EP1307442A2 - Procede de production d'acide lipoique et d'acide dihydrolipoique - Google Patents

Procede de production d'acide lipoique et d'acide dihydrolipoique

Info

Publication number
EP1307442A2
EP1307442A2 EP01971775A EP01971775A EP1307442A2 EP 1307442 A2 EP1307442 A2 EP 1307442A2 EP 01971775 A EP01971775 A EP 01971775A EP 01971775 A EP01971775 A EP 01971775A EP 1307442 A2 EP1307442 A2 EP 1307442A2
Authority
EP
European Patent Office
Prior art keywords
acid
dihydroliponic acid
dihydroliponic
extraction
organic solvent
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.)
Withdrawn
Application number
EP01971775A
Other languages
German (de)
English (en)
Inventor
Martin Jochen Klatt
Markus Niebel
Joachim Paust
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.)
BASF SE
Original Assignee
BASF SE
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
Priority claimed from DE2000138038 external-priority patent/DE10038038A1/de
Priority claimed from DE2000144000 external-priority patent/DE10044000A1/de
Application filed by BASF SE filed Critical BASF SE
Publication of EP1307442A2 publication Critical patent/EP1307442A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/18—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by addition of thiols to unsaturated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • C07C321/02—Thiols having mercapto groups bound to acyclic carbon atoms
    • C07C321/04—Thiols having mercapto groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton

