Preparation method of avibactam sodium

A crystallization method and compound technology, applied in the field of preparation of Avibatana, can solve the problems of low yield, long reaction route, unsuitable for industrialization and the like, and achieve the effect of high yield

Pending Publication Date: 2020-10-16
HAINAN HAILING CHEMIPHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This method has a long reaction route and low yield, and a lot of column separation is used in the intermediate treatment, which is not suitable for industrialization

Method used

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  • Preparation method of avibactam sodium
  • Preparation method of avibactam sodium
  • Preparation method of avibactam sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0038] The synthesis of embodiment 1 intermediate II

[0039] Add 1000g of starting material I, 8L of water, and 6L of dichloromethane to a 20L reactor in sequence, stir to dissolve, add 548.6g of NaHCO3 in batches, stir at room temperature for 1 hour, let stand to separate layers, take the dichloromethane layer, and wash the water layer with dichloromethane Extracted with methane, combined dichloromethane layers, dried with saturated brine and anhydrous sodium sulfate successively, distilled dichloromethane under reduced pressure, added 3L ethyl acetate, 421.4g DIPEA (N,N-diisopropylethylamine), controlled Warm at 10°C-20°C, slowly add 690.7g of Fmoc-Cl 3L ethyl acetate solution dropwise to the reaction liquid, react at room temperature for 1h after dropping, add 162.15g CDI to the reaction liquid, stir and react at 40-50°C for 14h, Add 497.4g of diethylamine to the reaction liquid and react at room temperature for 10h, filter, wash the filtrate with hydrochloric acid and sat...

Embodiment 2

[0040] Embodiment 2, the synthesis of intermediate III

[0041] Add 2.75L tetrahydrofuran, 1.1L tap water, and 550g intermediate II to a 20L reactor, stir to dissolve, cool down to -5-0°C, control the temperature at 0-5°C, and add dropwise 1.65L aqueous solution of 79.6g lithium hydroxide monohydrate, Insulate and react for 1 hour, add 2.75L ethyl acetate, let stand to separate and take the lower water phase, extract the water phase with ethyl acetate, take the water phase, adjust the pH value to 2-3 with 1N hydrochloric acid in the water phase, and extract with ethyl acetate , take the ethyl acetate layer, dry it with saturated brine and anhydrous sodium sulfate successively, filter, and distill the filtrate under reduced pressure at 35-40°C, add 11.0L of n-heptane dropwise, crystallize at -5±5°C for 1h, filter, 40 °C drying to obtain an off-white solid with a yield of 60-70%.

Embodiment 3

[0042] Embodiment 3, the synthesis of intermediate IV

[0043] Add 6L of dichloromethane and 300g of intermediate III to a 20L reactor, stir to dissolve, add 164.8g of triethylamine, cool down to below -10°C, add 222.5g of isobutyl chloroformate dropwise below -5°C, dropwise add After the completion, continue to lower the temperature to below -10°C, add 0.9L ammonia water dropwise below -10°C, stir at room temperature for 1 hour after the dropwise addition is completed, add 3.0L drinking water, let stand to separate and take the organic layer, and the organic layer is sequentially washed with 1N hydrochloric acid, Wash with saturated brine, take the organic layer, dry with anhydrous sodium sulfate, filter, distill the filtrate under reduced pressure at 35-40°C, add 6L of n-heptane dropwise, stir and crystallize at 20-25°C for 2h, filter and dry to obtain an off-white solid, and collect The rate is 75-85%.

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Abstract

The invention discloses a synthesis method of avibactam sodium. (2S,5R)-benzyloxyamino piperidine-2-ethyl formate oxalate (I) is used as an initial raw material; and the method comprises the followingsteps: reacting the raw material with a protecting group, carrying out carbonylation cyclization, carrying out hydrolysis of ester, ammoniating, sulfonating with a sulfur trioxide complex, salifyingwith an ammonium ion source, and salifying with a sodium salt to obtain avibactam sodium, and has the advantages of simple operation, easily controlled conditions, easy industrial production and wideapplication prospect.

Description

technical field [0001] The invention relates to a preparation method of avibactaner. Background technique [0002] Ceftazidime Avibactam for injection was the first Actavis listed on the FDA in February 2015, under the trade name Avycaz. Compound patents CN1289500C, CN103649051B, and CN105294690B disclose a method for preparing Avibatana. The basic route of the method is as follows: [0003] [0004] This method has used a lot of column separation, is not suitable for industrialized production. [0005] Patent CN103328476B discloses a preparation method of Avibatana intermediate, the basic route of the method is as follows: [0006] [0007] The method has a long reaction route and a low yield, and a lot of column separation is used in the intermediate treatment, which is not suitable for industrialization. Contents of the invention [0008] The object of the present invention is to overcome the shortcoming and the deficiency that existing Aviba Tanner synthetic m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
CPCC07D471/08Y02P20/55
Inventor 韩勇蔡亲路国荣王远景
Owner HAINAN HAILING CHEMIPHARMA CORP
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