Method for preparing cefoperazone deuterated internal standard substance

A technology of cefoperazone and internal standard, which is applied in the field of preparation of cefoperazone deuterated internal standard, can solve problems such as poor effect, and achieve the effect of controllable experimental process, high purity and low price

Active Publication Date: 2020-02-04
FOOD INSPECTION CENT OF CIQ SHENZHEN +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] Cefoperazone is a third-generation cephalosporin that is effective against Enterobacteriaceae such as Escherichia coli, Klebsiella, Proteus, Salmonella typhi, Shigella, Citrobacter and Pseudomonas aeruginosa Bacteria have good antibacterial effect, but have poor effect on Enterobacter aerogenes, Enterobacter cloacae, Salmonella typhimurium and Acinetobacter spp.

Method used

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  • Method for preparing cefoperazone deuterated internal standard substance
  • Method for preparing cefoperazone deuterated internal standard substance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Synthesis of N-Boc-N'-ethylethylenediamine-D5(III)

[0042] Boc-ethylenediamine (1g) and triethylamine (1.8mL, 2.0eq) were dissolved in tetrahydrofuran (10mL), cooled to 0-5°C, and deuterobromoethane ( 0.7g, 1.0eq), the addition was completed, and the temperature was slowly raised to room temperature for 15h. The reaction was monitored by TLC (DCM:MeOH=10:1). After the reaction was completed, it was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product, which was used on a FLASH column Purified by chromatography to obtain N-Boc-N'-ethylethylenediamine-D5(III) (0.65g) with a yield of 54.1%. LCMS (ESI+): m / z = 194.2 [M+H]+.

Embodiment 2

[0044] Synthesis of N-Boc-N'-ethylethylenediamine-D5(III)

[0045] The raw materials Boc-ethylenediamine (1g), p-toluenesulfonic acid (D5-ethyl) ester (1.3g, 1.0eq) were dissolved in acetonitrile (10mL), potassium carbonate (0.9g, 1.5eq) was added, and the reaction mixture Put it in an oil bath at 85°C and heat it for 14 hours. After the reaction, add 20mL of water and 50mL of ethyl acetate, separate the organic layer, concentrate under reduced pressure to obtain a crude product, and purify it by FLASH column chromatography to obtain N-Boc-N' -Ethylethylenediamine-D5(III) (0.7g), yield 58.3%. LCMS (ESI+): m / z = 194.2 [M+H]+.

[0046] 1H NMR (400MHz, Chloroform-d) δ4.99(s, 1H), 3.23(q, J=5.9Hz, 2H), 2.74(t, J=5.9Hz, 2H), 1.44(s, 9H).

Embodiment 3

[0048] Synthesis of N-ethyl-2,3-diketopiperazine-D5(V)

[0049] Intermediate (III) (0.5 g) was dissolved in methanolic hydrochloric acid solution (3N, 20 mL, 40 V) under ice-cooling, slowly warmed to room temperature, and stirred for 5 h. After the reaction, it was concentrated to obtain 0.45 g of intermediate (IV).

[0050] Intermediate (IV) (0.45g) was suspended in ethanol (50mL), triethylamine (1mL, 2eq) was added at room temperature, and stirred for 30min. The ethanol solution of diethyl oxalate (0.4g, 1.0 eq), after addition, react at room temperature for 15h. TLC (DCM:MeOH=10:1) monitors the reaction. After the reaction is completed, the reaction mixture is concentrated to obtain a crude product, which is purified by FLASH column chromatography to obtain N-Boc-N'-ethylethylenediamine-D5 (0.3g), yield 75.0%. LCMS (ESI+): m / z = 148.1 [M+H]+.

[0051] 1H NMR (400MHz, Deuterium Oxide) δ3.69 (dd, J=7.4, 4.7Hz, 4H), 3.56 (dd, J=7.3, 4.7Hz, 4H).

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Abstract

The invention provides a method for preparing a cefoperazone deuterated internal standard substance. The method comprises the following steps: (1) subjecting Boc-ethylenediamine to alkylation and deprotection, so as to obtain an intermediate IV; (2) subjecting the intermediate IV to cyclization, so as to obtain an intermediate V; (3) subjecting the intermediate V and an intermediate VI to condensation, so as to obtain an intermediate VII, wherein the intermediate VI is D(-)-p-hydroxybenzene glycine; and (4) subjecting the intermediate VII and an intermediate VIII to condensation, so as to obtain cefoperazone-D5 target compound IX, wherein the intermediate VIII is a cefmenoxime intermediate. According to the method provided by the invention, the process design is reasonable, the employed deuterating reagent is cheap, the operation is simple and convenient, an experimentation process is controllable, and the purity of the prepared target product is high and reaches 99% or more.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a preparation method of a cefoperazone deuterated internal standard. Background technique [0002] Cefoperazone is a third-generation cephalosporin that is effective against Enterobacteriaceae such as Escherichia coli, Klebsiella, Proteus, Salmonella typhi, Shigella, Citrobacter and Pseudomonas aeruginosa Saccharomyces has good antibacterial effect, but it has poor effect on Enterobacter aerogenes, Enterobacter cloacae, Salmonella typhimurium and Acinetobacter spp. Haemophilus influenzae, Neisseria gonorrhoeae and Neisseria meningitidis are highly sensitive to this product. It is used for infections of the respiratory tract, urinary tract, peritoneum, pleura, skin and soft tissues, bones and joints, and five sense organs caused by various sensitive bacteria. It can also be used for sepsis and meningitis. [0003] In the field of medical testing, the detection of cephalosporin a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36C07D501/06
CPCC07B2200/05C07D501/06C07D501/36
Inventor 岳振峰赵凤娟肖陈贵罗耀张磊韩世磊
Owner FOOD INSPECTION CENT OF CIQ SHENZHEN
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