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WO2008129562A2 - Procédé amélioré pour la préparation d'atorvastatine amorphe hémicalcique stable et de ses sels - Google Patents

Procédé amélioré pour la préparation d'atorvastatine amorphe hémicalcique stable et de ses sels Download PDF

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Publication number
WO2008129562A2
WO2008129562A2 PCT/IN2008/000249 IN2008000249W WO2008129562A2 WO 2008129562 A2 WO2008129562 A2 WO 2008129562A2 IN 2008000249 W IN2008000249 W IN 2008000249W WO 2008129562 A2 WO2008129562 A2 WO 2008129562A2
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Prior art keywords
mixture
product
aliphatic
addition
solvent
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PCT/IN2008/000249
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English (en)
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WO2008129562A3 (fr
Inventor
Sanjay Suri
Tapan Kashyap
Madan Pal Tanwar
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Morepen Laboratories Ltd
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Morepen Laboratories Ltd
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Publication of WO2008129562A2 publication Critical patent/WO2008129562A2/fr
Anticipated expiration legal-status Critical
Publication of WO2008129562A3 publication Critical patent/WO2008129562A3/fr
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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

Definitions

  • the present invention relates to an improved process for the preparation of stable amorphous atorvastatin hemi calcium and their salts .It also relates to a stable pure amorphous atorvastatin calcium and a process thereof.
  • Atorvastatin calcium salt of formula (I) chemically hemicalcium salt of [R-(R*,R*)]-2-(4- fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrole-l- heptanoic acid is marketed under the brand name LipitorTM. It has the structure as given below:
  • Atorvastatin hemi calcium salt is a reductase inhibitor of the enzyme 3-hydroxy-3- methylglutarate-coenzyme A (HMG-CoA) and therefore is a useful anti hyperlipoproteinemic agent. It has proven to be a highly effective medicament for the treatment of disorders such as hyperlipidemia and hypercholesterolemia which are the known risk factors for arteriosclerosis and coronary heart disease.
  • US patent 5,273,995 reported the inhibition of the biosynthesis of cholesterol by the R isomer of Atorvastatin hemi calcium salt
  • US patent 5,969,156 discloses novel crystalline forms of Atorvastatin hemi calcium salt of formula (I) and their preparation.
  • a procedure for the conversion of crystalline form to the amorphous form of Atorvastatin hemi calcium salt of formula (I) has been reported in US patent 6,274,740B 1.
  • Atorvastatin hemi calcium salt of formula (I) can be prepared by various methods described in the above mentioned patents but the product obtained is not of high purity.
  • the present invention provides to stable pure amorphous atorvastatin calcium and a process therefore.
  • the invention provides methods for the purification of crude atorvastatin hemi calcium salt and preparation of amorphous Atorvastatin hemi calcium salt of formula (I) using different solvent mixtures in variable ratios in the presence of antioxidant and an amine. It resulted in the increased purity of Atorvastatin hemi calcium salt of formula (I) in amorphous form. This ultimately will result in the better stability of the product.
  • amorphous Atorvastatin hemi calcium salt of formula (I) which comprises, a) hydrolyzing 1,3-dioxane ring of compound of formula (II) by aq. hydrochloric acid in methanol. b) in situ hydrolysis of tert-butyl group with sodium hydroxide to form Atorvastatin sodium salt solution followed by its washing with a mixture of ethyl acetate-hexane. c) addition of a single or a mixture of two or more antioxidants and or optionally in presence of an amine. d) addition of the Atorvastatin sodium salt solution to an aqueous calcium chloride or calcium acetate solution.
  • Fig 1 shows the synthetic route of amorphous Atorvastatin calcium salt of formula (I).
  • the main aspect of this invention is to provide amorphous Atorvastatin calcium salt of high purity i.e. almost impurity free product.
