Method for continuously preparing 7-ACT

Abstract

The invention discloses a method for continuously preparing 7-ACT, and belongs to the technical field of chemical synthesis. The method comprises the following steps: (1) simultaneously and continuously introducing a 7-ACA acetonitrile solution and a boron trifluoride acetonitrile solution into a first-stage pipeline mixer for mixing, simultaneously introducing the obtained mixed solution and a triazine ring acetonitrile solution into a second-stage pipeline mixer for quickly mixing and simultaneously reacting to obtain a 7-ACT reaction solution; (2) introducing the 7-ACT reaction liquid and water into a third-stage pipeline mixer, quickly mixing and hydrolyzing at the same time to obtain 7-ACT hydrolysate; (3) sequentially and continuously passing the 7-ACT hydrolysate through an activated carbon column and an aluminum oxide column, and filtering to obtain a 7-ACT liquid to be crystallized; and (4) crystallizing the 7-ACT liquid to be crystallized, filtering, washing and drying to obtain the product 7-ACT. The continuous mixing, reaction, hydrolysis, purification and crystallization processes are realized by controlling the material dosage, the mixing temperature and the mixing time, and the problems of long working hours, low mass and heat transfer efficiency, more side reactions, poor product quality and the like in traditional tank batch production are solved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical synthesis, and particularly relates to a method for continuously preparing 7-ACT. BACKGROUND

[0002] 7-ACT (7-aminocephalosporanic acid triazine ring derivative) is a key intermediate for synthesizing the third generation of cephalosporin antibiotics (such as ceftriaxone, cefotaxime, etc.), and its molecular structure containing a β-lactam ring and a triazine ring side chain endows the downstream antibiotics with broad-spectrum antibacterial activity and excellent clinical efficacy, and has an irreplaceable position in the field of anti-infective drugs. With the continuous growth of the demand for cephalosporin antibiotics in the clinic, the industrialized preparation process efficiency and quality control of 7-ACT have become the core link restricting the development of the industrial chain.

[0003] At present, a plurality of patents on the preparation method of 7-ACT have been disclosed in the prior art, and the core process is to use 7-ACA (7-aminocephalosporanic acid) as the starting material, triazine acid as the acylating reagent, acetonitrile as the solvent, and perform acylation reaction under the catalysis of a Lewis acid such as boron trifluoride acetonitrile complex, and then obtain the product through subsequent steps such as hydrolysis termination reaction, alkaline solution pH adjustment crystallization, filtration and washing (such as Chinese patents CN107955021A, CN102702233A, etc.). Although these methods realize the synthesis of 7-ACT, they all adopt a batch kettle reaction mode, and have the following inherent defects: Poor reaction uniformity: in the kettle stirring, the mixing of materials depends on mechanical stirring, and local high concentration (such as triazine acid aggregation) or uneven distribution of catalysts are prone to occur, resulting in an increase in side reactions (such as 7-ACA self-degradation and triazine acid hydrolysis), low product purity, and large quality fluctuations between batches; Long process cycle: the single batch reaction needs 20-30 minutes, plus auxiliary operations such as feeding, temperature rising, temperature falling and discharging, and the total cycle is as long as 4-6 hours, and the production efficiency is low; Difficult impurity control: in the batch reaction, the reaction endpoint needs to be detected by manual sampling, and the hysteresis is easy to cause over-reaction, so that the residual amount of 7-ACA is increased (usually >0.5%), which affects the safety of downstream drug synthesis.

[0004] In addition, the traditional batch kettle production also has significant safety hazards and energy consumption problems, such as high safety risk, high energy consumption, and limited scale, etc.

[0005] Therefore, in view of the problems of low efficiency, large quality fluctuation, high safety risk and scale difficulty in the existing 7-ACT preparation process, it is an urgent technical requirement in the field to develop a continuous, efficient, safe and easy-to-scale 7-ACT preparation method. SUMMARY

[0006] The present application aims to overcome the defects of traditional batch production of 7-ACT, and provides a continuous preparation method to shorten the working hours, improve the mass transfer and heat transfer efficiency, reduce the side reactions, improve the product quality, and reduce the equipment investment and energy consumption.

