CN104140420A - Synthesis process of thiothiamine - Google Patents
Synthesis process of thiothiamine Download PDFInfo
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- CN104140420A CN104140420A CN201410332224.2A CN201410332224A CN104140420A CN 104140420 A CN104140420 A CN 104140420A CN 201410332224 A CN201410332224 A CN 201410332224A CN 104140420 A CN104140420 A CN 104140420A
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- C07—ORGANIC CHEMISTRY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a synthesis process of thiothiamine. The synthesis process comprises the following steps of dissociating acetamidine hydrochloride with liquid sodium methoxide and then filtering to retain the solution, placing the solution into a reactor, adding alpha-(o-chloroaniline)ylmethenyl-beta-formylaminopropionitrile (enamine), and then recovering methanol and carrying out cyclization reaction to obtain a cyclized solution; adding an aqueous phase to the cyclized solution, distilling, wherein the distillation temperature of vapor is 120 DEG C; after o-chloroaniline is completely stripped out, adding a caustic soda liquid, hydrolyzing and then adding water, adding carbon disulfide, reacting, finally adding gamma-chloro-gamma-acetyl propanol, carrying out condensation and filtering to obtain a thiothiamine crude; dissolving with hydrochloric acid, reacting, adding activated carbon, decolorizing, filtering to remain filtrate, neutralizing with the caustic soda liquid; and after a solid is precipitated, filtering and drying the solid to obtain the finished thiothiamine. The synthesis process of thiothiamine disclosed by the invention has the advantages that the process steps are simple, the yield of thiothiamine is high, the generation of wastes is reduced, the environment friendliness is achieved and the production cost is reduced.
Description
Technical field
The present invention relates to VITAMIN production technical field, relate in particular to a kind of synthesis technique of thiothiamine.
Background technology
The synthesis technique of domestic and international VITMAIN B1, comparatively ripe route mainly contains vinyl cyanide acetyl pyrimidine route, vinyl cyanide formyl pyrimidine route and propane dinitrile route at present.And the domestic vinyl cyanide formyl pyrimidine route synthesise vitamins B1 that generally adopts, the method mainly comprises the operations such as aminopropionitrile, sodium generation, enamine, pyrimidine, chlorine ester, salt acid ether, thiothiamine, thiothiamine oxidation, nitric acid-sulfuric acid thiamine neutralization and thiamine hydrochloride.Wherein thiothiamine is the important intermediate of the method synthesise vitamins B1, and above-mentioned preparation method exists following defect: 1, in the preparation process of pyrimidine, need to be filtered dry after cyclization finishes, be about to solid and liquid separation, lock out operation bothers on the one hand, and process labour intensity is larger; The easy like this loss that causes solute and solvent on the other hand, from enamine to thiothiamine, associating yield is lower, and has produced many solid wastes, and smell is larger, and energy consumption is larger, is unfavorable for the protection to environment.2, in the preparation process of thiothiamine, need to use solvent add dithiocarbonic anhydride reaction after hydrolysis finishes before, as methyl alcohol, increased the generation of waste gas and waste water.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of synthesis technique of thiothiamine, reduces and pollutes on the one hand, improves on the other hand thiothiamine yield, reduces production costs.
For solving the problems of the technologies described above, the invention provides a kind of synthesis technique of thiothiamine, comprise the following steps:
(1) with liquid methanol sodium free hydrochloric acid ethanamidine, then filter, leave and take the solution after filtration, described solution is put into reactor, and in described reactor, add α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine), then reclaim methyl alcohol and carry out ring-closure reaction, making cyclization liquid;
(2) in described cyclization liquid, add water to carry out wet distillation, the temperature of described wet distillation is 120 degrees Celsius, is then condensed to lower leaf on solution, and described solution lower floor is Ortho-Chloro aniline, finishes reaction after Ortho-Chloro aniline is all taken out of;
(3) wet distillation finishes, after adding liquid caustic soda, be hydrolyzed, then add water, then add dithiocarbonic anhydride in 30～40 degrees Celsius of reactions 1～3 hour, finally add γ-chloro-γ-ethanoyl propyl alcohol to carry out condensation reaction, after question response finishes, filter to obtain thiothiamine crude product;
(4) described thiothiamine crude product dissolving with hydrochloric acid, after being warmed up to 70～95 degrees Celsius, react 1 hour, then add gac 1.6-2g decolouring after 32-35 minute, filter, leave and take filtered liquid, described filtered liquid is neutralized to PH7.2-7.3 with liquid caustic soda, after solid is separated out, filters, leave and take described solid, dry solid and make thiothiamine fine work.
