A method for preparing cefminox sodium in a continuous flow

Abstract

The present invention provides a continuous flow method for preparing cefminox sodium, belonging to the technical field of pharmaceutical chemical synthesis. The method comprises the following steps: introducing a 7-ACA solution and an MMT solution into a continuous flow microreactor for a substitution reaction; then introducing chloroacetyl chloride for an acylation reaction; then introducing a D-cysteine ​​solution for a condensation reaction to obtain an intermediate 2 reaction solution, which is then acidified and crystallized to obtain intermediate 2; dissolving intermediate 2 in an organic solvent, and introducing the intermediate 2 solution, tert-butyl hypochlorite, and a sodium methoxide solution into a continuous flow microreactor for a methoxylation reaction; then introducing glacial acetic acid for quenching, cooling, hydrolysis, and crystallization to obtain the product. The method of the present invention has high conversion rate, high yield, and high purity. #imgabs0#

Description

Technical Field

[0001] The invention relates to a method for preparing cefminox sodium in a continuous flow manner, and belongs to the technical field of pharmaceutical chemical synthesis. Background Art

[0002] Cefminox sodium, chemical name: (6R,7S)-7β-[(S)-2-(2-amino-2-carboxyethylmercapto)acetylamino]-7α-methoxy-3-[(1-methyl-1H-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-ene-2-carboxylate sodium, mainly exists in the form of heptahydrate crystals, the molecular formula is: C 16 H 20 N7NaO7S3·7H2O belongs to the β-lactam cephalosporin.

[0003]

[0004] Cefminox sodium

[0005] Existing synthetic routes for cefminox sodium, whether starting with 7-ACA (patents CN102268021A and CN110590812A), 7-MAC (patent CN101696214A), or GCLE (patent US4357331A), essentially involve adding side chains to the C3 and C7 positions of 7-ACA. These routes, due to the multiple reaction steps and the use of various solvents, suffer from long processing times, low conversion rates, demanding conditions, and complex post-processing. For example, patent documents CN102268021A and patent document CN110590812A both use 7ACA as the starting material, introduce methoxy groups by means of ketene imine intermediates, and the reaction temperature reaches -60~-70°C. The final molar yields are only 50.2% and 64.7%, respectively. Patent documents CN101696214A and US4357331A respectively start the synthesis with the more expensive raw materials 7MAC and GCLE, and the final products are not cost-effective.

[0006] Therefore, it is urgent to develop a preparation method for cefminox sodium with continuous reaction, short reaction time and high purity yield. Summary of the Invention

[0007] In response to the shortcomings of the prior art, the present invention provides a continuous flow method for preparing cefminox sodium. In the preparation of cefminox sodium of the present invention, water is used as the solvent for the 3-position substitution and 7-position acylation and condensation steps of 7ACA. The substitution, acylation, and condensation reactions are carried out in a microreactor under pressure, resulting in a short reaction time, low impurities, and continuous synthesis that reduces the isolation of intermediates. The present invention uses a continuous flow microreactor for the methoxylation reaction, which has milder conditions than the original ultra-low temperature reaction, fast reaction speed, high yield, and significantly reduced production costs. The method of the present invention uses a microreactor to synthesize cefminox sodium, with short working hours, high conversion rate, mild and controllable reaction conditions, and high yield and purity.

[0008] The technical solutions of the present invention are as follows:

[0009] A method for preparing cefminox sodium in a continuous flow process comprises the following steps:

[0010] (1) 7-aminocephalosporanic acid (7-ACA) and NaHCO3 were added to water to obtain material A; 1-methyl-5-mercaptotetrazole (MMT) and NaOH were added to water to obtain material B; chloroacetyl chloride was used as material C; D-cysteine ​​hydrochloride and NaOH were added to water to obtain material D;

[0011] (2) Material A and material B are introduced into a continuous flow microreactor respectively to carry out a substitution reaction; then material C is introduced into the continuous flow microreactor, mixed with the reaction solution obtained by the substitution reaction, and an acylation reaction is carried out; then material D is introduced into the continuous flow microreactor, mixed with the reaction solution obtained by the acylation reaction, and a condensation reaction is carried out to obtain an intermediate 2 reaction solution, which is acidified and crystallized to obtain intermediate 2;

[0012] ;

[0013] (3) Dissolve the intermediate 2 in an organic solvent to obtain material F, methanol solution of sodium methoxide as material E, and tert-butyl hypochlorite as material G. The materials E, F, and G are introduced into a continuous flow microreactor respectively to carry out a methoxylation reaction; then, glacial acetic acid is introduced into the continuous flow microreactor and mixed with the reaction solution obtained from the methoxylation reaction to carry out a neutralization reaction. After cooling, a cefuroxime sodium reaction solution is obtained, which is hydrolyzed and crystallized to obtain cefuroxime sodium.

[0014] According to the preferred embodiment of the present invention, the mass ratio of the number of moles of 7-aminocephalosporanic acid (7-ACA) in the material A to water in step (1) is 0.1-0.15 mol:80 g, the molar ratio of NaHCO3 to 7-aminocephalosporanic acid (7-ACA) in the material A is (1-1.5):1, more preferably 1.2:1, and the NaHCO3 is added to the water at 0-10°C.

[0015] According to the preferred embodiment of the present invention, the mass ratio of the number of moles of 1-methyl-5-mercaptotetrazolyl (MMT) in the material B to water in step (1) is 0.1-0.2 mol:40 g; and the molar ratio of sodium hydroxide to 1-methyl-5-mercaptotetrazolyl (MMT) in the material B is 2:1.

[0016] According to the preferred embodiment of the present invention, the mass ratio of the number of moles of D-cysteine ​​hydrochloride in the material D to water in step (1) is 0.1-0.15 mol:50 g; the molar ratio of NaOH to D-cysteine ​​hydrochloride in the material D is 3:1, and the NaOH is added to the water at 0-10°C.

[0017] According to the preferred embodiment of the present invention, the molar ratio of 1-methyl-5-mercaptotetrazole (MMT) in material B to 7-aminocephalosporanic acid (7-ACA) in material A in step (2) is (1-2):1, more preferably 1.2:1.

