Preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid
By hydrolyzing the aminotaxime acid ester at low temperature by organic amine reagents and concentrating and acidification of nanofiltration, the problem of poor selectivity of the hydrolysis reaction of amyotaxime acid is solved, and the preparation of amyotaxime acid with high purity and high yield is achieved, reducing production costs and environmental pressure.
Patent Information
- Application Number
- CN202510426334.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-07
- Publication Date
- 2025-07-08
AI Technical Summary
The prior art has poor reaction selectivity in the hydrolysis process of amyotaxime acid, resulting in high impurity content of amyotaxime acid dimer and high cost of removing activated carbon, which affects product yield and production costs.
Organic amine reagent is used to hydrolyze with (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetate at low temperature, and concentrate and acidify and crystallization in combination with nanofiltration to inhibit side reactions, improve selectivity and avoid the use of activated carbon.
The hydrolysis reaction time is significantly shortened, the impurities of amyozoxime acid dimer are controlled within 0.5%, and the product purity is as high as 99.5%, reducing production costs and reducing environmental protection pressure.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical intermediate preparation, and particularly relates to a preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid. Background Art
[0002] (Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetic acid, also known as aztreonam acid, has a molecular formula of C6H7N3O3S, and its structural formula is shown in Formula 1. It is a raw material for synthesizing the third-generation cephalosporin, namely cefazolin, and is mainly used for synthesizing cephalosporin antibiotic preparations (the side chains of cefotaxime sodium, ceftriaxone, cefotaxidine, etc.). This class of antibiotics called aztreonam cephalosporins has strong antibacterial activity, is effective against infections caused by some drug-resistant bacteria and difficult-to-control pathogenic bacteria, has low toxicity, broad-spectrum and long-acting properties, and its efficacy is dozens of times higher than that of penicillin.
[0003]
[0004] Formula 1 Currently, the commonly used method for producing aztreonam acid is as follows: Using ethyl acetoacetate or methyl acetoacetate as the starting material, through oximation, methylation, bromination or chlorination, distillation, and cyclization reactions to obtain ethyl (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetate (abbreviated as ethyl aztreonam acid) or methyl (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetate (abbreviated as methyl aztreonam acid), and then through hydrolysis, acid adjustment for crystallization, and purification to obtain aztreonam acid. For the hydrolysis process, the most commonly used method is: putting ethyl aztreonam acid or methyl aztreonam acid into 3 times the mass of water, and dropping 0.8 times the mass of 30% liquid caustic soda. After dissolution and clarification, activated carbon is added for decolorization. First, the pH is adjusted to 7 with hydrochloric acid. After decolorization, the pH is adjusted to 2.5 - 3.0 to obtain the crude product of aztreonam acid.
[0005] In the prior art hydrolysis process, it is inevitable to produce aztreonam acid dimer, with a molecular formula of C 12 H 12N6O5S2, see Formula 2 for the structural formula. Determined by high performance liquid chromatography (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2020), the relative retention time of the aztreonam acid dimer in aztreonam acid is 1.60 (RRT = 1.60). Calculated by the area normalization method, the content of this impurity in the existing process of producing aztreonam acid is above 2.0%. The aztreonam acid dimer will enter the production process of downstream drugs along with aztreonam acid, thus affecting the efficacy of the drugs. Therefore, activated carbon is needed for removal. The above method has disadvantages such as low reaction yield, high cost, large reaction volume, difficult determination of the amount of intermediate products, large consumption of organic solvents, and long reaction cycle. The use of activated carbon also increases the environmental protection pressure. How to improve the selectivity of the hydrolysis reaction, while increasing the product yield and reducing the production cost, is a technical problem urgently to be solved in the current field.
[0006]
[0007] Formula 2 Summary of the Invention The present invention aims to overcome the deficiencies of the prior art. Aiming at the problems of poor reaction selectivity in the hydrolysis process, high cost of impurity removal by activated carbon and loss of product yield, the present invention proposes a preparation method of aztreonam acid. By adopting a special hydrolysis method and combining with an organic amine reagent, the reaction time can be shortened, side reactions can be inhibited, the production cost can be reduced, and at the same time, the double improvement of the purity and yield of aztreonam acid is achieved. The preparation method disclosed in the present invention is simple to operate and has significant economic and environmental benefits.
