WO2006072963A1 - Procédé de synthèse en trois étapes de la simvastatine à partir de sels d'amine de la lovastatine - Google Patents

Procédé de synthèse en trois étapes de la simvastatine à partir de sels d'amine de la lovastatine Download PDF

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Publication number
WO2006072963A1
WO2006072963A1 PCT/IN2005/000066 IN2005000066W WO2006072963A1 WO 2006072963 A1 WO2006072963 A1 WO 2006072963A1 IN 2005000066 W IN2005000066 W IN 2005000066W WO 2006072963 A1 WO2006072963 A1 WO 2006072963A1
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WO
WIPO (PCT)
Prior art keywords
compound
simvastatin
lovastatin
structural formula
formula iii
Prior art date
Application number
PCT/IN2005/000066
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English (en)
Inventor
Sudhir Vaid
Pradeep Dr. Narula
Original Assignee
Concord Biotech 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 Concord Biotech Limited filed Critical Concord Biotech Limited
Publication of WO2006072963A1 publication Critical patent/WO2006072963A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D309/30—Oxygen atoms, e.g. delta-lactones

Definitions

  • the present invention relates to a novel process and a Novel intermediates for preparing of Simvastatin (Ha) starting from the materials Lovastatin Amine Salts or any other salts of Mevinolinic Acid.
  • Simvastatin (II) a more potent HMG-COA reductase inhibitor than lovastatin (Ia), has provide a need for a high yielding process which is more economically efficient and environmentally sound than those disclosed in the prior art.
  • Simvastatin has also been prepared by the ⁇ -alkylation of the ester moiety as described in U.S. Pat. Nos. 4,582,915 and 4,820,850.
  • U.S. Pat no. 4,582,915 (1986) discloses the direct methylation of the natural 2- (S)-methyl butyryloxy side chain of mevinolin in a single chemical step using a metal alkyl amide and a methyl halide to give simvastatin.
  • This process suffers from poor conversion rate of the C-methylation step. Additionally, many side reactions take place due to methylation at other sites of the molecule. The C-methylation conversion rate may be improved to some extent by a second or a third charge of the amide base and methyl halide. Even so, the overall yields are moderate. Also, the purity of simvastatin obtained by this process is close to borderline for use as a human health-care product.
  • U.S. Pat. No. 4,820,850 (1989) discloses a process wherein high conversion C-methylation of the 2-(S)-methyl butyrloxy side chain of mevinolin takes place with a single charge of amide base and alkyl halide.
  • the process described in this patent comprises six steps and is not economical as it involves the protection and deprotection of the two hydroxy groups of the intermediate lovastatin butyl amide using an expensive silylating agent, tertbutyldimethylsilyl chloride.
  • the present invention provides a novel process and novel intermediates for the preparation of simvastatin (Ha).
  • the novel process may be depicted by the following reaction scheme:
  • the starting material Lovastatin amine salt can be prepared from Lovastatin or any other salt of Mevinolinic acid.
  • Simvastatin may be prepared from a salt of mevinolinic acid as the stating material rather than lovastatin.
  • Simvastatin is prepared in a four step process which does not include the protection and deprotection of the two hydroxy groups of the open pyranone ring.
  • the first intermediate is isolated as crystalline solid
  • the methods described in the prior art describe the first intermediate as oils and then methylation via protection of the hydroxy groups as essential steps for the preparation of simvastatin.
  • the novel intermediate lovastatin amine salt (III a/b/c) is prepared from the starting material (lovastatin or a salt form of mevinolinic acid). This novel intermediate is then converted into a second novel intermediate (IV).
  • Simvastatin prepared by the inventive process has certain advantages in commercial manufacture.
  • the purity and yield of simvastatin from the inventive process is high, with less consumption of reagents, time, labor, and cost, and in fewer steps.
  • the amine R 3 - NH 2 is t-octylamine or cyclopropylamine and the intermediate that is formed is lovastatin cyclopropylamine salt (III a or III b).
  • the intermediate amine salt Ilia or IHb thus prepared is dissolved in dry tetrahydrofuran and is added to a solution of alkali metal amide, e.g., lithium pyrrolidide in THF at a temperature of about-35° C. to -40° C Lithium pyrrolidide is generated in situ by the reaction of n-BuLi with pyrrolidine in THF.
  • the solution of intermediate amine salt Ilia or IHb 5 and the in situ generated base is aged at about -30° C to -25°C. for 1 hour, and dried alkyl halide, preferably methyl iodide (2 to 3 mol.eq.), is added in a single charge.
  • the contents are stirred at about -30° C. for 1 hour, warmed to -10° C. and aged at this temperature for 20 minutes. Water is added to the reaction mixture and the layers are separated.
  • the THF layer is washed with a mineral acid, preferably hydrochloric acid, and then with ammonium chloride solution.
  • the THF layer concentrated under vacuum at 40-45° C to almost dryness.
  • the oily residue was then dissolved in ethyl acetate. From the solvent phase the compound is directly isolated as Simvastatin ammonium salt by adding methanolic solution of ammonium hydroxide.
  • the compound was now directly converted to crude Simvastatin by heating in a hydrocarbon solvent such as toluene.
  • a hydrocarbon solvent such as toluene.
  • the mixture is suspended in toluene, heated and stirred at about 100°-110° C. for 2 to 10 hours, preferably at about 105° for 5 hours, under a sweep of nitrogen gas.
  • the mixture is then cooled to about 35° C, carbon treated, filtered, and the filtrate is concentrated under reduced pressure at about a 60° C. bath temperature to one-tenth of its original volume.
  • the lactone is crystallized from a hydrocarbon solvent such as cyclohexane to give simvastatin (Ha) of high purity.
  • Step- 1 N-Cyclopropyl-7[l,2,6,7,8,8a®-hexahydro-2(S),6(R)-dimethyl-8(S)- [l2(S)-methylbutanoyl]oxy]-l(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid amine salt (IHb).
  • Lovastatin (12.5 g, 0.031moles) was suspended in methanol (25 ml). To the reaction mixture was added solution of sodium hydroxide in water(1.25 g in 50 ml of water). The mixture was heated and stirred at 35°-40°C for 45 minutes till hydrolysis is deemed complete. Added 50 ml of water and the pH of the reaction mixture is now adjusted to 4.0-4.2. The compound is now converted as acid was extracted in ethyl acetate(50ml) twice. The ethyl acetate layer separated was dried over sodium sulphate. To the E.A layer separated added cyclopropyl amine (2.15 ml) and acetone(20 ml) .
  • the above mentioned amine can also be prepared directly from Mevinolinic acid or it's salt form by above mentioned method.
  • Step-2 N-Cyclopropyl-7-[l,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-
  • the layers were separated and the upper THF layer was treated with IN HCL (50 ml).
  • the THF layer was concentrated at reduced pressure to a volume of about 20 ml to give Simvastatin acid in oil form.
  • the acid was dissolved in ethyl acetate(50 ml) and added methanolic solution of ammonium hydroxide 5 ml in 10 ml of methanol.
  • Simvastatin acid is precipitated as ammonium salt.
  • Step-3 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl- l,2,6,7,8,8a(R)-hexahydro-l(S)-naphthyl]ethyl]-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one (Ha) (Simvastatin)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)