[0018] Preferably, according to the present invention, the flow rate of material A in step (2) is 23-24 g / min; the flow rate of material B is 11.9-15.9 g / min; the temperature for the substitution reaction of material A and material B is 125-135°C, the back pressure is 15-20 bar, and the substitution reaction time is 30-90 s.

[0019] According to the preferred embodiment of the present invention, the molar ratio of chloroacetyl chloride in material C to 7-aminocephalosporanic acid (7-ACA) in material A in step (2) is (1-1.5):1, more preferably 1.2:1.

[0020] According to the preferred embodiment of the present invention, the flow rate of the material C in step (2) is 2.2-3.4 g / min; the temperature of the acylation reaction is 105-115° C., the back pressure is 15-20 bar, and the acylation reaction time is 20-60 s.

[0021] According to the preferred embodiment of the present invention, the molar ratio of D-cysteine ​​hydrochloride in material D to 7-aminocephalosporanic acid (7-ACA) in material A in step (2) is (1.0-1.5):1, more preferably 1.3:1.

[0022] According to the preferred embodiment of the present invention, the flow rate of the material D in step (2) is 15.9-18.9 g / min; the temperature of the condensation reaction is 100-110° C., the back pressure is 15-20 bar, and the condensation reaction time is 30-90 s.

[0023] According to a preferred embodiment of the present invention, in step (2), after the condensation reaction is completed, the reaction mixture is cooled to 10-30° C. to obtain an intermediate 2 reaction solution; the obtained intermediate 2 reaction solution flows out from the continuous flow microreactor and is acidified and crystallized.

[0024] According to the preferred embodiment of the present invention, the acidification crystallization step in step (2) is as follows: adding acetone or ethanol in an amount equal to the volume of the reaction solution to the intermediate 2 reaction solution, then adding an aqueous hydrochloric acid solution with a mass concentration of 18 wt% or an aqueous sulfuric acid solution with a mass concentration of 10 wt% to adjust the pH to 2.5-3.0, and crystallizing at 10-20°C for 1-2 h; then filtering, washing the obtained solid with acetone or ethanol, and vacuum drying at 35-40°C to constant weight to obtain intermediate 2.

[0025] According to the preferred embodiment of the present invention, the ratio of the molar number of sodium methoxide to the volume of methanol in the material E in step (3) is 0.5-1 mol:150 mL.

[0026] According to the preferred embodiment of the present invention, the molar ratio of sodium methoxide in material E to 7-aminocephalosporanic acid (7-ACA) in material A in step (3) is (5-10):1, more preferably 6:1.

[0027] According to the preferred embodiment of the present invention, the organic solvent in step (3) is one or a combination of two or more of dichloromethane, chloroform, DMF, and acetonitrile; and the mass fraction of the intermediate 2 in the material F is 10-20%.

[0028] According to the preferred embodiment of the present invention, the molar ratio of tert-butyl hypochlorite in material G to 7-aminocephalosporanic acid (7-ACA) in material A in step (3) is (1-2):1, and more preferably 1.2:1.

[0029] According to the preferred embodiment of the present invention, the flow rate of material E in step (3) is 18.2-21.6 g / min; the flow rate of material F is 25-60 g / min; the flow rate of material G is 1.3-2.8 g / min; the temperature of the methoxidation reaction is 100-110°C, the back pressure is 15-20 bar, and the methoxidation reaction time is 20-60 s.

[0030] According to the preferred embodiment of the present invention, the molar ratio of the glacial acetic acid to the 7-aminocephalosporanic acid (7-ACA) in material A in step (3) is (2.5-3.0):1; the flow rate of the glacial acetic acid is 1.8-2.3 g / min; the temperature of the neutralization reaction is 35-40°C, and the neutralization reaction time is 12-24 s; and then the reaction mixture is cooled to 10-30°C to obtain a cefuroxime sodium reaction solution.

[0031] According to the preferred embodiment of the present invention, the hydrolysis and crystallization steps in step (3) are as follows: adding water to the cefminox sodium reaction solution, wherein the added volume of the water is 0.5-5 times the volume of the organic solvent for dissolving the intermediate 2, and then hydrolyzing at 0-10°C for 0.5-1h; then separating the liquids, distilling the obtained aqueous phase under reduced pressure to remove the organic solvent, adding a 10% by mass fraction of NaOH aqueous solution to adjust the pH to 4-6, adding acetone or ethanol for crystallization, and after precipitation, growing the crystals at room temperature for 1-2h, filtering, washing with acetone or ethanol, and then vacuum drying at 30-35°C to constant weight to obtain the cefminox sodium product; the volume of acetone or ethanol added for crystallization is the same as the volume of water added to the cefminox sodium reaction solution.

[0032] The present invention adopts a continuous flow microreactor to carry out the methoxidation reaction, and the conditions are milder than the original ultra-low temperature reaction, and the reaction is fast and the yield is high, which significantly reduces the production cost.

[0033] The continuous flow microreactor used in the present invention is a Corning G1 glass reactor, which is a reactor composed of 21 reaction modules in series. The liquid holding capacity of each reaction module is about 10 mL. The reaction module is designed with multiple heart-shaped channels in series. After the feed liquid enters the reaction module, it can be fully mixed. A high-pressure pump can be used to feed the front and middle of each reaction module. There is a gas-liquid separator at the rear end for back pressure and gas-liquid separation. The reactor is resistant to high temperature and high pressure.

[0034] During the reaction process of the present invention, the substitution reaction of material A and material B uses the 1st to 5th reaction modules, material A and material B are simultaneously introduced into the 1st reaction module, and the resulting mixed solution flows through the 1st to 5th reaction modules for substitution reaction; the acylation reaction at position 7 uses the 6th to 9th reaction modules, specifically, the reaction solution obtained by the substitution reaction flows out of the 5th reaction module and is simultaneously introduced into the 6th reaction module with material C, and the resulting mixed solution flows through the 6th to 9th reaction modules for reaction; the condensation reaction with D-cysteine ​​hydrochloride uses the 10th to 15th reaction modules, specifically, the reaction solution obtained by the acylation reaction flows out of the 9th reaction module and is simultaneously introduced into the 10th reaction module with material D. The obtained mixed solution is reacted in the 10th to 14th reaction modules, and the obtained reaction liquid is cooled and discharged from the 15th reaction module, and is acidified and crystallized to obtain intermediate 2; after the intermediate 2 is dissolved in an organic solvent, it is subjected to a methoxylation reaction in the 16th to 19th reaction modules, specifically, materials E, F, and G are simultaneously introduced into the 16th reaction module, and the obtained mixed solution is passed through the 16th to 19th reaction modules for reaction, and the reaction liquid obtained by the methoxylation reaction flows out of the 19th reaction module and is simultaneously introduced into the 20th reaction module with glacial acetic acid for neutralization reaction, and the reaction liquid obtained by the neutralization reaction is passed into the 21st reaction module for cooling and discharged to obtain a cefminox sodium reaction liquid.

