CN112661716A - Preparation method of trityl aminothiazoly loximate - Google Patents
Preparation method of trityl aminothiazoly loximate Download PDFInfo
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- CN112661716A CN112661716A CN202011621175.6A CN202011621175A CN112661716A CN 112661716 A CN112661716 A CN 112661716A CN 202011621175 A CN202011621175 A CN 202011621175A CN 112661716 A CN112661716 A CN 112661716A
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Abstract
The invention belongs to the field of organic compound preparation, and particularly relates to a preparation method of trityl aminothiazoly loximate, which comprises the following steps: 1. dissolving aminothiazoly loximate and diisopropylethylamine in dichloromethane, and dropwise adding triphenylchloromethane for reaction to obtain a reaction solution; 2. adding an acidic solution into the reaction solution obtained in the step 1, adjusting the solution to be acidic, separating the solution and retaining an organic phase; 3. dropwise adding an alkaline solution into the organic phase in the step 2, filtering, and respectively leaching with dichloromethane and water to obtain precipitates; and 4, adding water into the precipitate obtained in the step 3 for pulping, dripping an acidic solution into the precipitate in the pulping process, adjusting the pH value to be acidic, filtering, and drying to obtain trityl aminothiazoly loximate. By using the method, DMF is not used as a solvent, the generated waste is less, the subsequent operation steps are simple, and the yield of the obtained trityl aminothiazoly loximate is more than 94 percent and the purity is more than 99 percent.
Description
Technical Field
The invention belongs to the field of organic compound preparation, and particularly relates to a preparation method of trityl aminothiazoly loximate.
Background
Trityl aminothiazoly loximate, its chemical name is: (Z) -2- (2-tritylamino-thiazol-4-yl) -2-methoxyimino-acetic acid, molecular formula C25H21N3O3S, molecular weight: 443.13, the structural formula is:
trityl aminothiazoly loximate is an important intermediate for synthesizing cephalosporin antibiotic preparations such as cefmenoxime, cefixime, cefotaxime sodium, ceftriazine and the like, because trityl in the intermediate can protect amino when condensing with amine with carboxyl, and is removed after reaction, and the aminothiazoly loximate is introduced as a side chain. Trityl aminothiazoly loximate is used as a raw material for synthesizing third-generation cephalosporin, namely cephalosporin, and the cephalosporin is effective to infection caused by drug-resistant bacteria and pathogenic bacteria which are difficult to control, and has low nephrotoxicity and lasting curative effect, so that the intermediate is widely applied to the field of drug synthesis.
However, the current techniques for the synthesis of trityl aminothiazoly loximate are relatively rare. The invention of Chinese patent CN101550150A relates to the synthesis of trityl aminothiazoly loximate, which discloses that the aminothiazoly loximate and triphenylchloromethane are used as raw materials, and react for four hours in dimethylformamide at room temperature, isopropyl ether is slowly added, the mixture is stirred, solid is separated out, and the trityl aminothiazoly loximate hydrochloride is obtained by filtering and drying. However, this patent uses dimethylformamide as a solvent, is not easy to recover and handle, is relatively complicated in steps, and gives trityl aminothiazoloxime acid hydrochloride, and does not mention a purification process, and is not suitable for industrial production.
Therefore, there is a need in the art for a process that is simple in steps, generates less waste, and further improves the yield and purity of the product.
Disclosure of Invention
The present inventors have obtained the present invention through a great deal of research on the basis of avoiding the use of DMF solvent while adjusting the reaction process.
The invention provides a method for preparing trityl aminothiazoly loximate, which comprises the following steps:
step 1, dissolving aminothiazoly loximate and diisopropylethylamine in dichloromethane, and dropwise adding triphenylchloromethane for reaction to obtain a reaction solution;
step 3, dropwise adding an alkaline solution into the organic phase in the step 2, filtering, and respectively leaching with dichloromethane and water to obtain precipitates; and
and 4, adding water into the precipitate obtained in the step 3 for pulping, dripping an acidic solution into the precipitate in the pulping process, adjusting the pH value to be acidic, filtering, and drying to obtain trityl aminothiazoly loximate.
