A kind of synthetic method of avibactam intermediate

A synthesis method and a technology for intermediates, applied in the field of medicinal chemistry synthesis, can solve problems such as affecting product quality and yield, easy ignition of sodium hydride, strong alkali activity, etc., and achieve carbonate safety, less by-products, and simple operation. Effect

Active Publication Date: 2020-04-24
ZHUHAI UNITED LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The strong alkali process has the following problems: (1) strong alkali has high requirements on equipment and operation, sodium hydride is easy to catch fire when it meets moisture, and has a large safety hazard. Water, process control is more difficult; (2) Strong base has strong activity, many by-products, and the hydroxide ion generated after the strong base deteriorates will react with functional groups such as ester groups, resulting in increased impurities, affecting product quality and yield

Method used

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  • A kind of synthetic method of avibactam intermediate
  • A kind of synthetic method of avibactam intermediate
  • A kind of synthetic method of avibactam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] In a 3L three-necked flask, add 900mL dimethylsulfoxide, 55.2g (2.0eq, 250.9mmol) trimethylsulfoxide iodide, 70.0g (4.0eq, 506.9mmol) potassium carbonate and 40.0g (1.0eq, 125.4 mmol) N-Boc-benzyl pyroglutamate, heated to 50°C for 23h. After that, the heating was stopped, and 500 mL of saturated ammonium chloride aqueous solution was added dropwise. After the dropwise addition, 500 mL of purified water was added for dilution, and extracted with ethyl acetate (500 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 49.5 g of a light yellow solid product with a yield of 96% and a purity of 96.0%. figure 1 , see Table 2 for liquid chromatography data, ESI-MS m / z: 412.2 ([M+H] + ).

[0038] The liquid phase spectrogram data of table 2 embodiment 1 product

[0039]

Embodiment 2

[0041] In a 3L three-necked flask, add 1000mL dimethylsulfoxide, 50.0 (1.8eq, 227.3mmol) trimethylsulfoxide iodide, 61.0g (3.5eq, 441.7mmol) potassium carbonate, 40.0g (1.0eq, 125.4mmol) N-Boc-benzyl pyroglutamate, heated to 45°C for 20h. Heating was stopped, and 500 mL of saturated aqueous ammonium chloride was added dropwise, followed by 500 mL of purified water for dilution, and extracted with ethyl acetate (500 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 47.4 g of a yellow solid product with a yield of 92% and a purity of 94.9%.

Embodiment 3

[0043]In a 3L three-necked flask, add 900mL dimethylsulfoxide, 55.2g (2.0eq, 250.9mmol) trimethylsulfoxide iodide, 78.0g (4.5eq, 564.8mmol) potassium carbonate, 40.0g (1.0eq, 125.4 mmol) N-Boc-benzyl pyroglutamate, heated to 55°C for 25h. Heating was stopped, and 500 mL of saturated aqueous ammonium chloride was added dropwise, followed by 500 mL of purified water for dilution, and extracted with ethyl acetate (500 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 49.1 g of a yellow solid product with a yield of 95% and a purity of 95.7%.

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Abstract

The invention discloses a synthesis method of an Avibactam intermediate, and belongs to the technical field of the medicine chemical synthesis. The synthesis method comprises the following steps: reacting pyroglutamate containing an amino protecting group with trimethylsulfoxonium iodide in a reaction solvent under the effect of the carbonate to obtain the Avibactam intermediate. The problems thata strong alkali process method in the prior art is large in potential safety hazard, relatively difficult in process control and high in impurity content are avoided, and the synthesis method disclosed by the invention is mild in reaction condition, simple in operation, high in process operability security, high in yield, high in product purity and suitable for the industrial production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a method for synthesizing an avibactam intermediate. Background technique [0002] [0003] The chemical name of Avibactam (NXL104) is ((2S,5R)-2-aminocarbonyl-7-oxo-1,6-diazabicyclo[3,2,1]oct-6-yl)sulfate mono Ester is a non-β-lactam β-lactamase inhibitor developed by Novexel. Avibactam belongs to the diazabicyclooctone compound, which does not have obvious antibacterial activity itself, but works by inhibiting β-lactamase. Avibactam can inhibit type A (including ESBL and KPC), part of type C and part of type D β-lactamases. Therefore, when used in combination with penicillium, cephalosporin and carbapenem antibiotics, it has broad-spectrum antibacterial activity, especially against Escherichia coli and Klebsiella pneumoniae containing extended-spectrum β-lactamases, containing super The Escherichia coli containing AmpC enzyme and the Escherichia ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C381/00
CPCC07C381/00Y02P20/55
Inventor 刘斌乔明福窦振国孙超许华锋蔡泽江徐静
Owner ZHUHAI UNITED LAB
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