Warner-lambert Company

Other

James N Wemple

James R Zeller

Victor Fedij

Kenneth Thomas Porter

Gary Jay Dozeman

Mark J Suto

Tung Van Le

F Gregory Spence

John Michael Domagala

Timothy L Stuk

Denis Martin Sobieray

Bradley Dean Tait

Christopher Andrew Gajda

Floyd G Spence

Brian Keith Huckabee

James Vande Vusse

Timothy P Puls

Gregory L Karrick

Brian Stuart Moon

The present invention relates to methods of making dihydropyrone HIV inhibitors.

Methods of making dihydropyrone HIV protease inhibitors

The present invention provides a method of making quinolone carboxylic acids or naphthyridine carboxylic acids in free base form, the method comprising dissolving a quinolone carboxylic acid salt or naphthyridine carboxylic acid salt in a solvent system to form a solution; combining the solution containing the quinolone carboxylic acid salt or naphthyridine carboxylic acid salt with a calcium salt in an amount in the range of about 0.01% to about 5.0% by weight of the quinolone carboxylic acid salt or naphthyridine carboxylic acid salt and a base, the combination resulting in the formation of a precipitate; and collecting the precipitate. Also provided is a solid bulk pharmaceutical chemical composition comprising 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-o xoquinoline-3-carboxylic acid or 7-�3-S-(2-S-aminopropionylamino)pyrrolidin-1-yl!-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; and calcium in an amount in the range of 0.001% to about 1.0% by weight of the 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-o xoquinoline-3-carboxylic acid or 7-�3-S-(2-S-aminopropionylamino) pyrrolidin-1-yl!-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridin e-3-carboxylic acid.

Solid bulk compositions containing quinolone carboxylic acids or

The present invention provides a method of making quinolone carboxylic acids or naphthyridine carboxylic acids in free base form, the method comprising dissolving a quinolone carboxylic acid salt or naphthyridine carboxylic acid salt in a solvent system to form a solution; combining the solution containing the quinolone carboxylic acid salt or naphthyridine carboxylic acid salt with a calcium salt in an amount in the range of about 0.01% to about 5.0% by weight of the quinolone carboxylic acid salt or naphthyridine carboxylic acid salt and a base, the combination resulting in the formation of a precipitate; and collecting the precipitate. Also provided is a solid bulk pharmaceutical chemical composition which is the product resulting from the precipitation.

Method for making quinoline carboxylic acids or naphthyridine carboxylic

Chiral 3-cyanopyrrolidines of the following formula are disclosed, wherein R' is as defined herein. The compounds are useful as intermediates for naphthyridine and quinoline antibiotics. ##STR1##

Chiral 3-cyano-1-substituted-pyrrolidines

The process for the preparation of chiral 3-(1-amino-1,1-bisalkylmethyl)-1-substituted-pyrrolidines used as key intermediates for the preparation of naphthyridine and quinolone antibacterial agents which comprises reacting readily available chiral 1-substituted-3-pyrrolidinols to their corresponding chiral sulfonate esters; converting the sulfonate esters to chiral 1-substituted-3-cyanopyrrolidines having an inverse configuration, and then dialkylating the chiral cyanopyrrolidines with alkyl lithium in the presence of a Lewis acid without racemization at the asymmetric carbon atom is described.

Process for chiral

A novel process for preparing a stereospecific (S)-3-amino-1-substituted pyrrolidine used as a key intermediate in preparing quinolone and naphthyridone antibacterial agents where the 7-position is occupied with a sterospecific 3-aminopyrrolidine side chain is described starting from inexpensive L-aspartic acid. L-aspartic acid is converted to the desired (S)-3-aminopyrrolidine via a novel, high yield transformation of a substituted aziridine.

Process for the manufacture of (S)-3-amino-1-substituted-pyrrolidines

A novel process for preparing a stereospecific (S)-3-amino-1-substituted pyrrolidine used as a key intermediate in preparing quinolone and naphthyridone antibacterial agents where the 7-position is occupied with a sterospecific 3-amino-pyrrolidine side chain is described starting from inexpensive L-aspartic acid. L-aspartic acid is converted to the desired (S)-3-aminopyrrolidine via a novel, high yield transformation of a substituted aziridine.

An improved process for the preparation of 3-chloro-2,4,5-trifluorobenzoic acid is described which involves reaction of a diester of 3,4,5,6-tetrafluoro-1,2-benzenedicarboxylic acid with a substituted amine to afford 3-amino-2,4,5-trifluorobenzoic acid followed by subsequent conversion of the amio intermediate into 3-chloro-2,4,5-trifluorobenzoic acid.

Process for the synthesis of 3-chloro-2,4,5-trifluorobenzoic acid

An improved process for the preparation of 2,3,4,5-tetrafluorobenzoic acid is described which involves decarboxylation of tetrafluorophthalic acid in the presence of a base catalyst. Also described is an improved method for preparing tetrafluorophthalic acid and, in turn, a one-pot process for tetrafluorobenzoic acid using the combination of the two improvements.

Process for tetrafluorobenzoic acid

An improved process for the preparation of 7-substituted amino-1-alkyl- or cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids is described where tetrafluorobenzoyl chloride is converted in three operations via 1-alkyl or 1-cycloalkyl-1,4-dihydro-6,7,8-trifluoro-4-oxoquinoline-3-carbonitrile which in a separate step or in situ is displaced and hydrolyzed to the desired product.

Growing community of inventors

Holland, MI, United States of America

James N Wemple