WO2006048888A1 - Nouveau procede de preparation du sel de calcium d’atorvastatine amorphe - Google Patents

Nouveau procede de preparation du sel de calcium d’atorvastatine amorphe Download PDF

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Publication number
WO2006048888A1
WO2006048888A1 PCT/IN2004/000338 IN2004000338W WO2006048888A1 WO 2006048888 A1 WO2006048888 A1 WO 2006048888A1 IN 2004000338 W IN2004000338 W IN 2004000338W WO 2006048888 A1 WO2006048888 A1 WO 2006048888A1
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Prior art keywords
atorvastatin calcium
mixture
group
solvent
process according
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Ceased
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PCT/IN2004/000338
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English (en)
Inventor
Sreenivas Rao Bhatraju
Pratima Jain
Rajesh Kumar Thaper
Sushil Kumar Dubey
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Jubilant Organosys Ltd
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Jubilant Organosys Ltd
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Priority to PCT/IN2004/000338 priority Critical patent/WO2006048888A1/fr
Publication of WO2006048888A1 publication Critical patent/WO2006048888A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention in general relates to a process for preparing amorphous form of atorvastatin calcium. More specifically, but without restriction to the particular embodiments hereinafter described in accordance with the best mode of practice, this invention relates to a novel process for the preparation of amorphous atorvastatin calcium employing suitable solvent system.
  • atorvastatin is known to be therapeutically useful compound.
  • Atorvastatin calcium a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease.
  • open dihydroxy carboxylic acid, lactone and various salt forms of atorvastatin have been synthesized.
  • US Patent No. 4,681,893 discloses certain trans-6-[2-(3- or 4-carboxamido substituted- pyrrol-l-yl)alkyl]-4-hydroxy-pyran-2-ones, which includes trans(+)-5-(4- fluorophenyl)-2-( 1 -methylethyl)-N,4-diphenyl- 1 -[2-(tetrahydro-4-hydroxy-6-oxo-2H- pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide, whereas US Patent No.
  • Atorvastatin calcium produced by the processes described in the above-mentioned US patents does not give amorphous form consistently but gives a mixture of crystalline and amorphous forms, which has unsuitable filtration and drying characteristics and are not suitable for large-scale production.
  • Atorvastatin calcium is very slightly water-soluble, and it has been found that in comparison to amorphous form, crystalline forms are less readily soluble and adversely affect the bioavailability of atorvastatin in the body.
  • PCT International Application WO 97/03959 discloses novel crystalline forms of atorvastatin calcium designated as form I, form II and form IV and process for their preparation having more favorable filtration and drying characteristics.
  • PCT application WO 97/03960 and US Patent No. 6,274,740 describe the processes for the preparation of amorphous form, by conversion of the crystalline form of atorvastatin. Process isc ose t ere n comp ses sso v ng atorvastat n crysta ne orm n a non- hydroxylic solvent like tetrahydrofuran or mixtures of tetrahydrofuran and toluene.
  • PCT International Application WO 00/71116 describes the process for the preparation of amorphous atorvastatin, which involves dissolving crystalline form in non- hydroxylated solvent followed by precipitation of amorphous atorvastatin by adding non-polar hydrocarbon solvent. In this case high levels of hydrocarbon are necessary to obtain the desired product.
  • PCT International Application WO 00/71116 describes the process for the preparation of amorphous atorvastatin, which involves dissolving crystalline form in non- hydroxylated solvent followed by precipitation of amorphous atorvastatin by adding non-polar hydrocarbon solvent. In this case high levels of hydrocarbon are necessary to obtain the desired product.
  • PCT International Application WO 00/71116 describes the process for the preparation of amorphous atorvastatin, which involves dissolving crystalline form in non- hydroxylated solvent followed by precipitation of amorphous atorvastatin by adding non-polar hydrocarbon solvent. In this case high levels of hydrocarbon are necessary to obtain the desired product.
  • PCT International Application WO 01/28999 describes the purification of crude amorphous atorvastatin calcium by dissolving qrude amorphous material in a large excess of boiling ethanol or 2-propanol and filtering the hot solution and recovering the material at low temperature.