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, the mass ratio of liquid methanol sodium described in step (1), described acetamidine hydrochloride and described α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) is 4:2:3.
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, described in step (1), reclaim methyl alcohol reaction and be under vacuum pressure at-0.06～-0.09MPa, the temperature condition of 50～100 degrees Celsius and carry out.
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, the ring-closure reaction time described in step (1) is 2～4 hours.
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, described in step (2), water is water.
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, the add-on of water described in step (2) is 3.5 to 4 times of add-on of α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) described in step (1).
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, described in step (3), the mass ratio of liquid caustic soda and described water is 1:2, and the mass ratio of described dithiocarbonic anhydride and described γ-chloro-γ-ethanoyl propyl alcohol is 1:1.5～1:2.
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, described in step (3), hydrolysis temperature is 100～130 degrees Celsius, and the time is 2 hours.
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, described in step (3), setting-up point is 40～50 degrees Celsius, and the time is 2～5 hours.
As a kind of preferred version of the synthesis technique of thiothiamine of the present invention, described in step (4), the mass concentration of hydrochloric acid is 6～9%, and the mass concentration of liquid caustic soda is 30%.
The synthesis technique of thiothiamine of the present invention; be characterized in; pass through process modification; make former need before adding dithiocarbonic anhydride with an organic solvent, as methyl alcohol, changing what before adding dithiocarbonic anhydride, use into is water; its processing step is simple, thiothiamine yield is high to more than 76.7%; and quality better, avoided, because organic solvent causes too high production cost, cost recovery, reduced the generation of waste material, having protected environment.
Embodiment
For above-mentioned purpose of the present invention, feature and advantage can be become apparent more, below in conjunction with embodiment, the present invention is further detailed explanation.
The synthesis technique of the thiothiamine that the present invention proposes, it comprises the steps or operates.
Step 1, with liquid methanol sodium free hydrochloric acid ethanamidine, then filter, leave and take the solution after filtration, described solution is put into reactor, and in described reactor, add α – (Ortho-Chloro aniline) base time first base – β – formamido group propionitrile (enamine), and then reclaim methyl alcohol and carry out ring-closure reaction, make cyclization liquid.
In one embodiment, this step can specific as followsly be carried out: with liquid methanol sodium free hydrochloric acid ethanamidine, then filter, leave and take the solution after filtration, described solution is put into reactor, and in described reactor, add α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine), described liquid methanol sodium, the mass ratio of described acetamidine hydrochloride and described α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) is 4:2:3, then in the vacuum pressure of-0.06～-0.09MPa, under the temperature condition of 50～100 degrees Celsius, reclaim methyl alcohol and carry out ring-closure reaction, the described ring-closure reaction time is 2～4 hours, make cyclization liquid.
Step 2 adds water to carry out wet distillation in described cyclization liquid, and the temperature of described wet distillation is 120 degrees Celsius, is then condensed to lower leaf on solution, and described solution lower floor is Ortho-Chloro aniline, finishes reaction after Ortho-Chloro aniline is all taken out of.
In one embodiment, this step can specific as followsly be carried out: in described cyclization liquid, add water to carry out wet distillation, the add-on of described water is 3.5 to 4 times of add-on of α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) described in step (1), the temperature of described wet distillation is 120 degrees Celsius, then be condensed to lower leaf on solution, described solution lower floor is Ortho-Chloro aniline, finishes reaction after Ortho-Chloro aniline is all taken out of.
Step 3, wet distillation finishes, and is hydrolyzed after adding liquid caustic soda; then add water; add again dithiocarbonic anhydride in 30～40 degrees Celsius of reactions 1～3 hour, finally add γ-chloro-γ-ethanoyl propyl alcohol to carry out condensation reaction, after question response finishes, filter to obtain thiothiamine crude product.
