CN111533710A - Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method - Google Patents
Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method Download PDFInfo
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- 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
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Abstract
The invention discloses a method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by a one-pot method; the technical key points are as follows: step 1): 1) using water as a solvent, and using thiourea and 4-chloroacetoacetic acid ethyl ester to perform ring closure at a proper temperature and in a proper molar ratio to generate 2-aminothiazole-4-acetic acid ethyl ester; after the reaction is finished, directly carrying out the next reaction on the reaction solution; 2) adding a certain amount of alkali into the reaction liquid at a proper temperature to carry out hydrolysis reaction; 3) after the reaction is finished, adding a certain amount of acid into the reaction liquid at a proper temperature to adjust the pH value, and separating out a product.
Description
Technical Field
The invention relates to the field of organic synthesis, and discloses a method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by a one-pot method.
Background
The current preparation methods for synthesizing the compound are three types:
reference 1: journal of Heterocyclic Chemistry,2017, vol.54, #5, p.2703-2707, discloses the following synthetic methods:
the method comprises the steps of carrying out reflux reaction on 4-chloroacetoacetic acid ethyl ester and pyrrolidine in cyclohexane, and catalyzing with p-toluenesulfonic acid in the process. Removing solvent from the obtained reaction solution by rotary evaporation, dissolving with methanol, and adding S8And cyanamide and the resulting and used ethyl 2-aminothiazole-4-acetate. The yield thereof was found to be 79%. The reaction process is complicated, the used solvents are various, and the raw material cyanamide is toxic and easy to polymerize. The organic solvent methanol is also used in the hydrolysis, and the yield is 89.7 percent by hydrolysis in alkali liquor. The yield of the two steps is 70.8%.
Reference 2: synthesis of xanthene et al, mirabegron intermediate 2-aminothiazole-4-acetic acid [ J ] synthetic chemistry,2017, discloses the following synthetic method:
thiourea and ethyl 4-chloroacetoacetate are blocked at high temperature to form ethyl 2-aminothiazole-4-acetate, which is then hydrolyzed to form 2-aminothiazole-4-acetic acid.
Disclosure of Invention
The invention aims to provide a method for preparing a cefotiam intermediate 2-aminothiazole-4-acetic acid by a one-pot method aiming at the defects of the prior art, and develops a one-pot method process which is simple and convenient to operate, low in generation cost and beneficial to industrial production.
1. The method for preparing the cefotiam intermediate 2-aminothiazole-4-acetic acid by a one-pot method comprises the following steps:
1) using water as a solvent, and using thiourea and 4-chloroacetoacetic acid ethyl ester to perform ring closure at a proper temperature and in a proper molar ratio to generate 2-aminothiazole-4-acetic acid ethyl ester;
after the reaction is finished, directly carrying out the next reaction on the reaction solution;
2) adding a certain amount of alkali into the reaction liquid at a proper temperature to carry out hydrolysis reaction;
3) after the reaction is finished, adding a certain amount of acid into the reaction solution at a proper temperature to adjust the pH value, and separating out a product;
the synthetic route is as follows:
further, suitable temperatures in step 1) refer to: 20-45 ℃ and a suitable molar ratio is 4-chloroacetoacetic acid ethyl ester: 1.25-1.0 parts of thiourea; thiourea and 4-chloroacetoacetic acid ethyl ester, and the volume ratio of the thiourea to the 4-chloroacetoacetic acid ethyl ester to the water is 2-3 v/w.
Further, in step 1), a suitable molar ratio means that ethyl 4-chloroacetoacetate: 1.1-1.0 parts of thiourea; suitable temperatures are: 20-30 deg.C
Further, suitable temperatures in step 2) refer to: 20-45 deg.C, and the alkali is NaOH, KOH or Na2CO3、K2CO3Any one of them, the equivalent of the base is 2.1-2.5.
Further, the equivalent of the base is 2.1 to 2.2.
Further, in step 3) the suitable temperature is between 0 and 20 ℃, the acid species being HCl, H2SO4、HNO3At a pH of 3.1-5.5.
