PROCESS FOR THE PREPARATION OF METHYLPHENIDATE AND PHARMACEUTICAL SALTS THEREOF

摘要

The present invention is directed to an improved process for the preparation of methylphenidate, stereoisomer, mixture of stereoisomers and pharmaceutically acceptable salts thereof, more particularly, the sulfate and hydrochloride salts of methylphenidate, di-threo-methylphenidate and dex-methylphenidate. Methods of removing or reducing the amount of impurities from the above described process are also disclosed.

主权项

1. A process for the preparation of a compound of formula (I-S) or a stereoisomer or mixture of stereoisomers, comprising the steps of:STEP A:
providing a compound of formula (I-A) or stereoisomer, mixture of stereoisomers or pharmaceutically acceptable salt thereof; andSTEP B, comprising the steps of:
i. reacting the compound of formula (I-A) with dimethylcarbonate to form a reaction mixture; wherein the dimethylcarbonate is present in an amount in the range of from about 2.5 to about 8.0 molar equivalents; ii. adding methanol to the reaction mixture; wherein the methanol is present in an amount in the range of from about 0.75 to about 5.0 molar equivalents; wherein said methanol is added as a separate component; and wherein the amount of methanol added, in one or more portions or aliquots, is independent of any methanol which may be later introduced into the reaction mixture; iii. adding sulfuric acid to the reaction mixture; wherein the sulfuric acid is present in an amount in the range of from about 1.05 to about 2.5 molar equivalents; wherein the reaction mixture is at a temperature in the range of from about room temperature to about 90° C.; to yield the corresponding compound of formula (I-S).