WO1994012460A1 - Process for preparing substantially pure enantiomers of phenylpropionic acids - Google Patents
Process for preparing substantially pure enantiomers of phenylpropionic acids Download PDFInfo
- Publication number
- WO1994012460A1 WO1994012460A1 PCT/EP1993/003376 EP9303376W WO9412460A1 WO 1994012460 A1 WO1994012460 A1 WO 1994012460A1 EP 9303376 W EP9303376 W EP 9303376W WO 9412460 A1 WO9412460 A1 WO 9412460A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- enriched
- ibuprofen
- methylbenzylamine
- stage
- salt
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
Definitions
- the present invention relates to the production of substantially pure enantiomers of phenylpropionic acids selected from ibuprofen, flurbiprofen and pharmaceutically acceptable salts thereof, in particular their ⁇ -methylbenzylamine, lysine and sodium salts.
- Ibuprofen the chemical name of which is 2-(4- isobutylphenyl)propionic acid and flurbiprofen, the chemical name of which is 2-(2-fluoro-4-biphenylyl)- propionic acid are well known medicaments with anti- inflammatory, antipyretic and analgesic activities.
- ibuprofen and flurbiprofen include the treatment of pain and inflammation in musculoskeletal disorders such as rheumatic disease, and the treatment of pain in a variety of other disorders, for example headache, neuralgia and dysmenorrhoea.
- Both ibuprofen and flurbiprofen contain a single chiral centre at an asymmetrically substituted carbon atom and therefore both exist in two enantiomeric forms. It is known that S(+)-ibuprofen is the active agent and that R(-) -ibuprofen may be incompletely converted into S (+)-ibuprofen in humans. It is also known that S.+)- flurbiprofen is the active agent. R(-)-flurbiprofen is not converted into the (S)-enantiomer in humans, although it has been suggested that R(-)-flurbiprofen has analgesic activity only (international patent application WO 92/04018 [Paz]).
- Ibuprofen and flurbiprofen have been marketed previously as the racemic mixture. However in certain circumstances it may be advantageous to administer substantially one enantiomer only. Therefore it is desirable to provide improved processes for production of a product enriched in a desired enantiomer of a phenylpropionic acid selected from ibuprofen and flurbiprofen.
- European Patent Application 0362476 describes the separation of enantiomeric forms of aryl propionic acids by selective crystallisation of a diastereomeric salt in a polar solvent. Use of polar solvents are stated to be more favourable than apolar solvents, which teaches away from using the specific solvent mixture in the process of the present invention.
- United States Patent 5,015,764 Manimaran relates to the preparation of aliphatic carboxylic acids including ibuprofen and flurbiprofen by treating a solution of their salts with a chiral organic base to selectively precipitate the less soluble diastereoisomer. There is no disclosure of the use of the specific solvent mixture used in the process of the present invention.
