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Method for preparing avibactam sodium through one-pot method

A technology of avibactam sodium and reaction solution, applied in the field of medicine, can solve the problems of being unsuitable for industrial scale-up production, cumbersome reaction operation process, and high reduction risk, and achieve the advantages of increasing safety factor, reducing production cost and improving yield. Effect

Active Publication Date: 2017-06-20
QILU TIANHE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The patent document (CN103649051A) reports the preparation method of avibactam sodium as shown in route 2. The hydrogenation process of this route uses hydrogen as the hydrogen donor, which has a high risk of reduction, the reaction operation process is cumbersome, and some intermediates are unstable after treatment. The process is easy to decompose and produce impurities, which is not suitable for industrial scale-up production

Method used

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  • Method for preparing avibactam sodium through one-pot method
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  • Method for preparing avibactam sodium through one-pot method

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Example 1: Preparation of [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]sulfuric acid monosodium salt

[0045]Add 20g of compound I into a 1000ml reaction flask, add 400ml of tetrahydrofuran, add 35g of diisopropylethylamine under stirring, and add 11.3g of triphosgene dropwise at a controlled temperature of -10 to 10°C. TLC detects that the reaction is complete. Warm up to room temperature, add a saturated solution of lithium hydroxide dropwise, control the pH value of the feed solution to about 10 and stir for 1 hour. After the reaction is detected by TLC, the reaction solution is adjusted to acidity with hydrochloric acid, and 300ml of dichloromethane is added for extraction. The organic layer was dried over anhydrous sodium sulfate, suction filtered, washed, 7.7g triethylamine and 8.2g n-butyl chloroformate were added, and 37g concentrated ammonia water (mass fraction 25%-28% ), TLC detects that after the completion of the reaction, the layers...

Embodiment 2

[0046] Example 2: Preparation of [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]sulfuric acid monosodium salt

[0047] Add 20g of compound I into a 1000ml reaction flask, add 400ml of tetrahydrofuran, add 35g of diisopropylethylamine under stirring, and add 11.3g of triphosgene dropwise at a controlled temperature of -10 to 10°C. TLC detects that the reaction is complete. Warm up to room temperature, add a saturated solution of lithium hydroxide dropwise, control the pH value of the feed solution to about 10 and stir for 1 hour. After the reaction is detected by TLC, the reaction solution is adjusted to acidity with hydrochloric acid, and 300ml of dichloromethane is added for extraction. The organic layer was dried over anhydrous sodium sulfate, suction filtered, washed, 7.7g triethylamine and 8.2g n-butyl chloroformate were added, and 37g concentrated ammonia water (mass fraction 25%-28% ), TLC detects that after the completion of the reaction, the layer...

Embodiment 3

[0048] Example 3: Preparation of [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]sulfuric acid monosodium salt

[0049] Add 20g of compound I into a 1000ml reaction flask, add 400ml of tetrahydrofuran, add 35g of diisopropylethylamine under stirring, and add 11.3g of triphosgene dropwise at a controlled temperature of -10 to 10°C. TLC detects that the reaction is complete. Warm up to room temperature, add a saturated solution of lithium hydroxide dropwise, control the pH value of the feed solution to about 10 and stir for 1 hour. After the reaction is detected by TLC, the reaction solution is adjusted to acidity with hydrochloric acid, and 300ml of dichloromethane is added for extraction. The organic layer was dried over anhydrous sodium sulfate, suction filtered, washed, 7.7g triethylamine and 8.2g n-butyl chloroformate were added, and 37g concentrated ammonia water (mass fraction 25%-28% ), TLC detects that after the completion of the reaction, the layer...

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Abstract

The invention discloses a method for preparing avibactam sodium through a one-pot method. The method comprises the following steps: by taking (2S,5R)-5-[(benzyloxy)amino]pyridine-2-ethyl carboxylate oxalate as a starting material, firstly generating a compound II by reacting with triphosgene, hydrolyzing, adding ammonia water to perform ammoniation, thereby obtaining a compound III, performing hydrogenation by taking formic acid, ammonium formate or hydrazine hydrate as a hydrogen donor in hydrogenation reaction, and then salifying to obtain the avibactam sodium. The avibactam sodium is prepared by use of the one-pot method, the raw material is cheap and easy to obtain, the reaction condition is mild, the operation is simple, the safety is higher, the yield is high, the purity is good, and the method is suitable for large scale industrial production. Formulae are shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of avibactam sodium. Background technique [0002] Avibactam sodium, English name: avibactam sodium, chemical name: [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane -6-yl] sulfuric acid monosodium salt, the chemical structural formula is as follows. Avibactam sodium and ceftazidime, a cephalosporin antibacterial drug, form a compound preparation with a fixed ratio, which was approved by the US FDA on February 15, 2015, for the treatment of complicated intra-abdominal infections and complicated urinary tract infections in adults , for the treatment of patients with kidney infections (pyelonephritis). [0003] [0004] Avibactam belongs to the diazabicyclooctone compound, which itself has no obvious antibacterial activity, but can inhibit type A (including ESBL and KPC) and type C β-lactamases. Therefore, when used in combina...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 李法东李卓华周显峰左景冉吴柯张兆珍董廷华
Owner QILU TIANHE PHARMA
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