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Method for preparing (6S)-5-methyltetrahydrofolate calcium

A technology of calcium methyltetrahydrofolate and folic acid, which is applied in the direction of organic chemistry, can solve the problems of affecting product purity and yield, large environmental pollution, and high production cost, and achieve the effects of complete reaction, reduced environmental pollution, and stable products

Inactive Publication Date: 2018-08-03
ZHEJIANG SHENGDA BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this patent, 5-methyltetrahydrofolate calcium may dissociate during the resolution, which affects the purity and yield of the product; in addition, the resolution reaction uses an organic base ((±)-α-phenylethylamine), and the entire reaction Carried out in an organic system, the production cost is high and the environmental pollution is large

Method used

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  • Method for preparing (6S)-5-methyltetrahydrofolate calcium
  • Method for preparing (6S)-5-methyltetrahydrofolate calcium
  • Method for preparing (6S)-5-methyltetrahydrofolate calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] In an alkaline environment (concentration is 25% NaOH solution) drop 22.4 grams of sodium borohydride, dropwise add 128 g of a mixture of folic acid and water at a temperature of 25 ° C (the mass ratio of folic acid and water is: 1:3), After the dropwise addition, react at 85-90°C for 1 hour. After the reaction, adjust the pH to 9.0 with concentrated hydrochloric acid. After the adjustment, add 16ml of formaldehyde dropwise at 5-10°C and react at this temperature for 0.5 hours. After the reaction Add dropwise 27.2g of 40% sodium borohydride aqueous solution, keep it warm for 1 hour, heat up to 55°C and react for 0.5 hour, add 160ml of water, adjust the pH to 7.5 with concentrated hydrochloric acid, let stand at 0-10°C for 5 hours, pump Boron salts were removed by filtration, the filtrate was adjusted to pH 7.5 with hydrochloric acid, 64ml of 9% calcium chloride solution was added dropwise, stirred and crystallized at 0-10°C for 4 hours, and 5-methyltetrahydrofolate calci...

Embodiment 2

[0045] Add 22.4 grams of sodium borohydride in an alkaline environment (25% NaOH solution), add 96 ml of a mixture of folic acid and water dropwise at a temperature of 25°C (the ratio of folic acid and water is: 1:3), dropwise After the addition, react at 80-85°C for 1 hour. After the reaction, adjust the pH to 8.0 with concentrated hydrochloric acid. After the adjustment, add 16ml of formaldehyde dropwise at 5-10°C and react at this temperature for 0.5 hours. After the reaction, drop Add 27.2g of 40% sodium borohydride aqueous solution, keep it warm for 1 hour, raise the temperature to 50°C for 0.5 hour, add 160ml of water, adjust the pH to 7.5 with concentrated hydrochloric acid, let stand at 0-10°C for 8 hours, and filter with suction Boron salts were removed, the filtrate was adjusted to pH 7.5 with hydrochloric acid, 110ml of 5% calcium chloride solution was added dropwise, stirred and crystallized at 0-10°C for 8 hours, and the wet powder of calcium 5-methyltetrahydrofola...

Embodiment 3

[0049] Add 22.4 grams of sodium borohydride in an alkaline environment (25% NaOH solution), add 96 ml of a mixture of folic acid and water dropwise at a temperature of 25°C (the ratio of folic acid and water is: 1:3), dropwise After the addition, react at 95-100°C for 1 hour. After the reaction, adjust the pH to 10.0 with concentrated hydrochloric acid. After the adjustment, add 16ml of formaldehyde dropwise at 5-10°C and react at this temperature for 0.5 hours. After the reaction, drop Add 27.2g of 40% sodium borohydride aqueous solution, keep it warm for 1 hour, raise the temperature to 60°C for 0.5 hour, add 160ml of water, adjust the pH to 7.5 with concentrated hydrochloric acid, let stand at 0-10°C for 12 hours, and filter with suction Boron salts were removed, the filtrate was adjusted to pH 7.5 with hydrochloric acid, 40ml of 15% calcium chloride solution was added dropwise, stirred and crystallized at 0-10°C for 6 hours, and 5-methyltetrahydrofolate calcium wet powder w...

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Abstract

The invention belongs to the technical field of organic synthesis and relates to a method for preparing (6S)-5-methyltetrahydrofolate calcium. The method comprises the following steps: in an alkali environment, adding sodium borohydride, dropping a mixture of folic acid and water at a normal temperature, and performing a heating reaction to generate tetrahydrofolic acid; firstly, dropping a formaldehyde and sodium borohydride solution to implement a reaction, after the reaction is completed, cooling, leaving to stand for a certain time, and performing suction filtration to remove boron; dropping a calcium chloride solution into filtrate, performing stirring crystallization, and performing suction filtration so as to obtain 5-methyltetrahydrofolate calcium; mixing the obtained crystal withwater, adding EDTA (Ethylene Diamine Tetraacetic Acid) and S-(-)-N-ethyl-2-aminomethyl pyrrolidine, performing a resolution reaction, after the reaction is completed, cooling to separate an R-type antipode and an S-type antipode in sequence, continuously dropping the calcium chloride solution into the obtained S-type antipode, performing stirring crystallization, and performing suction filtration,thereby obtaining (6S)-5-methyltetrahydrofolate calcium. The (6S)-5-methyltetrahydrofolate calcium produced by using the method provided by the invention is high in product purity, stable in reactionand good in environment protection.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a preparation method of calcium (6S)-5-methyltetrahydrofolate. Background technique [0002] (6S)-5-Methyltetrahydrofolate is the main form of tissue and blood folic acid, it does not need to go through tedious enzymatic steps in the human body, and can directly participate in a variety of important biochemical reactions in the human body (such as purine and thymine synthesis, etc.). (6S)-5-methyltetrahydrofolate can be used as medicine and food additives, vitamin preparations, prevention of neural tube defects, treatment of depression, treatment of megaloblastic anemia, etc. Studies have shown that (6S)-5-methyltetrahydrofolate Hydrofolate is the only folic acid drug that can penetrate the blood-brain barrier and has the effect of preventing and treating Alzheimer's disease (senile dementia). Therefore, it has incomparable advantages compared with other folic acid drugs...

Claims

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Application Information

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IPC IPC(8): C07D475/04
Inventor 庞正查张仲景梁超刘露陈敏王程鹏陈天松
Owner ZHEJIANG SHENGDA BIO PHARM
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