WO2005058861A1 - Procede de preparation de simvastatine - Google Patents

Procede de preparation de simvastatine Download PDF

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Publication number
WO2005058861A1
WO2005058861A1 PCT/KR2003/002754 KR0302754W WO2005058861A1 WO 2005058861 A1 WO2005058861 A1 WO 2005058861A1 KR 0302754 W KR0302754 W KR 0302754W WO 2005058861 A1 WO2005058861 A1 WO 2005058861A1
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WO
WIPO (PCT)
Prior art keywords
formula
simvastatin
dimer
acid
diol lactone
Prior art date
Application number
PCT/KR2003/002754
Other languages
English (en)
Inventor
Jong-Min Kim
Bong-Youl Chung
Joon-Seop Kim
Jae-Gu Choi
Shin-Wook Kang
Sang-Won Yi
Hyun-Jin Ahn
Original Assignee
Uk Chemipharm Co., Ltd.
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 Uk Chemipharm Co., Ltd. filed Critical Uk Chemipharm Co., Ltd.
Priority to PCT/KR2003/002754 priority Critical patent/WO2005058861A1/fr
Priority to AU2003289546A priority patent/AU2003289546A1/en
Publication of WO2005058861A1 publication Critical patent/WO2005058861A1/fr

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    • 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 process for preparing simvastatin in a high yield by hydrolyzing lovastatin with an inorganic base, forming a diol lactone, selectively protecting the diol lactone to form a lactone dimer, acylating the lactone dimer to produce simvastatin dimer, and then deprotecting the simvastatin dimer.
  • Simvastatin used as an HMG-CoA reductase inhibitor, is a kind of statin antihyperlipidemic.
  • a process for preparing simvastatin from lovastatin is known in the art.
  • Korean - Patent Publication No. 10-1985-669 and US Patent No. 4,444,784 disclose a method of preparing silyl derivative of simvastatin of formula B and then deprotecting it to produce simvastatin, as illustrated in the following Scheme 1. [Scheme 1]
  • Simvastatin The process of preparing simvastatin as shown in Scheme 1 is characterized in hydrolyzing lovastatin with lithium hydroxide as an inorganic base and then forming a diol lactone of formula B in toluene; and selectively introducing t-butylmethylsilyl protecting group into the secondary alcohol in 4- position of the diol lactone to produce an intermediate, a silyl derivative of simvastatin of formula B.
  • the reaction time required for hydrolysis is so long as 72 hours, and the yield is a little low as 69 % in the step of silyl introduction.
  • the use of expensive t-butyldimethylsilyl chloride causes the increase of total cost of production.
  • PCT Publication WO 03/057684 discloses a method of preparing simvastatin from lovastatin, which is similar to that disclosed in Korean Patent Publication No. 10-1985-669 and US Patent No. 4,444,784. In this method, a large quantity of rather expensive phase transfer agent is used in acylation step and the reaction carried out in organic solvent such as toluene at high temperature for a long time results in the production of lots of by-products.
  • Korean Patent Laid-open Publication No. 10-2003-40858 discloses a process for preparing simvastatin characterized in that hydrolyzing lovastatin with an inorganic base through the medium of phase transfer agent and then heating with reflux to produce a diol lactone in a consecutive process without separation, and selectively introducing tetrahydropyranyl group into the secondary alcohol of pyranone ring to produce 4-THP-diol lactone.
  • a process for preparing simvastatin of formula 1 comprising the steps of: reacting a diol lactone of formula 4 with a di-substituted silyl dichloride (dichlorosilane) to produce a diol lactone dimer of formula 5; subsequently acylating the diol lactone dimer with 2,2-dimethylbutyryl chloride to produce a simvastatin dimer of formula 6; and deprotecting the simvastatin dimer to produce simvastatin.
  • a diol lactone of formula 4 with a di-substituted silyl dichloride (dichlorosilane) to produce a diol lactone dimer of formula 5
  • subsequently acylating the diol lactone dimer with 2,2-dimethylbutyryl chloride to produce a simvastatin dimer of formula 6
