Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-09-04
2000-11-07
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D20504, C07B 5700
Patent
active
061439037
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE97/00675, filed Apr. 22, 1997.
FIELD OF THE INVENTION
This invention relates to a process for the production of enantiomerically pure azetidine-2-carboxylic acid.
PRIOR ART
L-Azetidine-2-carboxylic acid (L-AzeOH) 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.
Previously documented preparations of enantiomerically-pure AzeOH (i.e. D- and/or L-AzeOH) from the racemate (DL-AzeOH) involve long and relatively complicated multi-step methodology.
A four step preparation involving the protection, resolution and subsequent deprotection of DL-AzeOH is known from J. Heterocyclic Chem. (1969) 6, 993. In this method, N-carbobenzoxy-protected DL-AzeOH is resolved using L-tyrosine hydrazide as resolution agent, and then isolated before a final deprotection step. This process has the further disadvantage that L-tyrosine hydrazide is expensive.
Other reported preparations of L-AzeOH 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, 669) 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).
DESCRIPTION OF THE INVENTION
Tartaric acid has been known for many years to exist in three stereochemical forms, the L-form, the D-form and the meso-form. Two of these diastereoisomers, L- and D-tartaric acid are enantiomers.
We have now surprisingly found that one enantiomer of AzeOH may be converted to the other in an enantiomerically-pure form and in extremely high yields via a novel and efficient process which comprises the selective crystallisation of a diastereomerically-pure AzeOH-tartrate salt from a mixture of AzeOH, optically-active tartaric acid, an organic acid and an aldehyde, followed by liberation of the free amino acid.
In particular, we have found that selective crystallisation of AzeOH with D-tartaric acid, under anhydrous conditions in the presence of an organic acid and an aldehyde produces extremely high yields of diastereomerically-pure L-AzeOH-D-tartrate in the crystalline form, from which optically-pure L-AzeOH may be liberated. Similarly, crystallisation using L-tartaric acid produces extremely high yields of diastereomerically-pure D-AzeOH-L-tartrate, from which optically-pure D-AzeOH may be liberated.
According to the invention there is provided a process for the production of enantiomerically-pure AzeOH which comprises: salt from a homogeneous solution of AzeOH, optically-active tartaric acid, an organic acid and an aldehyde; followed by process according to the invention",
By "optically active" tartaric acid we mean D- or L-tartaric acid or a mixture thereof. However, we prefer that the D- or L-tartaric acid which is used in the process according to the invention is enantiomerically pure, for example with an optical purity (enantiomeric excess; e.e.) of greater than 95%.
The process according to the invention may be used to produce diastereomerically-pure AzeOH-tartrate salts from mixtures of AzeOH including racemic AzeOH or enantiomerically-enriched AzeOH.
By "enantiomerically-enriched" we mean any mixture of the isomers of is AzeOH in which one isomer is present in a greater proportion than the other.
Moreover, the process according to the invention may be used to convert one enantiomer of AzeOH to the other.
According to a second aspect of the invention there is provided a process for the conversion of one enantiomer of AzeOH to the other which comprises: diastereomerically-pure L-AzeOH-D-tartrate salt from a homogeneous solution of D-AzeOH, D-tartaric acid, an organic acid and an aldehyde, followed by liberation of the free amino acid; or diastereomerically-pure D-AzeOH-L-tartrate salt from a homogeneous solution of L-AzeOH, L-tartaric acid, an organic acid and an aldehyde, followed by liberation of the free amino acid.
Although the
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Barth Philipp
Pfenninger Armin
Astra Aktiebolag
Higel Floyd D.
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