Patent ID: 8754212
Filing Date: 2014-06-17
Classification: A61P,C07D

Abstract:
1. A calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V prepared by: (a) 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; (b) warming the resulting solution to a temperature from 44° C. to 46° C.; (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; (d) filtering off crystalline (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV at a temperature in the range from 44° C. to 46° C.; (e) isolating (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV; (f) suspending the (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV of step (e) in water at a temperature from 35° C. to 41° C.; (g) continuously adding a sodium hydroxide solution to the aqueous suspension containing (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV of step (f) to adjust the pH to a range from 6.7 to 6.9; (h) adding 0.90 equivalents of calcium chloride to the solution of step (g) with respect to each equivalent of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula IV; (i) adjusting the concentration of the compound of Formula IV in the resulting mixture of step (h) to a value in the range from 14% by weight to 16% by weight by the addition or by removal of water; (j) starting the precipitation of the calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the mixture of step (i) by the addition of a small amount of previously prepared compound of Formula V; (k) maintaining the mixture of step (j) at a temperature of 40° C. for one hour; (l) lowering the temperature of the mixture of step (k) from 40° C. to a temperature of 23° C. over two hours; (m) maintaining the mixture of step (l) at 23° C. for a period of 16 hours to 18 hours; and (n) isolating the amorphous calcium salt of (6S)—N(5)-methyl-5,6,7,8-tetrahydrofolic acid of the Formula V from the mixture of step (m), and having: (i) the differential scanning calorimetric profile of (ii) the thermogravimetric profile of (iii) the X-ray powder diffraction diagram of (iv) the Raman spectrum of