In one embodiment, this step can specific as followsly be carried out: wet distillation finishes, after adding liquid caustic soda, be hydrolyzed, described hydrolysis temperature is 100～130 degrees Celsius, time is 2 hours, then add water, add again dithiocarbonic anhydride in 30～40 degrees Celsius of reactions 1～3 hour, finally add γ-chloro-γ-ethanoyl propyl alcohol to carry out condensation reaction, described setting-up point is 40～50 degrees Celsius, time is 2～5 hours, after finishing, filters question response to obtain thiothiamine crude product, the mass ratio of wherein said liquid caustic soda and described water is 1:2, the mass ratio of described dithiocarbonic anhydride and described γ-chloro-γ-ethanoyl propyl alcohol is 1:1.5～1:2.
Step 4, described thiothiamine crude product dissolving with hydrochloric acid, after being warmed up to 70～95 degrees Celsius, react 1 hour, then add gac 1.6-2g decolouring after 32-35 minute, filter, leave and take filtered liquid, described filtered liquid is neutralized to PH7.2-7.3 with liquid caustic soda, after solid is separated out, filter, leave and take described solid, dry solid and make thiothiamine fine work.
In one embodiment, this step can specific as followsly be carried out: described thiothiamine crude product dissolving with hydrochloric acid, and the mass concentration of described hydrochloric acid is 6～9%, reacts 1 hour after being warmed up to 70～95 degrees Celsius, then add gac 1.6-2g decolouring after 32-35 minute, filter, leave and take filtered liquid, described filtered liquid is neutralized to PH7.2-7.3 with liquid caustic soda, the mass concentration of described liquid caustic soda is 30%, after solid is separated out, filter, leave and take described solid, dry solid and make thiothiamine fine work.
It is elaborated to production method of the present invention below in conjunction with specific embodiment.
Embodiment mono-
With liquid methanol sodium free hydrochloric acid ethanamidine, then filter, leave and take the solution after filtration, described solution is put into reactor, and in described reactor, add α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine), described liquid methanol sodium, the mass ratio of described acetamidine hydrochloride and described α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) is 4:2:3, then in the vacuum pressure of-0.06MPa, under the temperature condition of 50 degrees Celsius, reclaim methyl alcohol and carry out ring-closure reaction, the described ring-closure reaction time is 2 hours, make cyclization liquid.
In described cyclization liquid, add water to carry out wet distillation, the add-on of described water is 3.5 times of add-on of above-mentioned α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine), the temperature of described wet distillation is 120 degrees Celsius, then be condensed to lower leaf on solution, described solution lower floor is Ortho-Chloro aniline, finishes reaction after Ortho-Chloro aniline is all taken out of.
Wet distillation finishes; after adding liquid caustic soda, be hydrolyzed; described hydrolysis temperature is 100 degrees Celsius; time is 2 hours; then add water; add again dithiocarbonic anhydride in 30 degrees Celsius of reactions 1 hour; finally add γ-chloro-γ-ethanoyl propyl alcohol to carry out condensation reaction; described setting-up point is 40 degrees Celsius; time is 2 hours; after question response finishes, filter to obtain thiothiamine crude product, the mass ratio of wherein said liquid caustic soda and described water is 1:2, and the mass ratio of described dithiocarbonic anhydride and described γ-chloro-γ-ethanoyl propyl alcohol is 1:1.5.
Described thiothiamine crude product dissolving with hydrochloric acid, the mass concentration of described hydrochloric acid is 6%, after being warmed up to 70 degrees Celsius, react 1 hour, then add gac 1.6g decolouring after 32 minutes, filter, leave and take filtered liquid, described filtered liquid is neutralized to PH7.2 with liquid caustic soda, and the mass concentration of described liquid caustic soda is 30%, after solid is separated out, filters, leave and take described solid, dry solid and make thiothiamine fine work.
After testing, gained fine work mass percentage content 99.6%, thiothiamine fine work is Yu the mol ratio of α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) is yield 76.7%.
