Method for preparing oxacillin sodium by using microchannel reactor

Abstract

The invention provides a method for preparing oxacillin sodium by using a microchannel reactor. The oxacillin sodium is prepared by adopting micro-channel reactors, firstly, a 6-APA dissolved clear solution, liquid-state oxacillin acyl chloride, a sodium hydroxide solution and a sulfuric acid solution are prepared in advance, the 6-APA dissolved clear solution and molten-state oxacillin acyl chloride are oppositely added in the first micro-channel reactor, fine liquid drops are formed through atomization and collide with each other to be fully reacted, and then the oxacillin sodium is prepared. The collided and mixed liquid flows through a second micro-channel reactor and then enters a four-opening bottle, butyl acetate is added after the liquid reacts in the four-opening bottle for a period of time, acidification and phase splitting are conducted, a sodium acetate solution is fed into the four-opening bottle, crystallization, filtering, washing and drying are conducted, and a finished oxacillin sodium product is obtained. According to the method for preparing the oxacillin sodium by using the microchannel reactor, the molar yield of the oxacillin sodium prepared by using the method is relatively high, the time of an acylation reaction stage is greatly shortened, and the total impurities of the oxacillin sodium are effectively reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of preparation of oxacillin sodium, in particular to a method for preparing oxacillin sodium using a micro-channel reactor. BACKGROUND

[0002] Oxacillin sodium is a semi-synthetic antibiotic of penicillin class synthesized from 6-APA, which has the same antibacterial spectrum and mode of action as penicillin, is resistant to penicillinase, and is effective against penicillin-resistant staphylococcus. Oxacillin sodium can be clinically used for various infections caused by sensitive bacteria, such as pneumonia, septicemia, purulent meningitis and osteomyelitis, tonsillitis, apical tissue inflammation and pyoderma, etc.

[0003] The existing synthesis route and specific conditions of oxacillin sodium are optimized and designed under laboratory scale, and the synthesis route is mainly acyl chloride method, i.e. the side chain acid is prepared into acyl chloride, and the reaction is carried out under low temperature and near neutral conditions.

[0004] The patent application file CN 102161668 A discloses a preparation method of oxacillin sodium and oxacillin sodium for injection. It uses 6-APA and benzyl isoxazolyl chloride as raw materials, and synthesizes oxacillin sodium through condensation, acidification, crystallization, washing, crushing and packaging steps. By optimizing multiple parameters such as temperature, pH value and feeding ratio, oxacillin sodium is synthesized in high yield, high purity and high stability on an industrial scale, and through the control of production environment and process, oxacillin sodium product for injection is directly obtained.

[0005] In the patent application file CN 102161668 A, the first step is condensation reaction of 6-APA and benzyl isoxazolyl chloride, and the reaction time is 2 hours. After the reaction is completed, pharmaceutical activated carbon is added and reacted for 5-10 minutes; the second step of acidification takes a total of 100 minutes. It can be seen that the reaction time is as long as 4 hours. Therefore, the synthesis efficiency of oxacillin sodium needs to be improved at present. SUMMARY

[0006] The purpose of the present application is to provide a method for preparing oxacillin sodium using a micro-channel reactor, so as to solve the problems of long synthesis time and low efficiency of oxacillin sodium at present, and the oxacillin sodium prepared by the method has low impurities and high yield.

[0007] The present application is implemented as follows: A method for preparing oxacillin sodium using a micro-channel reactor, comprising the following steps: (1) preparing 6-APA solution and liquid oxazacyl chloride in advance; (2) two micro-channel reactors are set, which are connected by an intermediate opening, and are respectively denoted as a first micro-channel reactor and a second micro-channel reactor; and the second micro-channel reactor is further connected with a four-necked flask; (3) the 6-APA solution and the liquid phenazocyl chloride are respectively introduced into the first micro-channel reactor from two ends of the first micro-channel reactor, the 6-APA solution and the liquid phenazocyl chloride are mixed and reacted in the first micro-channel reactor, and then enter the four-necked flask through the second micro-channel reactor; (4) the 6-APA solution and the liquid phenazocyl chloride are reacted in the four-necked flask until the slurry forms milky white, butyl acetate is added into the four-necked flask, cooling is performed, then acidification is performed by using a sulfuric acid solution, and then phase separation and crystallization are performed; (5) the crystallization solution is filtered, washed and dried, and then oxacillin sodium is obtained.

