CN106831772B - Synthetic method of avibactam intermediate - Google Patents
Synthetic method of avibactam intermediate Download PDFInfo
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Abstract
the invention provides a method for synthesizing an avibactam intermediate, which comprises the following steps: (1) reacting the (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, triethylamine and a sulfur trioxide trimethylamine complex; (2) washing the reaction solution, adding a solution of quaternary ammonium chloride salt in water, and continuing to react; (3) extracting the product, concentrating, pulping, filtering, washing and drying; the method has the advantages of simple and convenient operation, labor hour and energy consumption saving, higher purity of the obtained quaternary ammonium salt intermediate, and reduction of the impurity content from 5.3% in the prior art to below 0.14%, and is more suitable for process production amplification.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry synthesis, in particular to a synthesis method of an avibactam intermediate.
Background
Abamebactam sodium, English name is avibactam sodium, chemical name: [ (1R, 2S, 5R) -2- (aminocarbonyl) -7-oxo-1, 6-diazabicyclo [3.2.1] oct-6-yl ] sulfuric acid monosodium salt. The abamectin sodium and the cephalosporin antibacterial drug ceftazidime form a compound preparation with fixed proportioning dose, and the compound preparation is approved by the FDA in 2.15.20Hnd 2015 to be marketed, is used for treating complicated intra-abdominal infection and complicated urinary tract infection of adults, and is suitable for treating patients with renal infection (pyelonephritis).
The preparation method of the abamectin sodium reported in the literature at present mainly comprises the following two methods: patent literature (CN1468242A) reports a preparation method of avibactam sodium as shown in a route 1, raw materials used in the route are not easy to obtain, a hydrolysis process is complicated, hydrogen used in a hydrogenation process has high reduction risk, a reaction operation process is complicated, and a part of intermediates are unstable and are easily decomposed to generate impurities, so that the preparation method is not suitable for industrial scale-up production.
In patent CN103649051A, a preparation method of avibactam sodium is reported, which is as follows:
This patent protects a process for the conversion of tetrabutylammonium salts as an aminating agent and tetrabutylammonium salts to sodium salts.
In the method, high-boiling-point solvents of n-butyl acetate (boiling point: 126.5 ℃) and 4-methyl-2-pentanone (boiling point: 115.8 ℃ and high toxicity) are used, which are not beneficial to complete removal, and the tetrabutyl quaternary ammonium salt intermediate prepared by the process route is not purified and has low purity, which is not beneficial to quantitative feeding in the subsequent steps and product purity control.
Disclosure of Invention
The synthesis method is improved aiming at the defects, and the improved process has high operation safety, stable yield and good product quality, and is suitable for production amplification. The synthesis process specifically comprises the following chemical formula:
Dissolving (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide in a mixed solution of ethanol and water, adding triethylamine and a sulfur trioxide trimethylamine complex, stirring until the reaction is completed, washing the reaction solution with ethyl acetate, then adding a solution of quaternary ammonium chloride salt in water, and stirring until the reaction is completed. The product was extracted with dichloromethane, the organic layer was concentrated to dryness, ethyl acetate was added and slurried, then filtered, washed and dried to obtain a white crystalline solid. Dissolving the obtained white crystalline solid in 95% ethanol, dropwise adding a 95% ethanol solution of sodium isooctanoate into the solution, separating out the solid, filtering and drying to obtain the target product, namely the abamectin sodium.
(2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide, as described above, was dissolved in a mixed solution of ethanol and water in a volume of 1: 1.
The quaternary ammonium chloride salt is one of benzyl tripropyl ammonium chloride, methyl tributyl ammonium chloride and benzyl tributyl ammonium chloride. Benzyl tributyl ammonium chloride is preferred.
In the above step, the feeding ratio of the quaternary ammonium chloride salt to the (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide is 1: 1 to 2: 1; preferably 1: 1 to 1.5: 1, more preferably 1.2: 1.
In the process, benzyl tributyl ammonium chloride, benzyl tripropyl ammonium chloride and methyl tributyl ammonium chloride are used as reagents for synthesizing ammonium salt, so that the synthesis of the intermediate of abamectin is initiated, the price is low, the raw materials are easily obtained, and the experimental effect is excellent.
Meanwhile, the ethyl acetate is used as a reaction post-treatment solvent instead of 4-methyl-2-pentanone, so that toxic solvent residue is reduced; in addition, the quaternary ammonium salt intermediate is obtained by stirring, pulping, filtering and extracting instead of concentrating and extracting, so that the method has the advantages of simplicity and convenience in operation, labor hour saving, energy consumption saving and the like, can obtain the intermediate with higher purity, and is more suitable for process production amplification.
