Preparation process of 7-AMCA

Abstract

The invention discloses a preparation process of 7-AMCA, and relates to the technical field of preparation of 7-AMCA. The method comprises the following steps: adjusting the pH value of a starting material D-7-ACA ultrafiltrate to uniformly crystallize D-7-ACA; growing the crystal to enable the crystal to grow; processing the D-7-ACA crystal subjected to crystal growing into D-7-ACA dry powder; and reacting the D-7-ACA dry powder with a methylation reagent under the action of a strong acid catalyst to obtain a 7-AMCA solution. The method provided by the invention improves the crystallization efficiency, purity and yield of D-7-ACA by optimizing crystallization process parameters of D-7-ACA, including crystal adjustment duration, crystal adjustment stirring speed and crystal growing duration, so that the lactone content in 7-AMCA reaction liquid is reduced, and the product purity of 7-AMCA is improved.

Description

Technical Field

[0001] This invention belongs to the field of 7-AMCA preparation technology, specifically relating to a 7-AMCA preparation process that can reduce the amount of lactone in 7-AMCA. Background Technology

[0002] 7-Amino-3-methoxymethyl-3-cephalosporin-4-carboxylic acid (7-AMCA) is a key intermediate in the synthesis of cefpodoxime proxetil. Cefpodoxime proxetil is a third-generation cephalosporin product, effective against many Gram-positive and Gram-negative bacteria, rarely exhibiting resistance, and is stable against β-lactamases. It is primarily used to treat upper and lower respiratory tract infections, urinary tract infections, otitis media, skin and soft tissue infections, and erythema folliculitis.

[0003] There are two main synthetic routes for 7-AMCA, using 7-aminocephalosporanic acid (7-ACA) and 7-amino-3-hydroxymethyl-3-cephalosporin-4-carboxylic acid (D-7ACA) as starting materials, respectively. The 7-AMCA prepared using 7-ACA as the starting material generally suffers from low product purity, complex reaction steps, low yield, high production cost, and difficult solvent handling. The preparation of 7-AMCA using D-7ACA as the starting material employs a large amount of strongly acidic catalysts, followed by direct hydrolysis after the reaction. The excessively low pH leads to the degradation of the β-lactam ring, reducing the product yield, and the resulting product also exhibits low purity and poor stability.

[0004] Patent CN102746322B discloses a method for preparing 7-AMCA, in which the reactant 7-ACA is reacted with BF3-methanol as a catalyst, dimethyl carbonate or sulfolane as an organic solvent, and a methoxyalkali metal as a methoxylating agent, and then obtained by crystallization, filtration, washing, and drying. This patented method uses hazardous and expensive methoxyalkali metals in its production process, resulting in high production costs.

[0005] Patent CN106046024A discloses a method for preparing 7-AMCA, using D-7-ACA as a raw material, trimethyl orthoformate as a methylating agent, boron trifluoride / diethyl ether as a catalyst, and acetonitrile as a solvent. This process requires operation at -30°C, has stringent equipment requirements, and the mixed solvent of diethyl ether and acetonitrile is difficult to recycle and poses safety hazards. Furthermore, it suffers from low product yield.

[0006] Patent WO2017153824A discloses a method for preparing 7-AMCA, using D-7-ACA as a raw material, trimethyl orthoformate as a methylating agent, and alkyl sulfonic acid as a catalyst. After the reaction, brine is added for separation, and an alkaline reagent is added for crystallization. The 7-AMCA product prepared using this method has low purity, relatively low content, and poor stability.

[0007] Patent CN109956958A discloses a method for synthesizing 7-amino-3-methoxymethyl-3-cephalosporin-4-carboxylic acid, using D-7ACA as a raw material to prepare 7-AMCA. In the later stages of the reaction, a strongly acidic catalyst is precipitated as a salt. After filtering off the byproduct salt, the mixture is hydrolyzed, crystallized, filtered, and dried. This method controls the reaction endpoint by the residual amount of D-7-ACA. Post-processing requires multiple steps, including monitoring the reaction progress, adding the byproduct precipitation solution, filtration, hydrolysis, cooling, adding an alkaline solution, crystal growth, readjusting the pH value, washing, and drying. The process is cumbersome, and deviations in any step can affect product quality and yield, while also consuming significant time and labor costs.

