WO2007108572A1 - Procédé d'élaboration de l-carnitine - Google Patents

Procédé d'élaboration de l-carnitine Download PDF

Info

Publication number
WO2007108572A1
WO2007108572A1 PCT/KR2006/002003 KR2006002003W WO2007108572A1 WO 2007108572 A1 WO2007108572 A1 WO 2007108572A1 KR 2006002003 W KR2006002003 W KR 2006002003W WO 2007108572 A1 WO2007108572 A1 WO 2007108572A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
gamma
carnitine
butyrolactone
acyloxy
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2006/002003
Other languages
English (en)
Inventor
Soon Ook Hwang
Sun Ho Chung
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Enzytech Ltd
Original Assignee
Enzytech 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.)
Filing date
Publication date
Application filed by Enzytech Ltd filed Critical Enzytech Ltd
Publication of WO2007108572A1 publication Critical patent/WO2007108572A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K71/00—Manufacture or treatment specially adapted for the organic devices covered by this subclass
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/38—Compounds containing oxirane rings with hydrocarbon 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
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon 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 by ester radicals
    • G—PHYSICS
    • G02—OPTICS
    • G02F—OPTICAL DEVICES OR ARRANGEMENTS FOR THE CONTROL OF LIGHT BY MODIFICATION OF THE OPTICAL PROPERTIES OF THE MEDIA OF THE ELEMENTS INVOLVED THEREIN; NON-LINEAR OPTICS; FREQUENCY-CHANGING OF LIGHT; OPTICAL LOGIC ELEMENTS; OPTICAL ANALOGUE/DIGITAL CONVERTERS
    • G02F1/00—Devices or arrangements for the control of the intensity, colour, phase, polarisation or direction of light arriving from an independent light source, e.g. switching, gating or modulating; Non-linear optics
    • G02F1/01—Devices or arrangements for the control of the intensity, colour, phase, polarisation or direction of light arriving from an independent light source, e.g. switching, gating or modulating; Non-linear optics for the control of the intensity, phase, polarisation or colour 
    • G02F1/13—Devices or arrangements for the control of the intensity, colour, phase, polarisation or direction of light arriving from an independent light source, e.g. switching, gating or modulating; Non-linear optics for the control of the intensity, phase, polarisation or colour  based on liquid crystals, e.g. single liquid crystal display cells
    • G02F1/1303—Apparatus specially adapted to the manufacture of LCDs
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K71/00—Manufacture or treatment specially adapted for the organic devices covered by this subclass
    • H10K71/50—Forming devices by joining two substrates together, e.g. lamination techniques
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10P—GENERIC PROCESSES OR APPARATUS FOR THE MANUFACTURE OR TREATMENT OF DEVICES COVERED BY CLASS H10
    • H10P72/00—Handling or holding of wafers, substrates or devices during manufacture or treatment thereof
    • H10P72/30—Handling or holding of wafers, substrates or devices during manufacture or treatment thereof for conveying, e.g. between different workstations
    • H10P72/32—Handling or holding of wafers, substrates or devices during manufacture or treatment thereof for conveying, e.g. between different workstations between different workstations
    • H10P72/3218—Conveying cassettes, containers or carriers
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10P—GENERIC PROCESSES OR APPARATUS FOR THE MANUFACTURE OR TREATMENT OF DEVICES COVERED BY CLASS H10
    • H10P72/00—Handling or holding of wafers, substrates or devices during manufacture or treatment thereof
    • H10P72/70—Handling or holding of wafers, substrates or devices during manufacture or treatment thereof for supporting or gripping
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J2209/00—Apparatus and processes for manufacture of discharge tubes

