US 5,665,880 AGranted

Method of preparation of physostigmine carbamate derivatives from eseretholes

AssigneeHoechst Marion Roussel, Inc.

InventorsThomas B. K. Lee, Zhongli Gao

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Abstract

This invention relates to a process for the preparation of a product of the formula ##STR1## wherein R is loweralkyl; R.sub.1, is hydrogen, loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralyl; R.sub.2 is lower alkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl; or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a group of the formula (Ia) ##STR2## 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 R.sub.1 NCO 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 R.sub.1 R.sub.2 NH herein in the presence of a carboxylic acid of the formula R.sub.5 COOH and forming and isolating the product of Formula (I).

Claims10

Dependent claims

A process for the preparation of a compound of the formula ##STR13## wherein R is loweralkyl;

R.sub.1 is hydrogen, loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl;
R.sub.2 is loweralkyl, lowercycloalkyl, lowercycloalkylloweralkyl, lowerbicycloalkyl, aryl or arylloweralkyl;
or
R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached form a group of the formula (Ia) ##STR14## wherein Y is hydrogen or loweralkyl and Z is hydrogen, loweralkyl, halogen, loweralkoxy or hydroxy;
X is loweralkyl, loweralkoxy, halogen or trifiuoromethyl;
and
m is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof;
which process comprises
(a) contacting a compound of formula (II) ##STR15## wherein R, X and m are as defined above and R.sub.3 is loweralkyl, with fortified hydrogen bromide to afford a compound of formula (III) ##STR16## wherein R, X and m are as defined above;
(b) contacting the reaction mixture containing the compound of Formula (III) either
(1) with an isocyanate of the formula R.sub.1 NCO and isolating a product of formula (I) wherein R.sub.2 is hydrogen;
or
(2) with a compound of formula (IV) ##STR17## wherein R.sub.4 is hydrogen or loweralkyl to afford a compound of formula (V) ##STR18## wherein R, R.sub.4, X and m are as above;
(c) contacting the reaction mixture containing the compound of formula (V) obtained in step (b) with a compound of the formula
R.sub.1 R.sub.2 NH
wherein R.sub.1 and R.sub.2 are as above in the presence of a carboxylic acid of the formula
R.sub.5 COOH
wherein R.sub.5 is loweralkyl;
and forming and isolating the product of formula (I).

17 more elements

Dependencies are inferred from the claim text.