Marion Laboratories

David R Borcherding

Wolter Ten Hoeve

Hans Wynberg

Johannes Nicolaas Koek

Daniel E Martin

Gerrit A Barf

Certain 1,5-benzothiazepines are useful intermediates or pharamceuticals.

Benzothiazepines

2-Aromatic-3-HALobenzothizepines are prepared by reaction of a 2,3-dihydro-2-aromatic-3-hydroxybenzothiazepine with a thionyl HALide. For example, dl-cis-2-(4-methoxyphenyl)-2,3-dihydro-3-hydroxy-1, 5-benzothiazzepin-4(5H)-one relfuxed with thionyl chloride can prepare E-2-(4-methoxyphenyl)-3-chloro-1,5-benzothiazepin-4(5H)-one in 66 percent yield.

Process for preparing 2-aromatic-3-halobenzothiazepines

An alpha-hydroxyl-alpha,alpha-di(inert-substituted)-gamma',delta'-yne ketone can be prepared by a procedure comprising contacting an acetylenic Grignard reagent with an alpha-hydroxyl-alpha,alpha-di(inert substituted)-alpha',beta'-ene ketone, and the alpha-hydroxyl-alpha,alpha-di(inert-substituted)-alpha',beta'-ene ketone can be prepared by a procedure comprising steps of contacting, first, an alkoxy allene with a lithium donating organic agent, second, product of the first step with a di(inert-substituted)ketone, and third, product of the second step with an acidic substance. For example, 1-cyclobutyl-7-(N,N-dimethylamino)-1-hydroxy-1-phenylhept-5-yn-2-one, hydrochloride salt (ML-1012), can be prepared by the reaction of 1-cyclobutyl-1-hydroxy-1-phenylbut-3-en-2-one and 1-(N,N-dimethylamino)-2-propyn-3-magnesium chloride, followed by salt formation with hydrogen chloride gas, and the 1-cyclobutyl-1-hydroxy-1-phenylbut-3-en-2-one can be prepared by the serial reactions of (1) 1-methoxy allene with n-butyllithium, (2) product of this first step with cyclobutylphenyl ketone, and (3) product of this second step with sulfuric acid.

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Roeland Park, KS, United States of America

David R Borcherding