CN1459449A

CN1459449A - New method of preparing ritamin B1 hydrochloride using thiohydrothiamine

Info

Publication number: CN1459449A
Application number: CN 02109717
Authority: CN
Inventors: 朱树森; 杨亚圣; 王晓丽
Original assignee: DONGBEI PHARMACEUTICAL FACTORY
Current assignee: Northeast Pharmaceutical Group Co., Ltd.
Priority date: 2002-05-22
Filing date: 2002-05-22
Publication date: 2003-12-03
Anticipated expiration: 2022-05-22
Also published as: CN1186343C

Abstract

A new process for preparing vitamine B, hydrochloride from thiohydroxy thiamine includes such steps as oxidizing the raw material by H2O2 to obtain VB1 sulfate ,and reaction on barium chloride for transforming to VB1 to hydrochloride. Its advantages are simple process, high quality of product, and less pollution.

Description

Prepare vitamins B with the thiol thiamines 1The novel method of hydrochloride

Technical field

The present invention relates to pharmaceutical methods, a kind of with vitamins B ₁Intermediate thiol thiamines is the feedstock production vitamins B ₁The novel method of hydrochloride.

Background technology

Vitamins B ₁Hydrochloride is called for short VB ₁Hydrochloride, different name: thiamine hydrochloride;

English name: Aneurine Hydrochloride; Thiamine Hydrochloride

Chemical name: 3-(4-amino-2-methyl-5-pyrimidyl) methyl-5-(beta-hydroxyethyl)-4-methyl chlorination thiazole hydrochloride;

3-(4-Amino-2methyl-5-pyrimidinyl)methyl-5-(β-hydroxyethyl)-4-methyl?thiazolium?chloride?hydrochloride

Structural formula

Molecular formula: C ₁₂H ₁₇ClN ₄OSHCl molecular weight: 337.27

This product has the function of keeping human homergy and nerve conduction, is used for thiamine deficiency.

The industrial production vitamins B ₁Hydrochloride, generally all adopting the thiol thiamines is intermediate, becomes vitamins B through hydrogen peroxide oxidation ₁Vitriol utilizes VB then ₁Nitrate and VB ₁The difference of vitriol solubleness in water is with VB ₁Vitriol changes into VB earlier ₁Nitrate is separated out, and converts it into VB with hydrogen chloride methanol solution again ₁The hydrochloride crude product, final refining gets VB ₁The hydrochloride finished product.(draw from national raw material and recommended the technology compilation-1980 years, P664)

Concrete operational path is as follows:

But this processing method is just utilized their VB because the nitric acid and the hydrochloric acid that are adopted are strong acid behind the salify ₁The difference of salt solubleness in methyl alcohol and reach VB ₁Transform to hydrochloride from nitrate, so VB ₁In the hydrochloride finished product, be difficult to Ex-all nitrate ion (NO ^- ₃), easily at VB ₁Brown ring quality problem, that is: nitrate ion (NO in the finished product appear in the hydrochloride inspection after construction ^- ₃) limit the quantity of and exceed standard, do not reach the requirement of American Pharmacopeia and British Pharmacopoeia.Prior art is being carried out nitrate in the hydrochloride conversion reaction in addition, the hydrochloric acid methanol that uses because the chlorsulfonic acid ingress of air easily decomposes, is emitted a large amount of hydrogen chloride gas with the chlorsulfonic acid preparation, serious environment pollution is so also there is big problem in existing technology aspect environmental protection.

Summary of the invention

The purpose of this invention is to provide a kind of with vitamins B ₁Intermediate thiol thiamines is a raw material, the preparation vitamins B ₁The novel method of hydrochloride.

