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Preparation method of biapenem intermediate

A technology for biapenem and intermediates, which is applied in the field of preparing compound 4-bromo-1, can solve the problems of many by-products, harsh operation requirements, poor selectivity, etc., achieve reduced reaction time, mild reaction conditions, The effect of reducing production costs

Inactive Publication Date: 2011-09-14
TONGJI UNIV
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  • Summary
  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 1, literature (Heterocycles, 1994, Vol.37 (3): 1521 ~ 1527) reported the use of hydrazine hydrate and epichlorohydrin as the main raw materials to prepare the corresponding five-membered ring structure by a one-pot method, but this method is There are many products, the selectivity is not good, and the yield is only 19%;
[0006] 2. The literature (Journal of Organic Chemistry, 1998, Vol.63(23): 8145-8149) uses hydrazine hydrate, acetone and ethyl formate as starting materials to prepare the corresponding five-membered ring structure through a five-step reaction, but Among them, the conditions of the hydrolysis step are difficult to control, the operation requirements are relatively harsh, and the obtained product is difficult to purify;
[0007] 3. In the literature (The Journal of Antibiotics, 1993, Vol.46(12): 1866-1882), protected hydrazine hydrate and protected 1,3-dibromopropanol are used as raw materials, and this method only requires one-step reaction. The corresponding five-membered ring structure is prepared, but the raw materials are relatively expensive and the market supply is limited, which also limits the promotion of this method

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Experimental program
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Effect test

Embodiment 1

[0027] A. Preparation of 1,2-diethoxycarbonyl hydrazine hydrate (II)

[0028] In the reactor equipped with mechanical stirring, mercury thermometer, and constant pressure dropping funnel, add hydrazine hydrate 50g (1.0mol), anhydrous sodium bicarbonate 184.8g (2.2mol), water 600ml, mechanically stir to dissolve the solid, the system Mix well and cool to 0°C in an ice bath. Add 238.7 g (2.2 mol) of ethyl chloroformate into the constant pressure dropping funnel, and drop this into the reactor under stirring, and the drop is completed within 1 hour. After the dropwise addition, the ice bath was removed, and it was naturally raised to room temperature, and the stirring reaction was continued for 4 hours. After the reaction was completed, the white solid separated out was collected by filtration, washed with water and dried to obtain 170 g of white powder, which was 1,2-diethoxycarbonyl hydrazine hydrate ( II), yield 96.6%, M.P.127-128°C.

[0029] B. Preparation of 1-allyl-1,2-di...

Embodiment 2

[0036] Other steps are identical with embodiment 1, just the 1 of A step, the preparation method of 2-diethoxycarbonyl hydrazine hydrate (II) is as follows:

[0037] In a reactor equipped with mechanical stirring, a mercury thermometer, and a constant pressure dropping funnel, add 50 g (1.0 mol) of hydrazine hydrate, 168 g (2.0 mol) of anhydrous sodium bicarbonate, and 400 ml of water, stir mechanically to dissolve the solid, and mix the system homogeneous, cooled to 0°C in an ice bath. Add 217 g (2.0 mol) of ethyl chloroformate into the constant-pressure dropping funnel, and drop it into the reactor while stirring, and finish dropping within 1 hour. After the dropwise addition, the ice bath was removed, and it was naturally raised to room temperature, and the stirring reaction was continued for 4 hours. After the reaction was completed, the white solid separated out was collected by filtration, washed with water, and dried to obtain 161 g of white powder, which was 1,2-dietho...

Embodiment 3

[0039] Other steps are identical with embodiment 1, just the 1 of A step, the preparation method of 2-diethoxycarbonyl hydrazine hydrate (II) is as follows:

[0040] In the reactor equipped with mechanical stirring, mercury thermometer, and constant pressure dropping funnel, add hydrazine hydrate 50g (1.0mol), anhydrous sodium bicarbonate 176.4g (2.1mol), water 500ml, mechanically stir to dissolve the solid, the system Mix well and cool to 0°C in an ice bath. Add 227.8 g (2.1 mol) of ethyl chloroformate into the constant-pressure dropping funnel, and drop it into the reactor while stirring, and finish dropping within 1 hour. After the dropwise addition, the ice bath was removed, and it was naturally raised to room temperature, and the stirring reaction was continued for 4 hours. After the reaction was completed, the white solid separated out was collected by filtration, washed with water, and dried to obtain 167 g of white powder, which was 1,2-diethoxycarbonyl hydrazine hydra...

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Abstract

The invention provides a preparation method of a biapenem intermediate and relates to a preparation method of an antibiotic medicament biapenem intermediate 4-bromine-1,2-ethoxycarbonyl pyrazolidine. The method comprises the following steps: successively carrying out a reaction on hydrazine hydrate as a raw material and ethyl chloroformate and allyl bromide; and then carrying out addition reaction with bromide, and finally, carrying out cyclization reaction under the alkaline condition so as to obtain the product. The invention provides a bran-new synthesis route; and used raw material sources are wide and abundant, the prices of the raw materials are cheap, reaction condition is mild, process is simple, reactions in various steps are conventionally operated, and product cost is reduced.

Description

technical field [0001] The invention relates to a method for preparing a biapenem intermediate, in particular to a method for preparing a compound 4-bromo-1,2-diethoxycarbonylpyrazolidine. Background technique [0002] Carbopenem antibiotics are β-lactam antibiotics with a new structure developed in the 1970s, which have broad-spectrum and high-efficiency antibacterial activity. [0003] Imipenem is the first carbapenem antibiotic. Since then, Ertapenem and Biapenem (Biapenem) and other varieties have been listed in the carbapenem antibiotic market. Compared with other antibiotics, the most prominent antibacterial and pharmacological characteristics of apenem are enzyme resistance, which is extremely stable to inactivated enzymes including extended-spectrum β-lactamases, and is resistant to enzyme-producing bacteria and multidrug-resistant bacteria. In particular, it has a unique antibacterial effect on drug-resistant Gram-negative aerobic bacteria, and its effect is superi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/04
Inventor 蒋忠良段辉王闻达
Owner TONGJI UNIV
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