CN1850781A - Method for preparing venlafaxin - Google Patents
Method for preparing venlafaxin Download PDFInfo
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- CN1850781A CN1850781A CN 200610050889 CN200610050889A CN1850781A CN 1850781 A CN1850781 A CN 1850781A CN 200610050889 CN200610050889 CN 200610050889 CN 200610050889 A CN200610050889 A CN 200610050889A CN 1850781 A CN1850781 A CN 1850781A
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- venlafaxin
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- hexalin
- methoxy
- phenyl
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Abstract
This invention relates to wan pull way new preparation method, it belongs to chemical industry and chemical medical treatment fields. Firstly, 4-methoxyl group benzyl cyanide is used as material, it is condensed with cyclohexanone through phase shift catalyst function in alkaline liquor to get 1-[cyano-1-(4-methoxyl group phenyl group) ethyl] cyclohexanol. Secondly, the 1-[cyano-1-(4-methoxyl group phenyl group) ethyl] cyclohexanol is reduced by reducer and through methylation to generate 1-[1-(N,n-dimethyl formamidine)-1-(4-methoxyl group phenyl group) methanol] cyclohexanol in alcohol solvent. Thirdly, the product in second step is dissolved in alcohol solvent and reduced by reducer to get 1-[2-(dimcthylamine group)-1-(4- methoxyl group phenyl group) ethyl] cyclohexanol. The operation is simple, cost is low, yield is high, the reaction condition is easy to realized, and it is propitious to industrial manufacture.
Description
Technical field
The present invention relates to the preparation method of a kind of venlafaxin (1-[2-(dimethylin)-1-(4-p-methoxy-phenyl) ethyl] hexalin), belong to chemical industry and chemical field of medicaments.
Background technology
Venlafaxin (venlafaxine), (1-[2-(dimethylin)-1-(4-p-methoxy-phenyl) ethyl] hexalin), its structural formula is shown in general formula 1:
Venlafaxin is a kind of thymoleptic, is a kind of novel antidepressant that is different from unique chemical structure of having of other antidepressant drugs and neuropharmacology effect.This product is brought into play antidepressant effect by the reuptake of remarkable inhibition serotonin and norepinephrine.Acceptors such as this product and choline, histamine and adrenergic do not have avidity, thereby do not have these acceptor mesomeric related side effects yet, as calmness, dry, constipation, uroschesis and blurred vision etc.
The preparation of existing venlafaxin, as J.Med.Chem, 1990,33, described in the 2899-2905, the 4-p-methoxybenzeneacetonitrile under-70 ℃, by with the n-Butyl Lithium effect, again with the pimelinketone condensation, through the Rh/Al reduction, methylating through formaldehyde/formic acid makes again then.This method needs very low temperature, and yield is low, and the cost height is not suitable for suitability for industrialized production.And described in the WO03/080560,4-p-methoxybenzeneacetonitrile and pimelinketone condenses Raney's nickel hydro-reduction under 8.5 kilograms pressure, methylating through formaldehyde/formic acid makes again, and this method is used inflammable Raney Ni, and need the reaction under high pressure condition, operation is inconvenience comparatively.And for example described in the EP1466889, the 4-p-methoxybenzeneacetonitrile is-78 ℃ of following and di-isopropyl lithium effects, again with the pimelinketone condensation, then through NaBH
4Reduction obtains venlafaxin again after formaldehyde/formic acid methylates.This method needs very low temperature, is not suitable for suitability for industrialized production, and when reduction NaBH
4Consumption very big, yield is low, the cost height.
Summary of the invention
The purpose of this invention is to provide a kind of easy and simple to handlely, cost is low, and yield height, reaction conditions are easy to realize and the preparation method of the venlafaxin of suitable suitability for industrialized production.
The present invention is the preparation method of venlafaxin, it is characterized in that may further comprise the steps:
The first step is a raw material with the 4-p-methoxybenzeneacetonitrile, in alkali lye, by the phase-transfer catalyst effect, with the pimelinketone condensation, obtains 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin;
Second step is with 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin in alcoholic solvent, by reductive agent reduction and methylation, generate 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl] hexalin;
The 3rd step is with 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl] hexalin is dissolved in the alcoholic solvent, obtains 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl) ethyl through the reductive agent reduction] hexalin (venlafaxin).
