Orion-yhtyma Oy Fermion

Orion Corporation, Fermion

Martti Hytonen

Pekka Kairisalo

Olli Aaltonen

Anneli Hase

Martti Alkio

Veikko Komppa

Oskari Sundholm

Liisa Kanerva

A method for the preparation of 3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-b enzothiazepine-4(5H)-one and use of the product prepared by this method for making pharmaceutical compositions and pharmaceutically active compounds is disclosed starting with N-alkylation of 3-hydroxy-2,3-dihydro-4-(methoxyphenyl)-1,5-benzothiazepin-4(5H)-one with a (dimethylamino)ethyl halide wherein the N-alkylation reaction is carried out in a reaction mixture comprising 2-butanone and water. The product of this reaction and its salts have utility as pharmaceutically active compounds and as intermediates for making pharmaceutically active compounds. The disclosed method and use is simpler, more efficient and safer than prior known methods and produces a product of superior purity.

Method for the preparation of

A process is provided for preparing cis-(+)-hydroxy-5-[2-(dimethylamine)ethyl]-2,3-dihydro-2-(4-methoxyphenyl) -benzothiazepin-4(5H)-one that is a useful intermediate in the preparation of diltiazem. It has been found that the requisite N-alkylation reaction proceeds rapidly and with an excellent yield when the solvent is a mixture of toluene and N-methylpyrrolidin-2-one and the base is finely-divided sodium carbonate under anhydrous conditions. Such diltiazem commonly is used in the treatment of angina pectoris.

Process for preparing diltiazem

An enzymatic method for the preparation of (2S,3S)-threo-alkyl-2-hydroxy-3-(4-methoxyphenyl)-3-(2-X-phenylthio)propio nate, where X=NO.sub.2, NH.sub.2, NHCOCH.sub.3, NHCOCF.sub.3, NHCO.sub.2 CH.sub.3, NHCO.sub.2 C(CH.sub.3).sub.3 or NHCHO and R is an alkyl group, e.g., CH.sub.3, or CH.sub.2 CH.sub.3 in an essentially anhydrous organic solvent is described. In this method a lipase which stereospecifically acylates the (2R,3R)-enantiomer of the racemic mixture is used. After enzymatic reaction, the (2S,3S)-enantiomer and the acylated (2R,3R)-compound are separated, e.g., by flash-chromatography or by fraction crystallization of the (2S,3S)-compound from the reaction mixture.

Chiral resolution of an intermediate in diltiazem synthesis using lipase

A method is provided for supplying the desired optical isomer of a derivative of epoxypropionic acid from a racemix mixture. A representative derivative of epoxypropionic acid is an ester of (p-methoxyphenyl)epoxypropionic acid. The racemic mixture initially is dissolved in carbon dioxide and the resulting solution is passed through a chromatographic column. The desired isomer is subsequently separated from the resulting eluant. In a preferred embodiment the chromatographic column is packed with microcrystallized cellulosetriacetate, cellulose-tris-(3,5-dimethylphenylcarbamate), or cellulose-tris-(p-methylphenylcarbamate).

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Espoo, Finland

Martti Hytonen