Definitions

  • the invention relates to processes for the production of R- and S-lipoic acid and R- and S-dihydrolipoic acid.
  • the invention relates to processes for producing pure R- or S-dihydrolipoic acid, which is either used directly or is further processed to R- and S-lipoic acid.
  • Dihydrolipoic acid and lipoic acid are naturally occurring substances that are of particular importance in cell metabolism.
  • R-lipoic acid plays as a coenzyme, e.g. pyruvate dehydrogenase, a central role in energy production.
  • R-Lipoic acid is activated in the metabolism to fully develop its very good anti-oxidative properties to dihydrolipoic acid. Since they are converted into one another in vivo, dihydrolipoic acid and lipoic acid can be used for the same fields of application.
  • R-Lipoic acid has a positive effect on age-related changes in the metabolism and is therefore also of interest in the cosmetic field.
  • Lipoic acid and dihydrolipoic acid can be used as nutraceutical in the food sector.
  • R-lipoic acid increases insulin sensitivity and can therefore be used as an anti-diabetic, also for the prevention and relief of late diabetic damage.
  • R- and S-lipoic acid or dihydrolipoic acid are known.
  • the enantiomerically pure lipoic acid and dihydrolipoic acid are produced in various ways such as chemical or enzymatic cleavage of the racemate, with the help of chiral templates, by enantioselective synthesis or microbiological transformation.
  • the yields of lipoic acid with respect to (1) are 65%; the material obtained has only a purity in the GC of 98% when introducing S with KSAc, which could be problematic for human applications.
  • Ms for -S0 -R 'and R and R' independently of one another represent 10 Cx-C ö alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, aryl or aralkyl, preferably methyl, with sodium sulfide and sulfur in ethanol and subsequent reaction with a complex hydride of pure dihydroliponic acid
  • This reaction is preferably carried out without isolating the intermediates.
  • Ms mesylate or tosylate.
  • the process according to the invention achieves a higher chemical purity of R- or S-lipoic acid in comparison with the process described in EP 487 986.
  • the compound (2) is e.g. prepared by reacting the corresponding 6, 8-dihydroxyoctanoic acid alkyl ester (1) with triethylamine and 30 mesyl chloride.
  • the preferred alkyl esters are C 1 -C 6 -alkyl, methyl is particularly preferred.
  • Aryl or Ar in aralkyl preferably denotes phenyl, naphthyl, which can each be substituted by one, two or three Ci- -t-alkyl radicals;
  • "alkyl" in aralkyl or cycloalkyl-alkyl means preferably -CC 4 alkyl, particularly preferably -CH-.
  • reaction of the sulfonic acid derivatives 2, e.g. of the mesylate is preferably carried out in an ethanolic NaS-S mixture with over
  • the ethanolic mixture preferably contains at least equimolar amounts of NaS, S and mesylate and at most one 100% molar excess of NaS and S based on mesylate. A 25 to 35% molar excess is preferred
  • the ethanolic Na -S mixture is preferably boiled beforehand.
  • Complex hydrides are preferably boranates, in particular alkali boranates such as NaBH 4 .
  • the reaction with complex hydrides is preferably carried out in an alkaline solution, especially in a concentrated alkali hydroxide solution.
  • a borol solution (12% NaBH 4 in 14M NaOH) is particularly preferred.
  • dihydroliponic acid is obtained in high yield.
  • the dihydrolipoic acid obtained in this way is oxidized and crystallized to lipoic acid, very pure lipoic acid (GC> 99.5%, ee HPLC (CSP)> 99% (detection limit)) is obtained in high yield.
  • the oxidation can be carried out with FeCl / air, the crystallization preferably in heptane / toluene (WO 00/08012).
  • dihydrolipoic acid can be decomposed without substantial decomposition in a temperature range from 160 to 220 ° C, preferably even at 180 to 210 ° C, particularly preferably at 200 ° C ⁇ 5 ° C, at pressures of 0.5 to 5 mbar, particularly preferably at 1 to 3 mbar, distill.
  • the distillation is preferably carried out continuously (Sambay, falling film or thin film evaporator). This pressure range can be realized technically without considerable effort.
  • Sambay falling film or thin film evaporator
  • the protic solution of dihydroliponic acid is extracted with an organic solvent at a pH of 9 to 10, preferably at 9.5, more yield of crystals is obtained after working up to lipoic acid. If the protic solution of dihydrolipoic acid is extracted into a pH of 4 to 5, preferably 4.5, in organic solvent, more yield of crystallizate is obtained after working up to lipoic acid.
  • Protic solutions are solvent mixtures with at least 30% water, preferably more than 50% water, particularly preferably more than 75% water.
  • the other components are polar solvents such as DMF or alcohols, especially ethanol.
  • Organic solvents for extraction are preferably apolar solvents, e.g. halogenated solvents such as methylene chloride or chloroform, glycol ethers, ethers such as diethyl ether or methyl-t.
