WO2005033078A1 - Procede de production d'atorvastatine calcique - Google Patents

Procede de production d'atorvastatine calcique Download PDF

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Publication number
WO2005033078A1
WO2005033078A1 PCT/IN2003/000328 IN0300328W WO2005033078A1 WO 2005033078 A1 WO2005033078 A1 WO 2005033078A1 IN 0300328 W IN0300328 W IN 0300328W WO 2005033078 A1 WO2005033078 A1 WO 2005033078A1
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WO
WIPO (PCT)
Prior art keywords
formula
phenyl
compound
solvent
reaction
Prior art date
Application number
PCT/IN2003/000328
Other languages
English (en)
Inventor
Joy Mathew
Madhavan Sridharan
Sambasivam Ganesh
Tom Thomas Puthiaparampil
Original Assignee
Biocon Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biocon Limited filed Critical Biocon Limited
Priority to US10/483,484 priority Critical patent/US7361772B2/en
Priority to PCT/IN2003/000328 priority patent/WO2005033078A1/fr
Priority to AU2003272082A priority patent/AU2003272082A1/en
Publication of WO2005033078A1 publication Critical patent/WO2005033078A1/fr

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Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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 a novel process for the production of atorvastatin calcium.
  • the present invention relates to a novel process for the production of amorphous atorvastatin calcium from (6- ⁇ 2-[2-(4-Fluoro-phenyl)-5- isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-l-yl]-ethyl ⁇ -2- phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester.
  • Atorvastatin calcium is known by synonyms like [R- (R*, R*)]-2-(4-fluorophenyl)- ⁇ , 6- dihydroxy-5- (l-methylethyl)-3- phenyl-4- [(phenylamino) carbonyy-lh-pyrrole-1-heptanoic acid hemicalcium salt; ( ⁇ R, ⁇ R)- 2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- / lH-Pyrrole-1- heptanoic acid hemicalcium salt; [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-, l
  • Hemicalcium salt of [R-(R* / R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ - dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, lH-Pyrrole-1-heptanoic acid, 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.
  • WO 97/03958 and WO 97/03959 disclose novel crystalline forms of atorvastatin calcium designated as Form I, Form II, Form III and Form IV and method for their preparation which provide more favorable filtration and drying characteristics.
  • WO 97/03960 and US Patent 6087511 describe the procedures for converting the crystalline form of atorvastatin calcium to the amorphous form. The process disclosed therein involve dissolving form I atorvastatin calcium in a non-hydroxylic solvent like tetrahydrofuran or a mixture of tetrahydrofuran and toluene.
  • WO 00/71116 describes the procedure for converting the crystalline form-I by dissolving it in a non-hydroxylic solvent like tetrahydrofuran and precipitating amorphous atorvastatin calcium by the addition of nonpolar hydrocarbon solvents like, n-hexane, cyclohexane or n-heptane. It is the object of the present invention to provide a novel process for the preparation of atorvastatin calcium, which is unique with respect to its simplicity, cost effectiveness and scalability.
  • the instant invention relates to a novel process of the preparation of atorvastatin calcium.
  • the novel process of instant invention comprises conversion of compound of formula II to atorvastatin calcium (formula I).
  • the novel process of instant invention comprises treating compound of formula II with calcium oxide.
  • the process of instant invention is novel, simple, one step, economic and industrially scalable.
  • the novel process of instant invention has following advantages: 1. De-protection of boronate ester and cleavage of tert-butyl ester and formation of calcium salt is done in one step employing a single reagent. 2. Simple procedure involving inexpensive CaO. 3. Calcium salt is obtained directly without need for making sodium salt or any other intermediates and thereby reducing number of steps.
  • the novel process of instant invention comprises conversion of (6- ⁇ 2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrolidin-l-yl]-ethyl ⁇ -2-phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester to [R-(R*,R*)]-2-(4- fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-, IH-Pyrrole-l-heptanoic acid hemicalcium, its stereoisomers or polymorphic forms, which is simple, one step, economic and industrially scalable.
  • the novel process of instant invention comprises treating (6- ⁇ 2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrrolidin-l-yl]-ethyl ⁇ -2-phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester with calcium oxide in a suitable solvent.
  • the suitable solvent of the instant invention can be selected from water, water miscible or water immiscible solvent.
  • the solvent system used can be single or mixture of two or more solvents.
  • the water miscible solvent can be selected from one or more among methanol, ethanol, isopropanol, acetone, THF or acetonitrile.
  • the reaction of the instant invention can be carried out at suitable reaction conditions required for satisfactory conversion of the starting material (formula II) to atorvastatin calcium.
  • the reaction of the instant invention can be carried out at a temperature between 25 to 100° C.
  • the reaction of the instant invention is carried out at a temperature between 40 to 70° C.
  • the reaction of the instant invention can be carried out for a time period between 1 to 24 hours.
  • the reaction is carried out for a time period between 5 to 15 hours.
  • the product can be isolated with or without further purification.
  • Example 2 A mixture of (6- ⁇ 2-[2-(4-Fluor.o-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrolidin-l-yl]-ethyl ⁇ -2-phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester (50 g, 0.07 mol), water (2 L), THF (2 L) and calcium oxide (50 g, 0.9 mol) was stirred at 50-60° C for 8 hours. After filtering the reaction mixture, clear filtrate was concentrated to about 1.5 L and washed with methyl tert-butyl ether (500 ml).
  • Example 3 A mixture of (6- ⁇ 2-[2-(4-Fluoro-phenyl)-5-isopropyl-3- phenyl-4-phenylcarbamoyl-pyrrolidin-l-yl]-ethyl ⁇ -2-phenyl- [1,3,2] dioxaborinan-4-yl)-acetic acid tert-butyl ester (100 g, 0.14 mol), water (3.0 L), acetonitrile (3.0 L) and calcium oxide (75 g, 1.35 mol) was stirred at 50-60° C for 12 hours.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de production d'un sel hémicalcium phénylamide d'acide 5-(4-fluoro-phényl)-2-isopropyl-4-phényl-1-(3,5,7-trihydroxy-heptyl)-1H-pyrrole-3-carboxylique, de son stéréoisomère ou polymorphe issu d'un tert-butyle ester d'acide (6-{2-[2-(4-fluoro-phényl)-5-isopropyl-3-phényl-4-phénylcarbamoyl-pyrrolidine-1-yl]-éthyl}-2-phényl-[1,3,2]dioxaborinan-4-yl)-acétique.
PCT/IN2003/000328 2001-08-16 2003-10-07 Procede de production d'atorvastatine calcique WO2005033078A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US10/483,484 US7361772B2 (en) 2001-08-16 2003-10-07 Process for the production of atorvastatin calcium
PCT/IN2003/000328 WO2005033078A1 (fr) 2003-10-07 2003-10-07 Procede de production d'atorvastatine calcique
AU2003272082A AU2003272082A1 (en) 2003-10-07 2003-10-07 Process for the production of atorvastatin calcium

