Novel preparation method and intermediate for aripiprazole

A general formula and compound technology, applied in the field of drug synthesis, can solve the problems of unfavorable industrialized large-scale production, harsh reaction conditions, and poor reaction selectivity, and achieve the effects of simple operation, high selectivity, and mild reaction conditions

Active Publication Date: 2009-09-23
四川弘远药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] This reaction is a Friedel-Crafts alkylation reaction, which has the disadvantages of harsh reaction conditions, low yield, poor reaction selectivity, and high discharge of three wastes, which is not conducive to large-scale industrial production.

Method used

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  • Novel preparation method and intermediate for aripiprazole
  • Novel preparation method and intermediate for aripiprazole
  • Novel preparation method and intermediate for aripiprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1 general formula (I) intermediate 3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-nitrophenyl)propyl Preparation of ethyl acetate

[0045] Step 1: Put 4-methyl-3-nitrophenol VIII (90.0g, 0.588mol) in a 500mL round bottom flask, add acetic anhydride (66.7mL, 0.706mol) and 4-N,N-di Aminopyridine (3.6g, 0.029mol), react at room temperature for 1 hour, then add drinking water (300mL), stir for 1 hour, filter, wash the filter cake with drinking water until the filtrate is neutral, drain the filter cake, and then It was dried at constant temperature for 3 hours at °C, and then dried in vacuum for 24 hours to give 4-methyl-3-nitrophenyl acetate VII (112 g, 97.6%) as a white solid, mp 68.4-70.1 °C.

[0046] Step 2 Put the product 4-methyl-3-nitrophenyl acetate VII (112g, 0.573mol) obtained in step 1 into a 1000mL three-necked flask, add carbon tetrachloride (450mL), stir until dissolved, and then Add N-bromosuccinimide (112.5 g, 0.631 mol) and benzoyl pero...

Embodiment 2

[0057] Example 2 General formula (I) intermediate 3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-nitrophenyl) Preparation of ethyl propionate

[0058] Step 1, put 4-methyl-3-nitrophenol VIII (100g, 0.653mol) in a 1000mL round bottom flask, add acetic anhydride (75mL, 0.784mol) and 4-N,N-dimethylamino under stirring Pyridine (3.98 g, 0.033 mol), acetic acid (50 mL). After reacting at room temperature for 2 hours, slowly add drinking water (600mL) to the reaction bottle, stir for 1 hour, filter, wash the filter cake with drinking water until the filtrate is neutral, drain the filter cake, and then dry at 40°C for 3 hours. Drying in vacuo for 24 h afforded 4-methyl-3-nitrophenylacetate VII (121 g, 95%) as a white solid, mp 68.4-70.1°C.

[0059] Step 2, put the product 4-methyl-3-nitrophenyl acetate VII (27.8g, 0.142mol) obtained in step 1 into a 500mL three-necked flask, add carbon tetrachloride (180mL), and stir until dissolved , then add N-bromosuccinimide (30.5g, 0...

Embodiment 3

[0068] Example three general formula (I) intermediate 3-(4-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-nitrophenyl) Preparation of ethyl propionate

[0069] Steps 1, 2, 4, 5, 6, and 7 can refer to the corresponding steps of Embodiment 1 or Embodiment 2 respectively, and Step 3 is replaced by:

[0070] Diethyl malonate (25.67g, 0.160mol) was placed in a 500mL three-necked flask, and toluene (180mL) was added, and the reaction solution was lowered to about 0°C in an ice-water bath while stirring, and sodium tert-butoxide ( 19.8g, 0.206mol), stirred for 0.5 hours after adding, added dropwise the toluene (40mL) solution of yellow solid product VI (31.4g, 0.115mol) obtained in step 2, stirred at room temperature for 3 hours after adding, then added drinking water ( 100ml), extracted with toluene (70ml×3), dried over magnesium sulfate and spin-dried to obtain yellow liquid product 2-(4-acetoxy-2-nitrobenzyl)diethyl malonate V (38.8g, 95.9 %).

[0071] Embodiment four uses ...

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PUM

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Abstract

The invention relates to the field of medicine synthesis and discloses a novel preparation method and an intermediate for aripiprazole. In order to solve the technical problems of rigorous reaction conditions, high three waste discharge and low yield lying in the synthesis of aripiprazole in the prior art, the invention provides a new intermediate general formula (I) compound for synthesizing aripiprazole and a preparation method thereof. Simultaneously, the invention provides two synthesis methods for preparing aripiprazole through the general formula (I) intermediate. The preparation method comprises the following steps: taking 4-methyl-3-nitrophenol as raw material, obtaining the intermediate after the reactions of acylation, bromination, substitution, hydrolysis and decarboxylation, esterification, substitution, condensation, and the like, carrying out the reduction and ring closure reaction of the intermediate or carrying out the reduction reaction of the intermediate firstly and then the ring closure reaction of the intermediate, and obtaining aripiprazole. The method has moderate reaction conditions, simple operation, high yield, low cost and little environmental pollution, and is more suitable for the industrialized production.

Description

technical field [0001] The present invention relates to the field of drug synthesis, in particular, to a novel intermediate compound and its preparation method, and a new method for preparing chemical raw materials using the intermediate compound. Background technique [0002] Aripiprazole (Aripiprazole) is an atypical antipsychotic drug, which was approved by the US FDA on November 15, 2002. Co-mediated by the antagonistic activity of the serotonin 5HT2A receptor. With its unique mechanism of action and safety evaluation, aripiprazole is known as the third-generation antischizophrenia drug. [0003] Aripiprazole is a quinolinone derivative, developed by Japan Otsuka Pharmaceutical Company, its chemical name is: 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy Base}-3,4-dihydroquinolone, the structural formula is as follows: [0004] [0005] Regarding the preparation of aripiprazole, the Japanese patent EP 0367141A2 of Otsuka Pharmaceutical Company, and its related p...

Claims

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Application Information

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IPC IPC(8): C07D295/088C07D215/227
Inventor 杜小春秦欣荣蔡付波许冠兵李雯
Owner 四川弘远药业有限公司
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