CN107417686B - Method for synthesizing avibactam sodium - Google Patents

Method for synthesizing avibactam sodium Download PDF

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CN107417686B
CN107417686B CN201710852184.8A CN201710852184A CN107417686B CN 107417686 B CN107417686 B CN 107417686B CN 201710852184 A CN201710852184 A CN 201710852184A CN 107417686 B CN107417686 B CN 107417686B
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diazabicyclo
octane
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CN107417686A (en
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乔仁忠
周航
陈照行
赵静
李超
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Jingdezhen Fuxiang Pharmaceutical Co ltd
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Beijing University of Chemical Technology
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Abstract

The invention discloses a synthesis method of abamectin sodium, which comprises the steps of taking (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-formamide as an initial raw material, constructing a urea ring through carbonyl diimidazole under the action of dimethyldichlorosilane to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, removing benzyl through hydrogenation reaction, carrying out sulfonation reaction with a sulfonation reagent, synthesizing a quaternary ammonium salt intermediate with quaternary ammonium salt, and finally obtaining the abamectin sodium through ion exchange. The improved process has low cost, simple operation and good product quality, and is suitable for industrial production. In the process of synthesizing the intermediate (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, the invention selects the dimethyldichlorosilane with low price, thereby greatly reducing the production cost.

Description

Method for synthesizing avibactam sodium
Technical Field
The invention belongs to the field of medicinal chemical synthesis, and particularly relates to a synthesis method of avibactam sodium.
Background
Abamebactam is a novel β -lactamase inhibitor developed by Novexel company, has the advantages of long acting, reversible covalent bonding with enzyme, no induction of β -lactamase and the like compared with three β -lactamase inhibitors (sulbactam, tazobactam and clavulanic acid) on the market, has broad-spectrum antibacterial activity when being combined with various cephalosporin and carbapenem antibiotics, and particularly has remarkable activity on escherichia coli containing ultra-broad-spectrum β -lactamase and Klebsiella pneumoniae, escherichia coli containing ultra-high ampC enzyme and escherichia coli containing both AmpC and ultra-broad-spectrum β -lactamase in 2012, Dubreui and other researches show that ceftazidime-abamectin-metronidazole combined application (8:8:1) inhibits anaerobic strains of 91.8% (290/316), and no strains have synergistic effect or synergistic effect, so the research on a new synthetic route of ababactam has great application value.
Abamebactam (Avibactam, NXL-104) belongs to a diazabicyclooctanone compound, has two chiral centers, is greatly different from the structure of a classical β -lactamase inhibitor, can be recovered through a reverse reaction, and has a long-acting enzyme inhibiting effect, and the Abamebactam is clinically applied in the form of a sodium salt thereof, has the chemical name of sulfuric acid mono [ (1R,2S,5R) -2-aminocarbonyl-7-oxo-1, 6-azabicyclo [3.2.1] oct-6-yl ] ester sodium salt, and has the specific molecular structure as follows:
Figure BDA0001412335730000011
CN1468242 and CN102834395 disclose a method for synthesizing avibactam by using oxalate of (2S) -5- ((benzyloxy) amino) piperidine-2-benzyl formate, and the synthetic route is as follows:
Figure BDA0001412335730000021
patent CN103328476, applied by japan mingmuiguo pharmaceutical co, discloses a synthesis route of avibactam starting from (2S,5R) -5- ((benzyloxy) amino) piperidine-2-carboxylic acid tert-butyl ester as follows:
Figure BDA0001412335730000022
in the process of synthesizing abamectin, the construction of the urea ring has great influence on the yield of the whole route and the quality of a final product, and the patents all use the diphosphonate in the process of synthesizing the urea ring, so that the toxicity is high, the reaction is not easy to control, the reaction yield is not high, and the industrial amplification production is not facilitated; in the process of preparing (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide from (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxylic acid, the former needs to be activated, the use of activating reagent increases the cost to some extent, and the ammonolysis reaction yield is not ideal.
