WO2015037018A1 - Procédé de préparation de rosuvastatine par le biais de nouveaux intermédiaires - Google Patents

Procédé de préparation de rosuvastatine par le biais de nouveaux intermédiaires Download PDF

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WO2015037018A1
WO2015037018A1 PCT/IN2014/000591 IN2014000591W WO2015037018A1 WO 2015037018 A1 WO2015037018 A1 WO 2015037018A1 IN 2014000591 W IN2014000591 W IN 2014000591W WO 2015037018 A1 WO2015037018 A1 WO 2015037018A1
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formula
compound
acid
rosuvastatin
solvent
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PCT/IN2014/000591
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English (en)
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Rajesh Vinodrai Naik
Anshul Kumar Jain
Gurdeep Singh Sarin
Vinay Kumar SAINI
Vijay Kumar
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Ind-Swift Laboratories Limited
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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

  • Rosuvastatin represented by formula I is a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG- Co A) reductase inhibitor from the class of statin drugs.
  • HMG- Co A 3-hydroxy-3-methyl-glutaryl coenzyme A
  • Rosuvastatin was marketed under trade name as Crestor having rosuvastatin calcium of formula la as active ingredient which is chemically known as bis
  • statins specifically rosuvastatin and its salts
  • novel intermediates which can address the problems being encountered during scale up for achieving purity and meeting cost concerns. Therefore, the present invention intends to provide an easy to scale up and cost effective process which is found to be more convenient to use, provides product in a better yield, reduces the number of steps involved, and ⁇ make use of intermediates which are novel, when compared to previously known processes.
  • Another objective of the present invention is to provide a process for the preparation of pure rosuvastatin or pharmaceutically acceptable salts thereof using novel amide intermediate.
  • Another objective of the present invention is to provide a novel sulfone intermediate and a process for its preparation.
  • Another objective of the present invention is to provide a novel amide intermediate and a
  • the present invention provides a process for preparation of pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof, comprising the steps of; a), condensing substituted pyrimidine intermediate of compound of formula II;
  • Accord present invention provides a process for preparation of
  • the present invention provides a process for preparation of triazolyi su ne intermediate of formula Ila,
  • R is selected from hydrogen, straight or branched chain alkyl group preferably ( i-( I _ ' ⁇ ⁇ ' , comprising the steps of: ⁇
  • R is selected from hydrogen, straight or branched chain alkyl group preferably in the presence of a suitable base in a suitable solvent to obtain triazolyl sulfanylmethyl pyrimidine compound of formula VIII; '
  • the present invention provides a process for preparation of novel amide intermediate of formula III comprising the steps of:
  • the present invention provides a process for preparation of pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof comprising the steps of:
  • the present invention provides a novel triazolyl sulfonylmethyl pyrimidine compound of formula Ila and process for its preparation.
  • the present invention provides a novel amide intermediate of compound of formula III and process for its preparation.
  • the present invention provides a novel triazolyl sulfanylmethyl pyrimidine compound of formula VIII and process for its preparation. According to another embodiment, the present invention provides a novel hydroxy amide compound of formula XI and process for its preparation.
  • Figure-1 represents powder X-ray diifractogram of acetonide protected amide compound of formula IV
  • Figure-2 represents DSC thermogram of acetonide protected amide compound of formula IV DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides an industrially advantageous and cost efficient process for the preparation of pure rosuvastatin of formula I or pharmaceutically acceptable salts thereof.
  • the present invention provides a process for preparation of rosuvastatin or its pharmaceutically acceptable salts via condensation of substituted pyrimidine compound of
  • R is selected from PO(Pb) 2 an( j / v selected from hydrogen, straight or branched chain alkyl group preferably C1-C4.
  • X is selected from halogen.
  • substituted pyrimidine compound of formula II when then substituted pyrimidine compound of general formula II is represented by formula Ila as provided earlier.
  • X is selected from halogen
  • Formula lie The process comprises condensation of triazolyl sulfonylmethyl pyrimidine compound of formula Ila with novel amide intermediate of formula III via Julia-olefinic condensation.
  • condensation of substituted pyrimidine compound of formulae lib and lie with novel amide intermediate of formula III is achieved through Wittig reaction. Therefore condensation of substituted pyrimidine compound of general formula II with novel amide intermediate of formula III forms an inventive part of invention.
  • the suitable base used in condensation reaction can be selected from alkali metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal bicarbonates such as potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, or the like; alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium tertiary butoxide, potassium methoxide, potassium ethoxide, potassium tertiary butoxide, magnesium tertiary butoxide, or the like; amines such- as lithium diisopropylamine, lithium hexamethylpyrimidine or the like; metal disilazides such as sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, or the like, or mixtures thereof.
  • alkali metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate,
  • Organic solvent used for condensation reaction includes but are not limited to polar aprotic solvents, such as acetonitrile, dimethyl sulfoxide, dimethyl acetamide, dimethylformamide or the like; aliphatic ether solvent such as C 3 -C 8 ethers, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,2-dimethylether, 1 ,2-diethylether, hydrocarbons such as benzene, toluene and xylene, or the like, or mixtures thereof.
  • polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethyl acetamide, dimethylformamide or the like
  • aliphatic ether solvent such as C 3 -C 8 ethers, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,2-dimethylether, 1 ,2-diethylether, hydrocarbons such as benzene, toluene and
  • the process involves condensation reaction at a temperature of -30 to 90°C for few minutes to several hours, preferably at -20 to 50°C, more ' preferably from -10 to 10°C for 3-4 hours or till the completion of the reaction.
  • the completion of reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (IXC), high pressure liquid chromatography (HPLG), fast liquid chromatography (FLC), and the like.
  • the reaction mass is quenched with water and the resulting compound can be isolated from the reaction mixture by using suitable techniques known in the art.
  • the resulting acetonide protected amide compound of formula IV can be isolated from the reaction mixture by generation of biphasic system in reaction mixture.
  • the organic layer can be washed with aqueous solution of acid, base or pure water.
  • the solvent at this stage can be selected from water immiscible solvents such as halogenated solvents, aliphatic esters, aliphatic ethers or hydrocarbons or mixtures thereof.
  • solvent can be distilled off under reduced pressure. The resulting solid, thus obtained, can optionally be purified using suitable solvent.
  • the substituted pyrimidine compound of formulae lib and lie can be condensed with amide compound of formula III in presence of a suitable base and solvent at a suitable temperature.
  • the suitable base for use herein include, but are not limited to, alkali metal carbonates, such as sodium carbonate, potassium carbonate, magnesium carbonate and the like; alkali metal hydroxides such as sodium hydroxides, potassium hydroxides, lithium hydroxides and the like and mixtures thereof.
  • the base may be present in the range of greater than 2 mole equivalents per molar equivalent of Wittig reagent and preferably about 2.2 to about 4.5 molar equivalents per equivalent of Wittig reagent.
  • the solvent for the condensation reaction can be selected from an aprotic solvent which includes, but are not limited to, dimethylsulfoxide, dimethylformamide, dimethylacetamide and the like and mixtures thereof.
  • the condensation reaction can be carried out at temperatures in the range of 50-90°C and preferably between 70-85°C.
  • acetonide protected amide compound of formula IV can be isolated from the reaction mixture, by quenching the , reaction mass with water or acid followed by extraction of desired compound using water immiscible solvent, which includes but are not limited to halogenated solvents, aliphatic esters, aliphatic ethers or hydrocarbons or mixtures thereof.
  • reaction mass can be cooled and filtered to remove unreacted base, present in reaction, followed by pH adjustment using acid solution followed by extraction of desired compound in organic layer, then organic solvent can be distilled off under reduced pressure.
  • organic solvent can optionally be purified using suitable solvent such as alcohols, water or mixtures thereof.
  • the amide compound of formula III can be condensed with the substituted pyrimidine compound of formula II, but it is not the limitation of the present invention. Further amide intermediate of formula III can be condensed with any substituted pyrimidine intermediate having facile leaving group.
  • the acetonide protected amide compound of formula IV can be in any form, solid or oil or solvated form or mixtures thereof.
  • the acetonide protected amide compound of formula IV is crystalline in nature and is characterized by PXRD and differential scanning thermogram.
  • the X-ray diffraction patterns, as obtained for the acetonide protected amide compound of formula IV, is represented in Figure 1 and differential scanning thermogram is represented in Figure 2. . '
  • the X-ray diffraction patterns were measured on PAN analytical, X'pert PRO powder diffractrometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu-anode X-ray tube was operated at 40kV and 30mA.
  • the experiments were conducted over the 2 ⁇ range of 2.0°-40.0°.
  • the DSC measurements were carried out on TA Q1000 of ' TA instrument. The experiments were performed at a heating rate of 5 or 10.0°C/min over a temperature range of 50°C to 250°C purging with nitrogen at a flow rate of 50ml/min. .
  • the condensation product, acetonide protected amide compound of formula IV can be hydrolyzed insitu and converted to rosuvastatin or pharmaceutically acceptable salts thereof such as formula la.
  • rosuvastatin acid can be converted into any salt of rosuvastatin i.e., to its lithium, sodium, potassium or calcium or amine salt, by simple adding respective source in a solvent to rosuvastatin acid.
  • the acetonide protected amide compound of formula IV can be deprotected and/or hydrolyzed to . give a dihydroxy amide compound of formula IVa
  • the acidic hydrolysis can be carried out using an inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, or like; organic acid such as methane or ethane sulphonic acid, formic acid, acetic acid, trifluoroacetic acid or like; and/or basic hydrolysis can be carried out using inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, or like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, or like
  • organic acid such as methane or ethane sulphonic acid, formic acid, acetic acid, trifluoroacetic acid or like
  • basic hydrolysis can be carried out using inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, or like.
