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Preparation method of asenapine key intermediate

An intermediate and key technology, applied in the field of chemical synthesis, can solve the problems of high reaction temperature, complicated operation, low yield and the like, and achieve the effects of simplified reaction steps, simple operation and low cost

Active Publication Date: 2014-10-15
成都明德至远医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved in the present invention is to overcome the high reaction temperature existing in the preparation method of the key intermediate formula (Ⅲ) compound in the prior art and the operational route for preparing asenapine by the intermediate formula (Ⅲ) compound, and the operation The technical problems of cumbersome, low yield and environmental pollution, in order to solve the above technical problems, the present invention provides a key intermediate formula (Ⅲ) compound preparation method with simple operation, high yield, environment-friendly, low cost and stable process, And the method for preparing asenapine by intermediate formula (Ⅲ) compound

Method used

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  • Preparation method of asenapine key intermediate
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  • Preparation method of asenapine key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Add 30ml of dichloromethane into a 100ml there-necked flask, add 5.6g of starting material 2-(4-chlorophenoxy)phenylacetic acid, cool to 0~5°C, dropwise add pivaloyl chloride / dichloromethane=12.1g / 10ml, add 5.6g of sarcosine methyl ester hydrochloride to another 250ml three-necked bottle, cool down to below 10°C, add 4.1g of triethylamine and stir for 30 minutes, slowly add the dichloromethane solution of mixed anhydride (5.6g / 20ml) dropwise. ), and added dropwise under the control of 15°C; after adding, keep stirring for 3-4 hours, add 50ml purified water and stir for 5 minutes, extract and separate the liquid, extract the organic phase again with 50ml purified water, and concentrate the organic phase to constant weight to obtain a brown color or tan oily substance, namely the intermediate compound of formula (I) 6.2g, the yield is 83.8%.

Embodiment 2

[0036] Add 30ml of dichloromethane into a 100ml three-necked flask, add 5.6g of 2-(4-chlorophenoxy)phenylacetic acid, cool down to -30~5°C, dropwise add methanesulfonyl chloride / dichloromethane=2.3g / 10ml, in In addition, add 2.8g of sarcosine methyl ester hydrochloride to a 250ml three-necked flask, cool the temperature to below 10°C, add 2.0g of triethylamine and stir for 30 minutes, and slowly add the dichloromethane solution of mixed anhydride (5.6g / 20ml) dropwise, Control the dropwise addition below 15°C; after the addition, maintain stirring for 1 to 3 hours, add 50 ml of purified water and stir for 5 minutes, extract and separate, extract the organic phase again with 50 ml of purified water, and concentrate the organic phase to constant weight to obtain brown or brown. The brown oil, namely the intermediate compound of formula (I), was 6.1 g, and the yield was 82.4%.

Embodiment 3

[0038] Add 25ml of toluene and 1.2g of potassium tert-butoxide into a 50ml three-necked flask, add the toluene solution (3.5g / 25ml) of the intermediate of formula (I) prepared in the above example below 20°C, stir at room temperature overnight, add 75ml of purification Water extraction, the water phase was extracted three times with 25ml EA, the organic phase was combined, extracted once again with 25ml purified water, and the water phase was combined; the water phase was adjusted to pH=1.0 with 1N hydrochloric acid (turbidity), and the crystal was stirred for 3 to 4 hours, and filtered. , the filter cake was rinsed once with 20 ml of purified water, and the solid was dried under reduced pressure at 40° C. for 5 to 6 hours to obtain 2.3 g of the intermediate compound of formula (II) with a yield of 71.8%.

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Abstract

The invention provides a chemical synthesis method, in particular to a preparation method of a key intermediate [formula (III)] compound of asenapine capable of serving as a schizophrenia drug. In an anhydrous system, the intermediate [formula (III)] compound is obtained through dehydration of an intermediate [formula (II)] compound and anhydride under the action of a catalyst. The invention further provides a novel method for preparing asenapine by the intermediate [formula (III)]. The provided method has the advantages of simple operation, high yield, environment-friendliness, lower cost, stable technology and the like.

Description

technical field [0001] The invention relates to a chemical synthesis method, in particular to a preparation method of a key intermediate of Asenapine which can be used as a schizophrenic drug. Background technique [0002] Asenapine is the precursor for the preparation of asenapine maleate. It is a broad-spectrum and highly effective antagonist of serotonin, norepinephrine and dopamine. It has strong antipsychotic activity. It is necessary to study the drug on a large scale, and the study of the intermediate three of the drug is crucial. [0003] The chemical name for asenapine is: trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenzo[2,3:6,7]oxazepine [4,5-c]pyrrole, its chemical structural formula is: [0004] [0005] The preparation method of asenapine has been reported in a number of patents and documents at home and abroad, wherein patent documents such as US2006229352, US2010152461, WO2011159903 disclose the following methods to prepare asenapine: [0006] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/044
CPCC07D491/044
Inventor 雷朗熊波李善伟
Owner 成都明德至远医药科技有限公司
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