Patent CN103649051 filed by the company asikang discloses the following synthetic route of avibactam sodium:
Figure BDA0001412335730000031
in the process of synthesizing the urea ring, fluorenyl methoxycarbonyl is selected as a protecting group to protect a nitrogen atom on a piperidine ring, and then carbonyl diimidazole is used for constructing the urea ring. Meanwhile, in the method, the selected sulfonation reagent is a sulfur trioxide trimethylamine complex, the weak sulfonation performance of the sulfonation reagent enables the reaction to take longer time, and the higher price of the sulfonation reagent increases the cost to a certain extent. Then, 4-methyl-2-pentanone with high toxicity is used in the process of synthesizing quaternary ammonium salt by using tetrabutylammonium salt as an ammonification agent, and the higher boiling point (115.8 ℃) of the 4-methyl-2-pentanone is not beneficial to removal, thereby directly influencing the quality of the final product in the next step.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a novel synthesis method of abamectin sodium, which takes (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-formamide as an initial raw material.
The technical scheme of the invention is as follows:
the invention provides a method for synthesizing abamectin sodium, which comprises the following steps:
(1) reacting (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide with dimethyldichlorosilane in the presence of a base to construct a urea ring via carbonyldiimidazole, yielding (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide;
(2) reacting (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide with hydrogen under the catalysis of a catalyst to obtain (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide;
(3) adding alkali and a sulfonating reagent into (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide to react to obtain (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide;
(4) reacting (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide with quaternary ammonium salt to obtain a quaternary ammonium salt intermediate;
(5) and (3) dropwise adding a sodium isooctanoate solution into the quaternary ammonium salt intermediate to react, precipitating a solid, filtering and drying to obtain the abamectin sodium.
The synthesis method of abamectin sodium (shown in figure 1) comprises the steps of firstly, taking (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-formamide as an initial raw material, constructing a urea ring through carbonyl diimidazole under the action of dimethyldichlorosilane to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, then removing benzyl through hydrogenation reaction, selecting a sulfonation reagent for sulfonation reaction, synthesizing a quaternary ammonium salt intermediate with quaternary ammonium salt, and finally obtaining the abamectin sodium through ion exchange. The improved process has low cost, simple operation and good product quality, and is suitable for industrial production.
Further, in the step (1), the base is triethylamine, diisopropylamine, N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine, preferably N, N-diisopropylethylamine. Under the selected alkaline condition, the reaction can be smoothly carried out to generate the product. The solvent used for the reaction is acetonitrile, acetone, isopropanol or tetrahydrofuran, preferably acetonitrile.
Further, in the step (1), the reaction temperature of (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide and dimethyldichlorosilane is 0-10 ℃, preferably 5-8 ℃.
Further, in the step (2), the catalyst is palladium carbon, preferably 10% by weight of palladium carbon; the reaction temperature is 15-35 ℃, preferably 25-30 ℃ and the reaction time is 1-6 h.
Further, in the step (2), the solvent used for the reaction is an isopropanol-water mixed solution, an ethanol-water mixed solution, a methanol-water mixed solution or a 1, 4-dioxane-water mixed solution, preferably an isopropanol-water mixed solution.
Further, in the step (3), the sulfonation reagent is sulfur trioxide-1, 4 dioxane complex, and the charging ratio of the sulfonation reagent to (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide is 1-1.5: 1, preferably 1.2: 1. the sulfonation performance of the sulfur trioxide-1, 4 dioxane complex is superior to that of other sulfonation reagents, and the yield of the generated product is high.
Further, in the step (3), the base is potassium carbonate, sodium carbonate, calcium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, N diisopropylethylamine or pyridine, preferably triethylamine. The solvent used in the reaction is acetonitrile-water mixed solution, 1,4 dioxane-water mixed solution or isopropanol-water mixed solution, preferably isopropanol-water mixed solution.
Further, in the step (3), the reaction temperature is 15-35 ℃, preferably 25-30 ℃; the reaction time is 0.5 to 2 hours, preferably 1 hour.
