Novel method for preparing O-desvenlafaxine

A technology of desvenlafaxine and a new method, applied in the field of chemical pharmacy, can solve the problems of expensive sales, increased production cost and high production cost, and achieves the effects of simple operation, reduced production cost and high yield

Active Publication Date: 2008-02-06
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method can make desvenlafaxine with higher yield, but the production cost is higher, mainly because the starting material venlafaxine of the reaction belongs to the raw material drug, and it is more expensive to sell on the market, resulting in the production cost of the whole process greatly increase

Method used

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  • Novel method for preparing O-desvenlafaxine
  • Novel method for preparing O-desvenlafaxine
  • Novel method for preparing O-desvenlafaxine

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Experimental program
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Effect test

Embodiment 1

[0024] Compound I (1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol) (Zhejiang Zhongbei Chemical Co., Ltd.) 50g, sodium methoxide (28%, Zibo Xusheng Chemical Co., Ltd.) 40g, dodecanethiol (Shanghai Nanxiang Reagent Co., Ltd.) 60g and PEG400 (molecular weight 380-430, Shanghai Qingxi Chemical Technology Co., Ltd.) React for 4 hours. Then cool to 80°C, add 100ml of water, then cool to normal temperature, let stand, separate layers, and filter the lower water layer. The aqueous phase was extracted four times with 100 ml of dichloromethane each time, and the dichloromethane was combined. Then, concentrated hydrochloric acid was added dropwise to the aqueous phase until the isoelectric point, pH = 9.5, and a large amount of solids were precipitated. Stir at room temperature for 30 minutes, then cool to 0-5°C and keep warm for 1 hour, filter to obtain a white solid, and dry to obtain intermediate compound II (1-[2-amino-1-(4-hydroxyphenyl)ethyl ] cyclohexanol) 38.1g. Purity (H...

Embodiment 2

[0027] Add 50g of compound I (1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol), 40g of sodium methoxide, 60g of dodecanethiol and 133g of PEG400 into the reactor, stir and raise the temperature To 150°C, react at 150-155°C for 5 hours. Then cool to 80°C, add 100ml of water, then cool to normal temperature, let stand, separate layers, and filter the lower water layer. The aqueous phase was extracted four times with 100 ml of dichloromethane each time, and the dichloromethane was combined. Then, concentrated hydrochloric acid was added dropwise to the aqueous phase until the isoelectric point, pH = 10, and a large amount of solids were precipitated. Stir at room temperature for 30 minutes, then cool to 0-5°C and keep warm for 1 hour, filter to obtain a white solid, and dry to obtain intermediate compound II (1-[2-amino-1-(4-hydroxyphenyl)ethyl ] cyclohexanol) 31.3g. Purity (HPLC): 90.4%.

[0028] 31.3 g of the obtained compound II was added to 400 ml of dichloromethane, hea...

Embodiment 3

[0030] Add 50g of compound I (1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol), 40g of sodium methoxide, 60g of dodecanethiol and 133g of PEG400 into the reactor, stir and raise the temperature To 210°C, react at 215-220°C for 2 hours. Then cool to 80°C, add 100ml of water, then cool to normal temperature, let stand, separate layers, and filter the lower water layer. The aqueous phase was extracted four times with 100 ml of dichloromethane each time, and the dichloromethane was combined. Then, concentrated hydrochloric acid was added dropwise to the aqueous phase until the isoelectric point, pH = 9.5, and a large amount of solids were precipitated. Stir at room temperature for 30 minutes, then cool to 0-5°C and keep warm for 1 hour, filter to obtain a white solid, and dry to obtain intermediate compound II (1-[2-amino-1-(4-hydroxyphenyl)ethyl ] cyclohexanol) 36.1g. Purity (HPLC): 96.2%.

[0031] 36.1 g of the obtained compound II was added to 400 ml of dichloromethane, he...

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Abstract

The invention provides a new method for preparation ODV, which comprises the following procedures:1. the compound I(1-[2-amino-1-(4- methoxybenzyl)ethyl] cyclohexanol) is made a demethylation reaction, the adopted catalyzer chooses from mercaptide anion, nickel, cobalt, metal sulphide, diphenylphosphine lithium or trialky borohydrid, the product is further purified to obtain the high pure compound II (1-[2-amino-1-(4-hydroxyphenyl)ethyl] cyclohexanol; 2. the compound II is included by the inclusion agent and is made a N, N-dimethylation reaction with the methylation reagent, the PH value is adjusted to precipitate a large quantity of solids (namely ODV), the inclusion agent is alpha- cyclodextrin hydrate, beta- cyclodextrin hydrate or gamma cyclodextrin hydrate; 3. the precipitated solids are dissolved by the methylene dichloride, are evaporized and are crystallized by the isopropanol. The invention has simple and quick operation, single preparation products, high yields, high purity, and greatly decreased production cost.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and relates to O-desmethylvenlafaxine, in particular to a preparation method of O-desmethylvenlafaxine, specifically a new method for preparing O-desmethylvenlafaxine. Background technique [0002] O-desmethylvenlafaxine is the active metabolite of venlafaxine, and it is very likely to replace venlafaxine in drug treatment in the future. There are many methods for preparing O-desvenlafaxine at present, and these preparation methods basically all carry out methylation reaction to obtain venlafaxine first by compound I, then venlafaxine is obtained in different catalysts and solvents. Under these conditions, a demethylation reaction is carried out to obtain O-desvenlafaxine. [0003] [0004] Venlafaxine can be prepared according to methods known in the art, for example, the methods described in US Patent No. 4,535,186. [0005] Quite a number of patents relate to the improvement ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C215/64
Inventor 徐建康徐明东蔡亚祥胡剀张达
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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