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A kind of improved method of dibenzyl biotin debenzylation d-biotin

A technology of dibenzyl biotin and biotin, applied in the field of chemical synthesis of d-biotin, which can solve the problems of poor environmental protection, poor product quality and high cost

Active Publication Date: 2017-01-25
FUYANG KEXING BIOCHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The present invention aims to solve the problems of cumbersome production operations, poor product quality, high cost, low yield, large consumption of raw materials, poor environmental protection, etc. , for this purpose, an improved method for debenzylation of dibenzyl biotin to d-biotin is provided. More than 90%, it has the advantages of high production efficiency, high product purity, almost no high-salt wastewater, low production cost, etc., and has a good industrial application prospect

Method used

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  • A kind of improved method of dibenzyl biotin debenzylation d-biotin
  • A kind of improved method of dibenzyl biotin debenzylation d-biotin
  • A kind of improved method of dibenzyl biotin debenzylation d-biotin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063]20g of dibenzyl biotin shown in formula II is placed in a three-necked flask, adding 200g (about 135ml) concentration is 48% hydrobromic acid, warming up to reflux, and separating bromobenzyl, keep reflux until TLC detection (developing Agent: ethyl acetate: ethanol=1:1) When showing no raw material point, the reaction ends. Cool down to room temperature, add 20ml×3 toluene for extraction three times, separate the aqueous phase, and combine the organic phases. The organic phase was distilled, and about 45 ml of toluene was distilled off. The distillation residue was cooled to room temperature, allowed to stand for 10 hours, and filtered to obtain 2.8 g of monobenzyl biotin of formula IVa and / or formula IVb. About 7ml of the filtered organic phase crystallization mother liquor is to be applied to the next batch.

[0064] The aqueous phase was distilled to dryness under reduced pressure to recover hydrobromic acid. Add 50ml of pure water to the distillation residue, sti...

Embodiment 2

[0068] With 20g of dibenzyl biotin shown in formula II and 2.8g of monobenzyl biotin recovered in Example 1, add 250g (about 175ml) of hydrobromic acid with a concentration of 40%, heat up to reflux, and separate bromine Benzyl, keep refluxing until TLC detection (developing solvent: ethyl acetate: ethanol = 1:1) shows no raw material point, the reaction is over. Cool down to room temperature, add 60ml of cumene to extract once, and separate the aqueous phase and the organic phase. The organic phase was combined with the organic phase crystallization mother liquor in Example 1, and evaporated under reduced pressure to distill out about 52 ml of the mixed solvent. The distillation residue was cooled to -5°C, allowed to stand for 2 hours, filtered and recrystallized with pure water to obtain 4.4 g of monobenzyl biotin of formula IVa and / or formula IVb. About 8ml of the filtered crystallization mother liquor is to be applied to the next batch.

[0069] The aqueous phase was con...

Embodiment 3

[0073] With 20g of dibenzyl biotin shown in formula II and 4.4g of monobenzyl biotin recovered in Example 2, add 120g (about 80ml) of hydrobromic acid with a concentration of 55%, heat up to reflux, and separate the bromine Benzyl, keep refluxing until TLC detection (developing solvent: ethyl acetate: ethanol = 1:1) shows no raw material point, the reaction is over. Cool down to room temperature, add 15ml×5xylene for extraction five times, separate the aqueous phase, and combine the organic phases. The organic phase is combined with the organic phase crystallization mother liquor in Example 2, back-extracted three times with 15% NaOH solution 10ml × 3, the organic phase is separated, the aqueous phase is combined, the pH value is adjusted to 2 with 15% hydrobromic acid, and left to stand for 8 hours , and filtered to obtain 6.5 g of monobenzyl biotin.

[0074] The separated aqueous phase was concentrated to dryness under reduced pressure to recover hydrobromic acid. Add 20ml...

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Abstract

The invention relates to an improved method for preparing d-biotin from bisbenzyl biotin by debenzylation, which has the advantages of high product quality, low cost and high environment friendliness. The method comprises the following steps: putting bisbenzyl biotin 5-[(3aS,4S,6aR)]-1,3-dibenzyl-2-oxohexahydro-1H-thieno[3,4-d]imidazolyl-4-yl]valeric acid in a reaction kettle; adding hydrobromic acid, stirring and heating to reflux, and reacting under reflux conditions until no raw material dots by TLC (thin layer chromatography) detection; adding an aromatic solvent for extraction, and separating an organic phase from a water phase; concentrating the water phase under reduced pressure to a dry state; adding pure water, stirring, standing to crystallize, and filtering to obtain a d-biotin crystal; concentrating the filtrate, standing to crystallize, filtering to obtain a diamido substance 5-[(2S,3S,4R)-3,4-diamidotetrahydrothienyl-2-yl]valeric acid hydrobromide, adding the diamido substance and an inorganic alkali solution into a reaction kettle, and adding phosgene to carry out cyclization reaction; after the cyclization reaction finishes, regulating the pH value to acidity with an inorganic acid solution, and standing to crystallize; and filtering to obtain the d-biotin 5-[(3aS,4S,6aR)]-2-oxohexahydro-1H-thieno[3,4-d]imidazolyl-4-yl]valeric acid. The method is used for producing d-biotin from bisbenzyl biotin.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a chemical synthesis method of d-biotin whose structure is shown in formula I. [0002] Background technique [0003] d-Biotin (d-Biotin), also known as vitamin H or coenzyme R, scientific name 5-[(3aS,4S,6aR)]-2-oxohexahydro-1H-thieno[3,4-d]imidazole- 4-base] pentanoic acid, its structure is as shown in formula I. d-Biotin is a soluble B vitamin, which is widely used in the fields of medical treatment, feed and biotechnology. [0004] Due to the slow progress in the biological preparation technology of d-biotin, almost all d-biotin on the market is produced by chemical synthesis. The industrial production technology of d-biotin almost all uses dibenzyl biotin as an intermediate, undergoes debenzylation / ring opening, and then uses phosgene to close the ring. [0005] Dibenzyl biotin, scientific name 5-[(3aS,4S,6aR)]-1,3-dibenzyl-2-oxohexahydro-1H-thieno[...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 刘美星毛一清孙武军莫一平
Owner FUYANG KEXING BIOCHEM
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