The Upjohn Co.

Thomas A Hylton

Jerry A Walker

Francis L Shenton

Michael F Lipton

Paul A Meulman

Muniraj D Pillai

Steve Nichols

Burris D Tiffany

Crystalline, non-hygroscopic adinazolam methanesulfonate, per se, preparable from xylene or preferably from a C.sub.1 to C.sub.2 -alkanol/C.sub.4 to C.sub.6 -alkyl acetate liquid mixture, aids processability of adinazolam methanesulfonate in pharmaceutical production plants.

Non-hygroscopic adinazolam methanesulfonate salt and process therefor

Novel processes for making arylpropionic acids are described. One process comprises carboxylating particular Grignard compounds which are the products of a catalyzed reaction between corresponding arylmagnesium bromides and ethylene. Furthermore, the reaction making the particular Grignard compounds is itself novel. Also, an improved method is disclosed for making coupled aryl compounds useful as intermediates for making compounds having a pharmaceutical use. For example, particular biaryls may be used to make some of the Grignard compounds herein from which the arylpropionic acids are made. Finally, an improved bromination is disclosed giving high yields of 4-bromo-2-fluoroaniline, which is thereafter coupled with benzene, then used to make the arylmagnesium bromide reacted with ethylene to obtain the particular Grignard compound and subsequent desired arylpropionic acid, i.e. 2-(2-fluoro-4-biphenylyl)propionic acid.

Processes for the preparation of hydratropic acids

The invention concerns the novel compounds dialkyl 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate IIIa and dialkyl 2-(3-fluoro-4-aminophenyl)-2-methylmalonate IVa useful as intermediates in an improved process for making 2-(2-fluoro-4-biphenylyl)propionic acid, known as flurbiprofen, having the formula ##STR1## and ester thereof. It has anti-inflammatory activity which is about 240 times that of aspirin and analgesic activity which is about 180 times that of aspirin in standard laboratory tests. However, despite this high activity, the toxicity (LD.sub.50) is only 1.2 to 2.4 times greater than that of aspirin in standard laboratory tests. Also within the invention is a novel method of making the above intermediates and analogs thereof useful to prepare corresponding biaryl compounds which have pharmaceutical uses.

Processes for the preparation of hydratropic acids and esters

An improved multistep process for the production of intermediates for hypotensive compounds, which intermediates are of the formula V: ##STR1## wherein R.sub.1 and R.sub.2 are lower alkyl of 1 to 4 carbon atoms, inclusive, alkenyl of 3 or 4 carbon atoms, cycloalkyl from 3 to 7 carbon atoms, phenylalkyl in which the alkyl group is defined as above, or the group ##STR2## is a heterocyclic moiety of 4 to 8 ring members, e.g., azetidinyl, piperidino, pyrrolidinyl, hexahydroazepinyl, or heptamethyleneimino, each of which can be substituted by one or two methyl groups, N-alkylpiperazino, wherein alkyl is defined as above, morpholino, or thiomorpholino, and wherein R.sub.3 is hydrogen or alkyl of 1 to 4 carbon atoms, inclusive, starts with the corresponding secondary amine I ##STR3## wherein R.sub.1 and R.sub.2 have the significance of above. SU

Process for preparing 3-(cyanimino)-3-amino-propionitriles

The present invention is a chemical method for obtaining an optically pure 2-aminonitrile or a 2-aminoamide from (1) an optically impure mixture, (2) a racemic mixture, or (3) the optically pure enantiomer of the opposite configuration, in an amount greater than actually present, by use of optically active acids with a ketone or an aldehyde catalyst. Yields of greater than 70 percent of one enantiomer are obtained from racemic mixtures in very short time periods.

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Kalamazoo, MI, United States of America

Thomas A Hylton