  • amorphous Atorvastatin hemi calcium salt of formula (I) which comprises, a) hydrolyzing 1,3-dioxane ring of compound of formula (II) by aq. hydrochloric acid in methanol. b) in situ hydrolysis of tert-butyl group with sodium hydroxide to form Atorvastatin sodium salt solution followed by its washing with a mixture of ethyl acetate-hexane. c) addition of a single or a mixture of two or more antioxidants and or optionally in presence of an amine. d) addition of the Atorvastatin sodium salt solution to an aqueous calcium chloride or calcium acetate solution.
  • step (i) optionally seeding with amorphous atorvastatin calcium.
  • step (i) optionally seeding with amorphous atorvastatin calcium.
  • step (i) filtering the slurry to get wet cake.
  • step (h) washing of wet cake by stirring in a binary, ternary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant.
  • h) filtering the product and optionally drying under vacuum.
  • i) dissolving the wet product of step (h) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent, j) addition of mass of step (i) to an anti - solvent or addition of an anti-solvent to the mass of step (i).
  • k) filtering and drying the product by conventional methods to afford amorphous
  • the invention provides a purification process for the preparation of stable amorphous Atorvastatin calcium salt of formula (I) which comprises;
  • Atorvastatin calcium of formula (I) by stirring in a binary, ternary or quaternary mixture of aliphatic alcohol, aliphatic ether, aliphatic nitrile, halogenated aliphatic hydrocarbon and water using antioxidant.
  • II. filtering the product and optionally drying under vacuum.
  • III. dissolving the wet product of step (II) in single organic solvent or a mixture of two or more organic solvents followed by addition of antioxidant and optionally concentrating the solution by recovery of solvent.
  • the organic amines used in step (c) are amines like N, N-diisopropylethylamine, tert-butyl amine, triethyl amine, N-methyl glucamine etc.
  • the antioxidant used in step (c), (g), (i), I and III are taken from butylated hydroxyl toluene, butylated hydroxyl anisole, t-butyl hydroquinone, hydroquinone monomethyl ether or some sulphur compounds like l-(merca ⁇ tomethyl) cyclopropane acetic acid, its methyl ester, thiophenol and compounds like chromophore EL etc. It may be pertinent to mention here that employing antioxidant optionally with amine in step (c), (g), & I is new. The use of sulphur compounds as antioxidant in all steps is a new concept.
  • the aliphatic alcohols are selected from Ci -C 4 aliphatic alcohols preferably methanol, ethanol, propanol, butanol or a mixture thereof;
  • the aliphatic ethers are selected from tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, tert-butyl methyl ether or a mixture thereof.
  • Halogenated aliphatic hydrocarbons are selected from methylene chloride, chloroform, carbon tetrachloride or their mixture.
  • the ratio of various solvents in the binary mixture used in step (g) & I is taken as 1-20 : 20-1.
  • the ratio of various solvents in the ternary mixture used in step (g) & I is taken as 1-20: 1-20: 1-20.
  • the ratio of various solvents in the quaternary mixture used in step (g) & I is taken as 1-15: 1-15: 1-15: 1-15.
  • the temperature in step (g) & I for washing of Atorvastatin hemi calcium salt of formula (I) 5 is ranging from O 0 C to 100 0 C.
  • the organic solvents used for dissolution of product in step (i) are selected from aliphatic esters like ethyl acetate, propyl acetate, butyl acetate; aliphatic nitrites like acetonitrile, propionitrile; chlorinated hydrocarbons like methylene chloride, chloroform, carbon tetrachloride or a mixture of two or more above mentioned solvents.
  • the anti-solvent used for crystallization of the final product in step (j) & IV are selected from C4-C8 aliphatic long or branched chain hydrocarbons like butane, pentane, hexane, heptane, octane ; aliphatic ethers like diisopropyl ether, t- butylmethyl ether or a mixture of two or more of these solvents. Water can be used as anti- solvent for the crystallization of final product.
  • the drying temperature of product in step (k) & V is ranging from 2O 0 C to 100 0 C.
  • step (g) & I the washing of crude or impure atorvastatin hemi calcium salt using binary, ternary or quaternary mixtures of organic solvents in step (g) & I resulted in the increase in purity from 98.0% to 99.90% i.e. almost impurity free product is obtained.
  • the solvent is removed at reduced pressure to reduce the volume to one third and a mixture of methanol (l.Oltr) and water (3.01tr) is added and stirred for 30 minutes.
