Process for the preparation of optically pure diastereoisomers of tetrahydrofolate compounds using 10-formyltetrahydrofolate synthetase from clostridium
A process for the preparation of optically pure diastereoisomers of tetrahydrofolate compounds is described, comprising the conversion, for example, of only the 5,6S,7,8-tetrahydrofolic acid component of a racemic mixture of 5,6,7,8-tetrahydrofolic acid to 10-formyl-5,6S,7,8-tetrahydrofolic acid in the presence of a formyl tetrahydrofolate synthetase, followed by cyclizing, hydrolyzing and derivatizing. The process is also useful to make a desired substantially pure (6R or 6S) enantiomer of a derivative of (radiolabeled) tetrahydrofolic acid or a salt or ester thereof.
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.
A process for preparing (6S)-5-methyltetrahydrofolic acid by resolution of racemic (6R,S)-5-methyltetrahydrofolic acid using a base, wherein the base is N-ethyl-2-aminomethylpyrrolidine or its optical isomers.
