Process for the preparation and separation of diastereomeric salts of folinic acid

A process for the preparation of essentially pure (6S) diastereoisomer of the calcium salt of folinic acid which comprises the steps of:

• 1) reacting the racemic mixture of (6RS) -5,10-methenyl-5,6,7,8-tetrahydrofolic acid chloride hydrochloride of formula (I) ##STR4## with a diamine which is a member selected from the group consisting of ethylenediamine, 1,2-diamino-propane, 1,3-diamino-propane, 1,3-diamino-2-hydroxy-propane, (cis)-1,2-diamino-cyclohexane, (trans)-1.2-diamino-cyclohexane, (trans)-1,2-diamino-cyclohexane, piperazine, 2-methyl-piperazine 1,4-dimethyl-piperazine, 2,5-dimethyl piperazine in a reaction medium which is water or a water/aprotic dipolar solvent mixture in a ratio of 1:05-1-20 by weight, said aprotic dipolar solvent being a member selected from the group consisting of dimethylformamide, dimethyl-acetamide, dimethylsulphoxide, N-methyl-pyrrolidone and hexa-methylfosphoramide;
• whereby said compound of formula (I) is hydrolyzed to give the racemic salt of (6 R,S) folinic acid with said diamine in a molar ratio of 1:1;
• 2) crystallizing the most insoluble diastereoisomeric salt of said amino (6 R,S) folinate by cooling the reaction solution from step 1) and adding an amount of said aprotic dipolar solvent up to a maximum water/aprotic dipolar solvent ratio of 1:60 by weight;
• 3) a) when in the most insoluble diastereoisomeric salt of step 2) is the (6S) diastereoisomer, reacting said amino (6S) folinate with calcium chloride in a (6S) salt/CaCl.sub.2 ratio ranging from 1:1 to 1:6 by weight, in an aqueous solution, at a temperature from 5 to 25.degree. C. and at a pH from 6.5 to 7.5;
• b) when the most insoluble diastereoisomeric salt from step 2) is the (6 R) diastereoisomer, removing the same and then crystallizing the amino (6S) folinate from the mother liquors by adding one of the aprotic dipolar solvents of step 1) and finally treating said amino (6S) folinate with CaCl.sub.2 as described in step 3 a) or directly treating said mother liquors with CaCl.sub.2 as described in step 3 a).