[0008] In summary, existing technologies for preparing 7-AMCA products using 7-ACA as a raw material suffer from problems such as low purity, complex processes, low yield, use of toxic catalysts, high production costs, and difficulty in recovering mixed solvents; while 7-AMCA products prepared using D-7-ACA as a raw material suffer from problems such as low product purity and poor stability. Summary of the Invention

[0009] To address the shortcomings of existing technologies, the present invention aims to provide a 7-AMCA preparation process that can reduce the lactone content in 7-AMCA and improve the purity of the 7-AMCA product.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] A process for preparing 7-AMCA, characterized in that the process steps include:

[0012] The pH value of the starting material D-7-ACA ultrafiltrate was adjusted to make D-7-ACA crystallize uniformly; then crystals were grown; the grown D-7-ACA crystals were processed into D-7-ACA dry powder.

[0013] Under the action of a strong acid catalyst, D-7-ACA dry powder reacts with a methylating agent to obtain a 7-AMCA solution.

[0014] Furthermore, the 7-AMCA preparation process described above includes the following steps:

[0015] S1. Take D-7-ACA ultrafiltrate, and within the set temperature and crystallization time, use an acidic solution to adjust the pH value of D-7-ACA ultrafiltrate to 4.5-5.5, and stir at the set crystallization stirring speed to make D-7-ACA crystallize uniformly.

[0016] S2. At the set temperature, the crystal growth time is set;

[0017] S3. The cultured D-7-ACA crystals are sequentially filtered, washed with water and acetone, and then dried in a vacuum drying oven to obtain D-7-ACA dry powder.

[0018] S4. Add a measured amount of dimethyl carbonate to the reaction flask and cool it to 0-10℃. Then add measured amounts of trimethyl orthoformate and D-7-ACA dry powder in sequence, and stir rapidly while cooling. When the temperature drops to -5-5℃, stop cooling and start adding a measured amount of methanesulfonic acid dropwise to the reaction flask. After the methanesulfonic acid is added, quickly heat the reaction solution to 30-40℃ with hot water and time the reaction for 30-50 minutes. After the reaction is completed, a 7-AMCA reaction solution is obtained, and the temperature of the solution is lowered to 20-30℃.

[0019] Furthermore, the 7-AMCA preparation process described above optimizes the crystallization process parameters of D-7-ACA to improve the crystallization efficiency, purity, and yield of D-7-ACA, thereby reducing the lactone content of 7-AMCA. The key crystallization process parameters of D-7-ACA include the crystallization adjustment time, crystallization stirring speed, and crystal growth time.

[0020] Furthermore, in the 7-AMCA preparation process described above, in step S1, the acidic solution is either hydrochloric acid or sulfuric acid solution, and the mass concentration of the acidic solution is 5-20%.

[0021] Furthermore, in the 7-AMCA preparation process described above, the set temperature in step S1 is 10-15℃.

[0022] Furthermore, in the 7-AMCA preparation process described above, in step S1, the crystallization time is set to 5-60 min.

[0023] Furthermore, in the 7-AMCA preparation process described above, in step S1, the set crystal stirring speed is 150-350 r / min.

[0024] Furthermore, in the 7-AMCA preparation process described above, the crystal growth time in step S2 is 5-60 min.

[0025] Furthermore, in the 7-AMCA preparation process described above, in step S2, crystals are grown at 0–15°C.

[0026] Furthermore, in the 7-AMCA preparation process described above, in step S4, the molar ratio of each reagent is D-7-ACA: dimethyl carbonate: trimethyl orthoformate: methanesulfonic acid = 1: 10-20: 2.5-3.0: 5.5-6.5.

