Preparation method of d-biotin

A biotin, bibenzyl biotin technology, applied in the direction of organic chemistry, etc., can solve the problems such as the decrease of d-biotin yield, the influence of d-biotin yield, the decrease of valeric acid yield, etc. High product yield and the effect of reducing dosage

Active Publication Date: 2011-11-23
ZHEJIANG NHU CO LTD
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0009] CN101195611A uses bisbenzyl biotin diester as raw material, and uses 50-52% hydrobromic acid to deeply open the ring to form 5-[(2S, 3S, 4S)-3,4-diamino-tetrahydrothiophen-2-yl] Valeric acid, 5-[(2S, 3S, 4S)-3,4-diamino-tetrahydrothiophen-2-yl] pentanoic acid recyclates into d-biotin, which is greatly damaged during deep ring opening, resulting in d- Biotin yield decreased
[0014] Since the Grignard reagent used is a double Grignard reagent, it is inevitable that both ends will be connected with ketone groups in the reaction, resulting in another double-polymer impurity, resulting in 5-(3aS, 6aR)-1,3-dibenzyl-hexa The yield of hydrogen-2-oxo-1H-thieno[3,4-d]imidazol-4-enyl]valeric acid decreased, which indirectly affected the yield of d-biotin

Method used

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  • Preparation method of d-biotin
  • Preparation method of d-biotin

Examples

Experimental program
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Effect test

Embodiment 1

[0038] In a 250ml three-necked flask equipped with mechanical stirring, a thermometer, and a reflux condenser, 13.8g (0.1mol) of ethyl 2,2-dicyanoacetate, 13.8g (0.1mol) of potassium carbonate, and N,N-dimethyl Acetyl formamide 100ml, heated to 60°C for 0.5 hours under stirring, and added (3aR, 8aS, 8bS)-1,3-dibenzyl-2-oxo-decahydroimidazo[4,5-c at 60°C ]Thieno[1,2-a]sulfonium bromide 44.5g (0.1mol), stirred and reacted at 60°C for 1 hour, raised the temperature to 100-105°C for 1 hour, after the reaction was completed, N,N -Dimethylformamide, to obtain a viscous substance, add 50ml of water, add 300ml of toluene, stir to dissolve, adjust pH=5.0 with hydrochloric acid, separate layers, wash the toluene layer twice with 10ml×2 water, and extract the combined water layer with 100ml×2 toluene Twice, the toluene layer was combined, fully dehydrated, the toluene was evaporated under reduced pressure, and 50ml of petroleum ether (90-120°C) was added to the residue, stirred for 1 hou...

Embodiment 2

[0040] In a 250ml three-necked flask equipped with mechanical stirring, a thermometer, and a reflux condenser, 13.8g (0.1mol) of ethyl 2,2-dicyanoacetate, 13.8g (0.1mol) of potassium carbonate, and N,N-dimethyl Acetyl formamide 100ml, heated to 60°C for 0.5 hours under stirring, and added (3aR, 8aS, 8bS)-1,3-dibenzyl-2-oxo-decahydroimidazo[4,5-c at 60°C ]Thieno[1,2-a]sulfonium chloride 40.1g (0.1mol), stirred and reacted at 60°C for 1 hour, raised the temperature to 100-105°C for 1 hour, after the reaction was completed, evaporated under reduced pressure to remove N,N -Dimethylformamide, to obtain a viscous substance, add 50ml of water, add 300ml of toluene, stir to dissolve, adjust pH=5.0 with hydrochloric acid, separate layers, wash the toluene layer twice with 10ml×2 water, and extract the combined water layer with 100ml×2 toluene Twice, the toluene layer was combined, fully dehydrated, the toluene was evaporated under reduced pressure, and 50ml of petroleum ether (90-120°C...

Embodiment 3

[0042] In a 250ml three-neck flask equipped with mechanical stirring, a thermometer, and a reflux condenser, put 13.8g (0.1mol) of ethyl 2,2-dicyanoacetate, 20.2g (0.2mol) of triethylamine, and N-methylpyrrolidone 100ml, heated to 60°C for 0.5 hours under stirring, then added (3aR, 8aS, 8bS)-1,3-dibenzyl-2-oxo-decahydroimidazo[4,5-c]thieno at 60°C [1,2-a] 44.5g (0.1mol) of sulfonium bromide, stirred and reacted at 60°C for 1 hour, raised the temperature to 100-105°C and reacted for 1 hour, after the reaction was completed, N-methylpyrrolidone, Triethylamine, to obtain a viscous substance, add 50ml of water, add 300ml of toluene, stir to dissolve, adjust pH=5.0 with hydrochloric acid, separate layers, wash the toluene layer twice with 10ml×2 water, and extract the combined water layer twice with 100ml×2 toluene, Combine the toluene layers, fully dehydrate, evaporate the toluene under reduced pressure, add 50ml of petroleum ether (90-120°C) to the residue, stir for 1 hour, cool ...

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Abstract

The invention discloses a preparation method of d-biotin. Existing d-biotins can be obtained from debenzylation reactions of bisbenzylbiotin, and can be obtained from debenzylation and decarboxylation reactions of bisbenzylbiotin diester. However, d-biotins obtained from the two methods are not ideal. The preparation method of d-biotin provided by the invention comprises the following steps that: (1) sulfonium halide is adopted as a raw material, and is condensed with 2,2-diethyl acetoacetate, such that bisbenzylbiotin diethyl ester is obtained; the bisbenzylbiotin diethyl ester is processed through debenzylation, hydrolysis, decarboxylation and loop opening reactions; (2) d-biotin which is not processed form the loop opening reaction is separated from the product obtained from the previous step; d-biotin-separated ring-opened object is cyclized with triphosgene, such that d-biotin is obtained. According to the invention, 2,2-diethyl acetoacetate is adopted as a raw material. Bisbenzylbiotin dimer is not generated from obtained bisbenzylbiotin diethyl ester. The reaction yield is high, and the yield of d-biotin is high.

Description

technical field [0001] The invention relates to the field of fine chemical industry, in particular to a preparation method of d-biotin. Background technique [0002] d-Biotin is also known as vitamin H and coenzyme R, and its chemical name is (3aS, 4S, 6aR)-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4-pentane Acids, belonging to the water-soluble B vitamins, are used as medicines and feed additives. D-biotin is distributed in animal and plant tissues and can be isolated from liver extract and egg yolk. It is a component of various carboxylase prosthetic groups and is an essential substance for the growth and development of animals and plants. [0003] The structure of d-biotin is as follows: [0004] [0005] d-biotin is generally obtained by chemical synthesis. d-Biotin can be obtained from the debenzylation reaction of bisbenzyl biotin, and can also be obtained from the debenzylation and decarboxylation reactions of bisbenzyl biotin diester. [0006] Chemical Journal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 车来滨钱洪胜姜延平贾慧明邱贵生
Owner ZHEJIANG NHU CO LTD
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