[0008] In the above scheme, preferably, one atomizing membrane is arranged on each side of the middle part of the first micro-channel reactor; in step (3), the 6-APA solution and the liquid phenazocyl chloride are atomized by the atomizing membranes after being introduced into the first micro-channel reactor, and then form liquid drops and react by opposite collision, and the liquid after the collision reaction enters the four-necked flask through the second micro-channel reactor.

[0009] In the above scheme, preferably, in step (3), a sodium hydroxide solution is introduced into the first micro-channel reactor, and the pH value of the reaction system is adjusted to 6.0-9.0 by the sodium hydroxide solution.

[0010] In the above scheme, preferably, in step (3), the concentration of the sodium hydroxide solution is 3-6 mol / L, and the flow rate of the sodium hydroxide solution is 1-2 mL / min.

[0011] In the above scheme, preferably, in step (3), the flow rate of the 6-APA solution introduced into the first micro-channel reactor is 25-40 mL / min, and the flow rate of the liquid phenazocyl chloride is 2-4 mL / min.

[0012] In the above scheme, preferably, in step (3), the reaction temperature in the two micro-channel reactors is 25-35℃, and in step (4), the reaction temperature in the four-necked flask is 25-35℃.

[0013] In the above scheme, preferably, in step (4), the concentration of the sulfuric acid solution is 3-6 mol / L.

[0014] In the above scheme, preferably, in step (4), crystallization is performed by adding a sodium acetate methanol solution, and the crystallization temperature is 25-50℃.

[0015] In the above scheme, preferably, in step (4), the solid-liquid ratio of sodium acetate to methanol in the sodium acetate methanol solution is 1 g:11 mL.

[0016] In the above scheme, preferably, after filtering the crystallization liquid in step (5), it is washed with butyl acetate and acetone respectively, and then vacuum dried at 70°C for 1-2 h.

[0017] This invention uses a microchannel reactor to prepare oxacillin sodium. First, prepare 6-APA solution, liquid oxacillin chloride, sodium hydroxide solution, and sulfuric acid solution in advance. Then, add the 6-APA solution and liquid oxacillin chloride in opposite directions to each other in the first microchannel reactor. The 6-APA solution and liquid oxacillin chloride collide and react in the first microchannel reactor. The resulting liquid continues to react in the second microchannel reactor and then enters a four-necked flask. After reacting in the four-necked flask for a period of time, add butyl acetate for phase separation and acidification. Then, add sodium acetate solution to crystallize. Filter, wash, and dry to obtain the finished oxacillin sodium product.

[0018] Furthermore, by setting two atomizing membranes inside the first microchannel reactor, the 6-APA solution and liquid benzoyl chloride are atomized into fine droplets within the reactor, which then collide and react fully. The mixed liquid then enters a four-necked flask via the second microchannel reactor. The atomizing membranes in this invention ensure a more complete reaction.

[0019] This invention proposes a method for preparing oxacillin sodium using a microchannel reactor. The oxacillin sodium prepared by this method has a high molar yield, greatly shortens the time of the acylation reaction stage, and effectively reduces the total impurities of oxacillin sodium. Attached Figure Description

[0020] Figure 1 This is a flowchart of the method for preparing oxacillin sodium using a microchannel reactor according to the present invention.

[0021] Figure 2 This is a schematic diagram of the reaction process for preparing oxacillin sodium using a microchannel reactor according to the present invention. Detailed Implementation

[0022] The present invention will be further described below with reference to the accompanying drawings. The specific embodiments described are only for explaining the present invention and are not intended to limit the present invention. In the following embodiments, the processes and methods not described in detail are all conventional methods known in the art, and the reagents used are all commercially available analytical grade or chemically pure.

