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Preparation method of 4-AA key intermediate epoxy butylamide

A technology of epoxybutyramide and epoxybutyramide, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of low yield, limited industrial production, long route, etc., shorten the reaction time, reduce the cost of raw materials, avoid The effect of using

Pending Publication Date: 2019-10-25
SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] (1) N1-C2 forms a ring, represented by Lynch of Merck Company in the United States. The disadvantage of this route is that the yield is low and the route is long;
[0006] (2) N1-C4 ring formation, proposed by Fujisawa Pharmaceuticals, a Japanese company, introduces acetoxy groups after ring formation by electrolysis, with low yield and limited industrial production;
In the existing preparation process of epoxybutyric acid, the diazotization reaction needs to use cuprous salt which is environmentally friendly and difficult to handle as a catalyst. Due to the high solubility of epoxybutyric acid in water, a large amount of organic solvent is required in the later stage and Most of the epoxybutyric acid products can be extracted with the assistance of a phase transfer catalyst; in the preparation process of epoxybutyramide, the raw material epoxybutyric acid needs to use two reagents: N-methylmorpholine and ethyl chloroformate to catalytic activation, ethyl chloroformate is a highly toxic substance, and the two occupy a certain proportion in the cost of raw materials

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation of embodiment 1 (2R, 3R)-N-(4-methoxyphenyl)-N-(2-oxopropyl)-epoxybutyramide (R is methyl)

[0030] Step 1: Preparation of (2R,3R)-epoxybutyric acid

[0031] Add 50g (1.0eq) of the main raw material L-threonine and 297g of concentrated hydrochloric acid into a 2000ml reaction bottle, cool down to 0±2°C, add 108g (1.5eq) of sodium nitrite solution with a mass concentration of 40%, dropwise Insulate at 0±2°C until the diazotization is complete;

[0032] The system was extracted twice with 300 g of ethyl acetate, and separated to obtain an organic phase. To the obtained organic phase, 106 g (2.2 eq) of sodium hydroxide solution with a mass ratio concentration of 35% was added, separated, and the organic phase was set aside. Heat the water phase at 20±2°C until the reaction is complete. After the reaction is complete, add 120 g (2.2 eq) of hydrochloric acid solution with a mass concentration of 25% to the system to adjust the pH to 1.0; 2 times, liquid sep...

Embodiment 2

[0041] The preparation of embodiment 2N-(4-methoxyphenyl)-2-[(2'R, 3'R)-epoxybutanylamino]-acetate (R is ethoxy)

[0042] Step 1: Preparation of (2R,3R)-epoxybutyric acid

[0043]Add 50g (1.0eq) of the main raw material L-threonine and 297g of concentrated hydrochloric acid into a 2000ml reaction bottle, cool down to 0±2°C, add 108g (1.5eq) of sodium nitrite solution with a mass concentration of 40%, dropwise Insulate at 0±2°C until the diazotization is complete;

[0044] The system was extracted twice with 400 g of dichloromethane, and separated to obtain an organic phase. To the obtained organic phase, 149 g (2.2 eq) of potassium hydroxide solution with a mass ratio concentration of 35% was added, separated, and the organic phase was set aside. Heat the water phase at 20±2°C until the reaction is complete. After the reaction is complete, add 120 g (2.2 eq) of hydrochloric acid solution with a mass concentration of 25% to the system to adjust the pH to 1.0; 2 times, liquid ...

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Abstract

The invention relates to a preparation method of 4-AA key intermediate epoxy butylamide. The preparation method comprises the steps that (1) synthesis of epoxy butyric acid is conducted: a starting material L-threonine is cyclized under diazotization and strong alkaline conditions to obtain the epoxy butyric acid; (2) synthesis of amino compounds is conducted: aminoanisole and chloroacetyl compounds (including ketone and esters) under the action of organic base are refluxed and react to obtain the amino compounds; and (3) synthesis of the epoxy butylamide is conducted: under the catalytic activation of acyl chloride, an amidation of the epoxy butylamide and the amino compounds is conducted to obtain the target product epoxy butylamide. The preparation method has the technical advantages that dosage of alkali and water is greatly reduced, dosage of organic extractants is correspondingly reduced, and at the same time, use of a phase transfer catalyst is avoided; the cost of raw materialsis lowered, and reaction time is shortened.

Description

technical field [0001] The invention relates to a method for synthesizing a pharmaceutical intermediate, in particular to a method for preparing a key intermediate of 4-AA, epoxybutyramide. Background technique [0002] 4-AA, whose chemical name is (3R,4R)-3-[(1R)-tert-butyldimethylsilyloxyethyl]-4-acetoxy-2-azetidinone, is a synthetic carbon An important intermediate of pendene antibiotics, high-efficiency antibacterial drugs carbapenem antibiotics play an important role in clinical anti-infection treatment, especially in the treatment of infections caused by drug-resistant bacteria, due to their strong antibacterial effect and small side effects. status. The chemical structural formula of 4-AA is as follows: [0003] The molecular skeleton of 4-AA is characterized by a four-membered lactam ring, a silane-protected α-hydroxyethyl group on the 3rd carbon, three chiral centers, and an acetoxy group on the 4th carbon. The establishment of quaternary lactam ring and three ch...

Claims

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Application Information

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IPC IPC(8): C07D303/48C07D301/02
CPCC07D303/48C07D301/02
Inventor 宋广慧管西博张林
Owner SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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