Syntex (u.s.a.) Inc.

Syntex Pharmaceuticals International Limited

Syntex LLC

Syntex Pharmaceutical International Limited

George C Schloemer

Hiralal N Khatri

Michael P Fleming

Peter John Harrington

Yeun-Kwei Han

Eric Lodewijk

Sam Linh Nguyen

Gregory P Withers

5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxamides of the formula

Preparation of ketorolac

(S)-ibuprofen may be separated from a mixture of (S)-ibuprofen and (R)-ibuprofen in high yield and enantiomeric purity in a single resolution step using an N-alkyl-D-glucamine as the resolving agent.

Resolution of ibuprofen

A process for the preparation of acyclovir includes contacting an at least partially silylated guanine or mixture of at least partially silylated guanines with 1,3-dioxolane in the presence of a selective alkylation catalyst selected from the group consisting of trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, and bistrimethylsilyl sulfonate, and hydrolyzing the product thus formed.

Preparation of acyclovir using 1,3 dioxolane

The invention relates to efficient and selective processes for the synthesis of the antiviral N-9 substituted guanine compounds acyclovir and ganciclovir.

Preparation of N-9 substituted guanine compounds

Optically active naphthyl alpha-substituted alkyl ketones, are a class of ketones useful as intermediates in the production of optically active alpha-naphthylalkanoic acids which exhibit anti-inflammatory, analgesic and anti-pyretic activity.

Optically active alpha-naththylalkyl ketones

2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates of the formula, ##STR1## in which each R is independently H or lower alkyl, are prepared from from di(lower alkyl) 1,3-acetone-dicarboxylates.

Process for preparing

Pharmaceutically useful optically active .alpha.-arylalkanoic acids or esters, ortho esters, or amides thereof are stereoselectively prepared by contacting an aryl magnesium Grignard reagent with an optically active .alpha.-substituted acyl halide to form the optically active aryl .alpha.-substituted alkyl ketone, which is ketalized and rearranged to the desired optically active .alpha.-arylalkanoic acid or the corresponding ester, ortho ester or amide. In an alternate embodiment, the aryl .alpha.-substituted alkyl ketone is reduced to the corresponding alkanol, which is rearranged to the .alpha.-arylalkanal. The alkanal so produced is converted to the desired optically active .alpha.-arylalkanoic acid by conventional methods.

Preparation of .alpha.-arylalkanoic acids

2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid compounds of the formula, ##STR1## in which Y is OH;

2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates of the formula, ##STR1## in which each R is independently H or lower alkyl, are prepared from di(lower alkyl) 1,3-acetonedicarboxylates.

2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate intermediates of the formula, ##STR1## in which each R is independently H or lower alkyl, are prepared from di(lower alkyl) 1,3-acetonedicarboxylates.

2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylates of the formula, ##STR1## in which each R is independently H or lower alkyl, are prepared from di(lower alkyl) 1,3-acetone-dicarboxylates.

Preparation of stereoisomers of ketals

.alpha.-Arylalkanoic acids or esters, orthoesters or amides thereof are prepared by forming an .alpha.-hydroxy ketal or thioketal of an aryl alkyl ketone, activating the .alpha.-hydroxy substituent with an esterifying agent to form the corresponding ketal or thioketal ester substrate, wherein the ester group is sufficiently labile to non-catalytically disassociate from the substrate in a protic or dipolar, aprotic solvent, maintaining the ester substrate in contact with the protic or dipolar, aprotic solvent or mixtures thereof for a time sufficient to form the corresponding .alpha.-arylakanoic acid or ester, orthoester or amide thereof, and optionally concomitantly or sequentially hydrolyzing any ester, orthoester or amide formed to the corresponding .alpha.-arylalkanoic acid.

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Longmont, CO, United States of America

George C Schloemer