Further, in the step (4), the quaternary ammonium salt is tetraoctyl ammonium bromide, tetrapentyl ammonium bromide, tetraheptyl ammonium bromide, tetrahexyl ammonium bromide, trioctylmethyl ammonium bromide or tributylhexyl ammonium bromide, preferably tetraoctyl ammonium bromide; the reaction temperature is 25-35 ℃, and the reaction time is 1-2 h. The selected quaternary ammonium salt can ensure that the reaction can be smoothly carried out to generate a product.
Further, in the step (5), the solvent used for the reaction is ethanol, methanol or isopropanol, preferably ethanol.
The invention has the beneficial effects that:
(1) in the process of synthesizing the intermediate (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-formamide is used as a starting material, and the cheaper dimethyldichlorosilane is selected, so that the production cost is greatly reduced.
(2) The method adopts the sulfur trioxide-1, 4 dioxane complex with better sulfonation performance as the sulfonation reagent, and uses tetraoctyl ammonium bromide (tetrapentylammonium bromide, tetraheptylammonium bromide, tetrahexylammonium bromide, trioctylmethylammonium bromide or tributylhexylammonium bromide) as the ammonization reagent to synthesize the quaternary ammonium salt, thereby shortening the reaction time, simplifying the reaction operation, improving the reaction yield and ensuring that the whole route is more suitable for industrial production.
Drawings
FIG. 1 is a technical route chart of the avibactam sodium synthesis method of the invention.
Detailed Description
The invention is further illustrated by the following examples. The raw materials and reagents used in the examples are all commercially available products. Carbonyldiimidazole is abbreviated CDI and thin layer chromatography is indicated by TLC.
Example 1
The synthesis method of avibactam sodium comprises the following steps:
(1) acetonitrile (100mL) was weighed out and added to a reaction flask, (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide (10g), temperature was controlled at 5-8 ℃ and 20mL (3eq) of N, N-diisopropylethylamine was added to the system, followed by dropwise addition of 6.4mL (1.3eq) of dimethyldichlorosilane and completion of the reaction was detected by TLC. Adding 8.5g CDI (1.3eq) into the system, heating to 45 ℃ and stirring, after TLC detection reaction is completed, adding 9.2mL (3eq) of isopropanol, continuing stirring at 45 ℃, after the reaction is completed, stopping stirring, naturally cooling to room temperature, adding 50mL of toluene into the system, then adding 140mL of 2mol/L HCl solution, after the system is layered, collecting an organic phase, concentrating to obtain a light yellow solid, and washing with methyl tert-butyl ether to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (9.8g, yield 90%).
(2) 50mL each of isopropyl alcohol and water was measured, the obtained (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide and 1g of palladium on carbon were added thereto, and the mixed system was treated with hydrogen until the reaction was complete. The catalyst was removed by suction filtration and the filter cake was washed with water and the filtrate was collected and used directly in the next reaction.
(3) At 0 ℃, 1mL (0.2eq) of triethylamine is added into the reaction liquid of the obtained (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, 7.3g (1.2eq) of sulfur trioxide-1, 4 dioxane complex is weighed and added into a reaction bottle, the mixture is stirred for 0.5h under heat preservation, the mixture is moved to room temperature and is stirred for 1h continuously, and the reaction liquid of (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide is obtained.
(4) To a reaction solution of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide was added 24g (1.22eq) tetraoctylammonium bromide at room temperature, and after stirring for 1h, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil.
(5) And (3) dissolving the light yellow oily substance obtained in the previous step into 10mL of ethanol, dropwise adding an ethanol solution of sodium isooctanoate (12g, 2eq) into the solution, and performing suction filtration, washing and drying to precipitate a solid to obtain 8.3g of abamectin sodium. The total yield of the reaction is 72 percent, and the purity of the obtained avibactam sodium product is 99.5 percent.
