CN101823969A - Preparation method of desmethylvenlafaxine - Google Patents
Preparation method of desmethylvenlafaxine Download PDFInfo
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- CN101823969A CN101823969A CN200910079133A CN200910079133A CN101823969A CN 101823969 A CN101823969 A CN 101823969A CN 200910079133 A CN200910079133 A CN 200910079133A CN 200910079133 A CN200910079133 A CN 200910079133A CN 101823969 A CN101823969 A CN 101823969A
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- acetic acid
- hydrogen bromide
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Abstract
The invention discloses a preparation method of antidepressive desmethylvenlafaxine, which is characterized by comprising the step that: a compound of formula II is placed in hydrobromic acid or mixed liquid of the hydrobromic acid and acetic acid to react so as to generate a compound of formula I and a method of addition salt can be accepted pharmaceutically.
Description
Technical field
The present invention relates to prepare 4-[2-(dimethylin)-1-(1-hydroxy-cyclohexyl) ethyl]-method of phenol (formula I compound), this compound and pharmaceutically acceptable addition salt thereof can be used for antidepressant treatment.
Background technology
Desmethylvenlafaxine and pharmaceutically acceptable addition salt thereof have good pharmacology and curative properties, are used for the treatment of and prevent melancholia and recurrence thereof, especially to just sending out and accidental melancholia and recurrence thereof have good curative effect.
About the preparation method of formula I compound, it is that raw material prepares through demethylation with Venlafaxine (formula II compound) that WO03/103603A2, CN1658861A and US0105358A1 provide four kinds of methods, and its reaction conditions is as follows:
1): dodecyl mercaptans, sodium methylate, PEG-400,190 ℃ of 2h
2): benzenethiol sodium salt, PEG-400,160 ℃ of 5h
3): dodecyl mercaptans, sodium ethylate, PEG-400,150 ℃, 2day
4): dodecyl mercaptans sodium, PEG-400,190 ℃, 3h.Yield 85-90%.
Among the above-mentioned preparation method, alkaline environment adopts sodium hydride and thiol reactant to generate sodium mercaptides down, remove methyl with the Venlafaxine reaction again and prepare desmethylvenlafaxine, the mercaptan play is smelly, last handling process produces a large amount of acute smelly waste liquids, and reaction adopts sodium hydride palpus guarantee system anhydrous, is difficult to realize suitability for industrialized production.
WO00/76955A1 and US2002/0022662 mention and adopt BBr
3With the methylene dichloride solvent low temperature-30 ℃～0 ℃ reaction demethylation down, but this method yield only 35%, and reaction impurities is more.
For these reasons, be necessary to develop a kind of simple effectively, easy handling, the method for preparation I compound economically.
We grope through experiment, have found the preparation yield up to 75% formula I compound method.
Summary of the invention
The purpose of this invention is to provide a kind of simple effectively, the preparation method of easy handling, economic formula I compound.
The invention provides the preparation method of compound shown in the formula I,
It is characterized in that formula II compound is placed the mixed solution reaction production I compound of Hydrogen bromide or itself and acetic acid, formula I compound and pharmaceutically acceptable addition salt thereof can be used for antidepressant treatment.
The present invention also provides a kind of method further, and the hydrobromic concentration of using is 20-50%, and preferred 40%.
The present invention also provides a kind of method further, and adopting Hydrogen bromide and acetic acid is reaction solvent with the mixed solution of arbitrary proportion.
The present invention also provides a kind of method further, selects 1: 1 mixed solution of 40% Hydrogen bromide and acetic acid as solvent.
The present invention also provides a kind of method further, and temperature of reaction is 60 ℃-110 ℃, and preferable reaction temperature is 90-100 ℃.
The present invention also provides a kind of method further, and the reaction times is 0.5-15h, and the preferred reaction time is 2-5h.
Embodiment
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Embodiment one:
50 gram Venlafaxines, 250ml acetic acid, 250ml40% Hydrogen bromide are added in the reaction flask, stir heating reflux reaction 2～5h down, reaction finishes to reduce pressure and steams solvent, obtains resistates and adds the stirring of 100ml water, suction filtration, filter cake stirs with 100ml acetone again, and suction filtration obtains the off-white color solid, 60 ℃ of forced air drying 8h, get 38 gram off-white color solids, yield 77%, chemical purity: 97.43%.MP：232～235℃.
