A process for the preparation of the stable, amorphous calcium salt of (6s)-n(5)-methyl-5,6,7,8-tetrahydrofolic acid

A process for the preparation of an aqueous solution of the calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the formula III,

• whereby (6S)-5,6,7,8-tetrahydrofolic acid of the formula II having a content of the corresponding (6R)-diastereoisomer in the range from 4% by weight to 8% by weight is methylated in water,
• comprising
• adding to the methylated reaction mixture from 0.70 to 0.82 equivalents of calcium chloride relative to the THF,
• crystallizing selectively and separating the calcium salt of (6RS)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid from the resulting aqueous solution, and
• obtaining an aqueous solution of the calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the formula III having a content of the corresponding (6R)-diastereoisomer of ≦2% by weight.

A process for the preparation of stable, crystalline (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the formula IV,

• comprising
• adding to an aqueous solution of the calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the formula III having a content of the corresponding (6R)-diastereoisomer of ≦2% by weight either acetic acid or a sulfonic acid in such an amount, until a pH-value of 5.5 is obtained,
• warming the resulting solution to a temperature from 44° C. to 46° C.,
• adding to the warmed solution either acetic acid or a sulfonic acid in such an amount, until a pH-value in the range from 4.3 to 4.4 is obtained, whereby the crystallization of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the formula IV begins, and whereby during this crystallization the pH-value is maintained in the range from 4.3 to 4.4 by continuous addition of either acetic acid or of a sulfonic acid, and
• filtering off the resulting crystalline solid at a temperature in the range from 44° C. to 46° C. and isolating it.