CN102336721B - Method for synthesizing AE-active ester by using water-containing 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid - Google Patents
Method for synthesizing AE-active ester by using water-containing 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid Download PDFInfo
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Abstract
The invention discloses a method for synthesizing AE-active ester by using water-containing 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid. The method comprises the following steps of: performing azeotropic dehydration on water-containing 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid by using a solvent in a reaction container; and directly synthesizing the AE-active ester. The method has the advantages of reducing filtering and drying processes in the original production process, increasing the utilization rate of 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid, saving investment and lowering the production cost of the AE-active ester along with extremely high industrial popularization value.
Description
Technical field
The present invention relates to a kind of method of utilizing the synthetic 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester of moisture ainothiazoly loximate, be applicable to the production process of antibiotic intermediates.
Background technology
2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, be called again 2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid sulfo-benzothiazole ester, English by name: 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic, thiobenzothiazole ester, referred to as MAEM, CAS is numbered 80765-85-0, molecular formula is: C13H10N3O2S3, molecular weight is: 350.44, and fusing point, at 128～130 ℃, is off-white color or faint yellow needle crystal powder.Ainothiazoly loximate, be called again 2-methoxy imino-2-(2-aminothiazole)-4-acetic acid, its English name is (Z)-2-(2 – aminothiazol-4-yl)-2-methoxyiminoacetic acid, referred to as ATMAA, CAS is numbered 65872-41-5, and molecular formula is C
6h
7n
3o
3s, molecular weight is 201.21.Anhydrous ainothiazoly loximate is white or off-white powder shape crystal, 182～184 ℃ of fusing points.Moisture ainothiazoly loximate is white or off-white color needle-like crystal, and molecular formula is C
6h
7n
3o
3s1.5H2O, 167～170 ℃ of fusing points.
The 4th generation the developing rapidly of cynnematin, also accelerated the development of the Intermediates Industry supporting with it.Be subject to stimulation and the promotion of cynnematin great market, the demand of domestic pharmaceutical intermediate is doubled and redoubled, output is developed rapidly.At present, China becomes topmost medicine intermediate producing country in the world gradually.Ainothiazoly loximate and 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, as the important intermediate of Cephalosporins, can synthesize multiple important cynnematins such as comprising ceftriaxone, cefpirome, cefotaxime.China is the major country of production of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, and annual production surpasses 2000 tons, still can not meet the needs of international and domestic market.
What the technique of production 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester generally adopted at present is to take methyl aceto acetate as starting raw material, through oximate, methylate, bromination, distillation, ring-closure reaction obtain Ethyl Methylaminothiazolyloximate, in alkaline aqueous solution, be hydrolyzed, by acid adjustment crystallization, obtain moisture ainothiazoly loximate.Through solvent dehydration is refining, obtain anhydrous ainothiazoly loximate, the condensation reaction under triphenylphosphine and triethylamine catalysis with anhydrous ainothiazoly loximate and dibenzothiazyl disulfide, then obtain 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester through purifying.Reaction principle is as follows:
The synthetic of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester must react in anhydrous solvent, so moisture ainothiazoly loximate must be refined and obtain anhydrous ainothiazoly loximate through solvent dehydration.In order to remove the crystal water in moisture ainothiazoly loximate, at present industrially generally moisture ainothiazoly loximate is dissolved in methyl alcohol or ethanolic soln, after high temperature reflux certain hour, filter, vacuum drying obtains anhydrous ainothiazoly loximate.While dewatering with alcoholic solvent, the moisture in raw material enters in solvent and causes the moisture in solution constantly to increase, so weaken to the water separation capability of later stage alcoholic solvent, dewatering time is extended.In addition, the alcoholic solvent compound that while dewatering with alcoholic solvent, the last product forming is ainothiazoly loximate must just can obtain anhydrous ainothiazoly loximate after alcoholic solvent is sloughed in vacuum-drying, for synthesizing of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.The shortcomings such as this production technique reactions steps is many, reaction time is long, manipulation strength is large, yield is low and the three wastes are many.
