Eprova Ag

Merck Patent Gesellschaft MIT Beschrankter Haftung

Merck & Cie

Eprova Akteingesellschaft

Hans R Muller

Martin Ulmann

Josef Conti

Rudolf Moser

Viola Groehn

Gunter Murdel

Benoit Pugin

Thomas Ammann

Willi Wintermeyer

Fritz Reiff

Process for the preparation of tetrahydropterin and tetrahydropterin derivatives by hydrogenating pterin and pterin derivatives with hydrogen in the presence of a hydrogenating catalyst, in which the hydrogenation is carried out in a polar reaction medium and metal complexes that are soluble in the reaction medium are employed as the hydrogenation catalysts. The process is suited to the hydrogenation, particularly asymmetric hydrogenation, of folic acid, folic acid salts, folic acid esters, folic acid ester salts or dihydroforms thereof, with the proviso that in the event of using folic acid, carboxylic acid salts thereof or dihydroforms thereof the reaction medium is aqueous, and in the event of using folic acid esters, folic acid ester salts or dihydroforms thereof the reaction medium is an alcohol. The process opens up straightforward access to achiral and chiral pterin derivatives.

Process for the preparation of optically pure tetrahydropterins and derivatives, and specifically of optically pure tetrahydrofolic acid and derivatives thereof, by stereospecific hydrogenation

A process for preparing and concentrating (6S,&#x3b1;S) or (6S,&#x3b1;R) tetrahydrofolic acid ester salts and (6S,&#x3b1;S) or (6S,&#x3b1;R) tetrahydrofolic acid, characterized by preparing or dissolving equimolar or concentrated mixtures of diastereomers of addition salts of tetrahydrofolic acid esters with aromatic sulphonic acids in organic solvents, followed by crystallizing them at least once, and then if applicable hydrolyzing the crystallizate to produce (6S,&#x3b1;S) or (6S,&#x3b1;R) tetrahydrofolic acid, crystallizing the latter as a free acid or isolating it in the form of a salt.

Process for the preparation of pure stereoisomers of tetrahydrofolic acid esters salts and tetrahydrofolic acid by fractionated crystallization of tetrahydrofolic acid esters salts

This invention relates to the use of tetrahydrofolates in natural stereoisomeric form for the production of a pharmaceutical preparation suitable for influencing the homocysteine level, particularly for assisting the remethylation of homocysteine. Clinical areas of application include all anomalies of the homocysteine level, particularly the prevention and treatment of cardiovascular diseases and the prevention of neural tube deficiencies. The present invention also relates to pharmaceutical preparations comprising at least one compound selected from the group consisting of 5-formyl-(6S)-tetrahydrofolic acid, 5-methyl-(6S)-tetrahydrofolic acid, 5,10-methylene-(6R)-tetrahydrofolic acid, 5,10-methenyl-(6R)-tetrahydrofolic acid, 10-formyl-(6R)-tetrahydrofolic acid, 5-formimino-(6S)-tetra-hydrofolic acid or (6S)-tetrahydrofolic acid or pharmaceutically compatible salts thereof, together with pharmaceutically compatible active and adjuvant substances, for influencing the homocysteine level, particularly when a methylene tetrahydrofolate reductase deficiency exists, such as when thermolabile methylene tetrahydrofolate reductase exists for example.

Use of tetrahydrofolates in natural stereoisomeric form for the

This invention relates to stable crystalline salts of (6R,S)-, (6S)- and (6R)-tetrahydrofolic acid, to methods of preparing these salts and to their use as an ingredient for the production of drugs and pharmaceutical preparations.

Stable crystalline tetrahydrofolic acid salts

The invention relates to novel cyclodextrin inclusion compounds of 5,10-methylenetetrahydrofolic acid. The surprisingly good stability of these compounds makes possible their pharmaceutical use for the first time. The invention additionally relates to a process for the preparation of the said substances and their use for the preparation of medicaments.

5,10-methylenetetrahydrofolic acid-cyclodextrin inclusion compounds

For the preparation of (6S)- and (6R)-tetrahydrofolic acid and their addition salts with a sulfonic acid or with sulfuric acid, (6R,S)-tetrahydrofolic acid is reacted with a sulfonic acid or with sulfuric acid, the resulting acid addition salt is fractionally crystallized and, if desired, the (6S)- or (6R)-tetrahydrofolic acid is liberated from the resulting diastereomeric acid addition salts by treatment with a base and isolated.

Process for the preparation of (6S)- and (6R)-tetrahydrofolic acid

Salts of 5,10-methylene-(6R)-, (6R,S)-, and (6S)-tetrahydrofolic acid with sulfuric acid or a sulfonic acid are stable in solid form and can be used as a constituent and/or as a starting material for the production of pharmaceutical compositions.

Stable salts of 5,10-methylenetetrahydrofolic acid

For the preparation of 5,10-methenyl-(6R)-, 5-formyl-(6S)- or 5-methyl-(6S)-tetrahydrofolic acid or salts thereof, 5,10-methenyl-(6R,S)-tetrahydrofolic acid, the inner salt thereof or one of the salts thereof with strong acids is subjected to diastereomer separation by fractional crystallization and, if desired, the resulting 5,10-methenyl-(6R)-tetrahydrofolic acid is converted by treatment with a hydrolyzing agent into 5-formyl-(6S)-tetrahydrofolic acid or by treatment with a reducing agent into 5-methyl-(6S)-tetrahydrofolic acid, and the resulting free acid may be converted into one of its salts by treatment with a base.

Process for the preparation of tetrahydrofolates

Racemic 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline can be resolved by seeding the supersaturated solution of racemic 1-(4-methoxybenzyl)-octahydroisoquinolinium acetate with its enantiomeric forms and crystallizing the optically active acetate corresponding to the configuration of the seed crystals. The continuous form of the process permits obtaining the two enantiomers together.

Growing community of inventors

Schaffhausen, Switzerland

Hans R Muller