[0007] The present application is realized by the following technical solutions: A 7-ACT product with a purity of ≥99.2% and a T400nm value of ≥66%.

[0008] A method for continuously preparing the above-mentioned 7-ACT, comprising the following steps: (1) continuously feeding 7-ACA acetonitrile solution and boron trifluoride acetonitrile solution into a first-stage pipeline mixer for mixing, controlling the mixing temperature to be 0-10℃; the obtained mixed solution is simultaneously fed into a second-stage pipeline mixer with triazine ring acetonitrile solution for rapid mixing and reaction, controlling the reaction temperature to be 30-35℃, and the reaction residence time to be 120-180s, to obtain 7-ACT reaction liquid; (2) rapidly mixing the 7-ACT reaction liquid with water in a third-stage pipeline mixer for hydrolysis, controlling the hydrolysis temperature to be 5-12℃, and the hydrolysis residence time to be 60-90s, to obtain 7-ACT hydrolysis liquid; (3) the 7-ACT hydrolysis liquid sequentially passes through an activated carbon column and an alumina column, and is filtered to obtain 7-ACT crystallization liquid; (4) the 7-ACT crystallization liquid is crystallized, filtered, washed, and dried to obtain the product 7-ACT.

[0009] Further, the preparation method of the 7-ACA acetonitrile solution, the boron trifluoride acetonitrile solution, and the triazine ring acetonitrile solution in step (1) is as follows: 7-ACA acetonitrile solution: controlling the temperature to be 0-10℃, mixing 7-ACA with acetonitrile at a mass / volume ratio (g / ml) of 0.8-1.1∶1, and uniformly stirring rapidly for standby; boron trifluoride acetonitrile solution: controlling the temperature to be 0-5℃, mixing boron trifluoride acetonitrile complex with acetonitrile at a mass / volume ratio (g / ml) of 1∶6.8-7.2, and uniformly stirring rapidly for standby; triazine ring acetonitrile solution: controlling the temperature to be 30-40℃, mixing triazine ring with acetonitrile at a mass / volume ratio (g / ml) of 1∶3.8-4.2, and uniformly stirring rapidly for standby.

[0010] Further, the flow rate ratio of the 7-ACA acetonitrile solution, the boron trifluoride acetonitrile solution, and the triazine ring acetonitrile solution in step (1) is 9-9.2∶6-6.2∶4, wherein the flow rate of the 7-ACA acetonitrile solution ranges from 15 to 20 ml / min.

[0011] Further, the residence time of the mixing of the 7-ACA acetonitrile solution and the boron trifluoride acetonitrile solution in the first pipeline mixer of step (1) is 10-50s, preferably 20-30s.

[0012] Further, the flow ratio of the 7-ACT reaction solution to water of step (2) is 4:1-1.2.

[0013] Further, the residence time of the 7-ACT hydrolysis solution in the activated carbon column and the alumina column of step (3) is 15-20min.

[0014] Further, the crystallization of step (4) is to add the 7-ACT crystallization solution into the 7-ACT crystallization bottom solution, while maintaining the pH at 2.3-2.7 with 5-10% ammonia water, and after the feeding is completed, stirring at 15-20HZ for 30-60min.

[0015] Further, the amount of the crystallization bottom solution is that the stirring device can reach, and the preparation method is as follows: adding 60-150 mesh 7-ACT into water with pH 2.3-2.7, and stirring quickly under the condition of 0-12℃ to obtain the crystallization bottom solution. The mass / volume ratio (g / ml) of the 7-ACT to water is 3-8:50.

