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Preparation method of O-desmethylvenlafaxine

A technology of methyl ethylene and butyl lithium, which is applied in the preparation of organic compounds, preparation of amino hydroxyl compounds, chemical instruments and methods, etc., can solve the problem of difficult control of methylation reaction conditions, difficulty in obtaining highly toxic starting materials, cyanide Harsh base reduction conditions and other problems, to achieve the effect of mild reaction conditions, simplified reaction steps, and reduced pollution

Inactive Publication Date: 2010-07-21
CHEMINNO SHANGHAI
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Problems solved by technology

[0009] In this method, p-methoxyphenacetin is used as the starting material, and firstly it is nucleophilicly added to cyclohexanone, then the cyano group is directly reduced, and then the amine is methylated, and finally the O-methyl group is removed to obtain the O-de Methylvenlafaxine; the starting material of this scheme is highly toxic and difficult to obtain, the conditions for cyano group reduction are harsh, the conditions of methylation reaction are not easy to control, and there are many by-products

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[0034] The preferred implementation of the present invention will be described in detail below according to the examples.

[0035] 1, 2-(4-hydroxyphenyl)-N, the preparation of N-dicarboxamide (3)

[0036] Add p-hydroxyphenylacetic acid 2 (10g) and dichloromethane (50ml) into a 100ml reaction flask, cool down to 0°C, and slowly add 10ml of thionyl chloride dropwise. After reacting for 2h, dichloromethane was distilled off to obtain acid chloride.

[0037] Add 50ml of dimethylamine aqueous solution into a 100ml reaction flask, add acid chloride dropwise, react for 1h, and use pure ethyl acetate thin-layer chromatography (TLC), R f After the thin layer showed that the reaction was complete, the product (3) was obtained by filtration, and dried to obtain 9.8 g of off-white powdery solid (purity 98%). 1 H NMR (DMSO-d6) δ: 9.22(1H), 7.01(2H), 6.71(2H), 3.54(2H), 2.96(3H), 2.81(3H).

[0038] 2. Preparation of 2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dicarboxamide (4)

[00...

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Abstract

The invention relates to a preparation method of O-desmethylvenlafaxine. The method comprises the following special steps: 1. performing chlorination to p-hydroxyphenylacetic acid in aprotic organic solvent at room temperature, then reacting with dimethylamine aqueous solution to prepare 2-(4-hydroxyphenyl)-N,N-dimethylformamide; 2. using 2-(4-hydroxyphenyl)-N,N-dimethylformamide and cyclohexanone to perform condensation reaction at 0 to -78 DEG C under the action of butyl lithium and prepare 2-(1-hdroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylformamide; and 3. using lithium aluminium hydride to reduce 2-(1-hdroxycyclohexyl)-2-(4-hydroxyphenyl)-N,N-dimethylformamide. The preparation method of O-desmethylvenlafaxine provided by the invention is characterized in that the raw materials are accessible, the entire preparation contains only three steps, the preparation processes are simplified, the reaction conditions are mild, the operation is convenient and safe and the yield is high.

Description

technical field [0001] The invention relates to a new preparation process of O-desmethylvenlafaxine. Background technique [0002] Venlafaxine, namely (±)-1-[2-(dimethylamino)-1-(4-ethoxyphenyl)ethyl]cyclohexanol, is a class of antidepressants, The role of venlafaxine is to inhibit the reuptake of norepinephrine and serotonin, and it can replace tricyclic antidepressants and selective reuptake inhibitors. Venlafaxine has the following structural formula: [0003] [0004] O-desmethylvenlafaxine (O-desmethylvenlafaxin), that is, 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, the English name is 4-(2- (dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenol, its structural formula is: [0005] [0006] It is the active metabolite of venlafaxine; at present, the Wyeth Company of the United States has completed the relevant clinical trials, and obtained the FDA's production approval in March 2007. The mechanism of action of O-desmethylvenlafaxine is the same as t...

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Application Information

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IPC IPC(8): C07C215/64C07C213/02
Inventor 吴剑峰周航吕华
Owner CHEMINNO SHANGHAI
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