[0008] To solve the above technical problems, the technical solution provided by the present invention is: A preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, comprising the following steps: S1, adding (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetate, organic amine and strong base solution into water in sequence, and carrying out a hydrolysis reaction at 10°C to 20°C to obtain a crude aztreonam acid solution; S2, subjecting the crude aztreonam acid solution to acidification crystallization and purification in sequence to obtain (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid.
[0009] Compared with the prior art, in the preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid provided by the present invention, the organic amine polarizes the ester carbonyl of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetate (aztreonam acid ester) through hydrogen bond interaction, promoting OH -The nucleophilic attack simultaneously inhibits the ammonolysis reaction (as ammonolysis requires higher activation energy), improves the selectivity for the hydrolysis reaction, and significantly shortens the hydrolysis reaction time (the hydrolysis time can be shortened to within 2 h); the hydrolysis reaction of the present invention is carried out at a relatively low temperature (10°C to 20°C), which can ensure the normal progress of the hydrolysis reaction. At the same time, the organic amine can form a protection with the carboxyl group of the hydrolysis product and can effectively inhibit the intermolecular polymerization of the aminothioxoester, controlling the level of the aminothioxoic acid dimer impurity within 0.5%, and the product purity is as high as over 99.5%. The present invention avoids the use of activated carbon and catalysts, reduces the production cost, saves the cost of subsequent waste solid treatment, and is environmentally friendly.
[0010] Preferably, in S1, the organic amine includes at least one of diethylamine, triethylamine or diisopropylamine.
[0011] Preferably, in S1, the (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate includes (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) methyl acetate or (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) ethyl acetate.
[0012] Preferably, in S1, the strong base solution includes a sodium hydroxide solution with a mass concentration of 25% to 35%.
[0013] Preferably, in S1, the molar ratio of the (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate, the organic amine and the strong base is 1:(0.05 to 0.1):(1.1 to 1.3).
[0014] It should be noted that the dosage of the strong base solution in the present invention is calculated based on the molar amount of the strong base (sodium hydroxide).
[0015] Preferably, in S1, the mass-volume ratio of the (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate and water is 1 g:(10 to 20) mL.
[0016] In the present invention, the concentration of the aminothioxoester is relatively low, which is more unfavorable for the occurrence of the ammonolysis reaction, thereby further reducing the content of the aminothioxoic acid dimer impurity. Through a large number of experiments, the present invention finds that if the concentration of the aminothioxoester is relatively high, for example, the mass-volume ratio of the aminothioxoester and water is 1 g:3 mL, the content of the aminothioxoic acid dimer during the hydrolysis reaction is more than 2%.
[0017] Preferably, in S1, the hydrolysis reaction time is 1 h to 2 h.
[0018] Preferably, after S1, it further includes: After adjusting the pH of the obtained reaction solution to neutral, nanofiltration concentration is carried out to obtain the crude product solution of amoxicillin acid.
[0019] In the present invention, nanofiltration concentration is carried out on the reaction solution, which can remove the excess solvent (water) in the reaction solution; the solvent has a certain solubility for the crude product of amoxicillin acid. By nanofiltration concentration, the material concentration of the reaction solution can be increased, which is beneficial to the subsequent acidification crystallization, reduces the crystallization system to reduce the mother liquor residue, and thus improves the yield of amoxicillin acid.
[0020] Further preferably, in S1, the neutrality is pH = 6.5 - 7.5.
[0021] Exemplarily, in S1, a hydrochloric acid solution is used to adjust the pH of the obtained reaction solution to 6.5 - 7.5.
[0022] Further preferably, in S1, during the whole nanofiltration concentration process, the temperature is increased from 40°C to 45°C to 55°C to 60°C in a gradient manner.
[0023] Further preferably, in S1, the pressure of the nanofiltration concentration is 0.1 MPa - 1 MPa, and a nanofiltration membrane with a molecular weight cut-off value of 200 D - 250 D is used.
[0024] Further preferably, in S1, the volume ratio of the crude product solution of amoxicillin acid to the reaction solution is (1.5 - 2.5):10.