Example 2
The synthesis method of avibactam sodium comprises the following steps:
(1) acetonitrile (100mL) was weighed out and added to a reaction flask, (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide (10g), temperature was controlled at 5-8 ℃ and 20mL (3eq) of N, N-diisopropylethylamine was added to the system, followed by dropwise addition of 6.4mL (1.3eq) of dimethyldichlorosilane and completion of the reaction was detected by TLC. Adding 8.5g CDI (1.3eq) into the system, heating to 45 ℃ and stirring, after TLC detection reaction is completed, adding 9.2mL (3eq) of isopropanol, continuing stirring at 45 ℃, after the reaction is completed, stopping stirring, naturally cooling to room temperature, adding 50mL of toluene into the system, then adding 140mL of 2mol/L HCl solution, after the system is layered, collecting an organic phase, concentrating to obtain a light yellow solid, and washing with methyl tert-butyl ether to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (9.8g, yield 90%).
(2) 50mL each of isopropyl alcohol and water was measured, the obtained (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide and 1g of palladium on carbon were added thereto, and the mixed system was treated with hydrogen until the reaction was complete. The catalyst was removed by suction filtration and the filter cake was washed with water and the filtrate was collected and used directly in the next reaction.
(3) At 0 ℃, 1mL (0.2eq) of triethylamine is added into the reaction liquid of the obtained (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, 7.3g (1.2eq) of sulfur trioxide-1, 4 dioxane complex is weighed and added into a reaction bottle, the mixture is stirred for 0.5h under heat preservation, the mixture is moved to room temperature and is stirred for 1h continuously, and the reaction liquid of (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide is obtained.
(4) To a reaction solution of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide was added 16.8g (1.22eq) of tetrapentylammonium bromide at room temperature, and after stirring for 1 hour, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil.
(5) And (3) dissolving the light yellow oily substance obtained in the previous step into 10mL of ethanol, dropwise adding an ethanol solution of sodium isooctanoate (12g, 2eq) into the solution, and performing suction filtration, washing and drying to precipitate a solid to obtain 8.1g of abamectin sodium. The total yield of the reaction is 70%, and the purity of the obtained avibactam sodium product is 99.4%.
Example 3
The synthesis method of avibactam sodium comprises the following steps:
(1) acetonitrile (100mL) was weighed out and added to a reaction flask, (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide (10g), temperature was controlled at 5-8 ℃ and 20mL (3eq) of N, N-diisopropylethylamine was added to the system, followed by dropwise addition of 6.4mL (1.3eq) of dimethyldichlorosilane and completion of the reaction was detected by TLC. Adding 8.5g CDI (1.3eq) into the system, heating to 45 ℃ and stirring, after TLC detection reaction is completed, adding 9.2mL (3eq) of isopropanol, continuing stirring at 45 ℃, after the reaction is completed, stopping stirring, naturally cooling to room temperature, adding 50mL of toluene into the system, then adding 140mL of 2mol/L HCl solution, after the system is layered, collecting an organic phase, concentrating to obtain a light yellow solid, and washing with methyl tert-butyl ether to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (9.8g, yield 90%).
(2) 50mL each of isopropyl alcohol and water was measured, the obtained (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide and 1g of palladium on carbon were added thereto, and the mixed system was treated with hydrogen until the reaction was complete. The catalyst was removed by suction filtration and the filter cake was washed with water and the filtrate was collected and used directly in the next reaction.
(3) At 0 ℃, 1mL (0.2eq) of triethylamine is added into the reaction liquid of the obtained (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, 7.3g (1.2eq) of sulfur trioxide-1, 4 dioxane complex is weighed and added into a reaction bottle, the mixture is stirred for 0.5h under heat preservation, the mixture is moved to room temperature and is stirred for 1h continuously, and the reaction liquid of (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide is obtained.
(4) To a reaction solution of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide was added 21.8g (1.22eq) of tetraheptylammonium bromide at room temperature, and after stirring for 1 hour, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil.
(5) And (3) dissolving the light yellow oily substance obtained in the previous step into 10mL of ethanol, dropwise adding an ethanol solution of sodium isooctanoate (12g, 2eq) into the solution, and performing suction filtration, washing and drying to precipitate a solid to obtain 8g of abamectin sodium. The total yield of the reaction is 69%, and the purity of the obtained avibactam sodium product is 99.4%.