[0035] The synthetic route of cefminox sodium of the present invention is as follows:

[0036]

[0037] The technical features and beneficial effects of the present invention are as follows:

[0038] 1. In the preparation of cefminox sodium of the present invention, water is used as a solvent, and a microreactor is used at high temperature to carry out substitution, acylation and condensation reactions. The reaction time is short, impurities are few, and continuous synthesis reduces the separation of intermediates. It also avoids dust or solvent volatilization generated during manual feeding, inaccurate local temperature control, long feeding time, running, bubbling, dripping, and leakage during material transfer, and occupational hazards caused by manual operation and contact with materials. Automated control is achieved, and the risk and cost of manual operation are reduced, thereby achieving safe, environmentally friendly, healthy, and efficient green chemical production.

[0039] 2. The present invention adopts a continuous flow microreactor to carry out the methoxylation reaction, which has milder conditions than the original ultra-low temperature reaction, and has a fast reaction and high yield, which significantly reduces production costs.

[0040] 3. Compared with processes starting with 7MAC and GCLE, the process route of the present invention has a shorter process length and significantly improved yield due to the specificity and high efficiency of the continuous flow microreaction, the absence of complex protection and deprotection steps, and a significantly improved yield. The molar yield of the present invention reaches 80% based on 7ACA, which is more advantageous than the 50.2% yield of patent document CN102268021A and the 64.7% yield of patent document CN110590812A, which also start with 7ACA. DETAILED DESCRIPTION

[0041] The present invention will be further described below with reference to the embodiments, but the protection scope of the present invention is not limited thereto.

[0042] The raw materials used in the examples are commercially available unless otherwise specified; the methods used are all existing methods unless otherwise specified.

[0043] The continuous flow microreactor used in the embodiment is a Corning G1 glass reactor, which consists of 21 reaction modules. The liquid holding capacity of each reaction module is about 10 mL. The reaction module is designed with multiple heart-shaped channels in series. After the feed liquid enters the reaction module, it can be fully mixed. A high-pressure pump can be used to feed the front and middle of each reaction module. There is a gas-liquid separator at the rear end for back pressure and gas-liquid separation. The reactor is resistant to high temperature and high pressure.

[0044] Example 1

[0045] A method for preparing cefminox sodium in a continuous flow process comprises the following steps:

[0046] 1) Prepare material A: Add 0.1 mol 7-ACA to 80 g water, add 0.15 mol NaHCO3 and stir at 0-10°C until completely dissolved, the total mass is 119.8 g;

[0047] Prepare material B: Add 0.2 mol MMT and 0.4 mol NaOH to 40 g water and stir until completely dissolved. The total mass is 79.2 g.

[0048] Prepare material C: 0.15 mol of chloroacetyl chloride, mass 16.9 g;

[0049] Prepare material D: Add 0.10 mol of D-cysteine ​​hydrochloride to 50 g of water, add 0.30 mol of NaOH at 0-10°C and stir until completely dissolved, the total mass is 79.6 g;

[0050] Prepare material E: Dissolve 0.5 mol of sodium methoxide solid in 150 mL (118.7 g) of methanol and stir at room temperature to dissolve. The total mass is 145.7 g.

[0051] Prepare material G: 0.2 mol of tert-butyl hypochlorite, mass 21.7 g;

[0052] 2) The first to fifth reaction modules of the microreactor were heated to 130°C and a back pressure of 15 bar. Material A and material B were simultaneously pumped into the first reaction module of the microreactor via pumps PA and PB at flow rates of 23.96 g / min and 15.84 g / min, respectively. The resulting mixed solution flowed through the first to fifth reaction modules for a substitution reaction for 60 seconds.

[0053] The 6th to 9th reaction modules were heated to 110°C and a back pressure of 15 bar. At 61 seconds, material C was pumped into the 6th reaction module through pump PC at a flow rate of 3.38 g / min. At the same time, the reaction liquid obtained from the substitution reaction flowed out of the 5th reaction module and flowed into the 6th reaction module. The resulting mixed solution flowed through the 6th to 9th reaction modules for acylation reaction. The reaction time was 48 seconds.

[0054] The 10th to 14th reaction modules were heated to 100°C and a back pressure of 15 bar. At 109 seconds, material D was pumped into the 10th reaction module through the pump PD at a flow rate of 15.92 g / min. At the same time, the reaction liquid obtained from the acylation reaction flowed out of the 9th reaction module and flowed into the 10th reaction module. The resulting mixed solution flowed through the 10th to 14th reaction modules for a condensation reaction. The reaction time was 60 seconds.

[0055] The cooling temperature of the 15th reaction module (cooling module) is set to 30° C. The reaction liquid obtained by the condensation reaction flows out of the 14th reaction module, flows through the 15th reaction module, and is then taken out to obtain the intermediate 2 reaction liquid.

[0056] 3) The reaction mixture of intermediate 2 was temperature-controlled at 20°C. Acetone in an amount equal to the volume of the reaction mixture was added, and an 18 wt% aqueous hydrochloric acid solution was added dropwise to adjust the pH to 2.5. Crystals were precipitated and grown at 20°C for 1 h. The resulting solid was filtered and washed with acetone. The solid was then dried under vacuum at 40°C to constant weight to obtain 39.5 g of intermediate 2 with a molar yield of 80.6% and a purity of 98.2%.

[0057] 4) Prepare material F: Add the intermediate 2 obtained in step (3) to 110 mL (165 g) of chloroform, with a mass of 204.5 g;

[0058] The 16th to 20th reaction modules of the microreactor were heated to 105°C and a back pressure of 18 bar. Materials E, F, and G were simultaneously pumped into the 16th reaction module of the microreactor at flow rates of 18.21 g / min, 25.56 g / min, and 2.71 g / min, respectively. The resulting mixed solution flowed through the 16th to 19th reaction modules for methoxidation reaction with a reaction time of 48 s.