[0027] Compared with the prior art, the 7-AMCA preparation process provided by the present invention has the following beneficial effects:

[0028] This invention uses D-7-ACA ultrafiltrate as the starting material and optimizes the crystallization process of the raw material D-7-ACA, including adjusting three key parameters: crystallization adjustment time, crystal growth time, and crystallization stirring speed.

[0029] By reducing particle size and impurity encapsulation, and promoting the growth of suitable crystal forms and particle sizes, the goal of improving the crystallization efficiency, purity, and yield of D-7-ACA is achieved, resulting in high-quality D-7-ACA dry powder. Then, using this high-quality D-7-ACA dry powder as raw material, 7-AMCA with low lactone content and high purity is further prepared. Using the process provided by this invention, the lactone content in the 7-AMCA reaction solution can be reduced from 15-20% to 5-10%. Attached Figure Description

[0030] Figure 1 This is a flow chart of a 7-AMCA preparation process provided in an embodiment of the present invention. Detailed Implementation

[0031] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0032] Example 1

[0033] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 15℃, adjust the crystallization to 4.50-5.00 with 10-15% hydrochloric acid solution, grow crystals at T=0-15℃ for 5min, filter, wash with water, wash with acetone, and vacuum dry for 2h to obtain D-7-ACA dry powder.

[0034] (2) Preparation of 7-AMCA: 35 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–10 °C. 10 g of trimethyl orthoformate was added, followed by 10 g of the above-mentioned D-7-ACA. The mixture was stirred rapidly and cooled to -5–0 °C. 18 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–50 min. After the reaction was completed, a 7-AMCA reaction solution was obtained, and the temperature of the solution was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was measured to be 7.28%.

[0035] Example 2

[0036] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 15℃, adjust the crystallization to 4.50-5.00 with 10-15% hydrochloric acid solution, grow crystals at T=0-15℃ for 30 min, filter, wash with water, wash with acetone, and vacuum dry for 2 h to obtain D-7-ACA dry powder.

[0037] (2) Preparation of 7-AMCA: 35 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–10 °C. 10 g of trimethyl orthoformate was added, followed by 10 g of the aforementioned D-7-ACA. The mixture was stirred rapidly and cooled to -5–0 °C. 18 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–50 min. After the reaction was complete, a 7-AMCA reaction solution was obtained, and the temperature of the solution was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was determined to be 9.75%.

[0038] Example 3

[0039] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 15℃, adjust the crystallization to 4.50-5.00 with 10-15% hydrochloric acid solution, grow crystals at T=0-15℃ for 60 min, filter, wash with water, wash with acetone, and vacuum dry for 2 h to obtain D-7-ACA dry powder.

[0040] (2) Preparation of 7-AMCA: 35 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–10 °C. 10 g of trimethyl orthoformate was added, followed by 10 g of D-7-ACA. The mixture was stirred rapidly and cooled to -5–0 °C. 18 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–50 min. After the reaction was completed, a 7-AMCA reaction solution was obtained, and the temperature of the solution was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was measured to be 18.77%.

[0041] Example 4

[0042] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 15℃, adjust the crystallization to 5.00-5.50 with 10-20% hydrochloric acid solution within 5 min, grow crystals at T=10-15℃ for 10-30 min, filter, wash with water, wash with acetone, and vacuum dry for 2 h to obtain D-7-ACA dry powder;

[0043] (2) Preparation of 7-AMCA: 32 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–10 °C. 9.8 g of trimethyl orthoformate was added, followed by 10 g of the above-mentioned D-7-ACA. The mixture was stirred rapidly and cooled to -5–5 °C. 18 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–40 min. After the reaction was complete, a 7-AMCA reaction solution was obtained, and the solution temperature was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was measured to be 6.27%.