[0016] Compared with the prior art, the present application has the following beneficial effects: Continuous production: the use of high-efficiency pipeline mixer realizes multi-step continuous operation, which significantly improves the production efficiency; High efficiency of mass transfer and heat transfer: precise control of material dosage, mixing temperature and mixing time, reduction of local high concentration and temperature fluctuation, reduction of side reactions, 7-ACA residual amount of reaction solution from 4.37% to less than 0.4%, product purity improved to more than 99.2%; Excellent product quality: the product is white crystalline powder, the water content is as low as 0.65%, and the T400nm value is more than 66%, which is better than the traditional process of light yellow powder (water content 3.5%, T400nm 63%); Cost reduction: continuous process reduces equipment investment and production site, reduces energy consumption, and is suitable for industrialization. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 The present application is a production process flow diagram for continuously preparing 7-ACT. DETAILED DESCRIPTION

[0018] The present application is further described below in conjunction with specific embodiments and the accompanying drawings. The present application is implemented on the premise of the technical solution of the present application, and detailed implementation and specific operation process are given, but the protection scope of the present application is not limited to the following examples.

[0019] The process flow of the present application is shown in Figure 1 The working process is as follows: (1) 7-ACA acetonitrile solution, boron trifluoride acetonitrile solution and triazine ring acetonitrile solution are prepared respectively; 7-ACA acetonitrile solution and boron trifluoride acetonitrile solution are simultaneously transported to the first pipeline mixer by the feeding pump, and the obtained mixed solution is simultaneously transported to the second pipeline mixer at 30-35℃ with triazine ring acetonitrile solution for continuous reaction, and the reaction temperature and residence time are controlled to obtain 7-ACT reaction liquid. (2) The 7-ACT reaction liquid is simultaneously transported to the third pipeline mixer with water for continuous hydrolysis, and the hydrolysis temperature and residence time are controlled to obtain 7-ACT hydrolysis liquid. (3) The 7-ACT hydrolysis liquid passes through the activated carbon column and the aluminum oxide column in sequence, and is filtered through the first filter to obtain 7-ACT crystallization liquid. (4) The 7-ACT crystallization liquid is crystallized in the crystallizer, filtered through the second filter, and then washed and dried in sequence to obtain the product 7-ACT.

[0020] Example 1 (1) 7-ACA acetonitrile solution, boron trifluoride acetonitrile solution and triazine ring acetonitrile solution are prepared respectively: Preparation of 7-ACA acetonitrile solution: control temperature at 0-10℃, weigh 150g 7-ACA sieved through 80 mesh, mix with 1000ml acetonitrile, and uniformly stir at 40-45HZ, and reserve (total volume 1000ml); Preparation of boron trifluoride acetonitrile solution: control temperature at 0-5℃, weigh 460g boron trifluoride acetonitrile complex, mix with 500ml acetonitrile, and uniformly stir at 40-45HZ, and reserve; Preparation of triazine ring acetonitrile solution: control temperature at 30-40℃, weigh 85g triazine ring sieved through 80 mesh, mix with 400ml acetonitrile, and uniformly stir at 40-45HZ, and reserve (total volume 400ml).

[0021] (2) 7-ACA acetonitrile solution and boron trifluoride acetonitrile solution are simultaneously transported to the first pipeline mixer at 5℃ by the feeding pump, and the obtained mixed solution is transported to the second pipeline mixer at 32℃ after a total residence time of 25s in the first pipeline mixer, and continuous reaction is carried out to obtain 7-ACT reaction liquid.

[0022] (3) After the 7-ACT reaction liquid is in the second pipeline mixer for a total residence time of 150s, it is simultaneously transported to the third pipeline mixer at 8℃ with water for continuous hydrolysis to obtain 7-ACT hydrolysis liquid.

[0023] (4) After the 7-ACT hydrolysate was kept in the third stage pipe mixer for 75 s, it was sequentially passed through an activated carbon column and an alumina column, and the retention time was 18 min. The 7-ACT crystallization precursor was obtained by filtering through a filter.

[0024] (5) 5 g of 7-ACT sieved through a 100-120 mesh sieve was added to 50 ml of water with a pH of 2.5, and 45 HZ rapid stirring was performed at 3-8°C for 10 min to obtain a 7-ACT crystallization base solution. The 7-ACT crystallization precursor was added to the 7-ACT crystallization base solution, and 5-10% ammonia water was used to maintain a pH of 2.5. After the addition was completed, the stirring speed was reduced, and stirring was performed at a speed of 15-20 HZ for 60 min. After filtering through a second filter, the product 7-ACT was obtained by sequentially washing and drying.