[0059] The temperature of the 20th reaction module was set at 60°C, and 0.3 mol (18.0 g) of glacial acetic acid was pumped in at 49 seconds with a flow rate of 2.25 g / min. At the same time, the reaction liquid obtained from the methoxylation reaction flowed out of the 19th reaction module and flowed into the 20th reaction module for neutralization reaction. The reaction time was 12 seconds.

[0060] The cooling temperature of the 21st reaction module (cooling module) is set to 30° C. The reaction liquid obtained by the neutralization reaction flows out of the 20th reaction module, flows through the 21st reaction module, and is then taken out to obtain the cefminox sodium reaction liquid.

[0061] 5) 300 mL of water was added to the cefminox sodium reaction solution, and the mixture was hydrolyzed at 0-10°C for 1 h. The layers were separated, and the organic solvent was removed by evaporation of the aqueous phase. A 10% (mass fraction) aqueous NaOH solution was added to adjust the pH to 5.2. 300 mL of acetone was slowly added, and the crystals were grown for 2 h after precipitation. The resulting solid was washed with acetone and dried under vacuum at 30°C to constant weight to obtain 51.6 g of cefminox sodium product with a molar yield of 77.3% based on 7-ACA and a purity of 98.5%.

[0062] Example 2

[0063] A method for preparing cefminox sodium in a continuous flow process comprises the following steps:

[0064] 1) Prepare material A: Add 0.1 mol 7-ACA to 80 g water, add 0.12 mol NaHCO3 and stir at 0-10°C until completely dissolved, the total mass is 117.3 g;

[0065] Prepare material B: Add 0.11 mol MMT and 0.22 mol NaOH to 40 g water and stir until completely dissolved, the total mass is 61.6 g;

[0066] Prepare material C: 0.12 mol of chloroacetyl chloride, mass 13.6 g;

[0067] Prepare material D: Add 0.13 mol of D-cysteine ​​hydrochloride to 50 g of water, add 0.39 mol of NaOH at 0-10°C and stir until completely dissolved, the total mass is 88.4 g;

[0068] Prepare material E: Dissolve 0.6 mol of sodium methoxide solid in 150 mL (118.7 g) of methanol and stir at room temperature to dissolve. The total mass is 151.1 g.

[0069] Prepare material G: 0.12 mol of tert-butyl hypochlorite, mass 13.0 g;

[0070] 2) The first to fifth reaction modules of the microreactor were heated to 130°C and a back pressure of 15 bar. Material A and material B were simultaneously pumped into the first reaction module of the microreactor via pumps PA and PB at flow rates of 23.46 g / min and 12.32 g / min, respectively. The resulting mixed solution flowed through the first to fifth reaction modules for a substitution reaction for 60 seconds.

[0071] The 6th to 9th reaction modules were heated to 110°C and a back pressure of 15 bar. At 61 seconds, material C was pumped into the 6th reaction module through the pump PC at a flow rate of 2.72 g / min. At the same time, the reaction liquid obtained by the substitution reaction flowed out of the 5th reaction module and flowed into the 6th reaction module. The resulting mixed solution flowed through the 6th to 9th reaction modules for acylation reaction. The reaction time was 48 seconds.

[0072] The 10th to 14th reaction modules were heated to 100°C and a back pressure of 15 bar. At 109 seconds, material D was pumped into the 10th reaction module through the pump PD at a flow rate of 17.68 g / min. At the same time, the reaction liquid obtained from the acylation reaction flowed out of the 9th reaction module and flowed into the 10th reaction module. The resulting mixed solution flowed through the 10th to 14th reaction modules for a condensation reaction. The reaction time was 60 seconds.

[0073] The cooling temperature of the 15th reaction module (cooling module) is set to 20°C. The reaction liquid obtained by the condensation reaction flows out of the 14th reaction module, flows through the 15th reaction module, and is then taken out to obtain the intermediate 2 reaction liquid.

[0074] 3) The reaction mixture of intermediate 2 was temperature-controlled at 20°C. Acetone in an amount equal to the volume of the reaction mixture was added, and an 18 wt% aqueous hydrochloric acid solution was added dropwise to adjust the pH to 2.6. Crystals were precipitated and grown at 20°C for 1 h. The resulting solid was filtered and washed with acetone. The solid was then dried under vacuum at 40°C to constant weight to obtain 42.1 g of intermediate 2 with a molar yield of 85.8% and a purity of 98.8%.

[0075] 4) Prepare material F: Add the intermediate 2 obtained in step (3) to 220 mL (291.5 g) of dichloromethane, with a mass of 333.6 g;

[0076] The 16th to 20th reaction modules of the microreactor were heated to 105°C and a back pressure of 18 bar. Materials E, F, and G were simultaneously pumped into the 16th reaction module of the microreactor at flow rates of 18.89 g / min, 41.70 g / min, and 1.63 g / min, respectively. The resulting mixed solution flowed through the 16th to 19th reaction modules for methoxidation reaction with a reaction time of 48 s.

[0077] The temperature of the 20th reaction module was set to 40°C, and 0.28 mol (16.8 g) of glacial acetic acid was pumped in at 49 seconds with a flow rate of 2.10 g / min. At the same time, the reaction liquid obtained from the methoxylation reaction flowed out of the 19th reaction module and flowed into the 20th reaction module for neutralization reaction. The reaction time was 12 seconds.

[0078] The cooling temperature of the 21st reaction module (cooling module) is set to 10°C. The reaction liquid obtained by the neutralization reaction flows out of the 20th reaction module, flows through the 21st reaction module, and is then taken out to obtain the cefminox sodium reaction liquid.

[0079] 5) 300 mL of water was added to the cefminox sodium reaction solution, and the mixture was hydrolyzed at 0-10°C for 1 h. The layers were separated, and the organic solvent was removed by evaporation of the aqueous phase. A 10% (mass fraction) aqueous NaOH solution was added to adjust the pH to 5.2. 300 mL of acetone was slowly added, and the crystals were grown for 2 h after precipitation. The resulting solid was washed with acetone and dried under vacuum at 30°C to constant weight to obtain 53.9 g of cefminox sodium product, with a molar yield of 80.8% based on 7-ACA and a purity of 98.9%.

