CN103664819A - Preparation method of ethyl 2-amino-4-methylthiazole-5-carboxylate - Google Patents
Preparation method of ethyl 2-amino-4-methylthiazole-5-carboxylate Download PDFInfo
- Publication number
- CN103664819A CN103664819A CN201310685798.3A CN201310685798A CN103664819A CN 103664819 A CN103664819 A CN 103664819A CN 201310685798 A CN201310685798 A CN 201310685798A CN 103664819 A CN103664819 A CN 103664819A
- Authority
- CN
- China
- Prior art keywords
- methylthiazole
- amino
- carboxylate
- preparation
- sodium carbonate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Abstract
The invention discloses a preparation method of ethyl 2-amino-4-methylthiazole-5-carboxylate, which comprises the following steps: 1) preparing an ethyl acetate solution with the mass fraction of 10-35% by using ethyl alcohol as a solvent, and adding thiourea and sodium carbonate into the solution, wherein the weight ratio of the sodium carbonate to ethyl 2-chloroacetoacetate used in the step 2 is 0.01-0.1; 2) increasing the temperature to 40-55 DEG C, dropwise adding ethyl 2-chloroacetoacetate, heating to 60-70 DEG C after dripping off, and performing thermal insulation for 5-5.5 hours; 3) distilling to remove most of the solvent, then cooling to the room temperature, and filtering; 4) adding the filtrate into water, adjusting the pH value to be 9-10 through caustic soda liquid, and stirring; 5) filtering, and drying in vacuum to obtain ethyl 2-amino-4-methylthiazole-5-carboxylate. The technology has the advantages that the reaction time is short, the reaction temperature is low, the product yield is more than 98%, and the mp (melting point) is 172-173 DEG C.
Description
Technical field
The present invention relates to a kind of preparation method of the 5-of preparation thiazole amide pharmaceutical intermediate, say more specifically a kind of preparation method of 2-amino-4-methylthiazole-5-carboxylate.
Background technology
2-amino-4-methylthiazole-5-carboxylate is a kind of off-white powder, is mainly used in 5-thiazole amide compound or the acceptable steric isomer of its medicine in synthesizing antineoplastic medicament.
The molecular structure of 2-aromatic base substituted amido-4-methylthiazol-5-formic acid ester derivative is owing to having the aromatic ring structure of two fragrant planes, the basic pharmacophore structural framework with anti-HIV-1, mutually mate with the binding pocket of the substrate binding site of HIV1-RT (RT), be expected to the inhibitor design for HIV-1RT.
Reported that at present take 2-chloroacetyl acetacetic ester, thiocarbamide is raw material both at home and abroad, ethanol is the method that solvent reaction obtains, but its shortcoming is obvious: 1, long reaction time; 2, energy consumption is high.
Patent of invention, < < 5-thiazole amide compound and biological applications > >, patent No. CN101921268,2010: disclose that to take thiocarbamide and 2-chloroacetyl acetacetic ester be raw material, take ethanol as solvent, and backflow reaction overnight generates 2-amino-4-methylthiazole-5-carboxylate, and the shortcoming of the method is that the reaction times is oversize, temperature of reaction is high, and energy consumption is large.
Chinese science and technology paper is online, and 2010: disclose that to take thiocarbamide and 2-chloroacetyl acetacetic ester be raw material, take ethanol as solvent, under reflux state or microwave condition, generate 2-amino-4-methylthiazole-5-carboxylate, the shortcoming of the method is that return time reaches 10h, long reaction time; Microwave is not suitable for industrial production.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of 2-amino-4-methylthiazole-5-carboxylate preparation method, the problem such as overcome the ubiquitous long reaction time of prior art, temperature of reaction is high, energy consumption is high.
