CN101948446A - Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride - Google Patents
Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride Download PDFInfo
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- CN101948446A CN101948446A CN2010102736153A CN201010273615A CN101948446A CN 101948446 A CN101948446 A CN 101948446A CN 2010102736153 A CN2010102736153 A CN 2010102736153A CN 201010273615 A CN201010273615 A CN 201010273615A CN 101948446 A CN101948446 A CN 101948446A
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- acid hydrochloride
- thiazolamine
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Abstract
The invention provides a method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride represented by a chemical formula 1. In the method, thiourea and alpha-halo ethyl acetoacetate are used as raw materials to undergo stepwise reaction under an organic solvent condition. The method is characterized by comprising two steps: a first step of reacting 4-chloro ethyl acetoacetate represented by a chemical formula 2 with the thiourea represented by a chemical formula 3 in a water phase; and a second step of suspending and reacting white crystals obtained by the first step in cold concentrated hydrochloric acid. The reaction is performed under a more mild condition, and the 2-aminothiazol-4-ylacetic acid hydrochloride, which is a core intermediate of cephalosporin is prepared with high purity and high yield. Meanwhile, the 4-chloro ethyl acetoacetate serving as a starting material can be processed easily at low cost, the solvent used in reaction is water and therefore is safe to the environment. The production cost is thus reduced considerably, which is favorable for industrial development.
Description
Technical field
The present invention relates to a kind of manufacture method of medicine intermediate, the manufacture method of used intermediate thiazolamine-4-guanidine-acetic acid hydrochloride during particularly a kind of cephalosporins is made.
Background technology
7-[2-(thiazolamine-4-yl) acetylaminohydroxyphenylarsonic acid [3-[[[(N that represents with chemical formula 5, N)-and dimethyl-amino-ethyl-tetrazole-1-yl] sulphur] methyl]-8 oxos-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid] two hydrochloric acid (cefotiam chloride) are disclosed compounds in No. the 4755598th, United States Patent (USP) at first, it is a cephalosporins of Gram-negative bacteria and gram-positive microorganism being represented good anti-microbial effect, and announces in 80-1672 number, 83-1415 number etc. in Korean Patent and to disclose its manufacture method.
[chemical formula 5]
In the compound process of manufacturing chemistry formula 5, the manufacturing of the thiazolamine that Chemical formula 1 is represented-4-guanidine-acetic acid hydrochloride is the important step in the compound process of manufacturing chemistry formula 5, is the key that concerns its production cost.
[Chemical formula 1]
Domestic and foreign literature does not still have the manufacture method of the relevant Chemical formula 1 of concrete report at present.According to the synthetic experience of thiazole compound, its synthetic method is generally three-step approach: with thiocarbamide, alpha-halogen acetylacetic ester is raw material, the direct closed loop of the first step forms thiazolamine-4-acetic ester, second step obtained thiazolamine-4-sodium acetate through the basic solution saponification then, became target product through the 3rd step acidifying again.Reaction process is as follows:
Said process carries out in organic solvent, just can obtain corresponding product through repeatedly soda acid repeated treatments, this method exists aftertreatment complexity, shortcoming that environmental pollution is big, the method of electrocapillary phoresis is adopted in the aftertreatment that will obtain target thiazolamine-4-acetate usually, this method more complicated, and only limit the laboratory to carry out, be unsuitable for industrialization.Existing manufacture method is numerous and diverse, environmental pollution, and product yield is low, the product cost height, big to the purity influence of product own, manufacturing process is badly in need of improving.
Summary of the invention
For overcoming the deficiencies in the prior art, the present invention has carried out the achievement of concentrating on studies and obtaining in the artificial conventional art problem that solves of invention, a kind of new manufacture method is provided, can be under the generation of impurity be minimized, can produce thiazolamine-4-guanidine-acetic acid hydrochloride of using with intermediate as the cynnematin manufacturing with high purity and high yield simultaneously the friendly more condition of environment.
The technical scheme that the present invention deals with problems is: the manufacture method of a kind of thiazolamine-4-guanidine-acetic acid hydrochloride, with thiocarbamide, alpha-halogen acetylacetic ester is raw material, carry out stepwise reaction under the condition of solvent having, it is characterized in that: carry out in two steps, the first step makes the thiocarbamide shown in 4-chloracetyl acetic ester shown in the Chemical formula 2 and the chemical formula 3 react at aqueous phase; The white crystal that second step obtained the first step is suspended in the cold concentrated hydrochloric acid and reacts.