[0080] Example 3

[0081] A method for preparing cefminox sodium in a continuous flow process comprises the following steps:

[0082] 1) Prepare material A: Add 0.1 mol 7-ACA to 80 mL of water, add 0.1 mol NaHCO3 and stir at 0-10°C until completely dissolved, the total mass is 115.6 g;

[0083] Prepare material B: Add 0.11 mol MMT and 0.22 mol NaOH to 40 g water and stir until completely dissolved, the total mass is 61.6 g;

[0084] Prepare material C: 0.12 mol of chloroacetyl chloride, mass 13.6 g;

[0085] Prepare material D: Add 0.15 mol of D-cysteine ​​hydrochloride to 50 g of water, add 0.45 mol of NaOH at 0-10°C and stir until completely dissolved, the total mass is 94.3 g;

[0086] Prepare material E: Dissolve 1.0 mol of solid sodium methoxide in 150 mL (118.7 g) of methanol and stir at room temperature to dissolve. The total mass is 172.7 g.

[0087] Prepare material G: 0.2 mol of tert-butyl hypochlorite, mass 21.7 g;

[0088] 2) The first to fifth reaction modules of the microreactor were heated to 130°C and a back pressure of 15 bar. Material A and material B were simultaneously pumped into the first reaction module of the microreactor via pumps PA and PB at flow rates of 23.12 g / min and 12.32 g / min, respectively. The resulting mixed solution was passed through the first to fifth reaction modules for a substitution reaction for 60 seconds.

[0089] The 6th to 9th reaction modules were heated to 110°C and a back pressure of 15 bar. At 61 seconds, material C was pumped into the 6th reaction module through the pump PC at a flow rate of 2.72 g / min. At the same time, the reaction liquid obtained by the substitution reaction flowed out of the 5th reaction module and flowed into the 6th reaction module. The resulting mixed solution flowed through the 6th to 9th reaction modules for acylation reaction. The reaction time was 48 seconds.

[0090] The 10th to 14th reaction modules were heated to 100°C and a back pressure of 15 bar. At 109 seconds, material D was pumped into the 10th reaction module through the pump PD at a flow rate of 18.86 g / min. At the same time, the reaction liquid obtained from the acylation reaction flowed out of the 9th reaction module and flowed into the 10th reaction module. The resulting mixed solution flowed through the 10th to 14th reaction modules for a condensation reaction. The reaction time was 60 seconds.

[0091] The cooling temperature of the 15th reaction module (cooling module) is set to 20°C. The reaction liquid obtained by the condensation reaction flows out of the 14th reaction module, flows through the 15th reaction module, and is then taken out to obtain the intermediate 2 reaction liquid.

[0092] 3) The reaction mixture of intermediate 2 was temperature-controlled at 20°C. An equal volume of ethanol was added to the reaction mixture. An 18 wt% aqueous hydrochloric acid solution was added dropwise to adjust the pH to 3.0. Crystals were precipitated and grown at 20°C for 1 h. The resulting solid was filtered and washed with ethanol. The solid was then dried under vacuum at 40°C to constant weight to obtain 40.8 g of intermediate 2 with a molar yield of 83.4% and a purity of 98.6%.

[0093] 4) Prepare material F: Add the intermediate 2 obtained in step (3) to 460 mL (361.6 g) of acetonitrile, with a mass of 402.4 g;

[0094] The 16th to 20th reaction modules of the microreactor were heated to 105°C and a back pressure of 18 bar. Materials E, F, and G were simultaneously pumped into the 16th reaction module of the microreactor at flow rates of 21.59 g / min, 50.30 g / min, and 2.71 g / min, respectively. The resulting mixed solution was passed through the 16th to 19th reaction modules for methoxidation reaction with a reaction time of 48 s.

[0095] The temperature of the 20th reaction module was set to 40°C, and 0.30 mol of glacial acetic acid (18.0 g) was pumped in at 49 seconds with a flow rate of 2.25 g / min. At the same time, the reaction liquid obtained from the methoxylation reaction flowed out of the 19th reaction module and flowed into the 20th reaction module for neutralization reaction. The reaction time was 12 seconds.

[0096] The cooling temperature of the 21st reaction module (cooling module) is set to 10°C. The reaction liquid obtained by the neutralization reaction flows out of the 20th reaction module, flows through the 21st reaction module, and is then taken out to obtain the cefminox sodium reaction liquid.

[0097] 5) Add 250 mL of water to the cefminox sodium reaction solution and hydrolyze at 0-10°C for 1 h. Separate the layers, evaporate the aqueous phase to remove the organic solvent, add 10% (mass fraction) NaOH aqueous solution to adjust the pH to 5.2, slowly add 250 mL of ethanol, allow the crystals to precipitate, grow for 2 h, and filter. The resulting solid was washed with ethanol and dried under vacuum at 30°C to constant weight to obtain 53.5 g of cefminox sodium product, with a molar yield of 80.2% based on 7-ACA and a purity of 98.8%.

[0098] Comparative Example 1

[0099] A method for preparing cefminox sodium in a continuous flow process comprises the following steps:

[0100] 1) Prepare material A: Add 0.1 mol 7-ACA to 80 g water, add 0.12 mol NaHCO3 and stir at 0-10°C until completely dissolved, the total mass is 117.3 g;

[0101] Prepare material B: Add 0.11 mol MMT and 0.22 mol NaOH to 40 g water and stir until completely dissolved, the total mass is 61.6 g;

[0102] Prepare material C: 0.12 mol of chloroacetyl chloride, mass 13.6 g;

[0103] Prepare material D: Add 0.13 mol of D-cysteine ​​hydrochloride to 50 g of water, add 0.39 mol of NaOH at 0-10°C and stir until completely dissolved, the total mass is 88.4 g;

[0104] Prepare material E: Dissolve 0.6 mol of sodium methoxide solid in 150 mL (118.7 g) of methanol and stir at room temperature to dissolve. The total mass is 151.1 g.