[0044] Example 5

[0045] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 15℃, adjust the crystallization to 5.00-5.50 with 10-20% hydrochloric acid solution within 30 min, grow crystals at T=10-15℃ for 10-30 min, filter, wash with water, wash with acetone, and vacuum dry for 2 h to obtain D-7-ACA dry powder;

[0046] (2) Preparation of 7-AMCA: 32 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–10 °C. 9.8 g of trimethyl orthoformate was added, followed by 10 g of the above-mentioned D-7-ACA. The mixture was stirred rapidly and cooled to -5–5 °C. 18 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–40 min. After the reaction was completed, a 7-AMCA reaction solution was obtained, and the temperature of the solution was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was measured to be 10.21%.

[0047] Example 6

[0048] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 15℃, adjust the crystallization to 5.00-5.50 with 10-20% hydrochloric acid solution within 60 min, grow crystals at T=10-15℃ for 10-30 min, filter, wash with water, wash with acetone, and vacuum dry for 2 h to obtain D-7-ACA dry powder;

[0049] (2) Preparation of 7-AMCA: 32 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–10 °C. 9.8 g of trimethyl orthoformate was added, followed by 10 g of the above-mentioned D-7-ACA. The mixture was stirred rapidly and cooled to -5–5 °C. 18 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–40 min. After the reaction was completed, a 7-AMCA reaction solution was obtained, and the temperature of the solution was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was measured to be 12.23%.

[0050] Example 7

[0051] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 10℃, adjust the crystallization to 4.80-5.20 with 5-10% sulfuric acid solution at a speed of 150r / min, grow crystals at T=5-10℃ for 10-30min, filter, wash with water, wash with acetone, and vacuum dry for 2h to obtain D-7-ACA dry powder;

[0052] (2) Preparation of 7-AMCA: 30 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–5 °C. 10 g of trimethyl orthoformate was added, followed by 10 g of the above-mentioned D-7-ACA. The mixture was stirred rapidly and cooled to -5–5 °C. 20 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–40 min. After the reaction was completed, a 7-AMCA reaction solution was obtained, and the temperature of the solution was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was measured to be 15.27%.

[0053] Example 8

[0054] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 10℃, adjust the crystallization to 4.80-5.20 with 5-10% sulfuric acid solution at a speed of 250r / min, grow crystals at T=5-10℃ for 10-30min, filter, wash with water, wash with acetone, and vacuum dry for 2h to obtain D-7-ACA dry powder;

[0055] (2) Preparation of 7-AMCA: 30 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–5 °C. 10 g of trimethyl orthoformate was added, followed by 10 g of the above-mentioned D-7-ACA. The mixture was stirred rapidly and cooled to -5–5 °C. 20 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–40 min. After the reaction was completed, a 7-AMCA reaction solution was obtained, and the temperature of the solution was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was measured to be 11.65%.

[0056] Example 9

[0057] (1) Preparation of D-7-ACA: Take D-7-ACA ultrafiltrate, cool it to about 10℃, adjust the crystallization to 4.80-5.20 with 5-10% sulfuric acid solution at a speed of 350r / min, grow crystals at T=5-10℃ for 10-30min, filter, wash with water, wash with acetone, and vacuum dry for 2h to obtain D-7-ACA dry powder;

[0058] (2) Preparation of 7-AMCA: 30 ml of dimethyl carbonate was added to a 250 ml four-necked flask and cooled to 0–5 °C. 10 g of trimethyl orthoformate was added, followed by 10 g of the aforementioned D-7-ACA. The mixture was stirred rapidly and cooled to -5–5 °C. 20 g of methanesulfonic acid was then added dropwise. Cooling was stopped. After the methanesulfonic acid was completely added, the reaction solution was rapidly heated to 30–40 °C with hot water and the reaction time was set for 30–40 min. After the reaction was complete, a 7-AMCA reaction solution was obtained, and the temperature of the solution was lowered to 20–30 °C. Under uniform stirring conditions, a sample was taken and the lactone content of the reaction solution was determined to be 9.84%.

[0059] The process parameters and the statistical results of the 7-AMCA lactone ratio obtained in each embodiment are shown in Table 1.

