WO2003087112A1 - Intermediaire chiral et son procede de production - Google Patents

Intermediaire chiral et son procede de production Download PDF

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Publication number
WO2003087112A1
WO2003087112A1 PCT/KR2003/000707 KR0300707W WO03087112A1 WO 2003087112 A1 WO2003087112 A1 WO 2003087112A1 KR 0300707 W KR0300707 W KR 0300707W WO 03087112 A1 WO03087112 A1 WO 03087112A1
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Prior art keywords
formula
compound
optionally substituted
carbon atoms
group
Prior art date
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PCT/KR2003/000707
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English (en)
Inventor
Kwang-Min Lim
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Cls Laboratories, Inc.
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Publication date
Application filed by Cls Laboratories, Inc. filed Critical Cls Laboratories, Inc.
Priority to AU2003219592A priority Critical patent/AU2003219592A1/en
Publication of WO2003087112A1 publication Critical patent/WO2003087112A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to new chiral intermediates, process for the production thereof, and p rocess for the production of HMG-CoA reductase inhibitors using the same. More specifically, the present invention relates to new chiral intermediates which can be used for the preparation of HMG-CoA reductase inhibitors, a process for simply producing them under mild conditions with high yields, and a process for the production of HMG-CoA reductase inhibitors using the same.
  • statin Drugs having the effect of suppressing the biosynthesis of cholesterol by inhibiting the activity of HMG-CoA(3-hydroxy-3 -methyl- glutaryl coenzyme A) reductase are normally called "statin.”
  • the first generation of the statin includes simvastatin, lovastatin, and pravastatin, which are fermentation products, and the second generation of the statin includes atovastatin, fluvastatin, rosuvastatin, and pitavastain, which are synthetic drugs.
  • the chemical structures of the main statins are as follows:
  • U.S. Patent No. 5,354,772 discloses a process for the production of fluvastatin, which used the method of preparing racemates and then separating them as shown in the following reaction scheme.
  • the trans-cinnamyl aldehyde was first prepared, the beta-ketoester which had been converted to a di-anion with at least two equivalents of base was introduced to the trans-cinnamyl aldehyde, and then the selective reduction reaction was carried out to obtain two chirally different syn-l,3-diols (A) and (B), which were separated by chemical, enzymatic, or chromatographic method.
  • a diazo reaction should be carried out in ether solvent in order to obtain the final compound of formula (F) from the carboxylic acid.
  • An object of the present invention is to provide a process for simply producing chiral intermediates which can be used for the preparation of HMG-CoA reductase inhibitors under mild conditions with high yields, without the above mentioned complex and dangerous steps.
  • Another object of the present invention is to provide new intermediates produced by the above process. Further object of the present invention is to provide a process for the production of HMG-CoA reductase inhibitors using the above chiral intermediates.
  • the present invention relates to the chiral compound of formula (I), process for the production thereof, and process for the production of HMG-CoA reductase inhibitors using the same.
  • P is a hydroxy protecting group
  • the present process for the production of the chiral compound of formula (I) comprises the steps of:
  • R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and P is a hydroxy protecting group, for example silyl group.
  • the . compound of formula (III) is prepared from the compound of formula (II) by selective hyrolysis using a microorganism:
  • R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms.
  • lipase, protease, or esterase, etc. can be used, preferably with high substrate concentration of at least 10%.
  • the compound of formula (III) is prepared with high yield reaching 100% and high optical purity of about 99% starting from the compound of formula (II) which is a meso compound. Therefore, this step is very effective compared to the prior chemical resolution which has the yield of about 50 to 80% and the optical purity of 95 to 98%.
  • the compound of formula (IN) is prepared by the addition reaction of the compound of formula (HI) with isobutylene under acidic catalyst:
  • R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms.
