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The preparation method of 1-5-methyltetrahydrofolate amino acid salt

A technology of methyltetrahydrofolate and calcium methyltetrahydrofolate, which is applied in the field of preparation of organic drug L-5-methyltetrahydrofolate amino acid salt, can solve the problems of high cost, separation and purification of L-5-MTHF Difficulty and other issues

Inactive Publication Date: 2016-01-20
NAN JING RHINE PHARM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Generally speaking, it is difficult and expensive to extract, isolate and purify L-5-MTHF from human or animal tissues and blood

Method used

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  • The preparation method of 1-5-methyltetrahydrofolate amino acid salt
  • The preparation method of 1-5-methyltetrahydrofolate amino acid salt
  • The preparation method of 1-5-methyltetrahydrofolate amino acid salt

Examples

Experimental program
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Embodiment 1

[0029] Under nitrogen flow, in a 1000ml three-necked flask, suspend 49.7g (0.1mol) L-calcium tetrahydrofolate in 200ml ethanol, and take another 21.1g (0.1mol) L-arginine hydrochloride dissolved in 200ml water acid, while stirring, slowly add to the ethanol suspension of L-calcium tetrahydrofolate, keep the temperature at 0-20°C; adjust the pH to 6-6.8 with dilute hydrochloric acid; fully stir the above mixture at room temperature for 8 hours , add 200ml of acetone or 300ml of absolute ethanol dropwise, and stir for another 6 hours; let it stand for 24 hours; filter, wash with cold ethanol / water, and dry under vacuum at 20-40°C. Obtained 45.9 g of L-arginine salt crystalline powder of L-5-methyltetrahydrofolate, yield 72.5%, chemical purity 98.1%, [α] 20 D =+40.1° (C=1.5, water) optical purity ee≥99.0%. HNMR(D2O): 7.68(2H); 6.72(2H); 4.36(1H); 3.74(1H) 3.696(1H); 3.46(1H); 3.10~3.01(3H); 3.206(2H); 2.54(3H) ; 2.35(2H); 2.099+2.19(2H); 1.840(2H); 1.668(2H).

Embodiment 2

[0031] Under nitrogen flow, in a 1000ml three-necked flask, suspend 49.7g (0.1mol) of L-calcium tetrahydrofolate in 200ml of ethanol, and take another 17.4g (0.1mol) of arginine dissolved in 200ml of water, while While stirring, slowly add to the ethanol suspension of L-methyltetrahydrocalcium folate, keep the temperature at 0-20°C, adjust the pH to 6-6.8 with dilute hydrochloric acid; stir the above mixture at room temperature for 8 hours, add dropwise 200ml of acetone or 300ml of absolute ethanol, and stir for another 6 hours; let stand for 24 hours; filter, wash with cold ethanol / water, and vacuum dry at 20-40°C. Obtained 48.2 g of L-5-methyltetrahydrofolate arginine salt crystalline powder, yield 71.8%, chemical purity 98.2%, [α] 20 D =+43.1 ° (C=1.5, water), optical purity ee≥99.0%.HNMR (D2O): 7.68 (2H); 6.72 (2H); 4.36 (1H); 3.74 (1H) 3.696 (1H); 3.46 ( 1H); 3.10~3.01(3H); 3.206(2H); 2.54(3H); 2.35(2H); 2.099+2.19(2H); 1.840(2H); 1.668(2H).

Embodiment 3

[0033] Under nitrogen flow, in a 1000ml three-necked flask, suspend 49.7g (0.1mol) L-calcium tetrahydrofolate in 200ml ethanol, and take another 20.9g (0.1mol) L-histamine hydrochloride dissolved in 200ml water acid, while stirring, slowly add to the ethanol suspension of L-calcium tetrahydrofolate, keep the temperature at 0-20°C; adjust the pH to 6.0-6.8 with dilute hydrochloric acid; fully stir the above mixture at room temperature for 8 hours , add 200ml of acetone or 300ml of absolute ethanol dropwise, and stir for another 6 hours; let it stand for 24 hours; filter, wash with cold ethanol / water, and dry under vacuum at 20-40°C. Obtained 45.6 g of crystalline powder of L-5-methyltetrahydrofolate L-histidine salt, yield 72.2%, chemical purity 98.3%, [α] 20 D=+40.1° (C=1.5, water) optical purity ee≥99.0%. HNMR(D2O): 7.90(1H); 7.68(2H); 7.09(1H); 6.72(2H); 4.36(1H); 3.89(1H); 3.696(1H); 3.46(1H); 3.16(1H); 3.24(1H); 3.10~3.01(3H); 2.54(3H); 2.35(2H); 2.099+2.19(2H).

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Abstract

The invention discloses a preparation method of an L-5-methyl tetrahydrofolate amino acid salt. The preparation method comprises the following steps of suspending L-5-methyl calcium tetrahydrofolate in alcohol under nitrogen gas flow; slowly adding hydrochloric amino acid or free amino acid dissolved in water into L-methyl calcium tetrahydrofolate suspension; sufficiently stirring the mixture, keeping at 0 DEG C-20 DEG C, furtherstirring for 8 hours, regulating the pH value to 6.0-6.8; dropwise adding absolute ethyl alcohol or acetone, stewing for 24 hours; filtering, washing by cold alcohol / water, and drying in vacuum at 20 DEG C-40 DEG C to obtain the L-5-methyl tetrahydrofolate amino acid salt (for example L-5-methyl etrahydrofolate L-arginine salt).

Description

technical field [0001] The invention relates to the field of organic chemistry, in particular to a preparation method of an organic drug L-5-methyltetrahydrofolate amino acid salt. Background technique [0002] The chemical name of L-5-methyltetrahydrofolate is N-(5-methyl)-6(S)-5,6,7,8,-tetrahydropteroyl-L-glutamic acid, referred to as L- 5-MTHF or (6S)-5-MTHF. L-5-methyltetrahydrofolate is the main form of folic acid in tissues and blood, and participates 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 L-form, while its chemically synthesized optical isomer D-form is inactive and excreted through the kidneys; L-5-MTHF does not require tedious enzymatic metabolism in the human body steps can be used directly. (Zhang Yue et al., Fine and Chemicals, 13, (22), 13, 2005). [0003] Studies in recent years have shown that: L-5-MTHF is the only folic acid drug that can pen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/04
CPCC07D233/64C07D475/04
Inventor 陈新
Owner NAN JING RHINE PHARM TECH
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