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WO2016125086A1 - Procédé de préparation de rosuvastatine ou de sels pharmaceutiquement acceptables de celle-ci - Google Patents

Procédé de préparation de rosuvastatine ou de sels pharmaceutiquement acceptables de celle-ci Download PDF

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Publication number
WO2016125086A1
WO2016125086A1 PCT/IB2016/050542 IB2016050542W WO2016125086A1 WO 2016125086 A1 WO2016125086 A1 WO 2016125086A1 IB 2016050542 W IB2016050542 W IB 2016050542W WO 2016125086 A1 WO2016125086 A1 WO 2016125086A1
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Prior art keywords
rosuvastatin
compound
formula
salt
amino
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Inventor
Ravindra Babu Bollu
Venkata Pramod Kumar MANDADAPU
Venkata Sunil Kumar Indukuri
Seeta Rama Anjaneyulu GORANTLA
Satyanarayana Chava
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Laurus Labs Pvt Ltd
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Laurus Labs Pvt Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the present invention generally relates to processes for the preparation of rosuvastatin and pharmaceutically acceptable salts thereof using novel intermediates, and to a pharmaceutical composition containing the same.
  • Rosuvastatin calcium is an HMG-CoA reductase inhibitor and marketed under the name CRESTOR useful in the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis. Rosuvastati al structure:
  • U.S. Patent No. 5,260,440 disclosed rosuvastatin calcium and its process.
  • the process involves reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)- 5-pyrimidinecarbaldehyde with methyl(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6- triphenylphosphoranylidene hexanoate in acetonitrile, cleaving the silyl group with hydrogen fluoride, followed by reduction with diethylmethoxyborane and sodium borohydride to obtain rosuvastatin methyl ester. The ester is then hydrolyzed with sodium hydroxide to obtain sodium salt of rosuvastatin, which is then converted to the calcium salt by treating it with calcium chloride in water.
  • the above described process is schematically represented as follows:
  • U.S. Patent No. 7,312,329 discloses an alternate process for the preparation of rosuvastatin and its intermediates via Wittig reagents.
  • the process involved the condensation of Wittig reagent like triphenyl[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl) amino]pyrimidin-5-ylmethyl]phosphonium halide with tert- butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl ⁇ acetate in presence of a base to give tertiary butyl ester compound of rosuvastatin which is converted into free acid and then to calcium salt.
  • This process according to WO2007/125547 suffers from quality aspects as Z isomer formation is high (i.e., approximately 20%) in Wittig reactions.
  • PCT Publication No. 2015/074328 disclosed a process for the preparation of rosuvastatin by reacting Wittig salt with ((4R, 6S)-2-(furan-2-yl)-6-formyl-l,3-dioxane- 4-yl) acetate in the presence of a base.
  • U.S. Patent No. 8,524,914 patent disclosed a process for the preparation of rosuvastatin calcium by reacting chiral sulfones of 2-methyl-l-phenylpropan-2-yl 2-[(4R,6S)-6- formyl-2,2-dimethyl-l ,3 -dioxan-4-yl] acetate with N-(4-(4-fluorophenyl)-5-formyl-6- isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide in the presence of a base such as NaHMDS at -50°C to about -60°C to provide the trans olefin.
  • a base such as NaHMDS
  • PCT Publication No. 2012/098048 disclosed Julia Kocienski olefination of 2-((4R,6S)- 6-((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl) acetate tert- butyl ester with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N- methylmethane sulfonamide in the presence of a base such as NaHMDS and LiHMDS at -70°C to about -75 °C to provide the trans olefin.
  • a base such as NaHMDS and LiHMDS
  • PCT Publication No. 2012/098050 disclosed preparation of trans olefin by reacting 2- ((4R,6S)-6-((l -methyl- lH-tetrazol-5ylsulfonyl)methyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl) acetate methyl ester with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N- methylmethane sulfonamide in the presence of a base such as NaHMDS at -50°C to about -60°C to provide the trans olefin.
  • a base such as NaHMDS
  • PCT Publication No. 2011/121595 disclosed a process for the preparation of rosuvastatin calcium by methylation of tert-butyl 2-(6- ⁇ [5-(difluoromethoxy)-lH-l,3- benzodiazole-2-sulfonyl] methyl ⁇ -2,2-dimethyl-l,3-dioxan-4-yl) acetate with DMS followed by condensation with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2- yl)-N-methylme thane sulfonamide in the presence of NaHMDS at -78°C to about -70°C to provide the trans olefin which is later converted to rosuvastatin calcium via the preparation of rosuvastatin tertiary butyl ammonium salt.