  • step (a) dissolving atorvastatin calcium in an organic solvent selected from the group comprising 1,4-dioxane, acetonitrile, toluene, anisole and t- butanol or a mixture thereof; (b) adding an anti-solvent into the solution prepared in step (a) selected from the group comprising cyclohexane, n-hexane, w-heptane, methyl t- butyl ether and methanol or a mixture thereof to get the precipitate; and (c) separating the resultant precipitate to obtain the amorphous atorvastatin calcium.
  • an organic solvent selected from the group comprising 1,4-dioxane, acetonitrile, toluene, anisole and t- butanol or a mixture thereof.
  • step (c) adding the aqueous solution of calcium salt to solution prepared in step (a) or optionally in step (b);
  • step (e) adding an anti-solvent to the resultant solution prepared m the step (a) selected from the group comprising cyclohexane, /z-hexane, «-heptane, methyl r-butyl ether and methanol or a mixture thereof to get precipitate; and (f) separating the resultant precipitate to obtain amorphous atorvastatin calcium.
  • step (c) adding the aqueous solution of calcium salt to solution prepared in step (a) or optionally in step (b) and cooling the same to obtain crude atorvastatin calcium;
  • step (d) dissolving crude atorvastatin calcium obtained after step (c) in an organic solvent selected from the group comprising of 1,4-dioxane, acetonitrile, toluene, anisole and t-butanol or a mixture thereof;
  • step (e) adding anti-solvent to the solution prepared in the step (d) selected from the group comprising of cyclohexane, /j-hexane, «-heptane, methyl t- butyl ether, and methanol or a mixture thereof to obtain the precipitate; and
  • amorphous atorvastatin calcium wherein amorphous atorvastatin is prepared by dissolving atorvastatin calcium in 1,4-dioxane at room temperature to moderate temperature and then slowly adding to the suitable anti-solvent or mixture o suita e anti so vents un er stirring to o ain precipitate, wnicn are filtered and dried under vacuum.
  • amorphous atorvastatin calcium wherein amorphous atorvastatin is prepared by dissolving atorvastatin calcium in a mixture of ?-butanol and methanol at a moderate to high temperature and stirring at the same temperature for a period to obtain precipitate, which are filtered and dried under vacuum.
  • amorphous atorvastatin calcium wherein amorphous atorvastatin is prepared by dissolving atorvastatin calcium in a mixture of acetonitrile and toluene at a moderate to high temperature, concentrated and then slowly added to the solution of ?-butyl methyl ether under stirring to obtain the precipitate, which are filtered and dried under vacuum.
  • amorphous atorvastatin calcium wherein amorphous atorvastatin is prepared by dissolving atorvastatin calcium in a mixture of 1,4-dioxane and anisole at a moderate to high temperature, to which n-hexane is added to obtain the precipitate, which are filtered and dried under vacuum.
  • the disclosed embodiment of the present invention deals with a process for the preparation of amorphous atorvastatin employing suitable solvent system.
  • the process for the preparation of the amorphous atorvastatin calcium using atorvastatin calcium can be in any form and the solvent used herein is specifically an organic solvent selected from 1,4-dioxane, acetonitrile, toluene, anisole and t-butanol alone or in different combinations and the anti-solvent used herein is selected from the group comprising cyclohexane, n-hexane, «-heptane, methyl t-butyl ether or methanol alone or in different combinations.
  • the process for the preparation of the amorphous atorvastatin calcium using a compound of formula (II) comprises dissolving a compound of formula (II) in lower alcohol at room temperature to moderate temperature, adding water and calcium hydroxide solution with stirring at 55-6O 0 C, cooling the reaction mixture, diluting with lower alcohol, filtering the solution to remove unreacted calcium hydroxide, concentrating the filtrate to get viscous residue, further dissolving the residue in dioxane at room temperature to moderate temperature, removing insoluble impurities by filtration, slowly adding the solution to the mixture of cyclohexane and methyl ⁇ -butyl ether to obtain the precipitate, filtering the precipitate and drying under vacuum.
  • the compound of formula (II) used in the process is prepared by the same procedure as mentioned in the prior art.
  • Amorphous atorvastatin calcium is also be obtained by preparing the sodium salt from the compound of formula II and then converted into calcium salt followed by the procedure given above.
