Syntex (u.s.a.) Inc.

Roche Colorado Corporation

Syntex LLC

Michael P Fleming

George C Schloemer

Hiralal N Khatri

Michelangelo Scalone

Kurt Puentener

Yeun-Kwei Han

David A Johnston

Lewis M Hodges

Robert J Topping

Mark A Schwindt

Roger P Micheli

Chris R Roberts

Peter John Harrington

The present invention relates to a novel process for producing a &#x3b4;-lactone of the formula:using an acyl halide of the formula:wherein R, RRand X are described herein, as well as novel intermediates. In particular, the present invention relates to a process for enantioselectively producing the (R)-&#x3b4;-lactone.

Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one

A method of preparing 2-�2-{�3-(1H-benzimidazol-2-yl)propyl!methylamino)}ethyl!-6-fluoro-1-isopr opyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting 6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with the dianion of N-�3-(1H-benzimidazol-2-yl)propyl!-N-methylacetamide to form N-�3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3 ,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, reducing this to 2-�2-{�3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1,2,3,4-tetrahydronaphthalen-2-ol, and treating the 2-�2-{�3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1,2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (lS,2S)-2-�2-{�3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro- 1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N-�3-(1H-Benzimidazol-2-yl)propyl!-N-methylacetamide, and the acetic acid solvate of 2-�2- {�3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1 ,2,3,4-tetrahydronaphthalen-2-ol dioxalate, are new.

Preparation of mibefradil via an acetamide anion

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

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.

N-Vinyl carbazoles are prepared by reacting an N-unsubstituted carbazole with a dihaloethane in the presence of a phase transfer catalyst followed by reaction with an aqueous solution containing a highly basic agent. These N-vinyl carbazoles are useful, singly or in combination with other materials, as electrical capacitors and insulators, in thermal foam insulators, as components in copolymers and in image-recording systems, and as photoconductive materials in electrophotography.

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Longmont, CO, United States of America

Michael P Fleming