Eprova Ag

Merck Patent Gesellschaft MIT Beschrankter Haftung

Eprova Akteingesellschaft

Josef Conti

Martin Ulmann

Hans R Muller

Hans R Mueller

Gunter Muerdel

Gunter Murdel

Willi Wintermeyer

Fritz Reiff

Guenter Muerdel

The invention relates to a process for preparing (6S)-folinic acid and its salts by recrystallization of alkaline-earth salts of (6R,S)-folinic acid and, where necessary, liberation of the acid from the alkaline-earth folinates and/or, where necessary, conversion into the alkali salts by at least one recrystallization in the presence of a base. The invention also relates to calcium-, magnesium-, potassium- and sodium-(6S)-folinates and to (6S)-folinic acid prepared in accordance with the invention.

Sodium salt of (6S)-folinic acid

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

Pharmaceutical compositions containing (65)-folinic acid and salts

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

Process for separating folinic acid

A method for the resolution of (6R,S)-folinates into their diastereomers, comprising adding a water-soluble alkali metal, ammonium or alkaline earth metal salt of an inorganic or organic acid to an aqueous solution of a salt of (6R,S)-folinic acid, removing by filtration the salt which separates out, which consists predominantly of the corresponding (6R)-folinates, and isolating the desired (6S)-folinate from the filtrate.

Method for the resolution of folinic 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.

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Schaffhausen, Switzerland

Josef Conti