Amgen Inc.

Rhodia Pharma Solutions Inc.

Rhodia Chirex, Inc.

Jay Larrow

Michael J Martinelli

George Moniz

Charles Bernard

Matthew J Frizzle

Margaret M Faul

Matthew W Martin

Jean-Christophe P Harmange

Ryan D White

Joseph F Payack

Philippe Morel

Karl Bennett Hansen

Hocine Kabir

Serge Jasmin

Yi Liu

Roger Zanon

Liane Klingensmith

Yohannes Teffera

Raju Subramanian

Mina Dilmeghani Seran

Roger Nani

Karl Hemberger

Marcello Di Mare

The present invention relates to methods of making compounds that inhibit 11-hydroxysteroid dehydrogenase type 1 enzyme (11-HSD1). One method comprises (a) contacting a compound of formula (II) sequentially with a chiral base in the presence of an amine, and an alkylating agent R3-LG, (b) contacting the product of (a) with an acid to form a salt, and (c) reacting the salt with a base to form the compound of formula (I), wherein Z, R1, R2, and R3 are defined herein.

Process for making substituted 2-amino-thiazolones

The present invention relates to methods of making compounds that inhibit 11-&#x3b2;-hydroxysteroid dehydrogenase type 1 enzyme (11-&#x3b2; HSD1). One method comprises (a) contacting a compound of formula (II) with a chiral base, deprotonating agent, and an alkylating agent R-LG, (b) contacting the product of (a) with an acid to form a salt, and (c) reacting the salt with a base to form the compound of formula (I); wherein Z, R, R, and Rare defined herein. 

Selected benzomorpholine compounds, including 7-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-N-(5 -methyl-3-isoxazolyl)-2,3-dihydro-4H-1,4-benzoxazine-4-carboxamide, are effective for prophylaxis and treatment of diseases, such as VEGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Benzomorpholine derivatives and methods of use

A method for making a chiral transition metal-ligand catalyst complex that is active in catalyzing stereoselective ring opening reactions includes contacting an asymmetric tetradentate ligand, in an excess of a Br&oslash;nsted acid, with a salt of a first row transition metal, wherein the acidity of the conjugate acid of the salt is the same as or less than the acidity of the Br&oslash;nsted acid, under conditions effective to allow formation of the active chiral transition metal-ligand catalyst complex, and forming a solution of the complex in a water-miscible, protic solvent from which the active complex can be precipitated by the addition of water and adding water to the solution to precipitate at least a portion of the complex.

Active catalysts for stereoselective ring-opening reactions

A method for stereoselective chemical synthesis, includes the steps of: (A) reacting a nucleophile and chiral or prochiral cyclic subtrate, said substrate comprising a carbocycle or a heterocycle having a reactive center susceptible to nucleophilic attack by the nucleophile, in the presence of a chiral non-racemic catalyst to produce a product mixture comprising a stereomerically enriched product wherein the product mixture further comprises a catalyst residue, at least a portion of the catalyst residue is in a first oxidation state, and the catalyst residue in the first oxidation state is active in catalyzing degradation of the stereoisomerically enriched product, and (B) chemically or electochemically changing the oxidation state of the catalyst residue from the first oxidation state to a second oxidation state, wherein catalyst residue in the second oxidation state is less active in catalyzing degradation of the stereoisomerically enriched product than is catalyst residue in the first oxidation state. The method reduces erosion of the chiral purity of the stereoisomerically enriched product and reduces the chemical transformation to side products of the stereoisomerically enriched product and co-product(s). The deactivated catalyst is recoverable and recyclable.

Kinetic resolution method

A process for the preparation of (R)-1-(2,3-difluoro-6-nitrophenoxy)-propan-2-ol, which is a useful intermediate in the synthesis of the widely used antibiotic Levofloxacin is provided. A process for the preparation of (R)-1-(2,3-difluoro-6-nitrophenoxy)-2-trimethylsiloxypropane is also described. The process includes the ring opening of (R)-propylene oxide with 2,3-difluoro-6-nitrophenyl trimethylsilyl ether in the presence of an optically active Co(salen) catalyst. The trimethylsilyl group of the reactant is transferred to the product aryloxy alcohol, which serves to protect the secondary alcohol in situ. Upon isolation, the trimethylsilyl group is removed and the resulting regioisomeric mixture purified to yield the desired (R)-1-(2,3-difluoro-6-nitrophenoxy)-propan-2-ol in high purity and yield.

Process for preparation of (R)-1- (aryloxy)propan-2-ol

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Wakefield, MA, United States of America

Jay Larrow