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CN-121370882-B - Pharmaceutical composition of avibactam sodium and preparation method thereof

CN121370882BCN 121370882 BCN121370882 BCN 121370882BCN-121370882-B

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of avibactam sodium and a preparation method thereof. The pharmaceutical composition comprises the following components of avibactam sodium and 2- (5- (2-oxo azetidin-1-yl) thiophene-2-yl) benzo [ d ] thiazole-6-carboxylic acid, wherein the mass ratio of the avibactam sodium to the 2- (5- (2-oxo azetidin-1-yl) thiophene-2-yl) benzo [ d ] thiazole-6-carboxylic acid is 1 (2-3). The pharmaceutical composition has remarkable synergistic antibacterial effect.

Inventors

  • XU LEI
  • XU YAN
  • Cheng Moren
  • SUN HONGHONG
  • LIU PANPAN
  • Xiu Yannan
  • WANG ZHAOWEI
  • YIN XUELIANG
  • ZHAO QIUSHENG
  • SUI JIABIN
  • WANG XIAOGUANG

Assignees

  • 哈药集团技术中心
  • 哈药集团股份有限公司

Dates

Publication Date
20260512
Application Date
20251225

Claims (9)

  1. 1. A pharmaceutical composition of avibactam sodium is characterized by comprising the following components of avibactam sodium and 2- (5- (2-oxo azetidin-1-yl) thiophene-2-yl) benzo [ d ] thiazole-6-carboxylic acid, wherein the mass ratio of avibactam sodium to 2- (5- (2-oxo azetidin-1-yl) thiophene-2-yl) benzo [ d ] thiazole-6-carboxylic acid is 1 (2-3); The structural formula of the 2- (5- (2-oxo azetidin-1-yl) thiophen-2-yl) benzo [ d ] thiazole-6-carboxylic acid is as follows: 。
  2. 2. The pharmaceutical composition of avibactam sodium according to claim 1, wherein the process for the preparation of 2- (5- (2-oxo-azetidin-1-yl) thiophen-2-yl) benzo [ d ] thiazole-6-carboxylic acid comprises the steps of: (1) Adding tert-butyl 4-amino-3-mercaptobenzoate, (5-formylthiophene-2-yl) carbamate into ethanol, adding aqueous solution of sodium sulfite for heating reaction, and removing tert-butoxycarbonyl by hydrochloric acid/methanol treatment after the reaction is finished, and purifying to obtain a compound 1; the structural formula of the compound 1 is as follows: (2) Adding the compound 1 and 3-bromopropionic acid into dichloromethane, adding 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, reacting at room temperature, and purifying after the reaction is completed to obtain a compound 2; the structural formula of the compound 2 is as follows: (3) And (3) adding the compound 2 into anhydrous N, N-dimethylformamide, cooling, replacing nitrogen, adding sodium tert-butoxide in batches, reacting at room temperature, and purifying after the reaction is finished.
  3. 3. The pharmaceutical composition of avibactam sodium according to claim 2, wherein the dosage ratio of the tert-butyl 4-amino-3-mercaptobenzoate, (5-formylthiophene-2-yl) carbamate and the aqueous sodium sulfite solution in step (1) is 10mmol (10-15) mmol (17-26) mL, the concentration of the aqueous sodium sulfite solution is 0.1g/mL, and the concentration of the hydrochloric acid/methanol solution is 4mol/L.
  4. 4. The pharmaceutical composition of avibactam sodium according to claim 2, wherein the heating reaction in step (1) is carried out at a temperature of 70-90 ℃ for a period of 16-24 hours.
  5. 5. The pharmaceutical composition of avibactam sodium according to claim 2, wherein the molar ratio of the compound 1, 3-bromopropionic acid, 1-hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in step (2) is 5 (7.6-10.13): 7.6-10.13.
  6. 6. The pharmaceutical composition of avibactam sodium according to claim 2, wherein the reaction time in step (2) is 8-12h and the temperature at which 1-hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is added is-5~0 ℃.
  7. 7. The pharmaceutical composition of avibactam sodium according to claim 2, wherein the molar ratio of compound 2 to sodium tert-butoxide in step (3) is 5.11 (10.21-12.76).
  8. 8. The pharmaceutical composition of avibactam sodium according to claim 2, wherein the cooling to 0 ℃ in step (3) is performed, the temperature is controlled to be less than or equal to 3 ℃ during the addition of the sodium tert-butoxide, and the reaction time is 1-3h.
  9. 9. A process for the preparation of a pharmaceutical composition of avibactam sodium as claimed in any one of claims 1 to 8, comprising the steps of: according to the mass ratio, the avibactam sodium and the 2- (5- (2-oxo azetidin-1-yl) thiophene-2-yl) benzo [ d ] thiazole-6-carboxylic acid are uniformly mixed.

