Eli Lilly and Company

Lawrence J McShane

Gary A Koppel

Robin D Cooper

Bryan B Molloy

Edward R Lavagnino

The crystalline ethanol or methanol solvates of cephalexin hydrochloride are isolated in high yield from solutions of cephalexin hydrochloride in substantially anhydrous ethanol or methanol, respectively, by adding miscible C.sub.5 -C.sub.6 alkanes after initiating solvate crystallization. Ethanol or methanol solutions of cephalexin hydrochloride can be prepared by adding gaseous HCl to the respective alcohol slurries of cephalexin monohydrate or the novel crystalline ethanolate or desolvated ethanolate. Alternatively, the cephalexin bis-DMF solvate-derived cephalexin hydrochloride isopropanolate can be used to prepare the crystalline hydrochloride monohydrate in accordance with the disclosed improved method.

Process for cephalexin hydrochloride alcoholates

1,2,2-Trihalocyclopropane 1-carboxylic acids and derivatives thereof are useful in regulating the growth and flowering of plants when applied as a foliar spray or as a post emergent or pre-emergent soil treatment.

Method for plant growth regulation

3-Acetoxymethylcephalosporins are converted to 3-exomethylene cephalosporins by reaction with a metal and a bound proton source.

3-Exomethylene cephalosporins

3-Exomethylene cepham sulfones are converted to azetidinone sulfinic acids by reaction with activated zinc, magnesium, activated magnesium or amalgamated magnesium and a protonic acid.

Azetidinone sulfinic acids from cephalosporin sulfones

1-[.alpha.-(Carboxy)-4-hydroxybenzyl]-3.beta.-aminoazetidin-2-one esters are prepared by converting 2-acyl-3,3-dialkyl-7-oxo-.alpha.-[4-(benzyloxy)phenyl]-4-thia-2,6-diazabic yclo[3.2.0]-heptane-6-acetic acid esters with mercuric acetate in an aqueous organic solvent mixture, e.g., in aqueous methanol, to 7-oxo-3-phenyl-.alpha.-[4-(benzyloxy)phenyl]-4-oxa-2,6-diazabicyclo[3.2.0] hept-2-ene-1-acetic acid esters and the latter are reacted with PCl.sub.5 and pyridine to provide the monocyclic 1-[.alpha.-(carboxy)-4-benzyloxybenzyl]-3.beta.-(.alpha.-chlorobenzylidene -amino)-4-chloroazetidin-2-one esters. Reduction of the dichloro azetidin-2-one with an organo tin hydride and azobisisobutyronitrile affords the deschloro, 1-[.alpha.-(carboxy)-4-benzyloxybenzyl]-3.beta.-benzylideneaminoazetidin-2 -one ester. The latter is hydrolyzed and the 4-benzyloxy group is cleaved via catalytic hydrogenolysis to yield an ester of 1-[.alpha.-(carboxy)-4-hydroxybenzyl]-3.beta.-aminoazetidin-2-one. The 3.beta.-amino ester is useful for the preparation of the antibiotic FR 1923 (nocardicin).

Process for 3.beta.-aminoazetidin-2-ones

1-[.alpha.-(Carboxy)-4-hydroxybenzyl]-3.beta.-aminoazetidin-2-one esters are prepared by converting 2-acyl-3,3-dialkyl-7-oxo-.alpha.-[4-(benzyloxy)phenyl]-4-thia-2,6-diazabic yclo[3.2.0]heptane-6-acetic acid esters with mercuric acetate in an aqueous organic solvent mixture, e.g., in aqueous methanol, to 7-oxo-3-phenyl-.alpha.-[4-(benzyloxy)phenyl]-4-oxa-2,6-diazabicyclo[3.2.0] hept-2-ene-1-acetic acid esters and the latter are reacted with PCl.sub.5 and pyridine to provide the monocyclic 1-[.alpha.-(carboxy)-4-benzyloxybenzyl]-3.beta.-(.alpha.-chlorobenzylidene amino)-4-chloroazetidin-2-one esters. Reduction of the dichloro azetidin-2-one with an organo tin hydride and azobisisobutyronitrile affords the deschloro, 1-[.alpha.-(carboxy)-4-benzyloxybenzyl]-3.beta.-benzylideneaminoazetidin-2 -one ester. The latter is hydrolyzed and the benzyloxy group is cleaved via catalytic hydrogenolysis to yield an ester of 1-[.alpha.-(carboxy)-4-hydroxybenzyl]-3.beta.-aminoazetidin-2-one. The 3.beta.-amino ester is useful for the preparation of the antibiotic FR 1923 (nocardicin).