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000328 WO2005033078A1 (fr) 2003-10-07 2003-10-07 Procede de production d'atorvastatine calcique

Publications (1)

Publication Number Publication Date
WO2005033078A1 true WO2005033078A1 (fr) 2005-04-14

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000328 WO2005033078A1 (fr) 2001-08-16 2003-10-07 Procede de production d'atorvastatine calcique

Country Status (2)

Country Link
AU (1) AU2003272082A1 (fr)
WO (1) WO2005033078A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1784389A1 (fr) * 2004-08-27 2007-05-16 Biocon Limited Processus pour calcium d'atorvastatine amorphe

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5273995A (en) * 1989-07-21 1993-12-28 Warner-Lambert Company [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
WO2002059087A1 (fr) * 2001-01-23 2002-08-01 Lek Pharmaceutical And Chemical Company D.D. Preparation de calcium d'atorvastatine non cristallin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5273995A (en) * 1989-07-21 1993-12-28 Warner-Lambert Company [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof
WO2002059087A1 (fr) * 2001-01-23 2002-08-01 Lek Pharmaceutical And Chemical Company D.D. Preparation de calcium d'atorvastatine non cristallin

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1784389A1 (fr) * 2004-08-27 2007-05-16 Biocon Limited Processus pour calcium d'atorvastatine amorphe
EP1784389A4 (fr) * 2004-08-27 2009-03-25 Biocon Ltd Processus pour calcium d'atorvastatine amorphe

Also Published As

Publication number Publication date
AU2003272082A1 (en) 2005-04-21

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