Definitions

  • the present invention relates to the process for the preparation of L-carnitine represented by the general formula 7 in scheme 1.
  • racemic 3-acyloxy-gamma-butyrolactone represented by the general formula 1 is hydrolyzed stereospecifically using enzymes in the aqueous phase or organic phase including aqueous solvent, based on the above reaction,
  • (R)-3-acyloxy-gamma-butyrolactone represented by the general formula 2 is prepared therefrom, and (R)-3-hydroxy-gamma-butyrolactone is prepared by hydrolysis from either (R)-3-acyloxy-gamma-butyrolactone or (R)-4-chloro-3-hydroxybutyrate represented by the general fomula 4, followed by ring-opening reaction using both of halogen acid and carboxylic acid for the preparation of (R)-3-acyloxy-4-halobutyric acid represented by the general formula 5, epoxydation reaction for the preparation of (R)-3,4-epoxybutyric acid salt or (R)-3,4-epoxybutyric acid in the presence of a base consecutively. Then, L-carnitine is produced by well-known methods.
  • R is selected from substituted or unsubstituted alkyl groups or alkenyl groups, wherein the alkyl contains from C to C , benzyl groups, cycloalkyl groups
  • R is halogen group such as F, Cl, Br, and I
  • Carnitine occurrs as two enantiomers, L-carnitine and D-carnitine.
  • L-carnitime is normally present in the body, and plays a vital role in metabolism of the fatty acid and carrying fatty acid through the mitochindria membrane.
  • L-carnitine is a natural substance used in energy metabolism and elevation of the heart faculty. L-carnitine and their derivatives are used as an anticonvulsant and blood product supplements.
  • Optically resolving agent including L-tartaric acid(European Patent 157,315), dibenzoyl-D-tartaric acid(U.S. Pat. 4,933,490), dibenzoyl -L-tartaric acid(U.S. Pat. 4,610,828), D-mandelic acid(Japanese Unexamined Patent Publication Sho 59-231,048) and N-acetyl-D-glutamate(Japanese Unexamined Patent Publication Hei 1-131,143) were reacted with D,L-carnitine or the racemate of its derivatives. Then, L- carnitine was seperated using the difference of solubility in solvent. But the above method has some difficulties in recrystallization step.
  • L-carnitine is produced by stereoselective hydroxy lation of crotonobetain or gamma-butyrobetain using microorganisms or enzymes(U.S. Pat. 4,708,936, U.S. Pat. 4,371,618, U.S. Pat. 4,650,759).
  • (S)-3-hydroxy-gamma-butyrolactone as starting material is subjected to ring-opening reaction and epoxydation with an inversion of the chiral center, and nucleophilic substitution by trimethylamine(Korean Patent 0255039).
  • L-carnitine can be prepared from (R)-epichlorohydrin by ring-opening reaction using trimethylamine and the reaction with acetonitrile and crown ether in acidic condition(Korean Patent 10-2005-0010203). But this method is unsuitable becase starting material is too expensive.
  • (R)-3-hydroxy-gamma-butyrolactone is prepared by hydrolysis using enzymes(Korea Patent Application # 10-2005-0089119), or alkyl (R)-4-chloro-3-hydroxybutyrate using acid(Liebigs Ann. IRecueil, 1877-1879, 1997) or resin catalyst(H+ resin, Korean Patent Application # 10-2005-0010927),
  • (R)-3-hydroxy-gamma-butyrolactone is subjected to ring-opening reaction using both of halogen acid and carboxylic acid to prepare (R)-3-acyloxy-4-halobutyric acid.
  • (R)-3-acyloxy-4-halobutyric acid is subjected to epoxydation reaction to prepare (R)-3,4-epoxybutyric acid or it's salt.
  • L-carnitine is produced via a well-known reaction(Journal of Organic Chemistry, 53, 104-107, 1988).
  • the epoxy compound can be produced easily from (R)-3-hydroxy-gamma-butyrolactone because the inversion step is not required.
  • optically pure compound(99 ee%) can be produced by hydrolysis using enzyme, so L-carnitine with high optical purity can be obtained.
  • This invention does not include using expensive or unsafe agent. Low-price compounds are used compared to the traditional process. Based on these facts, the above method for preparing L-carnitine is expected to be economical in the industrial application.
  • (R)-3-hydroxy-gamma-butyrolactone is prepared from racemic 3-acyloxy-gamma-butyrolactone by sterospecific hydrolysis using lipases in aqeous phase or organic phase including aqueous solvent, or by hydrolysis from (R)-3-acyloxy-gamma-butyrolactone. And (R)-3-hydroxy-gamma-butyrolactone can be produced from alkyl (4)-4-chloro-3-hydroxyburtrate.
  • L-carnitine is produced from the above compound by ring-opening reaction using both of halogen acid and alkyl carboxylic acid to prepare (R)-3-acyloxy-4-halobutyric acid, and epoxydation of (R)-3-acyloxy-4-halobutyric acid to prepare (R)-3,4-epoxybutyric acid salt or (R)-3,4-epoxybutyric acid consecutively.
  • R is selected from substited or unsubstited alkyl groups or alkenyl groups, wherein the alkyl contains from C to C , benzyl groups, cycloalkyl
  • R is halogen group(F, Cl, Br, I)
  • R is alkyl groups comprising n 2n+l 4 from C 1 to C 8.
  • CAL B Novozyme 435, Novozyme
  • PS-D Mano
  • lipase producing microorganisms are also suitable as biocatalysts.
  • halogen acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid and C ⁇ C alkylcarboxyric acid such as acetic acid may be used.
  • Epoxydation reaction is carried out in aqeous solution or mixture of aqeous phase and organic phase, wherein bases according to this invention include the following;
  • Alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, and lithium hydroxide
  • Alkaline earth metal hydroxide such as magnesium hydroxide, calcium hydroxide and barium hydroxide
  • Alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium t- butoxide
  • Alkylamine such as NHR R (wherein,R and R are alkyl groups of Cl-I, respectively), and
  • Quaternary ammonium hydroxide such as tetrabutyl ammonium hydroxide, benzylt rimethyl ammonium hydroxide.
  • L-carnitine is prepared from (R)-3,4-epoxybutyric acid salt or (R)-3,4-epoxybutyric acid obtained from the above reaction by adding trimethylamine according to the general process.
  • NMR(Burker Inc., Model DPX300) and 3-hydroxy-gamma-butyrolactone, 3-acyloxy-gamma-butyrolactone, ethyl 4-chlro-3-hydroxybutyrate, 3-acetoxy-3-bromobutyric acid were analyzed by gas chromatography(Donam Instruments Inc., Model DS6200) eqipped with HP-FF AP(Agilent Inc., 3O m X 0.53 mm) column.
  • (R)-3,4-epoxybutyrate sodium salt was prepared by addition of the aqueous solution of 3N NaOH to (R)-3-acetoxy-4-bromo butyric acid which was prepared from Example 4. Then the solution was acidified to pH 3-4 and extracted with ethyl ether. The combined organic extracts were distilled under reduced pressure to (R)-3,4-epoxybutyric acid and was confirmed IH-NMR.
  • racemic 3-acyloxy-gamma-butyrolactone as a raw materal is hydrolyzed stereospecifically using enzymatic method or (R)-4-chloro-3-hydroxybutyrate is hydrolyzed to (R)-3-hydroxy-gamma-butyrolactone, followed by the ring-opening reaction, epoxydation, and nucleophilic substitution consecutively.
  • low- price compounds such as sulfuric acid, sodium hydroxide and trimethylamine are used. Therefore, this method is an economically useful process on the industrial scale.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Manufacturing & Machinery (AREA)
  • Physics & Mathematics (AREA)
  • Nonlinear Science (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Epoxy Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé d'élaboration de L-carnitine à partir de 3-acyloxy-gamma-butyrolactone ou d'alkyl (R)-4-chloro-3-hydroxybutyrate racémique, et plus précisément à partir de (R)-3-hydroxy-gamma-butyrolactone, élaboré à partir de 3-acyloxy-gamma-butyrolactone racémique par hydrolyse stéréospécifique au moyen d'une enzyme en phase aqueuse ou organique comprenant un solvant ou un alkyl (R)-4-chloro-3-hydroxybutyrate aqueux, suivi d'une réaction d'ouverture de chaîne, d'une époxydation et d'une substitution nucléophile par triméthylamine, pour l'élaboration de L-carnitine. Le procédé considéré est plus simple et plus économique que les procédés classiques et le produit résultant offre une pureté optique accrue.
PCT/KR2006/002003 2006-03-22 2006-05-26 Procédé d'élaboration de l-carnitine Ceased WO2007108572A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020060026015A KR100846673B1 (ko) 2006-03-22 2006-03-22 엘-카르니틴의 제조방법
KR10-2006-0026015 2006-03-22