Synthetic route of the present invention is:
Technical scheme of the present invention comprises the following steps:
1) take ethanol as solvent configuration quality concentration is 10%～35% ethyl acetate solution, add wherein thiocarbamide and sodium carbonate, wherein sodium carbonate and step 2) in the weight ratio of 2-chloroacetyl acetacetic ester be 0.01～0.1;
2) be warming up to 40～55 ℃, drip 2-chloroacetyl acetacetic ester, drip off and be warming up to 60～70 ℃ of insulation 5～5.5h;
3) after distillation remove portion solvent, being cooled to room temperature filters;
4) filtrate is added to the water, with liquid caustic soda, adjusting PH is 9～10 rear stirrings;
5) then after filtration, vacuum drying obtains 2-amino-4-methylthiazole-5-carboxylate.
On the basis of technique scheme, a kind of concrete preferred version is below provided, it comprises the following steps:
1) take ethanol as solvent configuration quality mark is as 10%～35% ethyl acetate solution 200ml, add wherein 30.4g thiocarbamide, 0.3g～3.3g sodium carbonate;
2) be warming up to 40～55 ℃, drip 33g2-chloroacetyl acetacetic ester, 20～30min drips off, and drips off and is warming up to 60～70 ℃ of insulation 5～5.5h;
3) after distillation remove portion solvent, being cooled to room temperature filters;
4) filtrate is added in 500ml water, with 30% liquid caustic soda, adjusting PH is 9～10, stirs 0.5h;
5) 25 ℃ are filtered and solid vacuum drying are obtained to 2-amino-4-methylthiazole-5-carboxylate.
Such scheme also can be more preferably:
In step 1), ethyl acetate preferred mass mark is 20%～25%.
In step 1), the preferable amount of sodium carbonate is 1.5g.
Step 2) in, the preferred dropping temperature of 2-chloroacetyl acetacetic ester is 43～45 ℃; Dripping off rear preferred holding temperature is 64～66 ℃; Holding temperature 5h.
With respect to existing technology, the present invention has following characteristics:
1, used mixed solvent and added sodium carbonate as catalyzer, having shortened the reaction times;
2, reduce temperature of reaction, removed backflow phenomenon in reaction, reduced the energy consumption of reaction.
Embodiment
The present invention is described by the following examples, but is not limited to this.
Embodiment 1:
In four-hole bottle, add the ethanol 200ml containing 25% ethyl acetate, add 30.4g thiocarbamide, 1.5g sodium carbonate, be warming up to 45 ℃, drip 33g2-chloroacetyl acetacetic ester, 20～30min drips off, drip off and be warming up to 65 ℃ of insulation 5h, normal pressure is cooled to room temperature after steaming most of solvent.Remove by filter unreacted thiocarbamide, filtrate is added in 500ml water, stirring and adjusting PH with 30% liquid caustic soda is 9～10, stirs 0.5h, and suction filtration final vacuum is dried 2h and obtained product 36.7g, yield 98.39%, mp:172～173 ℃.
Embodiment 2:
In four-hole bottle, add the ethanol 200ml containing 20% ethyl acetate, add 30.4g thiocarbamide, 0.5g sodium carbonate, be warming up to 45 ℃, drip 33g2-chloroacetyl acetacetic ester, 20～30min drips off, drip off and be warming up to 70 ℃ of insulation 5h, normal pressure is cooled to room temperature after steaming most of solvent.Remove by filter unreacted thiocarbamide, filtrate is added in 500ml water, stirring and adjusting PH with 30% liquid caustic soda is 9～10, stirs 0.5h, and suction filtration final vacuum is dried 2h and obtained product 36.6g, yield 98.12%, mp:172～173 ℃.
Embodiment 3:
In four-hole bottle, add the ethanol 200ml containing 10% ethyl acetate, add 30.4g thiocarbamide, 0.5g sodium carbonate, be warming up to 45 ℃, drip 33g2-chloroacetyl acetacetic ester, 20～30min drips off, drip off and be warming up to 65 ℃ of insulation 5h, normal pressure is cooled to room temperature after steaming most of solvent.Remove by filter unreacted thiocarbamide, filtrate is added in 500ml water, stirring and adjusting PH with 30% liquid caustic soda is 9～10, stirs 0.5h, and suction filtration final vacuum is dried 2h and obtained product 36.6g, yield 98.12%, mp:172～173 ℃.