  • the above described process is schematically represented as follows:
  • IN3028/MUM/2009 discloses a process for the preparation of rosuvastatin calcium by condensation of N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N- methylmethane sulfonamide with chiral diol sulfones in the presence of a base such as potassium tert-butoxide, sodium hydride, LiHMDS or NaHMDS at a temperature from about -60°C to about -90°C in an inert organic solvent to provide the trans olefin which is later converted to rosuvastatin calcium.
  • a base such as potassium tert-butoxide, sodium hydride, LiHMDS or NaHMDS
  • ammonium salts of rosuvastatin are not likely to be used for administration to a patient; they provide a method for purifying rosuvastatin through crystallization. Therefore, there is a need in the art for additional salts of rosuvastatin that allow for purification of rosuvastatin.
  • the present invention provides industrially feasible and cost effective processes for preparation of Rosuvastatin calcium or pharmaceutically acceptable salts thereof.
  • the present invention provides a process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof of formula I;
  • M is H, Na + ,K + ,Mg +2 ,Ca +2 ;
  • Rl is selected from alkyl tetrazole, pyridine-2-yl, pyrimidin-2-yl, benzothiazol- 2-yl, l-phenyl-lH-tetrazol-5-yl, 3,5-bis(trifluoromethyl)phenyl-l-yl, 1-methylimidazol- 2-yl, benzimidazol-2-yl, 4-methyl-l,2,4-triazol-3-yl and iso-quinolin-l-yl;
  • X is O or S; and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl, benzyloxycarbonyl; in the presence of an alkali metal base and a suitable solvent to obtain a compound of formula IV; and
  • the present invention provides a process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof of formula I; comprising:
  • the present invention provides an improved process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof of formula I, comprising:
  • organic amine salt of compound VIII to a compound of formula I; wherein the organic amine is selected from the group consisting of cyclohexane- 1,2-diamine, benzhydryl amine, 2-amino-l-butanol, 2-amino pyridine, furfuryl amine, (R)-l-amino-2-propanol and (R,S)-1 -amino -2-propanol.
  • the present invention provides a process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof of formula I; comprising:
  • organic amine salt of compound VIII converting the organic amine salt of compound VIII to rosuvastatin or pharmaceutically acceptable salts thereof of formula I; wherein the organic amine is selected from the group consisting of cyclohexane-l,2-diamine, benzhydryl amine, 2-amino-l-butanol, 2-amino pyridine, furfuryl amine, (R)-l- amino -2-propanol and (R,S)-1 -amino -2-propanol.
  • the present invention provides a compound of formula III;
  • Rl is selected from alkyl tetrazole, pyridine-2-yl, pyrimidin-2-yl, benzothiazol- 2-yl, l-phenyl-lH-tetrazol-5-yl, 3,5-bis(trifluoromethyl)phenyl-l-yl, 1-methylimidazol- 2-yl, benzimidazol-2-yl, 4-methyl-l,2,4-triazol-3-yl and iso-quinolin-l-yl;
  • X is O or S; and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl and benzyloxycarbonyl.
  • the present invention provides a compound of formula IV;
  • X is O or S; and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl and benzyloxycarbonyl.
  • the present invention provides novel compound of formula V;
  • X is O or S; and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl, benzyloxycarbonyl.
  • the present invention provides organic amine salt of rosuvastatin of formula VIII;
  • organic amine is selected from cyclohexane-l,2-diamine, benzhydryl amine, 2-amino-l-butanol, 2-amino pyridine, (R)-l -amino -2-propanol and l-amino-2- propanol.
  • the present invention provides an improved process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof of formula I, comprising:
  • R4, R5 and R6 are the same or different and are selected from linear or branched alkyl; cycloalkyl; aryl and aralkyl; with a compound of formula X;
  • X is O or S and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl, benzyloxycarbonyl; in the presence of a base and a suitable solvent to obtain a compound of formula IV; and
  • the present invention provides s compound of formula IX;
  • R4, R5 and R6 are the same or different and are selected from linear or branched alkyl; cycloalkyl; aryl and aralkyl.