Further, in step 3), a suitable temperature is 0 to 10 ℃ and a pH value is 4.4 to 5.1.
Further, the purity (by HPLC) of the 2-aminothiazole-4-acetic acid obtained after the step 3) was not less than 99.8 area%.
The invention has the beneficial effects that:
the first basic idea of the application is to meet the requirement of customers on low-cost production of 2-aminothiazole-4-acetic acid, and the 2-aminothiazole-4-acetic acid can be produced by adopting two modes of background technology; however, the cost of the two processes is more than 300 yuan/kg; it is the pressure based on cost that the team of inventors needs to make technological innovation.
The "one-pot method" is the main means for achieving the above object, however, what reagent is selected is the first thing to be faced when achieving the "one-pot method"?
In the face of this problem, the inventors' team saw reference 2 when the aqueous solvent was rejected; the reason is that the information obtained from reference 2 is: the reaction needs to be closed at the high temperature of 110-120 ℃ under the condition that thiourea and 4-chloroacetoacetic acid ethyl ester are subjected to reaction to generate 2-aminothiazole-4-acetic acid ethyl ester; while water with a boiling point of 100 c is obviously not suitable (the temperature of water can also reach 110 c and 120 c, which requires the addition of new high-pressure sealing equipment, requires new investment, and is even less suitable).
During the long time that research and development began, the research and development direction of the inventor group had been on searching for organic agents with boiling points over 120 ℃ and then conducting the tests. However, this search has not yielded a good result.
Secondly, the step 1 of the application is as follows: "use water as solvent, under the appropriate temperature, under the appropriate molar ratio, use thiourea and 4-chloroacetoacetic acid ethyl ester to carry on the ring closure, produce 2-aminothiazole-4-acetic ester", it is found through the experiment, it is at high temperature (for example: 80 ℃), will produce a large amount of impurity, namely, must overcome the technical prejudice that the reference 2 brings.
Third, the "one-pot" of the present application refers to: the reaction is directly carried out in the water phase, and the use of an organic solvent is avoided. After the ring closing reaction is finished, directly adding alkali into the reaction liquid for hydrolysis. After the hydrolysis reaction is finished, the product is separated out by adjusting the pH value of the reaction solution. After the product is filtered out, the filtrate can be used mechanically. The yield of the two steps is about 85 percent. The reaction intermediate is not required to be separated and purified, and is directly hydrolyzed in the reaction liquid in the first step, so that the one-pot reaction is realized, and the working procedures are simplified.
Fourthly, the one-pot method has the beneficial effects that: the method of reference 2, the cost is above 500 yuan/kg, the cost of comparative examples one, two is above 300 yuan/kg, the cost of example one is 120 yuan/kg; i.e., the process has enjoyed significant commercial success.
Fifth, the beneficial effects of the one-pot method are also embodied in that: if ethanol is used as a solvent (the proposal obtained by the applicant in the development process is comparative example one and comparative example two), activated carbon is also needed for decolorization; the method does not need activated carbon, and the production process of the method reduces one step.
Meanwhile, ethanol is used as a solvent, the yield is low, and the purity of the produced 2-aminothiazole-4-acetic acid does not reach the effect (not less than 99.8%) of the method.
Sixth, the production time can be reduced by 1/3 using the methods of examples one-third as compared to comparative example one; the time was reduced 2/3 compared to comparative example two using the methods of examples one-third.
That is, the beneficial effect of this application embodies reducing in manufacturing cost and reducing in production time by a wide margin simultaneously.
Description of the drawings:
FIG. 1 is a 1H NMR spectrum of 2-aminothiazole-4-acetic acid produced in example.
FIG. 2 is an HPLC chromatogram of 2-aminothiazole-4-acetic acid produced in example.
Detailed Description
The following examples will help those skilled in the art to understand the gist of the preparation technique of the present invention, but are not intended to limit the scope of the present invention.