The relevant reaction formula of the invention is as follows:
in some specific embodiments, the duration of the reaction of step 1 is 2 to 5 hours, preferably the duration of the reaction of step 1 is 3 to 4 hours, more preferably the duration of the reaction of step 1 is 3 hours.
In some specific embodiments, the molar ratio of the aminothiazoly loximate to the diisopropylethylamine in step 1 is 1:1.2 to 1: 3.
In some specific embodiments, the molar ratio of the aminothiazoly loximate to the triphenylchloromethane in step 1 is 1:1.1 to 1: 2.
In some specific embodiments, the temperature of the dropwise addition of the triphenylchloromethane in the step 1 is-5 to 5 ℃. More preferably-5 deg.C, with fewer by-products; the time for dripping the triphenylchloromethane in the step 1 is 10-50 min, and more preferably 30 min.
In a further embodiment, the triphenylchloromethane is dripped in the step 1, and then the mixture is stirred for 10-50 minutes, and more preferably for 30 minutes.
In some specific embodiments, after the triphenylchloromethane is dripped in the step 1, the temperature is raised to 20-40 ℃ for reaction for 1-5 hours, more preferably 20-30 ℃ for reaction for 2-4 hours, and even more preferably 25 ℃ for reaction for 3 hours, and the reaction can be finished. Preferably, the temperature increase may be performed after the above-mentioned stirring with heat preservation.
In the present invention, the term "reaction solution" refers to a reaction system containing a target product obtained by a corresponding chemical reaction. The target product may be an end product or an intermediate product related to an end product in the present invention.
In some specific embodiments, the acidic solution in step 2 includes, but is not limited to, hydrochloric acid, acetic acid, sulfuric acid, benzoic acid, and the like, and preferably, the acidic solution in step 2 is HCl.
In some specific embodiments, the concentration of the acidic solution in step 2 is 0.5-2M, and preferably, the concentration of the acidic solution in step 2 is 1M. For example, when the acidic solution is HCl, the concentration of HCl is 0.5-2M, and preferably the concentration of HCl is 1M.
In some specific embodiments, step 2 is carried out at a temperature of 0 to 25 ℃, more preferably 5 ℃.
In some specific embodiments, the alkaline solution in step 3 may include, but is not limited to, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, or potassium bicarbonate solution.
In some specific embodiments, the mass ratio of the precipitate to the water in step 4 is 1:5 to 1:15, and more preferably, the mass ratio of the precipitate to the water is 1: 10.
In some specific embodiments, the temperature of drying in step 4 is not more than 40 ℃, more preferably, the temperature of drying is 20 to 40 ℃, and more preferably, the temperature of drying is 40 ℃.
In some specific embodiments, the acidic solution in step 4 includes, but is not limited to, hydrochloric acid, acetic acid, sulfuric acid, benzoic acid, and the like, and preferably, the acidic solution in step 2 is HCl.
In some specific embodiments, the concentration of the acidic solution in step 4 is 0.5-2M, and preferably, the concentration of the acidic solution in step 4 is 1M. For example, when the acidic solution is HCl, the concentration of HCl is 0.5-2M, and preferably the concentration of HCl is 1M.
The method for preparing trityl aminothiazoly loximate avoids using DMF as a solvent, generates less waste, has simple subsequent operation steps, and obtains the trityl aminothiazoly loximate with the yield of more than 94 percent and the purity of more than 99.2 percent.
Drawings
Further objects, features and advantages of the present invention will become apparent from the following description of embodiments of the invention, with reference to the accompanying drawings, in which:
FIG. 1 is a nuclear magnetic hydrogen spectrum schematically showing the product of example 1.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that these specific embodiments and examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.