Publications (1)

Publication Number Publication Date
WO2007108572A1 true WO2007108572A1 (fr) 2007-09-27

Family

ID=38522592

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2006/002003 Ceased WO2007108572A1 (fr) 2006-03-22 2006-05-26 Procédé d'élaboration de l-carnitine

Country Status (2)

Country Link
KR (1) KR100846673B1 (fr)
WO (1) WO2007108572A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015040288A1 (fr) 2013-09-20 2015-03-26 Sunpartner Technologies Dispositif catadioptrique améliorant la visualisation d'une image placée devant un capteur solaire
CN112679570A (zh) * 2020-12-25 2021-04-20 武汉回盛生物科技股份有限公司 一种泰地罗新的合成与纯化方法
CN113735725A (zh) * 2021-09-27 2021-12-03 江苏福瑞康泰药业有限公司 一种左旋肉碱的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6284902B1 (en) * 1998-07-24 2001-09-04 Samsung Fine Chemicals Co., Ltd. Process for manufacturing an optically active (S)-3,4-epoxybutyric acid salt
US6342034B1 (en) * 1997-07-28 2002-01-29 Samsung Fine Chemicals Co., Ltd. Process for the preparation of L-carnitine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6084131A (en) 1998-06-01 2000-07-04 Board Of Trustees Operating Michigan State University Process for the preparation of protected dihydroxypropyl trialkylammonium salts and derivatives thereof
IT1301977B1 (it) 1998-07-31 2000-07-20 Sigma Tau Ind Farmaceuti Procedimento per la preparazione di r-(-)-carnitina