[0105] Prepare material G: 0.12 mol of tert-butyl hypochlorite, mass 13.0 g;

[0106] 2) Add A and B into the autoclave separately, seal it, heat it to 130℃, and keep it warm for 60 seconds;

[0107] The temperature was lowered to 110°C, material C was pumped into the autoclave, and the reaction was kept at this temperature for 48 seconds;

[0108] The temperature was lowered to 100°C, material D was pumped into the autoclave, and the reaction was carried out for 60 seconds;

[0109] 3) After the reaction, the temperature was lowered to 20°C, and an equal volume of acetone was added to the reaction solution. An 18 wt% aqueous hydrochloric acid solution was added dropwise to adjust the pH to 2.6 to precipitate crystals. The crystals were grown at 20°C for 1 hour. The feed solution and the product were both dark in color. The solid was filtered and washed with acetone. It was then vacuum-dried at 40°C to constant weight to yield 36.5 g of a dark viscous solid. The content of intermediate 2 was only 78%, and the molar yield was only 58%.

[0110] From the above comparison, it can be seen that the high temperature and high pressure conditions suitable for microreactors are not applicable in kettle reactions, and the color and yield of intermediate 2 product are significantly deteriorated.

[0111] Comparative Example 2

[0112] A method for preparing cefminox sodium in a continuous flow process comprises the following steps:

[0113] 1) Prepare material A: Add 0.1 mol 7-ACA to 80 g water, add 0.12 mol NaHCO3 and stir at 0-10°C until completely dissolved, the total mass is 117.3 g;

[0114] Prepare material B: Add 0.11 mol MMT and 0.22 mol NaOH to 40 g water and stir until completely dissolved, the total mass is 61.6 g;

[0115] Prepare material C: 0.12 mol of chloroacetyl chloride, mass 13.6 g;

[0116] Prepare material D: Add 0.13 mol of D-cysteine ​​hydrochloride to 50 g of water, add 0.39 mol of NaOH at 0-10°C and stir until completely dissolved, the total mass is 88.4 g;

[0117] Prepare material E: Dissolve 0.6 mol of sodium methoxide solid in 150 mL (118.7 g) of methanol and stir at room temperature to dissolve. The total mass is 151.1 g.

[0118] Prepare material G: 0.12 mol of tert-butyl hypochlorite, mass 13.0 g;

[0119] 2) The first to fifth reaction modules of the microreactor were heated to 110°C and a back pressure of 15 bar. Material A and material B were simultaneously pumped into the first reaction module of the microreactor via pumps PA and PB at flow rates of 23.46 g / min and 12.32 g / min, respectively. The resulting mixed solution flowed through the first to fifth reaction modules for a substitution reaction for 60 seconds.

[0120] The 6th to 9th reaction modules were heated to 90°C and a back pressure of 15 bar. At 61 seconds, material C was pumped into the 6th reaction module through the pump PC at a flow rate of 2.72 g / min. At the same time, the reaction liquid obtained by the substitution reaction flowed out of the 5th reaction module and flowed into the 6th reaction module. The resulting mixed solution flowed through the 6th to 9th reaction modules for acylation reaction. The reaction time was 48 seconds.

[0121] The 10th to 14th reaction modules were heated to 80°C and a back pressure of 15 bar. At 109 seconds, material D was pumped into the 10th reaction module through the pump PD at a flow rate of 17.68 g / min. At the same time, the reaction liquid obtained from the acylation reaction flowed out of the 9th reaction module and flowed into the 10th reaction module. The resulting mixed solution flowed through the 10th to 14th reaction modules for a condensation reaction. The reaction time was 60 seconds.

[0122] The cooling temperature of the 15th reaction module (cooling module) is set to 20°C. The reaction liquid obtained by the condensation reaction flows out of the 14th reaction module, flows through the 15th reaction module, and is then taken out to obtain the intermediate 2 reaction liquid.

[0123] 3) The reaction mixture of intermediate 2 was temperature-controlled at 20°C. Acetone in an equal volume to the reaction mixture was added, and an 18 wt% aqueous hydrochloric acid solution was added dropwise to adjust the pH to 2.6. Crystals were precipitated and grown at 20°C for 1 h. The resulting solid was filtered and washed with ethanol. The solid was then dried under vacuum at 40°C to constant weight to obtain 35.4 g of intermediate 2 with a molar yield of 72.4% and a purity of 95.6%.

[0124] 4) Prepare material F: Add the intermediate 2 obtained in step (3) to 220 mL (291.5 g) of dichloromethane, with a mass of 326.9 g;

[0125] The 16th to 20th reaction modules of the microreactor were heated to 105°C and a back pressure of 18 bar. Materials E, F, and G were simultaneously pumped into the 16th reaction module of the microreactor at flow rates of 18.89 g / min, 40.86 g / min, and 1.63 g / min, respectively. The resulting mixed solution flowed through the 16th to 19th reaction modules for methoxidation reaction with a reaction time of 48 s.

[0126] The temperature of the 20th reaction module was set to 40°C, and 0.28 mol (16.8 g) of glacial acetic acid was pumped in at 49 seconds with a flow rate of 2.10 g / min. At the same time, the reaction liquid obtained from the methoxylation reaction flowed out of the 19th reaction module and flowed into the 20th reaction module for neutralization reaction. The reaction time was 12 seconds.

[0127] The cooling temperature of the 21st reaction module (cooling module) is set to 10°C. The reaction liquid obtained by the neutralization reaction flows out of the 20th reaction module, flows through the 21st reaction module, and is then taken out to obtain the cefminox sodium reaction liquid.

[0128] 5) 300 mL of water was added to the cefminox sodium reaction solution, and the mixture was hydrolyzed at 0-10°C for 1 h. The layers were separated, and the organic solvent was removed by evaporation of the aqueous phase. A 10% (mass fraction) aqueous NaOH solution was added to adjust the pH to 5.2. 300 mL of acetone was slowly added, and the crystals were grown for 2 h after precipitation. The resulting solid was washed with acetone and dried under vacuum at 30°C to constant weight to obtain 42.9 g of cefminox sodium product, with a molar yield of 64.2% based on 7-ACA and a purity of 95.8%.