  • the process for the preparation of the amorphous atorvastatin calcium using a compound of formula (III) comprises dissolving a compound of formula (III) in lower alcohol at room temperature to moderate temperature and to which water and sodium hydroxide solution is added with stirring. Upon completion of hydrolysis water is added and then solution is washed with ethyl acetate and hexane twice. The solution is diluted with lower alcohol and calcium chloride solution is added to it at 6O 0 C with high agitation. Reaction mixture is cooled and then filtered to get precipitates of crude atorvastatin calcium.
  • Crude atorvastatin calcium is further dissolved in dioxane at room temperature to moderate temperature and insoluble impurities are removed by filtration, and then solution is slowly added to the .mixture of cyclohexane and methyl t-butyl ether to get the precipitate. Precipitate is filtered and dried under vacuum.
  • the compound of formula (III) used in the process is prepared by the same procedure as mentioned in the prior art.
  • Amorphous atorvastatin calcium is also be obtained by preparing the sodium salt from the compound of formula III and then converted into calcium salt followed by the procedure given above.
  • the lower alcohol used in the process is selected from the group comprising methanol, ethanol, isopropyl alcohol etc., preferably, methanol.
  • Atorvastatin calcium (3.0 g) was dissolved in 1,4-dioxane (9.0 ml) by stirring at 45- 50 0 C. The clear solution so obtained was slowly added to a mixture of cyclohexane and methyl r-butyl ether (150 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven for 48 hrs.
  • Example 2 Atorvastatin calcium (5.0 g) was dissolved in 1,4-dioxane (50.0 ml) at 45-50 0 C. The clear solution so obtained was slowly added to cyclohexane (500 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven for 48 hrs.
  • Atorvastatin calcium (1.0 g) was dissolved in 1,4-dioxane (10.0 ml) at 45-50 0 C. The clear solution so obtained was added to «-heptane (100 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven at for 15 hrs.
  • Atorvastatin calcium (1.0 g) was dissolved in 1,4-dioxane (10.0 mil) at 45-50 0 C. The clear solution so obtained was added to methyl t-butyl ether (100 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven for 15 hrs.
  • Atorvastatin calcium (3.0 g) was dissolved in 1,4-dioxane (9.0 ml) at 45-50 0 C. The clear solution so obtained was added to diisopropyl ether (150 ml) to get precipitate. .
  • the precipitated mate ⁇ al was stirred at the same temperature.
  • the product was tiltered under suction and dried under vacuum in oven for 48 hrs.
  • Atorvastatin calcium (1.0 g) was dissolved in a mixture of t-butanol (150 ml) and methanol (40 ml) at 80-85 0 C. After the material was dissolved, the clear solution so obtained was stirred. The recrystallized product was filtered under suction and dried under vacuum in oven for 15 hrs.
  • Atorvastatin Calcium (3.0 g) was dissolved in a mixture of acetonitrile (150 ml) and toluene (150 ml) at 70-75 0 C. After the material was dissolved, the solution was concentrated. This clear concentrated solution so obtained was slowly added to methyl t-butyl ether (150 ml) to get precipitate. The precipitated material was stirred at the same temperature. The product was filtered under suction and dried under vacuum in oven for 48 hrs.
  • Atorvastatin Calcium (0.5 g) was dissolved in a mixture of preheated 1,4-dioxane (5 ml) and anisole (45 ml) at 50-55 0 C. The clear solution was cooled to 25-3O 0 C, and then n-hexane (100 ml) was added. The precipitated material was stirred. Filtered the material and dried under vacuum for 15 hr.
  • Atorvastatin lactone III (5.0 g) was dissolved in 50ml of methanol followed by the addition of water (10ml). NaOH (0.8g) was added with stirring and monitored by HPLC. After the completion of hydrolysis, water (50 ml) was added, and then aqueous layer was washed with 1:1 mixture of ethyl acetate and cyclohexane. CaCl 2 .2H 2 O (0.98 g) in water (50 ml) was slowly added to the reaction mixture at 55-6O 0 C. After complete addition, reaction mixture was cooled and filtered. Material was dried at 50- 55 0 C in vacuum oven to give crude atorvastatin calcium.
  • the above crude atorvastatin calcium was dissolved in dioxane (10.5 ml) at 40-45 0 C. The clear filtrate was then slowly added to a mixture of cyclohexane & methyl t-butyl ether (175 ml) to get precipitate. The precipitated material was stirred at roora ⁇ temperature, then filtered and dried to get amorphous atorvastatin calcium.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L’invention décrit un nouveau procédé de préparation du calcium d’atorvastatine amorphe, qui utilise un système de solvants approprié.
PCT/IN2004/000338 2004-11-01 2004-11-01 Nouveau procede de preparation du sel de calcium d’atorvastatine amorphe Ceased WO2006048888A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/IN2004/000338 WO2006048888A1 (fr) 2004-11-01 2004-11-01 Nouveau procede de preparation du sel de calcium d’atorvastatine amorphe

