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Environment-friendly preparation method of synthetic folic acid

A technology of folic acid and environmental protection, applied in the direction of organic chemistry, etc., can solve the problems of environmental pollution, no industrial value, not easy to obtain, etc.

Active Publication Date: 2014-04-30
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the content of commercially available 1,1,3-trichloroacetone is generally only about 50%, and the industrial production of folic acid mainly uses the 50% 1,1,3-trichloroacetone to prepare folic acid crude product, wherein 1,3- Dichloroacetone, 1,1-dichloroacetone and 1,1,3,3-tetrachloroacetone will participate in the reaction, and the resulting folic acid is difficult to meet the requirements of the international pharmacopoeia, especially pteroic acid, which is required by the European Pharmacopoeia The content of pteroic acid is less than or equal to 0.6%
In addition, the preparation of folic acid from low-purity 1,1,3-trichloroacetone as a starting material requires cumbersome acid and alkali refining processes, resulting in a large amount of waste water and serious environmental pollution
In addition, it has been reported to use α, β-dibromopropionaldehyde in acetic acid-sodium acetate buffer solution to react with N-p-aminobenzoyl glutamic acid and 2,4,5-triamino-6-hydroxypyrimidine sulfate to prepare folic acid The crude product is refined to obtain folic acid containing two molecules of crystal water, but the synthesis route is complex, the conditions are harsh, the raw materials are unstable and not easy to obtain, the cost is high, and it has no industrial value

Method used

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  • Environment-friendly preparation method of synthetic folic acid
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  • Environment-friendly preparation method of synthetic folic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of folic acid

[0044] Add 250 g of 1,2-dichloroethane, 15 g of 90% sulfuric acid, 5.2 g of cuprous chloride, and 46 G (0.5 mole) glycerin, 30.2 g (0.2 mole) 2,4-diamino-5-nitroso-6-hydroxypyrimidine, under nitrogen protection, reflux to remove water for 7-9 hours (approximately 16-17 gram). Cool to room temperature 20°C, add 0.6 g of tetrabutylammonium chloride, 32 g of 35% concentrated hydrochloric acid, stir and reflux at 20°C for 3 hours. 2-Amino-4-hydroxy-6-chloromethylpteridine (III) is produced. Adjust the pH value to 5-6 with 20% sodium hydroxide at 20°C, add 50.5 g (0.19 moles) of p-aminobenzoyl-L-glutamic acid, raise the temperature to 40-45°C and stir for 4 hours, while adding 20% sodium hydroxide aqueous solution keeps the pH value at 5-6, and 2-amino-4-hydroxy-6-chloromethylpteridine is condensed with p-aminobenzoyl-L-glutamic acid to prepare folic acid. After the reaction is completed, cool to 20°C, pour the reaction liqui...

Embodiment 2

[0045] Embodiment 2: the preparation of folic acid

[0046] In a flask equipped with agitator, thermometer, nitrogen conduit, water trap with cross connector and reflux condenser, add 260 g of chlorobenzene, 15 g of 90% sulfuric acid, 6.8 g of zinc chloride dihydrate, 36.8 g (0.4 mol) Glycerin, 30.2 g (0.2 mol) of 2,4-diamino-5-nitroso-6-hydroxypyrimidine, under nitrogen protection, reflux to remove water for 11 hours (approximately 16-17 g of water was separated). Cool to room temperature 20°C, add 0.6 g of tetrabutylammonium chloride, 32 g of 35% concentrated hydrochloric acid, and stir at 20°C for 3 hours. Adjust the pH value to 5-6 with 20% sodium hydroxide at 20°C, add 53.0 g (0.2 moles) of p-aminobenzoyl-L-glutamic acid, raise the temperature to 40-45°C and stir for 4 hours, while adding 20% sodium hydroxide aqueous solution maintains a pH value of 5-6. After the reaction is completed, cool to 20°C, pour the reaction liquid into 450 grams of water, filter (recover the ...

Embodiment 3

[0047] Embodiment 3: the preparation of folic acid

[0048] In a flask equipped with stirring, thermometer, nitrogen conduit, water separator and reflux condenser, add 250 g of 2-methyltetrahydrofuran, 21 g of 75% phosphoric acid, 11 g of zinc chloride dihydrate, 36.8 g (0.4 mol) Glycerin, 30.2 g (0.2 mol) of 2,4-diamino-5-nitroso-6-hydroxypyrimidine, under nitrogen protection, reflux to remove water for 11 hours (approximately 16-17 g of water was separated). Cool to room temperature 20°C, add 0.6 g of tetrabutylammonium chloride, 32 g of 35% concentrated hydrochloric acid, and stir at 20°C for 3 hours. Adjust the pH value to 5-6 with 20% sodium hydroxide at 20°C, add 53.0 g (0.2 moles) of p-aminobenzoyl-L-glutamic acid, raise the temperature to 40-45°C and stir for 4 hours, while adding 20% sodium hydroxide aqueous solution maintains a pH value of 5-6. After the reaction is completed, cool to 20°C, pour the reaction liquid into 450 grams of water, filter (recover the solve...

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Abstract

The invention relates to an environment-friendly preparation method of synthetic folic acid. The method comprises the steps of forming 2-amino-4-hydroxyl-6-chloromethyl pteridine with 2,4-diamido-5-nitroso-6-hydroxyl pyrimidine and glycerol by the action of composite catalysis, and further allowing aminobenzene formyl-L-glutamic acid to react to prepare folic acid. The method reduces reduction of nitroso, and avoids acetone chlorination, and high-purity glycerol provides guarantee for preparing a high-purity intermediate. The raw materials used by the method are cheap and easy to obtain, a technological flow is short, the reaction operation is easy and simple, in addition, the reaction selectivity is high, and the product cost is low.

Description

technical field [0001] The invention relates to an environment-friendly preparation method for synthesizing folic acid, which belongs to the technical field of folic acid synthesis. Background technique [0002] Folic acid, also known as vitamin M, or pteroyl glutamic acid, belongs to one of the basic varieties of vitamins, and its structural formula is shown in formula (I): [0003] [0004] It can be seen from its structure that folic acid has three basic components: the pteridine core, p-aminobenzoic acid residues, and glutamic acid. required. [0005] Folic acid is named for its rich content in plant green leaves, and its content is relatively rich in animal tissue liver, so extraction from liver was used as the initial preparation method of folic acid. Chemical synthesis methods are mostly used now, and the traditional synthesis method is to use N-p-aminobenzoyl glutamic acid, 2,4,5-triamino-6-hydroxypyrimidine sulfate and 1,1,3-trichloroacetone to The crude produ...

Claims

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Application Information

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IPC IPC(8): C07D475/04
CPCC07D475/04
Inventor 戚聿新王全龙鞠立柱李新发
Owner XINFA PHARMA
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