CN1186343C - New method of preparing ritamin B1 hydrochloride using thiohydrothiamine - Google Patents
New method of preparing ritamin B1 hydrochloride using thiohydrothiamine Download PDFInfo
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- CN1186343C CN1186343C CNB021097178A CN02109717A CN1186343C CN 1186343 C CN1186343 C CN 1186343C CN B021097178 A CNB021097178 A CN B021097178A CN 02109717 A CN02109717 A CN 02109717A CN 1186343 C CN1186343 C CN 1186343C
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- hydrochloride
- thiol
- thiamines
- water
- proportioning
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Abstract
The present invention relates to a novel method for preparing vitamin B1 hydrochloride by using thiol thiamine. The present invention is characterized in that VB1 intermediate body thiol thiamine is used as raw materials, barium chloride is added for reaction after VB1 sulfate is generated through the oxidation of oxydol, and the VB1 sulfate is directly converted to VB1 hydrochloride. The conversion steps that ammonium nitrate and VB1 sulfate react to generate VB1 nitrate and VB1 nitrate is converted to VB1 hydrochloride with hydrochloric acid methanol in the prior art are omitted. The novel method simplifies operation process and improves environment. What is more important, the novel method ensures the quality of products so that the finished products no longer contain nitrate ions (-NO3<->).
Description
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 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?hydrochlo?ride
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 the Ex-all nitrate ion, easily at VB
1Occur brown ring quality problem in the hydrochloride inspection after construction, that is: limiting the quantity of of nitrate ion exceeds standard in the finished product, 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 method of hydrochloride.
The present invention prepares vitamins B
1The 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; (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, the distinctive brown ring reaction of no nitrate radical.
Wherein: thiol thiamines and hydrogen peroxide proportioning are 1: the 2.6-2.8 moles/mole
Thiol thiamines and bariumchloride proportioning are 1: the 2-2.8 moles/mole
Thiol thiamines and water proportioning are 1: the 1.6-1.8 grams per milliliter
The proportioning of thiol thiamines and absolute alcohol is 1: the 4.5-4.8 grams per milliliter
The proportioning of bariumchloride and water is 1: the 3.5-3.8 grams per milliliter
Absolute alcohol can select for use methyl alcohol also can select ethanol for use.
For the sulfate ion in the Ex-all reaction solution, bariumchloride add excessive, for removing barium ion excessive in the solution, utilize barium carbonate sediment that the ammonium hydrogencarbonate of 30% concentration makes it to generate by filtering, reaction solution is transferred PH with concentrated hydrochloric acid then, makes remaining ammonium hydrogencarbonate generate 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 the method that sulfate radical is removed, directly finish 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 14mlH 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 (2)
1, a kind ofly prepares vitamins B with the thiol thiamines
1The method of hydrochloride is characterized in that with VB
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, in being cooled to warm 10-15 ℃, drip the hydrogen peroxide of 34-35% content, drip when half is measured, add second half starting raw material, continuation is remaining 10-15 ℃ of dropping, drip to finish, 10-15 ℃ 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; (3): filter the barium carbonate in (2), 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: the 1.6-1.8 grams per milliliter
Thiol thiamines and hydrogen peroxide proportioning are 1: the 2.6-2.8 moles/mole
The proportioning of bariumchloride and water is 1: the 3.5-3.8 grams per milliliter
Thiol thiamines and bariumchloride proportioning are 1: the 2-2.8 moles/mole
The proportioning of thiol thiamines and absolute alcohol is 1: the 4.5-4.8 grams per milliliter
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 excessive in the reaction solution, add ammonium hydrogencarbonate, make it to generate the barium carbonate sediment filtering, remaining ammonium hydrogencarbonate in the reaction solution adds concentrated hydrochloric acid and transfers PH=1-2, makes it to generate NH
4Cl, water and carbonic acid gas.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021097178A CN1186343C (en) | 2002-05-22 | 2002-05-22 | New method of preparing ritamin B1 hydrochloride using thiohydrothiamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021097178A CN1186343C (en) | 2002-05-22 | 2002-05-22 | New method of preparing ritamin B1 hydrochloride using thiohydrothiamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1459449A CN1459449A (en) | 2003-12-03 |
| CN1186343C true CN1186343C (en) | 2005-01-26 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021097178A Expired - Fee Related CN1186343C (en) | 2002-05-22 | 2002-05-22 | New method of preparing ritamin B1 hydrochloride using thiohydrothiamine |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2008133248A (en) * | 2006-10-24 | 2008-06-12 | Sanyo Chem Ind Ltd | Method for producing imidazolium salt |
| CN103387573A (en) * | 2012-05-08 | 2013-11-13 | 江苏兄弟维生素有限公司 | Preparation process for thiamine hydrochloride |
| CN103804368A (en) * | 2012-11-07 | 2014-05-21 | 江苏兄弟维生素有限公司 | Recovery method of thiamine nitrate in thiamine nitrate mother liquor |
| CN102952126A (en) * | 2012-12-03 | 2013-03-06 | 华中药业股份有限公司 | Novel method for synthesizing vitamin B1 hydrochloride |
| CN104031038B (en) * | 2014-07-04 | 2016-06-08 | 东北制药集团股份有限公司 | The method of vitamin b1 hydrochloride prepared by a kind of sulphur hydroxyl thiamines |
| CN105315272B (en) * | 2015-10-19 | 2018-10-26 | 天津大学 | A kind of preparation method of thiamine hydrochloride crystal product |
| CN105884759A (en) * | 2016-05-27 | 2016-08-24 | 江苏兄弟维生素有限公司 | Synthetic process for chlorinated thiazole onium hydrochloride |
| CN107501254A (en) * | 2017-08-15 | 2017-12-22 | 江西森泰药业有限公司 | The preparation technology of feed addictive vitamin B1 |
| CN112209950A (en) * | 2019-07-11 | 2021-01-12 | 东北制药集团股份有限公司 | Vitamin B1Impurities and process for their preparation |
| CN111004230A (en) * | 2019-12-27 | 2020-04-14 | 江苏兄弟维生素有限公司 | Thiamine hydrochloride, its synthesis method and medicine |
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2002
- 2002-05-22 CN CNB021097178A patent/CN1186343C/en not_active Expired - Fee Related
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| CN1459449A (en) | 2003-12-03 |
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Effective date of registration: 20100419 Address after: 110026, No. 37, North Street, heavy industry, Tiexi District, Shenyang Patentee after: Northeast Pharmaceutical Group Co., Ltd. Address before: 110026, No. thirty-seven, North Street, heavy industry, Tiexi District, Liaoning, Shenyang Patentee before: Dongbei Pharmaceutical Factory Effective date of registration: 20100419 Address after: 110026, No. 37, North Street, heavy industry, Tiexi District, Shenyang Patentee after: Northeast Pharmaceutical Group Co., Ltd. Address before: 110026, No. thirty-seven, North Street, heavy industry, Tiexi District, Liaoning, Shenyang Patentee before: Dongbei Pharmaceutical Factory |
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