Resolution for 5-methyltetrahydrofolic acid and salifying method thereof

A technology of methyltetrahydrofolate and calcium methyltetrahydrofolate, which is applied in the directions of organic chemistry methods, chemical instruments and methods, separation of optically active compounds, etc. And other issues

Inactive Publication Date: 2008-03-19
NAN JING RHINE PHARM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] And Klaus.S et al. have proposed the organic base N-ethyl-2-aminomethylpyrrolidine or its enantiomer as a resolution agent from the racemate (6R, S)-5-methyl The method (U.S5,457,202,1992) for preparing (6S)-5-methyltetrahydrofolate from tetrahydrofolate created a precedent for the resolution of (6R, S)-5-MTHF, but due to N-ethyl- 2-Aminomethylpyrrole especially (+) or (-) enantiomeric market price is more expensive, has limited its application; Some documents used calcium chloride (Fedrico G, et al, U.S5,124,452,1992), and finally in the product (6S)-5-MTHF-Ca, a large amount of chloride ions are likely to remain and cause the chloride ion limit inspection that does not meet the requirements of drugs or food additives

Method used

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  • Resolution for 5-methyltetrahydrofolic acid and salifying method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Add 56.0g (0.4mol) (±)-α-phenylethylamine and 300ml water in a 1000ml three-necked flask, then add 300ml aqueous solution containing 107.1g (0.2mol) (6R, S)-5-MTHF, stir, Heat the reaction to 80°C, cool to 60°C, and filter to remove slightly soluble 6R-acid acid. Add activated carbon to the filtrate for decolorization, filter, cool to 20°C, crystallization occurs, vacuum filter to obtain 42.8g of 6S-salt acid crystals, yield 36.9%, [α] 20 D : +22.1° (C=1, ethanol).

[0017] Suspend the 6S-salt acid salt obtained above in 200ml of water, add 5.9g (0.08mol) of calcium hydroxide powder in portions, and heat to 40°C while stirring until it is completely dissolved; add 95% ethanol while cooling, gradually A white or light yellow precipitate is produced, filtered and dried to obtain (6S)-5-MTHF·Ca·5H 2 O39.1g, primary crystallization yield 95.1%, [α] 20 D : +34.5° (C=1, H 2 O) Optical purity ≥ 98.5%.

Embodiment 2

[0019] In a 1000ml three-necked flask, add 28.0g (0.2mol) (-)-α-phenylethylamine and 150ml of water, then add 300ml of aqueous solution containing 107.1g (0.2mol) of (6R, S)-5-MTHF, Heated to 75°C, cooled to 55°C, filtered to remove undissolved 6R-acid acid salt, added activated carbon to the mother liquor, filtered, cooled to 18-20°C, crystallization occurred, vacuum filtered to obtain 47.4g of crystalline 6S-acid acid salt, Yield 40.8%, [α] 20 D : +22.5° (C=1, ethanol).

[0020] Suspend the 6S-acid salt obtained above in water, add 10% sodium hydroxide solution, make the pH value 8-9, make the temperature not exceed 30°C, then add 7.4g (0.1mol) calcium hydroxide powder in portions, Warm while stirring. The temperature should not exceed 40°C. It should be completely dissolved. Add 95% ethanol while stirring, and a white precipitate or light yellow precipitate will form. Filter and dry to obtain 46.4g (6S)-5-MTHF·Ca·5H 2 O, primary crystallization yield 96.2%, [α] 20 D : ...

Embodiment 3

[0022] In a 1000ml three-necked flask, add 28.0g (0.2mol) (+)-α-phenylethylamine and 150ml of water, then add 300ml of aqueous solution containing 107.1g (0.2mol) of (6R, S)-5-MTHF, The operation is the same as in Example 1 to obtain 44.496S-acid acid salt with a yield of 38.2%, [α] 20 D : +21.8° (C=1, ethanol).

[0023] Suspend the 6S-acid salt obtained above in 200ml of water, add it to the aqueous sodium carbonate solution, make the pH value of the solution 7.5-8.5, then add 0.1mol calcium hydroxide powder in portions, and warm while stirring, the temperature should not exceed 40°C, it should be completely dissolved, under stirring, add 95% ethanol, a white precipitate or light yellow precipitate is formed, filter and dry to get 45.2g (6S)-5-MTHF·Ca·5H 2 O, primary crystallization yield 96.1%, [α] 20 D : +34.5° (C=1, H 2 O) Optical purity ≥ 99.0%.

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Abstract

The invention brings forward a preparation method, which utilizes organic alkali Alpha-phenylethylamine to obtain (6S)-5-methyltetrahydrofolate by splitting racemate (6R, S)-5-methyltetrahydrofolate, and utilizes the hydroxide of alkaline earth, particularly calcium hydroxide, to generate (6S)-5-methyltetrahydrofolate calcium salt.

Description

field of invention [0001] The invention relates to the field of organic chemistry, in particular to a method for splitting organic medicine (6S)-5-methyltetrahydrofolate from (6R, S)-5-methyltetrahydrofolate and forming a salt. Background technique [0002] The chemical name of (6S)-5-methyltetrahydrofolate is N-(5-methyl)-6(S)-5,6,7,8,-tetrahydropteroyl-L-glutamic acid, referred to as (6S)-5-MTHF, the structural formula is as follows: [0003] [0004] (6S)-5-Methyltetrahydrofolate is the major form of folic acid in tissues and blood. Participate in many important biochemical reactions in the body (such as the biosynthesis of purine and thymine, etc.). The naturally occurring 5-MTHF is only in the S form, while the synthetic R form is biochemically inactive and is excreted through the kidneys. (6S)-5-MTHF can be directly utilized in the human body without cumbersome enzymatic metabolic steps. (Zhang Yue et al., Fine and Chemicals, 13, (22), 13, 2005). [0005] Earli...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D475/04C07B57/00
CPCC07D475/04
Inventor 陈新朱光旭陈伟
Owner NAN JING RHINE PHARM TECH
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