Example 1
Adding 660g of dichloromethane, 36g of aminothiazoly loximate and 42g of diisopropylethylamine into a 1000ml reaction bottle, cooling to-5 ℃, slowly dropwise adding 54g of trityl aminothiazoly loximate, keeping the temperature at-5 ℃, dropwise adding for 30min, stirring, keeping the temperature for 30min, heating and keeping the temperature at 25 ℃ for reacting for 3 hours.
Cooling the reaction liquid to 5 ℃, adding hydrochloric acid to adjust the pH value to acidity, separating the mixed liquid, and washing with water for three times.
And transferring the organic phase into a reaction bottle, dropwise adding a sodium hydroxide solution to adjust the solution to be alkaline, separating out a large amount of solids, filtering, and leaching with dichloromethane and water.
The filter cake was transferred to a reaction flask and slurried with water, then hydrochloric acid was added thereto to adjust the pH to acidity, filtered, and the filter cake was dried at 40 ℃ to obtain 69.0g (yield 95%, purity 99.4%) of trityl aminothiazoly loximate.
The obtained product was subjected to nuclear magnetic hydrogen spectroscopy, and the obtained spectrum is shown in fig. 1.
Example 2
Adding 660g of dichloromethane, 36g of aminothiazoly loximate and 60g of diisopropylethylamine into a 1000ml reaction bottle, cooling to-5 ℃, slowly dropwise adding 90g of trityl aminothiazoly loximate, keeping the temperature at-5 ℃, dropwise adding for 30min, stirring, keeping the temperature for 30min, heating and keeping the temperature at 25 ℃ for reacting for 3 hours.
Cooling the reaction liquid to 10 ℃, adding hydrochloric acid to adjust the pH value to acidity, separating the mixed liquid, and washing with water for three times.
And transferring the organic phase into a reaction bottle, dropwise adding a sodium carbonate solution to adjust the solution to be alkaline, separating out a large amount of solids, filtering, and leaching with dichloromethane and water.
The filter cake was transferred to a reaction flask and slurried with water, then hydrochloric acid was added thereto to adjust the pH to acidity, filtered, and the filter cake was dried at 40 ℃ to obtain 70.1g (yield 97%, purity 99.2%) of trityl aminothiazoly loximate.
Example 3
Adding 660g of dichloromethane, 36g of aminothiazoly loximate and 30g of diisopropylethylamine into a 1000ml reaction bottle, cooling to-5 ℃, slowly dropwise adding 45g of trityl aminothiazoly loximate, keeping the temperature at-5 ℃, dropwise adding for 30min, stirring, keeping the temperature for 30min, heating and keeping the temperature at 40 ℃ for reacting for 3 hours.
Cooling the reaction liquid to 5 ℃, adding hydrochloric acid to adjust the pH value to acidity, separating the mixed liquid, and washing with water for three times.
And transferring the organic phase into a reaction bottle, dropwise adding a sodium carbonate solution to adjust the solution to be alkaline, separating out a large amount of solids, filtering, and leaching with dichloromethane and water.
The filter cake was transferred to a reaction flask and slurried with water, then hydrochloric acid was added thereto to adjust the pH to acidity, filtered, and the filter cake was dried at 40 ℃ to obtain 67.8g (yield 94%, purity 99.7%) of trityl aminothiazoloxime acid.
Example 4
Adding 500mL of ethyl acetate, 33g of aminothiazoly loximate and 28g of diisopropylethylamine into a 1000mL reaction bottle, cooling to-5 ℃, slowly dropwise adding 41g of trityl aminothiazoly loximate, keeping the temperature at-5 ℃, dropwise adding for 30min, stirring, keeping the temperature for 30min, heating and keeping the temperature at 40 ℃ for reacting for 3 hours.
Cooling the reaction liquid to 5 ℃, adding hydrochloric acid to adjust the pH value to acidity, separating the mixed liquid, and washing with water for three times.
Transferring the organic phase into a reaction bottle, dropwise adding a sodium carbonate solution to adjust the solution to be alkaline, separating out a large amount of solids, filtering, and leaching with ethyl acetate and water.