Embodiment 4:
In four-hole bottle, add the ethanol 200ml containing 35% ethyl acetate, add 30.4g thiocarbamide, 3.3g sodium carbonate, be warming up to 45 ℃, drip 33g2-chloroacetyl acetacetic ester, 20～30min drips off, drip off and be warming up to 70 ℃ of insulation 5.5h, normal pressure is cooled to room temperature after steaming most of solvent.Remove by filter unreacted thiocarbamide, filtrate is added in 500ml water, stirring and adjusting PH with 30% liquid caustic soda is 9～10, stirs 0.5h, and suction filtration final vacuum is dried 2h and obtained product 36.7g, yield 98.39%, mp:172～173 ℃.
Below be only the part exemplary embodiments of this programme; 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, at this, just do not repeat one by one.
Claims (5)
1. a preparation method for 2-amino-4-methylthiazole-5-carboxylate, is characterized in that, comprises the following steps:
1) take ethanol as solvent configuration quality concentration is 10%～35% ethyl acetate solution, add wherein thiocarbamide and sodium carbonate, wherein sodium carbonate and step 2) in the weight ratio of 2-chloroacetyl acetacetic ester be 0.01～0.1;
2) be warming up to 40～55 ℃, drip 2-chloroacetyl acetacetic ester, drip off and be warming up to 60～70 ℃ of insulation 5～5.5h;
3) after distillation remove portion solvent, being cooled to room temperature filters;
4) filtrate is added to the water, with liquid caustic soda, adjusting PH is 9～10 rear stirrings;
5) then after filtration, vacuum drying obtains 2-amino-4-methylthiazole-5-carboxylate.
2. the preparation method of 2-amino-4-methylthiazole-5-carboxylate according to claim 1, is characterized in that, comprises the following steps:
1) take ethanol as solvent configuration quality concentration is as 10%～35% ethyl acetate solution 200ml, add wherein 30.4g thiocarbamide, 0.3g～3.3g sodium carbonate;
2) be warming up to 40～55 ℃, drip 33g2-chloroacetyl acetacetic ester, 20～30min drips off, and drips off and is warming up to 60～70 ℃ of insulation 5h;
3) after distillation remove portion solvent, being cooled to room temperature filters;
4) filtrate is added in 500ml water, with 30% liquid caustic soda, adjusting PH is 9～10, stirs 0.5h;
5) 25 ℃ are filtered and solid vacuum drying are obtained to 2-amino-4-methylthiazole-5-carboxylate.
3. the preparation method of 2-amino-4-methylthiazole-5-carboxylate according to claim 2, is characterized in that, in step 1), ethyl acetate preferred mass concentration is 20%～25%.
4. the preparation method of 2-amino-4-methylthiazole-5-carboxylate according to claim 2, is characterized in that, in step 1), the preferable amount of sodium carbonate is 1.5g.
