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A kind of preparation method of asenapine key intermediate

An intermediate and key technology, applied in the field of chemical synthesis, can solve problems such as high reaction temperature, cumbersome operation, environmental pollution, etc., and achieve the effects of simplified reaction steps, simple operation, and easy access to raw materials

Active Publication Date: 2016-04-13
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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  • A kind of preparation method of asenapine key intermediate
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  • A kind of preparation method of asenapine key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

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

Embodiment 2

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

Embodiment 3

[0038] Add 25ml of toluene and 1.2g of potassium tert-butoxide to 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 overnight at room temperature, add 75ml of purified Water extraction, the water phase was extracted three times with 25ml EA, the organic phase was combined, extracted once more with 25ml purified water, and the water phase was combined; the water phase was adjusted to pH=1.0 with 1N hydrochloric acid (turbidity appeared), crystal growth 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 (Asenapine) is the precursor of preparing asenapine maleate, is a broad-spectrum efficient 5-hydroxytryptamine, norepinephrine and dopamine antagonist, has strong antipsychotic activity, therefore It is necessary to study the drug on a large scale, and the research on the intermediate 3 of the drug is very important. [0003] The chemical name of 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] There are many patents and documents at home and abroad that have reported the preparation method of asenapine, among which US2006229352, US2010152461, WO2011159903 and other patent documents disclose the following methods to prepare asenapine...

Claims

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Application Information

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Patent Type & Authority Patents(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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