  • deprotecting the simvastatin dimer to produce simvastatin.
  • the diol lactone of formula 4 can be prepared by deacylating lovastatin of formula 2 with an inorganic base to obtain a triol acid of formula 3 and refluxing the triol acid in the presence of toluene.
  • Ri and R 2 are independently an alkyl or an aryl group, and preferably methyl, ethyl, isopropyl, t-butyl or phenyl.
  • simvastatin is prepared from lovastatin in a high yield by hydrolyzing ester of lovastatin with an inorganic base, forming a diol lactone, selectively protecting the diol lactone to form a lactone dimer, introducing 2,2-dimethylbutyryl ester into the lactone dimer to produce a simvastatin dimer, and then deprotecting silyl group of the simvastatin dimer with fluoride salt or acid to produce simvastatin.
  • the process for preparing simvastatin according to the present invention consists of the following four steps: (1) deacylating lovastatin of formula 2 with an inorganic base such as potassium hydroxide to produce a triol acid of formula 3; (2) refluxing the triol acid of formula 3 in toluene to produce a diol lactone of formula 4; (3) selectively protecting the secondary alcohol of the diol lactone of formula 4 with dialkyl (or diaryl or arylalkyl) silyl dichloride (R 1 R 2 SiCl 2 , wherein Ri and R 2 are independently an alkyl or an aryl group, such as methyl, ethyl, isopropyl, t-butyl or phenyl) to produce a silyl-protected diol lactone dimer of formula 5, and subsequently (i.e., without interruption of reaction) acylating the diol lactone dimer with 2,2-dimethylbutyryl chloride to produce a silyl-protecte
  • step (1) lovastatin of formula 2 is added with an inorganic base such as potassium hydroxide and then heated with reflux for 5 to 15 hours to be deacylated and acidified, which results in the production of a triol acid of formula 3.
  • step (2) the triol acid of formula 3 is refluxed in toluene, successively removing water, to prepare a diol lactone of formula 4.
  • step (3) two secondary alcohols in two diol lactone molecules of formula 4 are selectively protected with dialkyl (or diaryl or arylalkyl) silyl group in the presence of base to obtain a silyl-protected diol lactone of formula 5.
  • silyl-protected diol lactone is directly subjected to coupling reaction with 2,2-dimethylbutyryl chloride in the presence of 4,4- dimethylaminopyridine catalyst to prepare a silyl-protected simvastatin dimer of formula 6 in the yield of 95 % or more.
  • Suitable dialkyl (or diaryl or arylalkyl) silyl dichlorides which may be used in step (3) are dichlorosilanes having two alkyl or aryl substitutes which are same or different each other, such as dimethyl silyl dichloride, diethyl silyl dichloride, diisopropyl silyl dichloride, methylvinyl silyl dichloride, di-t-butyl silyl dichloride, diphenyl silyl dichloride, methylphenyl silyl dichloride, etc.
  • dimethyl silyl dichloride is used in an amount of 0.5 to 1.0 equivalent, since it is low in price and easily removed in the system.
  • organic base used in step (3) are tertiary amine such as triethylamine, tributylamine, diisobutylethylamine, N- methylmorpholine, etc. and aromatic amine such as imidazole, 1- methylimidazole, pyridine, 2,6-lutidine, picoline, etc.
  • amines pyridine is preferred to be used.
  • 4,4-dimethylaminopyridine used as catalyst for coupling reaction is preferred to be added within the range of 0.1 to 1 equivalent. By adjusting the amount of the catalyst to be used it is possible to improve the reaction and minimize side-reaction.
  • Suitable reaction solvent in step (3) may includes pyridine, methylene dichloride, 1,2-dichloroethane, tetrahydrofuran, toluene, benzene, acetonitrile, etc. Methylene chloride is preferred to be used alone.
  • step (4) a silyl-protected simvastatin dimer of formula 6 is easily deprotected in the presence of fluoride salt or acid catalyst to produce simvastatin of formula 1 in a high yield.
