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Preparing technology for cyclohexanol derivatives used to prepare the intermediate of Venlafaxine

A preparation process and a derivative technology, applied in the field of preparation technology of cyclohexanol derivatives, can solve problems such as explosion and industrialized production impact, and achieve the effects of reducing production cost and mild preparation conditions

Inactive Publication Date: 2004-06-16
重庆凯林制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The condition control requirements of the two reactions are relatively strict, especially when lithium aluminum hydride is under the action of concentrated sulfuric acid, it is easy to cause explosion due to carelessness, so it has a very adverse effect on industrial production

Method used

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  • Preparing technology for cyclohexanol derivatives used to prepare the intermediate of Venlafaxine
  • Preparing technology for cyclohexanol derivatives used to prepare the intermediate of Venlafaxine
  • Preparing technology for cyclohexanol derivatives used to prepare the intermediate of Venlafaxine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1: Preparation of 1-[cyano(p-methoxyoxy)methyl]cyclohexanol (ie general formula 2) (intermediate (I)).

[0026] method 1

[0027] Add 10ml of n-hexane, 10ml of toluene and 710mg of NaH (60%, 17.8mmol) successively in a dry round bottom flask to make it a suspension, stir at room temperature for 15 minutes, slowly add 2.5g of p-methoxyphenylacetonitrile (17.0mmol) , Added within 10 minutes, stirred at room temperature for 50 minutes. Cool to -5 degrees Celsius, add dropwise 2.18g (22.0mmol) of cyclohexanone, complete the addition within 10 minutes, stir for 5 hours, TLC (developing solvent: petroleum ether: ethyl acetate = 4: 1) monitors until the reaction is complete (only a spot). Add 5% dilute hydrochloric acid dropwise thereto to adjust the pH to 6-7, stir for 15 minutes, filter with suction, wash the filter cake with water, and dry to obtain a crude product. Recrystallize with 3 times the amount of toluene (weight to volume ratio) to obtain 3.33 g of the ...

Embodiment 2

[0030] Example 2: Preparation of 1-[2-amino-1-(p-methoxyphenyl)ethyl]cyclohexanol and its hydrochloride (ie intermediate (II)).

[0031] 1. The preparation of the compound of general formula (1)

[0032] method 1

[0033]In a 50ml round bottom flask, intermediate (I) 2.45g (10mmol) and RaneyNi catalyst 1.0g were dispersed in 30ml methanol, and the air in the bottle was replaced with hydrogen more than 3 times, vigorously stirred at normal temperature and pressure, TLC It takes about 15 hours to monitor until no more hydrogen is absorbed. Stop stirring, let it stand, filter to remove the catalyst, and wash with methanol three times, combine the methanol solution, recover methanol, and obtain 2.50 g of crude product. with silica gel column chromatography (CH 2 Cl 2 : MeOH=30:1, volume ratio), 2.06g of the product was obtained, and the yield was 83%. TLC (developing solvent: methylene chloride: methanol = 30: 1, volume ratio) detected only one main spot, and the product coul...

Embodiment 3

[0038] Embodiment 3: Preparation of venlafaxine hydrochloride

[0039] Transfer the concentrated solution prepared by Method 2 of Example 2 to a 5000ml three-necked flask, add 3050ml of water, 332ml of formaldehyde and 438ml of formic acid, reflux for 12 hours, concentrate under reduced pressure until the raffinate is about 2000ml, add water to dilute to 4000ml, and wash with concentrated hydrochloric acid Adjust pH to 2, extract with ethyl acetate 3 times (300ml each time) to remove impurities (pink), treat the aqueous solution with concentrated KOH solution until alkaline, and extract 3 times with ethyl acetate. Concentrate the extract, acidify with isopropanol-HCl, add an appropriate amount of ether, and stand to obtain a white crystalline precipitate, which is filtered and dried to obtain 260-300 g of crude venlafaxine, with a yield of 80% and a melting point of 212-214 degrees Celsius. The crude product is recrystallized once with methanol-ethyl acetate to obtain the fini...

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Abstract

The invention discloses a process for preparing hexahydrophenol derivative for making the intermediate of venlafaxime, a novel antidepressant drug, comprising the steps of, choosing suitable dissolvent and reaction condition, by the action of initiation nitriles or polyamides compounds having general formula (3) with alkali metal chloride hydrogenated or organic lithium derivatives, compound having general formula (2) can be obtained, under suitable dissolvent and reaction conditions, compounds having general formula (2) can be transformed into compounds having general formula (1) through aluminium-hydrogen compounds reduction or catalytic hydrogenation with nickel presence. The product is antidepressant drug with proven curative effects.

Description

technical field [0001] The invention relates to a preparation process of cyclohexanol derivatives, in particular to a preparation process of cyclohexanol derivatives used to prepare intermediates of venlafaxine and venlafaxine derivatives. Background technique [0002] A number of nontricyclic antidepressants have recently been developed that reduce the propensity for the cardiovascular and antiparasympathetic physiological effects of tricyclic antidepressants. Some compounds have shown promise in anti-obesity drugs and in the treatment of brain disorders such as Parkinson's disease and Alzheimer's disease. As described in WO 94 / 00047 and WO 94 / 00114. Non-tricyclic compounds such as venlafaxine, whose chemical name is (±)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-cyclohexanol, have Numerous studies and reports have been made, such as those described in US Patent 4761501 and Drugs of the Future No. 13(9): 839-840 (1988), among others. In the United States, the hydroch...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C217/74C07C253/30C07C255/37
CPCC07C213/02C07C253/30C07C2101/14C07C2601/14C07C217/74C07C255/37
Inventor 兰志银石开云莫启壮李裕林
Owner 重庆凯林制药有限公司
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