Sepracor, Inc.

Stephen Alan Wald

Chris Hugh Senanayake

Charles M Zepp

David R Dodds

Roger P Bakale

Richard F Rossi

Yun Gao

Qun Kevin Fang

Stephen L Matson

Paul T Grover

Martin P Redmon

Donald L Heefner

Robert Hett

Kevin Q Fang

Yaping Hong

Kostas Saranteas

Patrick Koch

Polymorphic crystalline forms of the antihistaminic drug norasternizole are disclosed. Processes for the production of the preferred polymorph are also disclosed.

Norastemizole polymorphs

A method is disclosed for the preparation of optically pure isomers of formoterol by the reaction of an optically pure 4-benzyloxy-3-formamidostyrene oxide with an optically pure 4-methoxy-&agr;-methyl-N-(phenylmethyl)benzeneethanamine followed by debenzylation. Useful intermediates in the process are also disclosed, as are the novel L-tartrate salt of R,R-formoterol and pharmaceutical compositions thereof.

Formoterol process

A method of treating fungal infections with a mixture of isomers of 2R,4S-hydroxyitraconazole and their sulfate and phosphate derivatives is disclosed. Pharmaceutical compositions containing these compounds are also disclosed.

2R,4S-hydroxyitraconazole isomers

A method is disclosed for the preparation of optically pure isomers of formoterol by the reaction of an optically pure 4-benzyloxy-3-formamidostyrene oxide with an optically pure 4-methoxy-.alpha.-methyl-N-(phenylmethyl)benzeneethanamine followed by debenzylation. Useful intermediates in the process are also disclosed, as are the novel L-tartrate salt of R,R-formoterol and pharmaceutical compositions thereof.

Processes for preparing a single enantiomer of an .alpha.,.alpha.-disubstituted-.alpha.-hydroxy acetic acid, especially cyclohexylphenylglycolic acid (CHPGA), is disclosed. The processes employ cyclic 1,2-aminoalcohols as chiral auxiliaries by forming diastereomeric esters of aminoalcohols or diastereomeric amides of oxazolidines. ##STR1## Intermediates useful in the process are also disclosed.

Asymmetric grignard synthesis with cyclic 1,2 aminoalcohols

This invention relates to novel compositions of matter which are esters with enhanced water solubility, for use in aqueous enzymatic resolution reactions of racemic mixtures of these esters for producing the separate chiral isomers of the racemic mixture. The invention also relates to novel methods for preparing these esters. The importance of the production of the separate chiral isomers of the racemic mixtures resides in the isolation of the isomers which frequently have different biological activities. Of particular significance regarding the water soluble esters of this invention is that they are derivatized with groups which enhance their aqueous solubility and their reactivity with enzymatic resolving methods which are mediated in an aqueous environment.

Compounds useful in enzymatic resolution systems and their preparation

This invention relates to novel compositions of matter which are esters with enhanced water solubility, for use in aqueous enzymatic resolution reactions of racemic mixtures of these esters for producing the separate chiral isomers of the racemic mixture. The invention also relates to novel methods for preparing these esters. The importance of the production of the separate chiral isomers of the racemic mixtures resides in the isolation of the isomers which frequently have different biological activities. Of particular significance regarding the water soluble esters of this invention is that they are derivatized with groups which enhance their aqueous solubility and their reactivity with enzymatic resolving methods which are mediated in an aqueous environment. In addition, the importance of these compounds resides in their being useful in novel methods for facilitating the enzymatic resolution reactions of racemic mixtures of esters, which are derivatized with groups which enhance the esters' aqueous solubility, in 1) a homogeneous aqueous reaction system where an extractive phase is not present, 2) a multiphase dispersion extractive reaction where an extractive phase is present, and 3) an extractive membrane reactor where the enzyme is placed alternatively either (a) in the aqueous phase, (b) in association with the membrane, or (c) in the aqueous phase and in association with the membrane, wherein the aqueous ester phase is contacted with one side of the membrane, and where an organic extractive phase is contacted with the other side of the membrane, wherein the extractive phase serves to remove the resolving reaction product.

This invention relates to novel methods for facilitating the enzymatic resolution of racemic mixtures of esters, which are derivatized with groups which enhance the esters' aqueous solubility, in an extractive member reactor where the enzyme is placed alternatively either (1) in the aqueous phase, (2) in association with the membrane, or (3) in the aqueous phase and in association with the membrane, wherein the aqueous ester phase is contacted with one side of the membrane, and where an organic extractive phase is contacted with the other side of the membrane, wherein the extractive phase serves to remove the resolving reaction product. Of particular significance regarding this invention is its use of water soluble esters that are derivatized with groups which enhance their aqueous solubility and their reactivity with enzymatic resolving methods which are mediated in an aqueous environment. Novel methods were utilized to prepare these esters, for use in this invention's methods for enzymatically resolving the racemic mixtures of the esters, to produce the separate chiral isomers of the racemic mixture. The importance of the resolution of the separate chiral isomers of the racemic mixtures resides in the isolation of the isomers which frequently have different biological activities.

Method for membrane reactor resolution of stereoisomers

This invention relates to a novel method of effecting aqueous enzymatic and homogeneous resolutions of racemic esters which exhibit enhanced aqueous solubility. The preferred embodiment of this invention relates to the resolutions which are effected by placing the enzyme and racemic esters in an aqueous phase wherein one of the ester enantiomers is preferentially and stereospecifically de-esterified to effect the resolution of the initial racemic mixture. In another embodiment of this invention, the resolutions are effected by placing the enzyme and racemic esters in an aqueous phase, and contacting this aqueous phase with an organic phase. The preferential and stereospecific de-esterification of one of the ester enantiomers is effected, and the chiral acid product of the de-esterification reaction is extracted into the organic phase.

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Sudbury, MA, United States of America

Stephen Alan Wald