  • the present invention provides a compound of formula X;
  • the present invention provides a pharmaceutical composition comprising therapeutically effective amount of rosuvastatin or pharmaceutically acceptable salts thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 is a characteristic powder X-ray diffraction (XRD) pattern of rosuvastatin cyclohexyl- 1 , 2-diamine salt.
  • Figure 2 is a characteristic powder X-ray diffraction (XRD) pattern of rosuvastatin benzhydryl amine salt.
  • Figure 3 is a characteristic powder X-ray diffraction (XRD) pattern of rosuvastatin 2- amino-l -butanol salt.
  • Figure 4 is a characteristic powder X-ray diffraction (XRD) pattern of rosuvastatin 2- amino pyridine salt.
  • Figure 5 is a characteristic powder X-ray diffraction (XRD) pattern of rosuvastatin furfuryl amine salt.
  • Figure 6 is a characteristic powder X-ray diffraction (XRD) pattern of rosuvastatin 1- amino-2-propanol salt.
  • alkyl used herein the specification represents linear, branched or cyclic structures of from Ci_6 carbon atoms and is selected from, but not limited to methyl, ethyl, propyl, n-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, and the like.
  • cycloalkyl used herein the specification represents saturated or partially unsaturated cyclic hydrocarbon groups including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl containing 3 to 10 carbons forming the ring, and is selected from but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.
  • aryl used herein in the specification represents C -12 aryl and is selected from but not limited to phenyl, toluyl, napthyl and the like.
  • the aryl may be optionally substituted by 1 to 3 substituent's, for example, Ci_4 alkyl (such as methyl, ethyl, propyl), Ci_4 alkoxy (such as methoxy, ethoxy), halogen (such as Br, CI or I), amino, cyano, hydroxy and the like.
  • aralkyl used herein the specification refers to an Ci-4 alkyl group substituted by an C 6- i2 aryl group and is selected from but not limited to benzyl, phenyl ethyl, phenyl propyl and the like, which may be optionally substituted by 1 to 3 substituent's for example, alkyl, halogen, amino, cyano, hydroxyl and the like.
  • the term "pharmaceutically acceptable cation” refers to an alkali metal or alkaline-earth metal ion and an ammonium ion. Specific examples of the pharmaceutically acceptable cation include sodium, potassium, calcium, magnesium and the like.
  • the present invention relates to a process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof which is more convenient to use, more suitable on large scale and use less expensive reagents and solvents.
  • the present invention provides a process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof of formula I;
  • M is H, Na + ,K + ,Mg +2 ,Ca +2 ;
  • Rl is selected from alkyl tetrazole, pyridine-2-yl, pyrimidin-2-yl, benzothiazol 2-yl, l-phenyl- lH-tetrazol-5-yl, 3,5-bis(trifluoromethyl)phenyl- l-yl, 1-methylimidazol 2-yl, benzimidazol-2-yl, 4-methyl-l ,2,4-triazol-3-yl and iso-quinolin- l-yl;
  • X is O or S and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl, benzyloxycarbonyl; in the presence of an alkali metal base and a suitable solvent to obtain a compound of formula IV; and
  • the present invention provides an improved process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof of formula I, comprising:
  • organic amine salt of compound VIII to a compound of formula I; wherein the organic amine is selected from the group consisting of cyclohexane - 1,2-diamine, benzhydryl amine, 2-amino-l-butanol, 2-amino pyridine, furfuryl amine, (R)-l-amino-2-propanol and (R,S)-1 -amino -2-propanol.
  • Step a) of the foregoing process involves condensing a compound of formula II with a compound of formula III in the presence of alkali metal hydride to a obtain compound of formula IV.
  • the compound of Formula III is represented as follows:
  • Rl is selected from alkyl tetrazole, pyridine-2-yl, pyrimidin-2-yl, benzothiazol- 2-yl, l-phenyl-lH-tetrazol-5-yl, 3,5-bis(trifluoromethyl)phenyl-l-yl, 1-methylimidazol- 2-yl, benzimidazol-2-yl, 4-methyl-l,2,4-triazol-3-yl and iso-quinolin-l-yl;
  • X is O or S; and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl, benzyloxycarbonyl.