- European Patent Application 0437369 describes the preparation of (S)-ibuprofen-(S)-lysine salts by contacting racemic ibuprofen with an equimolar amount of
- the desired enantiomer of the phenylpropionic acid is the (S)-enantiomer and:
- the substantially racemic phenylpropionic acid and ( S)- ⁇ -methylbenzylamine are used in a respective molar ratio of about 1:0.35 to about 1:0.8, for example about 1:0.4 to about 1:0.6 and the preparation takes place in a mixture of methanol and toluene, in which the toluene comprises at least about 50%, more preferably from about 60% to about 90%, most preferably from about 70% to about 80%, of the total mixture by volume; the temperature of the mixture is in the range from about 30°C to about 70°C, preferably from about 40°C to about 60°C, to form a supersaturated solution; from which a phenylpropionic acid -(S)- ⁇ -methylbenzylamine salt enriched in the (S)-enantiomer of the phenylpropionic acid is crystallised, for example when the solution is cooled to a temperature in the range from about -10°C to about 30°C, preferably from about
- the preferred solvent is a mixture of methanol and toluene in which the toluene comprises at least about 25%, more preferably from about 50% to about 80%, most preferably from about 60% to about 70%, of the total mixture by volume; from which a phenylpropionic acid -(S)- ⁇ -methylbenzylamine salt further enriched in the (S) -enantiomer of the phenylpropionic acid is crystallised, for example when the solution is cooled to a temperature in the range from about -10°C to about 30°C, preferably from about 0°C to about 5°C;
- the (S)- ⁇ -methylbenzylamine salt of further-(S)-enriched-phenylpropionic acid, obtained from the recrystallisation stage is acidified (for example with hydrochloric acid) in a water-immiscible solvent to produce a solution of liberated (S) -enriched-phenylpropionic acid in the water-immiscible solvent and an aqueous solution of a salt of (S)- ⁇ -methylbenzylamine (for example, the hydrochloride salt) from which (S)- ⁇ - methylbenzylamine can be liberated so that it can be reused in a subsequent resolution stage (a), for example by basifying the solution and extracting the liberated base into toluene;
- the solution of further-(S)-enriched-phenylpropionic acid in the water-immiscible solvent obtained from the liberation stage (c) may be further processed by one or more of the following methods:
- step (ii) removal of the solvent by distillation to give a melt which can be used in step (v) below;
- steps d(i) to d(iii) above may be used in one or more of the following further steps:
- step d(i) the solid from step d(i) above or the melt from step d(ii) which is separated and reacted in an aqueous ethanolic solution with (S)-lysine in which the molar ratio of the phenylpropionic acid to (S)-lysine is in the range 1:0.5 to 1:1, to give, after crystallisation and separation, an (S)- lysine salt of the further-(S)-enriched- phenylpropionic acid;
- the phenylpropionic acid is ibuprofen and the desired enantiomer is the (S)-enantiomer.
- the desired enantiomer is the (S)-enantiomer.
- the resolution stage produces a (S)- ⁇ - methylbenzylamine salt of (S)-enriched ibuprofen of an enantiomeric purity from about 80% to about 95% by weight, and a first mother liquor comprising
- a first recrystallisation step comprising recrystallising the (S)-enriched-ibuprofen-
- (S)- ⁇ -methylbenzylamine produced from the resolution stage (a), to produce (S)- enriched-ibuprofen-(S)-methylbenzylamine preferably of an enantiomeric purity from about 90% to about 99.9%, more preferably from about 94% to about 99%, by weight, and a second mother liquor comprising (S) -enriched ibuprofen- (S) - ⁇ -methylbenzylamine of an enantiomeric purity from about 40% to about
- a second recrystallisation step comprising recrystallisation of the (S)-enriched- ibuprofen-(S)- ⁇ -methylbenzylamine produced from the first recrystallisation step (b) (i) to produce substantially enantiomerically pure (S)-ibuprofen-(S)- ⁇ -methylbenzylamine, preferably of an enantiomer purity of about 99%, and a third mother liquor comprising (S)-enriched-ibuprofen-(S)- ⁇ -methylbenzylamine of an enantiomeric purity from about 85% to about 95% by weight, preferably from about 88% to about 95% by weight, the third mother liquor being introduced as part of the solvent used in into a subsequent first recrystallisation step (b) (i).
- the first mother liquor from the resolution stage (a) is subjected to azeotropic distillation to remove substantially all the methanol at temperatures which avoid substantially the formation of by-products, the distillate being reused as part of the solvent in a subsequent resolution stage (a).
- the residue remaining after the distillation above may be acidified, with for example hydrochloric acid, to give an aqueous solution of a (S)- ⁇ -methylbenzylamine salt, for example (S)- ⁇ - methylbenzylamine hydrochloride, and an organic phase comprising (R) -enriched ibuprofen.
- the aqueous solution is then separated and basified to give free (S)- ⁇ - methylbenzylamine which is extracted into toluene and reused as the resolving agent at the start of a subsequent resolution stage (a) along with (S)- ⁇ - methylbenzylamine recovered in the liberation stage (s).