The present invention prepares vitamins B ₁The novel method of hydrochloride is with VB ₁Intermediate thiol thiamines is a starting raw material, (1) earlier that its 1/2 amount is soluble in water, transfer PH=4 with concentrated hydrochloric acid, be cooled to interior warm 10-15 ℃, drip the hydrogen peroxide of 34-35% content, drip to a half, add 1/2 starting raw material in addition, continuation drips remaining hydrogen peroxide at 10-15 ℃, drips and finishes insulation reaction 1-2 hour; (2) bariumchloride is dissolved in the hot water, is added drop-wise in (1) under stirring, then produce barium sulfate precipitate, filter, filtrate is neutralized to PH=7-8 with the ammonium hydrogencarbonate of 30% concentration, produces barium carbonate sediment (BaCO ₃); (3) BaCO in the filtration (2) ₃, filtrate is transferred PH=1-2 with concentrated hydrochloric acid, is concentrated into driedly then, adds absolute alcohol, be heated with stirring to complete molten after, cooling, crystallization, filter VB ₁The hydrochloride crude product; (4) crude product of (3) is added distilled water, be heated to moltenly entirely, add the 1-2% activated carbon decolorizing and filter, filtrate is dispersed in the hot ethanol, stirs and is cooled to 0 ℃, crystallization, filtration, washing, dry VB ₁The hydrochloride elaboration detects the requirement that meets American Pharmacopeia and British Pharmacopoeia, no nitrate radical (NO ₃) distinctive brown ring reaction.

Wherein: thiol thiamines and hydrogen peroxide proportioning are 1: 2.6-2.8 (mole ratio)

Thiol thiamines and bariumchloride proportioning are 1: 2-2.8 (mole ratio)

Thiol thiamines and water proportioning are 1: 1.6-1.8 (weight/volume)

The proportioning of thiol thiamines and absolute alcohol is 1: 4.5-4.8 (weight/volume)

The proportioning of bariumchloride and water is 1: 3.5-3.8 (weight/volume)

Absolute alcohol can select for use methyl alcohol also can select ethanol for use.

For the sulfate ion in the Ex-all reaction solution ( _-SO ^- ₄), BaCl ₂Add excessive, for removing excessive Ba in the solution ⁺⁺, utilize (the NH of 30% concentration ₄) HCO ₃Make it to generate BaCO ₃Precipitation is by filtering, and reaction solution is transferred PH with concentrated hydrochloric acid then ₃Make remaining (NH ₄) HCO ₃Generate HN ₄Cl, H ₂O and CO ₂

Because the present invention adopts bariumchloride and VB ₁The vitriol reaction generates VB ₁Hydrochloride and barium sulfate utilize the sedimentary character of barium sulfate solubleness I, then with sulfate radical-SO ^- ₄The method of removing is directly finished VB ₁Conversion from vitriol to the hydrochloride has prescinded in the former technology with nitrate and VB ₁The vitriol reaction generates VB ₁Nitrate carries out by VB with methanol hydrochloride solution again ₁Nitrate is to VB ₁The step of converting of hydrochloride, also saved simultaneously the process for preparing hydrochloric acid methanol with chlorsulfonic acid generation hydrogen chloride gas, both simplified operation, also improved operating environment, guaranteed the quality of product, avoid former technology because of quality problems, often needed repeatedly the refining financial loss that causes, solved in the prior art easily residual in finished product-NO ^- ₃Problem, also solved simultaneously problem of environmental pollution.

Embodiment

Example 1

(1) get 15 gram thiol thiamines (0.05mol), earlier its 1/2 amount is added in the 100ml four-necked bottle, add 27ml water, stir down, transfer to PH=4 with concentrated hydrochloric acid, make it dissolving, the ice bath cooling, drips 15ml H by interior temperature 10-15 ℃ ₂O ₂(content 34%) works as H ₂O ₂Drip to 1/2 o'clock, add 1/2 thiol thiamines in addition, keep interior warm 10-15 ℃, continue to drip remaining hydrogen peroxide, drip and finish insulation reaction 1 hour.

(2) 13.8 gram bariumchlorides (0.109mol) are dissolved in the 50ml hot water, stir and to add down in (1) reaction solution, produce barium sulfate precipitate, filter, filtrate is that 30% ammonium hydrogencarbonate is neutralized to PH=7.5 generation barium carbonate sediment with content;

(3) filter barium carbonate in (2), filtrate is transferred PH=1 with concentrated hydrochloric acid, is concentrated into driedly then, adds the 68ml anhydrous methanol, and heated and stirred is to molten entirely, cooling crystallization again, filter VB ₁Hydrochloride crude product 16 grams, yield 93.73%.