  • the condensation reaction is carried out in the presence of an alkali metal base such as sodium hydride, potassium hydride, lithium hydride and the like; preferably sodium hydride, in a suitable solvent selected from the group consisting of ethers such as tetrahydrofuran, dioxane, diethyl ether, 2-methyl tetrahydrofuran and the like; ketones such as acetone, methyl isobutyl ketone and the like; halogenated solvents such as dichlorome thane, chloroform and the like; amides such as dimethyl formamide, dimethyl acetamide and the like and mixtures thereof, preferably dimethyl formamide or tetrahydrofuran.
  • an alkali metal base such as sodium hydride, potassium hydride, lithium hydride and the like
  • a suitable solvent selected from the group consisting of ethers such as tetrahydrofuran, dioxane, diethyl ether, 2-methyl tetrahydro
  • the condensation reaction may be optionally carried out in presence of a catalytic amount of an additional base such as sodium hydroxide, potassium hydroxide and the like.
  • the condensation reaction may be advantageously carried out at a suitable temperature of from about -10°C to about 50°C. Preferably the reaction temperature is about -5°C to about 35°C.
  • the reaction may take from about 0.5 hours to about 24 hours depending upon the base, solvent and temperature chosen.
  • the base may be added at a temperature less than about 5°C followed by carrying out the condensation reaction at a temperature of less than about 35°C.
  • reaction of compound of Formula II with a compound of formula III is carried out in presence of sodium hydride in tetrahydrofuran solvent at a temperature of about 0°C to about 35°C.
  • the resultant reaction mass may be treated with an aqueous solution of base, for e.g. aqueous potassium carbonate to decomposing the unreacted base present, if any in the reaction mass and then the resultant compound of formula IV can be isolated by known techniques, for example, extraction with a water immiscible solvent such as ethyl acetate, dichloro methane, chloroform and the like and conventional separation of the organic layer from the reaction mixture.
  • the solvent from the organic layer may be concentrated under vacuum to get residue by any method known in the art, such as distillation, evaporation, rotational drying (such as with the Buchi Rotavapor).
  • additional purification may be carried out by process such as crystallization, solvent slurry techniques or any chromatography techniques.
  • the compound of Formula IV optionally may be purified by using a suitable solvent.
  • the suitable solvent is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and mixtures thereof.
  • the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like. The drying can be carried out at a temperature ranging from about 30°C to about 70°C, preferably from about 45°C to about 55°C.
  • the process of the invention involves Julia Kocienski olefination reaction of compound II with compound III at 0°C to about 35°C. Being able to perform a reaction at such temperatures is an enormous advantage, as it simplifies the process significantly, makes it possible to use less elaborate and simpler equipment, consequently representing a considerable advantage as regards to cost, also in terms of energy saving, from the process scale up point of view. Further, the process of the invention has a further advantage in use of alkali metal hydrides such as sodium hydride which is cheap due to the availability of the choice of solvent soluble bags which makes the process more suitable and economical to use on large scale. Further, process of the invention substantially reduces process-related impurities and/or product-related substances. For example, with the process of the invention using alkali metal hydride as base in the condensation reaction, an unwanted Z-isomer impurity is substantially reduced when compared to other reported processes.
  • the Z-isomer impurity is represented as follows:
  • the present invention provides a compound of formula IV, obtained by the process described herein with a diastereomeric purity of at least about 98% as measured by HPLC, preferably at least about 99% as measured by HPLC and substantially free of the Z-isomer impurity by HPLC.
  • the term “substantially free” refers to compound of formula IV having less than the detectable levels of Z-isomer impurity as measured by HPLC, preferably less than 0.5% of Z-isomer impurity as measured by HPLC.
  • Step b) of the aforementioned process involves deprotection of the hydroxy protecting groups by treatment with a suitable acid such as hydrochloric acid, acetic acid, sulfuric acid, oxalic acid, trifluoroacetic acid, phosphoric acid and formic acid in a suitable organic solvent.
  • a suitable acid such as hydrochloric acid, acetic acid, sulfuric acid, oxalic acid, trifluoroacetic acid, phosphoric acid and formic acid in a suitable organic solvent.
  • the organic solvent includes, but is not limited to halogenated solvents such as dichloromethane, chloroform and the like; alcohol solvents such as methanol, ethanol, isopropanol and the like; ether solvents such as tetrahydrofuran, diethyl ether and the like; ketone solvents such as methyl ethyl ketone, acetone and the like; ester solvents such as methyl acetate, ethyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like.