Embodiment bis-
With liquid methanol sodium free hydrochloric acid ethanamidine, then filter, leave and take the solution after filtration, described solution is put into reactor, and in described reactor, add α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine), described liquid methanol sodium, the mass ratio of described acetamidine hydrochloride and described α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) is 4:2:3, then in the vacuum pressure of-0.09MPa, under the temperature condition of 100 degrees Celsius, reclaim methyl alcohol and carry out ring-closure reaction, the described ring-closure reaction time is 4 hours, make cyclization liquid.
In described cyclization liquid, add water to carry out wet distillation, the add-on of described water is 4 times of add-on of α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) described in step (1), the temperature of described wet distillation is 120 degrees Celsius, then be condensed to lower leaf on solution, described solution lower floor is Ortho-Chloro aniline, finishes reaction after Ortho-Chloro aniline is all taken out of.
Wet distillation finishes; after adding liquid caustic soda, be hydrolyzed; described hydrolysis temperature is 130 degrees Celsius; time is 2 hours; then add water; add again dithiocarbonic anhydride in 40 degrees Celsius of reactions 3 hours; finally add γ-chloro-γ-ethanoyl propyl alcohol to carry out condensation reaction; described setting-up point is 50 degrees Celsius; time is 5 hours; after question response finishes, filter to obtain thiothiamine crude product, the mass ratio of wherein said liquid caustic soda and described water is 1:2, and the mass ratio of described dithiocarbonic anhydride and described γ-chloro-γ-ethanoyl propyl alcohol is 1:2.
Described thiothiamine crude product dissolving with hydrochloric acid, the mass concentration of described hydrochloric acid is 9%, after being warmed up to 95 degrees Celsius, react 1 hour, then add gac 2g decolouring after 35 minutes, filter, leave and take filtered liquid, described filtered liquid is neutralized to PH7.3 with liquid caustic soda, and the mass concentration of described liquid caustic soda is 30%, after solid is separated out, filters, leave and take described solid, dry solid and make thiothiamine fine work.
After testing, gained fine work mass percentage content 99.88%, thiothiamine fine work is Yu the mol ratio of α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) is yield 79.6%.
In sum; the synthesis technique of thiothiamine of the present invention; principal feature of the present invention is: pass through process modification; make former need before adding dithiocarbonic anhydride with an organic solvent, as methyl alcohol, changing what before adding dithiocarbonic anhydride, use into is water; its processing step is simple, thiothiamine yield is high to more than 76.7%; and quality better, avoided, because organic solvent causes too high production cost, cost recovery, reduced the generation of waste material, having protected environment.
It should be noted that, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can modify or be equal to replacement technical scheme of the present invention, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of claim scope of the present invention.
Claims (10)
1. the synthesis technique of thiothiamine, it comprises:
(1) with liquid methanol sodium free hydrochloric acid ethanamidine, then filter, leave and take the solution after filtration, described solution is put into reactor, and in described reactor, add α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine), then reclaim methyl alcohol and carry out ring-closure reaction, making cyclization liquid;
(2) in described cyclization liquid, add water to carry out wet distillation, the temperature of described wet distillation is 120 degrees Celsius, is then condensed to lower leaf on solution, and described solution lower floor is Ortho-Chloro aniline, finishes reaction after Ortho-Chloro aniline is all taken out of;
(3) wet distillation finishes, after adding liquid caustic soda, be hydrolyzed, then add water, then add dithiocarbonic anhydride in 30～40 degrees Celsius of reactions 1～3 hour, finally add γ-chloro-γ-ethanoyl propyl alcohol to carry out condensation reaction, after question response finishes, filter to obtain thiothiamine crude product;
(4) described thiothiamine crude product dissolving with hydrochloric acid, after being warmed up to 70～95 degrees Celsius, react 1 hour, then add gac 1.6-2g decolouring after 32-35 minute, filter, leave and take filtered liquid, described filtered liquid is neutralized to PH7.2-7.3 with liquid caustic soda, after solid is separated out, filters, leave and take described solid, dry solid and make thiothiamine fine work.
2. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: the mass ratio of liquid methanol sodium described in step (1), described acetamidine hydrochloride and described α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) is 4:2:3.
3. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: described in step (1), reclaim methyl alcohol reaction and be under vacuum pressure at-0.06～-0.09MPa, the temperature condition of 50～100 degrees Celsius and carry out.
4. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: the ring-closure reaction time described in step (1) is 2～4 hours.
5. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: described in step (2), water is water.
6. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: the add-on of water described in step (2) is 3.5 to 4 times of add-on of α – (Ortho-Chloro aniline) base Ci Jia Ji – β – formamido group propionitrile (enamine) described in step (1).
7. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: described in step (3), the mass ratio of liquid caustic soda and described water is 1:2, and the mass ratio of described dithiocarbonic anhydride and described γ-chloro-γ-ethanoyl propyl alcohol is 1:1.5～1:2.
8. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: described in step (3), hydrolysis temperature is 100～130 degrees Celsius, and the time is 2 hours.
9. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: described in step (3), setting-up point is 40～50 degrees Celsius, and the time is 2～5 hours.
10. the synthesis technique of thiothiamine as claimed in claim 1, is characterized in that: described in step (4), the mass concentration of hydrochloric acid is 6～9%, and the mass concentration of liquid caustic soda is 30%.
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Cited By (7)
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| CN104910142A (en) * | 2015-04-20 | 2015-09-16 | 江苏兄弟维生素有限公司 | Method for preparing vitamin B1 intermediate (pyrimidine) |
| 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 |
| CN107721879A (en) * | 2017-10-30 | 2018-02-23 | 江苏兄弟维生素有限公司 | A kind of liquid caustic soda methyl alcohol mixed liquor is used for the method for the free ethanamidine of ethenylamidine hydrochloride |
| CN109400555A (en) * | 2018-12-27 | 2019-03-01 | 江苏兄弟维生素有限公司 | A kind of α-acetyl group-gamma-butyrolacton sodium salt free hydrochloric acid ethanamidine technique |
| CN109503426A (en) * | 2018-12-24 | 2019-03-22 | 江苏兄弟维生素有限公司 | α-(o-chloraniline base) methine-β-formamido propionitrile method of purification |
| CN114180599A (en) * | 2021-12-23 | 2022-03-15 | 江苏兄弟维生素有限公司 | Process for recovering ammonium nitrate from thiamine nitrate mother liquor and application thereof |
| CN115724718A (en) * | 2022-11-28 | 2023-03-03 | 江苏兄弟维生素有限公司 | Method for recycling chlorohydrin and sodium formate in crude thiamine mother liquor and application |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910142A (en) * | 2015-04-20 | 2015-09-16 | 江苏兄弟维生素有限公司 | Method for preparing vitamin B1 intermediate (pyrimidine) |
| 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 |
| CN107721879A (en) * | 2017-10-30 | 2018-02-23 | 江苏兄弟维生素有限公司 | A kind of liquid caustic soda methyl alcohol mixed liquor is used for the method for the free ethanamidine of ethenylamidine hydrochloride |
| CN109503426A (en) * | 2018-12-24 | 2019-03-22 | 江苏兄弟维生素有限公司 | α-(o-chloraniline base) methine-β-formamido propionitrile method of purification |
| CN109503426B (en) * | 2018-12-24 | 2021-11-16 | 江苏兄弟维生素有限公司 | Method for purifying alpha- (o-chloroanilino) methine-beta-formamido propionitrile |
| CN109400555A (en) * | 2018-12-27 | 2019-03-01 | 江苏兄弟维生素有限公司 | A kind of α-acetyl group-gamma-butyrolacton sodium salt free hydrochloric acid ethanamidine technique |
| CN109400555B (en) * | 2018-12-27 | 2020-08-04 | 江苏兄弟维生素有限公司 | Process for α -acetyl-gamma-butyrolactone sodium salt free acetamidine hydrochloride |
| CN114180599A (en) * | 2021-12-23 | 2022-03-15 | 江苏兄弟维生素有限公司 | Process for recovering ammonium nitrate from thiamine nitrate mother liquor and application thereof |
| CN115724718A (en) * | 2022-11-28 | 2023-03-03 | 江苏兄弟维生素有限公司 | Method for recycling chlorohydrin and sodium formate in crude thiamine mother liquor and application |
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Application publication date: 20141112 |
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