WO2004048362A1 - Verfahren zur reinigung von liponsäure - Google Patents
Verfahren zur reinigung von liponsäure Download PDFInfo
- Publication number
- WO2004048362A1 WO2004048362A1 PCT/EP2003/012819 EP0312819W WO2004048362A1 WO 2004048362 A1 WO2004048362 A1 WO 2004048362A1 EP 0312819 W EP0312819 W EP 0312819W WO 2004048362 A1 WO2004048362 A1 WO 2004048362A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lipoic acid
- acid
- purified
- purification
- racemic
- Prior art date
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
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
Definitions
- the present invention relates to a process for the purification of racemic or non-racemic lipoic acid.
- the invention relates to a process for the purification of R- or S-lipoic acid which has an oligomer content in the range from about 0.1 to about 1.0% by weight.
- the invention further relates to the use of the lipoic acid purified in the manner according to the invention in medicaments, cosmetics and foods.
- 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. B. pyruvate dehydrogenase, a central role in energy production.
- R-Lipoic acid is activated to fully develop its very good antioxidative properties in the metabolism to dihydroliponic acid.
- Dihydrolipoic acid and lipoic acid since they are converted into one another in vivo, can be used for the same fields of application.
- R-lipoic acid has an advantageous 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.
- the use of dihydrolipoic acid and / or lipoic acid as a pharmaceutical is also possible.
- 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.
- lipoic acid or dihydrolipoic acid or their derivatives can be used for the treatment of glucose metabolism disorders (e.g. in the CNS), insulin resistance, cancer and hearing disorders.
- the contamination of the lipoic acid obtained by characteristic impurities which arise as a result of oligomerization or polymerization of the lipoic acid itself is particularly problematic. Even small amounts of these oligomers in the product lead to serious complications in further processing and cannot be tolerated with regard to the pharmaceutical use of the lipoic acid produced in this way.
- DE-A-100 44 000 and DE-A-100 59 718 describe a process for the purification of lipoic acid obtained by oxidation of dihydrolipoic acid by clarification, which is suitable for experiments on a laboratory scale.
- the object of the present invention was to develop a process for the purification of lipoic acid which can also be used economically on an industrial scale.
- a process for the purification of lipoic acid has now been found, which is characterized in that a solution of lipoic acid is mixed with at least 0.1 times the amount of an adsorbent, based on the mass of lipoic acid to be purified, and then the adsorbent is separated off.
- racemic or non-racemic lipoic acid with an oligomer content of less than 1% by weight, for example 0.1 to 1% by weight can be made available.
- Low-polar organic solvents in particular aliphatic, optionally heteroatom-substituted hydrocarbons with one to twelve carbon atoms, such as e.g. Pentane, hexane, cyclohexane, heptane or dichloroethane or aromatic, optionally alkyl or heteroatom-substituted hydrocarbons such as toluene, ethylbenzene or chlorobenzene or mixtures of the solvent classes mentioned.
- optionally heteroatom-substituted hydrocarbons with one to twelve carbon atoms, such as e.g. Pentane, hexane, cyclohexane, heptane or dichloroethane or aromatic, optionally alkyl or heteroatom-substituted hydrocarbons such as toluene, ethylbenzene or chlorobenzene or mixtures of the solvent classes mentioned.
- Preferred solvents for the cleaning process according to the invention are aliphatic hydrocarbons with one to twelve carbon atoms and alkyl-substituted aromatic hydrocarbons with up to twelve carbon atoms.
- Particularly preferred solvents are pentane, hexane, cyclohexane, heptane, octane, toluene and ethylbenzene, very particularly preferably heptane and toluene or mixtures of at least two of the solvents mentioned.
- Suitable adsorbents are commercially available adsorbents such as silica gels, neutral aluminum oxides, basic aluminum oxides and mixtures of the adsorbents mentioned, preferably silica gels.
- Particularly preferred adsorbents are silica gel 60 with a grain size of 0.04 -
- silica gel 40 (grain size 0.015 - 0.035 mm) and silica gel 100 (grain size 0.063 - 0.2 mm).
- the amount of the adsorbent to be used in the cleaning process according to the invention depends on the amount of lipoic acid to be cleaned and is generally at least 10% by weight of the amount of lipoic acid to be cleaned. This applies in particular when using the particularly preferred adsorbent silica gel.
- the use of at least 15% by weight of silica gel based on the amount of lipoic acid to be purified is particularly preferred. It is very particularly preferred to use 20 to 50% by weight of silica gel, based on the amount of lipoic acid to be purified.
