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Process for preparing O-desmethylvenlafaxine

A technology of methyl and aryl groups, applied in the field of preparing O-desmethyl venlafaxine, can solve the problems of inconvenient long-term reaction time, high temperature, long process and the like

Inactive Publication Date: 2011-01-19
GENERICS UK LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method has the disadvantage of requiring an inconvenient, long reaction time of about 30 hours
[0016] Consequently, the methods disclosed in the prior art suffer from many disadvantages, such as moderate to low yields; obtaining ODV(II) in an impure state; very high temperatures; lengthy processes; and / or the use of expensive, toxic and / or hazardous reagents, which are not recommended for commercial scale, such as L-tri-sec-butylsodium borohydride, ethanethiol, boron tribromide, and n-butyllithium

Method used

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  • Process for preparing O-desmethylvenlafaxine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Preparation of ODV base from venlafaxine base using 1,2-ethanedithiol:

[0112] Add 1,2-ethanedithiol (10.17 g, 0.11 mol) to a suspension of potassium tert-butoxide (30.29 g, 0.27 mol) in polyethylene glycol 400 (125 mL) at 25°C-30°C middle. To this stirred suspension was added venlafaxine base (25 g, 0.09 mol) and the reaction mixture was heated to 130°C-135°C for 24-28 hours. After the reaction was complete, the reaction mixture was cooled to 25°C-30°C and water (500 mL) was added, followed by concentrated hydrochloric acid (35-37% w / v, 30 mL). The solution was extracted with toluene (2 x 50 mL). To this aqueous solution was added 25% w / v ammonia solution (35 mL) to adjust the pH of the solution to >9.5. A solid precipitated and was filtered to provide crude ODV base. The resulting solid was further suspended in methanol (125 mL), and concentrated hydrochloric acid (35-37% w / v, 15 mL) was added to the suspension to dissolve the solid, followed by addition of 25% w...

Embodiment 2

[0114] Preparation of ODV base from venlafaxine hydrochloride using 1,2-ethanedithiol:

[0115] Add 1,2-ethanedithiol (10.17 g, 0.11 mol) to a suspension of potassium tert-butoxide (30.29 g, 0.27 mol) in polyethylene glycol 400 (125 mL) at 25°C-30°C middle. To this stirred suspension was added venlafaxine hydrochloride (28 g, 0.09 mol) and the reaction mixture was heated to 130°C-135°C for 24-28 hours. After the reaction was complete, the reaction mixture was cooled to 25°C-30°C, and water (500 mL) was added, followed by concentrated hydrochloric acid (35-37% w / v, 20 mL). The solution was extracted with toluene (2 x 50 mL). To this aqueous solution was added 25% w / v ammonia solution (25 mL) to adjust the pH of the solution to >9.5. A solid precipitated and was filtered to provide crude ODV base. The resulting solid was further suspended in methanol (140 mL), and concentrated hydrochloric acid (35-37% w / v, 17 mL) was added to the suspension to dissolve the solid, followed b...

Embodiment 3

[0117] Preparation of ODV base from venlafaxine base using 2-diethylaminoethanethiol:

[0118] Add 2-diethylaminoethanethiol hydrochloride (3.06 g, 0.018 mol) to a suspension of sodium methoxide (2.9 g, 0.054 mol) in polyethylene glycol 400 (50 mL) at 25°C-30°C in the liquid. To this stirred suspension was added venlafaxine base (2.5 g, 0.009 mol) and the reaction mixture was heated to 170°C-175°C for 24-28 hours. After the reaction was complete, the reaction mixture was cooled to 25°C-30°C, and water (200 mL) was added, followed by concentrated hydrochloric acid (35-37% w / v, 5 mL). The solution was extracted with toluene (2 x 25 mL). To this aqueous solution was added 25% w / v ammonia solution (7 mL) to adjust the pH of the solution to >9.5. A solid precipitated and was filtered to provide crude ODV base. The resulting solid was further suspended in methanol (12.5 mL), and concentrated hydrochloric acid (35-37% w / v, 7.5 mL) was added to the suspension to dissolve the solid...

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Abstract

The present invention provides a convenient and efficient process for the preparation of O-desmethylvenlafaxine (ODV), comprising the reaction of venlafaxine, or a salt thereof, with a thiol reagent such as a dithiol, an aminothiol or an inorganic thiol. The present invention also provides a process for purifying ODV base,said process comprising the steps of mixing crude ODV base with an alcohol to form a suspension and adding acid followed by base to generate ODV base with high purity.

Description

technical field [0001] The present invention provides a convenient and effective method for preparing O-desmethylvenlafaxine (ODV), comprising making venlafaxine, or a salt thereof, and a thiol reagent (thiolreagent) such as dithiol, Aminothiol or inorganic thiol reaction. The present invention also provides a method for purifying ODV base comprising the steps of mixing crude ODV base with alcohol to form a suspension and adding acid followed by base to produce ODV base with high purity. Background technique [0002] O-desmethylvenlafaxine (ODV, II), chemically named 1-[1-(4-hydroxyphenyl)-2-(dimethylamino)-ethyl]-cyclohexanol, is Venlafaxine The major metabolite of farxine. ODV is known to inhibit norepinephrine and serotonin uptake and has antidepressant activity. It has further been reported that oral administration of ODV succinate, especially the extended-release form of ODV succinate, resulted in less nausea, vomiting, diarrhea, abdominal pain, headache, vasovagal d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C213/10C07C215/64A61K31/137A61P25/24
CPCC07C2101/14C07C213/00C07C213/10C07C2601/14A61P13/00A61P15/00A61P15/10A61P21/00A61P25/00A61P25/16A61P25/18A61P25/22A61P25/24A61P25/30A61P25/32A61P3/04C07C215/64
Inventor 维纳亚克·G·戈雷维卡斯·S·库尔尼卡M·帕蒂尔
Owner GENERICS UK LTD
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