5. according to the preparation method of the arbitrary described 2-amino-4-methylthiazole-5-carboxylate of claim 1-4, it is characterized in that step 2) in the preferred dropping temperature of 2-chloroacetyl acetacetic ester be 43～45 ℃; Dripping off rear preferred holding temperature is 64～66 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310685798.3A CN103664819A (en) | 2013-12-16 | 2013-12-16 | Preparation method of ethyl 2-amino-4-methylthiazole-5-carboxylate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310685798.3A CN103664819A (en) | 2013-12-16 | 2013-12-16 | Preparation method of ethyl 2-amino-4-methylthiazole-5-carboxylate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103664819A true CN103664819A (en) | 2014-03-26 |
Family
ID=50303695
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310685798.3A Pending CN103664819A (en) | 2013-12-16 | 2013-12-16 | Preparation method of ethyl 2-amino-4-methylthiazole-5-carboxylate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103664819A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000024739A1 (en) * | 1998-10-23 | 2000-05-04 | Dow Agrosciences Llc | 3-(substituted phenyl)-5-(substituted heterocyclyl)-1,2,4-triazole compounds |
| WO2002046158A2 (en) * | 2000-11-20 | 2002-06-13 | Scios Inc. | Piperidine/piperazine-type inhibitors of p38 kinase |
| WO2010007482A2 (en) * | 2008-07-16 | 2010-01-21 | Glenmark Pharmaceuticals S.A. | Thiazole derivatives as stearoyl coa desaturase inhibitors |
| CN101675045A (en) * | 2007-05-11 | 2010-03-17 | 弗·哈夫曼-拉罗切有限公司 | Hetarylanilines as modulators for amyloid beta |
| 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 |
| CN102942565A (en) * | 2012-11-06 | 2013-02-27 | 江西天人生态股份有限公司 | 3,4-dichloro isothiazole derivatives, their preparation method and application |
-
2013
- 2013-12-16 CN CN201310685798.3A patent/CN103664819A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000024739A1 (en) * | 1998-10-23 | 2000-05-04 | Dow Agrosciences Llc | 3-(substituted phenyl)-5-(substituted heterocyclyl)-1,2,4-triazole compounds |
| WO2002046158A2 (en) * | 2000-11-20 | 2002-06-13 | Scios Inc. | Piperidine/piperazine-type inhibitors of p38 kinase |
| CN101675045A (en) * | 2007-05-11 | 2010-03-17 | 弗·哈夫曼-拉罗切有限公司 | Hetarylanilines as modulators for amyloid beta |
| WO2010007482A2 (en) * | 2008-07-16 | 2010-01-21 | Glenmark Pharmaceuticals S.A. | Thiazole derivatives as stearoyl coa desaturase inhibitors |
| 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 |
| CN102942565A (en) * | 2012-11-06 | 2013-02-27 | 江西天人生态股份有限公司 | 3,4-dichloro isothiazole derivatives, their preparation method and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105037062A (en) | Alcohol-based ternary deep-eutectic solvent and preparation method thereof | |
| CN102452902A (en) | Preparation method for phloroglucinol | |
| CN102746289B (en) | The preparation method of a kind of lurasidone hydrochloride | |
| CN102453011A (en) | Preparation method of high-purity naringenin | |
| CN105524042B (en) | A method of preparing bent Ge Lieting | |
| CN104496937A (en) | Synthetic method of 2-mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) isopropoxyiminoacetate | |
| CN103664819A (en) | Preparation method of ethyl 2-amino-4-methylthiazole-5-carboxylate | |
| CN104291818A (en) | ZrO2 doped molybdenum electrode and preparation method thereof | |
| CN105315198A (en) | Crystal form of pirfenidone and preparation method of crystal form | |
| CN104693025A (en) | Feeding manner for preparing L-monomenthyl glutarate | |
| CN101914041A (en) | Refining method for medicinal urea | |
| CN105670155A (en) | Liquid heat stabilizing agent | |
| CN101006044B (en) | Purification method of terephthal aldehyde | |
| CN104418810A (en) | New synthetic route of levosimendan | |
| CN105130924A (en) | Preparation method of 4-methylthiazole-5-ethyl formate | |
| CN107915694A (en) | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof | |
| CN102304027A (en) | Method for extracting magnolol from Magnolia officinalis tree leaves | |
| CN102718720B (en) | Method for preparing 4-[(4,6-dichloro-2-pyrimidyl) amino] cyanophenyl | |
| CN106632347B (en) | Preparation method of pyrrolopyrazine compound and salt thereof | |
| CN105237529A (en) | Refining method for high-purity anhydrous dasatinib | |
| CN104628627A (en) | Method for synthesizing 1-boc-4-aminopiperidine | |
| CN104926682A (en) | P-chlorophenylu hydrazine hydrochloride preparation method | |
| CN108570017A (en) | The synthesis of 2- amino-4-methylthiazole-5-carboxylates | |
| CN105418507A (en) | Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine | |
| CN105294503B (en) | A kind of purifying technique of diuron |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140326 |