Method and preparation of physostigmine carbamate derivatives from eseretholes

摘要

This invention relates to a process for the preparation of a product of the formula IMAGE (I) wherein R is loweralkyl; R1, is hydrogen, loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralyl; R2 is lower alkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; or R1 and R2 taken together with the nitrogen atom to which they are attached form a group of the formula (Ia) IMAGE (Ia) wherein Y is hydrogen or loweralkyl and Z is hydrogen, loweralkyl, halogen, loweralkoxy or hydroxy; X is loweralkyl, loweralkoxy, halogen or trifluoromethyl; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; which process comprises(a) contacting a compound of formula (II) as defined herein with fortified hydrogen bromide to afford a compound of formula (III) as defined herein; contacting the reaction mixture containing a compound of formula (III) with either (1) an isocyanate of formula R1NCO or (2) with a compound of formula (IV) as defined to afford a compound of formula (V) as defined herein and contacting the reaction mixture containing the compound of formula (V) with an amine of the formula R1R2NH herein in the presence of a carboxylic acid of the formula R5COOH and forming and isolating the product of Formula (I).