[0025] In the present invention, by defining the conditions of nanofiltration concentration (including the pH value, temperature and pressure of the reaction solution), the concentration of the crude product solution of amoxicillin acid is greatly increased, which is more beneficial to obtaining the yield of subsequent acidification crystallization, and the product yield is increased to more than 98%. Through a large number of experiments, it is found that if a constant temperature in the range of 40°C to 60°C is used for nanofiltration concentration, the pH of the reaction solution during nanofiltration concentration is acidic or alkaline, or the pressure value of nanofiltration concentration is too large or too small, the volume of the crude product solution of amoxicillin acid cannot reach less than 0.3 times that of the reaction solution (that is, the concentration of the crude product solution of amoxicillin acid is small), which will have an adverse effect on the stability of the crude product solution of amoxicillin acid and the subsequent acidification crystallization, resulting in a reduction in the product yield.
[0026] Exemplarily, in S2, a hydrochloric acid solution is added to the crude product solution of amoxicillin acid for acidification crystallization.
[0027] Preferably, in S2, the pH of the acidified crude product solution of amoxicillin acid is 2 - 3.
[0028] The present invention does not make special limitations on other conditions of acidification crystallization, and conventional operations in the art can be adopted.
[0029] Further preferably, in S2, after the acidification crystallization, it further includes: filtration to obtain the crude product of amoxicillin acid.
[0030] Preferably, in S2, the refining includes the following steps: Add the crude product of aminothioxoic acid obtained after acidification and crystallization into a dehydration reagent for reflux reaction, and filter to obtain (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid.
[0031] More preferably, in S2, the dehydration reagent includes methanol.
[0032] More preferably, in S1-S2, the mass-volume ratio of the (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetate to the dehydration reagent is 10 g:(28-32) mL.
[0033] More preferably, in S2, the time of the reflux reaction is 2.5 h-3.5 h.
[0034] The raw materials and equipment of the present invention are easily available. First, the aminothioxoic acid ester is protected with an organic amine and then a low-temperature hydrolysis reaction is carried out, which can effectively inhibit the occurrence of ammonolysis reaction. The reaction conditions are mild, the process is simple and controllable, and the operability is strong, and it has good industrial application prospects and other characteristics. The results of the specific implementation methods show that the yield of the aminothioxoic acid prepared by the preparation method of aminothioxoic acid provided by the present invention can reach more than 98%, the purity can reach more than 99.5%, and the use of activated carbon and catalyst is avoided, and it has high market application value. Specific implementation methods
[0035] In order to make the purpose, technical solution and advantages of the present invention clearer, the following examples are used to further illustrate the present invention in detail. It should be understood that the specific examples described herein are only used to explain the present invention and are not used to limit the present invention.
[0036] In the present invention, all materials are commercially available products without special instructions.
[0037] Example 1 This example provides a preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, including the following steps: S1, add 2.3 L of water, 229.26 g (1.0 mol) of ethyl aminothioxoate and 0.1 mol of diethylamine into the reaction kettle in sequence. After mixing evenly, add 30% sodium hydroxide solution dropwise at 10°C. The addition amount of sodium hydroxide is 1.1 mol. After dropping, keep warm for hydrolysis reaction. After 1.5 h, it becomes clear, and the hydrolysis reaction ends; The pH of the obtained reaction solution was adjusted to 6.5 with hydrochloric acid solution, and nanofiltration concentration was carried out at 0.5 MPa. The molecular weight cut-off value of the nanofiltration membrane was 250 D. During the whole nanofiltration concentration process, the temperature was increased from 40 °C to 55 °C in a gradient manner to obtain 460 mL of crude amoxicillin acid solution.
[0038] S2. Hydrochloric acid solution was added to the above-mentioned crude amoxicillin acid solution to adjust the pH of the system to 2.5. After acidification and crystallization, filtration was carried out to obtain crude amoxicillin acid.
[0039] S3. The above-mentioned crude amoxicillin acid was added to 690 mL of methanol for reflux reaction. After 3 h, filtration was carried out to obtain 197.42 g of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid. Through calculation and testing, the yield was 98.12% and the purity was 99.84%.