- non-racemic lipoic acid means all mixtures of R- and S-lipoic acid in which the two enantiomers are not present in equal parts.
- R- or S-lipoic acid with an enantiomeric excess (ee) of in each case greater than 80% ee, more preferably greater than 90% ee, very particularly preferably greater than 95% ee are preferably purified by the process according to the invention. Most preferably, R- or S-lipoic acid are purified with an enantiomeric excess of more than 99% ee.
- the cleaning method according to the invention is suitable for the production of chemically pure R- or S-lipoic acid. It is particularly suitable for the production of R- or S-lipoic acid with a chemical purity of at least 99%, very particularly at least 99.5%.
- the cleaning method according to the invention is particularly suitable for the production of R- or S-lipoic acid with an oligomer content of at most 0.2% by weight.
- the lipoic acid to be purified can be pre-cleaned or used as a solid or partially dissolved crude product from a previous process step in the cleaning process according to the invention.
- the cleaning process can be carried out on any scale. However, it is particularly suitable for cleaning lipoic acid on an industrial scale.
- the invention also relates to the further processing of the R- or S-lipoic acid purified according to the invention, e.g. B. in pharmacologically acceptable salts, such as alkali and alkaline earth metal salts or z.
- pharmacologically acceptable salts such as alkali and alkaline earth metal salts or z.
- the invention also relates to the use of racemic, non-racemic or enantiomerically pure liponic acid purified by the process according to the invention in medicaments, in cosmetics or in foods, for example as nutraceutical.
- the R-dihydrolipoic acid isolated in this way was taken up in water, a catalytic amount of iron (II) sulfate was added and the mixture was gassed with air until conversion was complete. It was then acidified with sulfuric acid (pH 2) and extracted with toluene. The toluene solution was mixed with heptane and pressed with a slight positive pressure over a pressure filter filled with 5 kg of silica gel 60.
- the filtered solution was cooled and the R-lipoic acid which crystallized out was isolated by pressure filtration and dried in a stream of nitrogen.
- R-lipoic acid (ee> 99.9%) was obtained in a yield of 73% of theory Regarding (6S) -6,8-di-hydroxyoctanoic acid methyl ester.
- the content of oligomers of lipoic acid was determined to be 0.3% by gel permeation chromatography (column: PL gel, eluent THF).
- the above example was repeated under the same conditions until the cleaning step.
- the toluene solution obtained after acidification with sulfuric acid was mixed with heptane and pressed over a pressure filter filled with 1 kg of silica gel 60 with a slight excess pressure.
- the filtered solution was cooled and the R-lipoic acid which crystallized out was isolated by pressure filtration and dried in a stream of nitrogen.
- R-lipoic acid (ee> 99.9%) was obtained in a yield of 73% of theory Regarding (6S) -6,8-di-hydroxyoctanoic acid methyl ester.
- the content of oligomers of lipoic acid was determined to be 2.5% by gel permeation chromatography (column: PL gel, eluent THF).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Endocrinology (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Cosmetics (AREA)
- Noodles (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Detergent Compositions (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003288079A AU2003288079A1 (en) | 2002-11-26 | 2003-11-17 | Method for the purification of liponic acid |
DE50303744T DE50303744D1 (de) | 2002-11-26 | 2003-11-17 | Verfahren zur reinigung von liponsäure |
US10/532,205 US7091368B2 (en) | 2002-11-26 | 2003-11-17 | Method for the purification of liponic acid |
EP03779948A EP1567516B1 (de) | 2002-11-26 | 2003-11-17 | Verfahren zur reinigung von liponsäure |
JP2004554367A JP2006510621A (ja) | 2002-11-26 | 2003-11-17 | リポ酸の精製方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10255242.8 | 2002-11-26 | ||
