Method for synthesizing (2S,3S,4S)-5-(3,4-diamino-tetrahydrothiophene-2-base) valeric acid

A technique for the synthesis of tetrahydrothiophene, which is applied in the direction of organic chemistry, can solve the problems of affecting the quality of d-biotin, low material yield, long reaction time, etc., and achieve easy reaction end point, high product yield and content, The effect of short reaction times

Active Publication Date: 2008-06-11
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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AI Technical Summary

Problems solved by technology

This method has a long reaction time and many side reactions, and the produced product diamino acid hydrohalide is light yellow crystalline powder, which contains impurities and hydrohalic acid, is easy to deteriorate, and will decompose due to the existence of hydrohalic acid, thereby affecting The mass of d-biotin
[0004] There are other methods for the preparation of d-biotin involving the intermediate product (2S,3S,4S)-5-(3,4-diamino-tetrahydrothiophen-2-yl)pentanoic acid, the above-mentioned method The reaction time is long, and the substance will be partially decomposed due to the presence of concentrated hydrohalic acid during the reaction, resulting in low yield of the substance, which directly affects the quality of d-biotin

Method used

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  • Method for synthesizing (2S,3S,4S)-5-(3,4-diamino-tetrahydrothiophene-2-base) valeric acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] Embodiment 1 synthesizes diamino acid 1 with diethyl malonate condensate 2

[0012] In the 2000ml three-necked flask, drop into 131g (0.25mol) diethyl malonate condensate 2, 1310g of 52% hydrobromic acid, stir, distillation is heated up to 90 DEG C, is incubated 1 hour, makes bromoethane and decarboxylation reaction complete, change Reflux and continue to heat up at 125-126 ° C, keep warm for 3 hours, TLC (thin layer spot plate analysis) detection (developing agent: toluene: glacial acetic acid: methanol = 10: 10: 3) shows that the reaction system is dibenzyl biotin content 0.8%, 5% biotin and hydrobromide of diamino acid 1, lower the temperature to 110°C, slowly add 400g of glacial acetic acid dropwise, reflux at this temperature for about 2 hours to remove the remaining small amount of monobenzyl biotin, d-bio The prime debenzylation ring is completely opened. Vacuum recover hydrobromic acid and glacial acetic acid, entrain the acid three times with 100ml of water ea...

Embodiment 2

[0018] Embodiment 2 synthesizes diamino acid 1 with cyano compound 4

[0019] In 1000ml there-necked flask, drop into 40.5g (0.1mol) cyano compound 4, 500g of 50% hydrobromic acid, stir, heat up at 125-126 ℃, keep warm for 6 hours, TLC detects (developing agent: ethyl acetate: ethanol=1 : 1) shows that the reaction system is basically 0.6% of dibenzyl biotin content, biotin 7% hydrobromide of diamino acid 1, lower the temperature to 110°C, slowly add 100g of glacial acetic acid dropwise, and reflux at this temperature for about 2 Hours, the remaining small amount of monobenzyl biotin and d-biotin are completely debenzylated and ring-opened. Vacuum recover hydrobromic acid and glacial acetic acid, entrain with 150ml of water three times, add 500ml of absolute ethanol to reflux for 1 hour, cool in an ice-water bath at 0°C, slowly add 8.4g of lithium hydroxide to neutralize, precipitate white solid crystals, filter, filter cake Rinse three times with absolute ethanol, vacuum dry...

Embodiment 3

[0020] Embodiment 3 synthesizes diamino acid 1 with bisbenzyl biotin 3

[0021] In a 2000ml three-necked flask, drop 85g (0.2mol) of bisbenzyl biotin 3, 800g of 51% hydrobromic acid, stir, heat up at 125-126°C, keep warm for 5 hours, TLC detection (developing agent: ethyl acetate: ethanol = 1:1) shows that the reaction system is basically 1% of bisbenzyl biotin, 10% of biotin and hydrobromide of diamino acid 1, lower the temperature to 110°C, slowly add 200g of glacial acetic acid dropwise, and reflux at this temperature In about 2 hours, the remaining small amount of monobenzyl biotin and d-biotin are completely debenzylated and ring-opened. Vacuum recover hydrobromic acid and glacial acetic acid, entrain with 200ml of water three times, add 1000ml of absolute ethanol to reflux for 1 hour, cool in an ice-water bath at 0°C, slowly add 16.8g of lithium hydroxide to neutralize, precipitate white solid crystals, filter, and filter cake Rinse three times with absolute ethanol, an...

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Abstract

The invention discloses a synthesis method of (2S, 3S, 4S)-5-(3, 4-diamino-thiophane-2-group) valeric acid, while prior method has long reaction and partial decomposition of product in reaction caused by concentrated halogen acid, to affect the quality of d-biotin. The invention processes reflux reaction on diethyl malonate condensate, cyano compound or bis-benzyl biotin in halogen acid, adds glacial acetic acid later, refluxes until no single-benzyl biotin and d-biotin exist in product, concentrates to remove unreacted halogen acid and glacial acetic acid, adds absolute ethyl alcohol, freezes to 0-5DEG C, adds lithium hydrate to neutralize and precipitate white solid crystals, filters, poaches filter cake via absolute ethyl alcohol, and dries to obtain target product. The invention has short reaction and controllable reaction end, which leads glacial acetic acid in later reaction to effectively avoid diamino acid being decomposed in concentrated halogen acid, to improve product yield and content.

Description

technical field [0001] The invention relates to a synthetic method for preparing high-purity d-biotin intermediate (2S, 3S, 4S)-5-(3,4-diamino-tetrahydrothiophen-2-yl)pentanoic acid. Background technique [0002] (2S, 3S, 4S)-5-(3,4-Diamino-tetrahydrothiophen-2-yl)pentanoic acid (referred to as diamino acid) is a precursor compound for the synthesis of d-biotin, which can be synthesized by phosgene or solid Phosgene ring closure to prepare d-biotin, its quality and purity determine the quality of the finished d-biotin. [0003] The Chinese invention patent with publication number CN1374312 discloses a synthetic method of d-biotin, which combines 5-[(1R, 3aS, 6aR)-4,6-dibenzyl-5-oxohexahydro-1H- Thieno[3,4-d]imidazol-1-yl]valeric acid, 47%-48% hydrobromic acid and xylene or cumene were refluxed for 12-60 hours, debenzylation / ring-opening synthesis (2S, 3S, 4S)-5-(3,4-diamino-tetrahydrothiophen-2-yl)pentanoic acid hydrohalide (referred to as diamino acid hydrohalide), and th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/36
Inventor 陈建辉魏昂锋顾立新丁建清
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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