RESOLUTION PROCESS

摘要

The invention provides a process for the production of the enantiomers of an aminophosphonous acid having the formula (I), or the corresponding zwitterion form: in which R and R min are different and each is hydrogen; C1-C6alkyl; C1-C6alkyl substituted by i) one or two -COOR<2>, -OR<2>, -SR<2> or -CONH2 groups, in which R<2> is hydrogen, phenyl, or C1-C3alkyl which is optionally substituted by a C6-C10aryl radical; ii) by an -SS-CH2-CH(NH2)-PO2H2 group; iii) by -NH2 or protected amino; iv) by an -NH-C(=NH)NH2 group; v) by a C6-C10aryl radical which is optionally substituted by one or two hydroxyl groups; or vi) by a heterocyclic ring having 3 to 7 ring atoms including one or more nitrogen atoms, which ring is optionally fused to a benzene ring; and R sec is hydrogen or C1-C6alkyl or R sec , together with the -NH-C(R)(R min )- residue to which it is bonded, are the atoms required to complete a pyrrolidin-2-yl or piperidin-2-yl ring which is optionally substituted by a hydroxyl group or by a group R<2>; which process comprises: a) selectively cleaving, using Penicillin-G-amidase, one enantiomer of a racemic mixture of N-acyl derivatives of the aminophosphonous acid of formula I, the N-acyl derivative having the formula II: wherein R, R min and R sec are as defined under formula I, and R<3> is a straight- or branched C1-C6alkyl group which is optionally substituted by one or more of halogen, hydroxy, C1-C3alkoxy, phenyl, phenoxy and/or thienyl, the phenyl- or phenoxy substituents being themselves optionally substituted by C1-C3alkyl, hydroxy, nitro, amino, halogen and/or C1-C3alkoxy; b) separating the mixture of free amino acid and unhydrolysed N-acyl derivative of formula II; and c) de-acylating, non-enzymatically, the un-hydrolysed material. r