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Crystal form A of 5-methyl-(6S)-tetrahydrofolic acid and preparation method thereof

A technology of tetrahydrofolate and methyl group, applied in the direction of organic chemistry, etc., can solve the problems such as complicated operation of the preparation method

Active Publication Date: 2014-04-02
SHANGHAI SYNCORES TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] WO2008144953 discloses a method for preparing 5-methyltetrahydrofolate, and at the same time obtained a new crystal form of 5-methyltetrahydrofolate, but the HPLC purity of the product obtained by this method is only 96.45%, and the preparation of this crystal form The operation of the method is relatively complicated, in which 5-methyltetrahydrofolate calcium salt is used as the raw material, the heating temperature must be strictly controlled at 44-46°C, and the pH value also needs to be strictly controlled within the range of 4.3-4.4

Method used

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  • Crystal form A of 5-methyl-(6S)-tetrahydrofolic acid and preparation method thereof
  • Crystal form A of 5-methyl-(6S)-tetrahydrofolic acid and preparation method thereof
  • Crystal form A of 5-methyl-(6S)-tetrahydrofolic acid and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 [Stability]

[0027] Liquid phase conditions:

[0028] Column: Hypersil-ODS, 5μm; 250 x 4.6 mm (Thermo Hypersil Keystone or equivalent)

[0029] Mobile Phase A: Dissolve 7.80g of 0.05 mol NaH 2 PO 4 2H 2 O was dissolved in 1000 ml water, adjusted to pH 6.5 with 32% NaOH, filtered and degassed

[0030] Mobile phase B: dissolve 5.07 g 0.03 mol NaH 2 PO 4 2H 2 O was dissolved in 350 ml methanol, adjusted to pH 8.0 with 32% NaOH, filtered, degassed

[0031] Time 0-14 min mobile phase A: mobile phase B (volume ratio) = 100-45: 0-55; 14-17 min mobile phase A: mobile phase B (volume ratio) = 45- 0: 55-100; 17 -24 min mobile phase A: mobile phase B (volume ratio) = 0: 100; 24.01-33 min mobile phase A: mobile phase B (volume ratio) = 100: 0

[0032] Injection volume: 10 μl

[0033] Flow rate: 1.1ml / min

[0034] Column temperature: 32°C

[0035] Detection wavelength: 280 nm.

[0036] The liquid-phase purity and related substances of 5-methyl-(6S)-tetrahydro...

Embodiment 2

[0039] Example 2 [Solubility]

[0040] The solubility of 5-methyl-(6S)-tetrahydrofolate crystal Form A in water at 25°C was compared with the crystal form obtained by the prior art (WO2008144953). See the table below for specific data.

[0041] Sample source Solubility Form A 0.5% Prior art patent WO2008144953 crystal form 0.08%

Embodiment 3

[0042] Example 3 5-methyl-(6S)-tetrahydrofolate crystal Form A

[0043] 2.0 g of 5-methyl-(6S)-tetrahydrofolic acid with a liquid phase purity of 96.3% was added to 50 ml of benzenesulfonic acid aqueous solution at 60°C (5.0 g of benzenesulfonic acid, 50 ml of water). The liquid is dissolved and clarified. The temperature was lowered to 20°C for crystallization for 2 hours, and the solid was vacuum-dried at 40°C to obtain 1.90 g of white 5-methyl-(6S)-tetrahydrofolate crystal Form A. The purity is 99.3%.

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Abstract

The invention relates to a crystal form A of 5-methyl-(6S)-tetrahydrofolic acid and a preparation method thereof. The crystal form A of the 5-methyl-(6S)-tetrahydrofolic acid has characteristic peaks at about 7.3, 9.3, 11.6, 12.1, 14.0, 14.4, 15.6, 16.7, 17.2, 18.2, 18.5, 18.9, 19.9, 20.8, 21.5, 21.8, 22.1, 22.6, 23.2, 23.5, 23.9, 24.4, 24.7, 25.6, 26.5, 27.1, 27.8, 28.4 and 29.1 in X-ray powder diffraction expressed by 2[theta] by utilization of Cu-K[alpha] radiation. The crystal form A of the 5-methyl-(6S)-tetrahydrofolic acid is good in stability, high in purity, good in reproducibility and good in dissolvability. The preparation method is simple and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a kind of 5-methyl-(6S)-tetrahydrofolate (N-4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo-5- New crystal form of methyl-(6S)-pteridinyl)methyl]amino]benzoyl-L-glutamic acid) and preparation method of the new crystal form Background technique [0002] The chemical name of (6S)-5-methyltetrahydrofolate is (6S)-N-[4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo- 5-methyl-6-pteridyl)methyl]amino]benzoyl]-L-glutamic acid, referred to as L-5-MTHF. Structural formula is as shown in formula I: [0003] [0004] L-5-methyltetrahydrofolate (L-5-MTHF) is the most biologically active and functional form of folic acid, the only way for folic acid to participate in physiological metabolism, and the only form of free folic acid in animal plasma and cells. Mainly used in pharmaceutical active ingredients and food additives to prevent fetal neural tube defects and arteriosclerosis, treat megaloblastic anemia, enhance the therapeutic effect o...

Claims

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Application Information

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IPC IPC(8): C07D475/04
CPCC07D475/04
Inventor 张席妮赵利杰武文举杜争鸣黄鲁宁
Owner SHANGHAI SYNCORES TECH INC
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