Merck + Co., Inc.

Ronald B Jobson

John M Williams

Ulf H Dolling

Karel M Brands

Karel M J Brands

Torleif Utne

Michael D Ward

Raymond Cvetovich

Louis S Crocker

Ian Frank Cottrell

Daniel Richard Sidler

Michael Stewart Ashwood

Mark Cameron

Amar J Mahajan

Antony J Davies

Elizabeth S Fisher

Gary H Rasmusson

David B Johnston

David G Melillo

Gerard R Kieczykowski

Donald F Reinhold

Robert M Wenslow, Jr

Renato T Skerlj

Alfred V Lovell

Robert M Wenslow

Charles Orella

A process for preparing a crystalline, carbapenem monosodium salt of formula IIa:characterized by the steps a) adding about 10 to 30% of an organic solvent to an aqueous solution of the carbapenem, b) cooling the resulting solution to less than &#x2212;5&#xb0; C., c) adjusting the pH using a solution containing an acid in an organic solvent to give the appropriate pH for crystallization, and d) crystallizing the compound by adding methanol, and a Calcohol at between &#x2212;5 and &#x2212;25&#xb0; C.

Crystalline forms of carbapenem antibiotics and methods of preparation

A process for preparing a crystalline, carbapenem monosodium salt of formula IIa: characterized by the steps a) adding about 10 to 30% of an organic solvent to an aqueous solution of the carbapenem, b) cooling the resulting solution to less than &#x2212;5&#xb0; C., c) adjusting the pH using a solution containing an acid in an organic solvent to give the appropriate pH for crystallization, and d) crystallizing the compound by adding methanol, and a Calcohol at between &#x2212;5 and &#x2212;25&#xb0; C.

A stabilized carbapenem intermediate compound represented by the formula 1:

Stabilized carbapenem intermediates and improved process for carbapenem synthesis

A process of synthesizing a compound of the formula 1: ##STR1## is described. A compound of the formula 2: ##STR2## is reacted with diphenylphosphinic chloride to activate the carboxylic acid group, and then reacted with methanesulfonyl chloride to produce a compound of formula 4: ##STR3## Compound 4 is then reacted with a group II metal sulfide source in water to produce a compound of formula 1.

Process for synthesizing carbapenem side chain intermediates

Crystalline 2S-cis-3-[[(4-mercapto-2-pyrrolidinyl) carbonyl]-amino]benzoic acid and salts and solvates thereof are disclosed. Three different crystalline types are described.

Crystalline forms of antibiotic side chain intermediates

A process for synthesizing a compound of the formula I: ##STR1## or a pharmaceutically acceptable salt or ester thereof, wherein each P independently represents H or a protecting group, and R.sup.1 and R.sup.2 independently represent H, C.sub.1-10 alkyl, aryl or heteroaryl, or substituted C.sub.1-10 alkyl, aryl or heteroaryl, comprising: reacting the compounds: ##STR2## or a pharmaceutically acceptable salt or ester thereof, and ##STR3## or a pharmaceutically acceptable salt or ester thereof, wherein X represents OP(O)(OR).sub.2, or OSO.sub.2 R, wherein R represents C.sub.1-6 alkyl, aryl or perfluoro C.sub.1-6 alkyl, in the presence of an amine selected from the group consisting of: diisopropylamine (DIPA), dicyclohexylamine (DCHA), 2,2,6,6-tetramethylpiperidine (TMP), 1,1,3,3-tetramethylguanidine (TMG), 1,8-diazabicyclo�4.3.0!undec-7-ene (DBU) and 1,5-diazabicyclo�4.3.0!non-5-ene to produce a compound of formula I.

Process for synthesizing carbapenem antibiotics

A process for the preparation of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid or salts thereof which comprises:

Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid

An optically impure diastereomeric salt is purified by treating a suspension of the salt in an appropriate solvent or solvent mixture with the required amount of the desired, optically pure, acid or base.

Displacement purification of salts

A method of preparing a compound of the formula: ##STR1## where Formula (I) may also have the structure of partial Formula (III); wherein, ##STR2## R' is hydrogen or methyl; R' is hydrogen or .beta.-methyl;

Preparation of 4-aza-17-substituted-5.alpha.-androstan-3-ones useful as

Biaryl coupling, particularly to form 2,4-difluorobiphenyl, is accomplished by diazotizing an aniline and coupling the benzenediazonium salt with a second aromatic component in the presence of a strong acid, an inert finely divided solid and copper powder or a copper salt.

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East Brunswick, NJ, United States of America

Ronald B Jobson