WO2006035286A2 - Procedes pour preparer du sodium de fluvastatine enantiomeriquement pur et nouvelle forme polymorphe de celui-ci - Google Patents

Procedes pour preparer du sodium de fluvastatine enantiomeriquement pur et nouvelle forme polymorphe de celui-ci Download PDF

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Publication number
WO2006035286A2
WO2006035286A2 PCT/IB2005/002843 IB2005002843W WO2006035286A2 WO 2006035286 A2 WO2006035286 A2 WO 2006035286A2 IB 2005002843 W IB2005002843 W IB 2005002843W WO 2006035286 A2 WO2006035286 A2 WO 2006035286A2
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WIPO (PCT)
Prior art keywords
formula
compound
hydrogen
enantiomerically pure
fluvastatin sodium
Prior art date
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PCT/IB2005/002843
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English (en)
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WO2006035286A3 (fr
Inventor
Shantanu De
Vinayak Tripathi
Swargam Sathyanarayana
Yatendra Kumar
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Ranbaxy Laboratories Limited
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Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to EP05791829A priority Critical patent/EP1817027A2/fr
Publication of WO2006035286A2 publication Critical patent/WO2006035286A2/fr
Publication of WO2006035286A3 publication Critical patent/WO2006035286A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • compositions comprising enantiomerically pure fluvastatin sodium.
  • novel polymorphic form of enantiomerically pure fluvastatin sodium is provided.
  • Fluvastatin sodium is the monosodium salt of a racemic mixture of (3R,5S) and (3S,5R) erythro-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]-3,5-dihydroxy-6- heptenoic acid of Formula A.
  • Fluvastatin sodium is a cholesterol lowering agent, which acts through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. It is indicated as an adjunct to diet to reduce elevated total cholesterol (Total-C), LDL-C, TG and Apo B levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type Ha and lib) whose response to dietary restriction of saturated fat and cholesterol and other non-pharmacological measures has not been adequate. It is also indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL cholesterol to target levels. Fluvastatin sodium is the first entirely synthetic HMG-CoA reductase inhibitor, and is in part structurally distinct from the fungal derivatives of this therapeutic class.
  • a process for preparing racemic fluvastatin sodium which involves lyophilization of an aqueous solution of fluvastatin sodium, has been reported. Also previously reported is a process for preparation of enantiomerically pure (3S, 5R) or (3R, 5S) forms of fluvastatin sodium which comprises resolution of racemic fluvastatin sodium by High Performance Liquid Chromatography (HPLC) and by using chiral auxiliaries.
  • HPLC High Performance Liquid Chromatography
  • Figure 1 is an XRD spectrum of Form I of the enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium.
  • Figure 2 is an FTIR spectrum of Form I of the enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium.
  • Enantiomerically pure (3 R, 5 S) is-fluvastatin sodium can now be prepared in excellent yields and in fewer steps by processes which do not utilize toxic reagents, as compared to previously known processes. The processes are easily scalable on commercial scale. Also provided is novel Form I of the enantiomerically pure (3R,5S) fluvastatin sodium. Thus in one aspect, provided are processes for preparing (3R,5S) enantiomer of fluvastatin sodium of Formula I,
  • FORMULA Ic and deprotecting the compound of Formula Ic" to form a diol of Formula Id, and c) converting the diol of Formula Id to enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium of Formula I by contacting the diol of Formula Id with one or more sodium-containing compounds.
  • the processes can include one or more of the following embodiments.
  • the reduction of the compound of Formula Ic or the compound of Formula Ic' in step b)(i) or b)(iii) can be carried out in the presence of one or more reducing agent selected from one or more borohydride.
  • Suitable borohydrides can be selected from sodium borohydride, potassium borohydride, calcium borohydride or mixtures thereof.
