Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing nitrogen-containing organic compound
Reexamination Certificate
2002-04-24
2004-06-01
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing nitrogen-containing organic compound
C435S129000, C435S130000, C435S135000, C435S136000, C435S146000, C435S197000, C435S198000
Reexamination Certificate
active
06743608
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a new process for the preparation of optically enriched substituted esters of 3-phenyl-propanoic acids and substituted 3-phenyl-propanoic acids.
BACKGROUND OF THE INVENTION
Yasuo Kato et. al. have shown that incubation of &agr;-benzyloxycarboxylic esters with grown cells of the bacterium Corynebacterium equi afforded chiral esters via asymmetric hydrolysis (Tetrahedron Letters, Vol. 28, No.12, 1303-1306, 1987).
Japanese Patent Application No. 61-208680 describes methods for the production of optically active &agr;-hydroxycarboxylic acid derivatives by the use of bacteria belonging to the genus Corynebacterium. In the patent application processes are described converting racemic esters (2 g/l) in culture solutions (where the microbe is capable of growing) during 24 to 65 h of shake culturing.
However, according to K. Faber in “Biotransformations in Organic Chemsitry”, 4
th
Ed., Springer Veriag 1999, p. 10, the usage of a growing cell culture has a number of disadvantages vs. isolated enzymes, such as more difficult process control, the handling of large biomass in a chemical plant, and more by-product formation.
Japanese Patent Application No. 63-107536 describes the use of a few lipases for the production of optically active 2-hydroxycarboxylic acids and esters.
Jean-Marc Ricca et al. found that &agr;-Chymotrypsin suspended in organic solvents was stereoselective with respect to the hydrolysis of L-amino acid derivatives, but no stereoselectivity was observed when &agr;-hydroxy esters were used as substrates (J. Chem. Soc. Perkin Trans., Vol. 1, 1225-1233, 1993).
David Haigh et al. showed that a Rhizopus delemar lipase catalysed hydrolysis of methyl 3-[4-[2-[N-(benzoxazolyl)-N-methylamino]ethoxy]-phenyl]-2-methoxypropanoate affords the (R)-(+) and (S)-(−) isomers in >84% enantiomeric excess. (Bioorganic and Medicinal Chemistry vol. 7, 821-830, 1999).
However, to achieve such optical purity for the (S)-acid, double enzymatic resolution was necessary: The (S)-acid was isolated from the initial enzymatic hydrolysis, re-esterified, and enzymatically rehydrolysed.
As described by Collins Sheldrake Crosby (Chirality in Industry, 1992 section 1.3.1) it is a big advantage for large-scale production to process a minimum of material. To be able to do this the chiral purification needs to be performed as early as possible in a synthetic route. This is the opposite of what is seen in the Haigh reference but in line with the process described in this patent application. The overall process cost as e.g. environmental cost (less waste is generated), operating costs and material cost are in general lower for processes where the chiral separation is performed early in the synthesis as seen for the present invention.
It has recently been shown, that &bgr;-aryl-&agr;-oxysubstituted alkylcarboxylic acids have hypolipidemic and antihyperglycemic uses (WO 99/19313).
The synthesis of these compounds involves several steps to achieve the pure enantiomeric form of the compounds, which show pharmacological activity.
WO 00/26200 discloses the synthesis of optical enriched &bgr;-aryl-&agr;-oxysubstituted alkylcarboxylic acids and esters related to the compounds mentioned in WO 99/19313.
The object of the present invention is therefore to provide a new process involving an enzymatic resolution step for the preparation of optically enriched substituted esters of 3-phenyl-propanoic acids and substituted 3-phenyl-propanoic acids which process is adaptable to large scale manufacture, provides good yields and high purity and reduces the cost of manufacture as e.g. environmental cost (less waste is generated).
SUMMARY OF THE INVENTION
The present invention relates to a process comprising hydrolysis or trans-esterification of one of the two enantiomeric forms of a racemic or enantiomerically enriched ester of formula I or IV by a higher rate than the other by an enzyme to give an ester (II) and an acid (III) or two different esters (V) and (VI) with different R groups both with increased enantiomeric purity and an esterification process of a racemic or enantiomerically enriched acid (VII) by an enzyme to give an ester (IX) and an acid (VIII) both with increased enantiomeric purity.
The process can be used to synthesise important building blocks for the preparation of compounds active at the Peroxisome Proliferator-Activated Receptors (PPAR) like the ones described in WO 99/19313 and in Haigh et al. (Bioorganic and Medicinal Chemistry vol. 7. 821-830. 1999).
REFERENCES:
patent: 5061629 (1991-10-01), Coffen et al.
patent: 5306726 (1994-04-01), Hulin
patent: 0 459 455 (1991-12-01), None
patent: WO9919313 (1998-01-01), None
Haigh et al., Bioorganic & Medicinal Chemistry. vol. 7, pp. 821-830 (1991).
Abstract of Japanese Patent 1-281098 (A) Nov.
J. Bryan Jones, Tetrahedron, vol. 42. pp. 3351-3403 (1986).
Deussen Heinz-Josef W.
Ebdrup Soren
Zundel Magali
Green Reza
Lilling Herbert J.
Novo Nordisk Pharmaceuticals, Inc.
Wilk-Orescan Rosemarie R.
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