Wherein,
[Chemical formula 1]
[Chemical formula 2]
[chemical formula 3]
[chemical formula 4]
The present invention represents with following reaction formula:
[reaction formula]
Can use methyl alcohol, ethanol as solvent, water or their mixed solvent are best with water.
Wherein Chemical formula 2 can be methyl esters, ethyl ester, the tert-butyl ester etc., is best with the ethyl ester.
The mol ratio of 4-chloracetyl acetic ester and thiocarbamide is 1: 1 to 1: 1.5 a scope.
The invention has the beneficial effects as follows, be reflected under the condition of milder and carry out, and make thiazolamine-4-guanidine-acetic acid hydrochloride as the core intermediate of cynnematin with high purity and high yield; Processing to the 4-chloracetyl acetic ester that uses as initial substance simultaneously is easy and cheap, especially the solvent that in reaction, uses be water this not only help the improvement of environment, and production cost descends significantly, helps industrialized developing.
Embodiment
The first step makes thiocarbamide (chemical formula 3) suspend in solvent and is cooled to-5 ℃～3 ℃, more preferably is cooled to after O～3 ℃, stirs 15～30 minutes, more preferably stirs 20～30 minutes.At this moment, can use methyl alcohol, ethanol, water or their mixed solvent, but water most preferably as solvent; Then, in the thiourea solution of having prepared in the above, keep on one side O～5 and ℃ more preferably keep O～3 ℃, with 2～3 hours 4-chloracetyl acetic ester (Chemical formula 2) is slowly added on one side, wherein Chemical formula 2 can be a methyl esters, ethyl ester, the tert-butyl ester etc., but preferred ethyl ester, under same temperature, stirred 2～3 hours, the mol ratio of control 4-chloracetyl acetic ester and thiocarbamide was 1: 1 to 1: 1.5 scope, maintaining O～5 at this mixed solution slowly adds ammoniacal liquor in ℃ more preferably below 5 ℃ and makes it pH value and equal 7～10, O.5～1 hour keep O～5 ℃ stirring, make white crystal.With this white crystal filtration under diminished pressure, utilize the tap water washing, obtain intermediate compound thiazolamine-4-yl acetate with chemical formula 4 statements.
Second step, concentrated hydrochloric acid is cooled to-5 ℃～3 ℃, more preferably is cooled to after O～3 ℃, to go up the step intermediate compound at this temperature low suspension in off-the-shelf cold hydrochloric acid, stirred 30～60 minutes, and more preferably 60 minutes, be warmed up to 50～100 ℃ then, more preferably 50～60 degree insulation hydrolysis are 3～6 hours, more preferably 6 hours, insulation finished postcooling to-5～0 ℃, filter the target product Chemical formula 1.
Embodiment 1
Thiocarbamide 40g is suspended in 100 ml waters, stirs and made its dissolving and reduced the temperature to 0 ℃ in 20 minutes, keep temperature O～3 ℃, about 2 hours, the 68.5ml4-chloroacetyl acetacetic ester is splashed into, drip off the back equality of temperature and stirred 3 hours.Insulation is transferred PH=7 with ammoniacal liquor after finishing, and separates out white crystal, filters to obtain molecular formula 4 intermediate compounds.
The 100ml concentrated hydrochloric acid is cooled to after O～3 ℃, the intermediate compound that the last step was obtained at this temperature low suspension in off-the-shelf cold concentrated hydrochloric acid, stirred 60 minutes, be warmed up to 60 ℃ then, insulation hydrolysis 6 hours, insulation finishes postcooling to-5～0 ℃, filter target product (Chemical formula 1) 90g, yield 92%. purity (HPLC) 99.5%.
Embodiment 2
Thiocarbamide 60g is suspended in 160 ml waters, stirs and made its dissolving and reduced the temperature to 0 ℃ in 20 minutes, keep 1～3 ℃ of temperature, about 2 hours, the 132.5ml4-chloroacetyl acetacetic ester is splashed into, drip off the back equality of temperature and stirred 3 hours.Insulation is transferred PH=7 with ammoniacal liquor after finishing, and separates out white crystal, filters the intermediate compound that obtains molecular formula 4 expressions.
The 150ml concentrated hydrochloric acid is cooled to after 1～3 ℃, the intermediate compound that the last step was obtained at this temperature low suspension in off-the-shelf cold concentrated hydrochloric acid, stirred 60 minutes, right liver is warmed up to 60 ℃, insulation hydrolysis 6 hours, insulation finishes postcooling to-3～0 ℃, filter target product (Chemical formula 1) 135.1g, yield 92%. purity (HPLC) 99.6%.