(4) crude product 10 grams with (3) add 11ml distilled water, heat molten entirely, add 0.2 gram activated carbon decolorizing 10-20 minute, filter, in the 70ml hot ethanol that reflux filtrate adding, stir and be cooled to 0 ℃ of crystallization, filter, filter cake gets white crystalline powder 9.5 grams, refining rate 95% with the cold washing with alcohol twice of 20ml, vacuum-drying.Product FeSo ₄Solution trial does not have brown ring reaction.Example 2:

(1) get 15 gram thiol thiamines (0.05mol), earlier its 1/2 amount is added in the 100ml four-necked bottle, add 24ml water, stir down and transfer to PH=4 with concentrated hydrochloric acid, make it dissolving, the ice bath cooling, drips 14ml H by interior temperature 10-15 ℃ ₂O ₂(content 34%) works as H ₂O ₂Drip to 1/2 o'clock, add second half thiol thiamines, temperature continues to drip remaining hydrogen peroxide in keeping, and drips and finishes insulation reaction 1 hour.

(2) 18 gram bariumchlorides (0.14mol) are dissolved in the 68ml hot water, stir and to add down in (1) reaction solution, produce barium sulfate precipitate, filter, filtrate is that 30% ammonium hydrogencarbonate is neutralized to PH=8, the generation barium carbonate sediment with content;

(3) filter barium carbonate in (2), filtrate is transferred PH=2 with concentrated hydrochloric acid, is concentrated into driedly then, adds the 72ml anhydrous methanol, and heated and stirred is to molten entirely, cooling crystallization again, filter VB ₁Hydrochloride crude product 15.5 grams, yield 90.8%.

(4) crude product 10 gram with (3) adds 11ml distilled water, heat moltenly entirely, adds 0.1 gram activated carbon decolorizing 10-20 minute, filtration.In the 70ml hot ethanol that reflux filtrate adding, stir and be cooled to 0 ℃ of crystallization, filter, the filter cake cold washing with alcohol twice of 20ml, vacuum-drying gets white crystalline powder, 9.6 grams, refining rate 96%.

Example 3 all the other with example 1, difference is that absolute alcohol described in (3) is an ethanol.

Example 4 all the other with example 2, difference is that absolute alcohol described in (3) is an ethanol.

Claims

1, a kind ofly prepares the novel method of vitamin b1 hydrochloride, it is characterized in that with VB with the thiol thiamines ₁Intermediate thiol thiamines is a raw material, (1): earlier that its 1/2 amount is soluble in water, transfer PH=4 with concentrated hydrochloric acid, and be cooled to interior warm 10-15 ℃, drip the hydrogen peroxide (H of 34-35% content ₂O ₂), drip when half measure, add second half starting raw material, continue at the 10-15 ℃ of remaining H of dropping ₂O ₂, drip to finish, 10-15 ℃ insulation reaction 1-2 hour; (2): with bariumchloride (BaCl ₂) be dissolved in the hot water, be added drop-wise in (1) under stirring, then produce barium sulfate (BaSO ₄) precipitation, to filter, filtrate is with the ammonium hydrogencarbonate (NH of 30% concentration ₄HCO ₃) be neutralized to PH=7-8, produce barium carbonate (BaCO ₃) precipitation; (3): filter the BaCO in (2) ₃, filtrate is transferred PH=1-2 with concentrated hydrochloric acid, is concentrated into driedly then, adds absolute alcohol, be heated with stirring to complete molten after, cooling, crystallization, filter VB ₁The hydrochloride crude product; (4): the crude product of (3) is added distilled water, be heated to moltenly entirely, add the 1-2% activated carbon decolorizing and filter, filtrate is dispersed in the hot ethanol, stirs and is cooled to 0 ℃, crystallization, filtration, washing, dry VB ₁The hydrochloride elaboration.

Wherein: thiol thiamines and water proportioning are 1: 1.6-1.8 (weight/volume)

Thiol thiamines and hydrogen peroxide proportioning are 1: 2.6-2.8 (mole ratio)

The proportioning of bariumchloride and water is 1: 3.5-3.8 (weight/volume)

Thiol thiamines and bariumchloride proportioning are 1: 2-2.8 (mole ratio)

Described absolute alcohol can be selected methyl alcohol for use, or selects ethanol for use.

2, a kind of the method for claim 1 is characterized in that: for removing barium ion (Ba excessive in the reaction solution ⁺⁺), add ammonium hydrogencarbonate, make it to generate barium carbonate (BaCO ₃) the precipitation filtering, remaining ammonium hydrogencarbonate in the reaction solution adds concentrated hydrochloric acid and transfers PH=1-2, makes it to generate NH ₄Cl, water H ₂O and carbonic acid gas CO ₂