  • Hydrolysis can be carried out in a suitable solvent for providing the reaction media and can be selected from water or water miscible solvents such as alcohols like methanol, ethanol, isopropyl alcohol, n- butanol, acetonitrile, tetrahydrofuran and the like or mixtures thereof. Usually hydrolysis can be carried out at a temperature of 0°C to 80°C for a period of 30 minutes to 10 hours. In general course of reaction, after the completion of hydrolysis reaction, the resulting dihydroxy amide compound of formula IVa, can be converted to rosuvastatin of formula I or its salts under the basic hydrolysis conditions, which can be optionally isolated.
  • a suitable solvent for providing the reaction media can be selected from water or water miscible solvents such as alcohols like methanol, ethanol, isopropyl alcohol, n- butanol, acetonitrile, tetrahydrofuran and the like or mixtures thereof.
  • Usually hydrolysis can be carried out at
  • the hydrolysis of dihydroxy amide compound can be carried out using a suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, tetraalkylammonium hydroxides including tetrabutylammonium hydroxide, or like and/or mixtures thereof.
  • a suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, tetraalkylammonium hydroxides including tetrabutylammonium hydroxide, or like and/or mixtures thereof.
  • the hydrolysis of dihydroxy amide compound of formula IVa can be carried out using potassium hydroxide along with tetrabutylammonium hydroxide.
  • the suitable solvent for hydrolysis, of dihydroxy amide compound can be selected from water, alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol, acetonitrile, tetrahydrofuran and the like or mixtures thereof.
  • hydrolysis can be carried out at a temperature of 0°C to 80°C for a period of 2 hour to 30 hours.
  • the resulting compound alone or as a mixture with lactone of formula XII is converted to pharmaceutically acceptable salts, preferably calcium salt using calcium chloride, calcium hydroxides or calcium acetate or the like.
  • compound of formula I can be converted into an amine salt by reacting it with an corresponding organic amine in a solvent.
  • the amine for formation of amine salts is selected from primary amines, secondary amines or tertiary amines or cyclic amines or the like.
  • the primary amine employed for salt formation in the present invention can be a specific isomer of l-(l-naphthyl)ethyl amine or mixture of isomers such as ( ⁇ )-l-(l-naphthyl)ethylamine, (R)-(+)- l -(l-naphthyl)ethylamine, (S)-(-)-l -(l- naphthyl)ethylamine or a mixture thereof.
  • Suitable solvent employed during salt formation can be selected from aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate; aliphatic nitriles such as acetonitrile, propionitrile; aliphatic or aromatic hydrocarbons such as toluene, 1 ,2-xylene, 1,4-xylene, n-hexane, n-heptane, cyclohexane; aliphatic ethers such as diethyl ethers, methyl tertiary butyl ethers, tetrahydrofuran, 2-methyl tetrahydrofuran,l ,2- dimethyl ether, 1,2-diethyl ether and the like or mixtures thereof.
  • aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate
  • aliphatic nitriles such as acetonitrile, propionit
  • the amine salt of rosuvastatin can be isolated from reaction mixture or can be in situ converted to rosuvastatin or pharmaceutically acceptable salts thereof of formula la by methods known in the prior art.
  • rosuvastatin amine salt can be isolated from reaction mixture by lowering reaction temperature or by adding an antisolvent to precipitate the desired compound.
  • the suitable antisolvent can be selected from aliphatic or aromatic hydrocarbon such as n-heptane, n-hexane, cyclohexane, toluene and the like or mixture thereof.
  • Resulting product can be isolated by suitable techniques such as filtration, centrifugation and the like.
  • Rosuvastatin l-(l-naphthyl)ethylamine salt of formula V can be optionally purified to enhance the purity and remove impurities so that final product of high purity can be obtained.
  • the suitable solvent for purification can be selected from ester such as ethyl acetate, methyl acetate; nitriles such as acetonitrile; aromatic solvent such as toluene; aliphatic hydrocarbon such as heptane and the like or mixtures thereof.
  • Rosuvastatin l-(l-naphthyl)ethylamine salts thus prepared can be further converted in to pure rosuvastatin or pharmaceutically acceptable salts thereof by neutralization using a suitable acid at a temperature of 0°C to 80°C for 10 minutes to 10 hours, preferably till the completion of the reaction.
  • Suitable acid employed for neutralization include organic acids such as formic acid, acetic acid, propionic acid, butyric acid and the like; and inorganic acids such as hydrochloric , acid, hydrobromic acid, phosphoric acid and the like.
  • Neutralization can be carried out in a suitable solvent for providing the reaction medium.
  • Suitable solvents includes water or water immiscible organic solvents which can be selected from but are not limited to aliphatic esters such as methyl acetate, ethyl acetate, propyl acetate; aliphatic ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether; hydrocarbon solvents such as toluene, 1 ,2- or 1 ,4-. xylene; halogenated solvents such as dichloromethane, chloroform, 1,2-dichloroefhane and the like or mixture thereof.
  • neutralization reaction can be carried out at a temperature of 10°C to 15°C for 10 minutes to 3 hours.
  • pure rosuvastatin can be isolated from the reaction mixture or can be in situ proceeded for the conversion to rosuvastatin or pharmaceutically acceptable salts thereof.
