Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-09-19
1999-08-24
Lambkin, Deborah C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D20504
Patent
active
059426306
DESCRIPTION:
BRIEF SUMMARY
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 a 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 (ie 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. Heterocylic 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 eg Japanese Patent Application N.sup.0 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 enantiomerically-pure AzeOH may be produced in extremely high yields via a novel and efficient process which comprises the formation of a homogeneous solution of racemic AzeOH and of either D- or L-tartaric acid, crystallisation of the resultant tartrate salt from solution, and subsequent liberation of the free amino acid.
In particular, we have found that crystallisation of racemic AzeOH with D-tartaric acid produces extremely high yields diastereomerically-pure of L-AzeOH-D-tartrate in the crystalline form, from which optically-pure L-AzeOH may be liberated. Similarly we have found that 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 selective crystallisation of a diastereomerically-pure tartrate salt thereof, followed by liberation of the free amino acid.
By "selective crystallisation" we mean crystallisation of a diastereomerically-pure AzeOH-tartrate salt from a homogeneous solution of racemic AzeOH and one or other of D- or L-tartaric acid.
Although the process according to the invention may be used to produce either L-AzeOH-D-tartrate or D-AzeOH-L-tartrate with a diasteromeric excess (d.e.) greater than 90%, by "diastereomerically-pure AzeOH-tartrate salt" we mean a AzeOH-tartrate salt with a d.e. of greater than 40%.
Although the process according to the invention may be used to produce either L-AzeOH or D-AzeOH with optical purities (enantiomeric excess; e.e.) of greater than 90%, by "enantiomerically-pure AzeOH" we mean an AzeOH enantiomer with an e.e. of greater than 50%.
Suitable solvent systems in which racemic AzeOH and tartaric acid may be dissolved include one or more organic solvents, with or without the presence of water. Organic solvents which may be employed include those which are miscible with and/or soluble in water and in which the diastereomerically-pure AzeOH-tartrate salts are poorly soluble at room temperature or below. Examples of suitable organic solvents include monofunctional alcohols (eg ethanol, methanol or isopropanol), difunctional alcohols (eg ethylene glycol), C.sub.1-8 mono- or divalent carboxylic acids (eg formic or acetic acid), C.sub.4-6 linear or cyclic ethers (eg monoglyme, diglyme, tetrahydrofuran or dioxane). Particularly preferred organic solvents include ethanol and C.sub.1-3 carboxylic acids
REFERENCES:
Fowden, L., "Azetidine-2-carboxylic Acid: A new Cyclic Imino Acid Occurring in Plants," Biochem. J., vol. 64, pp. 323-332 (1956).
Rodebaugh et al., "A Facile New Synthesis of DL-Azetidine-2-Carboxylic Acid (1a)," J. Heterocyclic Chem., vol. 6, pp. 435-437 (1969).
Rodebaugh et al., "Resolution of DL-Azetidine-2-carboxylic Acid," J. Heterocyclic Chem., vol. 6, pp. 993-994, Dec. 1996.
Cromwell et al., "The Azetidines, Recent Synthetic Developments," Chemical Reviews, vol. 79, No. 4, pp. 331-354 ((1979).
Yokoyama et al., "The Decomposition Product of Ethyl 2-Cyano-3-mercapto-3-methylthioacrylate," Bull. Chem. Soc. Japan, vol. 46, pp. 669-700 (1973).
Shiraiwa et al, "Asymmetric Transformations of Proline and 2-Piperidinecarboxylic . . . ," Bull. Chem. Soc. Jpn., vol. 64, pp. 3251-3255 (1991).
Barth Philipp
Fritschi Hugo
Nystrom Jan-Erik
Pfenninger Armin
Astra AB
Lambkin Deborah C.
Sackey Ebenezer
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