[0129] Comparative Example 3

[0130] A method for preparing cefminox sodium in a continuous flow process comprises the following steps:

[0131] 1) Prepare material A: Add 0.1 mol 7-ACA to 80 g water, add 0.12 mol NaHCO3 and stir at 0-10°C until completely dissolved, the total mass is 117.3 g;

[0132] Prepare material B: Add 0.11 mol MMT and 0.22 mol NaOH to 40 g water and stir until completely dissolved, the total mass is 61.6 g;

[0133] Prepare material C: 0.12 mol of chloroacetyl chloride, mass 13.6 g;

[0134] Prepare material D: Add 0.13 mol of D-cysteine ​​hydrochloride to 50 g of water, add 0.39 mol of NaOH at 0-10°C and stir until completely dissolved, the total mass is 88.4 g;

[0135] Prepare material E: Dissolve 0.6 mol of sodium methoxide solid in 150 mL (118.7 g) of methanol and stir at room temperature to dissolve. The total mass is 151.1 g.

[0136] Prepare material G: 0.12 mol of tert-butyl hypochlorite, mass 13.0 g;

[0137] 2) The first to fifth reaction modules of the microreactor were heated to 150°C and a back pressure of 15 bar. Material A and material B were simultaneously pumped into the first reaction module of the microreactor via pumps PA and PB at flow rates of 23.46 g / min and 12.32 g / min, respectively. The resulting mixed solution flowed through the first to fifth reaction modules for a substitution reaction for 60 seconds.

[0138] The 6th to 9th reaction modules were heated to 130°C and a back pressure of 15 bar. At 61 seconds, material C was pumped into the 6th reaction module through the pump PC at a flow rate of 2.72 g / min. At the same time, the reaction liquid obtained by the substitution reaction flowed out of the 5th reaction module and flowed into the 6th reaction module. The resulting mixed solution flowed through the 6th to 9th reaction modules for acylation reaction. The reaction time was 48 seconds.

[0139] The 10th to 14th reaction modules were heated to 120°C and a back pressure of 15 bar. At 109 seconds, material D was pumped into the 10th reaction module through the pump PD at a flow rate of 17.68 g / min. At the same time, the reaction liquid obtained from the acylation reaction flowed out of the 9th reaction module and flowed into the 10th reaction module. The resulting mixed solution flowed through the 10th to 14th reaction modules for a condensation reaction. The reaction time was 60 seconds.

[0140] The cooling temperature of the 15th reaction module (cooling module) is set to 20°C. The reaction liquid obtained by the condensation reaction flows out of the 14th reaction module, flows through the 15th reaction module, and is then taken out to obtain the intermediate 2 reaction liquid.

[0141] 3) The reaction mixture of intermediate 2 was temperature-controlled at 20°C. Acetone in an amount equal to the volume of the reaction mixture was added, and an 18 wt% aqueous hydrochloric acid solution was added dropwise to adjust the pH to 2.6. Crystals were precipitated and grown at 20°C for 1 h. The resulting solid was filtered and washed with acetone. The solid was then dried under vacuum at 40°C to constant weight to obtain 33.9 g of intermediate 2 with a molar yield of 69.3% and a purity of 96.2%.

[0142] 4) Prepare material F: Add the intermediate 2 obtained in step (3) to 220 mL (291.5 g) of dichloromethane, with a mass of 325.4 g;

[0143] The 16th to 20th reaction modules of the microreactor were heated to 105°C and a back pressure of 18 bar. Materials E, F, and G were simultaneously pumped into the 16th reaction module of the microreactor at flow rates of 18.89 g / min, 40.68 g / min, and 1.63 g / min, respectively. The resulting mixed solution flowed through the 16th to 19th reaction modules for methoxidation reaction with a reaction time of 48 s.

[0144] The temperature of the 20th reaction module was set to 40°C, and 0.28 mol (16.8 g) of glacial acetic acid was pumped in at 49 seconds with a flow rate of 2.10 g / min. At the same time, the reaction liquid obtained from the methoxylation reaction flowed out of the 19th reaction module and flowed into the 20th reaction module for neutralization reaction. The reaction time was 12 seconds.

[0145] The cooling temperature of the 21st reaction module (cooling module) is set to 10°C. The reaction liquid obtained by the neutralization reaction flows out of the 20th reaction module, flows through the 21st reaction module, and is then taken out to obtain the cefminox sodium reaction liquid.

[0146] 5) 300 mL of water was added to the cefminox sodium reaction solution, and the mixture was hydrolyzed at 0-10°C for 1 h. The layers were separated, and the organic solvent was removed by evaporation of the aqueous phase. A 10% (mass fraction) aqueous NaOH solution was added to adjust the pH to 5.2. 300 mL of acetone was slowly added, and the crystals were grown for 2 h after precipitation. The resulting solid was washed with acetone and dried under vacuum at 30°C to constant weight to obtain 38.1 g of cefminox sodium product, with a molar yield of 57.1% based on 7-ACA and a purity of 95.2%.

[0147] From the above comparison, it can be seen that due to the special structure of the microreactor, the reaction contact area is large and the mass transfer efficiency is high. In the first three steps, the temperature has the greatest impact on the reaction. Lowering it will affect the reaction efficiency, and increasing it will accelerate degradation. The temperature value screened by this patent is the optimal one.