  • Ri is hydrogen or a hydroxy protecting group and R 3 is hydrogen or Ci -4 alkyl group.
  • processes for preparing compounds of Formula Ic or compounds of Formula Ic' comprising the steps of: a) reacting an aldehyde of Formula Ia
  • Ri is hydrogen or a hydroxy protecting group
  • R 2 is aryl, aralkyl or alkyl
  • R 3 is hydrogen or C 1-4 alkyl
  • FORMULA Ic 1 In another aspect, provided are processes for preparing enantiomerically pure (3R,5S)- fluvastatin sodium of Formula I,
  • FORMULA I comprising the steps of: a) (i) reducing the compound of Formula Ic, wherein R 1 is hydrogen and R 3 is hydrogen or C 1 -4 alkyl, to form a diol of Formula Id,
  • Form I of enantiomerically pure (3R,5S) fluvastatin sodium can include one or more of the following embodiments.
  • Form I of enantiomerically pure (3R,5S) fluvastatin sodium can exhibit an XRD spectrum having 2 ⁇ values at about: 6.6, 9.9, 11.4, and 30.9.
  • Form I of enantiomerically pure (3R,5S) fluvastatin sodium can also exhibit an XRD pattern having 25 values at about 3.3, 6.6, 8.8, 9.9, 11.4, 13.2, 19.0, 21.9, 29.6 and/or 30.9.
  • Form I of enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium can exhibit an FTIR spectrum as depicted in Figure 2.
  • the Form I of enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium can have a moisture content of below about 5 % w/w.
  • pharmaceutical compositions comprising a therapeutically effective amount of Form I of enantiomerically pure (3R, 5S) fluvastatin sodium and optionally one or more pharmaceutically acceptable diluents or excipients.
  • kits for antagonizing HMG-CoA in mammal which comprises administering to the mammal a therapeutically effective amount of Form I of enantiomerically pure (3R,5S) fluvastatin sodium.
  • FORMULA I The process comprises the steps of: a) reacting an aldehyde of Formula Ia
  • FORMULA Ic and deprotecting the compound of Formula Ic" to form a diol of Formula Id, and converting the diol of Formula Id to enantiomerically pure (3R,5S) enantiomer of fluvastatin sodium of Formula I by contacting the diol of Formula Id with one or more sodium-containing compounds.
  • the aldehyde of Formula Ia can be prepared by previously reported methods (for example, U.S. Patent Nos. 4,739,073 and 5,354,772).
  • the aldehyde of Formula I can be condensed with a /3-hydroxyester of Formula Ib (wherein R 1 can be hydrogen or a hydroxy protecting group, R 2 can be aryl, aralkyl or alkyl, and R 3 can be hydrogen or C M alkyl) to form a compound of Formula Ic.
  • the condensation reaction can be carried out in presence of one or more organic solvents, for example, polar aprotic solvents, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents, acetonitrile, ethers or mixtures thereof.
  • the reaction can be carried out at temperatures between about 40 °C to the reflux temperature of the one or more solvents used.
  • the one or more solvents can be removed, and the product thus obtained can be contacted with one or more antisolvents, for example, cyclohexane, to yield a compound of Formula Ic, wherein Ri and R 3 are as defined earlier.
  • one or more antisolvents for example, cyclohexane
  • the compound of Formula Ic, wherein Ri can be hydrogen and R 3 can be hydrogen or C M alkyl can be reduced to form a diol of Formula Id.
  • the compound of Formula Ic, wherein Ri can be a hydroxy protecting group and R 3 can be hydrogen or Ci -4 alkyl can be deprotected to form a compound of Formula Ic' and the compound of Formula Ic' can then be reduced to form a diol of Formula Id.
  • the compound of Formula Ic wherein Ri can be a hydroxy protecting group and R 3 can be hydrogen or C 1-4 alkyl, can be reduced to form a compound of Formula Ic" and the compound of Formula Ic" can then be deprotected to form a diol of Formula Id.
  • Compounds of Formula Ic (wherein Ri is hydrogen) or Formula Ic' can be reduced using one or more trialkylboranes and optionally one or more metal borohydrides to form compounds of Formula Ic" or compounds Formula Id respectively.
  • Such reduction reactions can also be carried out in presence of one or more organic solvents, for example, one or more C 3-6 ethers (e.g., tetrahydrofuran, 1,4-dioxane, diethylether or mixture thereof), one or more C M alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert- butanol or mixtures thereof), or mixtures thereof.
  • C 3-6 ethers e.g., tetrahydrofuran, 1,4-dioxane, diethylether or mixture thereof