  • the acidic catalyst hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, polyphosphoric acid, silica having impregnated metal such as titanium, or zeolite, etc. can be used.
  • the acidic catalyst is preferably used in the amount of 0.000005-0.5 equivalents based on the compound of formula (Ifl).
  • the addition reaction can be carried out in aromatic solvent such as benzene, toluene, and xylene, ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, or halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • aromatic solvent such as benzene, toluene, and xylene
  • ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane
  • halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon
  • the reaction temperature is preferably less than 30°C, more preferably —30-10 °C. If the temperature is below -30 °C, the reaction rate slows down, and if the temperature is above 10 °C, isobutylene is vaporized so that an excessive amount of isobutylene should be used.
  • the compound of formula (V) is prepared by protecting the hydroxy group of the compound of formula (IN):
  • R2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and P is a hydroxy protecting group, for example silyl group such as t- butyldimethylsilyl group. If the hydroxy protecting group is a silyl group, for example t- butyldimethylsilyl group, the compound of formula (IN) is reacted with silyl halide, for example t-butyldimethylsilyl chloride in the presence of base.
  • silyl group such as t- butyldimethylsilyl group
  • the reaction solvent includes aromatic solvent such as benzene, toluene, and xylene, and halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • aromatic solvent such as benzene, toluene, and xylene
  • halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • the reaction temperature is preferably less than 60°C, more preferably 10-40 °C. If the temperature is below 10 °C, the reaction rate slows down, and if the temperature is above 40 °C, by-products occur.
  • amines such as trialkylamine, dialkylamine, alkylamine and imidazole, or inorganic compounds such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and calcium carbonate, etc. can be used, preferably in the amount of 1.0-10.0 equivalents based on the compound of formula (IN).
  • the compound of formula (I), the target product, is prepared by reacting the compound of formula (N) with the compound of formula (NI) in the presence of base.
  • X is or S(O)R ⁇ , wherein Ri is hydrogen, optionally substituted lower alkyl of 1 to 4 carbon atoms, optionally substituted lower alkoxy of 1 to 4 carbon atoms, or optionally substituted aryl; P2 is optionally substituted lower alkyl of 1 to 3 carbon atoms; and
  • the reaction solvent includes ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, and polar solvent such as dimethylformamide, dimethylacetamide, and hexamethylphosphoamide, etc.
  • the reaction temperature is preferably less than 100°C, more preferably -78-40 °C. If the temperature is below -78 °C, the reaction rate slows down, and if the temperature is above 40 °C, side reactions proceed.
  • the compound of formula (NI) is preferably used in 2.0-10.0 equivalents based on the compound of formula (V).
  • the present invention introduced the step of preparing the compound of formula (I) based on the fact that the nucleophilic substitution occurs selectively at the lower ester group of 1 to 3 carbon atoms among the lower ester group of 1 to 3 carbon atoms and t-butyl ester group.
  • the above-mentioned Bristol-Myers Squibb's prior method imposed the selectivity by using the ester group and carboxylate group, h this case, the addition reaction occurred only at the ester group, but at least 1.0 equivalent of base was further required.
  • the present invention can reduce the used amount of base by using two different ester groups.
  • the present chiral compound of formula (I) can be used as an intermediate for preparing various chiral medicaments, particularly HMG-CoA reductase inhibitors.
  • HMG-CoA reductase inhibitors for example, representative HMG-Co A reductase inhibitors, fluvastatin, rosuvastatin and pitavastatin of formula (XI) can be prepared, as shown in the below reaction scheme, by reacting the aldehyde compound of formula (Nil) with the chiral compound of formula (I), deprotecting the hydroxy group of the trans compound of formula (NIII), reducing the ketone group of the compound of formula (IX), and cleaving the t-butyl group of the 1,3-dihydroxyester of formula (X).
  • P is a hydroxy protecting group
  • the condensation reaction of the aldehyde compound of formula (NH) with the chiral compound of formula (I) is c arried out in the presence of base.
