A kind of preparation method of Avibactam sodium intermediate

A technology of avibactam sodium and intermediates, applied in the field of medicinal chemistry, can solve the problems of long route, high cost, low atom utilization rate and the like

Active Publication Date: 2021-08-24
ZHEJIANG HISOAR PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In summary, the existing synthetic routes of avibactam sodium have disadvantages such as unavailable raw materials, long route, high cost, and low utilization rate of atoms, and the total yield is generally only 20-50%.

Method used

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  • A kind of preparation method of Avibactam sodium intermediate
  • A kind of preparation method of Avibactam sodium intermediate
  • A kind of preparation method of Avibactam sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] Embodiment 1: the preparation of compound (I)

[0136] Compound (I) was prepared according to the method in the example of patent document CN105061425B.

Embodiment 2

[0137] Embodiment 2: the preparation of compound (V) oxalate

[0138] Step (1): Preparation of compound (II)

[0139] Trimethylsulfoxide iodide (77.4g, 352mmol, 1.0eq) and potassium tert-butoxide (39.5g, 352mmol, 1.0eq) were sequentially added to a solution of dimethylsulfoxide (500mL) at 10-15°C , and the mixture was stirred for 1-1.5 hours. The mixture was slowly added to a solution of compound (I) (100.0 g, 352 mmol, 1.0 eq) in dimethyl sulfoxide (500 mL) at 20-25° C., and the mixture was stirred at 20-25° C. for 1-2 hours until The HPLC method monitored the reaction until completion. The reaction was quenched by the addition of saturated aqueous ammonium chloride (900 mL). The product was extracted 3-4 times with ethyl acetate (1800 mL), and the resulting organic solution was washed with saturated brine. The organic solution was concentrated under vacuum to a final volume of 1000 mL to obtain a solution containing compound (II), which was directly carried out to th...

Embodiment 3

[0146] Embodiment 3: the preparation of compound (V) oxalate

[0147] Step (1): Preparation of compound (II)

[0148] Trimethylsulfoxide iodide (154.8g, 703mmol, 2.0eq) and sodium hydride (60%, 28.1g, 703mmol, 2.0eq) were sequentially added to a solution of dimethylsulfoxide (500mL) at 10-15°C , the mixture was stirred for 1-1.5 hours. The mixture was slowly added to a solution of compound (I) (100.0 g, 352 mmol, 1.0 eq) in dimethyl sulfoxide (500 mL) at 20-25° C., and the mixture was stirred at 20-25° C. for 1-2 hours until The HPLC method monitored the reaction until completion. The reaction was quenched by the addition of saturated aqueous ammonium chloride (900 mL). The product was extracted 3-4 times with isopropyl acetate (1800 mL), and the resulting organic solution was washed with saturated brine. The organic solution was concentrated under vacuum to a final volume of 1000 mL to obtain a solution containing compound (II), which was directly carried out to the n...

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Abstract

The invention relates to a preparation method of a key intermediate compound (VII) of avibactam sodium, wherein the compound (VII) is obtained from the compound (V) through cyclization and deprotection reactions. The preparation method of the present invention has good chiral selectivity, simple and easy operation, high yield, good purity, cheap and easy-to-obtain raw materials, and has industrial value

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of an avibactam sodium intermediate. Background technique [0002] Avibactam sodium, English name Avibactam sodium, chemical name: [(2S,5R)-2-carbamoyl-7-carbonyl-1,6-diazabicyclo[3.2.1]octane-6-yl ] Sulfuric acid monosodium salt, structural formula is as follows: [0003] [0004] Avibactam sodium belongs to the diazabicyclooctone class of compounds and is currently a promising new type of β-lactamase inhibitor. It has no obvious antibacterial activity by itself, but it has broad-spectrum antibacterial activity when used in combination with various cephalosporins and carbapenem antibiotics. Avibactam sodium was jointly developed by Forest Lab and AstraZeneca, and is now acquired by Pfizer; the avibactam sodium / ceftazidime compound preparation was approved by the FDA in 2015 and approved by the EMA in 2016. [0005] Patent documents CN1020...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/08C07D211/60
CPCC07D211/60C07D471/08Y02P20/55
Inventor 邱志海王智勇张富余黄启明褚长虎赵富录李洪明高君伟
Owner ZHEJIANG HISOAR PHARMA
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