Example 4
The synthesis method of avibactam sodium comprises the following steps:
(1) acetonitrile (100mL) was weighed out and added to a reaction flask, (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide (10g), temperature was controlled at 5-8 ℃ and 20mL (3eq) of N, N-diisopropylethylamine was added to the system, followed by dropwise addition of 6.4mL (1.3eq) of dimethyldichlorosilane and completion of the reaction was detected by TLC. Adding 8.5g CDI (1.3eq) into the system, heating to 45 ℃ and stirring, after TLC detection reaction is completed, adding 9.2mL (3eq) of isopropanol, continuing stirring at 45 ℃, after the reaction is completed, stopping stirring, naturally cooling to room temperature, adding 50mL of toluene into the system, then adding 140mL of 2mol/L HCl solution, after the system is layered, collecting an organic phase, concentrating to obtain a light yellow solid, and washing with methyl tert-butyl ether to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (9.8g, yield 90%).
(2) 50mL each of isopropyl alcohol and water was measured, the obtained (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide and 1g of palladium on carbon were added thereto, and the mixed system was treated with hydrogen until the reaction was complete. The catalyst was removed by suction filtration and the filter cake was washed with water and the filtrate was collected and used directly in the next reaction.
(3) At 0 ℃, 1mL (0.2eq) of triethylamine is added into the reaction liquid of the obtained (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide, 7.3g (1.2eq) of sulfur trioxide-1, 4 dioxane complex is weighed and added into a reaction bottle, the mixture is stirred for 0.5h under heat preservation, the mixture is moved to room temperature and is stirred for 1h continuously, and the reaction liquid of (2S,5R) -6- (sulfo-oxo) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide is obtained.
(4) 19.3g (1.22eq) of tetrahexylammonium bromide was added to a reaction solution of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide at room temperature, and after stirring for 1 hour, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil.
(5) And (3) dissolving the light yellow oily substance obtained in the previous step into 10mL of ethanol, dropwise adding an ethanol solution of sodium isooctanoate (12g, 2eq) into the solution, and performing suction filtration, washing and drying to precipitate a solid to obtain 7.8g of abamectin sodium. The total yield of the reaction is 68 percent, and the purity of the obtained avibactam sodium product is 99.3 percent.
Example 5
The synthesis method of avibactam sodium comprises the following steps:
(1) acetonitrile (100mL) was weighed out and added to a reaction flask, (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide (10g), temperature was controlled at 5-8 ℃ and 20mL (3eq) of N, N-diisopropylethylamine was added to the system, followed by dropwise addition of 6.4mL (1.3eq) of dimethyldichlorosilane and completion of the reaction was detected by TLC. Adding 8.5g CDI (1.3eq) into the system, heating to 45 ℃ and stirring, after TLC detection reaction is completed, adding 9.2mL (3eq) of isopropanol, continuing stirring at 45 ℃, after the reaction is completed, stopping stirring, naturally cooling to room temperature, adding 50mL of toluene into the system, then adding 140mL of 2mol/L HCl solution, after the system is layered, collecting an organic phase, concentrating to obtain a light yellow solid, and washing with methyl tert-butyl ether to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (9.8g, yield 90%).
(2) 50mL each of isopropyl alcohol and water was measured, the obtained (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide and 1g of palladium on carbon were added thereto, and the mixed system was treated with hydrogen until the reaction was complete. The catalyst was removed by suction filtration and the filter cake was washed with water and the filtrate was collected and used directly in the next reaction.
(3) Adding 1mL (0.2eq) of triethylamine into the reaction liquid of the (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide obtained in the previous step at 0 ℃, weighing 7.3g (1.2eq) of sulfur trioxide-1, 4 dioxane complex, adding the mixture into a reaction bottle, stirring for 0.5h under heat preservation, moving to room temperature, and continuing stirring for 1h to obtain the reaction liquid of the (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide.