  • base alkali metal carbonate, hydroxide, hydride, alkoxide, or alkyl, or alkaline earth metal carbonate, hydroxide, hydride, alkoxide, or alkyl, etc. can be used.
  • the base is preferably used in the amount of 1.0-5.0 equivalents based on the compound of formula (I), and the aldehyde is preferably used in the amount of 1.0-2.0 equivalents.
  • the reaction solvent includes lower alcohol such as methanol, ethanol, and isopropanol, ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane, and polar solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoamide, and acetonitrile, etc.
  • lower alcohol such as methanol, ethanol, and isopropanol
  • ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane
  • polar solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoamide, and acetonitrile, etc.
  • the deprotecting reaction of the hydroxy group of the trans compound of formula (NIII) can be simply carried put, in the presence of fluoride compound such as tetraalkylamonium fluoride and hydrofluoride in ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane, etc.
  • fluoride compound such as tetraalkylamonium fluoride and hydrofluoride in ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t- butylmethyl ether and dimethoxyethane, etc.
  • the fluoride compound is preferably used in the amount of 1.0-5.0 equivalents based on the compound of formula (NHT).
  • the reduction of the ketone group of the compound of formula (IX) is carried out using alkali metal borohydride, cyanoborohydri.de, alkoxyborohydride, aluminiumhydride, alkylaluminiumhydride, or alkoxyaluminiumhydride, or alkaline earth metal borohydride, cyanoborohydride, alkoxyborohydride, aluminiumhydride, alkylaluminiumhydride, or alkoxyaluminiumhydride, etc. as a reducing agent.
  • a chelatmg agent such as trialkyborane, alkoxydialkylborane, dialkoxyalkylborane, and trialkoxyborane is used.
  • the reducing agent and chelating agent are used preferably in the amount of 1.0-10.0 equivalents based on the compound of formula (IX).
  • the reaction solvent includes ether solvent such as tetrahydrofuran, dioxane, petroleum ether, diethyl ether, t-butylmethyl ether and dimethoxyethane, etc.
  • (X) is carried out preferably in the presence of acid, for example formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, alkylsulfonic acid, and toluenesulfonic acid.
  • acid for example formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, alkylsulfonic acid, and toluenesulfonic acid.
  • the acid is used preferably in the amount of 0.001-100 equivalents based on the compound of formula (X).
  • the reaction solvent includes organic acid such as formic acid and acetic acid, aromatic solvent such as benzene, toluene, and xylene, and halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • organic acid such as formic acid and acetic acid
  • aromatic solvent such as benzene, toluene, and xylene
  • halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, and trichlorobenzene, etc.
  • halogen solvent such as dichloromethane, dichloroethane, chloro
  • the process for the production of HMG-CoA reductase inhibitors using the chiral intermediates of the present invention does not have problem of removing by-products and disposing the waste, and therefore is suitable for being used industrially and commercially.
  • Rf 0.8 (n-hexane/ethyl acetate, 2/1)
  • rosuvastatin sodium salt 2.35g of the compound obtained in the above step was added to 100ml of round-bottomed flask equipped with a stirrer and thermometer, and 10ml of formic acid was added and stirred at room temperature. After the reaction was completed, the reactants were concentrated, and 40ml of ethanol and 50ml of 0.1N sodium hydroxide solution were added and stirred for 10 minutes at room temperature. Then, the reactants were concentrated, and 20ml of ethanol was added and stirred for 10 minutes, 5 times repeatedly. Afterwards, 50ml of ether was added to the resulting residue, and stirred for 1 hour at room temperature. The resulting white crystals were filtered through a filter paper, washed with 10ml of ether three times, and dried to give rosuvastatin sodium salt(yield: 89.7%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouvel intermédiaire chiral, son procédé de production et un procédé de production d'un inhibiteur de HMG-CoA réductase selon lequel on utilise ledit intermédiaire chiral.
PCT/KR2003/000707 2002-04-09 2003-04-09 Intermediaire chiral et son procede de production WO2003087112A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003219592A AU2003219592A1 (en) 2002-04-09 2003-04-09 Chiral intermediate and process for the production thereof