[0023] Comparative Example 1 (a) Condensation reaction: Add 170 mL of purified water and 10 g of 6-APA to a 1 L four-necked flask, cool to 15 °C, and add 3 mol / L sodium hydroxide solution dropwise until pH=7. Heat the system to 25 °C, add 11 g of benzoyl chloride (5-methyl-3-phenylisoxazole-4-acyl chloride), and add 3 mol / L sodium hydroxide solution dropwise, controlling the pH range of the reaction process to 6.0-7.0.

[0024] (b) Acidification reaction: Cool the system to 15°C, add 100 mL of butyl acetate, add 3 mol / L sulfuric acid dropwise, and adjust the pH to 1.5.

[0025] (c) Extraction and phase separation: Let the acidified solution stand for 30 min, separate the phases, discard the aqueous phase, and retain the organic phase.

[0026] (d) Washing with water: Add 100 mL of purified water to the organic phase and stir and wash for 10 min.

[0027] (e) Phase separation: Allow to stand for 30 minutes to separate phases, discard the lower aqueous phase and retain the organic phase.

[0028] (f) Crystallization: Heat the system to 25°C and add the pre-prepared sodium acetate solution (3.7 g sodium acetate + 40 mL anhydrous methanol) all at once. Add 0.1 g seed crystals, react for 30 min, then cool to 20°C, allow crystals to grow for 10 min, and then filter.

[0029] (g) Filtration and washing: After the reaction is complete, the mixture is soaked and washed successively with butyl acetate and acetone (30 mL each), and then filtered. Drying: After filtration, the mixture is vacuum dried at 70 °C for 2 h.

[0030] Comparative Example 2 (a) Condensation reaction: Add 270 mL of purified water and 10 g of 6-APA to a 1 L four-necked flask, cool to 15 °C, and add 4.5 mol / L sodium hydroxide solution dropwise until pH=7. Heat the system to 30 °C, add 12.3 g of benzoyl chloride (5-methyl-3-phenylisoxazole-4-acyl chloride), and add 4.5 mol / L sodium hydroxide solution dropwise, controlling the pH range of the reaction process to 7.0-8.0.

[0031] (b) Acidification reaction: Cool the system to 17.5°C, add 150 mL of butyl acetate, add 4.5 mol / L sulfuric acid dropwise, and adjust the pH to 2.0.

[0032] (c) Extraction and phase separation: Let the acidified solution stand for 30 min, separate the phases, discard the aqueous phase, and retain the organic phase.

[0033] (d) Washing with water: Add 100 mL of purified water to the organic phase and stir and wash for 10 min.

[0034] (e) Phase separation: Allow to stand for 30 minutes to separate phases, discard the lower aqueous phase and retain the organic phase.

[0035] (f) Crystallization: Heat the system to 35°C and add the pre-prepared sodium acetate solution (3.7 g sodium acetate + 40 mL anhydrous methanol) all at once. Add 0.1 g seed crystals, react for 30 min, then cool to 20°C, allow crystals to grow for 10 min, and then filter.

[0036] (g) Filtration and washing: After the reaction is complete, the mixture is soaked and washed successively with butyl acetate and acetone (30 mL each), and then filtered. Drying: After filtration, the mixture is vacuum dried at 70 °C for 2 h.

[0037] Comparative Example 3 (a) Condensation reaction: Add 370 mL of purified water and 10 g of 6-APA to a 1 L four-necked flask, cool to 15 °C, and add 6 mol / L sodium hydroxide solution dropwise until pH=7. Heat the system to 35 °C, add 13.2 g of benzoyl chloride (5-methyl-3-phenylisoxazole-4-acyl chloride), and add 6 mol / L sodium hydroxide solution dropwise, controlling the pH range of the reaction process to 8.0-9.0.

[0038] (b) Acidification reaction: Cool the system to 20°C, add 200 mL of butyl acetate, add 6 mol / L sulfuric acid dropwise, and adjust the pH to 2.5.

[0039] (c) Extraction and phase separation: Let the acidified solution stand for 30 min, separate the phases, discard the aqueous phase, and retain the organic phase.

[0040] (d) Washing with water: Add 100 mL of purified water to the organic phase and stir and wash for 10 min.

[0041] (e) Phase separation: Allow to stand for 30 minutes to separate phases, discard the lower aqueous phase and retain the organic phase.

