WO2007023503A1 - Procede de preparation de fluvastatine sodique - Google Patents

Procede de preparation de fluvastatine sodique Download PDF

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Publication number
WO2007023503A1
WO2007023503A1 PCT/IN2005/000288 IN2005000288W WO2007023503A1 WO 2007023503 A1 WO2007023503 A1 WO 2007023503A1 IN 2005000288 W IN2005000288 W IN 2005000288W WO 2007023503 A1 WO2007023503 A1 WO 2007023503A1
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WO
WIPO (PCT)
Prior art keywords
formula
solid
oil
iii
organic solvent
Prior art date
Application number
PCT/IN2005/000288
Other languages
English (en)
Inventor
Venkatasubramanian Radhakrishnan Tarur
Dhananjay Govind Sathe
Narayana Rao Mantripargada
Rajesh Bhopalkar
Umesh Sudhakar Mahajan
Original Assignee
Usv 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.)
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Publication date
Application filed by Usv Limited filed Critical Usv Limited
Priority to PCT/IN2005/000288 priority Critical patent/WO2007023503A1/fr
Publication of WO2007023503A1 publication Critical patent/WO2007023503A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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

Definitions

  • This invention relates to a process for the preparation of Fiuvastatin sodium of the formula (I).
  • This invention also relates to key intermediates of Fluvastatin sodium and processes for the preparation thereof.
  • Fluvastatin sodium [( ⁇ )-Erythro-(E)-7-[3'-(4"-Ruorophenyl)-l'-(l"-methylethyl)-lH-indol-2'-yl)- 3,5-dihydroxyhept-6-enoate sodium salt] is a white to pale yellow, hygroscopic powder. It is a water soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase. It is an important indole derivative that is used in the treatment of hyperlipoproteinaemia and arteriosclerosis.
  • HMG-CoA 3-hydroxy-3- methylglutaryl-coenzyme A
  • Fluva keto alcohol is further reacted with triethylborane / THF and sodium borohydride to get (+)- Erythro-(E)-7-[3'-(4"-Fluorophenyl)-l'-(l"-methylethyl)-indol-2'-yl]-3,5-dihydroxyhept-6- enoate, methyl ester (cyclic boronate complex) of the formula (III a) as yellow oil.
  • the cyclic boronate complex is further stirred with anhydrous methanol to get the Methyl (+)- erythro-(E)-3 ,5-dihydroxy-7-[3 ' -(4"-fluoro ⁇ henyl> 1 ' -( 1 "-methylethyl)indol-2' -yl]hept-6-enoate (fluva diol ester) of the formula (IV a) which is purified by column chromatography to obtain the fluva diol ester as an oil (61%).
  • the fluva diol ester is hydrolysed with aqueous solution of sodium hydroxide to get Fluvastatin sodium of formula I.
  • the overall yield of Fluvastatin sodium from Fluva aldehyde which can be calculated from the reported yields of the intermediates, is found to be 52.8 %.
  • This complex is further refluxed with methanol to get the diol ester of formula (IV a) in 87 % yield and having melting point 122-124° C.
  • This diol ester is then hydrolyzed with sodium hydroxide solution to get Fluvastatin sodium of formula I.
  • the overall yield of Fluvastatin sodium from Fluva aldehyde which can be calculated from the reported yields of the intermediates, is found to be 19.75 %.
  • EP 114,027 issued to Sandoz discloses the preparation of Fluvastatin sodium by methyl ester route where the intermediate Fluva keto alcohol of the formula (III a) is isolated as an oil. Fluva keto alcohol is treated with borane-t-butylamine complex to get fluva diol ester of the formula (IV a) as yellow oil. The oil is further hydrolyzed using a base and subsequently acidified to obtain fluvastatin as a free acid.
  • Fluva diol ester is purified by refluxing it with ethyl acetate to obtain 99.44% pure Fluva diol ester as solid having melting point 135-137°C.
  • the fluva diol ester is finally hydrolysed with aqueous sodium hydroxide to obtain Fluvastatin sodium.
  • the overall yield of Fluvastatin sodium from Fluva aldehyde is 37.97%.
  • WO2004080963 by Ciba describes a process for preparing (S)- fluva keto alcohol as yellow syrup in 86% yield which is treated with triethylborate and sodium borohydride to obtain (3R,5S)-diol ester as light yellow foam.
  • the foam is recrystallized from methylene chloride/hexane to obtain colourless crystals of the diol esters.
  • the diol ester of the formula (IV b) formed in the t-butyl ester route is resistant to lactone formation leading to better control over anti-isomer impurity but needs to be further purified by refluxing with ethyl acetate.
  • the t-butyl ester route also has other disadvantages as two key intermediates viz. keto alcohol of the formula (II b) and cyclic boronate complex of the formula (III b) are isolated as an oil or resin.
  • the isolation and handling of intermediates in the form of oil is cumbersome leading to material losses due to adhesion to the container walls. Oils cannot be completely dried and may lead to losses on drying and also while handling. Characterization of oil also poses difficulties.
  • An object of the invention is to provide a process for preparing Fluvastatin sodium, which is easy and convenient to carry out. Another object of the invention is to provide a process for preparing fluvastatin sodium, which is efficient, economical, industrially feasible and suitable for large scale production.
  • Another object of the invention is to provide a process for preparing fluvastatin sodium of high purity.
  • Another object of the invention is to provide Fluvastatin sodium obtained by the above process.
  • Another object of the invention is to provide Fluva keto alcohol of the formula (II b) as solid, which is an intermediate in the preparation of Fluvastatin sodium.
  • Another object of the invention is to provide a process for preparing Fluva keto alcohol of the formula (II b) as solid, which is an intermediate in the preparation of Fluvastatin sodium.
  • Another object of the invention is to provide a cyclic boronate complex of the formula (III b) as solid, which is an intermediate in the preparation of Fluvastatin sodium.