  • a mixture of n-hexane (l.Oltr), ethyl acetate (l.Oltr) is added, stirred for 15 minutes and aq. layer is separated.
  • the pH of aq. layer is adjusted to 8.0-8.5 and stirred for 30 minutes at 40-45 0 C. To this an aq.
  • the concentrated organic layer is added dropwise into precooled diisopropyl ether (2.5ltr) at 10- 15°C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 65g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity : 99.92%; Assay (OAB, HPLC) : 99.80%
  • the concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at
  • the concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 56g atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.80%; Assay (OAB, HPLC): 99.65%
  • Atorvastatin hemi calcium salt (10Og) is added followed by addition of butylated hydroxy anisole (0.5Og) and the reaction mixture is stirred at 40-45 0 C for 2-3hr.
  • the product is filtered and washed with a mixture of ter-butanol - acetonitrile - water (50ml:40ml:175mI).
  • the resulting solid mass is dissolved in methylene chloride (2.0Itr) at 25-35°C and aq. layer is separated and butylated hydroxy anisole (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-42 0 C at atmospheric pressure.
  • the concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 5Og of atorvastatin hemi calcium salt in amorphous form was obtained. HPLC purity: 99.75%; Assay (OAB, HPLC): 99.60%
  • the resulting solid mass is dissolved in a mixture of acetonitrile (0.5ltr) and methylene chloride (2.01tr) at 25-35 0 C and butylated hydroxy anisole (0.50g) is added to the organic layer. Then organic layer is concentrated up to about 800ml. at 40-50 0 C at atmospheric pressure. The concentrated organic layer is added dropwise into precooled diisopropyl ether (2.51tr) at 10- 15 0 C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 6Og atorvastatin calcium salt in amorphous form was obtained.
  • the resulting solid mass is dissolved in a mixture of ethylacetate (3.01tr) & methanol (l.Oltr) at 25-35°C and butylated hydroxy anisole (0.5Og) is added to it.
  • organic layer is concentrated up to about 800ml. at 40-50°C at reduced pressure.
  • the concentrated organic layer is added dropwise into precooled n-hexane (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively n-hexane can be added to the concentrated organic layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature.
  • the concentrated organic layer is added dropwise into pre cooled n-heptane (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively n-heptane can be added to the concentrated ethyl acetate layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 50g of atorvastatin hemi calcium salt in amorphous form was obtained.
  • the concentrated organic layer is added dropwise into pre cooled DM water (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively precooled DM water can be added to the concentrated organic layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature. The product is filtered under suction and material is dried at 40-50 0 C in a vacuum dryer for 24-48hr and 6Og atorvastatin calcium salt in amorphous form was obtained. HPLC purity: 99.70%; Assay (OAB, HPLC): 99.40%
  • Atorvastatin calcium salt To a mixture of methanol - tetrahydrofuran - water (400ml:500ml:1.751tr) at 40-45 0 C, wet sample of crude Atorvastatin hemi calcium salt (10Og) is added followed by addition of t-butyl hydroquinone (0.50g) and the reaction mixture is stirred at 40-45 0 C for 2-3hr. The product is filtered and washed with a mixture of methanol - tetrahydrofuran - water (40ml:50ml: 175ml).
  • the resulting solid mass is dissolved in a mixture of acetonitrile (0.501tr) and methylene chloride (2.01tr) at 25-35 0 C and the solvent is removed at reduced pressure.
  • the resulting solid is further dried under vacuum at 40-45 0 C for 12-16hr to get the product.
  • the resulting solid mass is dissolved in toluene (2.01tr) at 25-35 0 C and aq. layer is separated and butylated hydroxy anisole (0.50g) is added to the toluene layer.
  • organic layer is concentrated up to about 800ml. at 50-60 0 C at reduced pressure.
  • the concentrated organic layer is added drop wise into pre cooled diisopropyl ether (2.51tr) at 10-15 0 C under stirring in 45minutes (Alternatively diisopropyl ether can be added to the concentrated methylene chloride layer). After the complete addition, the reaction mass is further stirred for 30minutes at same temperature.

