The central nervous system disorders that may be treated by novel isoxazole compounds, particularly 3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, have been described in U.S. patent application, Ser. No. 08/118,079, filed Sep. 8, 1993, which is incorporated herein by reference. That Application teaches that a 2-oxopyrrolidine carboxylic acid ester (compound 21 of Scheme IV therein) may be condensed with a dianion of acetone oxime only when the pyrrolidine ring nitrogen substituent (R.sup.5 therein) is a C.sub.1 -C.sub.4 -alkyl group, and not when it is hydrogen. Further, said Application teaches (Example 22c) that the condensation reaction generates a racemic product. Also, the reported cyclization of a beta-keto oxime, wherein the oxime group is a functional group on a fused ring system and the product contains a fused oxazolidine ring (British Patent No. 1,354,097 and published German Application DE2166685) cannot be said to teach or suggest that cyclization with non-fused ring starting materials is possible or would result in an enantiomerically-pure product.
It has now been found that an enantiomerically-pure product may be obtained in a process wherein an alkyl ester of N-alkyl-L-proline, particularly N-methyl-L-proline, is converted into a compound having a keto-oxime grouping in an extended side-chain, which is then cyclized and dehydrated, and in an alternate process wherein an alkyl ester of L-pyroglutamic acid is converted into a compound having a keto-oxime grouping in an extended side-chain, which is cyclized and dehydrated, then N-alkylated, and more specifically N-methylated.
USPTO Backgrounds
USPTO Backgrounds