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Preparation method of improved avibactam sodium intermediate compound

A compound and sulfonation technology, applied in the field of medicinal chemistry, can solve the problems of being unsuitable for industrial scale-up production, cumbersome reaction operation process, high hydrogen reduction risk, avoiding hydrogenation catalytic operation, reducing safety risks, improving product yield and The effect of purity

Active Publication Date: 2016-07-13
QILU PHARMA HAINAN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The patent document (CN103649051A) reports the preparation method of avibactam sodium as shown in route 2, the hydrogenation process of this route uses hydrogen to reduce the risk of high, the reaction operation process is cumbersome, and some intermediates are unstable and easy to decompose during the post-treatment process. Impurities, not suitable for industrial scale-up production

Method used

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  • Preparation method of improved avibactam sodium intermediate compound
  • Preparation method of improved avibactam sodium intermediate compound
  • Preparation method of improved avibactam sodium intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 , ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-octane-6 Preparation of -yl]oxy}sulfonyl)tetrabutylammonium salt (compound III)

[0034] Add isopropanol (650ml) and purified water (650ml) into the reaction flask, add compound IV (140.0g) and palladium carbon (14.0g), control the temperature at 5-15°C, add triethylsilane (139.0g) dropwise , TLC detects that the reaction is complete and then suction filtered and washed. Triethylamine (13.1 g) and trimethylamine sulfur trioxide (79.6 g) were added to the filtrate. The temperature was controlled at 5-15°C, and the reaction was stirred for 2 hours. A 45% aqueous solution of tetrabutylammonium hydroxide (235.0 g) was added. Dichloromethane was added to the reaction solution for extraction, dried over anhydrous sodium sulfate, filtered with suction, washed, and concentrated to obtain an oil. Add 700ml of methyl tert-butyl ether, stir and crystallize, filter with suction, wash, and dry t...

Embodiment 2

[0035] Example 2 , ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-octane-6 Preparation of -yl]oxy}sulfonyl)tetrabutylammonium salt (compound III)

[0036] Add ethanol (650ml) and purified water (650ml) into the reaction flask, add compound IV (140.0g) and palladium carbon (14.0g), control the temperature at 5-15°C, add dropwise triethylsilane (139.0g), TLC After the detection reaction is complete, filter with suction and wash. Triethylamine (13.1 g) and trimethylamine sulfur trioxide (79.6 g) were added to the filtrate. The temperature was controlled at 5-15°C, and the reaction was stirred for 2 hours. A 45% aqueous solution of tetrabutylammonium acetate (235.0 g) was added. Dichloromethane was added to the reaction solution for extraction, dried over anhydrous sodium sulfate, filtered with suction, washed, and concentrated to obtain an oil. Add 700ml of methyl tert-butyl ether, stir and crystallize, filter with suction, wash, and dry to obtain 2...

Embodiment 3

[0037] Example 3 , ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-octane-6 Preparation of -yl]oxy}sulfonyl)tetrabutylammonium salt (compound III)

[0038] Add isopropanol (650ml) and purified water (650ml) into the reaction flask, add compound IV (140.0g) and palladium carbon (14.0g), control the temperature at 5-15°C, add triethylsilane (139.0g) dropwise , TLC detects that the reaction is complete and then suction filtered and washed. Triethylamine (13.1 g) and trimethylamine sulfur trioxide (79.6 g) were added to the filtrate. The temperature was controlled at 5-15°C, and the reaction was stirred for 2 hours. A 45% aqueous solution of tetrabutylammonium acetate (235.0 g) was added. Dichloromethane was added to the reaction solution for extraction, dried over anhydrous sodium sulfate, filtered with suction, washed, and concentrated to obtain an oil. Add 700ml of methyl tert-butyl ether, stir and crystallize, filter with suction, wash, and dry to o...

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PUM

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Abstract

The invention belongs to the technical field of medical chemistry and particularly relates to a preparation method of beta-lactamase inhibitor drug avibactam sodium and an intermediate of beta-lactamase inhibitor drug avibactam sodium. Triethyl-silane is adopted to realize benzyl removal, hydrogenation catalysis operation in the prior art is omitted, the reaction condition is milder, safety risk is reduced, the product yield and the purity are greatly improved, and the preparation method is more suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a beta-lactamase inhibitor drug avibactam sodium and an intermediate thereof. Background technique [0002] Avibactam sodium, the English name is avibactamsodium, 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 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 infection (pyelonephritis). [0003] Avibactam (avibactam, NXL-104) is a diazabicyclooctone compound, which itself has no obvious antibacterial activity, but can inhibit type A (including ESBL and KPC) and type C β-lactamases. There...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 田振平初乐玲张涛单茂华刘荣旺尹燕振
Owner QILU PHARMA HAINAN
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