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A kind of convenient preparation method of avibactam

A compound and solvent technology, applied in the field of simple preparation of avibactam, can solve the problems of high starting material price, unfavorable industrial production, and low atom utilization rate, and achieve low cost, high atom utilization rate, and simple preparation steps Effect

Active Publication Date: 2020-08-04
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] In summary, the intermediate 5R-benzyloxyaminopiperidine-2S-formate oxalate (Ⅷ), the intermediate (2S,5R)-6-benzyloxy-7 involved in the synthesis of avibactam - The synthetic route of oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (VII) is long, the starting material price is high, and a large amount of expensive palladium carbon catalyst is required, " The "three wastes" have large emissions and low atomic utilization, which is not conducive to environmental protection, and the operation is cumbersome, which is not conducive to industrial production

Method used

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  • A kind of convenient preparation method of avibactam
  • A kind of convenient preparation method of avibactam
  • A kind of convenient preparation method of avibactam

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Embodiment 1: Preparation of Avibactam (I)

[0090] Step (1): Methyl 5-methoxymethyloxyiminopiperidine-2S-carboxylate (Ⅲ 1 ) preparation

[0091] Add 200 grams of 1,2-dichloroethane, 23.5 grams (0.15 moles) of piperidin-5-one-2S-methyl carboxylate, 20.5 gram (0.18 moles) of methoxymethylhydroxylamine hydrochloride, 25 grams of triethylamine, stirred at 40-45°C for 4 hours, cooled to 20-25°C, added 100 grams of water, separated, and the water layer was mixed with 1, 2-dichloroethane was extracted twice, 50 grams of 1,2-dichloroethane each time, the organic layers were combined, and washed twice with saturated brine, 25 grams each time.

[0092] After the organic phase recovered the solvent, it was distilled under reduced pressure to obtain 31.3 g of light yellow liquid 5-methoxymethyloxyiminopiperidine-2S-methyl carboxylate, with a GC purity of 99.8% and a yield of 96.5%.

[0093] Step (2): 5R-methoxymethyloxyaminopiperidine-2S-formic acid methyl ester oxalate (IV 1 ...

Embodiment 2

[0115] Embodiment 2: Preparation of Avibactam (I)

[0116] Step (1): Methyl 5-tert-butyldimethylsilyloxyiminopiperidine-2S-carboxylate (Ⅲ 2 ) preparation

[0117] In the 500 milliliter four-necked flasks that stirring, thermometer and reflux condenser are equipped with, add respectively 200 gram dichloromethanes, 23.5 grams (0.15 moles) piperidin-5-ketone-2S-methyl formate, 36.5 grams (0.2 moles) Tert-butyldimethylsilyl hydroxylamine hydrochloride, 25 grams of triethylamine, stirred at 38-40°C for 5 hours, cooled to 20-25°C, added 100 grams of water, separated into layers, and extracted the water layer with dichloromethane Twice, 50 grams of dichloromethane each time, combined organic layers, washed twice with saturated brine, 25 grams each time. After the organic phase recovered the solvent, it was distilled under reduced pressure to obtain 41.0 g of light yellow liquid 5-tert-butyldimethylsilyloxyiminopiperidine-2S-methyl carboxylate, with a GC purity of 99.9% and a yield ...

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Abstract

The invention provides a simple and convenient preparation method of avibactam, which uses piperidine-5-ketone-2S-formate II as a raw material, undergoes a condensation reaction with O-protecting group hydroxylamine hydrochloride, and then undergoes reduction, chiral Resolution and hydrolysis under alkaline conditions to obtain 5R-substituent oxyaminopiperidine-2S-carboxylic acid V; and then "one-pot" cyclic urealation, acyl chloride and amidation with phosgene, solid phosgene or diphosgene Reaction, through deprotection, sulfuric acid esterification, tetrabutylammonium into salt to obtain {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazacyclo[3.2.1] Octane-6-yl]oxyl}sulfonyl tetra-n-butylammonium salt VII, and finally avibactam I was obtained by ion exchange. The invention has simple preparation route, easy operation, low raw material price, low cost, low discharge of "three wastes", high atom utilization rate, economical and environmental protection, and high yield of each step, which is beneficial to the industrialized production of avibactam.

Description

technical field [0001] The invention relates to a simple and convenient preparation method of avibactam, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Avibactam (I) belongs to the non-β-lactam inhibitors of diazabicyclooctone compounds. Avibactam can inhibit type A (including ESBL and KPC) and type C β-lactamase. When Verbactam is used in combination with various cephalosporins and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against E. The Escherichia coli and the Escherichia coli containing both AmpC and extended-spectrum β-lactamase have significant activity. The CAS number of Avibactam (I) is 1192491-61-4, and its chemical name is [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[ 3.2.1] octane-6-yl] sodium sulfate, the structural formula is as follows formula I: [0003] [0004] The existing synthetic technology of avibactam mainly involves two intermediates, namely intermed...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08
CPCC07D471/08C07B2200/07Y02A50/30A61K31/551A61P31/04C07D487/08
Inventor 戚聿新王保林徐欣鞠立柱李新发
Owner XINFA PHARMA
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