Embodiment 3
Thiocarbamide 100g is suspended in 250 ml waters, stirs and made its dissolving and reduced the temperature to 0 ℃ in 20 minutes, keep temperature O～2 ℃, about 2 hours, the 171.5ml4-chloroacetyl acetacetic ester is splashed into, drip off the back equality of temperature and stirred 3 hours.Insulation is transferred PH=7 with ammoniacal liquor after finishing, and separates out white crystal, filters to obtain molecular formula 4 intermediate compounds.
The 250ml concentrated hydrochloric acid is cooled to after 1～2 ℃, the intermediate compound that the last step was obtained at this temperature low suspension in off-the-shelf cold concentrated hydrochloric acid, stirred 60 minutes, be warmed up to 60 ℃ then, insulation hydrolysis 6 hours, insulation finishes postcooling to-5～-2 ℃, filter target product (Chemical formula 1) 228g, yield 92%. purity (HPLC) 99.4%.
Claims (4)
1. the manufacture method of the thiazolamine of representing with Chemical formula 1-4-guanidine-acetic acid hydrochloride, with thiocarbamide, alpha-halogen acetylacetic ester is raw material, carry out stepwise reaction under the condition of solvent having, it is characterized in that: carry out in two steps, the first step makes the thiocarbamide shown in 4-chloracetyl acetic ester shown in the Chemical formula 2 and the chemical formula 3 react at aqueous phase; The white crystal that second step obtained the first step is suspended in the cold concentrated hydrochloric acid and reacts.
2. according to the manufacture method of the described a kind of thiazolamine of representing with Chemical formula 1 of claim 1-4-guanidine-acetic acid hydrochloride, it is characterized in that: can use methyl alcohol, ethanol as solvent, water or their mixed solvent are best with water.
3. according to the manufacture method of the described a kind of thiazolamine of representing with Chemical formula 1 of claim 1-4-guanidine-acetic acid hydrochloride, it is characterized in that: wherein Chemical formula 2 can be methyl esters, ethyl ester, the tert-butyl ester etc., is best with the ethyl ester.
4. according to the manufacture method of the described a kind of thiazolamine of representing with Chemical formula 1 of claim 1-4-guanidine-acetic acid hydrochloride, it is characterized in that: the mol ratio of 4-chloracetyl acetic ester and thiocarbamide is 1: 1 to 1: 1.5 a scope.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201010273615 CN101948446B (en) | 2010-08-30 | 2010-08-30 | Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride |
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| CN 201010273615 CN101948446B (en) | 2010-08-30 | 2010-08-30 | Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride |
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| CN101948446A true CN101948446A (en) | 2011-01-19 |
| CN101948446B CN101948446B (en) | 2013-05-15 |
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| CN 201010273615 Expired - Fee Related CN101948446B (en) | 2010-08-30 | 2010-08-30 | Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827099A (en) * | 2012-08-20 | 2012-12-19 | 哈尔滨恒运科技开发有限公司 | Method for synthesis of 2-(2-aminothiazol-4-yl)acetic acid hydrochloride |
| CN111533710A (en) * | 2020-06-02 | 2020-08-14 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4260607A (en) * | 1976-08-10 | 1981-04-07 | Takeda Chemical Industries, Ltd. | Cephalosporin esters |
| US4391979A (en) * | 1980-02-18 | 1983-07-05 | Lonza Ltd. | Process for the preparation of (2-amino-thiazol-4yl)-acetic acid hydrochloride |
| US4725592A (en) * | 1983-08-10 | 1988-02-16 | Takeda Chemical Industries, Ltd. | 1-Acyloxyalkyl esters of cephalosporin |
-
2010
- 2010-08-30 CN CN 201010273615 patent/CN101948446B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4260607A (en) * | 1976-08-10 | 1981-04-07 | Takeda Chemical Industries, Ltd. | Cephalosporin esters |
| US4391979A (en) * | 1980-02-18 | 1983-07-05 | Lonza Ltd. | Process for the preparation of (2-amino-thiazol-4yl)-acetic acid hydrochloride |
| US4725592A (en) * | 1983-08-10 | 1988-02-16 | Takeda Chemical Industries, Ltd. | 1-Acyloxyalkyl esters of cephalosporin |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102827099A (en) * | 2012-08-20 | 2012-12-19 | 哈尔滨恒运科技开发有限公司 | Method for synthesis of 2-(2-aminothiazol-4-yl)acetic acid hydrochloride |
| CN111533710A (en) * | 2020-06-02 | 2020-08-14 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
| CN111533710B (en) * | 2020-06-02 | 2022-04-22 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
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| CN101948446B (en) | 2013-05-15 |
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