The purity of the quaternary ammonium salt intermediate obtained by the invention is higher and reaches more than 99.8 percent. In the technical field of chemical synthesis, the purity of the synthesis of bulk drugs is of great importance. Impurities in the raw material medicaments not only affect the subsequent preparation and other processes, so that the quality standard of the medicaments cannot meet the requirements, but also cause serious adverse reactions of human bodies and harm to the health of the human bodies. Therefore, the purity of the medicine is improved to the utmost extent, the effectiveness and the safety of the medicine are ensured, and the significance is great. Compared with the prior art, the purity of the product is reduced from 5.3% to below 0.14%, the reduction rate reaches 97%, and the method has outstanding contribution.
Detailed Description
Example 1:
(2S, 5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (10g, 36.2mmol, 1eq), palladium on carbon (0.8g, 10% palladium, 50% water), ethanol (50ml) and water (50ml) were mixed and added to a hydrogenation vessel, the mixture was treated with hydrogen until the reaction was complete, the palladium on carbon was removed by filtration and washed with water (20ml), triethylamine (1.3ml, 18mmol, 0.5eq) and the trimethylamine trioxide complex (6.07g, 43.4mmol, 1.2eq) were added to the combined filtrates and stirred until the reaction was complete, the reaction solution was washed with ethyl acetate (50ml), and then a solution of benzyltributylammonium chloride (13.6g, 43.4mmol, 1.2eq) in water (20ml) was added. The product was extracted with dichloromethane (50 mL. times.2), the combined organic layers were concentrated to dryness, and to the residue was added ethyl acetate (20mL), stirred and slurried, then filtered, washed (20mL ethyl acetate) and dried to give 15.3g of a white crystalline solid (83.2% yield in this step).
10g of the quaternary ammonium salt intermediate is taken to be dissolved in 95% ethanol (60mL), a 95% ethanol solution (60mL) of sodium isooctanoate (6.1g, 37.0mmo, 2eq) is added into the solution dropwise, and after solid is precipitated, the crude product of abamectin sodium is obtained by filtration and drying, namely 4.6g of crude product of abamectin sodium (the yield in the step is 86.8%).
Example 2:
(2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (3.35g, 18.1mmol, 1eq) was dissolved in 25mL ethanol and 25mL water, triethylamine (0.65mL, 4.7mmol, 0.25eq) and the sulfur trioxide trimethylamine complex (3.04g, 21.7mmol, 1.2eq) were added and stirred until the reaction was complete, the reaction solution was washed with ethyl acetate (25mL), and then a solution of benzyltributylammonium chloride (6.8g, 21.7mmol, 1.2eq) in water (10mL) was added. The product was extracted with dichloromethane (25 mL. times.2), the combined organic layers were concentrated to dryness, and to the residue was added ethyl acetate (10mL), stirred and slurried, then filtered, washed (10mL ethyl acetate) and dried to give 7.8g of a white crystalline solid (84.8% yield in this step).
5g of the quaternary ammonium salt intermediate is taken and dissolved in 95% ethanol (30mL), a 95% ethanol solution (30mL) of sodium isooctanoate (3.1g, 18.5mmol, 2eq) is added dropwise into the solution, and after solid is precipitated, the crude product of abamectin sodium 2.2g is obtained by filtration and drying (the yield in the step is 85.5%).
Example 3:
(2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (6.7g, 36.2mmol, 1eq) was dissolved in a mixed solution of 50mL of ethanol and 50mL of water, triethylamine (1.3mL, 18mmol, 0.25eq) and a sulfur trioxide trimethylamine complex (6.07g, 43.4mmol, 1.2eq) were added and stirred until the reaction was completed, the reaction solution was washed with ethyl acetate (50mL), and then a solution of methyltributylammonium chloride (10.2g, 43.4mmol, 1.2eq) in water (20mL) was added. The product was extracted with dichloromethane (50 mL. times.2), the combined organic layers were concentrated to dryness, and to the residue was added ethyl acetate (20mL), stirred and slurried, then filtered, washed (20mL ethyl acetate) and dried to give 12.7g of a white crystalline solid (75.6% yield in this step).
10g of the obtained white crystalline solid was dissolved in 95% ethanol (60mL), and a 95% ethanol solution (60mL) of sodium isooctanoate (7.2g, 43.1mmol, 2eq) was added dropwise to the solution to precipitate a solid, which was then filtered and dried to obtain 5.51g of crude avibactam sodium (88.9% yield in this step).
