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Preparation method of avibactam sodium

A technology of avibactam sodium and compound, applied in the field of drug synthesis, can solve the problems of affecting product quality, low yield, difficult to remove, etc., and achieve the effects of improving quality, high yield and stable properties

Pending Publication Date: 2022-07-01
BEIJING JIMEITANG MEDICINE RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first route has been patented by the original research company AstraZeneca and cannot be avoided
In the preparation process of the second route, one of the intermediates forms a salt with cyclohexylamine, and the yield of this step is relatively low
Patent CN105753836B discloses a reduction method, which uses triethylsilane as a reducing agent and reacts under the action of palladium carbon. The method is easy to operate and does not require special equipment, but the reaction of triethylsilane will generate triethylsilanol, triethylsilane Silanol can also be polymerized to form hexaethyldisiloxane. These two compounds are not easy to remove in the system, and it is difficult to detect by conventional detection methods, which affects the quality of the product.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Preparation of compound 2:

[0037] At room temperature, compound 1 (36.8 g, 0.1 mol) was put into 100 mL of dichloromethane, then 150 mL of 10% potassium carbonate solution was added, and after stirring for 0.5 h, the organic phase was separated. Then the organic phase was cooled to 0~5°C, DIPEA (19.4g, 0.15mol) was added, and a dichloromethane solution (150mL) of triphosgene (14.8g, 0.05mol) was slowly added dropwise. React at 5°C. When the reaction is complete, wash with 100 mL of 1M hydrochloric acid, 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, and filter. The solvent was then distilled off at 40°C. After distillation, 150 mL of methyl tert-butyl ether was added, stirred for 1 h, filtered and dried to obtain compound 2 (27.8 g, 0.0912 mol, 91.2%). HPLC%=99.2%, 1 H NMR (DMSO-d 6 , 400MHz)δ7.3365-7.4613(m, 5H), 4.8953-439658(m, 2H), 4.1339-4.1872(m, 2H), 3.9375-3.9550(d, 1H, ...

Embodiment 2

[0039] Preparation of compound 3

[0040] At room temperature, compound 2 (27.4 g, 0.09 mol) was dissolved in 150 mL of water and 150 mL of tetrahydrofuran, and then, under stirring, 32 mL of 10% lithium hydroxide solution was slowly added dropwise. Add 100 mL of ethyl acetate to the reaction solution, stir and separate the liquid to take the water phase, then use 1M hydrochloric acid to adjust pH=1~2, then add 200 mL of ethyl acetate to extract, add 24 g of 20% sodium carbonate solution to the reaction solution with stirring, and then stir Crystallize for 2 h, filter and dry to obtain compound 3 (24.6 g, 0.0824 mol, 91.6%). HPLC%=99.7%, 1 H NMR (DMSO-d 6 , 400MHz) δ7.3986-7.4727 (m, 5H), 4.9032-4.9434 (m, 2H), 3.6258-3.7052 (m, 2H), 2.9230-3.0288 (m, 2H), 1.5724-2.1069 (m, 4H). ESI-MS[M-Na] - m / z 275.

Embodiment 3

[0042] Preparation of compound 4

[0043] At room temperature, compound 3 (23.9 g, 0.08 mmol) was dissolved in 200 mL of dichloromethane, and then isobutyl chloroformate (10.9 g, 0.08 mmol) was slowly added, and after stirring for 0.5 h, the temperature was lowered to 0-5 °C, and then 20 mL of 25% ammonia water was slowly added dropwise, and after the dropwise addition was completed, the reaction was carried out for 1 h. After the reaction is completed, wash with 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated sodium chloride solution, dry with anhydrous sodium sulfate, and filter. After distillation, 100 mL of methyl tert-butyl ether was added for crystallization for 2 h, and the mixture was filtered and dried to obtain compound 4 (19.5 g, 0.071 mol, 88.7%). HPLC%=99.8%, 1 H NMR (DMSO-d 6 , 400MHz)δ7.2831-7.4622(m, 7H), 4.8953-4.9689(m, 2H), 3.6760-3.6930(d, 1H, J=6.8Hz), 3.6166-3.6306(m, 1H), 2.9022(s, 2H), 1.6030-2.0895 (m, 4H). ESI-MS[M+1] + m...

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Abstract

The invention discloses a preparation method of avibactam sodium, which comprises the following steps: carrying out salt decomposition on a compound 1, carrying out ring-closure reaction under the action of triphosgene to generate a compound 2, hydrolyzing the compound 2 to prepare a brand new intermediate alkali metal salt compound 3, and further condensing with ammonia water to prepare a compound 4. The compound 4 uses palladium on carbon as a catalyst, cyclohexene or 1, 4-cyclohexadiene is used for replacing hydrogen with high production safety risk as a reducing reagent, after reduction, the compound 4 reacts with sulfur trioxide trimethylamine and tetrabutylammonium acetate to generate a compound 5, and then the finished product avibactam sodium is obtained through salifying and crystal transformation.

Description

technical field [0001] The invention relates to the synthetic field of medicines, in particular to a preparation method of avibactam sodium. Contains brand new intermediates. Background technique [0002] Avibactam sodium was jointly developed by AstraZeneca and Forest Laboratories (a subsidiary of Allergan). Pfizer officially acquired the small molecule antibiotic business of AstraZeneca in December 2016. In addition to the commercialization rights in North America (the United States and Canada), which are owned by Allergan, Pfizer has the rights to R&D, marketing and commercial promotion and sales worldwide. , On February 15, 2015, the FDA approved the first combination of avibactam, Avycaz, a combination drug with ceftazidime; in June 2016, the drug was approved by the European Union, and another trade name Zavicefta was registered; It was approved for listing in China on May 21, 2019. [0003] Avibactam is a non-beta-lactam inhibitor of diazabicyclooctanone compounds....

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 任晓峰胡卫东孙长安
Owner BEIJING JIMEITANG MEDICINE RES CO LTD
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