  • Another object of the invention is to provide a process for preparing cyclic boronate complex of the formula (III b) as solid, which is an intermediate in the preparation of Fluvastatin sodium.
  • the aqueous layer is spray dried to obtain Fluvastatin sodium as solid.
  • Fluvastatin sodium of the formula (I) obtained by the above process.
  • keto alcohol of the formula (II b) as solid
  • HI b comprising reducing the keto alcohol of the formula (II b) as solid with sodium borohydride in the presence of methoxydiethyl borane in tetrahydrofuran at - 75° C to obtain the cyclic boronate complex of the formula (III b) as oil and treating the oil with an organic solvent at 25-35° C followed by cooling the resulting slurry to 0 to 2 ° C and filtering out the cyclic boronate complex of the formula (III b) as solid.
  • the organic solvent is selected from n-pentane, n-hexane, n-heptane or petroleum ether or combinations thereof.
  • the preferred organic solvent is n-hexane.
  • keto alcohol of the formula (II b) as solid.
  • the keto alcohol of the formula (II b) as solid has a purity of 92-94 % and melting point of 93° C.
  • the cyclic boronate complex of the formula (III b) as solid has a purity > 97 % and melting point 127° C.
  • the diol ester of formula (IV b) as solid has a purity greater than 97% with anti-isomer content less than 1.0%. This is further purified by treatment with acetonitrile to get the pure diol ester of formula (IV b) having purity > 99.5% and anti-isomer content less than 0.3 %.
  • the overall yield of Fluvastatin sodium from fluva aldehyde obtained is 54%.
  • the process of the invention eliminates the accumulation of byproducts by obtaining the intermediates of formula (II b) and (III b) as solids to give Fluvastatin sodium in high yield and purity. It employs cheaper and easily available solvents and renders the various steps easy and convenient to carry out, as all the intermediates are obtained as solids.
  • the solid forms of the intermediates of the invention make their characterization also easy.
  • the process of the invention is efficient and economical and suitable for industrial scale production.
  • the reaction mixture was quenched with cold dilute hydrochloric acid (470 ml concentrated hydrochloric acid in 5600 ml water) at - 15 to 0° C.
  • the reaction mixture was further stirred at -5 to 0 0 C for 15 minutes until pH of aqueous layer adjusted to 4 to 4.5.
  • the organic layer was separated and subsequently the aqueous layer was extracted with 1 L of toluene.
  • the combined organic layer was washed with 4500 ml saturated sodium chloride solution by maintaining the pH to 5 to 6.
  • the organic layer was dried over 500 gm sodium sulfate and concentrated at 45 to 50°C under reduced pressure until 1 kg of residual oil remains.
  • Dry weight of solid Fluva keto alcohol of the formula (II b) 703 gm (92%). Purity of solid Fluva keto alcohol of the formula (II b): 92 to 94% by HPLC. Melting point of solid Fluva keto alcohol of the formula (II b): 93 0 C.
  • Fluva keto alcohol of the formula (II b) was dissolved in a solvent mixture comprising 1036 ml tetrahydrofuran and 242 ml methanol.
  • the Fluva keto alcohol solution was added dropwise to the mixture (A) over period of 3 hour at a temperature of - 75 to -60 0 C and the resulting mixture was stirred for additional 2 hours.
  • 2300 ml of saturated sodium bicarbonate solution was added slowly maintaining the temperature below - 3O 0 C.
  • 5 L of ethyl acetate was added slowly over a period of 10 to 15 minutes maintaining the temperature below 0 0 C and was further stirred at O 0 C for 1 hour.
  • the resultant mixture was diluted with 1 IL water. This diluted mixture was stirred for 1 hour at 10 to 15°C. The reaction mass was warmed to 20-25 0 C and the organic layer was separated out. The aqueous layer was extracted with 2000 ml ethyl acetate. The combined organic layer was washed with 9 L (3x3L) of saturated sodium chloride solution. The organic layer was dried over 500 gm sodium sulfate and was concentrated at 45 to 50 0 C under reduced pressure to obtain residual oil. To the residual oil, 3 L of n-hexane was added and was stirred at 25 to 35°C for 3 hour. The slurry was cooled to 2°C and again stirred for 1 hour at 2°C. The solid cyclic boronate complex of the formula (III b) obtained was filtered under vacuum and the cake was washed with 1 L (2x500ml) of n-hexane. The solid was dried at 60 to 65°C in an oven.
  • the ethyl acetate layer was separated and treated with 3342 ml (2xl671ml) sodium chloride solution.
  • the organic layer was washed with 2500 ml (2xl250ml), 10% sodium sulfite solution at 15 to 2O 0 C and with 3342 ml (2x167 ImI) sodium chloride solution.
  • the organic layer was dried over 500 gm of sodium sulfate.
  • the ethyl acetate from the organic layer was distilled out completely under vacuum at 45 to 50 0 C till thick pasty mass remained. 3L of n-hexane was added to the thick pasty mass and mixture was heated to reflux for 1 hr. The mixture was cooled to 28 to 30 0 C and was stirred for 6 hour.
  • Fluva diol ester of the formula (IV b) was filtered and washed the product with n-hexane.
  • the Fluva diol ester of the formula (IV b) was dried at 60
  • NMT means Not More Than limit of the impurity according to USP standard.
  • the impurity profile indicates that the Fluvastatin sodium obtained by the process of the invention complies with the USP standard.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne un procédé efficace et économique de préparation de fluvastatine sodique de la formule (I) à pureté élevée et à haut rendement. Un procédé de préparation d'alcool fluva-céto de formule (II b) et de complexe de boronate cyclique de formule (III b) comme solides par traitement au solvant est également décrit.
PCT/IN2005/000288 2005-08-23 2005-08-23 Procede de preparation de fluvastatine sodique WO2007023503A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000288 WO2007023503A1 (fr) 2005-08-23 2005-08-23 Procede de preparation de fluvastatine sodique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2005/000288 WO2007023503A1 (fr) 2005-08-23 2005-08-23 Procede de preparation de fluvastatine sodique

