Hoechst Roussel Pharmaceuticals

American Hoechst Corporation

Hoechst Marion Roussel

Aventis Pharmaceuticals Inc.

Thomas B Lee

George E Lee

George S Wong

Richard C Allen

Arthur R McFadden

Keith E Goehring

Zhongli Gao

Gregory M Jobin

Franz J Weiberth

Donna M Borek

Gregory M Shutske

Barbara S Rauckman

The synthesis of memory enhancing, analgetic, and antidepressant N-alkyl-N-pyridinyl-1H-indol-1-armines is described.

Preparation of 1H-indol-1-amines

A process for the stereoselective synthesis of �R!- and �S!-2,3-dihydro-1,3-dimethyl-2-oxo-1H-indole-3-acetonitriles comprises reacting racemic and 5-alkoxy-substituted (.+-.)-1,3-dimethyloxindoles with a halogenated acetonitrile in the presence of a substituted N-benzyl cinchoninium, quinidinium, cinchonidinium, or quininium catalyst. The resulting alkylated oxindoles can be converted to primary amines by catalytic reduction in the presence of hydrogen gas. One of the primary amines, such as enantiomers of 3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-5-methoxy-2H-indol-2-one, can be enriched by contact with a chiral tartaric acid in an amount sufficient to preferentially precipitate a salt of the chiral acid and one of the enantiomers. The product can be used in the synthesis of stereospecific forms of physostigmine and related compounds having pharmaceutical activity.

Process for the enatioselective synthesis of intermediates used

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 arylloweralkyl; Rs 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) ##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).

Method of preparation of physostigmine carbamate derivatives from

The present invention relates to a novel process for the preparation of physostigmine carbamate derivatives and to pharmaceutically acceptable salts thereof. The present invention further relates to a novel process for the preparation of eseroline derivatives and to pharmaceutically acceptable salts thereof.

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).

The synthesis of memory enhancing, analgetic, and antidepressant N-alkyl-N-pyridinyl-1H-indol-1-amines is described.

Preparation of N-alkyl-N-pyridinyl-1H-indol-1-amines

This invention relates to a process of obtaining optically pure enantiomers of an alkylated oxindole selected from ##STR1## where R is methyl, ethyl or benzyl.

Process for the enantioselective synthesis of intermediates used in the

This application relates to a new process for the preparation of a product of the formula ##STR1## wherein R, R.sup.1, R.sup.2, X and m are as defined within, which process comprises preparing treating a compound such as physostigmine to form eseroline which is then treated with an appropriate compound or its equivalent. Acetic acid is added to the reaction mixture after the formation of eseroline.

Preparation of physostigmine carbamate derivatives from physostigmine

A compound of the formula ##STR1## is prepared by reacting an N-acylated-o-toluidine of the formula ##STR2## with n-alkyllithium to form a dilithio intermediate of the formula ##STR3## which can then be quenched with N-benzylidenemethylamine to fore compound II. Hydrolysis of compound(II) yields the free base ##STR4## or its salt, which can be cyclized to form 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or its physiologically acceptable salts, which are useful as pharmacological agents.

Method for the preparation of 4-phenyl-1,3-benzodiazepins

This invention relates to a process for the preparation of a product of the formula ##STR1## wherein R, R.sup.1, R.sup.2, X and m are defined within which process comprises

A process for chemically resolving a mixture of enantiomers of primary amines, such as enantiomers of 1,3-dimethyl-5-methoxyoxindolylethylamine, provides one of the enantiomers in the form of a tartaric acid salt. In carrying out the process, an enantiomeric mixture is contacted with a chiral acid in an amount sufficient to preferentially precipitate a salt of the chiral acid and one of the enantiomers. The resulting precipitate can then be recovered. The chiral acid is selected from the group consisting of dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, ditoluoyl-D-tartaric acid, and ditoluoyl-L-tartaric acid. The precipitates can be used in the synthesis of stereospecific forms of physostigmine.

Process for the chemical resolution of 5-alkoxy-substituted

A compound of the formula ##STR1## is prepared by reacting an N-acylated-o-toluidine of the formula ##STR2## with n-alkyllithium to form a dilithio intermediate of the formula ##STR3## which can then be quenched with N-benzylidenemethylamine to form compound II. Hydrolysis of compound(II) yields the free base ##STR4## or its salt, which can be cyclized to form 4,5-dihydro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine or its physiologically acceptable salts, which are useful as pharmacological agents.

Method for the preparation of 4-phenyl-1,3-benzodiazepins and precursors

This application relates to a new process for the preparation of a product of the formula ##STR1## wherein R is loweralkyl;

A process for the stereoselective synthesis of [R]- and [S]-2,3-dihydro-1,3-dimethyl-2-oxo-1H-indole-3-acetonitriles comprises reacting racemic and 5-alkoxy-substituted (.+-.)-1,3-dimethyloxindoles with a halogenated acetonitrile in the presence of a substituted N-benzyl cinchoninium, quinidinium, cinchonidinium, or quininium catalyst. The resulting alkylated oxindoles can be converted to primary amines by catalytic reduction in the presence of hydrogen gas. One of the primary amines, such as enantiomers of 3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-5-methoxy-2H-indol-2-one, can be enriched by contact with a chiral tartaric acid in an amount sufficient to preferentially precipitate a salt of the chiral acid and one of the enantiomers. The product can be used in the synthesis of stereospecific forms of physostigmine and related compounds having pharmaceutical activity.

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Whitehouse Station, NJ, United States of America

Thomas B Lee