Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol

A technology of methoxyphenyl and cyclohexanol, applied in the field of medicine, can solve the problems of difficulty in large-scale production of venlafaxine, difficulty in liquid separation steps, difficulty in post-processing, etc., and achieves good product purity, low cost, and high post-processing efficiency. Handling easy effects

Inactive Publication Date: 2009-08-12
CHENGDU QIAOFENG TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the currently disclosed reduction of 1-cyano-[(4-methoxyphenyl)methyl]cyclohexanol to obtain 1-[2-amino-1-(4-methoxyphenyl)ethyl] ring In the method of hexanol, either expensive and dangerous reducing reagents or reducing catalysts are involved, such as: world patent WO0250017 uses dangerous and flammable Raney Ni as a catalyst, Chinese patent CN1640867 uses expensive red aluminum as a reducing agent, and world patent WO2008062138 uses Expensive palladium and platinum compounds are used as catalysts; or post-processing is difficult, such as Chinese patent CN1504456, which uses lithium aluminum hydride as a reducing agent and aluminum trichloride as a catalyst. agent and catalyst hydrolysis, resulting in a large amount of aluminum hydroxide flocculent precipitation, making the liquid separation step in the post-treatment difficult and slow; or the yield is low, such as: the yield of the reduction reaction under various conditions in the US patent US2004181093 is only 60% ~70%
These drawbacks make cost-effective mass production of venlafaxine difficult

Method used

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  • Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol
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Examples

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Effect test

Embodiment 1

[0013] Synthesis of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol

[0014] Add 200 ml of anhydrous tetrahydrofuran to a 1000 ml three-neck flask equipped with a magnetic stirring bar, a reflux condenser and a drying tube, add 50 g of solid sodium hydroxide and 40 g of sodium borohydride, stir for 30 minutes, and then cool to -10°C , dropwise add 100 grams of iodine in 300 milliliters of anhydrous tetrahydrofuran solution, control the rate of addition to keep the reaction temperature between -10°C to 0°C, after the dropwise addition, keep the temperature range for 30 minutes. Dissolve 100 grams of 1-cyano-[(4-methoxyphenyl)methyl]cyclohexanol in 300 milliliters of anhydrous tetrahydrofuran, add it dropwise to the reaction solution, and control the rate of addition to keep the reaction temperature at -10 Between ℃ and 0℃, the dropwise addition is completed, and the reaction is maintained in this temperature range for 1 hour, and then the reaction system is heated to reflux fo...

Embodiment 2

[0016] Synthesis of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol

[0017] Add 20 liters of anhydrous tetrahydrofuran to a 100 liter reaction kettle equipped with a reflux condenser and a drying tube, add 5 kg of solid sodium hydroxide and 4 kg of sodium borohydride, stir for 30 minutes, cool to -10°C, and add 10 kg of 30 liters of anhydrous tetrahydrofuran solution of iodine, control the rate of addition to keep the reaction temperature between -10°C and 0°C, after the dropwise addition, keep the temperature range for 30 minutes. Dissolve 10 kilograms of 1-cyano-[(4-methoxyphenyl)methyl]cyclohexanol in 30 liters of anhydrous tetrahydrofuran, add it dropwise to the reaction solution, and control the rate of addition to keep the reaction temperature at -10 Between ℃ and 0℃, the dropwise addition is completed, and the reaction is maintained in this temperature range for 1 hour, and then the reaction system is heated to reflux for 30 minutes. Cool the reaction solution to roo...

Embodiment 3

[0019] Synthesis of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol

[0020] Add 200 ml of anhydrous tetrahydrofuran to a 1000 ml three-neck flask equipped with a magnetic stirring bar, reflux condenser and drying tube, add 50 g of solid sodium hydroxide and 55 g of potassium borohydride, stir for 30 minutes and then cool to -10°C , dropwise add 100 grams of iodine in 300 milliliters of anhydrous tetrahydrofuran solution, control the rate of addition to keep the reaction temperature between -10°C to 0°C, after the dropwise addition, keep the temperature range for 30 minutes. Dissolve 100 grams of 1-cyano-[(4-methoxyphenyl)methyl]cyclohexanol in 300 milliliters of anhydrous tetrahydrofuran, add it dropwise to the reaction solution, and control the rate of addition to keep the reaction temperature at 20°C Between ~25°C, the dropwise addition is completed, and the temperature range is maintained for 10 hours, and then the reaction system is heated to reflux for 2 hours. Cool th...

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Abstract

The invention discloses a method for preparing venlafaxine intermediate 1, (2- amino-1-(4- methoxyphenyl) ethide cyclohexanol. The method is characterized in that 1- cyano-((4- methoxyphenyl) methyl) cyclohexanol is deacidized by sodium borohydride or potassium borohydride under the catalysis of elemental iodine to obtain the 1, (2- amino-1-(4- methoxyphenyl) ethide cyclohexanol. The method has the advantages of mild reaction condition, simple post treatment, high yield, good product purity and low cost, and is suitable for commercial process.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of venlafaxine intermediate 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol. technical background: [0002] Venlafaxine is a non-tricyclic antidepressant drug, its chemical name is: 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol Hydrochloride, the structural formula is: [0003] [0004] Venlafaxine produces an antidepressant effect by inhibiting the recovery of serotonin and norepinephrine, and has the advantages of quick onset and few adverse reactions. Its main effect is not only used for antidepressant treatment, but also used for anti-obesity drugs and Anti-mania, hyperexcitability, epilepsy, etc. [0005] At present, in the preparation method of venlafaxine, most methods relate to intermediate 1-[2-amino-1-(4-methoxyphenyl) ethyl] cyclohexanol, and this compound can be said to be Wenlafaxine. The key intermediate in the pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/74C07C213/02A61P25/24A61P25/18A61P25/08A61P3/04
Inventor 余孝其杨军廖文武黎鹏王勇潘野
Owner CHENGDU QIAOFENG TECH DEV
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