CN115073459A - Continuous flow synthesis method of avibactam sodium intermediate - Google Patents
Continuous flow synthesis method of avibactam sodium intermediate Download PDFInfo
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Abstract
The invention discloses a continuous flow synthesis method of an avibactam sodium intermediate, relates to the technical field of pharmaceutical chemistry synthesis, and obtains an avibactam sodium intermediate II by carrying out a continuous flow hydrogenation process on an avibactam sodium intermediate I. The synthesis process comprises the steps of taking a suspension of a compound I, a catalyst and a solvent as a material I, taking hydrogen as a material II, and carrying out continuous flow hydrogenation to synthesize the intermediate II through a microchannel hydrogenation reactor, wherein the reaction temperature is 40-80 ℃, the reaction time is 60-350s, and the pressure is 15-100 bar. The process has short reaction time, small reaction liquid holding volume and no amplification effect; the use of a hydrogenation pressure reactor is avoided, and the process safety risk is low; the molar yield is more than 90 percent, the purity is more than 99 percent, and the method is favorable for industrial continuous production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a continuous flow synthesis method of an avibactam sodium intermediate.
Background
Abamebactam sodium, Chinese name: (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide sodium salt having the formula:
abamebactam, a novel beta-lactamase inhibitor developed by Novexel corporation), was patented in 2011, and Actavis was first marketed by FDA in 2015 for 2 months, with the domestic trade name of Sifutuo. Three similar mechanism drugs are on the market in domestic market, and compared with beta-lactamase inhibitors (sulbactam, tazobactam and clavulanic acid), the action time is long; form reversible covalent binding with beta-lactamase; and does not induce the generation of beta-lactamase. When the antibacterial composition is used in combination with other beta-lactam antibiotics (such as cephalosporin and carbapenem antibiotics), the antibacterial composition has broad-spectrum antibacterial activity, and particularly has remarkable antibacterial activity on escherichia coli and klebsiella pneumoniae with strong beta-lactam antibiotic resistance. In 2012, studies of Dubreui and the like find that, aiming at the bacteriostasis of 316 anaerobic strains, the ceftazidime-abamectin-metronidazole combination (8:8:1) inhibits 290 times, experiments show that the high-efficiency bacteriostatic activity is high, and the bacteriostasis of the anaerobic strains by the three-medicine combination is as high as 91.8%. The composition shows synergistic effect or synergistic effect on most strains, and no strain resistance is found. Therefore, the research on the new synthetic route of the avibactam sodium has great application value.
CN1468242 and CN102834395 disclose a method for synthesizing abamectin, and the synthetic route is as follows: the compound patents CN1289500C, CN103649051B and CN105294690B disclose
The compound patent CN107417686A discloses a synthesis method of abamectin, and the synthesis route is as follows:
in the course of researching compound II, referring to a plurality of patents, the compound II is used as a key intermediate for synthesizing the avibactam sodium after being finished, the method needs to synthesize the important intermediate avibactam sodium compound II by using a catalytic hydrogenation mode, and the synthesis method uses a traditional batch pressure hydrogenation reaction kettle for hydrogenation synthesis. The traditional intermittent pressure hydrogenation reaction kettle is difficult to avoid in production, consumes long time, has low conversion rate and more impurities, and has safety risk.
Disclosure of Invention
The invention aims to provide a new hydrogenation synthesis method suitable for realizing continuous and automatic future industry, optimizes the traditional hydrogenation process, and provides a continuous flow hydrogenation synthesis method of an avibactam sodium intermediate. Compared with the conventional catalytic hydrogenation process of an intermittent pressure hydrogenation reaction kettle, the method avoids the problems of high-pressure hydrogen, long reaction time and the like in the hydrogenation process, thereby ensuring the safety in the production process; the process has short reaction time, small liquid holding volume and no amplification effect, and essentially changes the safety of the reaction; compared with the batch reaction, the method avoids the dangerous process of reaction discharging, and is easier to realize the continuous and automatic industrial production; the conversion rate of the target product is more than 90 percent, the purity is more than 99 percent, and the method is beneficial to modern industrialization.