  • biphasic reaction mixture can be separated and organic layer can be optionally charcoalised, washed with water, and/or dried over suitable drying agent such as sodium sulfate.
  • Rosuvastatin can be isolated from the resulting organic layer by suitable techniques or organic layer can be used as such for the further conversion to pharmaceutically acceptable salts of rosuvastatin.
  • rosuvastatin of formula I or pharmaceutically acceptable salts of formula la, as obtained by above process has purity of more than 99.76% when analyzed by HPLC with 'Z' isomer at a level of less than 0.15%.
  • substituted pyrimidine compound of formula II and amide compound of formula III are also prepared in an inventive manner.
  • substituted pyrimidine compound of formula Ila is a novel compound and is prepared using the process of present invention
  • the compound of formula lib and lie, used as Wittig reagents in the present reaction can be prepared by methods known in the prior art or can be procured from available commercial source or can be prepared as described herein.
  • the novel triazolyl sulfonylmethyl pyrimidine compound of formula Ila is prepared by starting from halo methyl pyrimidin methyl- methansulfonamide of compound of formula VI.
  • the halo methyl pyrimidin methyl- methansulfonamide of compound of formula VI can be prepared by methods known in the art or can be procured from available commercial source.
  • halo methyl pyrimidin methyl-methansulfonamide of compound of formula VI can be prepared from hydroxylmethyl pyrimidin methyl-methansulfonamide compounds.
  • halomethyl pyrimidin methyl- methansulfonamide of compound of formula VI is prepared by halogenating the hydroxylmethyl pyrimidin methyl-methansulfonamide compounds namely N-[4-(4-fluoro- phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide with respective halogenating agent in a suitable solvent.
  • the N-[5-chloromethyl-4-(4- fluoro-phenyl)-6-isopropyl-pyrimidine-2-yl]-N-methyl-methanesulfonamide can be prepared by chlorinating the N-[4-(4-fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N- methyl-methanesulfonamide with methanesulfonyl chloride in presence of a suitable base and solvent.
  • N-[5-bromo methyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidine-2-yl]-N- methyl-methane sulfonamide can be prepared by brominating N-[4-(4-fluoro-phenyl)-5- hydroxymethyl-6r-isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide with phosphorous tribromide in presence of a suitable solvent.
  • the reaction can be carried ' out in halogenated solvents such as chloroform, carbon tetrachloride; aliphatic nitrile such as acetonitrile or hydrocarbon solvent.
  • halo methyl pyrimidin methyl-methansulfonamide of compound of formula VI can be condensed with triazolyl thiol compound of. formula VII in the presence of a base to obtain triazolyl sulfanylmethyl pyrimidine compound of formula VIII.
  • the triazolyl thiol compound of formula VII can be prepared by methods known in the prior art or can be procured from available commercial source.
  • the suitable base used in condensation reaction is preferably selected from organic or inorganic bases.
  • the organic base can be selected from trimethylamine, triethylamine, tributylamine, isopropylethylamine, pyridine, 8-diazabicyclo [5.4.0]undec-7-ene, 4-NiN-dimethylamino pyridine, or the like;
  • inorganic base is selected from metal hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such as lithium carbonate, cesium carbonate, sodium carbonate, potassium carbonate; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate or the like or mixtures thereof.
  • the solvent used for the condensation can be selected from halogenated solvents such as dichloromethane, chloroform, carbon , tetrachloride, or the like; aliphatic ketones such as acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone, or the like; aliphatic esters such as ethyl acetate, methyl acetate, tertiary butyl acetate, or the like; aliphatic nitriles such as acetonitrile, propionitrile or the like; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxy ether, 1 ,2-diethoxy ether, 1 ,4-dioxane, diethyl ether, isopropyl ether, methyl tertiary butyl ether or the like; aprotic polar organic solvents such as dimethyl formamide,
  • the suitable reaction temperature for condensation reaction can be selected from 0 to 50°C and maintained at this temperature for 30 minutes to 6 hours preferably the reaction mixture can be stirred over a period of 2 to 4 hours, more preferably till completion of the reaction.
  • the completion of reaction can be monitored by any one of chromatographic techniques such TLC, HPLC, FLC, and the like.
  • the compound of formula VIII can be isolated from the reaction mixture using any conventional method known in the art.
  • the obtained triazolyl sulfanylmethyl pyrimidine compound of formula VIII can be isolated from the reaction mixture by generation of biphasic system in reaction mixture. After layer separation, the organic layer can be washed with water or sodium chloride solution. Optionally, the solvent is distilled off under reduced pressure.
  • the solvent at this stage can be selected from any water immiscible solvent, such as . those described for the preparation of compound of formula II. Accordingly, the triazolyl sulfanylmethyl pyrimidine compound of formula VIII is considered as a novel compound of present invention and can be in any form such'as crystalline or amorphous or mixtures thereof.
  • triazolyl sulfanylmethyl pyrimidine compound of formula VIII is oxidized using an oxidizing agent under suitable reaction conditions.