[0040] Example 2 This example provides a preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, including the following steps: S1. 3.2 L of water, 215.23 g (1.0 mol) of amoxicillin acid methyl ester and 0.08 mol of triethylamine were successively added into the reaction kettle. After mixing evenly, 35% sodium hydroxide solution was added dropwise at 15 °C. The addition amount of sodium hydroxide was 1.2 mol. After the addition was completed, the mixture was kept warm for hydrolysis reaction. After 2 h, the solution became clear and the hydrolysis reaction was ended; The pH of the obtained reaction solution was adjusted to 7.5 with hydrochloric acid solution, and nanofiltration concentration was carried out at 0.1 MPa. The molecular weight cut-off value of the nanofiltration membrane was 250 D. During the whole nanofiltration concentration process, the temperature was increased from 45 °C to 60 °C in a gradient manner to obtain 485 mL of crude amoxicillin acid solution.
[0041] S2. Hydrochloric acid solution was added to the above-mentioned crude amoxicillin acid solution to adjust the pH of the system to 2. After acidification and crystallization, filtration was carried out to obtain crude amoxicillin acid.
[0042] S3. The above-mentioned crude amoxicillin acid was added to 603 mL of methanol for reflux reaction. After 2.5 h, filtration was carried out to obtain 197.52 g of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid. Through calculation and testing, the yield was 98.17% and the purity was 99.88%.
[0043] Example 3 This example provides a preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, including the following steps: S1. Add 4.5 L of water, 229.26 g (1.0 mol) of ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate, and 1.3 mol of diisopropylamine into the reaction kettle in sequence. After mixing evenly, add 25% sodium hydroxide solution dropwise at 20°C. The addition amount of sodium hydroxide is 1.3 mol. After the addition is completed, keep the temperature for hydrolysis reaction. After 1 h, the solution becomes clear, and the hydrolysis reaction is terminated; Adjust the pH of the obtained reaction solution to 7.0 with hydrochloric acid solution, and perform nanofiltration concentration at 1 MPa. The molecular weight cut-off value of the nanofiltration membrane is 200 D. During the whole nanofiltration concentration process, the temperature is increased from 42°C to 58°C in a gradient manner to obtain 1145 mL of crude ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate solution.
[0044] S2. Add hydrochloric acid solution to the above-mentioned crude ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate solution to adjust the pH of the system to 3. After acidification and crystallization, filter to obtain the crude ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate.
[0045] S3. Add the above-mentioned crude ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate into 730 mL of methanol for reflux reaction. After 3.5 h, filter to obtain 197.30 g of (Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid. After calculation and testing, the yield is 98.06% and the purity is 99.77%.
[0046] Comparative Example 1 This comparative example provides a preparation method of (Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid, which is similar to Example 1, except that in S1, diethylamine is replaced by tetrabutylammonium bromide with the same molar amount. The specific steps are as follows: S1. Add 2.3 L of water, 229.26 g (1.0 mol) of ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate, and 0.1 mol of tetrabutylammonium bromide into the reaction kettle in sequence. After mixing evenly, add 30% sodium hydroxide solution dropwise at 10°C. The addition amount of sodium hydroxide is 1.1 mol. After the addition is completed, keep the temperature for hydrolysis reaction. After 3 h, the solution becomes clear, and the hydrolysis reaction is terminated; Adjust the pH of the obtained reaction solution to 6.5 with hydrochloric acid solution, and perform nanofiltration concentration at 0.5 MPa. The molecular weight cut-off value of the nanofiltration membrane is 250 D. During the whole nanofiltration concentration process, the temperature is increased from 40°C to 55°C in a gradient manner to obtain 460 mL of crude ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate solution.
[0047] S2. Same as Example 1, details are not repeated.
[0048] S3. Add the above-mentioned crude ethyl 2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetate into 690 mL of methanol for reflux reaction. After 3 h, filter to obtain 197.50 g of (Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetic acid. After calculation and testing, the yield is 98.16% and the purity is 97.31%.