  • halogenated solvents such as dichloromethane, chloroform and the like
  • alcohol solvents such as methanol, ethanol, isopropanol and the like
  • ether solvents such as tetrahydrofuran, diethyl ether and the like
  • ketone solvents such as methyl ethyl ketone, acetone and the like
  • ester solvents such
  • the deprotection reaction may be carried out at a temperature in the range of, for example 0°C to about 50°C.
  • a convenient temperature to carry out the reaction is 25°C to 50°C.
  • the reaction mixture is maintained for lhr to about 4 hrs or until completion of the reaction, preferably 2-3 hrs.
  • the step c) of the aforementioned process involves hydrolysis of the dihydroxy compound of formula V with a suitable base like alkali metal hydroxide in a suitable solvent at a temperature from about 0°C to about 40°C to provide the alkali metal salt of compound of formula VI.
  • suitable alkali metal hydroxides include but are not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; preferably sodium hydroxide.
  • Suitable organic solvents include but is not limited to Ci_4 alcohols such as methanol, ethanol, isopropanol, n-propanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; preferable acetonitrile.
  • Ci_4 alcohols such as methanol, ethanol, isopropanol, n-propanol and the like
  • ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like
  • nitriles such as acetonitrile, propionitrile and the like
  • preferable acetonitrile preferable acetonitrile.
  • the compound of Formula IV can be further processed directly in the same reaction medium to preparing the rosuvastatin organic amine salt.
  • the solvent from the organic layer may be concentrated under vacuum to get the residue by any method known in the art, at the end of the reaction. For example distillation, evaporation, rotational drying (such as with the Buchi Rotavapor) and the like.
  • the reaction medium containing alkali metal salt of compound of Formula IV is directly converted in to rosuvastatin organic amine salt, which is an intermediate stage in the preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof.
  • Step d) of converting the compound of formula VI in to an organic amine salt of rosuvastatin of formula VIII involves mixing suitable organic amine and the compound of formula VI as obtained above at a temperature of about 10°C to about 45 °C in a suitable organic solvent and isolating the rosuvastatin organic amine salt of formula VIII.
  • conversion of compound of formula IV in to organic amine salt of formula VIII can be carried out in a single step without isolating the intermediate alkali metal salt products.
  • the compound of Formula IV may be neutralized with an acid such as hydrochloric acid to cleave the alkali metal cation prior to organic amine saltification, if the compound of Formula IV is having a salt with an alkali metal cation.
  • an acid such as hydrochloric acid to cleave the alkali metal cation prior to organic amine saltification, if the compound of Formula IV is having a salt with an alkali metal cation.
  • the organic amine used herein is selected from the group consisting of cyclohexane- 1 ,2- diamine, benzhydryl amine, 2-amino- l-butanol, 2-amino pyridine, furfuryl amine, (R)- l-amino-2-propanol and (R,S)- 1 -amino -2-propanol.
  • the organic amine used herein is cyclohexane- l ,2-diamine.
  • the suitable organic solvent used herein for organic amine saltification is selected from the group consisting of esters such as ethyl acetate, isopropyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; and mixtures thereof.
  • the organic amine salt of formula VIII can be isolated by cooling the reaction mass to about 0°C to about 10°C, stirring for an appropriate period of time in order for complete precipitation of the product.
  • Step e) of converting the organic amine salt of rosuvastatin of formula VIII in to pharmaceutically acceptable salt of rosuvastatin is carried out by first neutralizing the organic amine salt with a suitable acid such as hydrochloric acid, acetic acid and the like and stirring for an appropriate period of time to hydrolyze the organic amine salt, results in formation of rosuvastatin free acid.
  • a suitable acid such as hydrochloric acid, acetic acid and the like
  • the resultant rosuvastatin free acid may be treated with a suitable aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like to forming corresponding alkali metal salt of rosuvastatin.
  • converting the obtained alkali metal salt of rosuvastatin in to pharmaceutically acceptable salt thereof, for example calcium salt of rosuvastatin by treating with a suitable calcium source such as calcium hydroxide, calcium chloride or calcium acetate in a suitable solvent by a process well known in the art; for example calcium chloride is used as calcium source and water for solvent medium.