  • the oxidizing agent can be selected from permanganates such as potassium permanganates or the like; meta-chloroperbenzoic acid; peracetic acid; sodium hypochlorite; hydrogen peroxide; tertiary butyl hydrogen peroxide; cumene hydro peroxide; or oxone in presence of an appropriate catalyst such as ammonium molybdate, ammonium hepta molybdate tetra hydrate, alkali metal tungstate or like or without catalyst in a suitable solvent selected from halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, or the like; aliphatic ketones such as acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone, or the like; aliphatic esters such as ethyl acetate, methyl acetate, tertiary butyl acetate, or the like; alcoholic solvents such as methanol,
  • phase transfer catalysts selected from alkyl ammonium halides such as tetrabutyl ammonium bromide, tetraethyl ammonium chloride, or the like.
  • the suitable reaction temperature for oxidation reaction can be selected from 0 to, 40°C and maintained at this temperature for 30 minutes to 15 hours.
  • the reaction mixture can be stirred over a period of 4 to 12 hours, more preferably till completion of the reaction.
  • the completion of reaction can be monitored by any one of chromatographic techniques as described above.
  • the compound of formula Ila can be isolated from the reaction mixture by using any conventional method known in the art.
  • the obtained triazolyl sulfonylmethyl pyrimidine compound of formula Ila can be isolated from the reaction mixture by generation of biphasic system in reaction mixture. After layer separation, the organic layer can be washed with water or saturated sodium chloride solution. Optionally, solvent is distilled off under reduced pressure.
  • the solvent at this stage can be selected from halogenated solvent or hydrocarbons or mixtures thereof.
  • the resulting solid material can optionally be purified f using solvent selected from the group comprising alcohols, aliphatic esters; aliphatic ketones; aliphatic ethers; halogenated solvents; hydrocarbons; protic or aprotic solvents and mixtures thereof Purification, can be carried out by any method known in the art, such as crystallization, acid base treatment, dissolution and distillation of solvent, dissolution and precipitation by adding anti solvent etc.
  • the crude product is dissolved in solvent, at 30 to 50°C and crystallized or precipitated using the antisolvent, preferably, hydrocarbon such as n-hexane or n-heptane.
  • the antisolvent preferably, hydrocarbon such as n-hexane or n-heptane.
  • the solvent for crystallization is selected from aliphatic esters such as ethyl acetate.
  • the compound can be further purified using hydrocarbon solvent as described above.
  • triazolyl substitued pyrimidine compound of the formula Ila if in triazolyl substitued pyrimidine compound of the formula Ila, R / is hydrogen, then the reaction with a suitable alkylating agent is carried out to prepare triazolyl substitued pyrimidine compound of the formula Ila, wherein R / is alkyl.
  • alkylation is carried out using any alkylating agent such as dimethyl sulfate or methyl iodide or the like in presence of a suitable base selected from . alkali metal hydroxides, in a suitable solvent selected from halogenated solvents to provide an alkylated triazolyl pyrimidine compound of formula Ila.
  • the triazolyl substituted pyrimidine compound of the formula Ila should be considered as novel compound of present invention and can be isolated in any form such as crystalline or amorphous or mixtures thereof.
  • substituited pyrimidine compound of formula lib can be prepared by halogenating the corresponding hydroxymethyl sulfonylmethyl pyrimidine compound using a suitable halogenating agent in a suitable solvent at suitable temperature.
  • the suitable halogenating agent can be selected from halogen acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; and inorganic acid halides such as thionyl chloride, sulfur tetrafluoride, phosphorous trichloride, phosphorous pentachloride, phosphorous tribromide, phosphoryl chloride.
  • the suitable solvent can be selected from chloroform, dichloromethane, chlorobenzene, dichlorobenzene or like. Particularly for the purpose of present invention hydroxymethyl sulfonylmethyl pyrimidine compound can be brominated using phosphorous tribromide at a temperature -2 to 25°C for 10-60 minutes in dichloromethane.
  • bromomethyl sulfonylmethyl pyrimidine compound can be isolated from the reaction mixture or can be converted insitu to substituited pyrimidine compound of formula lib.
  • the isolation of bromomethyl sulfonylmethyl pyrimidine compound can be affected by generation of biphasic system in reaction mixture. After layer separation, the organic layer can be washed with acid, base or brine solution.
  • the solvent at this stage can be selected from water immiscible solvent such. as halogenated solvent, aliphatic ester or aliphatic ether or hydrocarbon or mixtures thereof.
  • solvent can be distilled off under reduced pressure and the resulting solid, thus obtained, can optionally be purified using suitable solvent.
  • the bromomethyl sulfonylmethyl pyrimidine compounds further converted to substituited pyrimidine compound of formula lib by reacting the bromomethyl sulfonylmethyl pyrimidine compound with a suitable phosphorous derivative, preferably triphenylphosphine in a suitable solvent at suitable temperature.
