Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1995-06-21
1997-02-04
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C07B 5700
Patent
active
055999697
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/03376 filed Nov. 30, 1993.
FIELD OF THE INVENTION
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 .alpha.-methylbenzylamine, lysine and sodium salts.
DESCRIPTION OF THE RELATED ART
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. Known uses of 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 (Paz) 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.
U.S. Pat. No. 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 (S)-lysine in an aqueous organic solvent mixture, separating any suspended solid from the mixture, cooling the clear mixture until it is supersaturated with respect to both the (R)-ibuprofen-(S)-lysine and the (S)-ibuprofen-(S)-lysine salts, contacting the supersaturated solution with a slurry of (S)-ibuprofen-(S)-lysine salt and separating the formed crystalline S)-ibuprofen-(S)-lysine salt.
International Patent Application WO 92/20334 Boots) describes the preparation of the sodium salt of (S)-ibuprofen.
SUMMARY OF THE INVENTION
The present invention provides a process for the production of a product which is enriched in a desired enantiomer of a phenylpropionic acid selected from ibuprofen and flurbiprofen which comprises the following stages: phenylpropionic acid is prepared which is enriched in the desired enantiomer by contacting, in a mixture of toluene and methanol as solvent, a substantially racemic mixture of the phenylpropionic acid with an enantiomer of .alpha.-methylbenzylamine, the respective molar ratio of the substantially racemic phenylpropionic acid to the .alpha.-methylbenzylamine being in the range of about 1:0.25 to about 1:1; recrystallised from a mixture of methanol and toluene to give an .alpha.-methylbenzylamine salt of the phenylpropionic acid which is further enriched in the desired enantiomer; further enriched
REFERENCES:
patent: 4994604 (1991-02-01), Tung
patent: 5015764 (1991-05-01), Manimaran
patent: 5200558 (1993-04-01), Kwan
patent: 5248813 (1993-09-01), Manimaran
patent: 5260482 (1993-11-01), Pringle
patent: 5278337 (1994-01-01), Manimaran et al.
Collet, Optical resolution by crystallization methods, in Chiral Separations by HPLC, Krstulovic, 1989.
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Jacques et al, Enantiomers, Racemates and Resolutions, Wiley, 1981, pp. 423-434.
Collet et al, Optical Resolution by Direct Crystallization of Enantiomer Mixtures, Chemical Reviews, 80(3), 1980, pp. 215-230.
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Coe Paul F.
Hardy Robert
Hirst Adrian
O'Donnell Hugh O.
Barts Samuel
Geist Gary
The Boots Company PLC
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