- the organic phase comprising (R)-enriched-ibuprofen may be racemised in a racemisation stage (e) by any known method to produce substantially racemic ibuprofen which may then be introduced as part of the solvent used at the start of a subsequent resolution stage (a).
- liquors not comprising the phenylpropionic acid enriched in the desired enantiomer may be recycled by using them in previous stages of the process.
- the recrystallisation stage in the process described above may include a third and/or subsequent recrystallisation step.
- Figure 1 is a diagrammatic flow chart of a preferred process of the invention for production of (S)-ibuprofen in which the letters refer to the stages or steps labelled (a), (b)(i), (b)(ii), (c), (d) and (e) in the above described processes and; the numbers 1 to 3 indicate the first to third mother liquors respectively, the number 4 indicates the recycled (S)- ⁇ -methylbenzylamine and the number 5 indicates the recycled racemised ibuprofen.
- dotted lines indicate recycled materials and solid lines indicates material increasing in enrichment of (S) -ibuprofen in the direction of the arrow.
- Resolution stage (a) yields an (S) -enriched- ibuprofen- (S) - ⁇ -methylbenzylamine product which is used as the starting material for the first recrystallisation step (b) (i).
- the first mother liquors (1) from the resolution stage (a) pass to a racemisation stage (e) from which racemic ibuprofen (5) is recycled to form part of the starting material for a subsequent resolution stage (a) and recovered (S)- ⁇ - methylbenzylamine (4) is recycled to be used as part of the resolving agent for a subsequent resolution stage (a).
- the second mother liquors (2) from the first recrystallisation step (b) (i) are recycled for use in a subsequent resolution step (a).
- the product of the first recrystallisation step (b) (i) undergoes a second recrystallisation step (b) (ii) to give (S)-ibuprofen- (S)- ⁇ -methylbenzylamine of increased enantiomeric purity and a third mother liquor which is recycled to form part of the solvent used in a subsequent first recrystallisation step (b) (i).
- the product from the second recrystallisation step (b) (ii) is then used in a liberation stage (c) to give (S)-ibuprofen of high enantiomeric purity.
- (S)- ⁇ -Methylbenzylamine (4) which is also liberated in the liberation stage (c) is recycled to be used as part of the resolving agent for a subsequent resolution stage (a).
- the liberated (S)- ibuprofen may then be used in an optional salt- preparation stage (d) to form salts (for example the sodium or (S)-lysine salt) containing (S)-ibuprofen of even higher enantiomeric purity.
- a product; of the above processes when the phenylpropionic acid is ibuprofen and the desired enantiomer is the (S)-enantiomer, may be used to prepare a (S)-lysine salt of (S)-enriched ibuprofen by contacting the liberated (S)-enriched- ibuprofen with
- (S)-lysine preferably with a stoichiometric amount or less of (S)-lysine to produce a (S)-lysine salt of further-(S)-enriched-ibuprofen, more preferably the molar ratio of ibuprofen to (S)-lysine being in the range from about 1:0.5 to about 1:1 preferably about 1:0.5 to about 1:0.95.
- the liberated (S)-enriched- ibuprofen can also be contacted with sodium hydroxide to produce further-(S)-enriched sodium ibuprofen (see for example International Patent Application WO 92/20334).
- the process of the present invention gives (S)-ibuprofen, and salts thereof, of high enantiomeric purity.
- (S)- enriched-flurbiprofen may be crystallised from toluene with the efficient removal of the other enantiomer to give (S)-flurbiprofen of a high enantiomeric purity.
- Examples 2(a) and 2(b) illustrate that a substantial upgrading in the enantiomeric purity of (S)- enriched-ibuprofen-(S)- ⁇ -methylbenzylamine can be achieved at the recrystallisation stage in the process of the present invention.
- the upper layer comprising a toluene solution of (S)-enriched-ibuprofen was washed with water (100 1) to give 920 kg of a solution containing 300 kg of (S)-enriched-ibuprofen of enantiomeric purity of 98.5% by weight.
- Examples 4.1 to 4.12 were performed as described below with reference to Table 1.