  • a suitable phosphorous derivative preferably triphenylphosphine
  • the suitable solvent can be selected from hydrocarbons such as toluene; aliphatic ketones such as acetone, diethyl ketone, ethyl methyl ketone or halogenated solvent such as dichloromethane, chloroform.
  • the reaction with phosphorous derivative can be generally carried out at a temperature 20-100°C in time ranging from 10 minutes to 2 hours. After completion of reaction, the reaction product is filtered and washed with a suitable hydrocarbon solvent.
  • the amide compound of formula III can be prepared by first hydrolyzing the compound of formula IX in a suitable solvent to obtain the hydroxy compound of formula X or salt thereof, preferably the hydroxy compound of formula X is prepared in its salt form.
  • the hydrolysis can be carried out in presence of alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, Jithium carbonate and cesium carbonate preferably sodium hydroxide.
  • the solvent for the hydrolysis reaction can be selected from alcohols such as C 1-C3 alcohols; alkyl nitriles such as acetonitrile, propionitrile, ethers such as tetrahydrofuran, 2-methyl hydrocarbon, 1 ,2-dimethoxyether, 1 ,2-diethyl ether; aliphatic ketones such as acetone, diethyl ketone, ethyl methyl ketone or the like or mixtures thereof.
  • alcohols such as C 1-C3 alcohols
  • alkyl nitriles such as acetonitrile, propionitrile
  • ethers such as tetrahydrofuran, 2-methyl hydrocarbon, 1 ,2-dimethoxyether, 1 ,2-diethyl ether
  • aliphatic ketones such as acetone, diethyl ketone, ethyl methyl ketone or the like or mixtures thereof.
  • the hydroxy compound of formula X or salt thereof can be condensed with a-methyl benzyl amine in presence of suitable coupling reagent and solvent at 0-40°C for 1-5 hours preferably till completion of reaction to give the hydroxy amide compound of formula XI.
  • suitable coupling agent conventionally used for amide synthesis are selected from N.JV'-dicyclo hexylcarbodiimide, N,N'-diisopropylcarbodiimide, N.jV'-carbonyldiimidazole and car bony 1-di - (1 ,2,4-triazole).
  • a catalytic auxiliary nucleophiles such as 1- hydroxybenzotriazole, 1 -hydroxy-7-aza-benzotriazole, ethyl 2-cyano-2-(hydroxyimino) acetate, (benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate, benzotriazole- 1 -yl- oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate, N-hydroxysuccinimide and N- hydroxy-5-norbene-endo-2,3-dicarboxamide and a like can also be used.
  • a catalytic auxiliary nucleophiles such as 1- hydroxybenzotriazole, 1 -hydroxy-7-aza-benzotriazole, ethyl 2-cyano-2-(hydroxyimino) acetate, (benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexa
  • the reaction can be carried out in suitable solvent selected from class of alcohols; halogenated solvents; ethers; aliphatic ketones; alkyl nitriles and the like or mixtures thereof.
  • Amide formation is carried out using a-methyl benzylamine, however another isomer or mixture of two can be used for the reaction, particularly R-(+)-a-methyl benzylamine is used.
  • the hydroxy amide compound of formula XI forms a novel part of invention.
  • the product can be isolated from the reaction mixture by employing any suitable techniques known in the art or used as such for further oxidation reaction.
  • intermediate of formula XI can be isolated from the reaction mixture by adding water to the reaction mixture followed by extraction with a suitable solvent: Suitable solvent used for the extraction can be any water immiscible solvent selected from esters; halogenated solvents; aliphatic or aromatic hydrocarbons, and the like or mixture thereof.
  • the resulting solution can be optionally washed with an aqueous solution of acid/base/water and/or brine.
  • Hydroxy amide compound of formula XI can be recovered from the resulting solution by removal of solvent using suitable techniques, preferably by evaporation, or distillation.
  • the hydroxy amide compound of formula XI can be optionally purified prior to oxidation reaction to enhance the purity of compound and/or remove impurities present in the product.
  • the hydroxy amide compound of formula XI can be purified using a suitable solvent such as isopropyl ether to get the purity greater than 98.50%. Any suitable purification method can be employed for purification, as described above for- purification.
  • hydroxy amide compound of formula XI is then converted to amide compound of formula III, via oxidation.
  • the hydroxy amide compound of formula XI is oxidized in a suitable solvent with sodium hypochlorite in the presence of sodium bicarbonate, sodium bromide or potassium bromide and a catalytic amount of (2,2,6,6-tetramethylpiperidin-l-yl)oxy (TEMPO) for a suitable period of time and temperature.
  • TEMPO (2,2,6,6-tetramethylpiperidin-l-yl)oxy
  • any oxidizing reagent described in literature, can be used to convert the alcohol group to aldehyde group.
  • the hydroxy ester compound of formula IX can be prepared by methods known in the prior art or procured from commercial source.
  • isolated final produc of formula I as well as its intermediates described herein, in the present invention may be optionally purified to enhance the purity of the product.
  • Any suitable purification procedure such as, for example, crystallization, derivatization, slurry wash, salt preparation, various chromatographic techniques, solvent-anti-solvent system or combination of these procedures, may be employed to get the purified material.
