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Process for synthesizing 4- acetoxy-2-azetidinone

A technology of azetidinone and acetoxy, which is applied in the field of compound synthesis technology, can solve the problems of environmental hazards and unfavorable industrial production, and achieve the effects of environmental friendliness, mild reaction conditions and simple raw materials

Active Publication Date: 2009-04-15
ZHEJIANG LEPU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with synthetic route 1, this reaction route has easy-to-obtain raw materials, but phosgene is used, which is a highly toxic gas, which is harmful to the environment and is not conducive to industrial production.

Method used

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  • Process for synthesizing 4- acetoxy-2-azetidinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] 1) Add 21.6g of p-phenylenediamine and 200ml of triethylamine in a 500ml three-necked flask, add 36.8g of chloroacetone dropwise under reflux, react under reflux for 2 hours, distill off triethylamine, and cool the reactant to 50°C. Add 80ml of water, filter, and dry the filter cake to obtain 40.0g of 1,4-bis[(oxypropyl)amino]benzene with a yield of 90.9%, which can be directly used in the next reaction.

[0024] 2) Add 350ml chloroform and 10.2g epoxybutyric acid into a 1000ml three-necked flask, cool to -10°C, add 10.0g nitrogen methylmorpholine and 10.8g methyl chloroacetate, react for 1 hour, add 1,4-di [(Oxopropyl)amino]benzene 11.0g, heat up to 40°C and react for 1 hour, add 200ml of 1N HCl, separate the layers, wash the chloroform layer with 100ml of saturated sodium bicarbonate and 100ml of saturated brine, and wash with 10g of anhydrous magnesium sulfate Dry, filter, evaporate the filtrate to dryness under reduced pressure, add 300ml of n-hexane, stir to obtain...

Embodiment 2

[0030] 1) Add 21.6g of p-phenylenediamine and 200ml of triethylamine in a 500ml three-necked flask, add 55.2g of chloroacetone dropwise under reflux, and react under reflux for 3 hours. The reactant is cooled to 60°C, and triethylamine is distilled off. Add 80ml of water, filter, and dry the filter cake to obtain 41.1g of 1,4-bis[(oxypropyl)amino]benzene with a yield of 93.5%, which can be directly used in the next reaction.

[0031] 2) Add 350ml chloroform and 10.2g epoxybutyric acid to a 1000ml three-necked flask, cool to -15°C, add 10.0g nitrogen methylmorpholine and 10.8g methyl chloroacetate, react for 2 hours, add 1,4-di [(Oxopropyl) amino] 11.0 g of benzene, heated up to 50 ° C for 2 hours, added 200 ml of 1N HCl, separated, the chloroform layer was washed with 100 ml of saturated sodium bicarbonate and 100 ml of saturated brine, and 10 g of anhydrous magnesium sulfate Dry, filter, evaporate the filtrate to dryness under reduced pressure, add 300ml of n-hexane, stir to ...

Embodiment 3

[0037] 1) Add 21.6g of p-phenylenediamine and 200ml of triethylamine into a 500ml three-necked flask, add 92g of chloroacetone dropwise under reflux, and react under reflux for 4 hours, cool the reactant to 60°C, distill out triethylamine, add 80ml of water was filtered and the filter cake was dried to obtain 42.0g of 1,4-bis[(oxypropyl)amino]benzene with a yield of 95.5%, which could be directly used in the next reaction.

[0038] 2) Add 350ml chloroform and 5.1g epoxybutyric acid into a 1000ml three-necked flask, cool to -20°C, add 10.0g nitrogen methylmorpholine and 10.8g methyl chloroacetate, react for 1 hour, add 1,4-di [(Oxopropyl)amino]benzene 11.0g, heat up to 40°C and react for 1 hour, add 200ml of 1N HCl, separate the layers, wash the chloroform layer with 100ml of saturated sodium bicarbonate and 100ml of saturated brine, and wash with 10g of anhydrous magnesium sulfate Dry, filter, evaporate the filtrate to dryness under reduced pressure, add 300ml of n-hexane, sti...

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Abstract

The invention discloses a process for synthesizing 4-acetoxy-2-azetidinone. Epoxy butyrate is used as raw material with 1,4-2((oxo-propyl) amino) benzene to generate (2R, 3R)-1, 4-2((N-oxo-propyl-N-2, 3-epoxy butyl) amino) benzene which closes ring under the effect of potassium carbonate to get (3R, 4R)-1, 4-2((-3-((1'-R-hydroxide radical) ethide)-4-acetyl-2-azetidinone-1-radical) benzene of three chiral centers; benzoyl hydroperoxide is added to have a reaction to obtain (3R, 4R)-1, 4-2((-3-((1'-R-hydroxide radical) ethide)-4-acetoxy-2-azetidinone-1-radical) benzene; compound (3R, 4R)-1, 4-2((-3-((1'-R-tert-butyl dimethyl silica) ethide)-4-acetoxy-2-azetidinone-1-radical) benzene is obtained by tert-butyl dimethyl chlorosilane protection; and finally, (3R, 4R)-4-acetoxy-3-((1'-R-tert-butyl dimethyl silica) ethide)-2-azetidinone is obtained through ozone oxidation and protecting group removal. The method has simple raw material, moderate reaction condition, environmental friendliness,and can be applied to large scale industrialization production.

Description

technical field [0001] The invention relates to a synthesis process of compounds, in particular to a synthesis process of 4-acetoxy-2-azetidinone. Background technique [0002] The early research on the synthesis of 4-acetoxy-2-azetidinone referred to the synthesis process of penicillin and cephalosporin, Martel A. (Can.J.Chem., 1987, 65, 2179-2181) with 6-amino Penicillanic acid (6-APA) is used as the raw material, the β-lactam ring is retained, and the structure is modified to introduce appropriate groups. This route is loaded down with trivial details, and total recovery is lower. Operations that are difficult to industrialize such as column chromatography cannot be eliminated, and heavily polluted reagents such as mercury sulfate must be used. [0003] In 1996, Seki M etc. (Tetrahedron Lett, 1996,37 (31): 5565-5568) reported the route by L-menthone as raw material, the reaction conditions of this reaction are not harsh, and the yield of each step is relatively high, bu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D205/08
CPCY02P20/55
Inventor 蒋成君颜剑波林义
Owner ZHEJIANG LEPU PHARMA CO LTD
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