CN107602503A - The synthetic method of the thiazolyl acetic acid of 2 sulfydryl, 4 methyl 5 - Google Patents
The synthetic method of the thiazolyl acetic acid of 2 sulfydryl, 4 methyl 5 Download PDFInfo
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- CN107602503A CN107602503A CN201710868503.4A CN201710868503A CN107602503A CN 107602503 A CN107602503 A CN 107602503A CN 201710868503 A CN201710868503 A CN 201710868503A CN 107602503 A CN107602503 A CN 107602503A
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- methyl
- acetic acid
- sulfydryl
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- thiazole acetic
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- Cephalosporin Compounds (AREA)
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Abstract
The present invention relates to a kind of synthetic method of 2- sulfydryls -4- methyl-5-thiazole acetic acid, levulic acid and organic solvent are added into reactor, add compound A, and catalyst stirring is slowly added to, 40-60 DEG C of insulation 2h-2.5h is warming up to, water is added and is washed, it is layered obtained organic phase, two thiocarbamate ammoniums, water and compound B are directly added into organic phase and carries out ring-closure reaction, reaction is layered to obtain aqueous phase after terminating, and aqueous phase is adjusted pH value and obtains 2- sulfydryl -4- methyl-5-thiazole acetic acid.The simple to operate, high income of the present invention, cost are low, easily controllable, and the operation cycle is short.Heterogeneous reaction is realized, the process for reducing distillation organic solvent, reduces reaction process, shortens the production time.And save power consumption.The loss of organic solvent in still-process is reduced, and then reduces pollution of the organic solvent to environment.
Description
Technical field
The present invention relates to a kind of synthetic method of 2- sulfydryls -4- methyl-5-thiazole acetic acid, belong to medical synthesis field.
Background technology
Cefodizime Sodium is semi-synthetic third generation cephalosporin, has antibacterial activity to gram positive bacteria, negative bacterium, to β
Lactamase is stable, to cephalosporinase and the mould stabilizer pole of penicillin.Clinic is mainly used in the sensitivities such as streptococcus, pneumococcus
Pneumonia, bronchitis, sphagitis, tonsillitis, urinary tract infections, cholecystitis, cholangitis, gynecological infection and tympanitis caused by bacterium
Deng.Cefodizime is German Hoechst AG's invention, in the world first third generation cephalo bacterium with immune enhancing function
Element；English trade name：Modivid, Chinese trade name：Cefodizime, English language Chemical name：Cefodizime, Chinese chemical name：Cephalo
Ground piperazine.Cefodizime has intensified response to immune response, shows that the medicine can activate in outer research inside animal model and people
Macrophage, improve its phagocytic activity and sterilizing rate.In vivo, Cefodizime can extend the survival rate of infection animal, including resistance to
Medicine bacterium infects or the survival rate of experimental immuno-compromised animals.Cefodizime is that third generation parenteral uses cynnematin.Cephalo
Ground piperazine has high affinity with the albumen for participating in Cell wall synthesis in sensitive bacteria.Cefodizime has extensive antimicrobial spectrum.
The synthetic method of document report 2- sulfydryl -4- methyl-5-thiazole acetic acid is using ethyl 4-oxopentanoate to be in fact former
Material, by halo, cyclization and hydrolysis, acid adjustment obtain, and total recovery 40%, process route is longer, complex operation；Pay ability and political integrity et al.
Reacted using carbon disulfide and ammonia in the case where ethyl acetate makees solvent and obtain ammonium salt, levulic acid reacts to obtain bromination with bromine
Thing, product is obtained with ammonium salt ring-closure reaction, then acid adjustment after distillation, pilot process complex operation, production cost is higher.
The content of the invention
It is an object of the invention to provide a kind of preparation method of 2- sulfydryls -4- methyl-5-thiazole acetic acid, simple to operate, receipts
Rate is high, cost is low, easily controllable, and the operation cycle is short, realizes heterogeneous reaction, the process for reducing distillation organic solvent, reduces
Reaction process, shorten production time.And save power consumption.The loss of organic solvent in still-process is reduced, and then is subtracted
Pollution of the rare solvent to environment.
A kind of preparation method of 2- sulfydryls -4- methyl-5-thiazole acetic acid of the present invention, added into reactor levulic acid and
Organic solvent, compound A is added, and be slowly added to catalyst stirring, be warming up to 40-60 DEG C of insulation 2h-2.5h, add water and carry out
Washing, is layered obtained organic phase, in organic phase in be directly added into two thiocarbamate ammoniums, water and compound B carry out cyclization
Reaction, reaction are layered to obtain aqueous phase after terminating, and aqueous phase is adjusted pH value and obtains 2- sulfydryl -4- methyl-5-thiazole acetic acid.
Catalyst is perchloric acid, hypochlorous acid or hydrogen peroxide.