  • other equivalent procedures such as acid-base treatment could, also be used, to purify the intermediates as well as final product.
  • the solvents used for the purification of final compound and intermediates of the present invention may be selected depending upon the nature of the compound to be purified, however the solvent can be chosen amongst water, Ci -6 alcohols, aliphatic C 3-6 ketones, aliphatic or aromatic hydrocarbons, C 2- io esters, C 3-6 ethers, Ci -3 alkyl nitrile, halogenated solvents, polar aprotic , solvents such as NN-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methyl pyrrolidinone, sulfolane and the like or mixtures thereof in suitable proportion.
  • the term "conventional methods for the isolation of intermediates as well as final product” may be varied depending upon the nature of the reactions, nature of product of the reaction, medium of the reaction and the like.
  • the suitable conventional methods can be selected . amongst but not limited to distillation of the solvent, addition of water to the reaction mixture followed by extraction with water immiscible solvents, removal of the insoluble particles from the reaction mixture, if present, by filtration or centrifugation or by decantation, addition of water immiscible organic solvent, . addition of a solvent to the reaction mixture which precipitate the product, neutralizing the reaction mixture with a suitable acid or base whichever is applicable.
  • the main advantage of the present invention is that it provide an industrially advantageous and cost efficient process for preparation of rosuvastatin or pharmaceutically acceptable salts thereof and provides product with high trans regioisomer contents through use of novel ' compounds of formulae II and III.
  • the process of present invention is cost effective, reproducible as well as industrially advantageous and employs very mild reaction conditions.
  • Method B 6-Hydroxymethyl-2,2-dimethyl-[l ,3]dioxan-4-yl)-acetic acid tert-butyl ester (420g) was hydrolyzed with sodium hydroxide (160g) in methanol (2.44L) at 20-25°C for 10- 12 hours. After completion of reaction, the solvent was distilled off completely to obtain a residue which was. dissolved in dichloromethane (3.28L) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (462g) and 4-hydroxybenzotrizole (262g) were added successively.
  • Method B 2-(6-Hydroxymethyl-2,2-dimethyl-[l,3]dioxan-4-yl)-N-(l -phenyl-ethyl)-acetamide (300. Og) was dissolved in dichloromethane (4.5L) and cooled to -10°C, 2,2,6,6- tetramethyIpiperidin-l-yl)oxy (7.80g) and potassium bromide (87g) were added followed by addition of sodium bicarbonate (123g). Thereafter, sodium hypochlorite (8-10%, 972ml) was added slowly at -lO ⁇ C.
  • Method B To a ' mixture of 4-methyl-4H-[l,2,4]triazole-3-thiol (1.52g) in ethyl acetate (50ml), potassium carbonate (8g) was added and stirred for 60 minutes at 25°C to 30°C. N-[5- Chloromethyl-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methyl-methane sulfonamide (5g) was added and temperature was raised to 30 to 35°C and stirred for . 12 hours. After completion of reaction, the reaction mass was quenched, with chilled water (50ml). The organic layer was separated and aqueous layer was extracted with ethyl acetate.
  • Method B [[4-(4-Fluorophenyl)-6-(l-methylethyl)-2-[N-methyl-N-methylsulfonyl)amino]-5- pyrimidinyl]methyl]triphenylphosphonium bromide (512.4g) and 2-(6-formyl-2,2-dimethyl- [l,3]dioxan-4-yl)-N-(l -phenyl-ethyl)-acetamide (210g) were dissolved in dimethyl sulfoxide (2.1L) and potassium carbonate (237.3g) was added. Reaction mass was heated to 80-85°C and stirred for 1 hour.
  • reaction mass was cooled to room temperature, filtered and pH of the reaction mass was adjusted to 4-5 with concentrated hydrochloric acid.
  • Water (2.1L) was added and the product was extracted with toluene (2.31L). Organic layer was washed with 5.0% aqueous .sodium bicarbonate solution (1.05L) and brine (1.05L).
  • Solvent was distilled off completely under vacuum and the product was isolated from aqueous ethanol (2.94L) and then purified from ethanol (1.44L) to obtain 262.5g of title compound having purity 99.71% by HPLC.
  • acetamide (lg) in tetrahydrofuran and methanol aqueous hydrochloric acid (IN) was added slowly and stirred for- 6 hours at 25-30°C. After reaction completion, aqueous sodium hydroxide solution (10%) was added to adjust pH tol2.0- 12.5 and stirred for 1 hour. The reaction mass was filtered and concentrated under vacuum. Methyl-tertiary butyl ether and water were added to the resulting residue and layers were separated. Dilute hydrochloric was added to aqueous layer and desired product was extracted in ethyl acetate. Organic layer x as washed with brine solution. To the resulting organic layer, l-(l-naphthyl) ethylamine was added and stirred for 10- 12 hours. The solid was filtered, washed with ethyl acetate and dried to get the title compound.
