2, wherein R is methyl.
5. The process of claim 1, wherein the halogen used in step c) is chloro.
6. 4-(4-Fluorophenyl)-6-isopropyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide of formula (VI)
Figure imgf000028_0003
(VI)
7. 4-(4-Fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5-carboxamide of formula (VII)
Figure imgf000029_0001
(VII)
8. Use of 4-(4-fluorophenyl)-6-isopropyl-2-oxo-1 ,2,3,4-tetrahydropyrimidine-5- carboxamide of formula (VI) for preparation of substantially pure amorphous rosuvastatin calcium (XVII).
9. Use of 4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidine-5-carboxamide of formula (VII) for preparation of substantially pure amorphous rosuvastatin calcium (XVII).
10. A process for the purification of acetonide protected tert-butyl ester of rosuvastatin (II) comprising crystallization of compound (II) in a solvent selected from a group of ethanol, n-butanol, sec-butanol, tert-butanol and mixture thereof.
11. The process of claim 10, wherein the alcoholic solvent is n-butanol.
12. A process for the preparation of substantially pure amorphous rosuvastatin calcium comprising:
a) removal of dihydroxy protecting group of pure acetonide protected tert-butyl ester of rosuvastatin (II) prepared by a process of claim 11 in an acidic medium;
b) hydrolyzing the tert-butyl ester group of the product of step a) in a basic medium;
c) converting the product of step b) to tert-butyl amine salt of rosuvastatin;
e) optionally purifying tert-butyl amine salt of rosuvastatin;
f) treating tert-butyl amine salt of rosuvastatin with alkali metal hydroxide and g) treating the product of step f) with an aqueous solution of calcium chloride.
13. A crystalline form of acetonide protected tert-butyl ester of rosuvastatin (II) having an X-ray powder diffraction pattern with one or more peaks at 2-theta 6.80, 7.60, 11.24, 15.24, 19.14 and 21.42 ±0.2 °.
14. A crystalline form of acetonide protected tert-butyl ester of rosuvastatin (II) having an X-ray powder diffraction pattern with one or more peaks at 2-theta 5.76, 6.80, 7.60, 8.52, 11.24, 14.40, 15.24, 16.16, 17.66, 18.10, 19,14, 19.82, 20.16, 21.42 and 24.88 ±0.2 °
15. The crystalline form of acetonide protected tert-butyl ester of rosuvastatin (II) according to claim 13 or 14, characterized by XRPD pattern as depicted in Fig. 1.
PCT/IN2012/000366 2011-05-25 2012-05-24 Process for preparation of rosuvastatin calcium WO2012172564A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1761/CHE/2011 2011-05-25
IN1761CH2011 2011-05-25
IN1198CH2012 2012-03-28
IN1198/CHE/2012 2012-03-28

Publications (1)

Publication Number Publication Date
WO2012172564A1 true WO2012172564A1 (en) 2012-12-20

Family

ID=47356617

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2012/000366 WO2012172564A1 (en) 2011-05-25 2012-05-24 Process for preparation of rosuvastatin calcium

Country Status (1)

Country Link
WO (1) WO2012172564A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104059024A (en) * 2014-06-16 2014-09-24 浙江大学 Preparation method of rosuvastatin intermediate and intermediate compound
CN104628653A (en) * 2015-01-28 2015-05-20 湖北益泰药业有限公司 Method for synthesizing key intermediate of rosuvastatin calcium
WO2016151104A1 (en) * 2015-03-26 2016-09-29 Dsm Sinochem Pharmaceuticals Netherlands B.V. Improved process for preparing a statin precursor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260440A (en) * 1991-07-01 1993-11-09 Shionogi Seiyaku Kabushiki Kaisha Pyrimidine derivatives
US6844437B1 (en) * 1999-02-17 2005-01-18 Astrazeneca Ab Process for the production of tert-butyl (E)-(6-[2-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsufonyl)amino]pyrimidin-5-yl]vinyl]4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
WO2008151510A1 (en) * 2007-06-11 2008-12-18 Anhui Qingyun Pharmaceutical And Chemical Co., Ltd. Preparation of 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260440A (en) * 1991-07-01 1993-11-09 Shionogi Seiyaku Kabushiki Kaisha Pyrimidine derivatives
US6844437B1 (en) * 1999-02-17 2005-01-18 Astrazeneca Ab Process for the production of tert-butyl (E)-(6-[2-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsufonyl)amino]pyrimidin-5-yl]vinyl]4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
WO2008151510A1 (en) * 2007-06-11 2008-12-18 Anhui Qingyun Pharmaceutical And Chemical Co., Ltd. Preparation of 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104059024A (en) * 2014-06-16 2014-09-24 浙江大学 Preparation method of rosuvastatin intermediate and intermediate compound
CN104628653A (en) * 2015-01-28 2015-05-20 湖北益泰药业有限公司 Method for synthesizing key intermediate of rosuvastatin calcium
WO2016151104A1 (en) * 2015-03-26 2016-09-29 Dsm Sinochem Pharmaceuticals Netherlands B.V. Improved process for preparing a statin precursor
CN107428702A (en) * 2015-03-26 2017-12-01 中化帝斯曼制药有限公司荷兰公司 The method of improved preparation statin precursor

Similar Documents

Publication Publication Date Title
US20090036680A1 (en) Salts of hmg-coa reductase inhibitors and use thereof
AU2010222683B2 (en) Process for the preparation of bosentan
NZ547094A (en) Process for the manufacture of the calcium salt of rosuvatatin (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R, 5S)-3,5-dihydroxyhept-6-enoic acid and crystalline intermediates thereof
WO2005077916A1 (en) Salts of hmg-coa reductase inhibitors and use thereof
JP2008526897A (en) Diastereomeric purification of rosuvastatin
CA2711043A1 (en) Method of synthesis of bosentan, its polymorphic forms and its salts
WO2010095145A1 (en) Process for the preparation of voriconazole
WO2012172564A1 (en) Process for preparation of rosuvastatin calcium
WO2016125086A1 (en) Processes for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof
WO2010035284A2 (en) An improved process for the preparation of rosuvastatin calcium
JP5558492B2 (en) Major intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof
US20140187569A1 (en) Crystalline forms of bosentan salts and processes for their preparation
JP2012523444A (en) Method for preparing an endothelial receptor antagonist (bosentan)
WO2009128091A2 (en) Crystalline form of(7-[4-(4-fluorophenyl)-6-isopropyl-2-(n- methyl-n-methylsulfonylamino)pyrimidin-5-yl]-(3r,5s)- dihydroxy-(e)-6-heptenoic acid intermediate, process for preparing the same and use thereof
WO2010015623A1 (en) Process for the preparation of endothelin receptor antagonists
WO2011024056A2 (en) An improved process for the preparation of bosentan
EP2603497B1 (en) A novel process for preparation of bosentan
US10626093B2 (en) Polymorphic form of crystalline rosuvastatin calcium and novel processes for crystalline as well as amorphous rosuvastatin calcium
WO2015104602A2 (en) A process for the preparation of anagliptin and its intermediates thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12800810

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12800810

Country of ref document: EP

Kind code of ref document: A1