CN103772315B - A kind of method of one-step synthesis 4-methylthiazole-5-carboxylate - Google Patents
A kind of method of one-step synthesis 4-methylthiazole-5-carboxylate Download PDFInfo
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- CN103772315B CN103772315B CN201410006251.0A CN201410006251A CN103772315B CN 103772315 B CN103772315 B CN 103772315B CN 201410006251 A CN201410006251 A CN 201410006251A CN 103772315 B CN103772315 B CN 103772315B
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- methylthiazole
- carboxylate
- step synthesis
- chloroacetyl acetacetic
- acetacetic ester
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
A method for one-step synthesis 4-methylthiazole-5-carboxylate, after 2-chloroacetyl acetacetic ester and ammonium thiocyanate mixing, at 100-180
oc reacts 2-6 hour, and be dissolved in water after having reacted the ammonium chloride generated, and then filtration, drying obtain 4-methylthiazole-5-carboxylate; The mol ratio of described 2-chloroacetyl acetacetic ester and ammonium thiocyanate is 1:1.01 ~ 1:1.5.Relative to existing technology, the present invention has following characteristics: 1, do not use solvent in reaction process; 2, one-step synthesis, step is few, easy and simple to handle; 3, do not use poisonous and harmful or inflammable and explosive raw material, environmental protection pressure reduces greatly.
Description
Technical field
The present invention relates to a kind of synthetic method of cefditoren pivoxil intermediate, is a kind of method of synthesizing 4-methylthiazole-5-carboxylate in particular.
Background technology
4-methylthiazole-5-carboxylate is a kind of faint yellow to white crystal, fusing point 27-28
oc, is mainly used in synthesizing cefditoren pivoxil.
The method of producing 4-methylthiazole-5-carboxylate both at home and abroad at present is mainly carried out according to following two lines:
Route 1, be that 2-chloroacetyl acetacetic ester and thiocarbamide are reacted in ethanol, generate 2-amino-4-methylthiazole-5-carboxylate, then carry out diazotization reaction and obtain 4-methylthiazole-5-carboxylate (as CN101921268, Tetrahedron, 69(22) 4436-4444; 2013, Bioorganic & Medicinal Chemistry Letters, 18 (23) 6231-6235; 2008, but this route yield when carrying out diazotization is not high, employs P contained compound simultaneously, and after acid-base neutralisation, waste liquid amount is large, and extensive process environmental protection difficulty is very large;
Route 2: be first dithiocarbonic anhydride and ammonia are reacted generate aminomethanesulfonic acid salt, then react with 2-chloroacetyl acetacetic ester, generate sulfur-bearing intermediate, then 4-methylthiazole-5-carboxylate is obtained after being oxidized with hydrogen peroxide (as JP2009256247, WO2006108701, but this route uses inflammable and explosive ammonia and dithiocarbonic anhydride, in hydrogen peroxide oxidation process, easily generate the by product of some sulfur-bearings, taste is very unpleasant simultaneously, bad to environment, industrialization difficulty is larger.
These two synthetic routes are polystep reaction simultaneously, and route is comparatively loaded down with trivial details, operation inconvenience.
In view of restriction and the shortcoming of above-mentioned technique, need to improve.
Summary of the invention
The object of the invention is to provide a kind of method of one-step synthesis 4-methylthiazole-5-carboxylate, overcomes the problems such as the ubiquitous operation steps of prior art is many, quantity of three wastes is large, environmental pollution is large.
The present invention relates to a kind of method of a step 4-methylthiazole-5-carboxylate, synthetic route is as follows:
Concrete technical scheme is: after 2-chloroacetyl acetacetic ester and ammonium thiocyanate mixing, at 100-180
oc reacts 2-6 hour, and be dissolved in water after having reacted the ammonium chloride generated, and then filters and obtains 4-methylthiazole-5-carboxylate; The mol ratio of described 2-chloroacetyl acetacetic ester and ammonium thiocyanate is 1:1.01 ~ 1:1.5.
What such scheme synthesis obtained is flaxen 4-methylthiazole-5-carboxylate, as obtained the product of white, this flaxen product can be carried out underpressure distillation.
Such scheme can more preferably:
The mol ratio of described 2-chloroacetyl acetacetic ester and ammonium thiocyanate is preferably 1:1.15.
Described temperature of reaction is preferably 160-165
oc, under this temperature condition, the degree that ammonium thiocyanate decomposes ammonification and thiocyanic acid is comparatively all thoroughly even.
Relative to existing technology, the present invention has following characteristics:
1, inapplicable solvent in reaction process;
2, one-step synthesis, step is few, easy and simple to handle;
3, do not use poisonous and harmful or inflammable and explosive raw material, environmental protection pressure reduces greatly.
Embodiment
Embodiment 1:
2-chloroacetyl acetacetic ester 164.5g(1mol is added) in reactor, ammonium thiocyanate 87.5g(1.15mol), open and stir, be warming up to 160 DEG C, at 160-165 DEG C, insulation reaction 5h, add water 150g after completion of the reaction, filter after stirring, natural air drying, obtain faint yellow 4-methylthiazole-5-carboxylate 158g, yield 92.28%.
Embodiment 2:
2-chloroacetyl acetacetic ester 164.5g(1mol is added) in reactor, ammonium thiocyanate 99g(1.3mol), open and stir, be warming up to 170 DEG C, at 170-175 DEG C, insulation reaction 3h, add water 130g after completion of the reaction, filter after stirring, natural air drying, obtain faint yellow 4-methylthiazole-5-carboxylate 144g, yield 84.10%.
