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The present invention is concerned with a process for the manufacture of chiral succinic acid derivatives of formula (I) wherein R1 is (C1 -C6) alkyl or benzyl, and the novel intermediates used therein.
Hydroxamic acid derivatives with tricyclic substitution, as shown in formula (X) below, are known for their pharmacological activity as cartilage protective agents and are particularly useful in the treatment and prevention of degenerative joint diseases such as atherosclerosis (U.S. Pat. No. 5,614,625, EP 684 240 A1).
Certain chiral succinic acid derivatives, as shown in formula (I) below, are valuable intermediates in the synthesis of the above compounds (EP 816 341 A1). Since these derivatives are chiral, it is important to develop a stereoselective reaction to most efficiently obtain the desired enantiomer. It is known that lithium bases such as LDA provide syn-selectivity (in ratios of up to 90:10) in reactions with succinic acid(cas:110-15-6) derivatives with an ester group and a free acid group (R. Becket et al., Synlett. 137, Feb. 1993). However sodium bases such as NaN(TMS)2are not specific, providing a 1:1 mixture of syn to anti addition products.
The present invention is concerned with a process for the manufacture of chiral succinic acid(cas:110-15-6) derivatives of formula (I)wherein R1 is (C1 -C6)alkyl or benzyl, which process comprises reacting a compound of formula (II) with a halohydantoin of formula (III) wherein R2 is halogen, in the presence of a strong, enolate-forming potassium base.
By means of this reaction, the compound of formula (I) is obtained as the result of a selective anti-addition of the compounds of formulae (II) and (III). This is accomplished by use of a strong potassium base capable of forming an enolate. Surprisingly, in the case of an acid amide such strong potassium bases, such as KN(TMS)2, KNH2, KH or C1 -C6 alkoxy potassium bases (for example potassium tert-butylate), achieve the necessary anti-selectivity required to efficiently produce the compound of formula (I)
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