Applications Claiming Priority (2)

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KR10-2002-0019340A KR100511533B1 (ko) 2002-04-09 2002-04-09 키랄 중간체, 그의 제조방법 및 그를 이용한 HMG-CoA환원저해제의 제조방법
KR10-2002-0019340 2002-04-09

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WO2005054207A1 (fr) * 2003-12-04 2005-06-16 Glenmark Pharmaceuticals Limited Procede de preparation de derives de pyrimidine
EP1682536A1 (fr) 2003-10-24 2006-07-26 AstraZeneca UK Limited Procede de fabrication du sel de calcium de l'acide rosuvastatine - (e)-7- 4- (4-fluorophenyl) -6-isopropyl-2- methyl (methylsulfonyl) amino ] pyrimidin -5-yl ] (3r, 5s) -3, 5-dihydroxyhept-6-enoique et de ses intermediaires cristallins
WO2007040940A1 (fr) * 2005-10-03 2007-04-12 Teva Pharmaceutical Industries Ltd. Purification diastéréomérique de la rosuvastatine
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WO2007022488A3 (fr) * 2005-08-16 2007-05-03 Teva Pharma Intermediaire de rosuvastatine sous forme cristalline
WO2006091770A3 (fr) * 2005-02-22 2007-05-31 Teva Pharma Rosuvastatine, sels de rosuvastatine exempts de son alkylether, procede d'elaboration correspondant
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US7396927B2 (en) 2003-08-28 2008-07-08 Teva Pharmaceutical Industries Ltd. Process for preparation of rosuvastatin calcium
US7416865B2 (en) 2000-05-09 2008-08-26 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
WO2008130638A2 (fr) * 2007-04-18 2008-10-30 Teva Pharmaceutical Industries Ltd. Procédé de préparation d'intermédiaires d'inhibiteurs des hmg-coa réductases
WO2009009152A1 (fr) 2007-07-12 2009-01-15 Teva Pharmaceutical Industries Ltd. Intermédiaires de la rosuvastatine et leur préparation
US7511140B2 (en) 2002-08-13 2009-03-31 Astrazeneca Ab Process for preparing the calcium salt of rosuvastatin
US7524955B2 (en) 2002-12-16 2009-04-28 Astrazeneca Uk Limited Process for the preparation of pyrimidine compounds
WO2009143776A1 (fr) 2008-05-27 2009-12-03 常州制药厂有限公司 Procédé de préparation de la rosuvastatine calcique et de ses intermédiaires
US7642363B2 (en) 2000-07-19 2010-01-05 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
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EP2223909A1 (fr) 2007-08-28 2010-09-01 Ratiopharm GmbH Procédé de fabrication de dérivés de diacide pentanoïque
WO2010098583A2 (fr) * 2009-02-24 2010-09-02 한미약품 주식회사 Nouveau procédé de préparation de composés de statine ou des sels de ceux-ci, et composés intermédiaires utilisés dans ce procédé
US7816528B2 (en) 2001-07-13 2010-10-19 Astrazeneca Uk Limited Preparation of aminopyrimidine compounds
US7851624B2 (en) 2003-12-24 2010-12-14 Teva Pharamaceutical Industries Ltd. Triol form of rosuvastatin and synthesis of rosuvastatin
WO2010140765A3 (fr) * 2009-06-05 2011-03-24 주식회사 종근당 Nouveau procédé de préparation de rosuvastatine, composés intermédiaires utiles pour préparer de la rosuvastatine, et procédé de préparation correspondant
WO2011106546A1 (fr) 2010-02-25 2011-09-01 Teva Pharmaceutical Industries Ltd. Procédé pour la préparation d'un intermédiaire de la rosuvastatine
US8034932B2 (en) 2004-12-24 2011-10-11 Astrazeneca Uk Limited Chemical process
CN102212081A (zh) * 2010-12-30 2011-10-12 北京双鹤药业股份有限公司 一种用于他汀类药物合成的手性中间体的制备方法
ITMI20100753A1 (it) * 2010-04-30 2011-10-31 Dipharma Francis Srl Procedimento per la preparazione di statine
WO2011141934A1 (fr) 2010-05-13 2011-11-17 Matrix Laboratories Ltd. Procédé amélioré pour la préparation d'un intermédiaire d'inhibiteurs de hmg-coa réductase
US8063213B2 (en) 2003-06-05 2011-11-22 Astrazeneca Uk Limited Production of rosuvastatin calcium salt
EP2383260A3 (fr) * 2010-04-30 2011-12-28 Dipharma Francis S.r.l. Procédé pour la production de Statines
CN102584717A (zh) * 2011-01-17 2012-07-18 浙江九洲药业股份有限公司 用于制备罗苏伐他汀的中间体及相关制备方法和用途
ITMI20110397A1 (it) * 2011-03-14 2012-09-15 Dipharma Francis Srl Procedimento per la preparazione di pitavastatina e analoghi
CN102816114A (zh) * 2011-06-09 2012-12-12 上海京新生物医药有限公司 一种HMG-CoA还原酶抑制剂的制备方法
US8436167B2 (en) 2003-09-10 2013-05-07 Astrazeneca Uk Limited Chemical compounds
WO2013080219A2 (fr) 2011-11-28 2013-06-06 Mylan Laboratories Ltd Nouveau procédé pour la préparation d'intermédiaires d'inhibiteurs de la hmg-coa réductase
JP2015533785A (ja) * 2013-02-20 2015-11-26 エッフェ・イ・エッセ − ファッブリカ・イタリアーナ・シンテテイチ・ソチエタ・ペル・アツィオーニＦ．Ｉ．Ｓ． − Ｆａｂｂｒｉｃａ Ｉｔａｌｉａｎａ Ｓｉｎｔｅｔｉｃｉ Ｓ．ｐ．Ａ． スタチン類の簡便な製造方法

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KR101710976B1 (ko) * 2015-04-08 2017-02-28 임광민 키랄 화합물의 제조방법 및 이를 이용한 HMG-CoA 환원저해제의 제조방법

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