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Synthesis of sulfomycin derivant

A synthesis method and a derivative technology are applied in the synthesis field of thiomycin derivatives, which can solve the problems of unseen industrialized production, harsh reaction conditions, long synthesis routes and the like, and achieve the advantages of low cost, easy availability of raw materials and reduced reaction cost. Effect

Inactive Publication Date: 2009-02-18
CHONGQING UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The intramolecular carbene insertion reaction has mild conditions and is easy to synthesize, but the synthetic route is long and the overall yield is low; the intramolecular Wittig reaction has a short synthetic route and a high overall yield, and is widely used, but Wittig reagents such as methylphosphite di Ethyl ester, ethyl diethyl phosphite, etc. have not been industrially produced, and can only be synthesized in the laboratory, and the synthesis uses toxic raw materials, harsh reaction conditions, and high cost

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  • Synthesis of sulfomycin derivant
  • Synthesis of sulfomycin derivant
  • Synthesis of sulfomycin derivant

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Embodiment one, the synthesis of thiamycin derivative

[0029] 1. (3S, 4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-{2-[2-(tert-butoxycarbonylamino)ethylthio Synthesis of ]carboxyethyl}-2-azetidinone-1-oxoacetic acid p-nitrobenzyl ester (V)

[0030] Dissolve 9 g (100 mmol) of anhydrous oxalic acid in 80 mL of anhydrous dichloromethane under nitrogen protection conditions, slowly add 23 mL of triethylamine dropwise at a temperature lower than 10 ° C, stir and react for 30 minutes after the dropwise addition, and then Slowly add 80 mL of anhydrous dichloromethane containing 16.2 g (75 mmol) of p-nitrobenzyl bromide dropwise at a temperature of 10°C. After the dropwise addition, stir and react for 36 hours, filter with suction, and extract the filtrate with water (80 mL×5 times). The water extract was adjusted to pH 2.5 with 10% hydrochloric acid solution by mass percentage, and then extracted with ethyl acetate (80mL×5 times), the extract was washed with saturated ...

Embodiment 2

[0041] Embodiment two, the synthesis of thiamycin derivative

[0042] 1. (3S, 4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-{2-[2-(tert-butoxycarbonylamino)ethylthio Synthesis of ]carboxyethyl}-2-azetidinone-1-oxoacetic acid p-nitrobenzyl ester (V)

[0043] The preparation method of single p-nitrobenzyl oxalate is identical with the method described in embodiment one;

[0044] Calculate the amount of raw materials according to the theoretical production amount of 4.4g of the product; under the condition of nitrogen protection, dissolve 6g (26.7mmol) of mono-p-nitrobenzyl oxalate in 20mL (280.6mmol) of thionyl chloride, and reflux at a temperature of 55°C Reacted for 3.5 hours, cooled to room temperature, and distilled off the solvent under reduced pressure to obtain 6.5 g of mono-p-nitrobenzyl oxalyl chloride as a white solid, which was dissolved by adding 40 mL of anhydrous toluene and directly used in the next reaction; compound IV 3 g (6.7 mmol ) was dissolved in 30m...

Embodiment 3

[0048] Embodiment three, the synthesis of thiamycin derivative

[0049] 1. (3S, 4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-{2-[2-(tert-butoxycarbonylamino)ethylthio Synthesis of ]carboxyethyl}-2-azetidinone-1-oxoacetic acid p-nitrobenzyl ester (V)

[0050] The preparation method of single p-nitrobenzyl oxalate is identical with the method described in embodiment one;

[0051] Calculate the amount of raw materials according to the theoretical production amount of 4.4g of the product; under the condition of nitrogen protection, dissolve 4.5g (20.1mmol) of mono-p-nitrobenzyl oxalate in 20mL (280.6mmol) of thionyl chloride. Reflux for 3.5 hours, cool to room temperature, and distill off the solvent under reduced pressure to obtain 4.9 g of mono-p-nitrobenzyl oxalyl chloride as a white solid, which was dissolved by adding 40 mL of anhydrous toluene and directly used in the next reaction; 3 g of compound IV ( 6.7mmol) was dissolved in 30mL of anhydrous toluene, and slowly ...

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Abstract

The present invention discloses a method for synthesizing a thienamycin derivative, which uses (3S, 4R)-3-[(1R)-1-(t-butyldilnethylsilyloxy)ethyl]-4-{2-[2-(Boc-amino)ethylsuleenyl]carboxyethyl}-2-azetidinone as a starting material and the commercialized triethyl phosphite as Wittig reagent and adopts two steps of reactions (acylation reaction and intramolecular Wittig reaction) to synthesize the thienamycin derivative; because the Wittig reagent does not need to be synthesized independently, the synthesization steps can be simplified, and the reaction cost can be reduced; and the starting material can be prepared from the commercialized (3S, 4R)-3-[(1R)-1-(t-butyldilnethylsilyloxy)ethyl]-4-acetoxy-2-azetidinone by three steps of reactions (allylation reaction, oxidation reaction and esterification reaction). The synthesis method has the advantages of short route, mild reaction conditions, ready availability of materials and low cost, and the obtained thienamycin derivative, which can be used as a midbody, is used for the synthesis of carbapenem antibiotics with pharmacological activity and the like.

Description

technical field [0001] The present invention relates to a synthetic method of a compound, in particular to a synthetic method of a thiamycin derivative. Background technique [0002] The β-lactamase produced by bacteria hydrolyzes the skeleton structure of typical β-lactam antibiotics such as penicillins and cephalosporins, making them lose their antibacterial activity, which is the main mechanism causing bacterial drug resistance. Carbapenems are both atypical β-lactam antibiotics and β-lactamase inhibitors, with broad antibacterial spectrum, strong antibacterial activity, rapid action, and high stability to most β-lactamases The characteristics of β-lactam antibiotics are one of the important directions in the field of research on β-lactam antibiotics. Thienamycin derivatives have been used clinically, and they are widely used in the treatment of severe infections caused by unknown pathogens. [0003] The research on the chemical synthesis of thiamycin derivatives is one ...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07D477/20
Inventor 夏之宁龙莎肖尚友邹小兵
Owner CHONGQING UNIV
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