The time added used in catalyst is 130-150min.
The preparation method of 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that with mole
Meter, the dosage of catalyst are 1.2-2.4 times of acetate propionate.
Compound A is sodium bromide or KBr.
Organic solvent used is chloroform, carbon tetrachloride or 1,2- dichloroethanes, preferentially from chloroform.
Organic solvent is chloroform.
Heating and heat preservation 2-2.5h is stirred after adding catalyst and organic compound A, heating and heat preservation temperature is 40-60 DEG C.
Layering obtains organic phase and two thiocarbamate ammoniums, water carry out ring-closure reaction, using two-phase heterogeneous reaction.
Compound B is sodium hydroxide, sodium carbonate or sodium acid carbonate, and compound B dosage is the 20%- of levulic acid
30%.
The preparation method of 2- sulfydryl -4- methyl-5-thiazole acetic acid：
Levulic acid and organic solvent are added into reactor, adds compound A, and is slowly added to catalyst stirring, is added
Enter catalyst time about 120-150min, be warming up to 40-60 DEG C of insulation 2h-2.5h, add water and washed, layering obtains organic
Phase, aqueous phase drain into wastewater treatment.It is anti-that two thiocarbamate ammoniums, water and compound B progress cyclizations are directly added into gained organic phase
Should.After reaction terminates, aqueous phase is layered to obtain, pH value 1.0-1.5 is adjusted in aqueous phase, obtains 2- sulfydryl -4- methyl-5-thiazole second
Acid.
Layering obtains being directly added into two thiocarbamate ammoniums in organic phase, water carries out ring-closure reaction, organic solvent without
Distillation is handled, and is reacted using two-phase heterogeneous reaction.
Compared with prior art, the invention has the advantages that：
The preparation method of 2- sulfydryls -4- methyl-5-thiazole acetic acid of the present invention, without using bromine, meet green at present
Technique theory.
The simple to operate, high income of the present invention, cost are low, easily controllable, and the operation cycle is short.
The present invention realizes heterogeneous reaction, the process for reducing distillation organic solvent, reduces reaction process, when shortening production
Between.And save power consumption.The loss of organic solvent in still-process is reduced, and then reduces dirt of the organic solvent to environment
Dye.
Yield of the present invention reaches 77%-81%, substantially increases yield.And the purity of product is in 99.86%-99.6%
More than, higher than market majority producer 97-99% quality purity indexes.
Embodiment
Embodiment is described further to the present invention.
Embodiment 1
100kg levulic acids and 1000L chloroforms are added into reactor, stirs, is slowly added dropwise after adding sodium bromide 176kg
Hydrogen peroxide 260kg, 40 DEG C of insulation 2h being warming up to, water is added and is washed, layering obtains organic phase, and aqueous phase carries out wastewater treatment,
The thiocarbamate ammoniums of 75kg bis-, 1000kg water and sodium hydroxide 10kg are directly added into organic phase and carries out ring-closure reaction, is layered,
Aqueous phase carries out acid adjustment pH=1.0, obtains 2- sulfydryl -4- methyl-5-thiazole acetic acid 130kg, purity 99.86%, yield
77.76%.
Wherein, the time used in addition catalyst is 140min.
Embodiment 2
100kg levulic acids and 1000L carbon tetrachloride are added into reactor, is stirred after adding sodium bromide 176kg, slowly
Hydrogen peroxide 260kg is added dropwise, is warming up to 60 DEG C of insulation 2.5h, adds water and washed, layering obtains organic phase, and aqueous phase carries out waste water
Processing.The thiocarbamate ammoniums of 75kg bis-, 1000kg water and sodium carbonate 22kg are directly added into organic phase and carries out ring-closure reaction, point
Layer, aqueous phase carry out acid adjustment pH=1.5, obtain 2- sulfydryl -4- methyl-5-thiazole acetic acid 132kg, purity 99.92%, yield
80.99%.
Wherein, the time used in addition catalyst is 130min.
Embodiment 3
100kg levulic acids and 1000L1,2- dichloroethanes are added into reactor, is stirred after adding KBr 203kg,
Hypochlorous acid 540kg is slowly added dropwise, is warming up to 50 DEG C of insulation 2.2h, adds water and washed, layering obtains organic phase, and aqueous phase is carried out
Wastewater treatment.The thiocarbamate ammoniums of 75kg bis-, 1000kg water and sodium acid carbonate 30kg are directly added into organic phase and carries out cyclization
Reaction, layering, aqueous phase carry out acid adjustment pH=1.3, obtain 2- sulfydryl -4- methyl-5-thiazole acetic acid 131kg, purity is
99.96%, yield 80.37%.
Wherein, the time used in addition catalyst is 150min.
