Asta Medica, Aktiengesellschaft

Degussa Aktiengesellschaft

Degussa Aktiengellschaft

Roland Moller

Horst Bethge

Gerhard Sator

Klaus Huthmacher

Thomas Beisswenger

Frank Hubner

Karlheinz Drauz

Herbert Klenk

Alfred Olbrich

Thomas Tacke

Herbert Tanner

Stephan Rautenberg

Rainer Gewald

Claus Rehren

Klaus Stingl

Jurgen Engel

Bernhard Kutscher

Matthias Kottenhahn

Joachim Goede

Michael Kraft

Gottfried Blaschke

Ursula Scheidemantel

Kurt Klostermann

The invention relates to the production and purification of salts of 6,8-bis (amidiniumthio)octanoic acid, its enantiomers (+)-6,8-bis(amidiniumthio)octanoic acid and (-)-6,8-bis (amidiniumthio)octanoic acid and of the esters of these compounds as well as to their use to produce dihydrolipoic acid and .alpha.-lipoic acid.

Production and use of salts of 6,8-bis (amidiniumthio)-octanoic acid

The present invention is relative to a method of producing dry thioctic acid in which a raw material in which concentrated thioctic acid is present is treated with liquid or supercritical CO.sub.2, thus yielding thioctic acid with low residual solvent contents in a simple industrial method.

Method of producing dry thioctic acid

There is provided a process for the work-up of this material having the formula ##STR1## because of its poor crystallizability has heretofore been available only with large yield losses. The yield losses are due to the fact that the crystals of this compound are associated with large amounts of residual solvent material which gives rise to complex and expensive drying procedures. In accordance with the present invention the crude LPE is dried by means of fluid or supercritical carbon dioxide which maces it possible to reduce drying times from the previous range of about 124 hours to about 10 hours for the same amount of product and thus produce a dry LPE which has smaller amounts of residual solvent, as well as smaller by-products than that obtained by conventional drying.

Process for the preparation of 1-(N 2-(S)-ethoxycarbonyl)--3

A method of isolating 1-�N.sup.2 -((S)-ethoxycarbonyl)-3-phenylpropyl)-N.sup.6 -trifluoroacetyl!-L-lysyl-L-proline (lisinopril (TFA) ethyl ester, LPE). The solvent or solvent mixture used for the extraction is also a main constituent of the solvent or solvent mixture from which the crystallization takes place. High yield as well as good purity of the end product are obtained, without distillation. 1-�N.sup.2 -((S)-ethoxycarbonyl)-3-phenylpropyl)-N.sup.6 -trifluoroacetyl!-L-lysyl-L-proline (lisinopril (TFA) ethyl ester, LPE) is described as a precursor for producing an ACE inhibitor.

Method of isolating 1-�N.sup.2

This disclosure describes two technical procedures for the high-yield synthesis of heterocyclic seven-membered ring-systems by Dieckmann-condensation avoiding usual dilution techniques and long reaction times. Thus, it significantly increases the overall yields of the pharmaceutically active ingredients azelastine and flezelastine, whose synthesis, starting from these seven-membered heterocyclic rings, is reported elsewhere. Yields range from 80-89%, avoiding waste and increasing economics of the synthesis.

Method for the preparation of hexahydroazepinones and hexahydroazepinoles

The invention relates to the production and purification of salts of 6,8-bis(amidiniumthio) octanoic acid, its enantiomers (+)-6,8-bis(amidiniumthio)octanoic acid and (-)-6,8-bis (amidiniumthio)octanoic acid and of the esters of these compounds as well as to their use to produce dihydrolipoic acid and .alpha.-lipoic acid.

Production and use of salts of 6, 8-bis (amidiniumthio) -octanoic acid

1. A method of producing flowable R,S-thioctic acid, R,S-thioctic acid and its use. 2.1. Known methods of preparing flowable thioctic acid which can be galenically further processed by pressing to highly-concentrated, solid presentations with active-substance contents of more than 200 mg pure substance require the mixing of the thioctic-acid forms of different origins and/or a spraying on of galenic adjuvants from aqueous solution and a subsequent grinding process in order to arrive at a pressable granulate. 2.2. As a result of the fact that thioctic acid of any origin is placed in the fluid bed of a device suited for producing a fluid bed and that a built-up granulate consisting of thioctic acid is obtained by spraying a solution of thioctic acid of any origin onto the matter placed in the fluid bed under simultaneous removal of the solvent, it is possible to make a thioctic-acid form available which does not adhere to the pressing tool or exhibit a tendency to form fissures on the tablet even when tablets with 600 mg or more active-substance content are prepared. The novel R,S-thioctic acid has a specific surface of &gt;0.7 m.sup.2 /g and a number of mesopores with a diameter between 2 and 30 nm.

Method of producing flowable R,S-thioctic acid, R,S-thioctic acid and

RS-thioctic acid with a novel morphology which is obtained by a recrystallization process.

RS-thioctic acid with novel morphology

The pure enantiomers of alpha-lipoic acid are obtained by formation of the diastereomeric salt pairs with the optical antipodes of alpha-methylbenzylamine in solution.

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Hammersbach, Germany

Roland Moller