  • a suitable calcium source such as calcium hydroxide, calcium chloride or calcium acetate in a suitable solvent
  • calcium chloride is used as calcium source and water for solvent medium.
  • the rosuvastatin calcium can be isolated by any method known in the art, such as filtration and drying.
  • high purity rosuvastatin calcium is obtained having a chemical purity of at least about 98%, as measured by HPLC, preferably at least about 99%, as measured by HPLC, and more preferably at least about 99.8%, as measured by
  • the present invention provides novel intermediates of rosuvastatin and their use in the preparation of rosuvastatin or pharmaceutically acceptable salts thereof.
  • Rl is selected from alkyl tetrazole, pyridine-2-yl, pyrimidin-2-yl, benzothiazol- 2-yl, l-phenyl-lH-tetrazol-5-yl, 3,5-bis(trifluoromethyl)phenyl-l-yl, 1-methylimidazol- 2-yl, benzimidazol-2-yl, 4-methyl-l,2,4-triazol-3-yl and iso-quinolin-l-yl;
  • X is O or S; and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl and benzyloxycarbonyl.
  • the present invention provides a compound of formula III;
  • the present invention provides a compound of formula Ilia
  • the present invention provides a compound of formula IV;
  • X is O or S; and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl and benzyloxycarbonyl.
  • the present invention provides a compound of Formula IV; wherein X is S and R2 is defined as above.
  • the present invention provides a compound of formula V;
  • X is O or S; and R2 is selected from CI- 10 alkyl, aryl, cycloalkyl, aralkyl, benzyloxycarbonyl.
  • the present invention provides a compound of Formula V; wherein X is S and R2 is defined as above.
  • the present invention provides organic amine salt of formula VIII;
  • the organic amine is selected from cyclohexane-l,2-diamine, benzhydryl amine, 2-amino-l-butanol, 2-amino pyridine, (R)-l-amino-2-propanol, (R,S)-1 -amino -2- propanol.
  • the ratio of rosuvastatin to the organic amine compound may be stoichiometric or non- stoichiometric according to the present invention. For example, 1:1, 1.5:1, 1:1.5, 2:1 and 1:2 ratios of rosuvastatin to organic amine compound are acceptable.
  • the present invention provides rosuvastatin cyclohexane- 1 ,2- diamine salt.
  • the present invention provides rosuvastatin cyclohexyl-1, 2- diamine salt characterized by powder X-ray diffraction spectra substantially in accordance with Figure 01.
  • the present invention provides rosuvastatin benzhydryl amine salt.
  • the present invention provides rosuvastatin benzhydryl amine salt characterized by powder X-ray diffraction spectra substantially in accordance with Figure 02.
  • the present invention provides rosuvastatin 2-amino-l- butanol salt.
  • the present invention provides rosuvastatin 2- amino-l-butanol salt characterized by powder X-ray diffraction spectra substantially in accordance with Figure 03.
  • the present invention provides rosuvastatin 2-amino pyridine salt.
  • the present invention provides rosuvastatin 2- amino pyridine salt characterized by powder X-ray diffraction spectra substantially in accordance with Figure 04.
  • the present invention provides rosuvastatin furfuryl amine salt.
  • the present invention provides rosuvastatin furfuryl amine salt characterized by powder X-ray diffraction spectra substantially in accordance with Figure 05.
  • the present invention provides rosuvastatin l-amino-2- propanol salt.
  • the present invention provides rosuvastatin 1- amino-2-propanol salt characterized by powder X-ray diffraction spectra substantially in accordance with Figure 06.
  • the present invention provides a process for the preparation of rosuvastatin or pharmaceutically acceptable salts thereof of formula I; wherein M is H, Na + ,K + ,Mg +2 ,Ca +2 ; comprising:
  • R4, R5 and R6 are the same or different and are selected from linear or branched alkyl; cycloalkyl; aryl and aralkyl; with a compound of formula X;
  • X is O or S and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl, benzyloxycarbonyl; in the presence of a base and a suitable solvent to obtain a compound of formula IV; and
  • Step a) of the foregoing process may involve reacting the Wittig salt of formula IX with an aldehyde of formula X in the presence of an alkali metal base in a suitable solvent.