[0049] Comparative Example 2 This comparative example provides a method for preparing (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, which is similar to Example 1, except that: in S1, the addition of diethylamine is omitted. The specific steps are as follows: S1, Add 2.3 L of water and 229.26 g (1.0 mol) of ethyl aminothioxamate into the reaction kettle in sequence. After mixing evenly, add 30% sodium hydroxide solution dropwise at 10°C. The addition amount of sodium hydroxide is 1.1 mol. After dropping, keep the temperature for hydrolysis reaction. After 4 h, the solution becomes clear, and the hydrolysis reaction is ended; Adjust the pH of the obtained reaction solution to 6.5 with hydrochloric acid solution, and carry out nanofiltration concentration at 0.5 MPa. The molecular weight cut-off value of the nanofiltration membrane is 250 D. During the whole nanofiltration concentration process, the temperature is raised from 40°C to 55°C in a gradient heating manner to obtain 460 mL of crude ethyl aminothioxamate solution.
[0050] S2, The same as Example 1, which will not be elaborated here.
[0051] S3, Add the above-mentioned crude ethyl aminothioxamate into 690 mL of methanol for reflux reaction. After 3 h, filter to obtain 197.10 g of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid. Through calculation and testing, the yield is 97.96% and the purity is 97.15%.
[0052] Comparative Example 3 This comparative example provides a method for preparing (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, which is similar to Example 1, except that: in S1, the addition of diethylamine is omitted, and activated carbon is added after the hydrolysis reaction is completed to remove the ethyl aminothioxamate dimer. The specific steps are as follows: S1, Add 2.3 L of water and 229.26 g (1.0 mol) of ethyl aminothioxamate into the reaction kettle in sequence. After mixing evenly, add 30% sodium hydroxide solution dropwise at 10°C. The addition amount of sodium hydroxide is 1.1 mol. After dropping, keep the temperature for hydrolysis reaction. After 4 h, the solution becomes clear, and the hydrolysis reaction is ended; Adjust the pH of the obtained reaction solution to 6.5 with hydrochloric acid solution, add 12 g of activated carbon, stir for 1 h and then filter. Then take the filtrate for nanofiltration concentration at 0.5 MPa. The molecular weight cut-off value of the nanofiltration membrane is 250 D. During the whole nanofiltration concentration process, the temperature is raised from 40°C to 55°C in a gradient heating manner to obtain 460 mL of crude ethyl aminothioxamate solution.
[0053] S2, The same as Example 1, which will not be elaborated here.
[0054] S3. Add the above-mentioned crude product of cefotaxime acid to 690 mL of methanol and carry out a reflux reaction. After 3 h, filter to obtain 191.55 g of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid. Through calculation and testing, the yield is 95.20% and the purity is 99.28%.
[0055] Comparative Example 4 This comparative example provides a preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, which is similar to Example 1, except that: in S1, the feeding order is different. The specific steps are as follows: S1. Add 2.3 L of water, 30% sodium hydroxide solution (the addition amount of sodium hydroxide is 1.1 mol), and 0.1 mol of diethylamine into the reaction kettle in sequence. After mixing evenly, add 229.26 g (1.0 mol) of ethyl cefotaxime acid at 10°C. After adding, keep the temperature for hydrolysis reaction. After 3.5 h, it becomes clear, and the hydrolysis reaction ends; Adjust the pH of the obtained reaction solution to 6.5 with hydrochloric acid solution, carry out nanofiltration concentration at 0.5 MPa, the molecular weight cut-off value of the nanofiltration membrane is 250 D, and adopt a gradient heating method to heat from 40°C to 55°C during the whole nanofiltration concentration process to obtain 460 mL of crude cefotaxime acid solution.
[0056] S2. The same as Example 1, which will not be elaborated here.
[0057] S3. Add the above-mentioned crude product of cefotaxime acid to 690 mL of methanol and carry out a reflux reaction. After 3 h, filter to obtain 196.49 g of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid. Through calculation and testing, the yield is 97.66% and the purity is 97.22%.