  • Method B 2-(6- ⁇ 2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonylmethylamino) pyrimidin-5-yl]vinyl ⁇ -2,2-dimethyl-[l ,3]dioxan-4-yl)-N-(l-phenyl-ethyl)-acetamide (250g) was taken in a mixture of isopropanol (2.5L) and water (250ml). Hydrochloric acid (125ml) was added slowly to the reaction mass and stirred for 30 minutes at 35-40°C.
  • reaction potassium hydroxide (125g) and tetrabutylammonium hydroxide (750ml) were added in reaction mass and stirred for 24 hour at 80-85°C.
  • Isopropanol was distilled out under vacuum and the reaction mass was filtered at 25-30°C and washed with methyl-tertiary butyl ether. pH of the reaction mass was adjusted to 1-2 from hydrochloric acid and product was extracted in methyl-tertiary butyl ether.
  • Organic layer was washed with brine (1.25L) and 1-(1- naphthyl)ethylamine (75. Og) was added and the solvent was distilled out completely.
  • Method B 2-(6- ⁇ 2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(rnethanesulfonyl-methylamino) pyrimidin-5-yl]vinyl ⁇ -2,2-dimethyl-
  • reaction mass was filtered and concentrated under vacuum. Layers were separated using water and methyl-tertiary butyl ether. Aqueous solution of calcium acetate was added in reaction mass and stirred for 1 hour, filtered, washed with water and dried under vacuum to give amorphous rosuvastatin calcium as a white to off-white powder.

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Abstract

Cette invention concerne un procédé industriellement avantageux et rentable de préparation de rosuvastatine de formule I ou de sels pharmaceutiquement acceptables de celle-ci, [Formule I à insérer ici], par le biais de nouveaux intermédiaires de formules II et III. [Formule II à insérer ici], R étant choisi parmi (voir formule), R1 étant choisi parmi un atome d'hydrogène, un groupe alkyle à chaîne droite ou ramifiée, de préférence C1-C4; [Formule III à insérer ici]. Cette invention concerne en outre des procédés nouveaux et efficaces de préparation de composés de formules II et III, et de conversion de ceux-ci en rosuvastatine de formule I ou en sels pharmaceutiques acceptables de celle-ci.
PCT/IN2014/000591 2013-09-14 2014-09-12 Procédé de préparation de rosuvastatine par le biais de nouveaux intermédiaires WO2015037018A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153039A (zh) * 2015-07-17 2015-12-16 江西富祥药业股份有限公司 一种瑞舒伐他汀钙中间体杂质的制备方法
CN106674281A (zh) * 2016-12-31 2017-05-17 安徽美诺华药物化学有限公司 一种瑞舒伐他汀中间体化合物、制备方法及其用途
CN112592336A (zh) * 2021-01-28 2021-04-02 安徽美诺华药物化学有限公司 一种瑞舒伐他汀钙的高级中间体及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000049014A1 (fr) * 1999-02-17 2000-08-24 Astrazeneca Ab Procede de production de tert-butyl (e)-(6-[2- [4-(4-fluorophenyl) -6-isopropyl-2-[ methyl (methylsulfonyl) amino] pyrimidin-5-yl] vinyl](4r, 6s)-2,2-dimethyl [1,3]dioxan-4-yl) acetate
WO2007125547A2 (fr) * 2006-05-03 2007-11-08 Manne Satyanarayana Reddy Nouveau procédé faisant intervenir des statines et leurs sels acceptables sur le plan pharmaceutique
WO2008044243A2 (fr) * 2006-10-09 2008-04-17 Manne Satyanarayana Reddy Nouveau procédé de préparation de statines et leurs sels pharmaceutiquement acceptables

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000049014A1 (fr) * 1999-02-17 2000-08-24 Astrazeneca Ab Procede de production de tert-butyl (e)-(6-[2- [4-(4-fluorophenyl) -6-isopropyl-2-[ methyl (methylsulfonyl) amino] pyrimidin-5-yl] vinyl](4r, 6s)-2,2-dimethyl [1,3]dioxan-4-yl) acetate
WO2007125547A2 (fr) * 2006-05-03 2007-11-08 Manne Satyanarayana Reddy Nouveau procédé faisant intervenir des statines et leurs sels acceptables sur le plan pharmaceutique
WO2008044243A2 (fr) * 2006-10-09 2008-04-17 Manne Satyanarayana Reddy Nouveau procédé de préparation de statines et leurs sels pharmaceutiquement acceptables

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153039A (zh) * 2015-07-17 2015-12-16 江西富祥药业股份有限公司 一种瑞舒伐他汀钙中间体杂质的制备方法
CN105153039B (zh) * 2015-07-17 2018-01-12 江西富祥药业股份有限公司 一种瑞舒伐他汀钙中间体杂质的制备方法
CN106674281A (zh) * 2016-12-31 2017-05-17 安徽美诺华药物化学有限公司 一种瑞舒伐他汀中间体化合物、制备方法及其用途
CN112592336A (zh) * 2021-01-28 2021-04-02 安徽美诺华药物化学有限公司 一种瑞舒伐他汀钙的高级中间体及其制备方法

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