Publications (1)

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WO2007023503A1 true WO2007023503A1 (fr) 2007-03-01

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104250222A (zh) * 2013-06-27 2014-12-31 上海朴颐化学科技有限公司 一种氟伐醇酮制备工艺改进方法
KR101473646B1 (ko) 2007-04-06 2015-01-02 안국약품 주식회사 3-[3-(4-플루오로페닐)-1-(1-메틸에틸)-1ｈ-인돌-2-일]-2-프로펜알의 제조방법
CN107663164A (zh) * 2016-07-28 2018-02-06 上海朴颐化学科技有限公司 一种氟伐醇酮的制备工艺
CN112322676A (zh) * 2020-11-10 2021-02-05 江苏八巨药业有限公司 一种酶催化制备氟伐二醇的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5189164A (en) * 1989-05-22 1993-02-23 Sandoz Ltd. Processes for the synthesis of syn-(E)-3,5-dihydroxy-7-substituted hept-6-enoic and heptanoic acids and derivatives and intermediates thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5189164A (en) * 1989-05-22 1993-02-23 Sandoz Ltd. Processes for the synthesis of syn-(E)-3,5-dihydroxy-7-substituted hept-6-enoic and heptanoic acids and derivatives and intermediates thereof

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, XP002165166, ISSN: 0040-4020 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101473646B1 (ko) 2007-04-06 2015-01-02 안국약품 주식회사 3-[3-(4-플루오로페닐)-1-(1-메틸에틸)-1ｈ-인돌-2-일]-2-프로펜알의 제조방법
CN104250222A (zh) * 2013-06-27 2014-12-31 上海朴颐化学科技有限公司 一种氟伐醇酮制备工艺改进方法
CN107663164A (zh) * 2016-07-28 2018-02-06 上海朴颐化学科技有限公司 一种氟伐醇酮的制备工艺
CN112322676A (zh) * 2020-11-10 2021-02-05 江苏八巨药业有限公司 一种酶催化制备氟伐二醇的方法
CN112322676B (zh) * 2020-11-10 2022-06-07 江苏八巨药业有限公司 一种酶催化制备氟伐二醇的方法

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