1H-NMR(400MHz，CDCl3)：δ：6.95～6.98(d，2H，J＝8.4，ph-CH
2)、6.62～6.64(d，2H，J＝8.4，ph-CH
2)、5.34(s，1H，-OH)、2.96～3.01(q，1H，J＝8.0，R-CH
2)、2.69～2.72(t，1H，J＝8.0，-CH)、231～2.36(q，1H，J＝6.4，-CH
2)、2.13(s，6H，-CH
3)、1.11～1.55(t，10H，R-CH
2)。
Embodiment two:
50 gram Venlafaxines, 250ml40% Hydrogen bromide are added in the reaction flask, stir heating reflux reaction 2～5h down, reaction finishes to reduce pressure and steams solvent, obtains resistates and adds the stirring of 100ml water, suction filtration, filter cake stirs with 100ml acetone again, and suction filtration obtains the off-white color solid, 60 ℃ of forced air drying 8h, get 35 gram off-white color solids, yield 74%, chemical purity: 98.63%.MP：232～235℃.
Embodiment three:
50 gram Venlafaxines, 100ml acetic acid, 250ml40% Hydrogen bromide are added in the reaction flask, stir heating reflux reaction 2～5h down, reaction finishes to reduce pressure and steams solvent, obtains resistates and adds the stirring of 100ml water, suction filtration, filter cake stirs with 100ml acetone again, and suction filtration obtains the off-white color solid, 60 ℃ of forced air drying 8h, get 34 gram off-white color solids, yield 77%, chemical purity: 97.62%.MP：232～235℃.
Embodiment four:
The preparation of fumaric acid desmethylvenlafaxine:
With desmethylvenlafaxine 23.0g, methyl alcohol 70ml, fumaric acid 11.2g add in the reaction flask, reflux 2h, and reaction solution becomes clarification.Add gac 5g, stir 0.5h.Suction filtration continues heating in the filtrate adding there-necked flask, the mixed solution of slow acetone 210ml of dropping in the back of refluxing and water 2g, and 1h dropwises, and separates out white solid.Stirring and crystallizing is spent the night under the room temperature, suction filtration.60 ℃ of forced air drying 8h of filter cake get white solid 28.2g, yield 81.3%.Chemical purity: 99.43%.MP：145～150℃。
Claims (6)
1. the formula I compound method of a new preparation desmethylvenlafaxine,
It is characterized in that formula II compound is placed the mixed solution reaction production I compound of Hydrogen bromide or itself and acetic acid, formula I compound and pharmaceutically acceptable addition salt thereof can be used for antidepressant treatment.
2. method according to claim 1 is characterized in that the hydrobromic concentration of using is 20-50%, preferred 40%.
3. method according to claim 1 is characterized in that Hydrogen bromide and acetic acid are reaction solvent with the mixed solution of arbitrary proportion.
4. according to the described method of claim 1 to 3, its feature at preferred 40% Hydrogen bromide and 1: 1 mixed solution of acetic acid as solvent.
5. method according to claim 1 is characterized in that temperature of reaction is 60 ℃-110 ℃, and preferable reaction temperature is 90-100 ℃.
6. method according to claim 1 is characterized in that the reaction times is 0.5-15h, and the preferred reaction time is 2-5h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910079133A CN101823969A (en) | 2009-03-04 | 2009-03-04 | Preparation method of desmethylvenlafaxine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910079133A CN101823969A (en) | 2009-03-04 | 2009-03-04 | Preparation method of desmethylvenlafaxine |
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| CN101823969A true CN101823969A (en) | 2010-09-08 |
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|---|---|---|---|
| CN200910079133A Pending CN101823969A (en) | 2009-03-04 | 2009-03-04 | Preparation method of desmethylvenlafaxine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5043466A (en) * | 1989-02-01 | 1991-08-27 | John Wyeth & Bro., Limited | Preparation of cyclohexanol derivatives and novel thioamide intermediates |
| US20050197392A1 (en) * | 1999-04-06 | 2005-09-08 | Sepracor Inc. | O-desmethylvenlafaxine and methods of preparing and using the same |
| CN101070288A (en) * | 2007-05-25 | 2007-11-14 | 上海中科合臣股份有限公司 | Process for preparing norvanlafaxine |
-
2009
- 2009-03-04 CN CN200910079133A patent/CN101823969A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5043466A (en) * | 1989-02-01 | 1991-08-27 | John Wyeth & Bro., Limited | Preparation of cyclohexanol derivatives and novel thioamide intermediates |
| US20050197392A1 (en) * | 1999-04-06 | 2005-09-08 | Sepracor Inc. | O-desmethylvenlafaxine and methods of preparing and using the same |
| CN101070288A (en) * | 2007-05-25 | 2007-11-14 | 上海中科合臣股份有限公司 | Process for preparing norvanlafaxine |
Non-Patent Citations (2)
| Title |
|---|
| DIPAKRANJAN MAL等: "Synthesis of chlorine-containing angucycline BE-23254 and its analogs", 《TETRAHEDRON》 * |
| MAGNUS BERGLUND等: "SAR studies of capsazepinoid bronchodilators 3: The thiourea part (coupling region) and the 2-(4-chlorophenyl)ethyl moiety (C-region)", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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Application publication date: 20100908 |