- Ibuprofen enriched in the (S)-enantiomer 100 g of a material containing 'a' % of the (S)-enantiomer
- ethanol 900 ml
- a solution of (S) -lysine monohydrate ('b' g) in a mixture of water ('c' ml) and ethanol ('d' ml) was prepared.
- the ibuprofen solution and the (S)-lysine solution were added simultaneously at equimolar rates over a period of one hour to a suspension of (S)-ibuprofen-(S)-lysine salt (9.5 g) in water (11 ml) and ethanol (125 ml) which had been stirred at 20°C for 10 minutes. The mixture was then cooled to 0°C over one hour and then cooled to -10°C. The mixture was stirred at -10°C for two hours.
- a mixture of the first mother liquors from the resolution stage was concentrated by distillation to remove methanol and toluene for recovery and subsequent reuse.
- Methanol (300 1) and concentrated sulphuric acid was heated under reflux for 2 hours.
- the upper organic layer was separated and heated under reflux with methanol (75 1) and concentrated sulphuric acid (15 1) for two hours.
- the upper layer was separated and heated with solid sodium hydroxide (175 kg).
- Methanol was removed by distillation and the residue acidified with a mixture of concentrated hydrochloric acid (353 kg) and water (1750 1).
- the upper toluene layer containing racemic ibuprofen was washed with water and used in the resolution stage of a subsequent preparation similar to that described in Example 1.
- Racemic flurbiprofen (61.0 g) was dissolved in a mixture of methanol (40 ml) and toluene (160 ml). The mixture was heated to 60°C and (S)- ⁇ -methylbenzylamine 16.9 ml was added over 10 minutes. A seed crystal of (S)-flurbiprofen-(S)- ⁇ -methylbenzylamine was added to the reaction mixture which was then cooled to 0 to 5°C, and held at that temperature for one hour.
- Racemic flurbiprofen (i) g was dissolved in a mixture of methanol (ii) ml, and toluene (iii) ml and optionally water (iv) ml. The mixture was heated to 55°C to form a solution and (R)- ⁇ - methylbenzylamine (v) ml was added over 10 minutes. A seed crystal of (R)-flurbiprofen-(R)- ⁇ -methylbenzylamine was added to the mixture which was cooled to 25°C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
RU95113445/04A RU2133733C1 (en) | 1992-12-02 | 1993-11-30 | Method of synthesis of phenylpropionic acid |
KR1019950702237A KR100280766B1 (en) | 1992-12-02 | 1993-11-30 | Method for preparing substantially pure enantiomer of phenylpropionic acid |
AU56504/94A AU672269B2 (en) | 1992-12-02 | 1993-11-30 | Process for preparing substantially pure enantiomers of phenylpropionic acids |
EP94901940A EP0672030B1 (en) | 1992-12-02 | 1993-11-30 | Process for preparing substantially pure enantiomers of phenylpropionic acids |
DE69309958T DE69309958T2 (en) | 1992-12-02 | 1993-11-30 | METHOD FOR PRODUCING THE MAIN ENANTIOMERS OF PHENYL PROPIONIC ACIDS |
CA002150355A CA2150355C (en) | 1992-12-02 | 1993-11-30 | Process of resolving phenylpropionic acids using alpha-methylbenzylamine |
JP6512791A JPH08504193A (en) | 1992-12-02 | 1993-11-30 | Method |
US08/424,517 US5599969A (en) | 1992-12-02 | 1993-11-30 | Process of resolving phenylpropionic acids using α-methylbenzylamine |
FI952677A FI110776B (en) | 1992-12-02 | 1995-06-01 | Process for the preparation of substantially pure enantiomers of substituted phenylpropionic acids |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929225203A GB9225203D0 (en) | 1992-12-02 | 1992-12-02 | Process |