(4) To a reaction solution of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide was added 20g (1.22eq) of trioctylmethylammonium bromide at room temperature, and after stirring for 1 hour, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily liquid.
(5) And dissolving the light yellow oily liquid obtained in the previous step into 10mL of ethanol, dropwise adding an ethanol solution of sodium isooctanoate into the solution, and performing suction filtration, washing and drying to precipitate a solid to obtain 8.1g of abamectin sodium. The total yield of the reaction is 70%, and the purity of the obtained avibactam sodium product is 99.3%.
Example 6
The synthesis method of avibactam sodium comprises the following steps:
(1) acetonitrile (100mL) was weighed out and added to a reaction flask, (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide (10g), temperature was controlled at 5-8 ℃ and 20mL (3eq) of N, N-diisopropylethylamine was added to the system, followed by dropwise addition of 6.4mL (1.3eq) of dimethyldichlorosilane and completion of the reaction was detected by TLC. Adding 8.5g CDI (1.3eq) into the system, heating to 45 ℃ and stirring, after TLC detection reaction is completed, adding 9.2mL (3eq) of isopropanol, continuing stirring at 45 ℃, after the reaction is completed, stopping stirring, naturally cooling to room temperature, adding 50mL of toluene into the system, then adding 140mL of 2mol/L HCl solution, after the system is layered, collecting an organic phase, concentrating to obtain a light yellow solid, and washing with methyl tert-butyl ether to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (9.8g, yield 90%).
(2) 50mL each of isopropyl alcohol and water was measured, the obtained (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide and 1g of palladium on carbon were added thereto, and the mixed system was treated with hydrogen until the reaction was complete. The catalyst was removed by suction filtration and the filter cake was washed with water and the filtrate was collected and used directly in the next reaction.
(3) Adding 1mL (0.2eq) of triethylamine into the reaction liquid of the (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide obtained in the previous step at 0 ℃, weighing 7.3g (1.2eq) of sulfur trioxide-1, 4 dioxane complex, adding the mixture into a reaction bottle, stirring for 0.5h under heat preservation, moving to room temperature, and continuing stirring for 1h to obtain the reaction liquid of the (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide.
(4) To a reaction solution of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide was added 20g (1.22eq) of tributylhexylammonium bromide at room temperature, and after stirring for 1 hour, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily liquid.
(5) And dissolving the light yellow oily liquid obtained in the previous step into 10mL of ethanol, dropwise adding an ethanol solution of sodium isooctanoate into the solution, and performing suction filtration, washing and drying to precipitate a solid to obtain 7.5g of abamectin sodium. The total yield of the reaction is 65%, and the purity of the obtained avibactam sodium product is 99.2%.
Example 7
The synthesis method of avibactam sodium comprises the following steps:
(1) acetonitrile (100mL) was weighed out and added to a reaction flask, (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide (10g), temperature was controlled at 5-8 ℃ and 20mL (3eq) of N, N-diisopropylethylamine was added to the system, followed by dropwise addition of 6.4mL (1.3eq) of dimethyldichlorosilane and completion of the reaction was detected by TLC. Adding 8.5g CDI (1.3eq) into the system, heating to 45 ℃ and stirring, after TLC detection reaction is completed, adding 9.2mL (3eq) of isopropanol, continuing stirring at 45 ℃, after the reaction is completed, stopping stirring, naturally cooling to room temperature, adding 50mL of toluene into the system, then adding 140mL of 2mol/L HCl solution, after the system is layered, collecting an organic phase, concentrating to obtain a light yellow solid, and washing with methyl tert-butyl ether to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide (9.8g, yield 90%).
(2) 50mL each of isopropyl alcohol and water was measured, the obtained (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide and 1g of palladium on carbon were added thereto, and the mixed system was treated with hydrogen until the reaction was complete. The catalyst was removed by suction filtration and the filter cake was washed with water, the filtrate was collected, and the solvent was distilled off under reduced pressure to give (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide.