  • the process is preferably carried out in the presence of a base selected from but not limited to alkali metal amides such as lithium diisopropylamide, LiHMDS, NaHMDS and the like; alkali or alkaline earth metal carbonates or hydroxides or hydrogen carbonates or alkoxides such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium methoxide, sodium tert butoxide and the like, alkali metal hydrides such as sodium hydride and the like, potassium phosphate and the like, calcium oxide and the like, and buffers like dipotassium hydrogen phosphate and the like.
  • alkali metal amides such as lithium diisopropylamide, LiHMDS, NaHMDS and the like
  • alkali or alkaline earth metal carbonates or hydroxides or hydrogen carbonates or alkoxides such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide
  • Suitable solvents include but are not limited to ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, methyl acetate and the like; ketones such as acetone, and the like; amides such as dimethyl formamide and the like; halogenated solvents such as dichloromethane, chloroform and the like; hydrocarbon solvents such as toluene and the like; sulfoxide solvents such as dimethyl sulfoxide and the like; nitriles such as acetonitrile, propionitrile and the like; or mixtures thereof.
  • ethers such as diethyl ether, tetrahydrofuran and the like
  • esters such as ethyl acetate, methyl acetate and the like
  • ketones such as acetone, and the like
  • amides such as dimethyl formamide and the like
  • halogenated solvents such as dichloromethane
  • the reaction may be optionally carried out in presence of a catalytic amount of an additives such as potassium iodide, sodium iodide, tetra butyl ammonium bromide, hydroxy benzotriazole, Imidazole or its salts, l,8-Diazabicyclo[5.4.0]undec-7-en; however the use of such catalyst in the reaction is not critical.
  • an additives such as potassium iodide, sodium iodide, tetra butyl ammonium bromide, hydroxy benzotriazole, Imidazole or its salts, l,8-Diazabicyclo[5.4.0]undec-7-en; however the use of such catalyst in the reaction is not critical.
  • Step b) of converting the above obtained compound of formula IV in to rosuvastatin or pharmaceutically acceptable salts can be carried according to any of the process known in the art or according to the process described herein before.
  • the compound of Formula IV obtained by this process is converted in to organic amine salt of rosuvastatin followed by conversion in to rosuvastatin or pharmaceutically acceptable salt thereof, for example calcium salt is as per the process described as above embodiments.
  • the present invention provides compound of formula IX;
  • R4, R5 and R6 are the same or different and are selected from linear or branched alkyl; cycloalkyl; aryl and aralkyl.
  • the present invention provides compound of formula IX; wherein R4, R5 and R6 are all phenyl.
  • the present invention rovides compound of formula X;
  • X is O or S; and R2 is selected from alkyl, aryl, cycloalkyl, aralkyl, and benzyloxycarbonyl.
  • the present invention provides compound of formula X; wherein X is S and R2 is as defined above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising therapeutically effective amount of rosuvastatin or pharmaceutically acceptable salts thereof, preferably rosuvastatin calcium salt prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • NaHMDS Sodium hexamethyldisilazane
  • LiHMDS Lithium hexamethyldisilazane
  • KHMDS Potassium hexamethyldisilazane
  • LDA Lithium diisopropyl amine
  • NaH Sodium hydride
  • DMS Dimethyl sulfate
  • n-Propane thiol (30.2 gms diluted with tetrahydrofuran) was added and the reaction mass maintained at -2°C to 2°C until reaction completion. Filtered the insoluble material and washed with THF (100 mL). Dichloromethane (500 ml) was added to the filtrate and washed with water and sodium chloride solution.
  • reaction mass was stirred for 30 min at 0°C to 5°C and then the temperature was gradually allowed to raise to 25 °C to 35 °C and stirred till reaction completion.
  • the reaction mass was quenched with 10% potassium carbonate solution (lOOOmL) and extracted with ethyl acetate. The organic layer was washed with 10 % NaCl solution and concentrated under vacuum. The obtained residue was triturated with methanol (500mL) ; the precipitated white solid was filtered and dried at 55°C to afford 120 gms of the title compound.
  • reaction mass was maintained for 30 min at -3°C to 3°C and then the temperature was gradually allowed to raise to 25 °C to 35 °C and stirred until reaction completion.
  • the reaction mass was quenched with 10% potassium carbonate solution (1000 mL) and extracted with ethyl acetate. The organic layer was washed with 10 % NaCl solution and concentrated under vacuum. The resulting residue was triturated with methanol (500 mL), filtered the precipitated white solid and dried at 55°C to afford 120 gms of the title compound.