[0148] The above description is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by any technician familiar with this technical field within the technical scope disclosed in the present invention should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing cefminox sodium by continuous flow, characterized in that: The following steps are involved: (1) 7-aminocephalosporanic acid and NaHCO3 were added to water to obtain material A; 1-methyl-5-mercaptotetrazole and NaOH were added to water to obtain material B; chloroacetyl chloride was used as material C; D-cysteine ​​hydrochloride and NaOH were added to water to obtain material D; (2) Material A and material B are introduced into a continuous flow microreactor respectively for substitution reaction; material C is then introduced into the continuous flow microreactor, mixed with the reaction solution obtained by the substitution reaction, and acylation reaction is carried out; material D is then introduced into the continuous flow microreactor, mixed with the reaction solution obtained by the acylation reaction, and condensation reaction is carried out to obtain an intermediate 2 reaction solution, which is acidified and crystallized to obtain an intermediate 2; the molar ratio of 1-methyl-5-mercaptotetrazole in the material B to 7-aminocephalosporanic acid in the material A is (1-2):1, and the temperature of the substitution reaction is 125-135°C; the molar ratio of chloroacetyl chloride in the material C to 7-aminocephalosporanic acid in the material A is (1-1.5):1, and the temperature of the acylation reaction is 105-115°C; the molar ratio of D-cysteine ​​hydrochloride in the material D to 7-aminocephalosporanic acid in the material A is (1.0-1.5):1, and the temperature of the condensation reaction is 100-110°C; ； (3) Dissolving the intermediate 2 in an organic solvent to obtain material F, sodium methoxide methanol solution as material E, and tert-butyl hypochlorite as material G, respectively introducing materials E, F, and G into a continuous flow microreactor to carry out an oxyacetic acid reaction; then introducing glacial acetic acid into the continuous flow microreactor, mixing with the reaction solution obtained from the oxyacetic acid reaction, carrying out a neutralization reaction, cooling to obtain a cefuroxime sodium reaction solution, and hydrolyzing and crystallizing to obtain cefuroxime sodium; the molar ratio of sodium methoxide in the material E to 7-aminocephalosporanic acid in the material A is (5-10):1; the molar ratio of tert-butyl hypochlorite in the material G to 7-aminocephalosporanic acid in the material A is (1-2):1; the temperature of the oxyacetic acid reaction is 100-110°C, and the back pressure is 15-20 bar.

2. The method for preparing cefminox sodium by continuous flow according to claim 1, wherein In step (1), the ratio of the number of moles of 7-aminocephalosporanic acid in material A to the mass of water is 0.1-0.15 mol:80 g, the molar ratio of NaHCO3 to 7-aminocephalosporanic acid in material A is (1-1.5):1, and the NaHCO3 is added to water at 0-10°C; the ratio of the number of moles of 1-methyl-5-mercaptotetrazole in material B to the mass of water is 0.1-0.2 mol:40 g; the molar ratio of sodium hydroxide to 1-methyl-5-mercaptotetrazole in material B is 2:1; the ratio of the number of moles of D-cysteine ​​hydrochloride in material D to the mass of water is 0.1-0.15 mol:50 g; the molar ratio of NaOH to D-cysteine ​​hydrochloride in material D is 3:1, and the NaOH is added to water at 0-10°C.

3. The method for preparing cefminox sodium by continuous flow according to claim 1, wherein The molar ratio of 1-methyl-5-mercaptotetrazole in material B to 7-aminocephalosporanic acid in material A in step (2) is 1.2:1; The flow rate of material A is 23-24 g / min; the flow rate of material B is 11.9-15.9 g / min; the time for the substitution reaction of material A and material B is 30-90 s, and the back pressure is 15-20 bar.

4. The method for preparing cefminox sodium by continuous flow according to claim 1, wherein The molar ratio of chloroacetyl chloride in material C to 7-aminocephalosporanic acid in material A in step (2) is 1.2:1; The flow rate of the material C is 2.2-3.4 g / min; the acylation reaction time is 20-60 s, and the back pressure is 15-20 bar.

5. The method for preparing cefminox sodium by continuous flow according to claim 1, wherein The molar ratio of D-cysteine ​​hydrochloride in material D to 7-aminocephalosporanic acid in material A in step (2) is 1.3:1; The flow rate of the material D is 15.9-18.9 g / min; the condensation reaction time is 30-90 s, and the back pressure is 15-20 bar.

6. The method for preparing cefminox sodium by continuous flow according to claim 1, wherein In step (2), after the condensation reaction is completed, the reaction mixture is cooled to 10-30° C. to obtain an intermediate 2 reaction solution; the obtained intermediate 2 reaction solution flows out from the continuous flow microreactor and is acidified and crystallized; The acidification crystallization step comprises: adding acetone or ethanol in an equal volume to the reaction solution of intermediate 2, then adding an 18 wt% aqueous hydrochloric acid solution or a 10 wt% aqueous sulfuric acid solution to adjust the pH to 2.5-3.0, and crystallizing at 10-20° C. for 1-2 hours; then filtering, washing the obtained solid with acetone or ethanol, and vacuum drying at 35-40° C. to constant weight to obtain intermediate 2.

7. The method for preparing cefminox sodium by continuous flow according to claim 1, wherein The ratio of the molar number of sodium methoxide to the volume of methanol in the material E in step (3) is 0.5-1 mol:150 mL; The molar ratio of sodium methoxide in the material E to 7-aminocephalosporanic acid in the material A is 6:

1.

8. The method for preparing cefminox sodium by continuous flow according to claim 1, wherein The organic solvent in step (3) is one or a combination of two or more of dichloromethane, chloroform, DMF, and acetonitrile; the mass fraction of intermediate 2 in the material F is 10-20%; The molar ratio of tert-butyl hypochlorite in the material G to 7-aminocephalosporanic acid in the material A is 1.2:

1.

9. The method for preparing cefminox sodium by continuous flow according to claim 1, wherein In step (3), the flow rate of material E is 18.2-21.6 g / min; the flow rate of material F is 25-60 g / min; the flow rate of material G is 1.3-2.8 g / min; and the methoxidation reaction time is 20-60 s.

10. The method for preparing cefminox sodium by continuous flow according to claim 1, characterized in that: The molar ratio of glacial acetic acid to 7-aminocephalosporanic acid in material A in step (3) is (2.5-3.0):1; the flow rate of the glacial acetic acid is 1.8-2.3 g / min; the temperature of the neutralization reaction is 35-40° C., and the neutralization reaction time is 12-24 s; then the reaction mixture is cooled to 10-30° C. to obtain a cefminox sodium reaction solution; The hydrolysis and crystallization steps in step (3) are as follows: adding water to the cefuroxime sodium reaction solution, wherein the added volume of the water is 0.5-5 times the volume of the organic solvent for dissolving the intermediate 2, and then hydrolyzing at 0-10°C for 0.5-1h; then separating the liquids, distilling the obtained aqueous phase under reduced pressure to remove the organic solvent, adding a 10% by mass fraction of NaOH aqueous solution to adjust the pH to 4-6, adding acetone or ethanol for crystallization, and after precipitation, growing the crystals at room temperature for 1-2h, filtering, washing with acetone or ethanol, and then vacuum drying at 30-35°C to constant weight to obtain the cefuroxime sodium product; the volume of acetone or ethanol added for crystallization is the same as the volume of water added to the cefuroxime sodium reaction solution.

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