Merck + Co., Inc.

Christopher Roberge

Michel M Chartrain

John Y Chung

Shieh-Shung T Chen

Gerald F Bills

George M Garrity

Raymond Cvetovich

Dalian Zhao

Ali Shafiee

Daniel Richard Sidler

Colleen S Taylor

Norihiro Ikemoto

Brian Heimbuch

This invention relates to crystalline pharmaceutically acceptable salts of an alpha 1a adrenergic receptor antagonist, Compound A, which are useful in the treatment of benign prostatic hyperplasia. Pharmaceutical compositions employing the crystalline salts, and processes for making and using the crystalline salts and pharmaceutical compositions of Compound A are also disclosed. This invention further relates to a process for obtaining enantiomerically pure intermediate useful for the synthesis of end product alpha 1a adrenergic receptor antagonists. The end product compounds are useful for the treatment of benign prostatic hyperplasia and for relaxing lower urinary tract tissue. The invention also relates to a process for preparing a class of dihydropyrimidinone compounds of which Compound A is a member, wherein the process involves deprotonating a dihydropyrimidinone compound and then coupling the deprotonated derivative with a primary amine.

Enzymatic process of making alpha 1a adrenergic receptor antagonists using protease

Asymmetric bioreduction of a ketone substrate with yeast produces the corresponding (R)-alcohol of structure: ##STR1## a key intermediate in the synthesis of a .beta..sub.3 -agonist of structure ##STR2##

N-(R)-(2-hydroxy-2-pyridine-3-yl-ethyl)-2-(4-nitro-phenyl)-acetamide

Compound 9 is prepared by a 9-step ##STR1## process in an overall yield of about 35% from 3-acetylpyridine. Compound 10 is prepared by a seven-step ##STR2## process in an overall yield of about 30% from 3-acetyl pyridine. These compounds are key intermediates in the synthesis of Compound 11, an important .beta.-3 agonist useful in the treatment of obesity and diabetes. ##STR3##

Process for

The present invention relates to a process for converting a racemic mixture of 3,3-diethyl-4-[(4-carboxy)phenoxy]-2-azetidinone esters into the corresponding (S)-acid using lipase derived from Pseudomonas sp. The process provides the target acid in high enantiomeric excess.

Enzymatic hydrolysis of 3,3-diethyl-4-[(4-carboxy)phenoxy]-2-azetidinone

The present invention provides a process for the stereoselective reduction of phenylalkyl ketones to their corresponding (S)-hydroxy compounds. The process utilizes the novel microorganism Microbacterium MB 5614 to effectuate the chiral reduction. The present invention also provides said novel Microbacterium, which has been deposited with the ATCC and assigned the accession number ATCC 55557.

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Clark, NJ, United States of America

Christopher Roberge