Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-12-16
2000-04-25
Ramsuer, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D20504
Patent
active
060545941
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a novel process for the production of enantiomerically enriched N-acylazetidine-2-carboxylic acids.
BACKGROUND TO THE INVENTION
Azetidine-2-carboxylic acid is an unusual amino acid, the (S)-enantiomer of which is known to be useful in the synthesis of inter alia high molecular weight polypeptides and in particular as an analogue of the well known amino acid proline.
This amino acid is of limited availability from natural sources, and in nature is found only as the (S)-enantiomer. The development of an efficient and economic synthetic method for producing both the pure racemic compound and either of the individual (R) or (S) single enantiomers is therefore desirable.
Previously documented chiral syntheses of (S)-azetidine-2-carboxylic acid include a five step preparation via homoserine lactone, starting from N-tosyl protected L-methionine (see e.g. Japanese Patent Application No. 14457/74 and Bull. Chem. Soc. Jpn. (1973) 46, 699) and a five step preparation via L-4-amino-2-chlorobutyric acid, starting from L-2,4-diaminobutyric acid (see Biochem. J. (1956) 64, 323).
Previously documented preparations of enantiomerically-pure azetidine-2-carboxylic acid from the racemate involve long and relatively complicated multi-step methodology.
For example, a four step preparation involving the protection, resolution and subsequent deprotection of racemic azetidine-2-carboxylic acid is known from J. Heterocyclic Chem. (1969) 6, 993. In this method, N-carbobenzoxy-protected racemic azetidine-2-carboxylic acid is resolved, using L-tyrosine hydrazide as resolution agent, and then isolated before a final deprotection step. This process has the disadvantage that L-tyrosine hydrazide is expensive as well as only being available in one enantiomeric form. This prior art also reports the additional problem that attempts to use common resolving agents in the resolution of several N-acyl derivatives of racemic azetidine-2-carboxylic acid results in the production of non-crystallizable oils.
Surprisingly we have found that N-acyl derivatives of azetidine-2-carboxylic acids may be efficiently and economically resolved using the common and inexpensive resolving agent 1-phenylethylamine.
DESCRIPTION OF THE INVENTION
According to the invention there is provided a process for obtaining an enantiomerically enriched N-acylazetidine-2-carboxylic acid, which comprises the selective crystallisation of a diastereoisomeric salt formed between the required enantiomer of the N-acylazetidine-2-carboxylic acid and an enantiomer of I-phenylethylamine (hereinafter referred to as "the process according to the invention").
Enantiomerically enriched N-acylazetidine-2-carboxylic acids may be obtained routinely from distereolsomeric salt products of the process according to the invention using methods which are well known to those skilled in the art, such as treatment of such a salt with a strong acid.
By "enantiomerically enriched" we mean any mixture of the enantiomers of an N-acylazetidine-2-carboxylic acid in which one enantiomer is present in a greater proportion than the other, for example mixtures with an enantiomeric purity (enantiomeric excess; e.e.) of greater than 50%, preferably at least 70% and more preferably at least 90%.
Preferred N-acyl derivatives of azetidine-2-carboxylic acid include the N-benzoyl derivative.
The process according to the invention is effected by seeding a supersaturated solution of a salt between a racemic N-acylazetidine-2-carboxylic acid and one or other enantiomer of 1-phenylethylamine with crystals of the pure diastereoisomeric salt formed between that enantiomer of 1-phenylethylamine and the required enantiomer of the N-acylazetidine-2-carboxylic acid.
By "pure diastereoisomeric salt" we mean a salt formed between an enantiomer of 1-phenylethylamine and an enantiomer of an N-acylazetidine-2-carboxylic acid with a diastereoisomeric excess (d.e.) of greater than 90% and preferably greater than 96%.
The process according to the invention may be optimised non-in
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Resolution of DL-Azetidine-2-carboxylic Acid, Richard M. Rodebaugh and Norman H. Crommell, Journal of Heterocyclic Chemistry, vol. 6, No. 6, pp. 993-994, Dec. 1969.
R.M. Rodebaugh: "Resolution of DL--Azetidine--2--carboxylic acid" Journal of Heterocyclic Chemistry, vol. 5, No. 6, 1969, Provo, US, pp. 993-994.
Chemical Abstracts, Vol. 82, No. 26, 30 Jun. 1997, Columbus, Ohio, US; abstract No. 171620, Boni R., et al: "Conformational properties of poly(L--azetidine--2--carboxylic acid) in solution as studied by carbon--13 and proton nuclear Magnetic resonance spectroscopy".
J.S. Davies et al.: "Conformational features of benzoyl N--alkylated amino--acids determined by nuclear magnetic resonance spectroscopy", Journal of The Chemical Society Perkin Transactions II, Vol. 11, 1978, pp. 1157-1163.
Mitsuru Furukawa et al.: "Asymmetric syntheses of beta--amino acid and aspartic acid by Reformatsky reaction", Chemical and Pharmaceutical Bulletin, Vol. 26, 1978, Tokyo, pp. 260-263.
Harris Michael C. J.
Potter Gerard Andrew
Astra AB
Ramsuer Robert W.
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