DE10255242A DE10255242A1 (de) | 2002-11-26 | 2002-11-26 | Verfahren zur Reinigung von Liponsäure |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004048362A1 true WO2004048362A1 (de) | 2004-06-10 |
Family
ID=32240454
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/012819 WO2004048362A1 (de) | 2002-11-26 | 2003-11-17 | Verfahren zur reinigung von liponsäure |
Country Status (9)
Country | Link |
---|---|
US (1) | US7091368B2 (de) |
EP (1) | EP1567516B1 (de) |
JP (1) | JP2006510621A (de) |
AT (1) | ATE328878T1 (de) |
AU (1) | AU2003288079A1 (de) |
DE (2) | DE10255242A1 (de) |
DK (1) | DK1567516T3 (de) |
ES (1) | ES2266885T3 (de) |
WO (1) | WO2004048362A1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010052310A1 (en) * | 2008-11-07 | 2010-05-14 | Segix Italia S.R.L. | Alpha-lipoic acid derivatives and their use in drug preparation |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8278358B2 (en) * | 2006-07-06 | 2012-10-02 | Omnica Gmbh | Lipoic acid derivatives |
KR20110103987A (ko) * | 2008-12-01 | 2011-09-21 | 인베이스크 테라퓨틱, 인크. | 레닌-안지오텐신 알도스테론계 억제제 및 리포산 화합물을 포함하는 조성물, 및 레닌-안지오텐신 알도스테론계 관련 질환의 치료를 위한 이의 용도 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10044000A1 (de) * | 2000-09-05 | 2002-03-21 | Basf Ag | Verfahren zur Herstellung von Liponsäure und Dihydroliponsäure |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4037440A1 (de) | 1990-11-24 | 1992-05-27 | Basf Ag | Verfahren zur herstellung von (6s)-6,8-dihydroxyoctansaeureestern |
DE4137773A1 (de) | 1991-11-16 | 1993-05-19 | Degussa | Herstellung und verwendung von salzen der reinen enantiomere der (alpha)-liponsaeure |
DE10022856A1 (de) | 2000-05-10 | 2001-11-15 | Basf Ag | Therapeutische Kombination von Liponsäure und C1-Donoren zur Behandlung von Störungen des Zentralen Nervensystems |
DE10027875A1 (de) | 2000-06-06 | 2001-12-13 | Basf Ag | Einsatz von Liponsäure mit einem (R)-Enantiomeren-Überschuss in Kosmetika und Dermatika |
JP2004514716A (ja) | 2000-11-30 | 2004-05-20 | ビーエーエスエフ アクチェンゲゼルシャフト | リポ酸およびジヒドロリポ酸の調製方法 |
-
2002
- 2002-11-26 DE DE10255242A patent/DE10255242A1/de not_active Withdrawn
-
2003
- 2003-11-17 ES ES03779948T patent/ES2266885T3/es not_active Expired - Lifetime
- 2003-11-17 US US10/532,205 patent/US7091368B2/en not_active Expired - Fee Related
- 2003-11-17 DE DE50303744T patent/DE50303744D1/de not_active Expired - Fee Related
- 2003-11-17 AU AU2003288079A patent/AU2003288079A1/en not_active Abandoned
- 2003-11-17 AT AT03779948T patent/ATE328878T1/de not_active IP Right Cessation
- 2003-11-17 EP EP03779948A patent/EP1567516B1/de not_active Expired - Lifetime
- 2003-11-17 JP JP2004554367A patent/JP2006510621A/ja not_active Withdrawn
- 2003-11-17 WO PCT/EP2003/012819 patent/WO2004048362A1/de active IP Right Grant
- 2003-11-17 DK DK03779948T patent/DK1567516T3/da active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10044000A1 (de) * | 2000-09-05 | 2002-03-21 | Basf Ag | Verfahren zur Herstellung von Liponsäure und Dihydroliponsäure |
Non-Patent Citations (2)
Title |
---|
BITAMIN, vol. 40, no. 3, 1969, ENG, pages 185 - 192 * |
CHEMICAL ABSTRACTS, vol. 71, no. 25, 1969, Columbus, Ohio, US; abstract no. 119752c, NAKATA,TARO: "BIOLOGICALLY ACTIVE LIPOIC ACID-LIKE SUBSTANCES IN URINE.II.PURIFICATION" page 24; column 2; XP002268589 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010052310A1 (en) * | 2008-11-07 | 2010-05-14 | Segix Italia S.R.L. | Alpha-lipoic acid derivatives and their use in drug preparation |
Also Published As
Publication number | Publication date |
---|---|
DE10255242A1 (de) | 2004-06-03 |
JP2006510621A (ja) | 2006-03-30 |
ES2266885T3 (es) | 2007-03-01 |
DE50303744D1 (de) | 2006-07-20 |
DE10255242A9 (de) | 2004-12-23 |
US7091368B2 (en) | 2006-08-15 |
US20060014823A1 (en) | 2006-01-19 |
EP1567516A1 (de) | 2005-08-31 |
EP1567516B1 (de) | 2006-06-07 |
DK1567516T3 (da) | 2006-10-09 |
ATE328878T1 (de) | 2006-06-15 |
AU2003288079A1 (en) | 2004-06-18 |
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