GB929225202A GB9225202D0 (en) | 1992-12-02 | 1992-12-02 | Process |
GB9225202.2 | 1992-12-02 | ||
GB9225203.0 | 1992-12-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994012460A1 true WO1994012460A1 (en) | 1994-06-09 |
Family
ID=26302084
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1993/003376 WO1994012460A1 (en) | 1992-12-02 | 1993-11-30 | Process for preparing substantially pure enantiomers of phenylpropionic acids |
Country Status (12)
Country | Link |
---|---|
US (1) | US5599969A (en) |
EP (1) | EP0672030B1 (en) |
JP (1) | JPH08504193A (en) |
KR (1) | KR100280766B1 (en) |
AT (1) | ATE151740T1 (en) |
AU (1) | AU672269B2 (en) |
CA (1) | CA2150355C (en) |
DE (1) | DE69309958T2 (en) |
ES (1) | ES2100037T3 (en) |
FI (1) | FI110776B (en) |
RU (1) | RU2133733C1 (en) |
WO (1) | WO1994012460A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0672029A1 (en) * | 1992-12-02 | 1995-09-20 | Hoechst Celanese Corporation | SELECTIVE PRECIPITATION OF $g(a)-ARYL CARBOXYLIC ACID SALTS |
WO2004065344A1 (en) * | 2003-01-23 | 2004-08-05 | Nagase & Co., Ltd. | Process for producing optically active flurbiprofen |
WO2010001103A1 (en) * | 2008-06-30 | 2010-01-07 | Aesica Pharmaceuticals Limited | Process for the manufacture of racemic 2-aryl-propionic acid |
WO2014045046A3 (en) * | 2012-09-21 | 2014-06-26 | Aesica Pharmaceuticals Limited | Drug substance preparations, pharmaceutical compositions and dosage forms comprising s-(+)-flurbiprofen |
WO2015145163A1 (en) * | 2014-03-26 | 2015-10-01 | Aesica Pharmaceuticals Limited | Process for the manufacture of s-(+)-flurbiprofen |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IN189741B (en) * | 1998-11-09 | 2003-04-19 | Council Scient Ind Res | |
AU2001257022B2 (en) * | 2000-04-13 | 2005-02-03 | Mayo Foundation For Medical Education And Research | Abeta 42 lowering agents |
JP2002069030A (en) * | 2000-08-30 | 2002-03-08 | Kyowa Hakko Kogyo Co Ltd | Method for manufacturing sodium 2-{4-[(2-oxocyclopentyl) methyl]phenyl)propionate 2 hydrate |
EP1603548A4 (en) * | 2003-02-05 | 2007-10-10 | Myriad Genetics Inc | Method and composition for treating neurodegenerative disorders |
AU2004311577A1 (en) * | 2003-07-11 | 2005-07-21 | Myriad Genetics, Inc. | Pharmaceutical methods, dosing regimes and dosage forms for the treatment of Alzheimer's disease |
US20070293538A1 (en) * | 2004-04-13 | 2007-12-20 | Myriad Genetics, Incorporated | Pharmaceutical Composition And Methods For Treating Neurodegenerative Disorders |
MXPA06012165A (en) * | 2004-04-29 | 2007-01-17 | Keystone Retaining Wall System | Veneers for walls, retaining walls and the like. |
WO2006020850A2 (en) * | 2004-08-11 | 2006-02-23 | Myriad Genetics, Inc. | Pharmaceutical composition and method for treating neurodegenerative disorders |
WO2006020852A2 (en) * | 2004-08-11 | 2006-02-23 | Myriad Genetics, Inc. | Pharmaceutical composition and method for treating neurodegenerative disorders |
CN101048139A (en) * | 2004-10-28 | 2007-10-03 | 艾德克斯实验室公司 | Compositions for controlled delivery of pharmaceutically active compounds |
KR20080039876A (en) * | 2005-07-22 | 2008-05-07 | 미리어드 제네틱스, 인크. | High drug load formulations and dosage forms |
