Preparation methods of sodium avibactam and intermediate compound thereof

A kind of technology of avibactam sodium and compound, which is applied in the field of chemical pharmacy, can solve the problems of high risk of hydrogen reduction, unsuitability for industrial production, cumbersome reaction operation process, etc., so as to avoid hydrogenation catalytic operation, maximize application value and reduce safety risk effect

Inactive Publication Date: 2018-04-06
SHANGHAI SUNTECH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] CN103649051A has reported the preparation method of avibactam sodium as shown in Reaction Formula 2, the hydrogenation process of this method uses hydrogen to reduce the risk is higher, the reaction operation process is loaded down with trivial details, and some intermediates are unstable and can be decomposed to generate impurities in the post-treatment process, which is not necessary. Suitable for industrial production

Method used

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  • Preparation methods of sodium avibactam and intermediate compound thereof
  • Preparation methods of sodium avibactam and intermediate compound thereof
  • Preparation methods of sodium avibactam and intermediate compound thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044](2S,5R)-6-Benzyloxy-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide (Compound J) preparation: (refer to patent document CN103649051) at 20°C, (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxamide (102g, 409mmol) and di Isopropylamine (76.2ml, 437.6mmol) and chlorobenzene (612ml) were mixed. 9-Perlenyl chloroformate (107.9 g, 417.2 mmol) was added to the reaction mixture as a solution in chlorobenzene (612 ml), and the mixture was stirred at 30°C until the reaction was complete. Carbonyldiimidazole (86.2 g, 531.7 mmol) was added and stirring continued until the reaction was deemed complete. Diethylamine (105.8ml, 1022.5mmol) was added and stirring continued until the reaction was deemed complete. Aqueous hydrochloric acid (640.0ml, 3N, 1920ml) was added and the mixture was cooled to 2°C. The solid was isolated by filtration, washed with water (2X, 200ml) and dried to afford the title compound (101g, 367.2mmol, 90%) as a white crystalline solid.

[0045] ...

Embodiment 2

[0049] ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-octyl-6- Base]oxy}sulfonyl)tetrabutylammonium salt (compound K): isopropanol (150ml) was added to the reaction flask, compound J (10.0g), palladium on carbon (1.0g), triethylamine (3.68g), ammonium formate (1.15g) and formic acid (3.34g), controlled temperature 30 ℃ ~ 35 ℃ reaction 2 ~ 3 hours, HPLC detection J after the reaction is complete, suction filtration, washing. Triethylamine (0.92 g) and trimethylamine sulfur trioxide (7.1 g) were added to the filtrate. The temperature is controlled at 30°C to 35°C, and the reaction is stirred for 3 to 4 hours. Add content and be 35% tetrabutylammonium acetate (16.5g) aqueous solution, stir and react at room temperature for 3 hours, the reaction solution is concentrated to 140g, dichloromethane (60g×2) is added to the concentrated reaction solution for extraction twice, after phase separation, the The organic phase was concentrated under vacuum at 40-50°C to o...

Embodiment 3

[0053] ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-octyl-6- Base]oxy}sulfonyl)tetrabutylammonium salt (compound K) preparation: isopropanol (150ml) was added in the reaction flask, compound J (10.0g) was added, palladium hydroxide (1.0g), triethyl Amine (3.68g), ammonium formate (1.15g) and formic acid (3.34g) were reacted at a controlled temperature of 30°C to 35°C for 2 to 3 hours. After the reaction was detected by HPLC, the mixture was suction filtered and washed. Triethylamine (0.9 g) and trimethylamine sulfur trioxide (7.1 g) were added to the filtrate. The temperature is controlled at 30°C to 35°C, and the reaction is stirred for 3 to 4 hours. Add content and be 35% tetrabutylammonium acetate (11g) aqueous solution, stir and react at room temperature for 3 hours, the reaction solution is concentrated to 150g, dichloromethane (60g×2) is added to the concentrated reaction solution and extracted twice, after phase separation, the organic Concentrate...

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Abstract

The invention provides a preparation method of sodium avibactam. The method comprises that sodium 2-ethylhexanoate reacts with an intermediate compound K, so that the sodium avibactam is obtained. Theinvention also provides a preparation method of the intermediate compound K. The preparation method comprises the following steps: (1) carrying out reaction on a compound J with ammonium formate, formic acid and triethylamine in presence of a catalyst, and removing benzyl, so that a compound K1 is obtained; (2) adding an acid binding agent, a sulfonation reagent and water into the K1 reaction liquid obtained in the step (1), and reacting; and (3) adding tetrabutylammonium acetate aqueous solution into the reaction liquid obtained in the step (2), stirring and reacting, then adding an extraction solvent, separating out an organic phase, drying, then distilling off the solvent, adding a crystallization solvent, stirring, and crystallizing, so that the compound K is obtained. The preparationmethods provided by the invention are low in cost, avoid a high-risk preparation method for debenzylation through hydrogenation, are high in safety performance, easy to operate and applicable to industrial production and have greater application value.

Description

technical field [0001] The invention relates to chemical pharmacy, in particular to a preparation method of medicine, in particular to a preparation method of antibiotic avibactam sodium and an intermediate thereof. Background technique [0002] Avibactam sodium, English name is avibactam sodium, chemical name: [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane -6-yl]sulfuric acid monosodium salt. Avibactam sodium and cephalosporin antibacterial drug ceftazidime form a compound preparation, which was approved by the US FDA on February 15, 2015. It is used for the treatment of complicated intra-abdominal infection and complicated urinary tract infection in adults, and is suitable for the treatment of kidney infection. (pyelonephritis) patients. [0003] Avibactam (NXL-104) is a novel, non-β-lactam β-lactamase inhibitor whose activity spectrum includes Ambler A class extended-spectrum β-lactamase (EBSL), KPC class A enzyme and class C enzyme (AmpC). Avibacta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 刘学军米伟洪辉意陈晓冬
Owner SHANGHAI SUNTECH PHARMA
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