The technical solution of the invention is as follows:
a continuous flow synthesis method of an avibactam sodium intermediate is characterized in that a mixed solution of an avibactam sodium intermediate I, a catalyst, a protic solvent and an acid-binding agent is used as a first material, hydrogen is used as a second material, hydrogenation reaction is carried out in a continuous micro-reaction hydrogenation reactor, and the avibactam sodium intermediate II is synthesized by continuous flow hydrogenation under proper conditions; the synthetic route is as follows:
wherein R is 1 Represents: a benzyl group;
wherein R is 2 Quaternary ammonium salts: represents tetraoctylammonium bromide, tetrahexylammonium bromide, trioctylmethylammonium bromide, tributylhexylammonium bromide;
wherein the avibactam sodium intermediate I is (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1]Octane-2-carboxamides, in which R 1 Represents: a benzyl group;
wherein the intermediate II of the avibactam sodium is (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-tetrabutyl quaternary ammonium salt positive ion, tetraoctyl ammonium quaternary ammonium salt positive ion and trioctylmethylammonium quaternary ammonium salt positive ion; wherein, R2 quaternary ammonium salt: n-tetrabutylammonium quaternary ammonium salt positive ion, tetraoctylammonium quaternary ammonium salt positive ion and trioctylmethylammonium quaternary ammonium salt positive ion;
further, in the reaction, the catalyst is one or two of palladium carbon or palladium hydroxide, preferably the palladium carbon is matched with the palladium hydroxide; preferably, the mass ratio of the palladium carbon to the palladium hydroxide is 1: 1.
Further, in the reaction, the palladium-carbon catalyst has a palladium loading of 5 to 10 wt%, preferably a palladium loading of 10 wt%,
further, in the reaction, the mass ratio of the avibactam sodium intermediate I to the catalyst amount is not limited to 1: 0.06-0.15, preferably in a ratio of 1: 0.06-0.1.
Further, in the reaction, the acid-binding agent includes but is not limited to triethylamine, N-diisopropylethylamine, and pyridine. N, N-diisopropylethylamine is preferred.
Further, in the reaction, the protic solvent includes, but is not limited to, methanol, ethanol, isopropanol, and water, and the solvent may be one or two of them, preferably isopropanol and water; the ratio of the two solvents is not limited to 1:1-10, and the ratio of water and isopropanol is preferably 1: 7.
Further, in the reaction, the mass ratio of the avibactam sodium intermediate I to the single or mixed solvent is not limited to 1:1-20, preferably the mass ratio of the intermediate I to the solvent is 1:20, and more preferably 1: 12.
Furthermore, the microchannel hydrogenation reactor comprises a first flow path, a second flow path, a third flow path, a preheating module, a reaction module and a gas-liquid separation device, wherein the materials sequentially pass through the preheating module, the reaction module and the gas-liquid separation device via the first flow path, the second material enters the reaction module via the second flow path, and the solvent, the catalyst and the acid binding agent separated from the third flow path are returned to the first flow path for reuse.
Further, in the reaction, the flow rate of the first material is 50-150g/min, preferably 80 g/min; the flow rate of the second material is 600-2000ml/min, preferably 1100ml/min under the standard condition (1 standard atmospheric pressure condition).
Further, in the reaction, the temperature of the preheating module is 40-80 ℃, and the reaction temperature refers to that the temperature in the reaction module is 40-80 ℃, and preferably 60 ℃; the reaction pressure is 15 to 100bar, preferably 20 bar.
Further, in the reaction, the reaction time is 60 to 350s, preferably 100 s.