Description

Pharmaceutical composition of avibactam sodium and preparation method thereof Technical Field The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of avibactam sodium and a preparation method thereof. Background Infectious diseases are caused by pathogenic microorganisms such as bacteria, fungi, viruses and the like, and long-term threat to human health. Among them, beta-lactam antibiotics block cell wall peptidoglycan cross-linking by binding to bacterial Penicillin Binding Proteins (PBPs), inhibiting their transpeptidase activity, leading to bacterial lysis and death, are core drugs for the treatment of such infections. However, with the widespread use of β -lactam antibiotics, bacterial resistance is gradually increased, and the sensitivity of some strains to existing β -lactam antibiotics is reduced, resulting in a decrease in therapeutic effect. The avibactam sodium is used as a novel beta-lactamase inhibitor, can effectively inhibit various beta-lactamases, protect beta-lactam antibiotics from hydrolysis, and restore the antibacterial activity. Therefore, the development of a pharmaceutical composition composed of avibactam sodium and proper beta-lactam antibiotics has important significance for improving the antibacterial effect and coping with drug-resistant bacterial infection. Disclosure of Invention In order to overcome the defects of the prior art, the first aim of the invention is to provide a pharmaceutical composition of avibactam sodium, which has remarkable synergistic antibacterial effect. The second aim of the invention is to provide a preparation method of the abamectin sodium pharmaceutical composition, which has simple process. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: A pharmaceutical composition of avibactam sodium comprises avibactam sodium, 2- (5- (2-oxo azetidin-1-yl) thiophen-2-yl) benzo [ d ] thiazole-6-carboxylic acid, wherein the mass ratio of avibactam sodium to 2- (5- (2-oxo azetidin-1-yl) thiophen-2-yl) benzo [ d ] thiazole-6-carboxylic acid is 1 (2-3); The structural formula of the 2- (5- (2-oxo azetidin-1-yl) thiophen-2-yl) benzo [ d ] thiazole-6-carboxylic acid is as follows: 。 further, the preparation process of the 2- (5- (2-oxo azetidin-1-yl) thiophen-2-yl) benzo [ d ] thiazole-6-carboxylic acid comprises the following steps: (1) Adding tert-butyl 4-amino-3-mercaptobenzoate, (5-formylthiophene-2-yl) carbamate into ethanol, adding aqueous solution of sodium sulfite for heating reaction, and removing tert-butoxycarbonyl by hydrochloric acid/methanol treatment after the reaction is finished, and purifying to obtain a compound 1; the structural formula of the compound 1 is as follows: (2) Adding the compound 1 and 3-bromopropionic acid into dichloromethane, adding 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, reacting at room temperature, and purifying after the reaction is completed to obtain a compound 2; the structural formula of the compound 2 is as follows: (3) And (3) adding the compound 2 into anhydrous N, N-dimethylformamide, cooling, replacing nitrogen, adding sodium tert-butoxide in batches, reacting at room temperature, and purifying after the reaction is finished. Further, in the step (1), the dosage ratio of the tert-butyl 4-amino-3-mercaptobenzoate, (5-formylthiophene-2-yl) carbamate and the aqueous solution of sodium sulfite is 10mmol (10-15 mmol) (17-26 mL), the concentration of the aqueous solution of sodium sulfite is 0.1g/mL, and the concentration of the hydrochloric acid/methanol solution is 4mol/L. Further, the temperature of the heating reaction in the step (1) is 70-90 ℃, and the reaction time is 16-24 hours. Further, the molar ratio of the compound 1, 3-bromopropionic acid, 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in the step (2) is 5 (7.6-10.13): 7.6-10.13. Further, the reaction time in the step (2) is 8-12h, and the addition temperature of the 1-hydroxybenzotriazole and the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is-5~0 ℃. Further, in the step (3), the molar ratio of the compound 2 to the sodium tert-butoxide is 5.11 (10.21-12.76). Further, in the step (3), the temperature is controlled to be less than or equal to 3 ℃ in the process of adding the sodium tert-butoxide, and the reaction time is 1-3h. The preparation method of the abamectin sodium pharmaceutical composition comprises the following steps: according to the mass ratio, the avibactam sodium and the 2- (5- (2-oxo azetidin-1-yl) thiophene-2-yl) benzo [ d ] thiazole-6-carboxylic acid are uniformly mixed. Compared with the prior art, the invention has the following main beneficial effects: The pharmaceutical composition of the avibactam sodium comprises avibactam sodium and 2- (5- (2-oxo azetidin-1-yl) thiophene-2-yl) benzo [ d ] thiazole-6-c