Preparation method of beta-lactamase inhibitor drug avibactam sodium intermediate

A technology of avibactam sodium and lactamase, which is applied in the field of medicinal chemistry, can solve the problems of affecting the yield of target product compounds, reducing the yield of compound III, poor stability of intermediate IIa, etc., and achieving safe, rapid and continuous reactions, Avoid excessive accumulation, the effect of less amount of chemicals

Inactive Publication Date: 2019-12-20
REYOUNG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] In addition, intermediate IIa has poor stability and is prone to self-decomposition reaction, which seriously affects the yield of target product compound III
For example, in the patent "CN 105753867", although the use of hydrogen is avoided, the step-by-step experiment results in a large accumulatio

Method used

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  • Preparation method of beta-lactamase inhibitor drug avibactam sodium intermediate
  • Preparation method of beta-lactamase inhibitor drug avibactam sodium intermediate
  • Preparation method of beta-lactamase inhibitor drug avibactam sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-octyl-6- Base] Oxygen} Sulfonyl) Tetrabutylammonium Salt (Compound III) Preparation

[0062] (1) Add isopropanol (500mL) and purified water (500mL) into the reaction flask, add compound II (100.0g), sulfur trioxide trimethylamine copolymer (100.0g), triethylamine (30g) and palladium carbon (10.0g), stirred evenly at room temperature for later use.

[0063] (2) Using Corning G1 reactor, the hydrogen pressure is set to 0.5MPa, the hydrogen flow rate is 0.5NL / min (22.3mmol / min), and the feed rate is 40g / min (according to intermediate II, it is 12.9mmol / min) , the reaction temperature was set at 35°C, and the equipment was operated stably.

[0064] (3) Turn on the feed pump, inject the reaction material into the reactor through the feed pump to start the reaction, and after about 1 min, the reaction liquid flows out from the reactor to the material collection tank.

[0065] (4) Filtrate and collect the fil...

Embodiment 2

[0068] ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-octyl-6- Base] Oxygen} Sulfonyl) Tetrabutylammonium Salt (Compound III) Preparation

[0069] (1) Add acetonitrile (500mL) and purified water (500mL) into the reaction flask, add compound II (100.0g), sulfur trioxide trimethylamine copolymer (100.0g), triethylamine (30g) and palladium carbon (10.0 g), stirring evenly at room temperature for subsequent use.

[0070] (2) Using Corning G1 reactor, the hydrogen pressure is set to 0.5MPa, the hydrogen flow rate is 0.5NL / min (22.3mmol / min), and the feed rate is 40g / min (according to intermediate II, it is 12.9mmol / min) , the reaction temperature was set at 35°C, and the equipment was operated stably.

[0071] (3) Turn on the feed pump, inject the reaction material into the reactor through the feed pump to start the reaction, and after about 1 min, the reaction liquid flows out from the reactor to the material collection tank.

[0072] (4) Filtrate and collect...

Embodiment 3

[0075] ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-octyl-6- Base] Oxygen} Sulfonyl) Tetrabutylammonium Salt (Compound III) Preparation

[0076] (1) Add isopropanol (10L) and purified water (10L) into the reaction flask, add compound II (2kg), sulfur trioxide trimethylamine copolymer (2kg), triethylamine (600g) and palladium carbon (200.0 g), stirring evenly at room temperature for subsequent use.

[0077] (2) Using Corning G4 reactor, the hydrogen pressure is set to 0.5MPa, the hydrogen flow rate is 15NL / min (0.67mol / min), and the feed rate is 1.2kg / min (0.39mol / min according to intermediate II) , the reaction temperature was set at 35°C, and the equipment was operated stably.

[0078] (3) Turn on the feed pump, inject the reaction material into the reactor through the feed pump to start the reaction, and after about 1 min, the reaction liquid flows out from the reactor to the material collection tank.

[0079] (4) Filtrate and collect the filtrate, ad...

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Abstract

Belonging to the technical field of medicinal chemistry, the invention particularly relates to a preparation method of a beta-lactamase inhibitor drug avibactam sodium intermediate. The method includes: adding a reaction solvent into a reaction container, then sequentially adding a compound II, a sulfur trioxide polymer, alkali and a catalyst, and stirring the substances uniformly; setting the reaction conditions of a micro-channel reactor, pumping the reaction materials into the micro-channel reactor for reaction, and collecting the reaction liquid; performing filtering and collecting the filtrate, adding an ammonium salt aqueous solution into the filtrate, and stirring the substances uniformly, finally adding an extraction agent for extraction, performing liquid separation, then collecting an organic phase and performing concentration to obtain a compound III crude product, and carrying out aftertreatment on the crude product to obtain a compound III. The method provided by the invention utilizes the micro-channel reactor to combine hydrogenation and sulfonation reactions into one, avoids decomposition of the reaction intermediate, and increases the yield; and the method also realizes safe, rapid and continuous reaction at the same time, greatly improves the productivity, and is more suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of a beta-lactamase inhibitor medicine avibactam sodium intermediate. Background technique [0002] Avibactam sodium, English name is avibactam sodium, chemical name: [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane -6-yl]sulfuric acid monosodium salt. Avibactam sodium and ceftazidime, a cephalosporin antibacterial drug, form a compound preparation with a fixed ratio, which was approved by the US FDA on February 15, 2015, for the treatment of complicated intra-abdominal infections and complicated urinary tract infections in adults , for the treatment of patients with kidney infection (pyelonephritis). [0003] Avibactam belongs to the diazabicyclooctone compound, which itself has no obvious antibacterial activity, but can inhibit type A (including ESBL and KPC) and type C β-lactamases. Therefore, when used in combin...

Claims

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Application Information

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IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 苗得足胡清文赵远超赵磊曾丽丽
Owner REYOUNG PHARMA
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