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PCT/IN2004/000338 WO2006048888A1 (fr) 2004-11-01 2004-11-01 Nouveau procede de preparation du sel de calcium d’atorvastatine amorphe

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2075246A1 (fr) 2007-12-27 2009-07-01 M. J. Institute of Research Procédé de préparation de forme amorphe de sel hémicalcium atorvastanine

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5969156A (en) * 1995-07-17 1999-10-19 Warner-Lambert Company Crystalline [R- (R*,R*)]-2-(4-Dfluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
WO2002083637A1 (fr) * 2001-04-11 2002-10-24 Cadila Healthcare Limited Procede de production d'atorvastatine calcique sous forme amorphe
US6528660B1 (en) * 1999-05-25 2003-03-04 Ranbaxy Laboratories Limited Process for the production of amorphous atorvastatin calcium
US6605728B2 (en) * 1999-12-17 2003-08-12 Warner-Lambert Company Process for producing crystalline atorvastatin calcium
US6613916B2 (en) * 1999-12-10 2003-09-02 Lek Pharmaceuticals D.D. Process for the preparation of amorphous atorvastatin
US6646133B1 (en) * 2000-10-17 2003-11-11 Egis Gyogyszergyar Rt. Process for the preparation of amorphous atorvastatin calcium
US6777552B2 (en) * 2001-08-16 2004-08-17 Teva Pharmaceutical Industries, Ltd. Processes for preparing calcium salt forms of statins

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5969156A (en) * 1995-07-17 1999-10-19 Warner-Lambert Company Crystalline [R- (R*,R*)]-2-(4-Dfluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)- 3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
US6528660B1 (en) * 1999-05-25 2003-03-04 Ranbaxy Laboratories Limited Process for the production of amorphous atorvastatin calcium
US6613916B2 (en) * 1999-12-10 2003-09-02 Lek Pharmaceuticals D.D. Process for the preparation of amorphous atorvastatin
US6605728B2 (en) * 1999-12-17 2003-08-12 Warner-Lambert Company Process for producing crystalline atorvastatin calcium
US6646133B1 (en) * 2000-10-17 2003-11-11 Egis Gyogyszergyar Rt. Process for the preparation of amorphous atorvastatin calcium
WO2002083637A1 (fr) * 2001-04-11 2002-10-24 Cadila Healthcare Limited Procede de production d'atorvastatine calcique sous forme amorphe
US6777552B2 (en) * 2001-08-16 2004-08-17 Teva Pharmaceutical Industries, Ltd. Processes for preparing calcium salt forms of statins

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THOMSON PDR.: "PHYSICIAN'S DESK REFERENCE", 2003, XP008050765 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2075246A1 (fr) 2007-12-27 2009-07-01 M. J. Institute of Research Procédé de préparation de forme amorphe de sel hémicalcium atorvastanine

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