| 摘要 |
#CMT# #/CMT# Preparing stable, amorphous calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid (V), comprises producing crystalline (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid (IV); suspending (IV) in water; adding sodium hydroxide solution to the suspension until the pH value is 6.7-6.9; adding calcium chloride to the solution; adjusting the concentration of (IV) in the solution to 14-16 wt.%; precipitating (V); leaving the mixture for 1 hour at 40[deg] C; reducing the temperature from 40[deg] C to 23[deg] C within 2 hours; maintaining the temperature of 23[deg] C for 16-18 hours; and isolating. #CMT# : #/CMT# Preparation of stable, amorphous calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid (V), comprises producing crystalline (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid (IV) by adding an aqueous solution of the calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid (III) to (6R)-diastereoisomers of 2 wt.% of either acetic acid or sulfonic acid until the pH value is 5.5, heating the solution at 44-46[deg] C, adding acetic acid or sulfonic acid to the hot solution in such a quantity until the pH value is 4.3-4.4, where: the crystallization of (IV) is started, and during the crystallization, the pH of 4.3-4.4 is obtained by the continuous addition of either acetic acid or sulfonic acid, filtering and isolating the obtained crystalline solid body at 44-46[deg] C; suspending (IV) in water at 35-41[deg] C; adding sodium hydroxide solution to the suspension until the pH value is 6.7-6.9; adding 0.9 equivalent of calcium chloride to the solution; adjusting the concentration of (IV) in the solution to 14-16 wt.% either by adding or removing water; precipitating (V) by the addition of a small quantity of previously prepared (V); leaving the mixture for 1 hour at 40[deg] C; reducing the temperature from 40[deg] C to 23[deg] C within 2 hours; maintaining the temperature of 23[deg] C for 16-18 hours; and isolating the obtained amorphous solid body. An independent claim is included for the stable, amorphous calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid (V). #CMT#USE : #/CMT# The process is useful for the preparation of amorphous calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid. #CMT#ADVANTAGE : #/CMT# The calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid exhibits high stability and a purity of 99%. #CMT#INORGANIC CHEMISTRY : #/CMT# Preferred Process: The process further comprises washing the crystalline solid body obtained at the end of the filtering and isolation step with water having a temperature of 40[deg] C; washing the solid body obtained at the end of the isolating step with water having a temperature of 10[deg] C, suspending the washed solid body in 94% of aqueous ethanol at room temperature and subsequently isolating the treated solid body by filtration. (III) is obtained by methylating (6S)-5,6,7,8-tetrahydrofolic acid (II) with 4-8 wt.% of corresponding (6R)-diastereoisomer, in water; adding 0.7-0.82 equivalent of calcium chloride, relative to the used quantity of tetrahydrofuran, to the obtained methylated reaction mixture; selectively crystallizing and separating the calcium salt of (6RS)-N-(5)-methyl-5,6,7,8-tetrahydrofolic acid from the obtained aqueous solution; and extracting the aqueous solution of (III) with 2 wt.% of the corresponding (6R)-diastereoisomer. The selective crystallization of the calcium salt of (6RS)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid takes place by inoculating the calcium salt of (6RS)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid, reducing the temperature from room temperature to a temperature of 3-5[deg] C, and maintaining this temperature for 16-18 hours. Preferred Components: The calcium chloride is in solid or an aqueous solution form. The calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid is characterized by differential scanning calorimetric profile, thermogravimetric profile, X-ray powder diffraction pattern and Raman spectrum. #CMT#ORGANIC CHEMISTRY : #/CMT# Preferred Components: The sulfonic acid is p-toluene sulfonic acid. #CMT#EXAMPLE : #/CMT# A crystalline solid body of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid (106.9 g) was suspended in water (400 ml) with a temperature of 40[deg] C. To this suspension, 20 wt.% of aqueous sodium hydroxide solution was slowly added until a clear solution with a pH of 6.8 was obtained. To the solution, calcium chloride dihydrate (0.90 equivalents) was added. The pH of the solution was adjusted to 6.8 by the addition of 20 wt.% aqueous sodium hydroxide solution (1 ml). Calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid was precipitated, and the mixture was maintained at 40[deg] C for 1 hour. The temperature was reduced to 23[deg] C within 2 hours for 18 hours. The concentration of the calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid in the mother liquor was under 7.5%, and the suspension was filtered. The obtained solid body was washed with water (50 ml), which had a temperature of 10[deg] C. The obtained compound was suspended in 94 vol/vol.% aqueous ethanol (250 ml) at 22[deg] C and stirred for 30 minutes. The suspension was filtered and washed twice with 94 vol/vol.% aqueous ethanol (50 ml) to obtain calcium salt of (6S)-N(5)-methyl-5,6,7,8-tetrahydrofolic acid (47.3 g). |