  • Suitable fluoride salts which may be used in step (4) include cesium fluoride, potassium fluoride, ammonium fluoride, pyridinium fluoride, triethylammonium fluoride, tetrabutylammonium fluoride, etc.
  • Representative examples of the acid catalyst include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc.
  • ammonium fluoride is used in an amount of 0.5 to 2.0 equivalents.
  • Suitable reaction solvent in step (4) may includes acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, tetrahydrofuran, 1,4- dioxane, ethylacetate, benzene, toluene, or mixtures thereof. Ethylacetate is preferred to be used.
  • Simvastatin of formula (1) may be crystallized by non-polar solvents such as hexane, cyclohexane, diethyl ether, petroleum ether, diisopropyl ether, t- butylmethyl ether, ethyl acetate/hexane, etc. Cyclohexane is preferred to be used alone. Best Mode
  • Example 1 Synthesis of 3,5-dihydroxy-7-(8-hvdroxy-2,6-dimethyl- 1,2,6,7,8, 8a-hexahydro-naphthalen-l-yr)heptanoic acid [step 1] 10 g (24.7 mmol) of lovastatin was added with 70 ml of 2- propanol/ethanol and 8.16 g (123.5 mmol) of potassium hydroxide, and then the resultant was stirred at room temperature for 30 minutes. The solution was heated to the reflux temperature, and then stirred at the temperature for 6 hours. After the reaction was finished, the resultant was cooled to room temperature, and then completely dissolved by adding 300 ml of water.
  • Example 2 Synthesis of 4-dihvdroxy-6-[2-(8-hydroxy-2,6-dimethyl- 1 ,2,6,7,8,8a-hexahydro-naphthalen- 1 -yl ethyll-tefaahydro-pyran-2-one [step 2] 7.53 g (22.25 mmol) of the triol acid produced in Example 1 was suspended in 40 ml of toluene, and then refluxed for 1 hour with successive removal of water. The resultant was distilled to leave 15 ml of toluene, and then stirred gently to cool down to room temperature. The crystal obtained by filtration was dried to yield 6.75 g (95%) of white diol lactone crystal.
  • Example 3 Synthesis of simvastatin dimer [step 3] 6.75 g (21.1 mmol) of the diol lactone produced in Example 2 was dissolved in 40 ml of methylene chloride, and 2.78 ml (31.65 mmol) of pyridine was added thereto. The resultant was added slowly with 1.39 ml (11.6 mmol) of dimethylsilyl dichloride for 30 minutes, and then stirred for another 30 minutes. After the reaction was completed, the resultant was added with 772 mg (30 mol%) of 4-dimethylaminopyridine and 5.49 g (63.3 mmol) of lithium bromide, and then 8.59 ml (105.5 mmol) of pyridine was slowly added thereto at 0 °C .
  • Example 4 Synthesis of 2,2-dimethyl-butyric acid 8-r2-(3-hvdroxy-5- oxo-cvclohexylVethyl]-3,7-dimethyl-l,2,6,7.8.8a-hexahydronaphthalen-l-yl ester (simvastatin [step 2] 8.94 g (10.0 mmol) of the protected simvastatin dimer produced in Example 3 was dissolved in 90 ml of ethylacetate, and the mixture was added with 370 mg (10.0 mmol) of ammonium fluoride at 0 ° C and then stirred for 3 hours.
  • imvastatin [step 2] 8.94 g (10.0 mmol) of the protected simvastatin dimer produced in Example 3 was dissolved in 90 ml of ethylacetate, and the mixture was added with 370 mg (10.0 mmol) of ammonium fluoride at 0 ° C and then stirred for 3 hours.
  • the present invention provides new protection group which is low in price and can be easily removed under fluoride salt and acid condition in manufacturing simvastatin and proves its industrial availability.
  • a diol lactone of formula A is subjected to two-step reaction to produce simvastatin intermediate.
  • a diol lactone is protected and then directly subjected to one-step reaction to proceed acylation, which simplify the overall procedures;
  • a diol lactone of formula 4 is an intermediate compound and two secondary alcohols in two diol lactone molecules are selectively protected by using dialkyl (or diaryl or arylalkyl) silyl dichloride (R ⁇ R 2 SiCl 2 ).
  • simvastatin is obtained in a high purity (>99%>) and high yield (96%> or more).
  • the process for preparing simvastatin according to the present invention is simple in overall manufacturing steps and uses cheap protecting agent. Further, it has an excellent productivity and economical effect.