[0060] Table 1

[0061]

[0062] The 7-AMCA preparation process provided by this invention uses D-7-ACA ultrafiltrate as the starting material. By optimizing the crystallization process of the raw material D-7-ACA, including adjusting three key parameters—crystallization time, crystal growth time, and crystallization stirring speed—the particle size is reduced, impurity encapsulation is minimized, and suitable crystal forms and particle sizes are promoted. This achieves the goal of improving the crystallization efficiency, purity, and yield of D-7-ACA, resulting in high-quality D-7-ACA dry powder. Then, using this high-quality D-7-ACA dry powder as raw material, 7-AMCA with low lactone content and high purity is further prepared. Using the process provided by this invention, the lactone content in the 7-AMCA reaction solution can be reduced from 15-20% to 5-10%.

[0063] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention is also intended to include these modifications and variations.

Claims

1. A process for preparing 7-AMCA, characterized in that, The process includes: The pH value of the starting material D-7-ACA ultrafiltrate was adjusted to make D-7-ACA crystallize uniformly; then crystals were grown; the grown D-7-ACA crystals were processed into D-7-ACA dry powder. Under the action of a strong acid catalyst, D-7-ACA dry powder reacts with a methylating agent to obtain a 7-AMCA solution.

2. The 7-AMCA preparation process according to claim 1, characterized in that, The process includes the following steps: S1. Take D-7-ACA ultrafiltrate, and within the set temperature and crystallization time, use an acidic solution to adjust the pH value of D-7-ACA ultrafiltrate to 4.5-5.5, and stir at the set crystallization stirring speed to make D-7-ACA crystallize uniformly. S2. At the set temperature, the crystal growth time is set; S3. The cultured D-7-ACA crystals are sequentially filtered, washed with water and acetone, and then dried in a vacuum drying oven to obtain D-7-ACA dry powder. S4. Add a measured amount of dimethyl carbonate to the reaction flask and cool it to 0-10℃. Then add measured amounts of trimethyl orthoformate and D-7-ACA dry powder in sequence, and stir rapidly while cooling. When the temperature drops to -5-5℃, stop cooling and start adding a measured amount of methanesulfonic acid dropwise to the reaction flask. After the methanesulfonic acid is added, quickly heat the reaction solution to 30-40℃ with hot water and time the reaction for 30-50 minutes. After the reaction is completed, a 7-AMCA reaction solution is obtained, and the temperature of the solution is lowered to 20-30℃.

3. The 7-AMCA preparation process according to claim 2, characterized in that, By optimizing the crystallization process parameters of D-7-ACA, the crystallization efficiency, purity, and yield of D-7-ACA can be improved, thereby reducing the lactone content of 7-AMCA. The key crystallization process parameters of D-7-ACA include the crystallization adjustment time, crystallization stirring speed, and crystal growth time.

4. The 7-AMCA preparation process according to claim 2 or 3, characterized in that, In step S1, the acidic solution is either hydrochloric acid or sulfuric acid, and the mass concentration of the acidic solution is 5-20%.

5. The 7-AMCA preparation process according to claim 4, characterized in that, In step S1, the set temperature is 10-15℃.

6. The 7-AMCA preparation process according to claim 5, characterized in that, In step S1, the crystal adjustment time is set to 5-60 minutes.

7. The 7-AMCA preparation process according to claim 6, characterized in that, In step S1, the set crystal stirring speed is 150-350 r / min.

8. The 7-AMCA preparation process according to claim 7, characterized in that, In step S2, the crystal growth time is 5 to 60 minutes.

9. The 7-AMCA preparation process according to claim 8, characterized in that, In step S2, crystals are grown at 0–15°C.

10. The 7-AMCA preparation process according to any one of claims 5-9, characterized in that, In step S4, the molar ratio of each reagent is D-7-ACA: dimethyl carbonate: trimethyl orthoformate: methanesulfonic acid = 1: 10-20: 2.5-3.0: 5.5-6.5.

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