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Synthetic method of β-lactamase inhibitor avibactam

A technology of β-lactamase and synthesis method, which is applied in the field of preparation of β-lactamase inhibitors, can solve the problems of cumbersome route process, low final yield, and difficult operation, and achieve stable process, few by-products, and post-processing Handle simple effects

Active Publication Date: 2019-10-29
YIYUAN XINQUAN CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route also adopts the ring-opening and ring-closing method in the synthesis of compound 29, the by-products are high, there are isomers in the synthesis of compound 30, and H is also used in the deprotection. 2 , the operation is difficult, the route process is cumbersome, and the final yield is low

Method used

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  • Synthetic method of β-lactamase inhibitor avibactam
  • Synthetic method of β-lactamase inhibitor avibactam
  • Synthetic method of β-lactamase inhibitor avibactam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) compound Synthesis:

[0033] Add (S)-5-oxo-2 piperidinecarboxylic acid (25.0g, 174.6mmol) and dichloromethane (300ml) into the three-necked flask and stir, add 2,6-lutidine (1g, 9mmol), Benzylamine hydrochloride (26.5g, 184.8mmol), warmed up and refluxed for 2h, washed with purified water and saturated sodium chloride solution, separated, concentrated to give light brown oily compound 3 (42.83g, 171.1mmol, yield 98% )

[0034] (2) compound Synthesis:

[0035] Add purified water (600ml), glucose (20g), citric acid (0.5g), PEG 2000 (0.1g), disodium hydrogen phosphate (0.5g), dry baker’s yeast (40g) into a three-necked flask, and stir at 30°C 1h, add compound 3 (40g, 172.2mmol) in ethyl acetate solution (300ml) in three batches, each batch was separated by 1h, after the addition was completed, it was kept at 30°C for 24h, filtered, separated, and the aqueous phase was extracted with ethyl acetate , the organic phases were combined, concentrated, crystallized wit...

Embodiment 2

[0049] Others are the same as in Example 1, the difference is:

[0050] (1) In the synthesis of compounds , compound 2 and R 1 NH 2 The reaction produces compound 3, R 1 It is Teoc; temperature is raised to reflux for 1h (yield 96%).

[0051] (2) in the synthesis of compounds During the process, the glucose was replaced by sucrose; the organic solvent ethyl acetate was replaced by acetone; after adding the raw materials, the reaction was incubated at 5°C for 72h (yield 94%, optical activity ee value 99%).

[0052] (3) In the synthesis of compounds At this time, trifluoroacetic anhydride was added dropwise to react for 0.5 h, and the temperature was maintained at -20°C (yield 96%).

[0053] (4) in the synthesis of compounds , after adding benzyloxyamine, maintain the temperature for 1h, wherein R 1 for Teoc, R 2 To Alloc (yield 96%).

[0054] (5) in the synthesis of compounds when (where R 1 for Teoc, R 2 For Alloc), the potassium carbonate solution was replac...

Embodiment 3

[0059] Others are the same as in Example 1, the difference is:

[0060] (1) In the synthesis of compounds , compound 2 and R 1 NH 2 The reaction produces compound 3, R 1 It is Dmb; temperature rises and refluxes for 20h (yield 97%).

[0061] (2) in the synthesis of compounds During the process, the glucose was replaced with sucrose; the organic solvent ethyl acetate was replaced with dichloromethane; after the raw materials were added, the reaction was incubated at 40° C. for 1 h (yield 95%, optical activity ee value 98%).

[0062] (3) In the synthesis of compounds , and reacted for 12 hours after adding trifluoroacetic anhydride dropwise, the temperature was maintained at 0°C (yield 96%).

[0063] (4) in the synthesis of compounds , after adding benzyloxyamine, maintain the temperature for 10h, wherein R 1 for Teoc, R 2 It is Fmoc (yield 96%).

[0064] (5) in the synthesis of compounds when (where R 1 for Teoc, R 2 For Fmoc), the potassium carbonate solution...

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Abstract

The invention relates to a method for synthesizing a beta-lactamase inhibitor Avibactam and belongs to the technical field of preparation of beta-lactamase inhibitors. The method disclosed by the invention comprises the following steps: (1) taking a compound 2 as a raw material, and reacting with R<1>NH2 so as to produce a compound 3; (2) enabling the compound 3 and a biocatalyst to produce a compound 4 in an organic solvent in the presence of glucose or sucrose; (3) enabling the compound 4 to react with trifluoroacetic anhydride so as to obtain a compound 5; (4) enabling the compound 5 to react with R<2>ONH2 so as to produce a compound 6; (5) hydrolyzing the compound 6 under alkaline conditions so as to produce a compound 7; (6) enabling the compound 7 to react with triphosgene so as to produce a compound 8; (7) enabling the compound 8 to react with ammonium formate in the presence of a catalyst so as to produce a compound 9 in the organic solvent, wherein the catalyst is a Pd / C system; and (8) enabling the compound 9 to react with a sulfonating agent, thereby obtaining the product 1. The method disclosed by the invention is stable in process, high in yield, simple and safe in operation and low in production cost.

Description

technical field [0001] The invention relates to a synthesis method of a beta-lactamase inhibitor avibactam, which belongs to the technical field of preparation of beta-lactamase inhibitors. Background technique [0002] In 2004, Novexel began to study DBOs compounds and found that avibactam has a good inhibitory effect on β-lactamase. Avibactam is a new type of β-lactamase inhibitor with a wide spectrum of inhibitory enzymes. Its mechanism of action is essentially different from that of classic β-lactamase inhibitors. It has long-acting and reversible covalent binding with enzymes. And does not induce β-lactamase production. In 2015, the compound product of ceftazidime and avibactam was approved for marketing in the United States, and the trade name was Avycaz. [0003] Avibactam belongs to DBOs compounds, Chinese chemical name: [(1R,2S,5R)-2-(carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane- 6-yl]sulfuric acid monoester. [0004] Patent WO086241 discloses a method for syn...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 刘成学唐锋张立明
Owner YIYUAN XINQUAN CHEM
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