Comparative example 1 (non one pot method)
25g of thiourea and 273mL of absolute ethanol are put into a 100mL four-neck flask, and the mixture is stirred for 0.5h and cannot be dissolved clearly. The temperature was controlled at 30-40 ℃ and 57.31g of ethyl 4-chloroacetoacetate was slowly added dropwise, after the addition was completed. The reaction solution becomes clear gradually, and a large amount of solid is separated out after about 1.5h of reaction. Samples were taken for approximately 3h of reaction and thiourea was < 0.5% detected in the liquid phase. 112.8ml of 20% NaOH solution was added dropwise directly to the above reaction system while controlling the temperature at 30-40 ℃. After the addition, the sample is kept for 0.5h, and the sample is sent to liquid phase analysis: 2-aminothiazol-4-yl) acetic acid ethyl ester < 0.5%. Stopping the reaction, and removing the ethanol in the system by spinning until the weight of the system is constant. 163.8ml of water was added to the system. Adding 2.73g of active carbon, controlling the temperature to be 30-40 ℃, stirring for 0.5h, and then carrying out suction filtration. The filtrate was cooled to 0-5 ℃ and 152.8ml of 2N HCl was added thereto until PH 3.8-4.1, and a solid precipitated. Controlling the temperature to be 0-5 ℃, stirring for 0.5h, and repeatedly measuring the pH value to be unchanged. And (4) carrying out suction filtration to obtain solid 2-aminothiazole-4-yl) acetic acid. The yield is 78.56%; purity: 99.44 percent.
Comparative example two (non one pot method)
25g of thiourea and 273mL of absolute ethanol are put into a 100mL four-neck flask, and the mixture is stirred for 0.5h and cannot be dissolved clearly. The temperature was controlled at 30-40 ℃ and 57.31g of ethyl 4-chloroacetoacetate was slowly added dropwise, after the addition was completed. The reaction solution becomes clear gradually, and a large amount of solid is separated out after about 1.5h of reaction. Samples were taken for approximately 3h of reaction and thiourea was < 0.5% detected in the liquid phase. Stopping heating, cooling to 0-5 ℃, keeping the temperature for 0.5h, and filtering to obtain 50.4g of 2-aminothiazole-4-yl) ethyl acetate hydrochloride. The yield was 68.9%, and the purity was 99.5%.
50g of the obtained solid was washed with 150g of water, and then, 94.73g of a 20% NaOH solution was added dropwise thereto while controlling the temperature at 30 to 40 ℃. After the addition, the sample is kept for 0.5h, and the sample is sent to liquid phase analysis: 2-aminothiazol-4-yl) acetic acid ethyl ester < 0.5%. Stopping the reaction, adding 2.5g of activated carbon into the system, controlling the temperature to be 30-40 ℃, stirring for 0.5h, and then carrying out suction filtration. The filtrate was cooled to 0-5 ℃ and 113.32ml of 2N HCl was added thereto until the PH was 3.8-4.4, and a solid precipitated. Controlling the temperature to be 0-5 ℃, stirring for 0.5h, and repeatedly measuring the pH value to be unchanged. Suction filtration gave 32.2g of solid 2-aminothiazol-4-yl) acetic acid. The yield is 89.5%, and the purity is 99.8%.
The first embodiment is as follows:
25.0g of thiourea and 110mL of water were put into a 500mL four-neck flask and stirred for 0.5h to ensure that the thiourea did not dissolve out. 54.61g of ethyl 4-chloroacetoacetate were slowly added dropwise at a controlled temperature of 20-25 ℃. After the addition, the reaction solution gradually clarified to a homogeneous phase. And (4) sampling for reaction for 2 hours, detecting the consumption of thiourea to be below 0.5% by using a liquid phase, and stopping the reaction. The temperature was controlled at 20-25 ℃ as well, and 93.24g of 30% NaOH solution was directly added dropwise to the reaction mixture. After the addition, the reaction solution was homogeneous. And (4) sampling a liquid phase for reaction for 0.5h, detecting that the ethyl 2-aminothiazole-4-acetate is consumed to be below 0.5 percent, and stopping the reaction. Adding 2.57g of activated carbon into the reaction solution, controlling the temperature to be 20-25 ℃, stirring for 0.5h, and then carrying out suction filtration to obtain filtrate. The temperature was controlled at 0-5 ℃ and 52.57ml of 6N HCl solution was added dropwise to the filtrate until the pH was 4.4-4.8, after which a solid precipitated. Keeping the temperature for 0.5h, and performing suction filtration to obtain a crude product (containing water) after repeatedly measuring the pH value and keeping the pH value unchanged. Adding 100ml water into the crude product, controlling the temperature at 0-5 ℃, pulping for 1 time, and filtering to obtain a solid. The solid was dried in vacuo to give 44.34g of pure product. The yield thereof was found to be 86.23% and the purity thereof was found to be 99.81%.
