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Synthesis method of Azasetron intermediate

A technology for azasetron and intermediates, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve problems such as reduction, incomplete reaction, and unsatisfactory product purity, and achieve high yield and reduction thorough effect

Inactive Publication Date: 2013-05-08
山东众诚生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the problems of incomplete reaction and unsatisfactory product purity in the prior art, the present invention provides a simple, effective, continuous and safe synthesis method of azasetron intermediate, the obtained product not only has good purity but also reduces the cost

Method used

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  • Synthesis method of Azasetron intermediate
  • Synthesis method of Azasetron intermediate
  • Synthesis method of Azasetron intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] (1) Add 20kg of 3-nitro-5-chlorosalicylic acid methyl ester to 100L of industrial glacial acetic acid and stir for 30 minutes, then add 100kg of water and heat up to 30-100°C; add 100-200 mesh industrial reduced iron powder 16kg, After adding in 3 hours, control the temperature at 60-70°C; after adding, react for 5 hours;

[0040] (2) Add 100 kg of glacial acetic acid in batches to the reaction solution of step (1), stir at 70° C. for 30 minutes, filter with diatomaceous earth, and remove iron sludge;

[0041] (3) The filter cake is rinsed with 200L of ethyl acetate, the combined filtrate is stirred for 10 minutes, left to stand for 30 minutes, and separated; and extracted once with 100L of ethyl acetate; the combined ethyl acetate solution is washed 3 times with water to obtain 5-chloro- 3 ethyl acetate solution of aminomethyl salicylate; standby;

[0042](4) Add the ethyl acetate solution of 5-chloro-3 aminosalicylic acid methyl ester of step (3) to saturated NaHCO ...

Embodiment 2

[0046] As described in Example 1, the difference is that the organic solvent of step (3), (5) uses chloroform to obtain 22kg of 3-(2-chloroacetylamino)-5 chloromethyl salicylate, yield 95 %, Mp: 163-164 °C HPLC: 99%.

Embodiment 3

[0048] As described in Example 1, the difference is that the reduced iron powder in step (1) is 15kg, and 22kg of 3-(2-chloroacetylamino)-5-chloromethyl salicylate is obtained, with a yield of 95%, Mp: 163 -164°C HPLC: 99%.

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Abstract

The invention relates to a synthesis method of an Azasetron intermediate, comprising the following steps of: reducing 5-chlorine-3 nitrosalicylic acid methyl ester in a glacial acetic acid medium to obtain 5-chlorine-3 aminosalicylic acid methyl ester through iron powder, processing the 5-chlorine-3 aminosalicylic acid methyl ester to obtain a solution containing the 5-chlorine-3 aminosalicylic acid methyl ester, and then directly reacting the solution with chloroacetic chloride to generate 3-(2-chloroacetic amido)-5 chlorosalicylic acid methyl ester with better purity and higher yield. The method has thorough reduction, solves the problem that the obtained 3-(2-chloroacetic amido)-5 chlorosalicylic acid methyl ester can not be refined when charging to next step due to the incomplete reduction and the poor product purity of the 5-chlorine-3 nitrosalicylic acid methyl ester in heterogeneous systems comprising toluene, hydrochloric acid / ammonium chloride and the like.

Description

technical field [0001] The invention belongs to the synthetic technical field of chemical drug intermediates, in particular to the synthesis of azasetron intermediates 3-amino-5 chlorosalicylic acid methyl ester and 3-(2-chloroacetylamino)-5 chlorosalicylic acid methyl ester production method. Background technique [0002] Azasetron hydrochloride (Azasetron hydrochloride) is an anti-cancer auxiliary drug, the main synthesis route is as follows [0003] [0004] In EP 0313393; JP 1989207290; JP 1990005415; US 4892872; Eur.Pat.Appl., 313393,, Chem pharm Bull, 1992,40 (3): 624-630 reported that the synthesis method of intermediate III is based on chlorination Ammonium and iron powder are used as the reducing agent, and the nitro base is dissolved in toluene and then added dropwise to the reducing medium. After research, it is found that this method has many shortcomings, mainly because the reaction cannot be completed, and the post-treatment is very troublesome. The obtaine...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/54C07C231/02C07C231/24
Inventor 李志勇丁伟达李义
Owner 山东众诚生物医药股份有限公司
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