Compared with the existing intermittent hydrogenation technology, the invention has the following beneficial effects:
1) compared with the traditional intermittent pressure hydrogenation reaction kettle, the continuous micro-reaction hydrogenation reactor is adopted for hydrogenation synthesis, so that the liquid holding volume in the reaction process is small, the potential safety hazard of hydrogenation reaction is reduced, and the safety of reaction and production is greatly improved; the process has short reaction time, small reaction liquid holding volume and no amplification effect, and essentially changes the safety of the reaction; the purity of the product in the reaction liquid is more than 90 percent; the related product (the avibactam sodium intermediate II) obtained by carrying out post-treatment steps of catalyst separation, organic solvent extraction, pH value adjustment, salt formation by ion pairing, organic solvent extraction, washing, concentration, decoloration, steaming, crystallization, drying and the like on the reaction liquid has the molar yield of more than 90 percent and the product purity of more than 99.0 percent, and is beneficial to industrial production.
2) The invention uses an acid-binding agent to reduce H + The corrosion to steel is more suitable for the microchannel reactor made of steel.
3) The reaction time of the invention is greatly shortened to 60 to 350s from 5 to 24 hours of the reaction in the batch pressure hydrogenation reaction kettle.
4) The process shows no amplification effect through test results of a plurality of groups of reaction modules, and provides a new continuous flow reaction method for preparing the avibactam sodium intermediate II from the avibactam sodium intermediate I.
5) The invention utilizes the high-efficiency mixing and excellent mass transfer and heat transfer performance of the microreactor, strengthens the interphase mass transfer and heat transfer capacity in the reaction process, can obviously reduce the volume of the reactor, improves the reaction yield and improves the production efficiency and safety. The method can solve the problems of low production efficiency, poor reaction purity, high device danger and the like in the batch type pressure hydrogenation reaction kettle process, can realize continuous automatic operation of the process, and has the advantages of high yield, good safety and the like.
Drawings
FIG. 1 is a continuous flow synthesis process flow of an avibactam sodium intermediate I.
Detailed Description
The objects, features and advantages of the present invention will be more clearly understood and appreciated from the following description taken in conjunction with the accompanying drawings, and the description of the invention will be further explained. Unless otherwise specified, the starting materials are all commercially available; a high-flux microchannel hydrogenation reactor G1-1 is adopted; corning incorporated, usa.
Example 1: preparation of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide n-tetrabutylammonium salt
1. The device comprises the following steps: a continuous flow microchannel hydrogenation reactor, wherein a microchannel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is ethanol;
2. as shown in fig. 1, flow path one: preparing feed liquid, stirring 50.0g of the compound (I), 3.0g of palladium hydroxide catalyst, 180ml of water and 420ml of isopropanol to form suspension, pumping the suspension into a microchannel reactor through a material pump, and setting the flow rate to be 50.0g/min through a metering module. Compound (I) is: (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide.
3. A second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 1100 ml/min;
4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 20 bar;
5. the system was set to a circulation temperature of 60 ℃ and after reaction for 300 seconds through 8 reaction modules (204ml volume) of the continuous flow reactor, the reaction solution was collected. The purity of (2S,5R) -6- (hydroxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide in the reaction mixture was 95.33%. Filtering to remove palladium carbon in the reaction liquid, transferring the reaction liquid into a sulfonation kettle for sulfonation (a sulfonation tester is a complex of sulfur trioxide), extracting the reaction liquid by butyl acetate organic phase, forming salt by ion pair (an ammonium ion source is n-tetrabutyl quaternary ammonium salt positive ion), extracting a product by dichloromethane, drying anhydrous sodium sulfate, concentrating under reduced pressure, performing evaporation crystallization by 4-methyl-2-pentanone, filtering, leaching by 4-methyl-2-pentanone, and drying under reduced pressure to obtain (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-tetrabutyl quaternary ammonium salt. The purity of the liquid chromatogram is 99.99 percent, the maximum single impurity is not detected, and the molar yield is 91.11 percent.
