Bristol-myers Squibb Compnay

Bristol-myers Company

Mead Johnson & Company

Monsanto Company

Gary D Madding

Ronald J Mattson

John J Venit

Tao P Li

Victor W Rosso

Jingyang Zhu

Jason G Chen

Michael E Randazzo

Atul S Kotnis

Joseph L Minielli

D David Hennings

Robert P Discordia

Francis J Okuniewicz

Susanne Kiau

Raymond A Franz

Michael D Thompson

Provided is a dynamic resolution method of enriching a desired isomer of an alpha-substituted carboxylic acid relative to an undesired isomer, the method comprising: (a) in a solvent, contacting the alpha-substituted carboxylic acid, wherein the alpha substitution is with a leaving group and wherein the alpha carbon is chiral, with a homochiral amine to form a salt that is partially insoluble under selected reaction conditions, wherein the homochiral amine is selected so that the solubility of the amine salt of the undesired alpha-substituted carboxylic acid is greater than that of the amine salt of the desired alpha-substituted carboxylic acid under the selected reaction conditions; (b) reacting under the selected reaction conditions the salt with a nucleophile, wherein the reacting is effective in producing a net increase in the less soluble amine salt of the alpha-substituted carboxylic acid, and wherein the selected conditions are selected to (i) promote nucleophilic substitution of the nucleophile and the leaving group or (ii) to produce the increase in the less soluble amine salt in the absence of a strong base; and (c) maintaining the reaction for a period of time effective to increase the amount of the desired alpha-substituted carboxylic acid isomer.

Dynamic resolution of isomers and resolved isomers

An improved process for preparation of certain useful azapirones, e.g. buspirone, gepirone, tandospirone, etc., comprises the reaction of a novel spiroquaternary piperazinium hydroxide with an appropriate imide to form imidate salts which are then converted to the azapirone by heating. This process is suitable for large scale adaptation and has advantages in greater safety and efficiency.

Process for preparing certain azapirones

An improved process, suitable for adaption to large-scale manufacture for synthesis of the cerebral function enhancing agent BMY 21502.

Process for large-scale production of BMY 21502

There are disclosed compounds of Formulas I and II: ##STR1## wherein R.sup.1 and R.sup.2 may be hydrogen, lower alkyl having from 1 to 8 carbon atoms, lower alkenyl having from 3 to 6 carbon atoms, lower alkoxy having from 1 to 6 carbon atoms, hydroxy, nitro, amino, halo including chlorine, bromine, iodine, and fluorine, phenyl, alkanoyl having from 2 to 6 carbon atoms or they are bonded to one another to form a cycloalkene ring fused to the thiophene ring and having a total of from 5 to 7 annular ring carbon atoms, and R.sup.3 is an aliphatic or an aromatic group such as lower alkyl, e.g., methyl or ethyl. Such compounds are useful as intermediates in the production of tiprinast and related compounds. There is also disclosed a process for the regioselective synthesis of a compound of Formula I wherein R.sup.1 is CH.sub.3 and R.sup.2 is (CH.sub.3).sub.2 CHCH.sub.2 which comprises reacting a mixture of compounds of the following formulas: ##STR2## and ##STR3## with trichloroacetonitrile under acidic conditions.

Intermediates useful in the preparation of

An improved process for the preparation of 5-ethyl-4-(2-phenoxyethyl)-1,2,4-triazolone, a useful intermediate in the synthesis of antidepressant 1,2,4-triazolones typified by 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-4-(2-phenoxethyl)-2 H-1,2,4-triazol-3(4H)-one, also known as nefazodone. The improved process is shorter and higher in yield than the former process, and the starting materials are cheap and readily available.

4-(2-phenoxyethyl)-1,2,4-triazolone process intermediates

An improved process for the preparation of 4-methoxy-2'-{2-(1-methyl-2-piperidyl)ethyl}benzanilide has been developed. The process comprises essentially three steps starting with methyl anthranilate and 2-picoline and features a novel low-pressure hydrogenation sequence.

Process for production of encainide

An improved process for the preparation of 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide has been developed. The process comprises essentially three steps starting with methyl anthranilate and 2-picoline and features a novel low-pressure hydrogenation sequence.

Styrene and benzene are simultaneously produced by heating a mixture of toluene and ethylbenzene in a mole ratio of at least 1:1 to a temperature from about 400.degree. to 900.degree.C at moderate pressures for a period of time up to about 15 seconds, cooling the reaction mixture quickly and recovering the styrene and benzene therefrom. Yields of both products can be improved by the addition of modifying agents such as benzenethiol or by conducting the reaction in the presence of a chromium-containing catalyst supported on an inorganic material which can be promoted by a compound of calcium, magnesium, copper or zinc.

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Evansville, IN, United States of America

Gary D Madding