[0042] (f) Crystallization: Heat the system to 50°C and add the pre-prepared sodium acetate solution (3.7 g sodium acetate + 40 mL anhydrous methanol) all at once. Add 0.1 g seed crystals, react for 30 min, then cool to 20°C, allow crystals to grow for 10 min, and then filter.

[0043] (g) Filtration and washing: After the reaction is complete, the mixture is soaked and washed successively with butyl acetate and acetone (30 mL each), and then filtered. Drying: After filtration, the mixture is vacuum dried at 70 °C for 2 h.

[0044] Example 1 CombinationFigure 1 The method for preparing oxacillin sodium using a microchannel reactor provided in this embodiment is as follows: (a) Mix 10 g of 6-APA with 170 mL of purified water, then add 3 mol / L sodium hydroxide solution to dissolve and obtain a 6-APA solution for later use; heat 11 g of solid benzoyl chloride at 40 °C to melt it into liquid benzoyl chloride for later use; prepare 3 mol / L sulfuric acid solution for later use; prepare 3 mol / L sodium hydroxide solution for later use.

[0045] (b) Combination Figure 2 Prepare two small microchannel reactors stacked one on top of the other and connected in the middle by an opening. Place two atomizing membranes (e.g., piezoelectric ceramic atomizing plates) in parallel near the middle of one of the microchannel reactors. The two atomizing membranes are located on both sides of the center of the microchannel reactor and are located at the cross-section of the microchannel reactor. The microchannel reactor with the atomizing membranes is referred to as the first microchannel reactor, and the other microchannel reactor is referred to as the second microchannel reactor. One end of the second microchannel reactor is connected to a four-necked bottle.

[0046] (c) 6-APA solution and liquid benzoyl chloride are fed into the first microchannel reactor from opposite ends using feed pumps. Simultaneously, 3 mol / L sodium hydroxide solution is fed into the first microchannel reactor from one end using a feed pump. The sodium hydroxide solution can be fed into the first microchannel reactor together with the 6-APA solution, or it can be fed into the first microchannel reactor together with the liquid benzoyl chloride.

[0047] The flow rate of 6-APA solution was 28.3 mL / min, the flow rate of liquid benzoyl chloride was 3.3 mL / min, and the flow rate of sodium hydroxide solution was 1.7 mL / min. The sodium hydroxide solution was added to adjust the pH of the system. In this embodiment, the pH of the system was controlled between 6.0 and 7.0.

[0048] The 6-APA solution and liquid benzoyl chloride enter the first microchannel reactor from both ends. After passing through the atomizing membrane, they disperse into fine droplets and collide with each other, thus achieving a thorough mixing reaction. The mixed 6-APA solution and liquid benzoyl chloride then enter the second microchannel reactor through the middle opening and enter a four-necked flask with a stirrer.

[0049] The second microchannel reactor is provided in this invention to allow the 6-APA solution and liquid benzoyl chloride to react more fully, and to provide a more adequate transport path for the 6-APA solution and liquid benzoyl chloride before entering the four-necked flask.

[0050] The two microchannel reactors and the four-necked flask were all used for the reaction at room temperature, approximately 25°C.

[0051] (d) After the 6-APA solution and liquid benzoyl chloride were reacted in a four-necked flask for 5 min, the slurry turned milky white. 100 mL of butyl acetate was added to the four-necked flask, the temperature was lowered to 15℃, and then acidified with 3 mol / L sulfuric acid solution to adjust the pH to 1.5. After standing and phase separation, the aqueous phase was discarded, and a methanol solution of sodium acetate was added to crystallize the solution. The solid-liquid ratio of sodium acetate to methanol was 1 g: 11 mL, and the crystallization temperature was 25℃.

[0052] (e) Filter the oxacillin sodium crystallization solution, wash the filter cake with butyl acetate and acetone in sequence, and dry it under vacuum at 70°C for 2 h.

[0053] Example 2 (a) Mix 10 g of 6-APA with 270 mL of purified water, then add 4.5 mol / L sodium hydroxide solution to dissolve and prepare 6-APA solution for later use; heat 12.3 g of solid benzoyl chloride at 45 °C to melt it into liquid benzoyl chloride for later use; prepare 4.5 mol / L sulfuric acid solution for later use; prepare 4.5 mol / L sodium hydroxide solution for later use.