[0058] Comparative Example 5 This comparative example provides a preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, which is similar to Example 1, except that: in S1, the temperature of the hydrolysis reaction is replaced by 40°C. The specific steps are as follows: S1. Add 2.3 L of water, 229.26 g (1.0 mol) of ethyl cefotaxime acid, and 0.1 mol of diethylamine into the reaction kettle in sequence. After mixing evenly, add 30% sodium hydroxide solution dropwise at 40°C, the addition amount of sodium hydroxide is 1.1 mol. After dropping, keep the temperature for hydrolysis reaction. After 1.5 h, it becomes clear, and the hydrolysis reaction ends; Adjust the pH of the obtained reaction solution to 6.5 with hydrochloric acid solution, carry out nanofiltration concentration at 0.5 MPa, the molecular weight cut-off value of the nanofiltration membrane is 250 D, and adopt a gradient heating method to heat from 40°C to 55°C during the whole nanofiltration concentration process to obtain 460 mL of crude cefotaxime acid solution.
[0059] S2 is the same as that in Example 1 and will not be elaborated here.
[0060] S3: Add the above-mentioned crude product of aminothioxoic acid to 690 mL of methanol for reflux reaction. After 3 h, filter to obtain 196.17 g of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid. Through calculation and testing, the yield is 97.50% and the purity is 95.21%.
[0061] Comparative Example 6 This comparative example provides a preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid (prior art), including the following steps: S1: Add 156 g of ethyl acetoacetate and 90 g of sodium nitrite to 400 mL of water. Dropwise add the solution prepared from 48 mL of 98% sulfuric acid and 200 mL of water at 5°C. After adding for 2 h, continue the reaction for 2 h; extract three times with 200 mL of chloroform to obtain the extract.
[0062] S2: Transfer the extract into a reaction kettle, add 700 mL of an aqueous solution dissolving 159 g of sodium carbonate and 5 g of polyethylene glycol, dropwise add 151.2 g of dimethyl sulfate, control the reaction temperature at 15°C. After adding for 2 h, continue the reaction for 4 h; let it stand for layer separation, extract with chloroform, and take the organic layer to dry with anhydrous magnesium sulfate.
[0063] S3: Transfer the obtained dried organic layer into a reaction kettle, control the reaction temperature at 5°C, dropwise add 60 g of bromine within 2 h, then introduce 55.5 g of chlorine gas within 3 h. After the chlorine gas is introduced, continue the reaction for 1 h; wash the reaction solution with water, separate the liquid, and then extract the aqueous layer with chloroform. Combine the organic phases, adjust the pH to 7.0 with 2% sodium bicarbonate solution, and distill off the solvent chloroform under reduced pressure.
[0064] S4: Add 600 mL of a methanol-water solution with a volume ratio of 1:1 to the reaction kettle, add thiourea, sodium acetate, and 3.0 g of the phase transfer catalyst polyethylene glycol. After completely dissolving and clearing, dropwise add the product prepared in S3 at 15°C. After adding for 3 h, continue the heat preservation reaction for 1 h, and then filter.
[0065] S5: Adjust the pH of the product obtained in S4 to 9.0 with sodium bicarbonate solution and carry out hydrolysis under the catalysis of 3.0 g of polyethylene glycol. The reaction temperature is 40°C. Then, carry out decolorization with activated carbon, and then acidify and crystallize with dilute hydrochloric acid to obtain the crude product of aminothioxoic acid, and the yield is 95.26%.
[0066] S6: Dissolve the crude product of aminothioxoic acid in a methanol-ethanol mixed solution with a volume ratio of 1:1, heat under reflux for 5 h, cool down and filter to obtain aminothioxoic acid. Through calculation and testing, the yield is 92.31% and the purity is 99.16%.
[0067] Comparative Example 7 This comparative example provides a preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid. Similar to Example 1, the difference is that: in S1, the temperature of the hydrolysis reaction is replaced from 10°C to 0°C. The specific steps are as follows: S1, sequentially add 2.3 L of water, 229.26 g (1.0 mol) of ethyl aminothioxamate, and 0.1 mol of diethylamine into the reaction kettle. After mixing evenly, add 30% sodium hydroxide solution dropwise at 0°C. The addition amount of sodium hydroxide is 1.1 mol. After dropping, keep the temperature for the hydrolysis reaction. It was still not clear after 20 h, and the reaction could not proceed smoothly, so the experiment was abandoned.
