A kind of recovery method of avibactam intermediate isomer

A recovery method and isomer technology, which is applied in the field of drug synthesis and recovery treatment, can solve the problems of unprotected NH groups, affecting the purity and quality of products, and strong oxidizing properties of oxidants, achieving mild reaction conditions, efficient recovery, and environmental protection. The effect of less pollution

Active Publication Date: 2020-07-03
TAIZHOU VOCATIONAL & TECHN COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It is recovered by direct oxidation, the reaction efficiency is low, and it needs to be repeatedly treated to achieve a high yield effect, and its NH group is not protected, and the oxidizing agent such as concentrated sulfuric acid is strong in oxidation, and it is easy to produce by-products, affecting Recovered product purity quality

Method used

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  • A kind of recovery method of avibactam intermediate isomer
  • A kind of recovery method of avibactam intermediate isomer
  • A kind of recovery method of avibactam intermediate isomer

Examples

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Embodiment 1

[0033] This example is for the recovery of formula II compound (2S,5S)-5-((benzyloxy)amino)piperidine-2-carboxylate intermediate from the mother liquor produced during the salt-forming process of the avibactam intermediate Isomers, wherein R in the compound of formula II is benzyl;

[0034]

[0035] The specific recycling process is as follows:

[0036] Take 18 g of the starting material (S)-N-tert-butyl formate-5-oxopyrrolidine-2-carboxylate, carry out the synthesis operation according to the example 1a method disclosed in the international patent application WO2012172368, and filter to obtain (2S, 5R)-5-((benzyloxy)amino)piperidine-2-carboxylic acid benzyl oxalate, collect about 100mL of the filtrate (mother liquor) after the salt-forming reaction, and then add 50mL of 5wt% sodium carbonate to the filtrate Stir and wash the aqueous solution once, adjust the pH value to 7-8, wash twice with 50mL of water, combine the organic phases, dry with anhydrous sodium sulfate, filt...

Embodiment 2

[0039] In this embodiment, the specific preparation process of the corresponding compound of formula III can be obtained by the following method, wherein the R group in the compound of formula IV corresponds to the benzyl group of the R group in the compound of formula II;

[0040]

[0041] Take 7 g of the recovered formula II compound (2S,5S)-5-((benzyloxy)amino)piperidine-2-carboxylate 7 g, add 40 mL of acetonitrile solvent and 2.3 g of triethylamine, and then add amino Protecting group Boc 2 O (di-tert-butyl dicarbonate) 4.9g, control the temperature and react at room temperature for 4 hours, after the reaction, remove the solvent by rotary evaporation, then add 80mL of ethyl acetate to dilute, and wash the organic phase with 50mL of 1% dilute hydrochloric acid Twice, stand still, separate the liquid, collect the organic phase and wash it once with 50 mL of water, dry the collected organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to remov...

Embodiment 3

[0043] In this embodiment, the specific preparation process of the corresponding compound of formula I can be obtained by the following method, wherein R in the compound of formula I is benzyl.

[0044]

[0045] Take 4.7g of the ketone intermediate represented by the compound of formula IV and put it into the reaction vessel, add 2.4g of benzyloxyamine hydrochloride, 2.3g of sodium acetate and 30mL of methanol solvent, then slowly raise the temperature and control the temperature at 60°C Condensation reaction was carried out for 3 hours, after the condensation reaction was completed, hydrogen chloride gas was introduced to carry out the deprotection reaction until the reaction was complete, the methanol solvent was evaporated under reduced pressure, 50 mL each of ethyl acetate and water were added to the residue, and stirred for 0.5 hours, Static extraction, liquid separation, the collected organic phase was washed twice with 30mL saturated sodium bicarbonate, then dried wit...

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Abstract

The invention relates to a recycling method of an avibactam intermediate isomer, belonging to the technical fields of pharmaceutical synthesis and recycling. According to the pharmaceutical synthesis,the existing complex recycling problem is solved. The recycling method comprises the following steps: reacting by virtue of (2S,5S)-5-((benzyloxy)amino)piperidine-2-carboxylate and an amino protection group Boc2O in the presence of weakly alkaline substances, so as to generate an intermediate product; carrying out catalytic hydrogenation reduction reaction in the presence of a palladium-containing catalyst; carrying out oxidation reaction under the effect of an oxidant, so as to obtain a corresponding ketone intermediate product; and carrying out condensation reaction on a compound represented by a formula I (shown in the description) and benzyloxyamine hydrochloride in the presence of an acid-binding agent, and carrying out deprotection reaction, so as to obtain a final product, namely the compound of the formula I. The recycling method has the advantages that the recycling is efficient, the process route is simple, reaction conditions are mild, and the environmental pollution is low.

Description

technical field [0001] The invention relates to a method for recovering an intermediate isomer of avibactam, belonging to the technical field of drug synthesis and recovery treatment. Background technique [0002] Avibactam (English name: Avibactam) is a new type of β-lactamase inhibitor that can reversibly bind to the enzyme covalently. In February 2015, Avycaz, a compound drug consisting of avibactam and ceftazidime jointly developed by Actavis and AstraZeneca, was approved by the US FDA for the treatment of complicated intra-abdominal infections in adults ( cIAI) and complicated urinary tract infection (cUTI), suitable for patients with kidney infection (pyelonephritis) with limited or no treatment options. Avibactam, ceftaroline, aztreonam and other compound products are in phase II and phase I clinical trials respectively. [0003] At present, what is disclosed in the prior art, such as the international patent application (WO2012172368), is mainly to use protected py...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/78
CPCC07D211/78Y02P20/55
Inventor 叶海伟周丽萍陈云华
Owner TAIZHOU VOCATIONAL & TECHN COLLEGE
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