Example 2: preparation of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide n-tetraoctylammonium Quaternary ammonium salt
1. The device comprises the following steps: a continuous flow microchannel hydrogenation reactor, wherein a microchannel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is ethanol;
2. as shown in fig. 1, flow path one: preparing feed liquid, stirring 50.0g of the compound (I), 3.0g of palladium hydroxide catalyst, 180ml of water and 420ml of isopropanol to form suspension, pumping the suspension into a microchannel reactor through a material pump, and setting the flow rate to be 50.0g/min through a metering module. Compound (I) is: (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide.
3. A second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 1100 ml/min; 4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 20 bar;
5. the system was set at a circulating temperature of 60 ℃ and reacted for 300 seconds through 8 reaction modules (204ml volume) of the continuous flow reactor, and then the reaction solution was collected. The purity of (2S,5R) -6- (hydroxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide in the reaction mixture was 95.13%. Filtering to remove palladium carbon in the reaction liquid, transferring the reaction liquid into a sulfonation kettle for sulfonation (a sulfonation tester is a complex of sulfur trioxide), extracting the reaction liquid by using butyl acetate organic phase, forming salt by ion pair (ammonium ion source is tetraoctyl ammonium quaternary ammonium salt positive ion), extracting a product by using dichloromethane, drying anhydrous sodium sulfate, concentrating under reduced pressure, performing evaporation crystallization by using 4-methyl-2-pentanone, filtering, leaching by using 4-methyl-2-pentanone, and drying under reduced pressure to obtain (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-tetraoctyl ammonium quaternary ammonium salt. The purity of the liquid chromatogram is 99.99 percent, the maximum single impurity is not detected, and the molar yield is 92.15 percent.
Example 3: preparation of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide n-trioctylmethylammonium Quaternary salt
1. The device comprises the following steps: a continuous flow microchannel hydrogenation reactor, wherein a microchannel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to the flow rate and the reaction residence time, and a heat exchange medium is ethanol;
2. as shown in fig. 1, flow path one: preparing feed liquid, stirring 50.0g of the compound (I), 3.0g of palladium hydroxide catalyst, 180ml of water and 420ml of isopropanol to form suspension, pumping the suspension into a microchannel reactor through a material pump, and setting the flow rate to be 50.0g/min through a metering module. Compound (I) is: (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide.
3. A second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 1100 ml/min; 4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 20 bar;
5. the system was set at a circulating temperature of 60 ℃ and reacted for 300 seconds through 8 reaction modules (204ml volume) of the continuous flow reactor, and then the reaction solution was collected. The purity of (2S,5R) -6- (hydroxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide in the reaction mixture was 95.82%. Filtering to remove palladium carbon in the reaction liquid, transferring the reaction liquid into a sulfonation kettle for sulfonation (a sulfonation tester is a complex of sulfur trioxide), extracting the reaction liquid by using butyl acetate organic phase, forming salt by ion pair (an ammonium ion source is n-trioctyl methyl ammonium quaternary ammonium salt positive ion), extracting a product by using dichloromethane, drying an anhydrous sodium sulfate, concentrating the product under reduced pressure, performing evaporation crystallization by using 4-methyl-2-pentanone, filtering, leaching by using 4-methyl-2-pentanone, and drying the product under reduced pressure to obtain (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-trioctyl methyl ammonium quaternary ammonium salt. The purity of liquid chromatography is 99.99 percent, the maximum single impurity is not detected, and the molar yield is 93.25 percent.
Example 4: preparation of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide n-trioctylmethylammonium Quaternary salt
1. The device comprises the following steps: the continuous flow microchannel hydrogenation reactor is characterized in that a microchannel connection mode is determined by referring to fig. 1, a mixed reaction module is determined according to flow rate and reaction residence time, and a heat exchange medium is ethanol;
2. as shown in fig. 1, flow path one: preparing feed liquid, stirring 50.0g of the compound (I), 1.5g of 10 wt% palladium carbon, 1.5g of palladium hydroxide catalyst, 180ml of water and 420ml of isopropanol to form suspension, pumping the suspension into a microchannel reactor through a material pump, and setting the flow rate to be 50.0g/min through a metering module. Compound (I) is: (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide.