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

Abstract

La présente invention porte sur la préparation d'un sel de calcium d'atorvastatine amorphe stable, hautement pure (c'est-à-dire satisfaisant les paramètres de qualité ICH par rapport aux substances apparentées). Ce procédé de préparation comprend les opérations suivantes : (a) hydrolyse d'un noyau 1,3-dioxane de (4R-cis)-1,1-diméthyléthyl-6-[2-[2-(4- fluorophényl)-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)carbonyl]-1lH-pyrrol-1-yl]éthyl]-2,2-diméthyl-1,3-dioxane-4-acétate représenté par la formule (I); (b) hydrolyse in situ du groupe t-butyle pour former la solution de sel de sodium d'atorvastatine; (c) addition d'un seul anti-oxydant ou d'un mélange de deux anti-oxydants ou davantage et éventuellement d'une amine; (d) addition de solution de sel de sodium d'atorvastatine à une solution aqueuse d'acétate de calcium ou de chlorure de calcium; (e) ensemencement facultatif par de l'atorvastatine amorphe calcique; (f) filtration et lavage du gâteau obtenu à l'aide de différents mélanges solvants en présence d'anti-oxydants; (g) dissolution du gâteau précité dans un solvant ou un mélange de deux solvants organiques ou davantage en faisant suivre par une cristallisation du produit à l'aide d'un anti-solvant.
PCT/IN2008/000249 2007-04-20 2008-04-17 Procédé amélioré pour la préparation d'atorvastatine amorphe hémicalcique stable et de ses sels Ceased WO2008129562A2 (fr)

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IN870DE2007 2007-04-20
IN870/DEL/2007 2007-04-20

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WO2008129562A2 true WO2008129562A2 (fr) 2008-10-30
WO2008129562A3 WO2008129562A3 (fr) 2009-12-30

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131605A1 (fr) 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production d'atorvastatine à faible teneur en impuretés éthers
WO2011131601A1 (fr) 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production d'atorvastatine à faible teneur en impuretés lactones
WO2012034958A1 (fr) 2010-09-16 2012-03-22 Dsm Sinochem Pharmaceuticals Netherlands B.V. Esters d'acides hexanoïques comme intermédiaires pour la préparation d'atorvastatine
CN109142586A (zh) * 2018-10-09 2019-01-04 河南师范大学 一种液相色谱法测定阿托伐他汀钙中间体ats-9及其杂质b含量的方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL156055A0 (en) * 2000-11-30 2003-12-23 Teva Pharma Novel crystal forms of atorvastatin hemi calcium and processes for their preparation as well as novel processes for preparing other forms
EP1572638A4 (fr) * 2001-08-31 2010-05-05 Morepen Lab Ltd Procede ameliore de preparation d'un sel d'atorvastatine calcique amorphe (2:1)
US7655692B2 (en) * 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131605A1 (fr) 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production d'atorvastatine à faible teneur en impuretés éthers
WO2011131601A1 (fr) 2010-04-19 2011-10-27 Dsm Ip Assets B.V. Production d'atorvastatine à faible teneur en impuretés lactones
CN103108863A (zh) * 2010-04-19 2013-05-15 中化帝斯曼制药有限公司荷兰公司 低醚杂质的阿托伐他汀的制备
CN103108863B (zh) * 2010-04-19 2015-08-19 中化帝斯曼制药有限公司荷兰公司 低醚杂质的阿托伐他汀的制备
WO2012034958A1 (fr) 2010-09-16 2012-03-22 Dsm Sinochem Pharmaceuticals Netherlands B.V. Esters d'acides hexanoïques comme intermédiaires pour la préparation d'atorvastatine
CN109142586A (zh) * 2018-10-09 2019-01-04 河南师范大学 一种液相色谱法测定阿托伐他汀钙中间体ats-9及其杂质b含量的方法

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