Intermediates for 3-aminoazetidin-2-ones

1-Phenyl-3-(optionally substituted phenoxy)-propylamines, inhibitors of norepinephrine uptake.

1-Phenyl-3-(substituted phenoxy)propylamines

1-[.alpha.-(Carboxy)-4-hydroxybenzyl]-3.beta.-aminoazetidin-2-one esters are prepared by converting 2-acyl-3,3-dialkyl-7-oxo-.alpha.-[4-(benzyloxy)phenyl]-4-thia-2,6-diazabic yclo[3.2.0]-heptane-6-acetic acid esters with mercuric acetate in an aqueous organic solvent mixture, e.g., in aqueous methanol, to 7-oxo-3-phenyl-.alpha.-[4-benzyloxy)phenyl]-4-oxa-2,6-diazabicyclo[3.2.0]h ept-2-ene-1-acetic acid esters and the latter are reacted with PCl.sub.5 and pyridine to provide the monocyclic 1-[.alpha.-(carboxy)-4-benzyloxybenzyl]-3.beta.-(.alpha.-chlorobenzylidene amino)-4-chloroazetidin-2-one esters. Reduction of the dichloro azetidin-2-one with an organo tin hydride and azobisisobutyronitrile affords the deschloro, 1-[.alpha.-(carboxy)-4-benzyloxybenzyl]-3.beta.-benzylideneaminoazetidin-2 -one ester. The latter is hydrolyzed and the 4-benzyloxy group is cleaved via catalytic hydrogenolysis to yield an ester of 1-[.alpha.-(carboxy)-4-hydroxybenzyl]-3.beta.-aminoazetidin-2-one. The 3.beta.-amino ester is useful for the preparation of the antibiotic FR 1923 (nocardicin).

4-Oxa 2,6 diazabicycloheptane derivatives

1-[.alpha.-(Carboxy)-4-hydroxybenzyl]-3.beta.-aminoazetidin-2-one esters are prepared by converting 2-acyl-3,3-dialkyl-7-oxo-.alpha.-[4-(benzyloxy)phenyl]-4-thia-2,6-diazabic yclo[3.2.0]-heptane-6-acetic acid esters with mercuric acetate in an aqueous organic solvent mixture, e.g., in aqueous methanol, to 7-oxo-3-phenyl-.alpha.-[4-(benzyloxy)phenyl]-4-oxa-2,6-diazabicyclo[3.2.0] hept-2-ene-1-acetic acid esters and the latter are reacted with PCl.sub.5 and pyridine to provide the monocyclic 1-[.alpha.-(carboxy)-4-benzyloxybenzyl]-3.beta.-(.alpha.-chlorobenzylidene amino)-4-chloroazetidin-2-one esters. Reduction of the dichloro azetidin-2-one with an organo tin hydride and azobisisobutyronitrile affords the deschloro, 1-[.alpha.-(carboxy)-4-benzyloxybenzyl]-3.beta.-benzylideneaminoazetidin-2 -one ester. The latter is hydrolyzed and the 4-benzyloxy group is cleaved via catalytic hydrogenolysis to yield an ester of 1-[.alpha.-(carboxy)-4-hydroxybenzyl]-3.beta.-aminoazetidin-2-one. The 3.beta.-amino ester is useful for the preparation of the antibiotic FR 1923 (nocardicin).

A process for preparing the compound represented by the formula ##STR1## wherein the indicated carbon has the D-configuration which comprises dissolution of the compound in the L-configuration or as a mixture of the D and L-configurations in aqueous pyridine from which the compound having the D-configuration selectively crystallizes.

Growing community of inventors

Indianapolis, IN, United States of America

Lawrence J McShane