US7754679B2 (en) * | 2005-11-16 | 2010-07-13 | Idexx Laboratories, Inc. | Pharmaceutical compositions for the administration of aptamers |
US8114440B2 (en) * | 2005-11-16 | 2012-02-14 | Idexx Laboratories Inc. | Pharmaceutical compositions for the administration of aptamers |
WO2008006099A2 (en) * | 2006-07-07 | 2008-01-10 | Myriad Genetics, Inc. | Treatment of psychiatric disorders |
CA2677125C (en) * | 2007-02-01 | 2018-07-10 | Myriad Genetics, Inc. | Drug substance preparations, pharmaceutical compositions and dosage forms |
US8828960B2 (en) * | 2007-07-17 | 2014-09-09 | Idexx Laboratories, Inc. | Amino acid vitamin ester compositions for controlled delivery of pharmaceutically active compounds |
CN115286501A (en) * | 2022-08-10 | 2022-11-04 | 浙江新和成股份有限公司 | Comprehensive utilization method of ibuprofen crystallization mother liquor |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55136245A (en) * | 1979-04-09 | 1980-10-23 | Sumitomo Chem Co Ltd | Optical resolution of alpha-isopropyl-p-chlorophenyl-acetic acid |
WO1993014056A1 (en) * | 1992-01-21 | 1993-07-22 | Ethyl Corporation | Profen resolution |
US5248813A (en) * | 1992-10-14 | 1993-09-28 | Ethyl Corporation | Enantiomeric resolution |
US5260482A (en) * | 1992-10-14 | 1993-11-09 | Ethyl Corporation | Enantiomeric resolution |
Family Cites Families (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1497044A (en) * | 1974-03-07 | 1978-01-05 | Prodotti Antibiotici Spa | Salts of phenyl-alkanoic acids |
IT1059677B (en) * | 1974-03-22 | 1982-06-21 | Neopharmed Spa | THERAPEUTIC ACTION LYSINE SALT |
DE3824353A1 (en) * | 1988-07-19 | 1990-01-25 | Paz Arzneimittelentwicklung | METHOD FOR SEPARATING MIXED ENANTIOMER ARYLPROPIONIC ACIDS |
CA2016887A1 (en) * | 1989-05-16 | 1990-11-16 | Henrich H. Paradies | Process for preparing optically active 2-aryl-alkanoic acids, in particular 2-aryl propionic acids |
DE69022678T2 (en) * | 1989-10-17 | 1996-03-21 | Merck & Co Inc | S (+) - ibuprofen-L-amino acid and S (+) - ibuprofen-D-amino acid as analgesics with greater pharmacological potential. |
US5200558A (en) * | 1989-10-17 | 1993-04-06 | Merck & Co., Inc. | S(+)-ibuprofen-L-amino acid and S(+)-ibuprofen-D-amino acid as onset-hastened enhanced analgesics |
US4994604A (en) * | 1990-01-10 | 1991-02-19 | Merck & Co., Inc. | Formation and resolution of ibuprofen lysinate |
US5015764A (en) * | 1990-06-18 | 1991-05-14 | Ethyl Corporation | Preparation of optically active aliphatic carboxylic acids |
DE4028906A1 (en) * | 1990-09-12 | 1992-03-19 | Paz Arzneimittelentwicklung | MEDICINAL PRODUCTS AND THEIR PREPARATION AND THEIR USE IN THE CONTROL OF PAIN AND / OR DEFENSE AND / OR FEVER OF ANIMALS AND PEOPLE |
HUT59692A (en) * | 1990-11-15 | 1992-06-29 | Puetter Medice Chem Pharm | Process for producing complexes containing s/+/-phenyl-alkanoic acids and aminosugars |
HUT59656A (en) * | 1990-11-15 | 1992-06-29 | Puetter Medice Chem Pharm | Process for producing s/+/-phenyl-alkanoic acids and alpha-amino-acids containing complexes and pharmaceutical compositions containing them as active components |
ATE143805T1 (en) * | 1991-03-22 | 1996-10-15 | Merck & Co Inc | MEDICINAL PREPARATION WITH A HIGH CONTENT OF IBUPROFENLYSINATE |
DE69231359T2 (en) * | 1991-05-13 | 2001-02-08 | The Boots Co., Plc | PHARMACEUTICAL COMPOSITION CONTAINING IBUPROFEN SALT |