Example two
25.0g of thiourea and 164mL of water were put into a 500mL four-necked flask and stirred for 0.5h to ensure that the thiourea did not dissolve out. 54.61g of ethyl 4-chloroacetoacetate were slowly added dropwise at a controlled temperature of 25-30 ℃. After the addition, the reaction solution gradually clarified to a homogeneous phase. And (4) reacting for 4 hours, sampling, detecting the consumption of thiourea to be below 0.5%, and stopping the reaction. Likewise, the temperature was controlled at 25-30 ℃ and 93.24g of 30% NaOH solution was added dropwise directly to the reaction mixture. After the addition, the reaction solution was homogeneous. And (4) sampling a liquid phase for reaction for 0.5h, detecting that the ethyl 2-aminothiazole-4-acetate is consumed to be below 0.5 percent, and stopping the reaction. Adding 2.57g of activated carbon into the reaction solution, controlling the temperature to be 25-30 ℃, stirring for 0.5h, and then carrying out suction filtration to obtain filtrate. The temperature was controlled at 5-10 ℃ and 42.0ml of 6N HCl solution was added dropwise to the filtrate until the pH was 4.8-5.1, after which a solid precipitated. Keeping the temperature for 0.5h, and performing suction filtration to obtain a crude product (containing water) after repeatedly measuring the pH value and keeping the pH value unchanged. Adding 100ml water into the crude product, controlling the temperature to be 5-10 ℃, pulping for 1 time, and filtering to obtain a solid. The solid was dried in vacuo to yield 43.2g of pure product. The yield was 84.01% and the purity was 99.83%.
EXAMPLE III
25.0g of thiourea and 110mL of water were put into a 500mL four-neck flask and stirred for 0.5h to ensure that the thiourea did not dissolve out. 54.61g of ethyl 4-chloroacetoacetate were slowly added dropwise at a controlled temperature of 20-25 ℃. After the addition, the reaction solution gradually clarified to a homogeneous phase. And (4) sampling for reaction for 2 hours, detecting the consumption of thiourea to be below 0.5% by using a liquid phase, and stopping the reaction. The temperature was controlled at 20-25 ℃ as well, and 93.24g of 30% NaOH solution was directly added dropwise to the reaction mixture. After the addition, the reaction solution was homogeneous. And (4) sampling a liquid phase for reaction for 0.5h, detecting that the ethyl 2-aminothiazole-4-acetate is consumed to be below 0.5 percent, and stopping the reaction. Adding 2.57g of activated carbon into the reaction solution, controlling the temperature to be 20-25 ℃, stirring for 0.5h, and then carrying out suction filtration to obtain filtrate. The temperature was controlled at 0-5 ℃ and 61.0ml of 6N HCl solution was added dropwise to the filtrate until the pH was 3.1-3.8, after which a solid precipitated. Keeping the temperature for 0.5h, and performing suction filtration to obtain a crude product (containing water) after repeatedly measuring the pH value and keeping the pH value unchanged. Adding 100ml water into the crude product, controlling the temperature at 0-5 ℃, pulping for 1 time, and filtering to obtain a solid. The solid was dried in vacuo to give 41.14g of pure product. The yield is 80 percent, and the purity is 99.80 percent.
In particular, the production time can be reduced 1/3 compared to comparative example one, using the methods of examples one-three; using the methods of examples one-third, the time was reduced 2/3 compared to comparative example two.