3. A second flow path: the material hydrogen passes through a gas circuit controller, and the gas flow rate is set to be 1100 ml/min;
4. controlling the pipeline pressure: the pressure of the nitrogen pressure-preparing pipeline is 20 bar;
5. the system was set at a circulating temperature of 60 ℃ and reacted for 300 seconds through 8 reaction modules (204ml volume) of the continuous flow reactor, and then the reaction solution was collected. The purity of (2S,5R) -6- (hydroxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide in the reaction solution was 96.89%. Filtering to remove palladium carbon in the reaction liquid, transferring the reaction liquid into a sulfonation kettle for sulfonation (a sulfonation tester is a complex of sulfur trioxide), extracting the reaction liquid by using a butyl acetate organic phase, forming salt by ion pair (an ammonium ion source is n-trioctyl methyl ammonium quaternary ammonium salt), extracting a product by using dichloromethane, drying an anhydrous sodium sulfate, concentrating the product under reduced pressure, performing evaporation crystallization by using 4-methyl-2-pentanone, filtering, leaching the product by using 4-methyl-2-pentanone, and drying the product under reduced pressure to obtain the (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-trioctyl methyl ammonium quaternary ammonium salt. The purity of the liquid chromatogram is 99.99 percent, the maximum single impurity is not detected, and the molar yield is 94.11 percent.
Comparative example 1: preparation of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide n-tetrabutyl ammonium salt using a conventional hydrogenation autoclave
1. The device comprises the following steps: a high pressure hydrogenation reactor;
2. preparing feed liquid: 80.0g of the compound (I), 2.4g of 10 wt% palladium on charcoal, 2.4g of a palladium hydroxide catalyst, 400ml of water, 400ml of isopropanol, 45.3g of sulfur trioxide trimethylamine, and 5.9g of triethylamine were placed in a high-pressure hydrogenation reactor, and nitrogen substitution, hydrogen substitution, and stirring were carried out. Compound (I) is: (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide.
3. Intermittently introducing hydrogen to maintain the hydrogen pressure of the system at 1.0 MPa;
4. maintaining the reaction pressure and stirring for reaction for 10 hours;
5. after the reaction time of the system is finished, the purity of (2S,5R) -6- (hydroxyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide in the reaction liquid is 88.89%, after palladium is filtered out and butyl acetate organic phase extraction is carried out, ion pairing is carried out to form salt (ammonium ion source is n-tetrabutyl quaternary ammonium salt positive ion), methylene dichloride extraction products are dried by anhydrous sodium sulfate, reduced pressure concentration is carried out, 4-methyl-2-pentanone is used for carrying out set evaporation crystallization, filtration is carried out, 4-methyl-2-pentanone is used for rinsing, drying under reduced pressure to obtain (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-tetrabutyl quaternary ammonium salt. The purity of the liquid chromatogram is 99.99 percent, the maximum single impurity is not detected, and the molar yield is 82.21 percent.
Comparative example 2: preparation of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide n-trioctylmethylammonium Quaternary salt Using a conventional hydrogenation autoclave
1. The device comprises the following steps: a high pressure hydrogenation reactor;
2. preparing feed liquid: 80.0g of the compound (I), 2.4g of 10 wt% palladium on charcoal, 2.4g of a palladium hydroxide catalyst, 400ml of water, 400ml of isopropanol, 45.3g of sulfur trioxide trimethylamine, and 5.9g of triethylamine were placed in a high-pressure hydrogenation reactor, and nitrogen substitution, hydrogen substitution, and stirring were carried out. Compound (I) is: (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide.
