Preparation method of L-5-calcium methyltetrahydrofolate

Abstract

The invention discloses a preparation method of L-5-calcium methyltetrahydrofolate. The preparation method comprises the following steps of (1) adopting folic acid as a raw material, and reducing to preparing an intermediate 6-(R,S)-tetrahydrofolic acid; (2) carrying out chiral resolution on the 6-(R,S)-tetrahydrofolic acid, and obtaining an intermediate 6-S-tetrahydrofolate; (3) carrying out methylation on the 6-S-tetrahydrofolate to obtain an intermediate L-5-methyltetrahydrofolate; (4) reacting the L-5-methyltetrahydrofolate and salt containing calcium to obtain the L-5-calcium methyltetrahydrofolate. According to the method provided by the invention, the problem that hydrogen, wastewater and waste residues are easily generated by using a large number of sodium borohydride is avoided.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of calcium L-5-methyltetrahydrofolate. Background technique [0002] The full chemical name of L-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, also referred to as (6S)-5-MTHF or L-5-MTHF, its structure is [0003] [0004] Because L-5-methyltetrahydrofolate (L-5-MTHF) is highly sensitive to air and moisture, it is easy to degrade, and its solubility in water is small. It often exists in the form of its salt on the market, especially the alkaline earth metal salt. Such as calcium salts, barium salts, etc. [0005] L-5-methyltetrahydrofolate (L-5-MTHF) is the main form of folic acid in tissues and blood, and participates in many important biochemical reactions in the human body, such as the biosynthesis of purine and thymine. The naturally occurring 5-MTHF is...

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Problems solved by technology

[0013] Tetrahydrofolate is unstable, easily oxidized and not resistant to high temperature

Among them, the pH of the reaction solution has a greater impact on the reaction, and NaBH 4 、KBH 4 、Na 2 S 2 o 4 , NaHSO 3 Reductants such as reducing agents have strong alkalinity, so that the pH value of the reaction solution will continue to rise during the dropping process. When the reaction solution is too alkaline, a large number of side reactions will occur, and the molecules will break to produce pterin and pterin. Aminobenzoyl glutamic acid (PADGA), thus the yield of tetrahydrofolate obtained by the reaction is low and the purity is not high, and separation is difficult

Sodium borohydride reduction of folic acid, as the current mainstream preparation method, has the advantages of mild conditions, high yield, high purity, and low cost. However, the disadvantages of this method are also obvious. Sodium (EP0608002A1, US5223500A is 24 equivalents, CN102329318B is 12 equivalents, CN1030079C is 6 equivalents), excessive sodium borohydride not only increases the pH value of the system and causes side reactions to occur, but also produces a large amount of explosive hydrogen during the reaction and post-treatment process and insoluble boric acid waste residue, so strict safety measures are required to ensure production and a large amount of washing water

1kg of sodium borohydride will theoretically release 26.3mol of hydrogen gas (about 590L), and produce 1.63kg of boric acid. Calculated based on the solubility of boric acid at 25°C as 5.74g / 100g of water, at least 28.4L of water needs to be consumed. It can be seen that a large amount of sodium borohydride is used. Production risks and post-processing issues are very prominent

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