[0025] Example 2 (1) 7-ACA acetonitrile solution, boron trifluoride acetonitrile solution, and triazine ring acetonitrile solution were prepared, respectively: Preparation of 7-ACA acetonitrile solution: control temperature at 0-10°C, weigh 150 g of 7-ACA sieved through an 80 mesh sieve, mix with 900 ml of acetonitrile, and uniformly stir at 40-45 HZ. Reserve (total volume 900 ml); Preparation of boron trifluoride acetonitrile solution: control temperature at 0-5°C, weigh 440 g of boron trifluoride acetonitrile complex and mix with 500 ml of acetonitrile, and uniformly stir at 40-45 HZ. Reserve; Preparation of triazine ring acetonitrile solution: control temperature at 30-40°C, weigh 80 g of triazine ring sieved through an 80 mesh sieve, mix with 400 ml of acetonitrile, and uniformly stir at 40-45 HZ. Reserve (total volume 400 ml).

[0026] (2) The 7-ACA acetonitrile solution and the boron trifluoride acetonitrile solution were simultaneously delivered to the first stage pipe mixer at 0°C through a feeding pump, and the obtained mixed solution was kept in the first stage pipe mixer for 20 s. The triazine ring acetonitrile solution was simultaneously delivered to the second stage pipe mixer at 30°C, and continuous reaction was performed to obtain a 7-ACT reaction solution.

[0027] (3) After the 7-ACT reaction solution was kept in the second stage pipe mixer for 120 s, it was simultaneously delivered to the third stage pipe mixer at 5°C with water, and continuous hydrolysis was performed to obtain a 7-ACT hydrolysate.

[0028] (4) After the 7-ACT hydrolysate was kept in the third stage pipe mixer for 60 s, it was sequentially passed through an activated carbon column and an alumina column, and the retention time was 15-20 min. The 7-ACT crystallization precursor was obtained by filtering through a filter.

[0029] (5) Take 7-ACT 3 g through 60-80 mesh sieve, add to 50 ml water with pH 2.3, 0 ℃, 45 HZ fast stirring for 10 min, get 7-ACT crystallization bottom liquid; Add 7-ACT crystallization bottom liquid to the above-mentioned 7-ACT crystallization bottom liquid, maintain pH 2.0 with 5-10% ammonia water, after the feeding is completed, reduce the stirring speed, 15-20 HZ stirring for 30-60 min, filter through the second filter, then wash and dry, get the product 7-ACT.

[0030] Example 3 (1) Prepare 7-ACA acetonitrile solution, boron trifluoride acetonitrile solution and triazine ring acetonitrile solution respectively: Preparation of 7-ACA acetonitrile solution: control temperature 0-10 ℃, weigh 150 g 7-ACA through 80 mesh sieve, mix with 900 ml acetonitrile, 40-45 HZ fast stirring, ready for use (total volume 900 ml); Preparation of boron trifluoride acetonitrile solution: control temperature 0-5 ℃, weigh 480 g boron trifluoride acetonitrile complex and mix with 500 ml acetonitrile, 40-45 HZ fast stirring, ready for use; Preparation of triazine ring acetonitrile solution: control temperature 30-40 ℃, weigh 90 g triazine ring through 80 mesh sieve, mix with 400 ml acetonitrile, 40-45 HZ fast stirring, ready for use (total volume 400 ml).

[0031] (2) Deliver 7-ACA acetonitrile solution and boron trifluoride acetonitrile solution to the first stage pipeline mixer at 10 ℃ through the feeding pump respectively, the obtained mixed solution stays in the first stage pipeline mixer for 30 s, then deliver the triazine ring acetonitrile solution to the second stage pipeline mixer at 35 ℃, carry out continuous reaction, get 7-ACT reaction liquid.

[0032] (3) After the 7-ACT reaction liquid stays in the second stage pipeline mixer for 180 s, deliver it to the third stage pipeline mixer at 12 ℃ with water respectively, continuously carry out hydrolysis, get 7-ACT hydrolysis liquid.