Summary of the invention
The invention provides a kind of and water has the solvent of azeotropic to deviate from the crystal water of ainothiazoly loximate and then the method for producing 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.The method does not need the process of vacuum-drying dealcoholysis kind solvent, thereby has greatly improved production efficiency.By solvent and water azeotropic, the moisture in solution is constantly taken out of, the crystal water of ainothiazoly loximate can be removed to very low level; This solvent is the solvent of synthetic 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester simultaneously, remove like this ainothiazoly loximate and this solvate of after crystal water, forming and just can directly carry out the synthetic of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, save filtration and baking operation while originally deviating from ainothiazoly loximate crystal water with alcohols, thereby can in a reactor, carry out the dehydration of ainothiazoly loximate and synthesizing of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.
Feature of the present invention is:
1. the solvent of employing and water azeotropic, first dissolves moisture ainothiazoly loximate at a certain temperature, and the crystal water of ainothiazoly loximate is dissolved in solvent, then by solvent azeotropic dehydration, has accelerated the process of ainothiazoly loximate dehydration.
2. the ainothiazoly loximate solution of sloughing after crystal water can directly carry out the synthetic of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.
3. by improving ainothiazoly loximate dewatering process, make to realize the dehydration of ainothiazoly loximate and synthesizing of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester in same reactor.Save filtration and baking operation after former technique ainothiazoly loximate dehydration, saved investment, improved the utilization ratio of ainothiazoly loximate, can reduce the production cost of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.
Technical scheme
The invention provides a kind of method of utilizing the synthetic 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester of moisture ainothiazoly loximate, it is characterized in that comprising the following steps: moisture ainothiazoly loximate is dissolved in and can be formed in the solvent of azeotrope with water, then carry out azeotropic, thereby water is removed.In the method for the invention, from being dissolved in, moisture ainothiazoly loximate can form the solvent of azeotrope to finally obtaining not using alcoholic solvent in the whole process of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, as methyl alcohol or ethanol etc. with water.Thereby do not use alcoholic solvent to avoid hyperthermia drying to remove the step of alcoholic solvent, thereby greatly enhance productivity.One skilled in the art will appreciate that when having alcohols material to exist, can greatly affect the generation of 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.
Described solvent is selected from the solvent system of acetonitrile, methylene dichloride, benzene,toluene,xylene, ethylene dichloride, trichloromethane, ethyl acetate, ether, tetracol phenixin, pyridine or its compositions of mixtures, or be selected from described solvent system and acetone, N, dinethylformamide, N, the mixed system that N-diethylformamide or N,N-dimethylacetamide form.
Described solvent is preferably anhydrous solvent, can make like this dewatering efficiency higher.
Method of the present invention also existed at the temperature of 35～90 ℃ and stirs so that the crystal water in ainothiazoly loximate is transferred to the step in solvent before carrying out azeotropic.More specifically, be at the temperature of 35～90 ℃, stir in reflux, return time is no more than 2 hours, preferably 0.5-2 hour.
Weight of solvent of the present invention is 1～5 times of moisture ainothiazoly loximate weight.
In method of the present invention, in azeotropic water removing process, if quantity of solvent is not enough, supplementing solvent more.
In method of the present invention, by azeotropic water removing, make moisture content in final solution preferably lower than 0.1wt%.
In method of the present invention, after azeotropic water removing, cool to 0～10 ℃, add dibenzothiazyl disulfide, triphenylphosphine, triethylamine to stir lower reaction 3 hours, filter and obtain 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.
Concrete reaction process of the present invention is in a reactor, moisture ainothiazoly loximate is dissolved in the solvent of 1～5 times of moisture ainothiazoly loximate weight, and in temperature, be 35～90 ℃, stir solvent is transferred to the crystal water in ainothiazoly loximate in solvent.Solvent and water generates azeotropic, thus water is taken out of to reactor.By supplementing anhydrous solvent, the moisture content in final solution lower than 0.1% time, stops dehydration, cools to 0～10 ℃, adds dibenzothiazyl disulfide, triphenylphosphine, triethylamine to stir lower reaction 3 hours, filters and obtains 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.
The present invention used solvent for there is the solvent of azeotropic with water, this solvent comprises the mixed system of two or more solvents of acetonitrile, methylene dichloride, benzene,toluene,xylene, ethylene dichloride, trichloromethane, ethyl acetate, ether, tetracol phenixin, pyridine equal solvent or above-mentioned solvent, or above-mentioned solvent and acetone, N, dinethylformamide, N, the mixed system of N-diethylformamide, N,N-dimethylacetamide.
The present invention's quantity of solvent used is preferably 1～5 times of moisture ainothiazoly loximate weight.