[0054] (b) Same as step (b) in Example 1.

[0055] (c) The 6-APA solution and liquid benzoyl chloride are fed into the first microchannel reactor from both ends using feed pumps. At the same time, the 4.5 mol / L sodium hydroxide solution is fed into the first microchannel reactor from one end using feed pumps.

[0056] The flow rate of 6-APA solution was 33.7 mL / min, the flow rate of liquid benzoyl chloride was 2.5 mL / min, and the flow rate of sodium hydroxide solution was 1.3 mL / min. The pH of the system was adjusted to 7.0-8.0 using sodium hydroxide solution.

[0057] The 6-APA solution and liquid benzoyl chloride are dispersed by atomization in the first microchannel reactor to form fine droplets, which then collide with each other to fully mix and react. The mixture is then introduced into a four-necked flask through the second microchannel reactor.

[0058] The reaction temperature of the two microchannel reactors and the four-necked flask was controlled at around 30°C.

[0059] (d) After the 6-APA solution and liquid benzoyl chloride were reacted in a four-necked flask for 7.5 min, the slurry turned milky white. 150 mL of butyl acetate was added to the four-necked flask, the temperature was lowered to 17.5℃, and then acidified with 4.5 mol / L sulfuric acid to adjust the pH to 2.0. After standing and phase separation, the aqueous phase was discarded, and a methanol solution of sodium acetate was added. The solid-liquid ratio of sodium acetate to methanol was 1 g: 11 mL. The crystallization temperature was 35℃.

[0060] (e) Filter the oxacillin sodium crystallization solution, wash the filter cake with butyl acetate and acetone in sequence, and dry it under vacuum at 70°C for 2 h.

[0061] Example 3 (a) Mix 10 g of 6-APA with 370 mL of purified water, then add 6 mol / L sodium hydroxide solution to dissolve and obtain 6-APA solution for later use. Melt 13.2 g of solid benzoyl chloride at 50 °C to obtain liquid benzoyl chloride for later use. Prepare 6 mol / L sulfuric acid solution for later use. Prepare 6 mol / L sodium hydroxide solution for later use.

[0062] (b) Same as step (b) in Example 1.

[0063] (c) The 6-APA solution and liquid benzoyl chloride are fed into the first microchannel reactor from both ends using feed pumps. At the same time, the 6 mol / L sodium hydroxide solution is fed into the first microchannel reactor from one end using feed pumps.

[0064] The flow rate of 6-APA solution was 37 mL / min, the flow rate of liquid benzoyl chloride was 2 mL / min, and the flow rate of sodium hydroxide solution was 1 mL / min. The pH of the system was adjusted to 8.0-9.0 using sodium hydroxide solution.

[0065] The 6-APA solution and liquid benzoyl chloride are dispersed by atomization in the first microchannel reactor to form fine droplets, which then collide with each other to fully mix and react. The mixture is then introduced into a four-necked flask through the second microchannel reactor.

[0066] The reaction temperature of the two microchannel reactors and the four-necked flask was controlled at around 35°C.

[0067] (d) After the 6-APA solution and liquid benzoyl chloride were reacted in a four-necked flask for 10 min, the slurry turned milky white. 200 mL of butyl acetate was added to the four-necked flask, and the temperature was lowered to 20 °C. Then, 6 mol / L sulfuric acid was used to acidify the solution and adjust the pH to 2.5. After standing and phase separation, the aqueous phase was discarded and a methanol solution of sodium acetate was added. The solid-liquid ratio of sodium acetate to methanol was 1 g: 11 mL. The crystallization temperature was 50 °C.

[0068] (e) Filter the oxacillin sodium crystallization solution, wash the filter cake with butyl acetate and acetone in sequence, and dry it under vacuum at 70°C for 2 h.

[0069] Example 4 Compared with Example 3, the reaction temperature of the two microchannel reactors and the four-necked flask in this example is controlled at around 25°C, while everything else is the same as in Example 3.

[0070] Example 5 Compared with Example 3, the reaction temperature of the two microchannel reactors and the four-necked flask in this example is controlled at around 30°C, while everything else is the same as in Example 3.