Abstract

L'invention concerne un procédé pour préparer de la simvastatine. Ce procédé comprend les étapes consistant à faire réagir une diol lactone de formule (4) avec du dichlorure de silyle bisubstitué (dichlorosilane) pour produire un dimère de diol lactone de formule (5), acyler subséquemment le dimère de diol lactone avec du chlorure 2,2-diméthylbutyryle pour produire un dimère de simvastatine de formule (6), et déprotéger le dimère de simvastatine pour produire de la simvastatine. Le procédé de l'invention est simple dans ces étapes de fabrication générales, et fait appel à un agent de protection peu onéreux, il permet également d'obtenir une excellente productivité et constitue un procédé très économique.
PCT/KR2003/002754 2003-12-16 2003-12-16 Procede de preparation de simvastatine WO2005058861A1 (fr)

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PCT/KR2003/002754 WO2005058861A1 (fr) 2003-12-16 2003-12-16 Procede de preparation de simvastatine
AU2003289546A AU2003289546A1 (en) 2003-12-16 2003-12-16 Process for preparing simvastatin.

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009013764A2 (fr) * 2007-07-24 2009-01-29 Jubilant Organosys Limited Procédé de production du 6(r)-[2-(8'(s)-2',2'-diméthylbutyryloxy-2'(s),6'(r)-diméthyl-1,2,6,7',8',8a'(r)-hexahydronaphtyl-l'(s))éthyl]-4(r)-hydroxy-3,4,5,6-tétrahydro-2h-pyran-2-one
WO2016161085A1 (fr) * 2015-04-01 2016-10-06 Cedars-Sinai Medical Center Analogues ou dérivés de lovastatine anti-méthanogènes et leurs utilisations
US9744208B2 (en) 2013-03-15 2017-08-29 Cedars-Sinai Medical Center Methods of diagnosis, selection, and treatment of diseases and conditions caused by or associated with methanogens
US9845511B2 (en) 2013-03-15 2017-12-19 Cedars-Sinai Medical Center Methods of diagnosis, selection, and treatment of diseases and conditions caused by or associated with methanogens
US9956292B2 (en) 2014-08-13 2018-05-01 Cedars-Sinai Medical Center Anti-methanogenic compositions and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444784A (en) * 1980-08-05 1984-04-24 Merck & Co., Inc. Antihypercholesterolemic compounds
US6100407A (en) * 1998-03-05 2000-08-08 Sython, B.V. Process for producing simvastatin and/or its derivatives
US6331641B1 (en) * 1998-12-10 2001-12-18 Kaneka Corporation Process for producing simvastatin
US6506929B1 (en) * 1998-06-18 2003-01-14 Apotex Inc. Process to manufacture simvastatin and intermediates
US6509479B1 (en) * 1999-02-04 2003-01-21 Lek Pharmaceuticals D.D. Process for the removal of a silyloxy protecting group from 4-silyloxy-tetrahydro-pyran-2-ones
WO2003057684A1 (fr) * 2002-01-09 2003-07-17 Hanmi Pharm. Co., Ltd. Procede de preparation de simvastatine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444784A (en) * 1980-08-05 1984-04-24 Merck & Co., Inc. Antihypercholesterolemic compounds
US6100407A (en) * 1998-03-05 2000-08-08 Sython, B.V. Process for producing simvastatin and/or its derivatives
US6506929B1 (en) * 1998-06-18 2003-01-14 Apotex Inc. Process to manufacture simvastatin and intermediates
US6331641B1 (en) * 1998-12-10 2001-12-18 Kaneka Corporation Process for producing simvastatin
US6509479B1 (en) * 1999-02-04 2003-01-21 Lek Pharmaceuticals D.D. Process for the removal of a silyloxy protecting group from 4-silyloxy-tetrahydro-pyran-2-ones
WO2003057684A1 (fr) * 2002-01-09 2003-07-17 Hanmi Pharm. Co., Ltd. Procede de preparation de simvastatine