3. Intermittently introducing hydrogen to maintain the hydrogen pressure of the system at 1.0 MPa;
4. maintaining the reaction pressure and stirring for reaction for 1 hour;
5. after the reaction time of the system is finished, the purity of (2S,5R) -6- (hydroxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide in the reaction liquid is 45.89%, after filtering palladium, extracting by butyl acetate organic phase, forming salt by ion pair (ammonium ion source is n-trioctylmethylammonium quaternary ammonium salt positive ion), extracting products by dichloromethane, drying by anhydrous sodium sulfate, concentrating under reduced pressure, carrying out batch evaporation crystallization by using 4-methyl-2-pentanone, filtering, rinsing by using 4-methyl-2-pentanone, drying under reduced pressure to obtain (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-trioctylmethylammonium quaternary ammonium salt. Liquid chromatography purity 92.12%, maximum single impurity: 7.12 percent and the molar yield is 30.22 percent.
Comparative example 3: preparation of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide n-trioctylmethylammonium Quaternary salt Using a conventional hydrogenation autoclave
1. The device comprises the following steps: a high pressure hydrogenation reactor;
2. preparing feed liquid: 80.0g of the compound (I), 2.4g of 10 wt% palladium on charcoal, 2.4g of a palladium hydroxide catalyst, 400ml of water, 400ml of isopropanol, 45.3g of sulfur trioxide trimethylamine, and 5.9g of triethylamine were placed in a high-pressure hydrogenation reactor, and nitrogen substitution, hydrogen substitution, and stirring were carried out. Compound (I) is: (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide.
3. Intermittently introducing hydrogen to maintain the hydrogen pressure of the system at 1.0 Mpa;
4. maintaining the reaction pressure and stirring for reaction for 10 hours;
5. after the reaction time of the system is finished, the purity of (2S,5R) -6- (hydroxyl) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide in the reaction liquid is 86.56 percent, after palladium is filtered out and butyl acetate organic phase extraction is carried out, ion pairing is carried out to form salt (the ammonium ion source is n-trioctyl methyl ammonium quaternary ammonium salt positive ion), methylene dichloride is used for extracting a product, after anhydrous sodium sulfate is dried, reduced pressure concentration is carried out, 4-methyl-2-pentanone is used for carrying out evaporation crystallization, filtration is carried out, 4-methyl-2-pentanone is used for leaching, drying under reduced pressure to obtain (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-trioctylmethylammonium quaternary ammonium salt. Purity of liquid chromatography 99.80%, maximum single impurity: 0.20% and 81.01% yield.
From the above examples and comparative examples, the molar yield of the product (avibactam sodium intermediate II) in the examples is above 90%, the product purity is above 99.0%, which is higher than that in the batch reaction in the comparative example, and the reaction time is greatly shortened (300 s in the example), while the reaction time in the batch pressure hydrogenation reaction kettle is 10 hours, and the molar yield is very low, and is only 30.22% in 1 hour of the batch reaction.
The foregoing is illustrative of embodiments of the present invention and is not to be construed as limiting thereof in any way. The scope of the present invention is defined by the claims and is not limited by the embodiments described above, and any simple modifications or equivalent changes and modifications made to the above embodiments according to the technical spirit of the present invention are included in the scope of the present invention.
Claims (10)
1. A continuous flow synthesis method of an avibactam sodium intermediate is characterized in that avibactam sodium intermediate II is obtained by continuous flow hydrogenation synthesis by taking a suspension of the avibactam sodium intermediate I, a catalyst and a solvent as a material I and hydrogen as a material II.
2. The continuous-flow synthesis method of the avibactam sodium intermediate according to claim 1, wherein the continuous-flow hydrogenation synthesis is performed in a microchannel hydrogenation reactor.
3. The continuous flow synthesis method of the avibactam sodium intermediate according to claim 2, wherein the microchannel hydrogenation reactor comprises a first flow path, a second flow path, a third flow path, a preheating module, a reaction module and a gas-liquid separation device, the materials sequentially pass through the preheating module, the reaction module and the gas-liquid separation device via the first flow path, the second material enters the reaction module via the second flow path, and the solvent, the catalyst and the acid binding agent separated from the third flow path are returned to the first flow path for reuse.
