Method for synthesizing avibactam intermediate 5 through asymmetric catalytic hydrogenation method

A technology for catalytic hydrogenation and intermediates, applied in organic chemistry and other directions, can solve the problems of cumbersome post-treatment process and boron pollution, and achieve the effects of easy control of reaction conditions, avoidance of post-treatment, and mild reaction conditions.

Active Publication Date: 2016-02-24
ENANTIOTECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this synthetic route, after passing through 8 intermediates, avibactam (AVB09) is finally obtained. However, in the synthesis process of avibactam intermediate 4 to intermediate 5, the prior art uses NaBH 4 Reduction process, cumbersome post-treatment process, and boron pollution

Method used

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  • Method for synthesizing avibactam intermediate 5 through asymmetric catalytic hydrogenation method
  • Method for synthesizing avibactam intermediate 5 through asymmetric catalytic hydrogenation method
  • Method for synthesizing avibactam intermediate 5 through asymmetric catalytic hydrogenation method

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Effect test

Embodiment 1

[0040] The solvent B is tetrahydrofuran, the base is potassium tert-butoxide, and the catalyst is β-BIMAH(S,S-4-1a). The molar ratio of the catalyst to the avibactam intermediate 4 was 0.01, and the molar ratio of the base to the catalyst was 100:1.

[0041] Concrete process: get 0.01mol of 5-(benzyloxy) imino) piperidine-2-carboxylate ethyl ester 4 (avibactam intermediate 4) dissolve with tetrahydrofuran 140ml, add the catalyst β-BIMAH of 0.0001mol ( S, S-4-1a), add 0.01mol of potassium tert-butoxide, feed 30bar hydrogen as a reducing agent, and stir at 30°C for 16h. Suction filtration, rotary evaporation to remove the solvent to obtain the off-white solid powder of product 5-(benzyloxy)amino)piperidine-2-carboxylate ethyl ester 5 (avibactam intermediate 5). The product purity is 99.5%, and the yield is 89.9%.

Embodiment 2

[0043] The solvent B is tert-butanol, the base is sodium hydroxide, and the catalyst is β-BIMAH (S, S-4-1a). The molar ratio of the catalyst to the avibactam intermediate 4 was 0.1, and the molar ratio of the base to the catalyst was 1:1.

[0044] Specific process: Take 0.1mol of ethyl 5-(benzyloxy)imino)piperidine-2-carboxylate and dissolve it in 140ml of tetrahydrofuran, add 0.01mol of catalyst β-BIMAH (S, S-4-1a), add 0.01 mol of sodium hydroxide was injected into 25 bar of hydrogen, and stirred at 60°C for 16 hours. Suction filtration, rotary evaporation to remove the solvent to obtain the off-white solid powder of the product ethyl 5-(benzyloxy)amino)piperidine-2-carboxylate. The product purity is 99%, and the yield is 88.9%.

Embodiment 3

[0046] The solvent B is tetrahydrofuran, the base is potassium tert-butoxide, and the catalyst is β-BIMAH(S,S-4-1a). The molar ratio of the catalyst to the avibactam intermediate 4 was 0.05, and the molar ratio of the base to the catalyst was 50:1.

[0047] Specific process: Dissolve 0.01mol of ethyl 5-(benzyloxy)imino)piperidine-2-carboxylate in 140ml of tetrahydrofuran, add 0.025mol of catalyst β-BIMAH(S,S-4-1a), Add 0.01 mol of potassium tert-butoxide, inject 25 bar of hydrogen, and stir at 60° C. for 16 h. Suction filtration, rotary evaporation to remove the solvent to obtain the off-white solid powder of the product ethyl 5-(benzyloxy)amino)piperidine-2-carboxylate. The product purity is 99.1%, and the yield is 88.8%.

[0048] Compared with the prior art, the present invention has the following advantages:

[0049] First, with traditional NaBH 4 Compared with the reduction process, the cumbersome post-treatment is avoided, and the environmental pollution caused by bor...

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Abstract

The invention discloses a method for synthesizing an avibactam intermediate 5 through an asymmetric catalytic hydrogenation method. The method comprises the following steps: providing a raw material namely an avibactam intermediate 4, and dissolving the avibactam intermediate 4 with a solvent B, so as to obtain a mixture of the raw material and the solvent B; adding a catalyst beta-BIMAH(S,S-4-1a) into the mixture of the raw material and the solvent B and adding alkali, wherein the mole ratio of the catalyst beta-BIMAH(S,S-4-1a) to the avibactam intermediate 4 is 0.1%-10% and the mole ratio of the alkali to the catalyst beta-BIMAH(S,S-4-1a) is (100:1)-(1:1), introducing hydrogen as a reducing agent, stirring for 8-16 h, carrying out suction filtration, and carrying out rotary evaporation to remove the solvent, so as to obtain white-like solid powder of the R type avibactam intermediate 5.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis asymmetric catalytic hydrogenation preparation, in particular to a method for synthesizing avibactam intermediate 5 by asymmetric hydrogenation catalytic method. Background technique [0002] Avibactam (Avibactam, NXL-104) belongs to the diazabicyclooctone compound and is currently the most promising new type of β-lactamase inhibitor. Compared with the three marketed β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam), it is long-acting and reversibly covalently bound to the enzyme, and does not induce β-lactam Enzymes are produced. [0003] In the past three years, the investment in domestic antibiotic projects has been cold, but the actual situation is that the sales proportion of antibiotics in hospitals has not declined in the past three years. Compound varieties of amidase inhibitors are on the rise. The appearance of Avibactam undoubtedly brought a new wind to the fi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 徐亮黄志鸿曾文彬李苏泳
Owner ENANTIOTECH CORP
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