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Preparation method of avibactam sodium

A technology of avibactam sodium and a synthesis method, which is applied in the field of preparation of avibactam sodium, can solve the problems of long reaction time, volatile ammonia, and high reduction risk, and achieves simple operation, increased safety factor, and reduced production. cost effect

Pending Publication Date: 2022-06-24
南京佰麦生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] Patent literature (CN201280029765) reports the preparation method of avibactam sodium as shown in route 2, ammonia methanol solution is used in the ammonolysis process of this route, ammonia is volatile, and smell is big, needs special protection, and causes reaction time Long, need to add ammonia methanol solution several times
The use of hydrogen as a hydrogen donor in the hydrogenation process has a high risk of reduction, the reaction operation process is cumbersome, and some intermediates are unstable and easy to decompose and produce impurities during the post-treatment process, which is not suitable for industrial scale-up production

Method used

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  • Preparation method of avibactam sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0048] (1) Preparation of compound III

[0049] The starting material (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethyl ester oxalate 200 g (0.543 mol), methanol 2L, ammonium carbonate 156.6g was added to a 3L three-necked flask (1.63 mol, 3eq), react at 20-30°C for 10h, filter, concentrate the filtrate under reduced pressure to dryness (vacuum degree≤-0.08 Mpa), add 1L toluene at 80°C for 1h, and filter. Dry the wet product under vacuum at 45°C for 10h (vacuum degree≤-0.09 Mpa). 121.7 g of compound III were obtained with a yield of 90% and a purity of 99.6%.

[0050] (2) Preparation of compound IV

[0051] The reaction system was always under nitrogen protection. To 120 g (0.481 mol) of compound III, 0.5 L of chlorobenzene and 69.5 g (0.538 mol) of N,N-diisopropylethylamine were added, and then fluorene methoxycarbonyl chloride (138.9 g, 0.538 g) was added dropwise at a temperature of 10-15 °C. mol) solution in chlorobenzene (0.5L), heated to 25-30 °C for 3 hours...

Embodiment 2

[0059] (1) Preparation of compound III

[0060] Add starting material (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethyl ester oxalate 50g (0.14 mol), methanol 0.5L, ammonium chloride 7.5L into a 1L three-necked flask g (0.14 mol, 1eq), react at 20-30°C for 10h, filter, concentrate the filtrate under reduced pressure to dryness (vacuum degree≤-0.08 Mpa), add 1L toluene at 80°C for 1h, and filter. Dry the wet product under vacuum at 45°C for 10h (vacuum degree≤-0.09 Mpa). 32.4 g of compound III was obtained with a yield of 93% and a purity of 99.8%.

[0061] (2) Preparation of compound IV

[0062] The reaction system was always under nitrogen protection. To 32 g (0.13 mol) of compound III, 0.2 L of chlorobenzene, 18.8 g (0.14 mol) of N,N-diisopropylethylamine were added, and fluorene methoxycarbonyl chloride (37.1 g, 0.14 mol) was added dropwise at a temperature of 10-15 °C. mol) in 0.5L of chlorobenzene solution, heated to 25-30°C and reacted for 3 hours, temperatu...

Embodiment 3

[0070] (1) Preparation of compound III

[0071] Add starting material (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethyl ester oxalate 50g (0.14 mol), methanol 0.5L, ammonium bicarbonate 110 to a 1L three-necked flask g (1.4 mol, 10eq), react at 20-30°C for 2h, filter, concentrate the filtrate under reduced pressure to dryness (vacuum degree≤-0.08 Mpa), add 1L toluene at 80°C for 1h, and filter. Dry the wet product under vacuum at 45°C for 10h (vacuum degree≤-0.09 Mpa). 32.5 g of compound III was obtained with a yield of 96% and a purity of 99.4%.

[0072] (2) Preparation of compound IV

[0073] The reaction system was always under nitrogen protection. To 32 g (0.13 mol) of compound III, 0.2 L of chlorobenzene, 18.8 g (0.14 mol) of N,N-diisopropylethylamine were added, and fluorene methoxycarbonyl chloride (37.1 g, 0.14 mol) was added dropwise at a temperature of 10-15 °C. mol) in 0.5L of chlorobenzene solution, heated to 25-30°C for 3 hours, and the temperature wa...

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Abstract

The invention discloses a preparation method of avibactam sodium, which comprises the following steps: carrying out ammonolysis on (2S, 5R)-5-[(benzyloxy) amino] piperidine-2-carboxylic acid ethyl ester oxalate II serving as a starting raw material to generate a compound III, then carrying out cyclization to obtain a compound IV, reacting the compound IV with a hydrogen donor under the action of a catalyst to obtain a compound V, and carrying out post-treatment on the compound V to obtain the avibactam sodium. And sulfonating and forming sodium salt to obtain avibactam sodium. The ammonolysis reagent is selected from ammonium chloride, ammonium carbonate, ammonium sulfate, ammonium bicarbonate and ammonium formate; the catalyst is selected from palladium on carbon, platinum dioxide or Raney nickel, and the hydrogen donor is selected from cyclohexene, cyclohexadiene or tetrahydronaphthalene. The method is high in yield, good in safety and mild in reaction condition.

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 structure is as follows. [0003] . [0004] Avibactam sodium and cephalosporin antibiotic ceftazidime form a fixed-dose compound preparation, which was approved by the US FDA on February 15, 2015 for the treatment of adult complicated intra-abdominal infection and complicated urinary tract infection , for the treatment of kidney infection (pyelonephritis) patients. [0005] The preparation method of this avibactam sodium reported in the current literature mainly includes the following: patent document (CN01816700) reported the preparation method of avibactam sodium as shown in route 1, and the amidation step of...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08C07B2200/07
Inventor 李桃园蒋玉伟于学珍
Owner 南京佰麦生物技术有限公司
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