Abiogen Pharma S.p.a.

Boehringer Ingelheim Pharmaceuticals, Inc.

Elio Napolitano

Denice Mary Spero

Suresh R Kapadia

Rita Fiaschi

Gabriella Brunetto

Chiara Bechini

A process for resolving a compound in racemic form comprising the following steps is described: a) reacting a compound in racemic form with a resolving agent, b) forming a diastereoisomeric complex of the resolving agent and an enantiomer of interest, c) separating the enantiomer of interest from the obtained diastereoisomer, wherein such a process is characterized in that said resolving agent is a compound of Formula (I). A diastereoisomeric complex between the resolving agent of Formula (I) and the enantiomer of interest is also described. The process according to the invention allows acid and basic racemic mixtures to be separated.

Process for resolving racemic mixtures and a diastereoisomeric complex of a resolving agent and an enantiomer of interest

It is disclosed a process for the preparation of 2-(4-hydroxy-3-morfolinyl)-2-cycloesenone (BTG-1675A) comprising the steps of: i) reacting N-hydroxymorpholine with cycloesanone in the presence of an oxidation agent thus obtaining an isoxazolidine of Formula IV; and ii) converting the isoxazolidine of Formula IV into 2-(4-hydroxy-3-morfolinyl)-2-cycloesenone. Advantageously, the oxidation agent of the step i) is selected from the group consisting of metal oxides, esters and amides of the azodicarboxylic acid and the step ii) of conversion is carried out by basic catalysis followed by trituration in an aromatic hydrocarbon, preferably toluene. The process disclosed allows to obtain BTG-1675A according to the invention in an amount of hundreds of grams and on an industrial scale. The invention further concerns a new process for preparing hydroxylamines, particularly N-hydroxymorpholine, which is used in the process for preparing BTG-1675A.

Process for the preparation of 2-(4-hydroxy-3-morfolynil)-2-cyclohexenone

An improved process for making chiral, .alpha.-methylated, .alpha.-substituted amino acids of the formula I ##STR1## wherein Y is a hydrogen atom and R.sub.2 is the residue of a natural or unnatural amino acid, in which process an oxazolidinone of the formula II ##STR2## is formed by reacting a protected amino acid of the formula IA ##STR3## wherein Y is a protecting group, with an aldehyde of the formula RCHO, or an equivalent thereof, in the presence of a chlorinating agent and a Lewis acid. The group R.sub.2 is introduced into the oxazolidinone intermediate of formula II in a conventional manner, and subsequent hydrolysis and deprotection, both carried out in a conventional manner, yield the chiral, .alpha.-methylated, .alpha.-substituted amino acid.

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Pisa, Italy

Elio Napolitano