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7-oxo-diazabicyclo [3, 2, 1] octane derivative compound, preparation method thereof and application

A technology of diazabicycle and compound, applied in the field of drug synthesis, can solve problems such as influence of drug activity, no report, etc., and achieve the effects of being beneficial to industrialized production, simple process and simple reaction route

Active Publication Date: 2017-12-22
上海海宸医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the structure of avibactam in the prior art is mainly to study the influence of different substituents connected to the amide bond on the activity of the drug, and there is no report on the amide bond in avibactam, the substituted triazole group Whether the substitution has an effect on the activity of the drug

Method used

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  • 7-oxo-diazabicyclo [3, 2, 1] octane derivative compound, preparation method thereof and application
  • 7-oxo-diazabicyclo [3, 2, 1] octane derivative compound, preparation method thereof and application
  • 7-oxo-diazabicyclo [3, 2, 1] octane derivative compound, preparation method thereof and application

Examples

Experimental program
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Embodiment 1

[0048] This embodiment is that the specific preparation process of the corresponding compound of formula III can be obtained by the following method, wherein, Bn in the compound of formula III is benzyl,

[0049]

[0050] Take a 250mL clean four-neck flask and add the compound of formula II (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3,2,1]octane-2-carboxylic acid Ethyl ester (25.0g, 82.2 mmol), methanol 180mL, lower the temperature to -5~-10°C, then add lithium borohydride (total 5.4g, 246.6mmol) in batches, and control the temperature below 0°C to continue stirring for 5h Finally, 200 mL of saturated sodium dihydrogen phosphate was added to quench the reaction. After the end, methanol was distilled off under reduced pressure, and methylene chloride was added to the residue for extraction three times (80 mL×3). Anhydrous sodium sulfate was added to the organic phase and dried for 0.5 hour, then filtered to remove anhydrous sodium sulfate, and the collected filtrate was conc...

Embodiment 2

[0056] This embodiment is that the specific preparation process of the compound of the corresponding formula IV can be obtained by the following methods:

[0057]

[0058] In a 250mL clean four-neck flask, add the compound of formula III (2S,5R)-6-benzyloxy-2-hydroxymethyl-1,6-diazabicyclo[3,2,1]octane- 7-ketone (7.9g, 30.0mmol) and dichloromethane 80mL, then, add triphenylphosphine (9.4g, 36.0mmol), imidazole (3.1g, 45.0mmol) and iodine (9.1g, 36.0mmol) under ice-cooling mmol), after adding, under stirring, gradually rise to room temperature for iodation reaction for 3h, after the reaction, add 80mL of saturated sodium sulfite to quench, extract with ethyl acetate (80mL×3), collect and combine the organic phases, and use anhydrous Dried over sodium sulfate, filtered, concentrated and subjected to column chromatography (n-hexane / ethyl acetate=5:1 (volume ratio)), it is generally understood that conventional column chromatography purification in this field includes column pa...

Embodiment 3

[0063] This example is specifically a 7-oxo-diazabicyclo[3,2,1]octane derivative compound, the structural formula of which is shown in Ia below:

[0064]

[0065] The 7-oxo-diazabicyclo[3,2,1]octane derivative compound of the above formula Ia compound is specifically prepared by the following method:

[0066] In a 100mL three-neck flask, add the compound of formula IV (2S,5R)-6-benzyloxy-2-iodomethyl-1,6-diazabicyclo[3,2,1]octan-7-one (2.4g, 9.0mmol), 1H-1,2,3-triazole (4.8g, 72.0mmol), sodium bicarbonate (0.1g, 1.5mmol), acetone 30mL and water 6mL, under stirring, control Condensation reaction is carried out at room temperature. During the reaction, TLC is used to detect and track the end of the reaction. Then, the acetone is evaporated under reduced pressure, and 45 mL of ethyl acetate is added to the residue for extraction. After standing, the layers are separated, and the organic layer is separated. , washed successively with saturated sodium bicarbonate and saturated ...

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Abstract

The invention relates to a 7-oxo-diazabicyclo [3, 2, 1] octane derivative compound, a preparation method thereof and an application, and belongs to the technical field of drug synthesis, and aims to solve the problem of how to obtain high-activity antibacterial drugs. The method includes the steps: performing condensation reaction of a compound in a formula IV and RH to obtain an intermediate product compound in a formula V in the presence of acid-binding agents; removing benzyl by hydrogenation deprotection treatment and then performing sulfonation or phosphorylation reaction to obtain the 7-oxo-diazabicyclo [3, 2, 1] octane derivative compound in a formula I. The RH is selected from substituted or unsubstituted 1H-1, 2, 3-triazole or 1H-1, 2, 4-triazole compound, and compounds in the formula VI or VII are in one-to-one correspondence to R2, R3 and R4 in the compound in the formula I. The derivative compound has good antibacterial activity and particularly has good inhibiting effects on pseudomonas aeruginosa and Escherichia coli, the method is simple in operation, and conditions are mild.

Description

technical field [0001] The invention relates to a 7-oxo-diazabicyclo[3,2,1]octane derivative compound and its preparation method and application, belonging to the technical field of drug synthesis. Background technique [0002] In recent years, the compound varieties of new β-lactamase inhibitors are on the rise. The emergence of new bactams such as Avibactam and Relebactam will undoubtedly bring a new wind to the trough antibiotic field. [0003] Avibactam, Relebactam, etc. are 7-oxo-diazabicyclo[3,2,1]octane derivatives, which have the same core structure, and the difference is that the amino group is substituted on the amide bond. In February 2015, Avycaz, a compound product composed of avibactam and ceftazidime, was approved by the US FDA for the treatment of complicated intra-abdominal infections and complicated urinary tract infections in adults. The compound products are in phase II and phase I of clinical trials respectively, and are currently the most promising non...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08C07F9/6561A61K31/439A61K31/675A61P31/04
CPCC07D471/08C07F9/6561Y02A50/30
Inventor 叶海伟周丽萍成碟徐峰
Owner 上海海宸医药科技有限公司
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