Degussa Aktiengesellschaft

Asta Medica, Aktiengesellschaft

Horst Bethge

Roland Moller

Axel Kleemann

Gerhard Sator

Klaus Huthmacher

Jurgen Martens

Thomas Beisswenger

Frank Hubner

Karlheinz Drauz

Herbert Klenk

Thomas Tacke

Herbert Tanner

Stephan Rautenberg

Rainer Gewald

Alfred Olbrich

Claus Rehren

Horst Weigel

Paul Scherberich

Joachim Goede

Klaus Stingl

Stefan Merget

Gottfried Blaschke

Rolf Braun

Ursula Scheidemantel

Roland Moeller

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

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

Method for the conversion of the enantiomers of .alpha.-lipoic acid into the corresponding racemic mixture by racemizing the .alpha.-lipoic acid (pure optical isomers of .alpha.-lipoic acid or mixtures of optical isomers of .alpha.-lipoic acid wherein one of the optical isomers is present in excess) at temperatures of between 110.degree. C. and 200.degree. C. at pressures of from normal pressure up to 50 bar for a reaction time of 10 to 48 hours.

Method for the racemization of enantiomers of .alpha.-lipoic acid

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.

Preparation and use of salts of the pure enantiomers of alpha-lipoic acid

An improved method of preparing 1,6-di(N.sup.3 -cyano-N.sup.1 -guanidino) hexane from alkali dicyanamide and a hexamethylene diammonium salt in alcoholic solution or suspension. The reaction is carried out in the presence of a limited amount of water and of a catalytic amount of a base, preferably a tertiary amine. The pH of the reaction mixture at the start of the reaction is 8 to 10. After the reaction is over, the reaction mixture is compounded with water at a temperature above 80.degree. C. and the coarse product which crystallizes out is separated from the liquid phase. Preferably, sodium dicyanamide and hexamethylene diamine dihydrochloride, preferably formed in situ from aqueous 1,6-diaminohexane and aqueous hydrochloric acid, are reacted at pH 9-9.5 in n-butanol in the presence of 0.1 to 20% by wt. water in relation to the solvent including water. 1,6-di(N.sup.3 -cyano-N.sup.1 -guanidino) hexane is obtained in a high yield (85-86%) and with great purity (95-97%) and with a considerably improved space-time yield.

Method of preparing 1,6-di(N.sup.3 -cyano-N.sup.1 -guanidino) hexane

To separate the racemate (R,S)-cysteine, the racemate is condensed in an inert solvent with an enantiomerically enantiomeric monosaccharide of the group of aldoses having 4 to 7 carbon atoms to form the corresponding 2-substituted thiazolidin-4-carboxylic acid and the mixture of diastereomers obtained separated from each other. Subsequently, the isolated unitary diastereomers are reacted in an inert solvent with a carbonyl reagent to split the ring and the enantiomerically pure cysteine in each case is isolated as such or as the corresponding cystine.

Process for the separation of the racemate (R,S)-cysteine

There is described the resolution of the racemate (1RS,2SR)-2-amino-1-phenyl-propan-1-ol. It is carried out by means of the optical isomers of S-(carboxymethyl)-cysteine.

Process for the resolution of the racemate

There is described the resolution of the racemate S-(carboxymethyl)-(RS)-cysteine. It is carried out by means of the optical isomers of 2-amino-1-phenyl-propan-1-ol. This process makes it possible to obtain in a simple manner S-(carboxymethyl)-(R)-cysteine which is important for pharmaceutical purposes and is made from synthetically produced cysteine.

There are produced thiazoline-(3) compounds which optionally are substituted or unsubstituted in the 2 and/or 5 positions by reaction of oxo compounds with a metal sulfides, ammonia and oxo compounds which are substituted by halogen in the position adjacent to the oxo group. In this process a mixture of oxo compounds, metal sulfides and ammonia is present and the halogen substituted oxo compound is introduced into the mixture. By using in this manner of mixing, high yields are obtained in a relatively short period of time.

Process for the production thiazolines-(3)

There is described the resolution of the racemate S-(carboxymethyl)-(RS)-cysteine. It is carried out by means of the optical isomers of 1-phenyl-ethylamine. This process makes it possible to obtain in a simple manner S-(carboxymethyl)-(R)-cysteine which is important for pharmaceutical purposes and is made from synthetically produced cysteine.

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Rodenbach, Germany

Horst Bethge