  • esters such as ethyl acetate, aliphatic and aromatic hydrocarbons such as cyclohexane, hexane, heptane, toluene, or mixtures thereof, hexane, heptane, toluene and ethyl acetate being preferred as solvents.
  • Pure liponic acid or pure dihydroliponic acid means chemically and in particular enantiomerically pure liponic acid or dihydroliponic acid.
  • R- or S-dihydroliponic acid and R-lipoic acid or S-lipoic acid mean material which preferably has an enantiomeric purity (ee value determined by HPLC, CSP) of greater than / equal to 70%, preferably 80%, particularly preferably 90%, very particularly preferably 95%, even more preferably 97% or 98%, most preferably 99% and larger, ie lying on the detection line.
  • enantiomeric purity ee value determined by HPLC, CSP
  • R- or S-dihydroliponic acid material is preferably with a purity greater than or equal to 80%, particularly preferably greater than or equal to 90%, very particularly preferably greater than or equal to 95% or 97%.
  • material is preferably greater than 99%, particularly preferably greater than 99.5%, very particularly preferably greater than 99.9%. This corresponds to the detection limit of the methods used.
  • the invention relates to the further processing of R-lipoic acid or S-lipoic acid obtained by the processes according to the invention in pharmacologically acceptable derivatives such as esters or amides of lipoic acid.
  • pharmacologically acceptable derivatives such as esters or amides of lipoic acid.
  • the implementation and derivatives are known from the literature.
  • the invention also relates to the further processing of the R- or S-lipoic acid prepared according to the invention into pharmacologically acceptable salts, such as alkali and alkaline earth metal salts or, for example, the trometamol salt of R-lipoic acid.
  • pharmacologically acceptable salts such as alkali and alkaline earth metal salts or, for example, the trometamol salt of R-lipoic acid.
  • the invention further relates to a new optically active trithiol of the formula
  • the 1, 6, 8-octanetrithiol results from the 1, 6, 8-octanetriol during the introduction of sulfur.
  • the triol is a minor component of the diol (1). It is enriched during extraction with pH 9 in the organic phase and can be isolated from it.
  • the octanetrithiol can be used as an optically active synthetic building block and as a selective catalyst poison.
  • the reaction mixture is mixed with 0.5 mol of the mesylate. It is diluted with demineralized water and 174 g (0.55 mol) of borol solution are added. The mixture is adjusted to pH 9 with sulfuric acid and extracted with toluene. The toluene phase is discarded. The mixture is then adjusted to pH 4 and extracted with toluene. The organic phase is freed from the solvent. The remaining oil is distilled in a falling film evaporator (1 to 3 mbar, 200 ° C). Yield: 95.2 g (97%, 88% with respect to diol 1).
  • Air is gassed until the conversion is complete.
  • the solution is adjusted to pH 2 and extracted with toluene.
  • the phases are separated and the organic phase is concentrated.
  • Technical heptane is added to the residue and pressed through a filter loaded with 5 g of silica gel.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Endocrinology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un procédé pour produire de l'acide lipoïque R ou de l'acide lipoïque S, comportant une opération sélectionnée dans le groupe comprenant (a) la distillation de l'acide dihydrolipoïque, (b) la mise en réaction de (2) ou de son stéréo-isomère, Ms signifiant SO2-R' et R et R' signifiant indépendamment l'un de l'autre alkyle C1-C6, cycloalkyle C3-C8, cycloalkylalkyle C3-C8, aryle ou aralkyle, avec du sulfure de sodium et du soufre dans de l'éthanol, et la mise en réaction avec un hydrure complexe, (c) l'extraction d'une solution protique d'acide dihydrolipoïque R ou d'acide dihydrolipoïque S au moyen de solvants organiques avec un pH allant de 9 à 10, ou (d) l'extraction d'acide dihydrolipoïque R ou d'acide dihydrolipoïque S au moyen de solvants organiques d'une solution protique dont le pH va de 4 à 5. Le procédé peut également être une combinaison de certaines opérations de (a) à (d) ou de plusieurs opérations de (a) à (d). L'invention porte aussi sur un procédé pour produire de l'acide dihydrolipoïque et sur le composé 1,6,8 octantriol.
EP01971775A 2000-08-02 2001-07-24 Procede de production d'acide lipoique et d'acide dihydrolipoique Withdrawn EP1307442A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10038038 2000-08-02
DE2000138038 DE10038038A1 (de) 2000-08-02 2000-08-02 Verfahren zur Herstellung von Liponsäure und Dihydroliponsäure
DE10044000 2000-09-05
DE2000144000 DE10044000A1 (de) 2000-09-05 2000-09-05 Verfahren zur Herstellung von Liponsäure und Dihydroliponsäure
PCT/EP2001/008523 WO2002010151A2 (fr) 2000-08-02 2001-07-24 Procede de production d'acide lipoique et d'acide dihydrolipoique

