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The preparation method of avibactam intermediate

A technology of intermediates and compounds, applied in the field of organic chemistry, can solve the problems of unfriendly environment and low yield, and achieve the effects of environmental friendliness, high purity and high chiral purity

Active Publication Date: 2022-04-08
ENANTIOTECH CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method not only has low yield, but also is very unfriendly to the environment

Method used

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  • The preparation method of avibactam intermediate
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preparation example Construction

[0033] A kind of preparation method of avibactam intermediate, comprises the following steps:

[0034] mixing a compound having a structure shown in formula 2, a chiral catalyst, an acid and a solvent, and stirring to prepare a compound having a structure shown in formula 1;

[0035]

[0036] Described chiral catalyst has the structure shown in formula (I):

[0037]

[0038] The R is selected from a hydrogen atom, a straight-chain alkyl group with 1-20 carbon atoms, a branched-chain alkyl group with 3-20 carbon atoms, a cycloalkyl group with 3-10 carbon atoms, or a substituted or unsubstituted Substituted phenyl.

[0039] The reaction scheme of said method is as follows:

[0040]

[0041] Among them, the chiral catalyst of the present invention is a biomimetic system green catalyst, belonging to the category of organic catalysis, which can avoid transition metal residues caused by the use of transition metals, reduce the pollution of transition metals, especially to...

Embodiment 1

[0073] This embodiment provides a kind of preparation method of avibactam intermediate, the steps are as follows:

[0074] (1) Preparation of chiral catalyst

[0075]

[0076] 2,2,6-Trimethyl-1,3-dioxin-4-one (142.2 mg, 1 mmol) was added dropwise to (S)-α-hydroxy-N-methyl-2-phenylacetamide ( 165.1mg, 1mmol) in a solution of toluene (0.5mL). After stirring at reflux overnight, the reaction mixture was cooled to 50°C and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (the volume ratio of n-hexane:ethyl acetate was 20:1) to obtain 187.0 mg of white solid compound a with a yield of 75%.

[0077] The above white solid compound a (498.6mg, 2mmol), ammonium acetate (77.1mg, 1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL), and heated at 100°C for 30 minutes . The reaction temperature was cooled to normal temperature, water was added, and extracted with dichloromethane. After the organic phase was...

Embodiment 2

[0082] This embodiment provides a preparation method of an avibactam intermediate, which is basically the same as in Example 1, the difference being that the structure of the chiral catalyst is different, and the steps are as follows:

[0083] (1) Preparation of chiral catalyst

[0084]

[0085] 2,2,6-Trimethyl-1,3-dioxin-4-one (142.2 mg, 1 mmol) was added dropwise to (S)-α-hydroxy-N-ethyl-2-phenylacetamide ( 179.2mg, 1mmol) in a solution of toluene (0.5mL). After stirring at reflux overnight, the reaction mixture was cooled to 50°C and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (the volume ratio of n-hexane:ethyl acetate was 20:1) to obtain 243.0 mg of white solid compound b with a yield of 82%.

[0086] The above white solid compound b (526.6mg, 2mmol), ammonium acetate (77.1mg, 1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL), and heated at 100°C for 30 minutes . The reaction tempera...

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Abstract

The invention relates to a preparation method of an avibactam intermediate. The preparation method comprises the steps of: mixing a compound having a structure shown in formula 2, a chiral catalyst, an acid and a solvent, and stirring to prepare a compound having a structure shown in formula 1; the chiral catalyst having a structure shown in formula (I) Structure. The method has high yield, purity and chiral purity, and is environmentally friendly.

Description

technical field [0001] The invention relates to the technical field of organic chemistry, in particular to a preparation method of an avibactam intermediate. Background technique [0002] Avibactam (Avibactam, NXL-104) belongs to the diazabicyclooctanone compound, and its structural formula is as follows: [0003] [0004] Avibactam is currently the most promising new β-lactamase inhibitor. Compared with the three marketed β-lactamase inhibitors, it has a long-acting and reversible covalent binding to the enzyme, and does not induce β-lactamase production. Its mechanism of action is: [0005] β-lactamase serine nucleophilic attack on the avibactam amide bond, open the ring to form a covalent conjugate, and obtain the enzyme-inhibitor complex, which is in the form of enzyme inhibition, and does not undergo hydrolysis, and then forms a lactam ring through cyclization Get Avibactam again. Nucleophilic attack leads to the rate of ring opening far greater than the rate of ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/60C07D211/90B01J31/02
CPCC07D211/60C07D211/90B01J31/0271B01J31/0247B01J2231/645
Inventor 李彦雄蒙发明徐亮郭俊
Owner ENANTIOTECH CORP
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