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Method for synthesizing avibactam intermediate compound

A synthesis method and compound technology, which can be used in organic chemistry, bulk chemical production, etc., can solve the problems of expensive raw materials, unfriendly environment, expensive process conditions, etc., and achieve the effect of mild reaction conditions, no heavy metal pollution, and environmental friendliness.

Pending Publication Date: 2019-11-12
CHENGDU CLIMB PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Harsh process conditions and expensive catalytic methods make it difficult to produce commercially
[0014] To sum up, the prior art preparation of the key intermediate compound E1 of avibactam has defects such as a long reaction route, or expensive raw materials, or being unfriendly to the environment, etc.

Method used

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  • Method for synthesizing avibactam intermediate compound
  • Method for synthesizing avibactam intermediate compound
  • Method for synthesizing avibactam intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment one: E1-2 preparation

[0041]

[0042] 1. Preparation of intermediate V11-2:

[0043] Under nitrogen protection, add 159kg of B1-2 and 776kg of ethyl acetate into a 1500 reactor, under nitrogen protection, add 78kg of O-benzylhydroxylamine hydrobromide, heat up to 50°C and stir for 2 hours. Cool down to room temperature, wash the reaction solution with 300kg of water, and then concentrate under reduced pressure to obtain V11-2. 1H NMR (400MHz, CDCl3) δ7.232 (w, 10H, PhH); 5.177~4.966 (m, 5H, 2PhCH2, NH); 4.272(w, 1H, NCH); 3.843~3.781(m, 2H, BrCH2); 2.405~2.268(m, 2H, NCCH2); 2.036(w, 1H, CH2); 1.866(w, 1H, CH2).

[0044] 1H NMR (400MHz, CDCl3, D2O) δ7.232(w, 10H, PhH), 5.276~4.949(m, 4H, 2PhCH2); 4.257(w, 1H, NCH); 3.841~3.766(m, 2H, BrCH2) ;2.396~2.268(m,2H,NCCH2);2.034(w,1H,CH2);1.843(w,1H,CH2).

[0045] 2. Preparation of intermediate V12-2:

[0046] Add V11-2 in the previous step to 500kg DMF, then add 85kg sodium bis(trimethylsilyl)amide, and rea...

Embodiment 2

[0050] Embodiment 2: Preparation of E1-1

[0051]

[0052] 1. Preparation of intermediate V11-3. Preparation process is the same as embodiment 1.

[0053]V11-3: 1H NMR (400MHz, CDCl3) δ7.268(w, 5H, ArH); 5.084~5.020(m, 3H, PhCH2O, NH); 4.217(w, 1H, COCH); 4.152~4.016(m, 2H, CH3CH2O); 3.839~3.576(m, 2H, ICH2); 2.385~1.787(m, 4H, 2CH2); 1.369(s, 9H, 3CH3); 1.176(q, 3H, J=8, CH3); 1H NMR(400MHz, CDCl3, D2O) δ7.268(w, 5H, ArH); 5.084~4.975(m, 2H, PhCH2O); 4.206(w, 1H, COCH); 4.135~4.015(m, 2H, CH3CH2O); 3.839~3.609(m,2H,ICH2); 2.400~1.850(m,4H,2CH2); 1.368(s, 9H,3CH3); 1.176(q,3H,J=8,CH3)

[0054] 2. Preparation of intermediate V12-1:

[0055] Preparation process is the same as embodiment 1.

[0056] V12-1 1H NMR (400MHz, CDCl3) δ7.281~7.216(m, 5H, PH); 5.007(s, 2H, PhO-CH2); 4.720~4.241(m, 2H, NCH2); 4.138~4.105(m ,2H,OCH2); 3.795(dd,1H,J1=15.2,J2=19.2,COCH); 2.774~1.941(m,4H,2CH2); 1.408~1.351(w,9H,3CH3);1.213~1.176(t ,J=6.4,3H,CH3)

[0057] 3. Preparation of intermed...

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Abstract

The invention relates to a method for synthesizing an avibactam intermediate compound. The specific synthetic route of the method is as described in the specification. According to a technical schemeof the invention, no precious metal catalyst is used, and no heavy metal pollution is produced; high yield and low cost are realized; and the method is mild in reaction condition and friendly to environment, and can realize industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to a synthesis method of an avibactam intermediate compound. Background technique [0002] Avibactam is a novel β-lactamase inhibitor that can reversibly bind to the enzyme covalently. As a new type of enzyme inhibitor, avibactam has significant and extensive enzyme inhibitory effects, can restore or enhance the activity of combined antibiotics, and is of great significance to the treatment of clinical bacterial infections, especially drug-resistant bacterial infections. [0003] Compound E1 is a key intermediate for the synthesis of avibactam, and its structural formula is: [0004] [0005] The synthetic method for preparing E1 in the prior art has more or less defects. For example, the synthetic route described in the patent document WO2013149136 is: [0006] [0007] This route requires the use of metal iridium [Ir(COD)Cl] 2 catalysts resulting in high cos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60C07D211/78
CPCC07D211/60C07D211/78Y02P20/55
Inventor 叶丁马清萍萧茂玲吕中建王晓玲张晓林
Owner CHENGDU CLIMB PHARMA TECH
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