Publications (1)

Publication Number Publication Date
EP1307442A2 true EP1307442A2 (fr) 2003-05-07

Family

ID=26006609

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01971775A Withdrawn EP1307442A2 (fr) 2000-08-02 2001-07-24 Procede de production d'acide lipoique et d'acide dihydrolipoique

Country Status (10)

Country Link
US (1) US6906210B2 (fr)
EP (1) EP1307442A2 (fr)
JP (1) JP2004509856A (fr)
CN (2) CN1218945C (fr)
AR (1) AR030108A1 (fr)
AU (1) AU2001291677A1 (fr)
BR (1) BR0112848A (fr)
CA (1) CA2417842A1 (fr)
TW (1) TW200519076A (fr)
WO (1) WO2002010151A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093433A1 (fr) 2006-02-17 2007-08-23 Carl Zeiss Smt Ag Système d'éclairage pour la MICRO-LITHOGRAPHIE, équipement d'éclairage par projection équipé d'un tel système d'éclairage

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7914815B2 (en) * 2000-08-16 2011-03-29 Encore Health, Llc Method for delivery of pharmaceuticals for treating or preventing presbyopia
US8647612B2 (en) * 2008-03-05 2014-02-11 Encore Health, Llc Dithiol compounds, derivatives, and treatment of presbyopia
US8147816B2 (en) * 2000-08-16 2012-04-03 Encore Health, Llc Presbyopia treatment by lens alteration
US8697109B2 (en) * 2000-08-16 2014-04-15 Encore Health, Llc Caged mercaptan and seleno-mercaptan compounds and methods of using them
US20050112113A1 (en) * 2000-08-16 2005-05-26 Till Jonathan S. Presbyopia treatment by lens alteration
US7935332B2 (en) * 2000-08-16 2011-05-03 Encore Health, Llc Presbyopia treatment by lens alteration
AU2002229576A1 (en) * 2000-11-30 2002-06-11 Basf Aktiengesellschaft Method for producing lipoic acid and dihydrolipoic acid
CN100387593C (zh) * 2006-01-26 2008-05-14 南京师范大学 连续逆流液液萃取分离二硫辛酸与乙醇及碱水溶液的方法
US20090078581A1 (en) * 2007-09-24 2009-03-26 Applied Intellectual Capital Configurations and Methods of Reduction of Lipoic Acid
WO2009111635A2 (fr) * 2008-03-05 2009-09-11 Encore Health, Llc Composés dithiols, dérivés et utilisations associées
US9044439B2 (en) * 2008-03-05 2015-06-02 Encore Health, Llc Low dose lipoic and pharmaceutical compositions and methods
JP2012510511A (ja) * 2008-12-01 2012-05-10 インヴアスク セラピューテイックス インコーポレイテッド レニン−アンジオテンシン−アルドステロン系阻害剤及びリポ酸化合物を含有する組成物、並びに、レニン−アンジオテンシン−アルドステロン系に関連した疾患の治療のためのそれらの使用
EP3069612A3 (fr) 2009-06-15 2016-10-19 Encore Health, LLC Composés dithiols, dérivés et leurs utilisations
WO2010147962A1 (fr) 2009-06-15 2010-12-23 Encore Health, Llc Esters de choline
CA2941518A1 (fr) 2014-03-03 2015-09-11 Encore Vision, Inc. Compositions d'ester de choline de l'acide lipoique et procedes d'utilisation correspondants
US9944960B2 (en) 2015-11-17 2018-04-17 Premier Research Labs, Lp Process for microbial production of dihydrolipoic acid and extraction of dihydrolipoic acid with edible oils
JP6794246B2 (ja) * 2016-12-26 2020-12-02 カーリットホールディングス株式会社 ジヒドロリポ酸及びその塩の製造方法
DE102017000811A1 (de) 2017-01-28 2018-08-02 Alzchem Trostberg Gmbh Verfahren zur Herstellung von Dihydroliponsäure
CN111377840A (zh) * 2018-12-29 2020-07-07 江苏同禾药业有限公司 一种r-(+)-二氢硫辛酸的制备方法
CN116102532B (zh) * 2023-01-09 2025-03-18 国药集团威奇达药业有限公司 从硫辛酸结晶母液中回收硫辛酸的方法

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DE4137773A1 (de) 1991-11-16 1993-05-19 Degussa Herstellung und verwendung von salzen der reinen enantiomere der (alpha)-liponsaeure
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007093433A1 (fr) 2006-02-17 2007-08-23 Carl Zeiss Smt Ag Système d'éclairage pour la MICRO-LITHOGRAPHIE, équipement d'éclairage par projection équipé d'un tel système d'éclairage

Also Published As

Publication number Publication date
CN1444580A (zh) 2003-09-24
AR030108A1 (es) 2003-08-13
BR0112848A (pt) 2003-06-24
JP2004509856A (ja) 2004-04-02
US6906210B2 (en) 2005-06-14
AU2001291677A1 (en) 2002-02-13
WO2002010151A3 (fr) 2002-11-14
WO2002010151A2 (fr) 2002-02-07
CN1218945C (zh) 2005-09-14
CN1680364A (zh) 2005-10-12
US20040044227A1 (en) 2004-03-04
TW200519076A (en) 2005-06-16
CA2417842A1 (fr) 2003-01-30

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