Abstract

La présente invention décrit un nouveau procédé de synthèse de la Simvastatine à partir de sels d'amine de la Lovastatine, en trois étapes. La Lovastatine est hydrolysée afin d'obtenir sa forme acide, puis isolée sous forme d'un sel d'amine par réaction avec une amine telle que la cyclopropylamine ou la t-octylamine, etc. Après avoir été isolés, les sels sont directement méthylés, sans étapes de protection et de déprotection des groupements hydroxy. Le sel d'ammonium de la Simvastatine est alors directement obtenu, avant d'être converti en Simvastatine par des méthodes usuelles, et purifié pour aboutir à la Simvastatine isolée.
PCT/IN2005/000066 2005-01-10 2005-02-25 Procédé de synthèse en trois étapes de la simvastatine à partir de sels d'amine de la lovastatine WO2006072963A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN25/MUM/2005 2005-01-10
IN25MU2005 2005-01-10

Publications (1)

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WO2006072963A1 true WO2006072963A1 (fr) 2006-07-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103773822A (zh) * 2013-12-31 2014-05-07 烟台只楚药业有限公司 一种由洛伐他汀开环物合成辛伐他汀的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0864569A1 (fr) * 1997-03-13 1998-09-16 Ranbaxy Laboratories, Ltd. Procédé de préparation de simvastatine a partir de lovastatin ou d'acide mévinolinique
WO2000017150A1 (fr) * 1998-09-18 2000-03-30 Lek Pharmaceutical And Chemical Company D.D. NOUVEAUX SELS D'INHIBITEURS DE LA HMG-CoA REDUCTASE

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0864569A1 (fr) * 1997-03-13 1998-09-16 Ranbaxy Laboratories, Ltd. Procédé de préparation de simvastatine a partir de lovastatin ou d'acide mévinolinique
WO2000017150A1 (fr) * 1998-09-18 2000-03-30 Lek Pharmaceutical And Chemical Company D.D. NOUVEAUX SELS D'INHIBITEURS DE LA HMG-CoA REDUCTASE

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DABAK, KADIR ET AL: "A convenient procedure for the methylation of lovastatin. Synthesis of simvastatin", HETEROCYCLIC COMMUNICATIONS , 10(1), 29-34 CODEN: HCOMEX; ISSN: 0793-0283, 2004, XP008050569 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103773822A (zh) * 2013-12-31 2014-05-07 烟台只楚药业有限公司 一种由洛伐他汀开环物合成辛伐他汀的制备方法

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