The alkali lye of the described the first step can be sodium hydroxide or potassium hydroxide solution.
The phase-transfer catalyst of the described the first step can be Tetrabutyl amonium bromide (TBAB) or 4-butyl ammonium hydrogen sulfate (TBAHS).
The temperature of reaction of the described the first step can be 0~30 ℃, and the reaction times is 1~5 hour.
The reductive agent in described second step can be CuCl, and the raw material that methylates can be dimethylamine solution.
The temperature of reaction in described second step is 64~78 ℃, and the reaction times is 20~25 hours.
The reductive agent in described the 3rd step can be KBH
4Or NaBH
4
The alcoholic solvent in described second step and the 3rd step can be methyl alcohol or ethanol.
The temperature of reaction in described the 3rd step can be 0~30 ℃, and the reaction times is 3~4 hours.
Described 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl) ethyl] hexalin (venlafaxin) can with the aqueous isopropanol prepared in reaction venlafaxin hydrochloride of hydrogenchloride.
The present invention has avoided use and the high-pressure hydrogenation of inflammable substance Raney Ni, the raw material that uses some low prices and be easy to get, and the 3rd step reduction reaction KBH
4Or NaBH
4Consumption few, the yield height, the venlafaxin purity height that makes has reduced cost significantly.Preparation condition gentleness of the present invention, operation is easy, total recovery 60%-65%, cost is low, is fit to industrialized production.
Embodiment
The specific embodiment of the present invention will be described in detail in following examples, but following enforcement should not be construed as the scope of the present invention that limits.
Concrete synthetic route is as follows:
In the above-mentioned reaction formula: 1 is venlafaxin (1-[2-(dimethylin)-1-(4-p-methoxy-phenyl) ethyl] hexalin); 2 is the 4-p-methoxybenzeneacetonitrile; 3 is pimelinketone; 4 is 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin; 5 is 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl] hexalin; 6 is the venlafaxin hydrochloride.
Embodiment 1:1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] preparation of hexalin (4)
Method 1: drop into 300g (2mol) 4-p-methoxybenzeneacetonitrile (2) in reaction flask, 500g10%NaOH (1.25mol) solution, 10g Tetrabutyl amonium bromide (TBAB) is reduced to 0~5 ℃, vigorous stirring 1 hour, in 15~20 ℃ of dropping 320g (3.2mol) pimelinketone (3), dropwise, in 20 ℃ of reactions 3~4 hours, filter, crude product 4, with toluene refining 450g 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin (4), yield 91.8%.
Method 2: drop into 300g (2mol) 4-p-methoxybenzeneacetonitrile (2) in reaction flask, 500g10%NaOH (1.25mol) solution, 10g 4-butyl ammonium hydrogen sulfate (TBAHS) is reduced to 5~10 ℃, vigorous stirring 1 hour, in 15~20 ℃ of dropping 320g (3.2mol) pimelinketone (3), dropwise, in 20 ℃ of reactions 3~4 hours, filter, crude product 4, with toluene refining 426g 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin (4), yield 87%.
Method 3: drop into 300g (2mol) 4-p-methoxybenzeneacetonitrile (2) in reaction flask, 700g10%KOH (1.25mol) solution, 10g Tetrabutyl amonium bromide (TBAB) is reduced to 0~5 ℃, vigorous stirring 1 hour, in 15~20 ℃ of dropping 320g (3.2mol) pimelinketone (3), dropwise, in 30 ℃ of reactions 2~3 hours, filter, crude product 4, with toluene refining 422g 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin (4), yield 86%.