FR2687673B1 (en) * | 1992-01-13 | 1995-07-07 | Jung Jean | AMINE SALTS OF ARYLCARBOXYLIC ACIDS, STERILIZABLE, WATER SOLUBLE, USED IN OPHTHALMOLOGY AND / OR IN THE OTORHINOLARYNGOLOGICAL SPHERE. |
US5288507A (en) * | 1992-07-29 | 1994-02-22 | Merck & Co., Inc. | Ibuprofen antacid combinations |
WO1994003209A1 (en) * | 1992-07-29 | 1994-02-17 | Merck & Co., Inc. | Dexibuprofen/antacid/simethicone combinations |
WO1994007471A1 (en) * | 1992-09-29 | 1994-04-14 | Merck & Co., Inc. | Ibuprofen-caffeine combinations |
US5278337A (en) * | 1992-10-14 | 1994-01-11 | Ethyl Corporation | Enantiomeric resolution of aryl-substituted aliphatic carboxylic acids |
US5380867A (en) * | 1992-12-02 | 1995-01-10 | Hoechst Celanese Corporation | Selective precipitation of α-aryl carboxylic acid salts |
-
1993
- 1993-11-30 DE DE69309958T patent/DE69309958T2/en not_active Expired - Lifetime
- 1993-11-30 JP JP6512791A patent/JPH08504193A/en active Pending
- 1993-11-30 AT AT94901940T patent/ATE151740T1/en not_active IP Right Cessation
- 1993-11-30 KR KR1019950702237A patent/KR100280766B1/en not_active IP Right Cessation
- 1993-11-30 CA CA002150355A patent/CA2150355C/en not_active Expired - Lifetime
- 1993-11-30 RU RU95113445/04A patent/RU2133733C1/en not_active IP Right Cessation
- 1993-11-30 EP EP94901940A patent/EP0672030B1/en not_active Expired - Lifetime
- 1993-11-30 ES ES94901940T patent/ES2100037T3/en not_active Expired - Lifetime
- 1993-11-30 WO PCT/EP1993/003376 patent/WO1994012460A1/en active IP Right Grant
- 1993-11-30 AU AU56504/94A patent/AU672269B2/en not_active Expired
- 1993-11-30 US US08/424,517 patent/US5599969A/en not_active Expired - Lifetime
-
1995
- 1995-06-01 FI FI952677A patent/FI110776B/en active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55136245A (en) * | 1979-04-09 | 1980-10-23 | Sumitomo Chem Co Ltd | Optical resolution of alpha-isopropyl-p-chlorophenyl-acetic acid |
WO1993014056A1 (en) * | 1992-01-21 | 1993-07-22 | Ethyl Corporation | Profen resolution |
US5248813A (en) * | 1992-10-14 | 1993-09-28 | Ethyl Corporation | Enantiomeric resolution |
US5260482A (en) * | 1992-10-14 | 1993-11-09 | Ethyl Corporation | Enantiomeric resolution |
Non-Patent Citations (1)
Title |
---|
PATENT ABSTRACTS OF JAPAN vol. 5, no. 8 (C - 39)<680> 20 January 1981 (1981-01-20) * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0672029A1 (en) * | 1992-12-02 | 1995-09-20 | Hoechst Celanese Corporation | SELECTIVE PRECIPITATION OF $g(a)-ARYL CARBOXYLIC ACID SALTS |
EP0672029A4 (en) * | 1992-12-02 | 1996-02-07 | Hoechst Celanese Corp | SELECTIVE PRECIPITATION OF -g(a)-ARYL CARBOXYLIC ACID SALTS. |
WO2004065344A1 (en) * | 2003-01-23 | 2004-08-05 | Nagase & Co., Ltd. | Process for producing optically active flurbiprofen |
US7214820B2 (en) | 2003-01-23 | 2007-05-08 | Nagase & Co., Ltd. | Process for producing optically active flurbiprofen |
WO2010001103A1 (en) * | 2008-06-30 | 2010-01-07 | Aesica Pharmaceuticals Limited | Process for the manufacture of racemic 2-aryl-propionic acid |
GB2477218A (en) * | 2008-06-30 | 2011-07-27 | Aesica Pharmaceuticals Ltd | Process for the manufacture of racemic 2-aryl-propionic acid |
WO2014045046A3 (en) * | 2012-09-21 | 2014-06-26 | Aesica Pharmaceuticals Limited | Drug substance preparations, pharmaceutical compositions and dosage forms comprising s-(+)-flurbiprofen |