[0068] The products (aminothioxamic acid) prepared in Examples 1 to 3 and Comparative Examples 1 to 6 were measured by gas chromatography (General Rules 0521, Volume IV, Chinese Pharmacopoeia 2020 Edition). The test results are shown in Table 1.
[0069] Table 1 Gas Chromatography Test Results of the Products in Examples and Comparative Examples
[0070] As can be seen from the table, the preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid provided in the examples of the present invention is simple in operation, the hydrolysis reaction time is generally short, the use of activated carbon and catalysts is avoided, it is green and environmentally friendly, and the product yield is above 98% and the purity is as high as above 99.5%. In Comparative Example 1, the organic amine in Example 1 was replaced by a phase transfer catalyst. Compared with the prior art, although the hydrolysis reaction time was slightly shortened, it did not inhibit the formation of aminothioxamic acid dimer or did not have the effect of separating and removing aminothioxamic acid dimer, resulting in a lower product purity; compared with Example 1, in Comparative Example 2, the addition of diethylamine was omitted, and the product purity decreased significantly; compared with Comparative Example 2, in Comparative Example 3, activated carbon was added after the hydrolysis reaction was completed. While adsorbing the aminothioxamic acid dimer impurity with activated carbon, the product yield also decreased; compared with Example 1, in Comparative Example 4, the addition order of the strong base solution and aminothioxamic acid ester was different, the hydrolysis reaction time was prolonged, and the alkaline environment led to an increase in the content of aminothioxamic acid dimer, resulting in a decrease in the final product purity; compared with Example 1, in Comparative Example 5, the hydrolysis temperature was too high, and the selectivity of the hydrolysis reaction became poor, resulting in a large increase in the content of aminothioxamic acid dimer.
[0071] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, or improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for preparing (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid, characterized in that, It includes the following steps: S1. Add (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate, organic amine and strong base solution into water in sequence, and carry out hydrolysis reaction at 10°C to 20°C to obtain a crude solution of aztreonam acid; S2. Acidify and crystallize and refine the crude aztreonam acid solution in sequence to obtain (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid.
2. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid according to claim 1, characterized in that, In S1, the organic amine includes at least one of diethylamine, triethylamine or diisopropylamine; In S1, the (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate includes methyl (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate or ethyl (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate.
3. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid according to claim 1, characterized in that, In S1, the strong base solution includes a sodium hydroxide solution with a mass concentration of 25% to 35%; In S1, the molar ratio of the (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate, organic amine and strong base is 1:(0.05 to 0.1):(1.1 to 1.3).
4. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid according to claim 1, characterized in that, In S1, the mass-volume ratio of the (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate and water is 1 g:(10 to 20) mL; In S1, the time of the hydrolysis reaction is 1 h to 2 h.
5. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid according to claim 1, characterized in that, In S1, after the hydrolysis reaction, it further includes: Adjust the pH of the obtained reaction solution to neutral, and then carry out nanofiltration concentration to obtain a crude solution of aztreonam acid.
6. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid according to claim 5, characterized in that, In S1, in the whole process of nanofiltration concentration, the temperature is increased from 40°C to 45°C to 55°C to 60°C in a gradient heating manner; In S1, the pressure of the nanofiltration concentration is 0.1 MPa to 1 MPa, and a nanofiltration membrane with a molecular weight cut-off value of 200 D to 250 D is used; In S1, the volume ratio of the crude aztreonam acid solution to the reaction solution is (1.5 to 2.5):
10.
7. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid according to claim 1, characterized in that, In S2, the pH of the crude aztreonam acid solution after acidification is 2 to 3.
8. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid according to claim 1, characterized in that, In S2, the refining includes the following steps: Add the crude aztreonam acid obtained after acidification and crystallization into a dehydration reagent for reflux reaction, and filter to obtain (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid.
9. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetic acid according to claim 8, characterized in that, In S2, the dehydration reagent includes methanol; In S1 to S2, the mass-volume ratio of the (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetate and the dehydration reagent is 10 g:(28 to 32) mL.
10. The preparation method of (Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetic acid according to claim 8, characterized in that, In S2, the time of the reflux reaction is 2.5 h to 3.5 h.