Embodiment 2:1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl] preparation of hexalin (5)
Method 1: in reaction flask, drop into 245g (1mol) 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin (4), 120g (1.2mol) CuCl, 1000ml methyl alcohol, under the vigorous stirring, drip 273g 33% dimethylamine solution in room temperature, dropwise and be warming up to 64 ℃, reacted 25 hours, and removed methyl alcohol under reduced pressure, reduce to room temperature, with reactant transfer to 1000ml 30%NaOH solution, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrate 232g 1-[1-(N, N-dimethyl carbonamidine)-and 1-(4-p-methoxy-phenyl) methyl] hexalin (5), yield 80%.
Method 2: in reaction flask, drop into 245g (1mol) 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin (4), 120g (1.2mol) CuCl, 1000ml ethanol, under the vigorous stirring, drip 273g 33% dimethylamine solution in room temperature, dropwise and be warming up to 64 ℃, reacted 25 hours, and removed ethanol under reduced pressure, reduce to room temperature, with reactant transfer to 1000ml 30%NaOH solution, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrate 232g 1-[1-(N, N-dimethyl carbonamidine)-and 1-(4-p-methoxy-phenyl) methyl] hexalin (5), yield 80%.
Method 3: in reaction flask, drop into 245g (1mol) 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin (4), 120g (1.2mol) CuCl, 1000ml ethanol, under the vigorous stirring, drip 273g 33% dimethylamine solution in room temperature, dropwise and be warming up to 70 ℃, reacted 25 hours, and removed ethanol under reduced pressure, reduce to room temperature, with reactant transfer to 1000ml 30%NaOH solution, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrate 242g 1-[1-(N, N-dimethyl carbonamidine)-and 1-(4-p-methoxy-phenyl) methyl] hexalin (5), yield 83.4%.
Method 4: in reaction flask, drop into 245g (1mo1) 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin (4), 120g (1.2mol) CuCl, 1000ml ethanol, under the vigorous stirring, drip 273g 33% dimethylamine solution in room temperature, dropwise and be warming up to 78 ℃, reacted 20 hours, and removed ethanol under reduced pressure, reduce to room temperature, with reactant transfer to 1000ml 30%NaOH solution, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrate 240g 1-[1-(N, N-dimethyl carbonamidine)-and 1-(4-p-methoxy-phenyl) methyl] hexalin (5), yield 82.8%.
Embodiment 3: the preparation of venlafaxin (1)
Method 1: drop into 145g (0.5mol) 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl in the reaction flask] hexalin (5), 500ml methyl alcohol is reduced to 0~5 ℃, drops into 108g KBH in batches
4(2mol).Finish, rose to room temperature reaction 3~4 hours.Remove methyl alcohol under reduced pressure, raffinate is transferred in the 500ml 30%NaOH solution, ethyl acetate extraction, washing, anhydrous sodium sulfate drying, concentrate 118g venlafaxin (1), yield 85%.
Method 2: method 1: drop into 145g (0.5mol) 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl in the reaction flask] hexalin (5), 500ml methyl alcohol is reduced to 5~10 ℃, drops into 108g KBH in batches
4(2mol).Finish, rose to room temperature reaction 3~4 hours.Remove methyl alcohol under reduced pressure, raffinate is transferred in the 500ml 30%NaOH solution, ethyl acetate extraction, washing, anhydrous sodium sulfate drying, concentrate 113.5g venlafaxin (1), yield 82%.
Method 3: method 1: drop into 145g (0.5mol) 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl in the reaction flask] hexalin (5), 500ml ethanol is reduced to 10~15 ℃, drops into 108g KBH in batches
4(2mol).Finish, rose to room temperature reaction 3~4 hours.Remove ethanol under reduced pressure, raffinate is transferred in the 500ml 30%NaOH solution, ethyl acetate extraction, washing, anhydrous sodium sulfate drying, concentrate 110.8g venlafaxin (1), yield 80%.
Method 4: drop into 145g (0.5mol) 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl in the reaction flask] hexalin (5), 500ml methyl alcohol is reduced to 0~5 ℃, drops into 76g NaBH in batches
4(2mol).Finish, rose to room temperature reaction 3~4 hours.Remove methyl alcohol under reduced pressure, raffinate is transferred in the 500ml 30%NaOH solution, ethyl acetate extraction, washing, anhydrous sodium sulfate drying, concentrate 110.8g venlafaxin (1), yield 80%.