  • reaction mass was quenched with 10% potassium carbonate solution (1000 mL) and extracted with ethyl acetate. The organic layer was washed with 10 % NaCl solution and concentrated under vacuum. The residue was triturated with methanol (400 mL) and the precipitated white solid was filtered and dried at 55 °C to afford 90 gms of the title compound.
  • the resulting reaction mass was processed according to example 12 to obtain a residue.
  • rosuvastatin salts have been prepared by following the procedure analogous to Example 15 and using appropriate amine and solvent for saltification:
  • EXAMPLE 18 Preparation of rosuvastatin calcium To a solution of rosuvastatin cyclohexane- 1 ,2-diamine salt (100 gms) in a mixture of water (500 mL) and ethyl acetate (500 mL) at 9°C to 15°C, was added 1M solution of aqueous HC1 (300 mL) to adjust pH to 3.2 to 3.4. The resulting layers were separated and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 10 % aqueous NaCl solution and concentrated under vacuum.
  • the residue obtained was dissolved in a mixture of MTBE (500 mL) and water (500 mL), cooled to i rC to 15°C and pH was adjusted to 9.8 to 10.2 with 2M aqueous solution of NaOH (-94 mL). The mixture was stirred for another 60 min and layers separated. The aqueous layer was degassed at 36°C to 40°C and added a solution of calcium chloride dihydrate (12.85 gms dissolved in 100 mL water), cooled the reaction mass to 21°C to 25 °C and maintained for 2 hrs. The precipitated material was filtered and dried to afford 65 gms of rosuvastatin calcium as an amorphous material.
  • rosuvastatin (R)-l -Amino 2-propanol salt 100 gms was converted to amorphous rosuvastatin calcium (60 gms).

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Abstract

La présente invention concerne des procédés pour la préparation de rosuvastatine calcique de formule I et de sels pharmaceutiquement acceptables de celle-ci à l'aide de nouveaux intermédiaires, et une composition pharmaceutique les contenant.
PCT/IB2016/050542 2015-02-03 2016-02-03 Procédé de préparation de rosuvastatine ou de sels pharmaceutiquement acceptables de celle-ci Ceased WO2016125086A1 (fr)

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CN107298675A (zh) * 2017-06-19 2017-10-27 浙江美诺华药物化学有限公司 一种瑞舒伐他汀钙中间体的制备方法
CN109574938A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种瑞舒伐他汀钠的合成方法
CN109574939A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种瑞舒伐他汀钠的制备方法
CN110627736A (zh) * 2019-09-26 2019-12-31 江苏阿尔法药业有限公司 一种1-苯基-5-羟基四氮唑的回收利用方法
CN113754650A (zh) * 2021-08-06 2021-12-07 湖北宇阳药业有限公司 一种瑞舒伐他汀钙中间体的高选择性合成方法
CN116589413A (zh) * 2023-05-17 2023-08-15 杭州新曦科技有限公司 一种制备瑞舒伐他汀钙的方法

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107298675A (zh) * 2017-06-19 2017-10-27 浙江美诺华药物化学有限公司 一种瑞舒伐他汀钙中间体的制备方法
CN107298675B (zh) * 2017-06-19 2020-08-11 浙江美诺华药物化学有限公司 一种瑞舒伐他汀钙中间体的制备方法
CN109574938A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种瑞舒伐他汀钠的合成方法
CN109574939A (zh) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 一种瑞舒伐他汀钠的制备方法
CN109574938B (zh) * 2017-09-28 2022-04-22 安徽省庆云医药股份有限公司 一种瑞舒伐他汀钠的合成方法
CN110627736A (zh) * 2019-09-26 2019-12-31 江苏阿尔法药业有限公司 一种1-苯基-5-羟基四氮唑的回收利用方法
CN113754650A (zh) * 2021-08-06 2021-12-07 湖北宇阳药业有限公司 一种瑞舒伐他汀钙中间体的高选择性合成方法
CN113754650B (zh) * 2021-08-06 2023-10-20 湖北宇阳药业有限公司 一种瑞舒伐他汀钙中间体的高选择性合成方法
CN116589413A (zh) * 2023-05-17 2023-08-15 杭州新曦科技有限公司 一种制备瑞舒伐他汀钙的方法

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