  • C M alcohols e.g., methanol, ethanol, n
  • the reactions can also be carried out at low temperatures, for example, from about -10 to about -80 0 C.
  • Suitable borohydrides include, for example, one or more of sodium borohydride, potassium borohydride, calcium borohydride, or mixtures thereof.
  • Borohydride if used in excess, can be quenched (using, for example one or more lower alcohols, e.g., methanol, ethanol) after completion of the reduction reaction.
  • the reaction mixture can then be basified and extracted with one or more suitable organic solvents (e.g., ethyl acetate, toluene, dichloromethane, dichloroethane, chloroform, hydrocarbons, including lower alkanes and cycloalkanes, such as cyclohexane).
  • suitable organic solvents e.g., ethyl acetate, toluene, dichloromethane, dichloroethane, chloroform, hydrocarbons, including lower alkanes and cycloalkanes, such as cyclohexane.
  • the (3R,5S)-diol of Formula Id can be contacted with one or more sodium-containing compounds, for example, sodium hydroxide, to form enantiomerically pure (3R,5S)- fluvastatin sodium of Formula I.
  • This reaction can also be carried out in presence of one or more organic solvents and water.
  • Suitable organic solvents include, for example, one or more C 1-4 alcohols (e.g., methanol, ethanol, n-propanol, isobutanol, n-butanol, isobutanol, tert- butanol or mixtures thereof).
  • Also provided are processes for preparing compounds of Formula Ic or compounds of Formula Ic' comprising the steps of: a) reacting an aldehyde of Formula Ia with a /3-hydroxyester of Formula Ib to form a condensation product of Formula Ic, wherein Ri is hydrogen or a hydroxy protecting group, R 2 is aryl, aralkyl or alkyl, and R 3 is hydrogen or C M alkyl; and b) optionally deprotecting the compound of Formula Ic, wherein Ri is a hydroxy protecting group, to form a compound of Formula Ic'.
  • processes for preparation of enantiomerically pure (3R,5S)-fluvastatin sodium comprising the steps of: a) (i) reducing the compound of Formula Ic, wherein Ri is hydrogen and R 3 is hydrogen or C M alkyl, to form a diol of Formula Id,
  • Form I of enantiomerically pure (3R,5S) fluvastatin sodium is provided.
  • Form I of enantiomerically pure (3R,5S) fluvastatin sodium can exhibit an XRD spectrum having one or more 2 ⁇ values at about: 6.6, 9.9, 11.4, and/or 30.9.
  • Form I of enantiomerically pure (3R,5S) fluvastatin sodium can also exhibit an XRD spectrum having one or more 20 values at about: 3.3, 6.6, 8.8, 9.9, 11.4, 13.2, 19.0, 21.9, 29.6 and/or 30.9.
  • Form I of enantiomerically pure (3R,5S) fluvastatin sodium can also exhibit an XRD spectrum having one or more 2 ⁇ values at about: 3.3, 6.6, 8.8, 9.9, 11.4, 13.2, 16.3, 16.9, 17.6, 18.1, 19.0, 19.9, 20.5, 20.8, 21.2, 21.9, 22.5, 22.9, 23.2, 23.9, 24.7, 25.0, 25.6, 26.3, 26.8, 27.1, 28.1, 29.2, 29.6, 30.0, 30.9, 31.6, 32.0, 32.5, 33.0, 33.0, 35.5, 35.9, 36.5, 37.1 and/or 37.5.
  • An example of an XRD spectrum of Form I of enantiomerically pure (3R,5S) fluvastatin sodium is depicted in Figure 1.
  • Form I of enantiomerically pure (3R,5S) fluvastatin sodium can also have a moisture content below about 5 % w/w.
  • An example of an FTIR spectrum of Form I of enantiomerically pure (3R,5S) fluvastatin sodium is depicted in Figure 2.
  • pharmaceutical compositions comprising therapeutically effective amounts of Form I of enantiomerically pure (3R, 5S) fluvastatin sodium optionally containing one or more pharmaceutically acceptable diluents or excipients are provided.
  • methods of antagonizing HMG-CoA in mammal which comprises administering to the mammal therapeutically effective amounts of Form I of enantiomerically pure (3R, 5S) fluvastatin sodium are also provided.
  • Powder XRD spectra of the samples can be determined by using a X-Ray Diffractometer manufactured by Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X- Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
  • FT-IR spectra of the samples can be determined by using a Perkin Elmer instrument,
  • the title compound is a compound of Formula Ic, wherein R 1 is tert- butyldimethylsilyl and R 3 is methyl.
  • the title compound is a compound of Formula Ic', wherein R 3 is methyl.
  • the title compound is a compound of Formula Id, wherein R 3 is methyl.
  • the title compound is a compound of Formula I.