Embodiment 4
100kg levulic acids and 1000L chloroforms are added into reactor, stirs, is slowly added dropwise after adding sodium bromide 176kg
Hydrogen peroxide 520kg, 45 DEG C of insulation 2h are warming up to, water is added and is washed, layering obtains organic phase, and aqueous phase carries out wastewater treatment.
The thiocarbamate ammoniums of 75kg bis-, 1000kg water and sodium hydroxide 15kg are directly added into organic phase and carries out ring-closure reaction, is layered,
Aqueous phase carries out acid adjustment pH=1.5, obtains 2- sulfydryl -4- methyl-5-thiazole acetic acid 131.7kg, purity 99.90%, yield
80.80%.
Wherein, the time used in addition catalyst is 120min.
Claims (10)
1. a kind of synthetic method of 2- sulfydryls -4- methyl-5-thiazole acetic acid, it is characterised in that levulinic is added into reactor
Acid and organic solvent, compound A is added, and be slowly added to catalyst stirring, be warming up to 40-60 DEG C of insulation 2h-2.5h, add water
Washed, be layered obtained organic phase, in organic phase in be directly added into two thiocarbamate ammoniums, water and compound B are carried out
Ring-closure reaction, reaction are layered to obtain aqueous phase after terminating, and aqueous phase is adjusted pH value and obtains 2- sulfydryl -4- methyl-5-thiazole acetic acid.
2. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that catalyst is height
Chloric acid, hypochlorous acid or hydrogen peroxide.
3. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that add catalyst
Time used is 130-150min.
4. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that with mole
Meter, the dosage of catalyst are 1.2-2.4 times of acetate propionate.
5. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that compound A is
Sodium bromide or KBr.
6. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that used is organic
Solvent is chloroform, carbon tetrachloride or 1,2- dichloroethanes.
7. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that organic solvent is
Chloroform.
8. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that add catalyst
With stirring heating and heat preservation 2-2.5h after organic compound A, heating and heat preservation temperature is 40-60 DEG C.
9. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that layering is had
Machine phase and two thiocarbamate ammoniums, water carry out ring-closure reaction, using two-phase heterogeneous reaction.
10. the synthetic method of the 2- sulfydryl -4- methyl-5-thiazole acetic acid described in claim 1, it is characterised in that compound B is
Sodium hydroxide, sodium carbonate or sodium acid carbonate, compound B dosage are the 20%-30% of levulic acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107857740A (en) * | 2017-12-15 | 2018-03-30 | 山东金城医药化工有限公司 | The synthetic method of the thiazolyl acetic acid of 2 sulfydryl of Cefodizime Sodium intermediate, 4 methyl 5 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR19990024623A (en) * | 1997-09-04 | 1999-04-06 | 윤재승 | Novel Preparation of 2-mercapto-4-methyl-1,3-thiazole-5-acetic acid |
| CN104031040A (en) * | 2014-06-05 | 2014-09-10 | 济南诚汇双达化工有限公司 | Synthesis method of 2-sulfydryl-4-pyridyl thiazole |
| CN104119211A (en) * | 2014-08-01 | 2014-10-29 | 黄山学院 | Method for preparing alpha-monobrominated ketone and alpha, alpha-dibrominated ketone compounds by selectively brominating ketone compounds |
-
2017
- 2017-09-22 CN CN201710868503.4A patent/CN107602503A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR19990024623A (en) * | 1997-09-04 | 1999-04-06 | 윤재승 | Novel Preparation of 2-mercapto-4-methyl-1,3-thiazole-5-acetic acid |
| CN104031040A (en) * | 2014-06-05 | 2014-09-10 | 济南诚汇双达化工有限公司 | Synthesis method of 2-sulfydryl-4-pyridyl thiazole |
| CN104119211A (en) * | 2014-08-01 | 2014-10-29 | 黄山学院 | Method for preparing alpha-monobrominated ketone and alpha, alpha-dibrominated ketone compounds by selectively brominating ketone compounds |
Non-Patent Citations (4)
| Title |
|---|
| RAMAN GUPTA等: "HClO4-SiO2: A Highly Efficient and Recyclable Catalyst for the Selective-Bromination of Carbonyl Compounds Using N-Bromosuccinimide", 《LETTERS IN ORGANIC CHEMISTRY》 * |
| 严德鹏等: "合成溴代丁酮的新工艺研究", 《化工时刊》 * |
| 傅德才等: "头孢地嗪钠中间体2-巯基-4-甲基-5-噻唑乙酸的合成", 《中国药物化学杂志》 * |
| 刘少华等: "有机合成中的溴代反应试剂", 《山东化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107857740A (en) * | 2017-12-15 | 2018-03-30 | 山东金城医药化工有限公司 | The synthetic method of the thiazolyl acetic acid of 2 sulfydryl of Cefodizime Sodium intermediate, 4 methyl 5 |
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Application publication date: 20180119 |