[0033] (4) After the 7-ACT hydrolysis liquid stays in the third stage pipeline mixer for 90 s, pass through the activated carbon column and the alumina column in turn, retention time 20 min, filter through the filter to get 7-ACT crystallization liquid.

[0034] (5) Take 7-ACT 8 g through 140-150 mesh sieve, add to 50 ml water with pH 2.7, 12 ℃, 45 HZ fast stirring for 10 min, get 7-ACT crystallization bottom liquid; The 7-ACT to be crystallized liquid is added into the above-mentioned 7-ACT crystallization bottom liquid, while the pH is maintained at 3.5 by using 5-10% ammonia water, the stirring speed is reduced after the addition is completed, and the stirring is performed at a speed of 15-20 HZ for 30 min. After being filtered through a second filter, the product 7-ACT is obtained by being sequentially washed and dried.

[0035] Comparative Example 1 The ACT is produced by using the conventional tank batch process in this comparative example, and the specific steps are as follows: 150 g of 7-ACA and 85 g of triazine ring are dissolved in 1200 ml of acetonitrile, and the temperature is reduced to 0-5°C. A solution containing 30 g of boron trifluoride in 700 ml of acetonitrile is added within 30 min, and the solution is fully stirred and dissolved. The temperature is controlled at 15°C, and the reaction is performed for 1 h. After the reaction is completed, the temperature is reduced to 0-5°C, 500 ml of water is added, and the stirring is performed for 30 min. The pH is adjusted to the crystallization by using 5% dilute ammonia water, the crystal is maintained, and the product 7-ACT is obtained by being centrifuged, washed, and dried.

[0036] Comparative Example 2 The influence of the material amount on the product quality is studied in this comparative example. Except that the data shown in Table 1 are different from those of Example 1, the remaining steps and parameters are the same as those of Example 1.

[0037] Table 1 .

[0038] Comparative Example 3 The residence time range of the material in the pipe mixer is verified in this comparative example. Except that the data shown in Table 2 are different from those of Example 1, the remaining steps and parameters are the same as those of Example 1.

[0039] Table 2 .

[0040] Comparative Example 4 The reaction temperature range of the material in the pipe mixer is verified in this comparative example. Except that the data shown in Table 3 are different from those of Example 1, the remaining steps and parameters are the same as those of Example 1.

[0041] Table 3 .

[0042] Comparative Example 5 The influence of different crystallization bottom liquid preparation conditions on the product quality is studied in this comparative example. Except that the data shown in Table 4 are different from those of Example 1, the remaining steps and parameters are the same as those of Example 1.

[0043] Table 4 .

[0044] The reaction time and process indicators of the above-mentioned embodiment 1 and comparative examples 1-5 are shown in Table 3: The reaction liquid 7-ACA residue refers to the residual amount of 7-ACA in the reaction liquid obtained by reacting the material in the second pipeline mixer, and the yield calculation formula is as follows: Yield = 7-ACT output / 7-ACA input x 100%.

[0045] Table 5 .

[0046] As can be seen from comparative example 2, whether boron trifluoride or less triazine ring, will lead to incomplete reaction, resulting in low yield, and when the amount of boron trifluoride is large, it does not improve the product quality much, but causes waste of raw materials, and if there are more triazine rings, the 7-ACT product will have residual triazine rings.

[0047] As can be seen from comparative example 3, the residence time of the material in the first pipeline mixer has little effect on the quality of 7-ACT product, but the residence time in the second or third pipeline mixer is too short, which will cause incomplete reaction or insufficient hydrolysis, resulting in low yield; if the residence time is too long, it will increase the side reaction, and finally affect the product purity and color.

[0048] As can be seen from comparative example 4, the temperature of the first pipeline mixer has little effect on the yield and quality of the product, but it will cause energy waste, and if the temperature is too high, it will cause the volatilization of boron trifluoride, resulting in more 7-ACA residues and triazine ring residues, and the yield will also be reduced; if the temperature of the second or third pipeline mixer is too low, the reaction will not be complete, and if it is too high, the side reaction will be serious.