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

L'invention concerne des procédés de préparation de sodium de fluvastatine énantiomériquement pur. L'invention concerne également des compositions pharmaceutiques comprenant du sodium de fluvastatine énantiomériquement pur pour servir d'antagoniste à HMG-CoA. En outre, l'invention concerne une nouvelle forme polymorphe de sodium de fluvastatine énantiomériquement pur.
PCT/IB2005/002843 2004-09-27 2005-09-26 Procedes pour preparer du sodium de fluvastatine enantiomeriquement pur et nouvelle forme polymorphe de celui-ci WO2006035286A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05791829A EP1817027A2 (fr) 2004-09-27 2005-09-26 Procedes pour preparer du sodium de fluvastatine enantiomeriquement pur et nouvelle forme polymorphe de celui-ci

Applications Claiming Priority (4)

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IN1842DE2004 2004-09-27
IN1842/DEL/2004 2004-09-27
IN1955/DEL/2004 2004-10-11
IN1955DE2004 2004-10-11

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WO2006035286A2 true WO2006035286A2 (fr) 2006-04-06
WO2006035286A3 WO2006035286A3 (fr) 2006-07-06

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5354772A (en) * 1982-11-22 1994-10-11 Sandoz Pharm. Corp. Indole analogs of mevalonolactone and derivatives thereof
WO2003064392A1 (fr) * 2002-01-31 2003-08-07 Novartis Ag Procede de preparation d'inhibiteurs de reductase hmg-coa
WO2003070717A1 (fr) * 2002-02-21 2003-08-28 Novartis Ag Procede de fabrication de derives d'acide mevalonique inhibiteurs de l'hmg-coa reductase
WO2005063728A2 (fr) * 2003-12-24 2005-07-14 Teva Pharmaceutical Industries Ltd. Procede de preparation de statines a rapport syn/anti eleve

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5354772A (en) * 1982-11-22 1994-10-11 Sandoz Pharm. Corp. Indole analogs of mevalonolactone and derivatives thereof
WO2003064392A1 (fr) * 2002-01-31 2003-08-07 Novartis Ag Procede de preparation d'inhibiteurs de reductase hmg-coa
WO2003070717A1 (fr) * 2002-02-21 2003-08-28 Novartis Ag Procede de fabrication de derives d'acide mevalonique inhibiteurs de l'hmg-coa reductase
WO2005063728A2 (fr) * 2003-12-24 2005-07-14 Teva Pharmaceutical Industries Ltd. Procede de preparation de statines a rapport syn/anti eleve

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TEMPKIN O ET AL: "Asymmetric Synthesis of 3,5-Dihydroxy-6(E)-heptenoate-containing HMG-CoA Reductase Inhibitors" TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 53, no. 31, 4 August 1997 (1997-08-04), pages 10659-10670, XP004105948 ISSN: 0040-4020 *

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EP1817027A2 (fr) 2007-08-15
WO2006035286A3 (fr) 2006-07-06

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