Method 5: drop into 145g (0.5mol) 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl in the reaction flask] hexalin (5), 500ml ethanol is reduced to 0~5 ℃, drops into 108g KBH in batches
4(2mol).Finish, rose to room temperature reaction 3~4 hours.Remove ethanol under reduced pressure, raffinate is transferred in the 500ml 30%NaOH solution, ethyl acetate extraction, washing, anhydrous sodium sulfate drying, concentrate 115g venlafaxin (1), yield 83%.
Embodiment 4: the preparation of venlafaxin hydrochloride (6)
The 118g venlafaxin (1) that obtains is dissolved in the 500ml ethyl acetate, transfers PH=2, filter, get 125g venlafaxin hydrochloride (6) crude product, get 106g venlafaxin hydrochloride elaboration, 215~217 ℃ of mp with the Virahol recrystallization with the HCl-aqueous isopropanol.
Claims (10)
1, a kind of preparation method of venlafaxin is characterized in that may further comprise the steps:
The first step is a raw material with the 4-p-methoxybenzeneacetonitrile, in alkali lye, by the phase-transfer catalyst effect, with the pimelinketone condensation, obtains 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin;
Second step is with 1-[cyano group-1-(4-p-methoxy-phenyl) ethyl] hexalin in alcoholic solvent, by reductive agent reduction and methylation, generate 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl] hexalin;
The 3rd step is with 1-[1-(N, N-dimethyl carbonamidine)-1-(4-p-methoxy-phenyl) methyl] hexalin is dissolved in the alcoholic solvent, obtains 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl) ethyl through the reductive agent reduction] hexalin (venlafaxin).
2, by the preparation method of the described venlafaxin of claim 1, the alkali lye that it is characterized in that the described the first step is sodium hydroxide or potassium hydroxide solution.
3, by the preparation method of the described venlafaxin of claim 1, the phase-transfer catalyst that it is characterized in that the described the first step is Tetrabutyl amonium bromide or 4-butyl ammonium hydrogen sulfate.
4, by the preparation method of the described venlafaxin of claim 1, the temperature of reaction that it is characterized in that the described the first step is 0~30 ℃, and the reaction times is 1~5 hour.
5, by the preparation method of the described venlafaxin of claim 1, it is characterized in that the reductive agent in described second step is CuCl, the raw material that methylates is a dimethylamine solution.
6, by the preparation method of the described venlafaxin of claim 1, it is characterized in that the temperature of reaction in described second step is 64~78 ℃, the reaction times is 20~25 hours.
7,, it is characterized in that the reductive agent in described the 3rd step is KBH by the preparation method of the described venlafaxin of claim 1
4Or NaBH
4
8,, it is characterized in that the alcoholic solvent in described second step and the 3rd step is methyl alcohol or ethanol by the preparation method of the described venlafaxin of claim 1.
9, by the preparation method of the described venlafaxin of claim 1, it is characterized in that the temperature of reaction in described the 3rd step is 0~30 ℃, the reaction times is 3~4 hours.
10, by the preparation method of the described venlafaxin of claim 1, it is characterized in that described 1-[2-(dimethylin)-1-(4-p-methoxy-phenyl) ethyl] the aqueous isopropanol prepared in reaction venlafaxin hydrochloride of hexalin (venlafaxin) and hydrogenchloride.
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CN105801437A (en) * | 2016-03-31 | 2016-07-27 | 常州大学 | Synthetic method of (methylamino)(phenyl)methyl alcohol |
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US6197828B1 (en) * | 1998-12-01 | 2001-03-06 | Sepracor, Inc. | Derivatives of (+)-venlafaxine and methods of preparing and using the same |
US6350912B1 (en) * | 2001-02-28 | 2002-02-26 | Council Of Scientific And Industrial Research | One pot process for the preparation of 1-[2-dimethylamino-(4-methoxyphenyl)-ethyl]cyclohexanol |
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