The above-mentioned embodiments are only for convenience of description, and are not intended to limit the present invention in any way, and those skilled in the art will understand that the technical features of the present invention can be modified or changed by other equivalent embodiments without departing from the scope of the present invention.
Claims (8)
1. The method for preparing the cefotiam intermediate 2-aminothiazole-4-acetic acid by the one-pot method is characterized by comprising the following steps:
1) using water as a solvent, and using thiourea and 4-chloroacetoacetic acid ethyl ester to perform ring closure at a proper temperature and in a proper molar ratio to generate 2-aminothiazole-4-acetic acid ethyl ester;
after the reaction is finished, directly carrying out the next reaction on the reaction solution;
2) adding a certain amount of alkali into the reaction liquid at a proper temperature to carry out hydrolysis reaction;
3) after the reaction is finished, adding a certain amount of acid into the reaction solution at a proper temperature to adjust the pH value, and separating out a product;
the synthetic route is as follows:
2. the one-pot process for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid according to claim 1, wherein the suitable temperature in step 1) refers to: 20-45 ℃ and a suitable molar ratio is 4-chloroacetoacetic acid ethyl ester: 1.25-1.0 parts of thiourea; thiourea and 4-chloroacetoacetic acid ethyl ester, and the volume ratio of the thiourea to the 4-chloroacetoacetic acid ethyl ester to the water is 2-3 v/w.
3. The one-pot process for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid according to claim 2, wherein in step 1), the suitable molar ratio is that the ratio of ethyl 4-chloroacetoacetate: 1.1-1.0 parts of thiourea; suitable temperatures are: 20-30 ℃.
4. The one-pot method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid according to claim 1, wherein the suitable temperature in step 2) refers to: 20-45 deg.C, and the alkali is NaOH, KOH or Na2CO3、K2CO3Any one of them, the equivalent of the base is 2.1-2.5.
5. The one-pot process for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid according to claim 4, wherein the equivalent of the base is 2.1-2.2.
6. The one-pot process for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid according to claim 1, wherein the suitable temperature in step 3) is 0-20 ℃, and the acid is HCl or H2SO4、HNO3At a pH of 3.1-5.5.
7. The one-pot process for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid according to claim 6, wherein the suitable temperature in step 3) is 0-10 ℃ and the pH is 4.4-5.1.
8. The one-pot process for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid according to any of claims 1 to 7, wherein the purity (measured by HPLC) of the 2-aminothiazole-4-acetic acid obtained after step 3) is not less than 99.8 area%.
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| CN114853691A (en) * | 2021-12-27 | 2022-08-05 | 浙江普洛得邦制药有限公司 | Method for continuously preparing (Z) -2- (2-amino-4 thiazole) acetic acid by using microchannel reactor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948446A (en) * | 2010-08-30 | 2011-01-19 | 江苏华旭药业有限公司 | Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride |
| CN109134508A (en) * | 2018-08-10 | 2019-01-04 | 齐鲁安替制药有限公司 | A kind of preparation method of the high yield high quality cefotiam hydrochloride suitable for industrialized production |
| CN109517002A (en) * | 2018-11-21 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of synthetic method of cefotiam hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948446A (en) * | 2010-08-30 | 2011-01-19 | 江苏华旭药业有限公司 | Method for preparing 2-aminothiazol-4-ylacetic acid hydrochloride |
| CN109134508A (en) * | 2018-08-10 | 2019-01-04 | 齐鲁安替制药有限公司 | A kind of preparation method of the high yield high quality cefotiam hydrochloride suitable for industrialized production |
| CN109517002A (en) * | 2018-11-21 | 2019-03-26 | 山东罗欣药业集团股份有限公司 | A kind of synthetic method of cefotiam hydrochloride |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114853691A (en) * | 2021-12-27 | 2022-08-05 | 浙江普洛得邦制药有限公司 | Method for continuously preparing (Z) -2- (2-amino-4 thiazole) acetic acid by using microchannel reactor |
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