[0071] Example 6 Compared with Example 5, this example does not include an atomizing membrane in the microchannel reactor, but everything else is the same as in Example 5.

[0072] This invention significantly improves the process efficiency and molar yield of oxacillin sodium by using a microchannel reactor. Without a microchannel reactor, the acylation reaction time is approximately 90 min, and the total reaction time is 240 min. Using a microchannel reactor increases the process efficiency by about 35% and the molar yield by about 20%. Furthermore, without an atomizing membrane in the microchannel reactor, the molar yield decreases by about 3%. Additionally, using a microchannel reactor eliminates the need for seed crystal addition, shortening the cycle time. See Table 1 below for details.

[0073] Table 1. Comparison of reaction time, yield, and content of Examples 1-6 and Comparative Examples 1-3 In Table 1, the yield improvement rates in Examples 1-3 are obtained by comparing them with those in Comparative Documents 1-3.

Claims

1. A method for preparing oxacillin sodium using a microchannel reactor, characterized in that, Includes the following steps: (1) Prepare 6-APA solution and liquid benzoyl chloride in advance; (2) Set up two microchannel reactors connected by a middle opening, which are referred to as the first microchannel reactor and the second microchannel reactor respectively; and the second microchannel reactor is also connected to a four-necked bottle; (3) The 6-APA solution and liquid benzoyl chloride are introduced into the first microchannel reactor from both ends. The 6-APA solution and liquid benzoyl chloride are mixed and reacted in the first microchannel reactor, and then enter the four-necked bottle after passing through the second microchannel reactor. (4) 6-APA solution and liquid benzoyl chloride react in a four-necked flask until the slurry turns milky white. Butyl acetate is added to the four-necked flask, the temperature is lowered, and then acidified with sulfuric acid solution. After phase separation, crystallization is performed. (5) Filter the crystallization liquid, wash and dry it to obtain oxacillin sodium.

2. The method for preparing oxacillin sodium using a microchannel reactor according to claim 1, characterized in that, in A misting membrane is set on both sides of the middle part of the first microchannel reactor; in step (3), the 6-APA solution and liquid benzoyl chloride are atomized by a misting membrane in the first microchannel reactor and dispersed into droplets and collide with each other. The liquid after the collision reaction enters the four-necked bottle after passing through the second microchannel reactor.

3. The method for preparing oxacillin sodium using a microchannel reactor according to claim 1, characterized in that, In step (3), sodium hydroxide solution is introduced into the first microchannel reactor to adjust the pH of the reaction system to 6.0-9.

0.

4. The method for preparing oxacillin sodium using a microchannel reactor according to claim 3, characterized in that, The concentration of the sodium hydroxide solution in step (3) is 3~6 mol / L, and the flow rate of the sodium hydroxide solution is 1~2 mL / min.

5. The method for preparing oxacillin sodium using a microchannel reactor according to claim 1, characterized in that, In step (3), the flow rate of the 6-APA solution introduced into the first microchannel reactor is 25-40 mL / min, and the flow rate of the liquid benzoyl chloride is 2-4 mL / min.

6. The method for preparing oxacillin sodium using a microchannel reactor according to claim 1, characterized in that, The reaction temperature in the two microchannel reactors in step (3) is 25~35℃, and the reaction temperature in the four-necked flask in step (4) is 25~35℃.

7. The method for preparing oxacillin sodium using a microchannel reactor according to claim 1, characterized in that, The concentration of the sulfuric acid solution in step (4) is 3~6 mol / L.

8. The method for preparing oxacillin sodium using a microchannel reactor according to claim 1, characterized in that, In step (4), crystallization is carried out by adding a methanol solution of sodium acetate at a temperature of 25-50°C.

9. The method for preparing oxacillin sodium using a microchannel reactor according to claim 8, characterized in that, The solid-liquid ratio of sodium acetate to methanol in the sodium acetate methanol solution is 1 g: 11 mL.

10. The method for preparing oxacillin sodium using a microchannel reactor according to claim 1, characterized in that, In step (5), the crystallization liquid is filtered, washed with butyl acetate and acetone respectively, and then vacuum dried at 70°C for 1-2 h.

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