Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-12-30
2000-11-21
Powers, Fiona T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548953, C07D20504
Patent
active
061505358
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process for producing azetidine-2-carboxylic acid from a 4-oxo-2-azetidinecarboxylic acid derivative via azetidine-2-methanol and, more particularly, to a process for producing, from an optically active 4-oxo-2-azetidinecarboxylic acid derivative, an optically active azetidine-2-methanol and an optically active carboxylic acid each corresponding to it.
Among the optical active azetidine-2-carboxylic acids, (S)-azetidine-2-carboxylic acid is a compound useful as an intermediate for the production of medicinals. In particular, it is a compound very useful as an intermediate for the production of a thrombin inhibitor described in International Patent Applications WO 93/06069 and WO 93/11152, among others.
BACKGROUND ART
The so-far known processes for producing (S)-azetidine-2-carboxylic acid are as follows: (1) The process which comprises reacting L-2,4-diaminobutyric acid with hydrochloric acid and nitrous acid to give L-2-chloro-4-aminobutyric acid and then subjecting the same to heat treatment in barium hydroxide to give L-azetidine-2-carboxylic acid (The Biochemical Journal, vol. 64, pp. 323 to 332, 1956); (2) The process which comprises reacting-.gamma.-butyrolactone with bromine in the presence of red phosphorus and treating the reaction product with benzyl alcohol saturated with hydrogen chloride gas to give benzyl DL-2,4-dibromobutyrate, reacting the same with benzhydrylamine to give benzyl DL-N-diphenylmethylazetidine-2-carboxylate, reducing this with hydrogen in methanol in the presence of palladium carbon to give DL-azetidine-2-carboxylic acid, and then subjecting it to reacting with benzyloxycarbonyl chloride (ZCl) to give DL-N-Z-azetidine-2-carboxylic acid, subjecting the latter to optical resolution using L-thyrosine hydrazide to give L-form, namely (S)-N-Z-azetidine-2-carboxylic acid (wherein Z represents a benzyloxycarbonyl group; hereinafter the same shall apply), and lastly reducing the same again with hydrogen in methanol in the presence of palladium carbon to give L-azetidine-2-carboxylic acid (Journal of Heterocyclic Chemistry, vol. 6, pp. 435 to 437, pp. 993 to 994, 1969); and (3) The process which comprises S-alkylating L-N-tosyl-methionine to give L-N-tosyl-methioninesulfonium salt, heating it in an aqueous solution of sodium hydroxide for conversion to L-N-tosyl-.alpha.-amino-.gamma.-butyrolactone, treating the latter with a gaseous hydrogen halide in an alcohol to give alkyl L-N-tosyl-2-amino-4-halobutyrate, treating this with sodium hydride in dimethylformamide to give (S)-N-tosyl-azetidine-2-carboxylic acid, and thereby effecting the cyclization reaction, and detosylating it with metallic sodium in liquid ammonia to give (S)-azetidine-2-carboxylic acid (Japanese Patent Application sho-49-14457, Chemistry Letters, pp. 5 to 6, 1973).
SUMMARY OF THE INVENTION
However, the above processes each has its problems, as follows.
In process (1), L-2,4-diaminobutyric acid is expensive and, in addition, it is necessary to carry out the reaction procedure in step 1 in a more strict manner, since its reaction temperature and reaction time influence the optical purity of the desired product.
In process (2), multiple steps are required and, in addition, benzhydrylamine is expensive and the unnecessary optical isomer produced by optical resolution must be discarded unless an advantageous method of racemization is discovered, hence the process is uneconomical.
In process (3), multiple steps are required and, in addition, a low-temperature apparatus is required and care should be taken in handling in the detosylation step since, in that step, metallic sodium is used in liquid ammonia. Further, an ion exchange resin is required in the last purification step for separating the desired product from the inorganic ion, hence the productivity is low.
Thus, when viewed as an industrial production process, every prior art process has problems to be solved.
In view of the above-mentioned state of the art, the present invention has for its object to prov
REFERENCES:
patent: 4855452 (1989-08-01), Verbrugge et al.
Rodebaugh, R. M. et al, "A facile New Synthesis of DL-Azetidine-2-Carboxylic Acid (1A) " , Journal Of Heterocyclic Chemistry, vol.6, No. 3, June 1, 1969, 435-437, XP002050008.
Rodebaugh, R.M. et al, "A Facile New Synthesis of DL-Azetidine-2-Carboxylic Acid (1A) ", Journal of Heterocyclic Chemistry, vol.6, No. 3, Jun. 1, 1969, 435-437, XP002050008.
Powden, L."Azetidine-2-carboxylic Acid: A new Cyclic Imino Acid Ocurring in Plants ", The Biochemical Journal, vol. 64, 1956, 323-332, XP000909526.
Awaji Hiroshi
Inoue Kenji
Matsumoto Shingo
Matsuo Kazuhiko
Kaneka Corporation
Powers Fiona T.
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