4. The continuous flow synthesis method of avibactam sodium intermediate as claimed in claim 1, wherein the flow rate of the first material is 50-150g/min, and the flow rate of the second material is 600-2000 ml/min.
5. The continuous flow synthesis method of the avibactam sodium intermediate according to claim 3, wherein the temperature in the preheating module and/or the reaction module is 40-80 ℃, and the reaction pressure of the reaction module is 15-100 bar.
6. The continuous flow synthesis method of avibactam sodium intermediate according to claim 3, wherein the reaction time in the reaction module is 60-350 s.
7. The continuous flow synthesis method of the avibactam sodium intermediate according to claim 1, wherein the synthetic route of the avibactam sodium intermediate II is as follows:
wherein R is 1 Represents: a benzyl group;
R 21 represents: the quaternary ammonium salt is n-tetrabutyl quaternary ammonium salt positive ion, tetraoctyl ammonium quaternary ammonium salt positive ion or trioctylmethyl ammonium quaternary ammonium salt positive ion.
8. The continuous flow synthesis method of avibactam sodium intermediate according to claim 1, characterized in that the avibactam sodium intermediate I is (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide;
the intermediate II of the abamectin sodium is at least one of (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide n-tetrabutyl quaternary ammonium salt positive ions, tetraoctyl ammonium quaternary ammonium salt positive ions and trioctylmethyl ammonium quaternary ammonium salt positive ions.
9. The continuous flow synthesis method of the avibactam sodium intermediate according to claim 1, wherein the catalyst is one or two of palladium carbon and palladium hydroxide, and/or the mass ratio of the avibactam sodium intermediate I to the catalyst is controlled to be 1: 0.06-0.15.
10. The continuous flow synthesis method of the avibactam sodium intermediate according to claim 1, wherein the first material further comprises an acid binding agent comprising at least one of triethylamine, N-diisopropylethylamine, and pyridine;
and/or the presence of a gas in the gas,
the solvent comprises one or two of methanol, ethanol, isopropanol, formic acid, acetic acid and water;
and/or the presence of a gas in the gas,
the mass ratio of the avibactam sodium intermediate I to the single or mixed solvent is 1: 1-20.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831772A (en) * | 2017-03-04 | 2017-06-13 | 丽珠医药集团股份有限公司 | A kind of synthetic method of AVM hereinafter Batan intermediate |
| CN107417686A (en) * | 2017-09-19 | 2017-12-01 | 北京化工大学 | A kind of synthetic method of AVM hereinafter Batan sodium |
| CN110590775A (en) * | 2019-09-29 | 2019-12-20 | 瑞阳制药有限公司 | Preparation method of intermediate of Abamebactam sodium of beta-lactamase inhibitor drug |
| CN111116587A (en) * | 2019-11-29 | 2020-05-08 | 北京耀诚惠仁科技有限公司 | Preparation method of avibactam intermediate compound |
| CN111732587A (en) * | 2020-06-05 | 2020-10-02 | 北京耀诚惠仁科技有限公司 | Abamebactam intermediate compound gemini quaternary ammonium disulfonate and preparation method thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831772A (en) * | 2017-03-04 | 2017-06-13 | 丽珠医药集团股份有限公司 | A kind of synthetic method of AVM hereinafter Batan intermediate |
| CN107417686A (en) * | 2017-09-19 | 2017-12-01 | 北京化工大学 | A kind of synthetic method of AVM hereinafter Batan sodium |
| CN110590775A (en) * | 2019-09-29 | 2019-12-20 | 瑞阳制药有限公司 | Preparation method of intermediate of Abamebactam sodium of beta-lactamase inhibitor drug |
| CN111116587A (en) * | 2019-11-29 | 2020-05-08 | 北京耀诚惠仁科技有限公司 | Preparation method of avibactam intermediate compound |
| CN111732587A (en) * | 2020-06-05 | 2020-10-02 | 北京耀诚惠仁科技有限公司 | Abamebactam intermediate compound gemini quaternary ammonium disulfonate and preparation method thereof |
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