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009013764A2 (fr) * 2007-07-24 2009-01-29 Jubilant Organosys Limited Procédé de production du 6(r)-[2-(8'(s)-2',2'-diméthylbutyryloxy-2'(s),6'(r)-diméthyl-1,2,6,7',8',8a'(r)-hexahydronaphtyl-l'(s))éthyl]-4(r)-hydroxy-3,4,5,6-tétrahydro-2h-pyran-2-one
WO2009013764A3 (fr) * 2007-07-24 2009-03-19 Jubilant Organosys Ltd Procédé de production du 6(r)-[2-(8'(s)-2',2'-diméthylbutyryloxy-2'(s),6'(r)-diméthyl-1,2,6,7',8',8a'(r)-hexahydronaphtyl-l'(s))éthyl]-4(r)-hydroxy-3,4,5,6-tétrahydro-2h-pyran-2-one
US10226505B2 (en) 2013-03-15 2019-03-12 Cedars-Sinai Medical Center Methods of diagnosis, selection, and treatment of diseases and conditions caused by or associated with methanogens
US9744208B2 (en) 2013-03-15 2017-08-29 Cedars-Sinai Medical Center Methods of diagnosis, selection, and treatment of diseases and conditions caused by or associated with methanogens
US9845511B2 (en) 2013-03-15 2017-12-19 Cedars-Sinai Medical Center Methods of diagnosis, selection, and treatment of diseases and conditions caused by or associated with methanogens
US10519515B2 (en) 2013-03-15 2019-12-31 Cedars-Sinai Medical Center Methods of diagnosis, selection, and treatment of diseases and conditions caused by or associated with methanogens
US10688149B2 (en) 2013-03-15 2020-06-23 Cedars-Sinai Medical Center Methods of diagnosis, selection, and treatment of diseases and conditions caused by or associated with methanogens
US9956292B2 (en) 2014-08-13 2018-05-01 Cedars-Sinai Medical Center Anti-methanogenic compositions and uses thereof
US10328151B2 (en) 2014-08-13 2019-06-25 Cedars-Sinai Medical Center Anti-methanogenic compositions and uses thereof
US10668159B2 (en) 2014-08-13 2020-06-02 Cedars-Sinai Medical Center Anti-methanogenic compositions and uses thereof
US11344501B2 (en) 2014-08-13 2022-05-31 Cedars-Sinai Medical Center Anti-methanogenic compositions and uses thereof
WO2016161085A1 (fr) * 2015-04-01 2016-10-06 Cedars-Sinai Medical Center Analogues ou dérivés de lovastatine anti-méthanogènes et leurs utilisations
US10736871B2 (en) 2015-04-01 2020-08-11 Cedars-Sinai Medical Center Anti-methanogenic lovastatin analogs or derivatives and uses thereof
US11590102B2 (en) 2015-04-01 2023-02-28 Cedars-Sinai Medical Center Anti-methanogenic lovastatin analogs or derivatives and uses thereof

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