Example (b): 4:
(2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (6.7g, 36.2mmol, 1eq) was dissolved in a mixed solution of 50mL of ethanol and 50mL of water, triethylamine (1.3mL, 18mmol, 0.25eq) and a sulfur trioxide trimethylamine complex (6.07g, 43.4mmol, 1.2eq) were added and stirred until the reaction was completed, the reaction solution was washed with ethyl acetate (50mL), and then a solution of benzyltripropylammonium chloride (11.7g, 43.4mmol, 1.2eq) in water (20mL) was added. The product was extracted with dichloromethane (50 mL. times.2), the combined organic layers were concentrated to dryness, and to the residue was added ethyl acetate (20mL), stirred and slurried, then filtered, washed (20mL ethyl acetate) and dried to give 12.2g of a white crystalline solid (67.8% yield in this step).
10g of the obtained white crystalline solid was dissolved in 95% ethanol (60mL), and a 95% ethanol solution (60mL) of sodium isooctanoate (6.7g, 40.0mmol, 2eq) was added dropwise to the solution to precipitate a solid, which was then filtered and dried to obtain 4.8g of crude avibactam sodium (82.8% yield in this step).
Example 5: investigation of quaternary ammonium salt reagent selection
(2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (6.7g, 36.2mmol, 1eq) was dissolved in a mixed solution of 50mL of ethanol and 50mL of water, triethylamine (1.3mL, 18mmol, 0.25eq) and a sulfur trioxide trimethylamine complex (6.07g, 43.4mmol, 1.2eq) were added and stirred until the reaction was completed, the reaction solution was washed with ethyl acetate (50mL), and then a certain amount of an aqueous solution of a quaternary ammonium salt (20mL) was added. The product was extracted with dichloromethane (50mL × 2), the combined organic layers were concentrated to dryness, ethyl acetate (20mL) was added, and slurried with stirring, then filtered, washed (20mL ethyl acetate) and dried.
TABLE 1 influence of selection of Quaternary ammonium salt reagents on the results of the experiment
| quaternary ammonium salt reagent | Feed amount | Yield of product | Purity of the product | Experimental phenomena |
| 1-ethyl-3-methylimidazolium chloride | 1.5eq | - | - | no product is obtained |
| 1-butyl-3-methylimidazolium chloride | 1.5eq | - | - | No product is obtained |
| Tetraethyl ammonium chloride | 1.5eq | - | - | no product is obtained |
| Tetrapropylammonium chloride | 1.5eq | - | - | No product is obtained |
| Benzyl triethyl ammonium chloride | 1.5eq | - | - | No product is obtained |
| Benzyl tripropyl ammonium chloride | 1.5eq | 67.8％ | 99.84％ | White solid |
| benzyl tributyl ammonium chloride | 1.5eq | 73.2％ | 99.90％ | White solid |
| Methyl tributyl ammonium chloride | 1.5eq | 75.6％ | 99.71％ | White solid |
And (4) conclusion: as can be seen from the experimental results, only benzyltributylammonium chloride, benzyltripropylammonium chloride and methyltributylammonium chloride can complete the experiment to obtain the product.
Example (b): 6: groping test of relation between inventory and yield of benzyl tributyl ammonium chloride
(2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (6.7g, 36.2mmol, 1eq) was dissolved in a mixed solution of 50mL of ethanol and 50mL of water, triethylamine (1.3mL, 18mmol, 0.25eq) and a sulfur trioxide trimethylamine complex (6.07g, 43.4mmol, 1.2eq) were added and stirred until the reaction was completed, the reaction solution was washed with ethyl acetate (50mL), and then a solution of benzyltributylammonium chloride (A g, B mmol, C eq) in water (20mL) was added. The product was extracted with dichloromethane (50mL × 2), the combined organic layers were concentrated to dryness, ethyl acetate (20mL) was added and slurried with stirring, then filtered, washed (20mL ethyl acetate) and dried to give a white crystalline solid.
TABLE 2 charge-yield of benzyltributylammonium chloride
And (4) conclusion: the experimental results show that the dosage of the benzyl tributyl ammonium chloride is related to the yield of the experimental product, and when the dosage of the benzyl tributyl ammonium chloride is controlled to be 1-2 equivalents, higher yield and purity can be obtained; when the feeding amount is 1.2 equivalents, the product yield is highest, and the experimental effect is optimal.
