Laboratorio Chimico Internazionale S.p.a.

Olon S.p.a.

Aptalis Pharma Limited

Adare Pharmaceuticals S.r.l.

Annibale Salvi

Antonio Nardi

Flavio Villani

Stefano Maiorana

Mara Sada

Bruno De Angelis

Paolo Magri'

Giovanna Falabella

Luigi Giovanni Mapelli

Luigi Boltri

Flavio Fabiani

Francesco Corcella

Giacomo Bruno

The present invention concerns a new composition based on pellets of lipoic acid in a lipophilic medium, if necessary combined with other active ingredients.

Lipoic acid pellet composition

Lipoic acid pellets are described, obtained from inert cores externally coated with lipoic acid. The so obtained active cores are coated with a first layer of insulating polymeric material and then with a polymeric coat that is insoluble at the gastric pH. Pellet are then formulated pharmaceutically, for instance in jelly capsules or controlled release capsules or as oral suspensions, dispersible powders, sachets, etc.

Lipoic acid pellets

This invention relates to the preparation of (R)-(&#x2212;)-3-(carbamoylmethyl)-5-methylhexanoic acid, in particular, the resolution of the acid racemate by means of salification with optically active amines and subsequent acidification to give the (R) enantiomer of the acid; this invention also concerns the salt intermediates formed with said amines and the conversion of said (R)-(&#x2212;)-3-(carbamoylmethyl)-5-methylhexanoic acid into biologically active molecules such as pregabalin.

Process for the preparation of (R)-(&#x2212;)-3-(carbamoylmethyl)-5-methylhexanoic acid and of pregabalin and synthesis intermediates

The invention concerns a new process for the preparation of high purity diacerein, by oxidization of the protected aloe-emodin in the presence of an oxidizing system and radical catalyst and subsequent substitution of the protector groups with acetyl groups.

Process for the preparation of DIACEREIN

The invention concerns a new process for the preparation of naphthoquinones, in particular an improved process for the preparation of 2,3-disubstituted 1,4-naphthoquinones, in the trans configuration.

Process for the preparation of trans-2,3-disubstituted naphthoquinones

Process for purifying thioctic acid in water comprising the following steps: a) dissolving the thioctic acid in an aqueous alkaline solution or alternatively dissolving a thioctic acid salt, if necessary adjusting the pH to alkaline values, b) acidifying the solution from step (a) with an acid chosen from the class consisting of sulfuric acid, phosphoric acid, methanesulfonic acid to a pH between 5.4 and 5.8. c) isolating the thioctic acid precipitated in step (b) by conventional methods.

Process for purifying thioctic acid in water

Salt of thioctic acid with L-carnitine with the formula:AY(X)where A is where Y is the cation of an alkaline metal, of an alkaline earth metal or is a quaternary ammonium group,X is A or OH,x is equal to 0 when Y is the cation of an alkaline metal or a quaternary ammonium group and equal to 1 when Y is an alkaline earth metal.

Basic salt of thioctic acid with L-carnitine

Process for the synthesis of R(+)&#x3b1;-lipoic acid comprising the following stages: a) Salifying of racemic 6,8-halo-octanoic acid with S(&#x2212;)&#x3b1;-methylbenzylamine; b) separation by filtration of the crystallized diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(&#x2212;)&#x3b1;-methylbenzylamine; c) purification by re-crystallization of the diastereoisomeric salt of R(+)6,8-di-halo-octanoic acid-S(&#x2212;)&#x3b1;-methylbenzylamine; (d) separation of the diastereoisomeric salt to obtain R(+)6,8-di-halo-octanoic acid by reation of said salt with strong mineral acids in an aqueous solution with a dilution between 2 and 10% by weight; e) esterification of R(+)6,8-di-halo-octanoic acid to obtain the corresponding alkyl ester; f) reaction of the alkyl ester of R(+)6,8-di-halo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in presence of a compound for phase transfer catalysis; g) hydolysis of the ester of R(+)&#x3b1;-lipoic acid.

Synthesis of r(+)&#x3b1;-lipoic acid

Process for the synthesis of racemic thioctic acid comprising the following stages: a) reaction of the alkyl ester of 6,8-di-halo-octanoic acid in an organic solvent with an aqueous solution of alkali disulfide in presence of a compound for phase transfer catalysis selected from the group consisting of quaternary ammonium or phosphonium salts having the following general formula: where: A is nitrogen of phosphorus, X is selected from the group consisting of Cl, Br, I, HSO, and HPOand the substitutents R, R, Rand Rare selection from the group consisting of linear or branched alkyl radicals having one to twenty carbon atoms (C1-C20), said substituents being identical or different one from the other, or only one of said substituents is selected from the group consisting of arylalkyl radicals having the following formula &#x2014;(CH)CHin which n=1-16; b) followed by the hydrolysis of the ester of racemic thiotic acid.

Process for the production of a racemic thioctic acid

Process for the synthesis of R(&plus;)&agr;-lipoic acid comprising the following stages: a) Salifying of racemic thioctic acid with R(&plus;)&agr;-methylbenzylamine; b) separation by filtration of the crystallized diastereoisomeric salt of R(&plus;)&agr;-lipoic acid-R(&plus;)&agr;-methylbenzylamine; c) purification by re-crystallization of the diastereoisomeric salt of R(&plus;) &agr;-lipoic acid-R(&plus;)&agr;-methylbenzylamine, in which the re-crystallization solvent consists of a mixture of non-polar/polar solvents; d) separation of the diastereoisomeric salt to obtain R(&plus;)&agr;-lipoic acid by reaction of said salt with acids selected from the group consisting of aliphatic hydroxy-carboxylic acids having 3 to 6 carbon atoms and aqueous phosphoric acid.

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Milan, Italy

Annibale Salvi