The filter cake was transferred to a reaction flask and slurried with water, then hydrochloric acid was added thereto to adjust the pH to acidity, filtered, and the filter cake was dried at 40 ℃ to obtain 64g of trityl aminothiazoly loximate (yield 89%, purity 98.7%).
As can be seen from this example, trityl aminothiazoly loximate prepared from the remaining starting materials was less productive and pure than the starting materials selected for use in the present invention.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
Claims (10)
1. A method of making trityl aminothiazoly loximate, the method comprising:
step 1, dissolving aminothiazoly loximate and diisopropylethylamine in dichloromethane, and dropwise adding triphenylchloromethane for reaction to obtain a reaction solution;
step 2, adding an acidic solution into the reaction solution obtained in the step 1, adjusting the solution to be acidic, separating the solution and retaining an organic phase;
step 3, dropwise adding an alkaline solution into the organic phase in the step 2, filtering, and respectively leaching with dichloromethane and water to obtain precipitates; and
and 4, adding water into the precipitate obtained in the step 3 for pulping, dripping an acidic solution into the precipitate in the pulping process, adjusting the pH value to be acidic, filtering, and drying to obtain trityl aminothiazoly loximate.
2. The method according to claim 1, wherein the duration of the reaction of step 1 is 2 to 5 hours.
3. The method according to claim 1, wherein the molar ratio of the aminothiazoly loximate to the diisopropylethylamine in the step 1 is 1:1.2 to 1:3, and the molar ratio of the aminothiazoly loximate to the triphenylchloromethane in the step 1 is 1:1.1 to 1: 2.
4. The method according to claim 1, wherein the temperature for dropwise adding the triphenylchloromethane in the step 1 is-5 to 5 ℃.
5. The method according to claim 1, wherein the temperature is raised to 20-40 ℃ for 1-5 hours after the dropwise addition of triphenylchloromethane in the step 1.
6. The method according to claim 1, wherein the concentration of the acidic solution in the step 2 is 0.5-2M.
7. The method according to claim 1, wherein the step 2 is carried out at a temperature of 0 to 25 ℃.
8. The method of claim 1, wherein the alkaline solution in step 3 is sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, or potassium bicarbonate solution.
9. The method according to claim 1, wherein the mass ratio of the precipitate to the water in the step 4 is 1: 5-1: 15.
10. The method according to claim 1, wherein the temperature of the drying in the step 4 is 20-40 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101550150A (en) * | 2009-05-07 | 2009-10-07 | 张锡芬 | Cefmenoxime compound and synthetic method thereof |
| CN102180843A (en) * | 2011-03-02 | 2011-09-14 | 河北科技大学 | Preparation method of 2-(2-amino-4-thiazolyl)-2(Z)-triphenylmethoxy imidoacetic acid |
| CN111448182A (en) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | Aztreonam derivative and application thereof |
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- 2020-12-31 CN CN202011621175.6A patent/CN112661716A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101550150A (en) * | 2009-05-07 | 2009-10-07 | 张锡芬 | Cefmenoxime compound and synthetic method thereof |
| CN102180843A (en) * | 2011-03-02 | 2011-09-14 | 河北科技大学 | Preparation method of 2-(2-amino-4-thiazolyl)-2(Z)-triphenylmethoxy imidoacetic acid |
| CN111448182A (en) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | Aztreonam derivative and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| JUNXIN AW ET AL: "Enzyme-Responsive Reporter Molecules for Selective Localization and Fluorescent Imaging of Pathogenic Biofilms", 《CHEMICAL COMMUNICATION》 * |
| MARIA ISABEL MONTA~NEZ ET AL: "Synthetic Approach to Gain Insight into Antigenic Determinants of Cephalosporins: In Vitro Studies of Chemical Structure IgE Molecular Recognition Relationships", 《CHEMICAL RESEARCH TOXICOLOGY》 * |
| 倪沛洲: "《有机化学》", 30 November 1999, 人民卫生出版社 * |
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Application publication date: 20210416 |