Embodiment 3:
2-chloroacetyl acetacetic ester 164.5g(1mol is added) in reactor, ammonium thiocyanate 80g(1.05mol), open and stir, be warming up to 130 DEG C, at 130-135 DEG C, insulation reaction 6h, add water 160g after completion of the reaction, filter after stirring, natural air drying, obtain faint yellow 4-methylthiazole-5-carboxylate 150g, yield 87.61%.
Embodiment 4:
2-chloroacetyl acetacetic ester 164.5g(1mol is added) in reactor, ammonium thiocyanate 114g(1.5mol), open and stir, be warming up to 100 DEG C, at 100-105 DEG C, insulation reaction 6h, add water 150g after completion of the reaction, filter after stirring, natural air drying, obtain faint yellow 4-methylthiazole-5-carboxylate 124g, yield 72.42%.
Embodiment 5:
2-chloroacetyl acetacetic ester 164.5g(1mol is added) in reactor, ammonium thiocyanate 80g(1.05mol), open and stir, be warming up to 180 DEG C, at 180-185 DEG C, insulation reaction 3h, add water 160g after completion of the reaction, filter after stirring, natural air drying, obtain faint yellow 4-methylthiazole-5-carboxylate 140g, yield 81.76%.
Below be only the part exemplary embodiments of this programme, wherein embodiment 1 is as preferred embodiment, and its yield is apparently higher than embodiment 2-5; In addition those skilled in the art can adopt other embodiment to realize completely within the protection domain of the technical program, and all can make the appropriate adjustments parameters such as proportioning raw materials, temperature of reaction, times, does not just repeat one by one at this.
Claims (6)
1. a method for one-step synthesis 4-methylthiazole-5-carboxylate, is characterized in that, after 2-chloroacetyl acetacetic ester and ammonium thiocyanate mixing, at 100-180
oc reacts 2-6 hour, and be dissolved in water after having reacted the ammonium chloride generated, and then filtration, drying obtain 4-methylthiazole-5-carboxylate; The mol ratio of described 2-chloroacetyl acetacetic ester and ammonium thiocyanate is 1:1.01 ~ 1:1.5.
2. the method for one-step synthesis 4-methylthiazole-5-carboxylate according to claim 1, is characterized in that, the mol ratio of described 2-chloroacetyl acetacetic ester and ammonium thiocyanate is preferably 1:1.15.
3. the method for one-step synthesis 4-methylthiazole-5-carboxylate according to claim 1, it is characterized in that, described temperature of reaction is preferably 160-165
oc.
4. the method for one-step synthesis 4-methylthiazole-5-carboxylate according to claim 1, it is characterized in that, the described reaction times is preferably 5 hours.
5., according to the method for the arbitrary described one-step synthesis 4-methylthiazole-5-carboxylate of claim 1-4, it is characterized in that, described amount of water is the 80%-100% of 2-chloroacetyl acetacetic ester quality.
6. the method for one-step synthesis 4-methylthiazole-5-carboxylate according to claim 5, is characterized in that, described drying mode is natural air drying.
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| CN201410006251.0A CN103772315B (en) | 2014-01-07 | 2014-01-07 | A kind of method of one-step synthesis 4-methylthiazole-5-carboxylate |
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| CN103772315B true CN103772315B (en) | 2015-10-21 |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105130924B (en) * | 2015-07-22 | 2017-03-15 | 蚌埠中实化学技术有限公司 | A kind of method for preparing 4 methylthiazol, 5 Ethyl formate |
| CN105483749B (en) * | 2015-11-27 | 2017-11-24 | 北京工业大学 | The paired electrosynthesis method of thiocyanogen α, β the unsaturated carbonyl class compound of 3 amido 2 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1152571A (en) * | 1995-09-14 | 1997-06-25 | 精细有机物有限公司 | Preparation of substituted thiazoles |
| CN101921268A (en) * | 2010-08-27 | 2010-12-22 | 中山大学肿瘤防治中心 | 5-thiazole amide compound and biology application thereof |
| CN103058949A (en) * | 2011-10-18 | 2013-04-24 | 华东理工大学 | Thiazole derivative acting as DHODH inhibitor and its application |
-
2014
- 2014-01-07 CN CN201410006251.0A patent/CN103772315B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1152571A (en) * | 1995-09-14 | 1997-06-25 | 精细有机物有限公司 | Preparation of substituted thiazoles |
| CN101921268A (en) * | 2010-08-27 | 2010-12-22 | 中山大学肿瘤防治中心 | 5-thiazole amide compound and biology application thereof |
| CN103058949A (en) * | 2011-10-18 | 2013-04-24 | 华东理工大学 | Thiazole derivative acting as DHODH inhibitor and its application |
Non-Patent Citations (2)
| Title |
|---|
| A one-pot synthesis of functionalized thiazoles from acid chlorides,secondary amines, ethyl bromopyruvate, and ammonium thiocyanate;Issa Yavari et al.;《Mol Divers》;20090210;第19卷;295-300 * |
| Chemistry of the thiazoles;K. Ganapathi et al.;《Proceedings of the Indian Academy of Sciences-Section A》;19451231;第22卷(第6期);362-378 * |
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Denomination of invention: A method for one-step synthesis of 4-methylthiazole-5-ethyl formate Effective date of registration: 20211130 Granted publication date: 20151021 Pledgee: Dongying Hekou District sub branch of China Post Savings Bank Co.,Ltd. Pledgor: SHANDONG HUIHAI PHARMACEUTICAL& CHEMICAL Co.,Ltd. Registration number: Y2021980013568 |