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6342034B1 (en) * 1997-07-28 2002-01-29 Samsung Fine Chemicals Co., Ltd. Process for the preparation of L-carnitine
US6284902B1 (en) * 1998-07-24 2001-09-04 Samsung Fine Chemicals Co., Ltd. Process for manufacturing an optically active (S)-3,4-epoxybutyric acid salt

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015040288A1 (fr) 2013-09-20 2015-03-26 Sunpartner Technologies Dispositif catadioptrique améliorant la visualisation d'une image placée devant un capteur solaire
CN112679570A (zh) * 2020-12-25 2021-04-20 武汉回盛生物科技股份有限公司 一种泰地罗新的合成与纯化方法
CN113735725A (zh) * 2021-09-27 2021-12-03 江苏福瑞康泰药业有限公司 一种左旋肉碱的制备方法

Also Published As

Publication number Publication date
KR100846673B1 (ko) 2008-07-16
KR20070095618A (ko) 2007-10-01

Similar Documents

Publication Publication Date Title
JP5214249B2 (ja) ベタインの製造方法
CA2298664A1 (fr) Procede de preparation de l-carnitine
WO2007139238A1 (fr) Procédé de préparation de l-carnitine et de chlorhydrure de l-carnitile d'acétyle
KR100846673B1 (ko) 엘-카르니틴의 제조방법
JP6169812B2 (ja) リパーゼを利用してベータ−ラクトンからｌ−カルニチンを生産する方法
WO2004003001A1 (fr) Procede de resolution enzymatique de 1,3-dioxolane-4-carboxylates
KR100910645B1 (ko) (알)-3,4-에폭시부틸산 및 그의 염을 제조하는 방법
US5087751A (en) Method of preparing optically active 3,4-dihydroxy butyric acid derivatives
CA1309683C (fr) Procede pour la preparation du chlorure de l(-)-carnitine a partir d'esters 3,4-epoxybutyriques et nouveaux composes intermediaires
KR100803548B1 (ko) 엘-카르니틴의 제조방법
KR100880816B1 (ko) (알)-3,4-에폭시부틸산 및 그의 염을 제조하는 방법
JP4843812B2 (ja) 酵素を使用するラセミα−置換ヘテロ環式カルボン酸の光学分割方法
JP3333184B2 (ja) 光学活性を有する（ｓ）−３，４−エポキシ酪酸塩の製造方法
EP0339618B1 (fr) Procédé de préparation de dérivés de l'acide 3,4-dihydroxybutyrique optiquement actifs
JP3704731B2 (ja) 光学活性３−ヒドロキシヘキサン酸類の製造方法
JP2003534808A (ja) 酵素を用いるＲ−体又はＳ−体のα−置換ヘテロサイクリックカルボン酸及びこれと反対鏡像の鏡像異性体のα−置換ヘテロサイクリックカルボン酸エステルの調製方法
JPH05227988A (ja) （２ｒ，３ｅ）−４−ハロ−３−ブテン−２−オールの製造方法
JP3095539B2 (ja) 光学活性α，β−エポキシカルボン酸およびそのエステルの製造法
KR20080110794A (ko) 엘-카르니틴 및 아세틸 엘-카르니틴 염산염의 제조방법
KR20040063264A (ko) 효모를 이용한 광학활성 (ｒ)-2-클로로만델릭산 및 그에스테르 유도체의 제조방법
WO2007078176A1 (fr) Procede de fabrication d'esters d'acide 2-chloromandelique optiquement actifs et d'acides 2-chloromandeliques par un procede enzymatique
KR100527231B1 (ko) 무수숙신산에 의한 광학활성 1,2-디올 유도체와 이의 에스테르 제조방법
JP3970898B2 (ja) 光学活性α−メチルアルカンジカルボン酸−ω−モノエステル及びその対掌体ジエステルを製造する方法
HK1194768A (en) Process for producing l-carnitine from beta-lactones employing lipases
JPWO1996002664A1 (ja) 光学活性トリアゾール化合物の製造方法および光学活性トリアゾール化合物をラセミ化する方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06768645

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC DATED 29.12.2008.

122 Ep: pct application non-entry in european phase

Ref document number: 06768645

Country of ref document: EP

Kind code of ref document: A1