WO2015145163A1 (en) * | 2014-03-26 | 2015-10-01 | Aesica Pharmaceuticals Limited | Process for the manufacture of s-(+)-flurbiprofen |
Also Published As
Publication number | Publication date |
---|---|
ATE151740T1 (en) | 1997-05-15 |
KR100280766B1 (en) | 2001-02-01 |
EP0672030B1 (en) | 1997-04-16 |
ES2100037T3 (en) | 1997-06-01 |
JPH08504193A (en) | 1996-05-07 |
DE69309958D1 (en) | 1997-05-22 |
FI952677A0 (en) | 1995-06-01 |
FI952677A (en) | 1995-06-01 |
DE69309958T2 (en) | 1997-07-24 |
RU95113445A (en) | 1997-06-10 |
KR950704226A (en) | 1995-11-17 |
EP0672030A1 (en) | 1995-09-20 |
AU5650494A (en) | 1994-06-22 |
US5599969A (en) | 1997-02-04 |
CA2150355C (en) | 2008-03-11 |
RU2133733C1 (en) | 1999-07-27 |
FI110776B (en) | 2003-03-31 |
AU672269B2 (en) | 1996-09-26 |
CA2150355A1 (en) | 1994-06-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU672269B2 (en) | Process for preparing substantially pure enantiomers of phenylpropionic acids | |
US5281722A (en) | Preparation and use of salts of the pure enantiomers of alpha-lipoic acid | |
US5380867A (en) | Selective precipitation of α-aryl carboxylic acid salts | |
US5332834A (en) | Racemization of an enantomerically enriched α-aryl carboxylic acid | |
CA2623355A1 (en) | Resolution of .alpha.-(phenoxy) phenylacetic acid derivatives with naphthyl-alkylamines | |
US4585595A (en) | Optically active derivatives of mercaptoisobutyric acid and methods of preparation thereof | |
US4546201A (en) | Process for the optical resolution of (±)2-(6'methoxy-2'-naphthyl)-propionic acid | |
US5235095A (en) | Preparation of optically active aliphatic carboxylic acids | |
US5220053A (en) | Preparation of optically active aliphatic carboxylic acids | |
US5621140A (en) | Resolution of ibuprofen | |
JP2004511476A (en) | Method for producing R (+) α-lipoic acid | |
US5574183A (en) | Preparation of optically active aliphatic carboxylic acids | |
US5235101A (en) | Preparation by flotation of optically active aliphatic carboxylic acids | |
US5578734A (en) | Method for the preparation of S-(+)-ethodolic acid and saline derivatives | |
EP0409044B1 (en) | A process for the optical resolution of dropropizine | |
WO1989005787A2 (en) | Processes and compounds useful for resolving 1-methyl-3-phenylpropylamine | |
CN1071733C (en) | Process | |
EP1029846A1 (en) | Resolution of alpha-arylpropionic acids | |
JPH0440349B2 (en) | ||
ITMI972257A1 (en) | PROCESS FOR PREPARATION OF PROPIONIC 2- (4-ISOBUTYLPHENYL) ACID | |
HU197866B (en) | Process for resolving cys-2,2-dimethyl-3-/2,2-disubsti-tuted-vinyl/-cyclopropane-carboxylic acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU LV MG MN MW NL NO NZ PL PT RO RU SD SE SK UA US VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1994901940 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2150355 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 952677 Country of ref document: FI |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1019950702237 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08424517 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1994901940 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWG | Wipo information: grant in national office |
Ref document number: 1994901940 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 952677 Country of ref document: FI |