[0049] As can be seen from comparative example 5, the quality of the crystallization bottom liquid will also affect the quality of the final 7-ACA product, when the particle size of 7-ACA in the crystallization bottom liquid is too low or the amount of 7-ACA added is too small, it will cause secondary crystallization, resulting in the aggregation of 7-ACA in the crystallization bottom liquid; when the particle size of 7-ACA in the crystallization bottom liquid is too large or the amount of 7-ACA added is too much, it will cause the crystallization bottom liquid to be slightly thick, and finally cause the impurity content of 7-ACA product to be high. When the preparation temperature or pH of the crystallization bottom liquid exceeds the specified range, the yield will be seriously affected due to the viscosity of the liquid or the degradation of the product.

Claims

1. A 7-ACT product characterized in that, Purity ≥ 99.2%, T400nm value ≥ 66%.

2. A process for the continuous preparation of 7-ACT according to claim 1, characterized in that, Comprising the following steps: (1) 7-ACA acetonitrile solution and boron trifluoride acetonitrile solution are continuously introduced into the first pipeline mixer for mixing, and the mixing temperature is controlled at 0-10℃; the obtained mixed solution and triazine ring acetonitrile solution are simultaneously introduced into the second pipeline mixer for rapid mixing and reaction, and the reaction temperature is controlled at 30-35℃, the reaction residence time is 120-180s, and 7-ACT reaction liquid is obtained; (2) 7-ACT reaction liquid and water are introduced into the third pipeline mixer for rapid mixing and hydrolysis, and the hydrolysis temperature is controlled at 5-12℃, the hydrolysis residence time is 60-90s, and 7-ACT hydrolysis liquid is obtained; (3) 7-ACT hydrolysis liquid passes through activated carbon column and alumina column in sequence, and 7-ACT crystallization liquid is obtained after filtration; (4) 7-ACT crystallization liquid is crystallized, filtered, washed and dried to obtain product 7-ACT.

3. The method of claim 2, wherein, The preparation method of 7-ACA acetonitrile solution, boron trifluoride acetonitrile solution and triazine ring acetonitrile solution in step (1) is as follows: 7-ACA acetonitrile solution: control temperature at 0-10℃, mix 7-ACA with acetonitrile at a mass-volume ratio (g / ml) of 0.8-1.1:1, and stir uniformly for use; Boron trifluoride acetonitrile solution: control temperature at 0-5℃, mix boron trifluoride acetonitrile complex with acetonitrile at a mass-volume ratio (g / ml) of 1:6.8-7.2, and stir uniformly for use; Triazine ring acetonitrile solution: control temperature at 30-40℃, mix triazine ring with acetonitrile at a mass-volume ratio (g / ml) of 1:3.8-4.2, and stir uniformly for use.

4. The method of claim 2, wherein, The flow rate ratio of 7-ACA acetonitrile solution, boron trifluoride acetonitrile solution and triazine ring acetonitrile solution in step (1) is 9-9.2:6-6.2:4, wherein the flow rate of 7-ACA acetonitrile solution is 15-20ml / min.

5. The method of claim 2, wherein, The residence time of 7-ACA acetonitrile solution and boron trifluoride acetonitrile solution in the first pipeline mixer in step (1) is 10-50s.

6. The method of claim 2, wherein, The flow rate ratio of 7-ACT reaction liquid and water in step (2) is 4:1-1.

2.

7. The method of claim 2, wherein, The residence time of 7-ACT hydrolysis liquid in activated carbon column and alumina column in step (3) is 15-20min.

8. The method of claim 2, wherein, The crystallization in step (4) is that 7-ACT crystallization liquid is added into 7-ACT crystallization bottom liquid, and 5-10% ammonia water is used to maintain pH at 2.3-2.7, and the feeding is completed, and the stirring is performed at 15-20HZ for 30-60min.

9. The method of claim 7, wherein, The amount of crystallization bottom liquid is determined according to the stirring device, and the preparation method is as follows: 60-150 mesh 7-ACT is added into water with pH at 2.3-2.7, and the stirring is performed rapidly under the condition of 0-12℃ to obtain the crystallization bottom liquid.

10. The method of claim 7, wherein, The mass-volume ratio (g / ml) of 7-ACT and water is 3-8:50.

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