Moisture ainothiazoly loximate of the present invention is in solvent, and temperature is 35～90 ℃, reflux 0.5 ~ 2 hour.
The present invention will make solvent carry out azeotropic dehydration preferably to carry out 0.5 ~ 2 hour, and extraction water-containing solvent supplements anhydrous solvent.
The present invention will make the moisture content in final solution low to being enough to not affect ainothiazoly loximate and dibenzothiazyl disulfide carries out condensation reaction under triphenylphosphine and triethylamine catalysis, and its moisture content is that those skilled in the art are confirmable.Preferably, moisture content during lower than 0.1wt%, stops dehydration, cools to 0～10 ℃, adds dibenzothiazyl disulfide, triphenylphosphine, triethylamine to stir lower reaction 3 hours, filters and obtains 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.
The present invention preferably in having carried out the solution that azeotropic water removing obtains, directly add dibenzothiazyl disulfide, triphenylphosphine and triethylamine stir under reaction add again after making 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester or adding the anhydrous solvent of appropriate amount dibenzothiazyl disulfide, triphenylphosphine and triethylamine stir under reaction make 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.This process does not comprise the step that solvent is dried.
Embodiment
By example, the present invention is described below, but does not limit the present invention.
Embodiment 1: the moisture ainothiazoly loximate of getting 50g, put into 500mL crystallizer, 200g solvent acetonitrile, is heated to boiling reflux 0.5hr, then extraction water-containing solvent, supplement anhydrous acetonitrile, moisture in solution is reduced to while being less than 0.1%, is cooled to 5 ℃, adds acetonitrile to the 150mL 150mL that adds methylene chloride again, add dibenzothiazyl disulfide, triphenylphosphine, triethylamine to stir 3 hours, filter and obtain 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.Product yield 94.3%.
Embodiment 2: the moisture ainothiazoly loximate of getting 50g, put into 500mL crystallizer, 300g solvent acetone, is heated to boiling reflux 1hr, then extraction water-containing solvent, supplement methylene dichloride, when the moisture in solution reaches requirement, be cooled to 10 ℃, add acetone and methylene dichloride to 400mL, add dibenzothiazyl disulfide, triphenylphosphine, triethylamine to stir 3 hours, filter and obtain 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester.Product yield 93.5%.
Claims (5)
1. a method of utilizing the synthetic 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester of moisture ainothiazoly loximate, comprise the following steps: moisture ainothiazoly loximate is dissolved in and can be formed in the solvent of azeotrope with water, then carry out azeotropic, thereby water is removed, it is characterized in that described solvent is selected from acetonitrile, the solvent system that methylene dichloride forms, or be selected from the mixed system that described solvent system and acetone form, by azeotropic water removing, make moisture content in final solution lower than 0.1wt%, after azeotropic water removing, cool to 0～10 ℃, add dibenzothiazyl disulfide, triphenylphosphine and triethylamine stir lower reaction 3 hours, filtration obtains 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester, the molecular formula of wherein said moisture ainothiazoly loximate is C
6h
7n
3o
3s1.5H
2o.
2. the method for claim 1, is characterized in that, also existed at the temperature of 35～90 ℃ and stirred so that the crystal water in ainothiazoly loximate is transferred to the step in solvent before carrying out azeotropic.
3. method as claimed in claim 2, is characterized in that, reflux when stirring at the temperature of 35～90 ℃, and return time is no more than 2 hours.
4. the method for claim 1, is characterized in that, weight of solvent is 1～5 times of moisture ainothiazoly loximate weight.
5. the method for claim 1, is characterized in that, in azeotropic water removing process, if quantity of solvent is not enough, and supplementing solvent more.
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| CN104387337A (en) * | 2014-12-15 | 2015-03-04 | 山东鑫泉医药有限公司 | Method for synthesizing 3-ethyl-2-sulfur ethyl benzothiazole perchlorate by AE (Active Ester) residues |
| CN111024847B (en) * | 2019-12-24 | 2022-03-01 | 河北合佳医药科技集团股份有限公司 | Method for determining purity of AE-active ester by pre-column derivatization method |
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Non-Patent Citations (2)
| Title |
|---|
| 氨噻肟酸与AE-活性酯合成的研究进展;肖海焕等;《河南化工》;20081231;第25卷(第7期);第4-7页 * |
| 肖海焕等.氨噻肟酸与AE-活性酯合成的研究进展.《河南化工》.2008,第25卷(第7期),第4-7页. |
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