(3) This was dissolved with 50mL of water and 25mL of 1, 4-dioxane. Adding 1mL (0.2eq) of triethylamine into the solution, weighing 7.3g (1.2eq) of sulfur trioxide-1, 4-dioxane complex, dissolving the sulfur trioxide-1, 4-dioxane complex in 1, 4-dioxane (25mL), dropwise adding the 1, 4-dioxane solution of the sulfur trioxide-1, 4-dioxane complex into a reaction bottle at 0 ℃, stirring for 0.5h at a constant temperature, and stirring for 1h continuously after moving to the room temperature to obtain a reaction solution of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide.
(4) To a reaction solution of (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide was added 24g (1.22eq) tetraoctylammonium bromide at room temperature, and after stirring for 1 hour, the product was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oily liquid.
(5) And dissolving the light yellow oily liquid obtained in the previous step into 10mL of ethanol, dropwise adding an ethanol solution of sodium isooctanoate into the solution, and performing suction filtration, washing and drying to precipitate a solid to obtain 8.2g of abamectin sodium. The total yield of the reaction is 71 percent, and the purity of the obtained avibactam sodium product is 99.3 percent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and simplifications made in the spirit of the present invention are intended to be included in the scope of the present invention.

Claims (5)

1. A method for synthesizing abamectin sodium is characterized by comprising the following steps:
(1) reacting (2S,5R) -5- [ (benzyloxy) amino ] piperidine-2-carboxamide with dimethyldichlorosilane in the presence of a base and a solvent used for the reaction, wherein the solvent used for the reaction is acetonitrile, acetone, isopropanol or tetrahydrofuran, the reaction temperature is 0-10 ℃, and a urea ring is constructed by carbonyldiimidazole to obtain (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide;
(2) reacting (2S,5R) -6- (benzyloxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide with hydrogen in a solvent used for reaction under the catalysis of a catalyst to obtain (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-carboxamide; the solvent used in the reaction is isopropanol-water mixed solution, ethanol-water mixed solution, methanol-water mixed solution or 1, 4-dioxane-water mixed solution;
(3) adding alkali and sulfur trioxide-1, 4-dioxane complex into (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide to react to obtain (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide; wherein the charging ratio of the sulfur trioxide-1, 4 dioxane complex to the (2S,5R) -6-hydroxy-7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide is 1-1.5: 1, the reaction temperature is 15-35 ℃, and the reaction time is 0.5-2 h;
(4) reacting (2S,5R) -6- (sulfooxy) -7-oxo-1, 6-diazabicyclo [3.2.1] octane-2-formamide with quaternary ammonium salt in a solvent used for reaction, and extracting with dichloromethane to obtain a quaternary ammonium salt intermediate; the quaternary ammonium salt is tetraoctyl ammonium bromide, tetrapentyl ammonium bromide, tetraheptyl ammonium bromide, tetrahexyl ammonium bromide, trioctylmethyl ammonium bromide or tributylhexyl ammonium bromide, the reaction temperature is 25-35 ℃, and the reaction time is 1-2 h;
(5) and (3) dropwise adding a sodium isooctanoate solution into the solvent used for the reaction to react, precipitating a solid, filtering and drying to obtain the abamectin sodium.
2. The method for synthesizing avibactam sodium according to claim 1, wherein in the step (1), the base is triethylamine, diisopropylamine, N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine.
3. The method for synthesizing avibactam sodium according to claim 1, wherein in the step (2), the catalyst is palladium carbon, the reaction temperature is 15-35 ℃, and the reaction time is 1-6 h.
4. The method for synthesizing abamectin sodium according to claim 1, wherein in the step (3), the base is potassium carbonate, sodium carbonate, calcium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, N-diisopropylethylamine or pyridine, and the solvent used in the reaction is acetonitrile-water mixed solution, 1,4 dioxane-water mixed solution or isopropanol-water mixed solution.
5. The method for synthesizing avibactam sodium according to claim 1, wherein in the step (5), the solvent used in the reaction is ethanol, methanol or isopropanol.
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