Example (b): 7: comparison of the product of the invention with the product of example 4a of the prior art CN103649051B
The purity of the intermediate benzyltributyl quaternary ammonium salt prepared in the embodiments 1 and 2 is compared with that of the intermediate tetrabutyl quaternary ammonium salt prepared in the embodiments 4 to 5 of CN103649051B, and the purity detection is performed by liquid chromatography (instrument model: LC-A-1508, manufacturer: Agilent), and the result shows that the purity of the product obtained in the embodiments 1 and 2 is higher and can reach more than 99.8%.
TABLE 3 comparison of sample purities
Example 8: groping test for beating purification
(2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (3.35g, 18.1mmol, 1eq) was dissolved in 25mL ethanol and 25mL water, triethylamine (0.65mL, 4.7mmol, 0.25eq) and the sulfur trioxide trimethylamine complex (3.04g, 21.7mmol, 1.2eq) were added and stirred until the reaction was complete, the reaction solution was washed with ethyl acetate (25mL), and then a solution of benzyltributylammonium chloride (6.8g, 21.7mmol, 1.2eq) in water (10mL) was added. The product was extracted with dichloromethane (25ml × 2), the combined organic layers were concentrated to dryness, various reagents were added and slurried with stirring to examine the experimental results.
TABLE 4 influence of beating with different reagents on the experimental results
| Reagent | experimental phenomena |
| Ethyl acetate | The system is well dispersed to obtain a solid product |
| Acetic acid methyl ester | The system is not dispersed and is in two phases, and a solid product cannot be obtained |
| Formic acid methyl ester | the system is not dispersed and is in two phases, and a solid product cannot be obtained |
| Isopropyl ether | The system is not dispersed and is in two phases, and a solid product cannot be obtained |
And (4) conclusion: the experimental result shows that when the ethyl acetate is selected as the reagent for pulping, the system is well dispersed, a solid product can be obtained, and the purpose of purification is achieved.
Claims (3)
1. A synthetic method of an avibactam intermediate is characterized by comprising the following steps:
(1) Reacting the (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, triethylamine and a sulfur trioxide trimethylamine complex;
(2) Washing the reaction solution with ethyl acetate, adding a solution of benzyl tributyl ammonium chloride in water, and continuing to react; wherein the feeding ratio of the benzyl tributyl ammonium chloride to the (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide is 1.2: 1;
(3) The product was extracted and concentrated, slurried with ethyl acetate, filtered, washed and dried.
2. The method according to claim 1, wherein the (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide in step (1) is dissolved in a mixed solution of ethanol and water.
3. The method according to claim 2, wherein the (2S, 5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide in step (1) is dissolved in a mixed solution of ethanol and water, wherein the volume ratio of ethanol to water is 1: 1.
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| CN107501265B (en) * | 2017-10-09 | 2019-05-28 | 台州职业技术学院 | A kind of 7- oxo-diazabicylo [3,2,1] octane derivatives compound and its preparation method and application |
| CN109956941B (en) * | 2017-12-25 | 2020-08-04 | 新发药业有限公司 | Simple preparation method of abamectin |
| 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 |
| CN111732587B (en) * | 2020-06-05 | 2022-11-25 | 北京耀诚惠仁科技有限公司 | Abamebactam intermediate compound gemini quaternary ammonium disulfonate and preparation method thereof |
| CN111777607A (en) * | 2020-07-21 | 2020-10-16 | 海南海灵化学制药有限公司 | Preparation method of abamectin |
| CN115073459A (en) * | 2022-07-07 | 2022-09-20 | 江西国药有限责任公司 | Continuous flow synthesis method of avibactam sodium intermediate |
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| CN103328476A (en) * | 2010-12-22 | 2013-09-25 | 明治制果药业株式会社 | Optically-active diazabicyclooctane derivative and method for manufacturing same |
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| CN105753867A (en) * | 2016-03-24 | 2016-07-13 | 齐鲁制药有限公司 | Preparation method of improved avibactam sodium intermediate compound |
| CN105873930A (en) * | 2012-12-11 | 2016-08-17 | 费多拉制药公司 | New bicyclic compounds and their use as antibacterial agents and [beta]-lactamase inhibitors |
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| CN103328476A (en) * | 2010-12-22 | 2013-09-25 | 明治制果药业株式会社 | Optically-active diazabicyclooctane derivative and method for manufacturing same |
| CN103649051A (en) * | 2011-06-17 | 2014-03-19 | 阿斯利康(瑞典)有限公司 | Process for preparing heterocyclic compounds including trans-7-oxo-6-(sulphooxy)-1, 6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof |
| CN105873930A (en) * | 2012-12-11 | 2016-08-17 | 费多拉制药公司 | New bicyclic compounds and their use as antibacterial agents and [beta]-lactamase inhibitors |
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