American Cyanamid Company

Wyeth

Wyeth Holdings Corporation

David Michael Blum

Yanzhong Wu

Jean Schmid

Jay Thomas Afragola

Timothy John Doyle

Kenneth E Green

William T Cain

Edward R Ruso

Ransom B Conrow

Ving J Lee

Diane H Boschelli

William V Curran

Semiramis Ayral-Kaloustian

Michael Peter Trova

Gregg Brian Feigelson

Mannching Sherry Ku

Joseph Zeldis

Arthur G Mohan

Ronald Stanley Michalak

Karen Sutherland

Henry Strong

Raghavan Krishnan

Jesse Gamble

Mel Jennings

Ian Cutting

Fang Fang Qi

Alex R Jurgens

Mellard N Jennings

Christine P Bellon

The present invention relates to novel methods for the preparation of glutamic acid derivatives and intermediates thereof, and such compounds prepared by the novel methods.

Methods for preparing glutamic acid derivatives

The invention provides 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine hemifumarate which is a tubulin inhibitor useful in the treatment of cancer and processes of making said hemifumarate.

Tubulin inhibitor and process for its preparation

The present invention relates to crystalline forms of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine salts; processes for the production thereof; pharmaceutical compositions thereof; and methods for inhibiting tumor growth therewith.

Crystalline forms of 5-chloro-6-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine salts

The present invention provides a process for the preparation of 6-[(substituted)phenyl]-triazolopyrimidine dicarboxylic acid salt and as a hydrated salt having the structural formula (I) wherein:

Process for the preparation of tubulin inhibitors

This invention discloses a process for the preparation of a 4-amino-3-quinolinecarbonitrile comprising combining an amine compound with a cyanoacetic acid and an acid catalyst to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline in an alcoholic solvent and a trialkylorthoformate to yield a 3-amino-2-cyanoacrylamide; combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride in acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 4-amino-3-quinolinecarbonitrile and also discloses a process for the preparation of a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile comprising combining a disubstituted 3-amino thiophene with a cyanoacetamide and trialkylorthoformate in an alcoholic solvent to obtain a 3-amino-2-cyanoacrylamide; and combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride and acetonitrile, butyronitrile, toluene or xylene, optionally in the presence of a catalyst to yield a 7-amino-thieno[3,2-b]pyridine-6-carbonitrile and also discloses a process for the preparation of a 4-amino-3-quinolinecarbonitrile by combining an amine compound with a cyanoacetic acid and a peptide coupling reagent to obtain a suspension; filtering the suspension to yield a cyanoacetamide; condensing the cyanoacetamide with an optionally up to tetra-substituted aniline, an alcoholic solvent, and triethylorthoformate to yield a 3-amino-2-cyanoacrylamide; and combining the 3-amino-2-cyanoacrylamide with phosphorus oxychloride to yield a 4-amino-3-quinolinecarbonitrile.

Process for preparation of 4-amino-3-quinolinecarbonitriles

The invention provides 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-amine hemifumarate which is a tubulin inhibitor useful in the treatment of cancer and processes of making hemifumarate compounds and compositioning of the present invention.

The invention relates to a process improvement for making [R-(R*,R*)]-5-[2-[5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl]propyl]-1,3-benz odioxole-2,2-dicarboxylic acid dimethyl ester an intermediate used in the synthesis of beta-3 agonist, [R-(R*,R*)]-5-[2-[5-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benz odioxole-2,2-dicarboxylic acid disodium salt.

Synthesis and purification of

The invention is the simultaneous addition of boron tribromide and a solution of [R-(R*,R*)]-5-(3-chlorophenyl-3-[2-(3,4-dimethoxyphenyl)-1-methylethyl]-2- oxazolidinone in methylene chloride to methylene chloride while maintaining a constant ratio of 2.10:1.00 of boron tribromide to the substrate [R-(R*,R*)]-5-(3-chlorophenyl-3-[2-(3,4-dimethoxyphenyl)-1-methylethyl]-2- oxazolidinone at a temperature of -5.degree. C. to 10.degree. C. gives [R-(R*,R*)]-5-(3-chlorophenyl-3-[2-(3,4-hydroxyoxyphenyl)-1-methylethyl]-2 -oxazolidinone in an isolated yield of 86.7% and a purity of 98.7%.

Process for the synthesis

The invention is an improved process for the large scale production of acetic acid, (dimethoxyphosphinyl) [[1,1-dimethylethyl)dimethylsilyl]oxy]-, (4-nitrophenyl)methyl ester.

Process for the synthesis of acetic acid, (dimethoxyphosphinyl)

A novel process for producing 5-[(substituted)amino]-8-[phenyl or substituted-phenyl]-3H,6H-1,4,5a,8a-tetraazaace-naphthylen-3-ones of the formula: ##STR1## Where R.sub.1, R.sub.2 and R.sub.3 are defined in the specification by reacting a 4,5-dihydro-7-[phenyl or substituted phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide with carbon disulfide and a suitable base and a lower alkyl iodide to give a 5-(lower alkylthio)-8-[phenyl or substituted phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one which is further reacted with an amine of the formula: ##STR2## to give the desired compounds is disclosed as well as 5-(loweralkylthio)-8-phenyl-3H,6H,1,4,5a,8a-tetra azaacenaphthylen-3-ones useful as intermediates in the process.

Process for the synthesis of 5-[(substituted amino]-8-[phenyl or

A process for the preparation of 2' and 3'-(halo-substituted)-2',3'-dideoxy nucleosides by reacting a protected anhydrothymidine compound with a halogenating composition containing a transition metal or lanthanide compound.

Process for the preparation of 3'- or

A process for producing the compound [2S-(2.alpha.,3.beta.,5.alpha.)]-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-yl-m ethyl)-4-thia-1-azabicyclo[3 2 0]-heptane-2-carboxylic acid, (4-nitrophenyl)methyl ester, 4,4-dioxide, which comprises reacting a solution of azidopenamsulfone, 4-methoxyphenol and vinylpropionate with a solution of bis(trimethylsilyl)acetamide and 4-methoxyphenol is toluene at 80.degree.-100.degree. C. for 18-30 hours followed by filtering the resulting solution and cooling the filtrate to 0.degree.-10.degree. C.

Process for producing .beta.-lactamase inhibitor

An improved, simplified process for producing 10-phenyl-10H-phenoxaphosphine in a yield of about 55% comprising reacting n-butyl lithium in a nonpolar hydrocarbon with diphenyl ether in tetramethylethylenediamine and diethyl ether, adding phenyl phosphonous dichloride and then water, and recovering the final product.

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Upper Saddle River, NJ, United States of America

David Michael Blum