CN104177268A - Preparation method of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol - Google Patents
Preparation method of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol Download PDFInfo
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- CN104177268A CN104177268A CN201410483328.3A CN201410483328A CN104177268A CN 104177268 A CN104177268 A CN 104177268A CN 201410483328 A CN201410483328 A CN 201410483328A CN 104177268 A CN104177268 A CN 104177268A
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Abstract
The invention relates to a preparation method of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol. The preparation method is characterized by comprising the following steps: adding Raney nickel and borohydride into a reaction solvent, adding 1-[cyano(p-methoxyphenyl)methyl]cyclohexanol, performing hydrogenation reaction, filtering reaction liquid, and performing reduced pressure concentration to obtain a light yellow viscous material, namely a reaction product-1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol. The preparation method has the advantages of high yield and purity, low cost, little wastewater and suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, relate in particular to a kind of VENLAFAXINE HCL intermediate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin.
Background technology
VENLAFAXINE HCL (Venlafaxine Hydrochloride) is a kind of non-tricyclic antidepressant, and chemical name is 1-[2-dimethylamino-1-(4-p-methoxy-phenyl) ethyl] hexalin hydrochloride, its structural formula is:
Venlafaxine is serotonin, the reuptake inhibitor of norepinephrine and Dopamine HCL, have rapid-action, the advantage that untoward reaction is few.And 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is key intermediate prepared by Venlafaxine;
Current preparation method has 1, US4535186 reported that one prepares 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] method of hexalin, the method is taking 1-[cyano group (p-methoxyphenyl) methyl] hexalin is raw material catalytic hydrogenation preparation under the effect of catalyst rhodium-aluminium sesquioxide, but catalyst rhodium is expensive. improper large-scale industrial production;
2, Chinese Journal of Pharmaceuticals 2004,35 (10) titles are VENLAFAXINE HCL reported in synthetic reduce 1-[cyano group (p-methoxyphenyl) methyl as raw material reductive agent by red aluminium and nickelous chloride/POTASSIUM BOROHYDRIDE] hexalin prepares 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin, the red aluminium of raw material and nickelous chloride price comparison high flow rate amount that these two kinds of methods are used are larger, and aftertreatment produces a large amount of waste water.
3, CN1847219A title is the synthetic method of hexalin formate " 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] ", has reported that use Lithium Aluminium Hydride reduces as reductive agent; CN101503365B title has reported under iodine catalysis to be that raw material carries out reduction reaction with POTASSIUM BOROHYDRIDE or sodium borohydride for " preparation method of Venlafaxine intermediate 1-［ 2-amino-1-(4-p-methoxy-phenyl) ethyl ］ hexalin ", and these two kinds of methods also exist above-mentioned identical problem.
4, WO03080560A1 title is Manufacture of phenyl ethyl amine compounds in particular venlafaxine, US2004181093A1 title is Process for preparation of phenethylamine derivatives, WO2007069277A2 title is that A process for the preparation of venlafaxine hydrochloride etc. mentions that to use Raney's nickel be catalyzer, at ammonia/ethanol (methyl alcohol, butanols) in solvent, under certain pressure, catalytic hydrogenation obtains product, but be not yield on the low side be exactly that purity is not high.
Summary of the invention
For above-mentioned shortcoming, the object of the invention is to provide that a kind of yield is high, purity good, with low cost, waste water produces less and the 1-[2-amino-1-of applicable suitability for industrialized production (4-p-methoxy-phenyl) ethyl] preparation method of hexalin.
Technology contents of the present invention is: 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized by the hydroborate of Raney's nickel and metal is joined in reaction solvent, then add 1-[cyano group (p-methoxyphenyl) methyl] hexalin, nitrogen replacement three times, hydrogen exchange three times, hydrogenation to 0.5～5Mpa, in 10～40 DEG C of reactions, detecting 1-[cyano group (p-methoxyphenyl) methyl by HPLC] hexalin is without reacting end; Nitrogen replacement, reaction solution, through filtering, obtains faint yellow dope after concentrating under reduced pressure is dry and is reaction product 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin;
Wherein reaction solvent is methyl alcohol or ethanol or Virahol, and the hydroborate of metal is sodium borohydride or POTASSIUM BOROHYDRIDE;
Raney's nickel consumption is 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight 20%～200%, hydroborate consumption is 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight 1%～10%, solvent load is 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight 4～20 times.
Reaction formula of the present invention is:
In the present invention, metal borohydride is not as raw material reductive agent but as catalyzer.
The advantage that the present invention compared with prior art had is: the present invention uses Raney's nickel and metal borohydride as composite catalyst, and its aftertreatment is easy, and Raney's nickel is recyclable to be applied mechanically, product yield is high, and purity is good, low production cost, waste water produces few, is applicable to suitability for industrialized production.
Embodiment
Example 1,
In 1L hydriding reactor, add successively 400 grams of methyl alcohol, 30 grams of Raney's nickels, 2 grams of sodium borohydrides and 50 grams of 1-[cyano group (p-methoxyphenyl) methyl] hexalin, nitrogen replacement three times, hydrogen exchange 3 times, then hydrogenation starts hydrogenation to 1Mpa, maintenance temperature is 20-30 DEG C, hydrogenation approximately 5 hours, HPLC detects raw material 1-[cyano group (p-methoxyphenyl) methyl] hexalin is without reacting complete, nitrogen replacement, feed liquid is through filtering, after concentrating under reduced pressure is dry faint yellow dope is 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] 50 grams of hexalin, molar yield 98.4%, purity 97.8%.
Example 2
In 1L hydriding reactor, add successively 400 grams of ethanol, 40 grams of Raney's nickels, 3 grams of POTASSIUM BOROHYDRIDE and 50 grams of 1-[cyano group (p-methoxyphenyl) methyl] hexalin, nitrogen replacement three times, hydrogen exchange 3 times, then hydrogenation starts hydrogenation to 1Mpa, maintenance temperature is 20-30 DEG C, hydrogenation approximately 5 hours, HPLC detects raw material 1-[cyano group (p-methoxyphenyl) methyl] hexalin is without reacting complete, nitrogen replacement, feed liquid is through filtering, after concentrating under reduced pressure is dry faint yellow dope is 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] 50.5 grams of hexalin, molar yield 99.3%, purity 98.1%.
Claims (1)
1. a 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized by the hydroborate of Raney's nickel and metal is joined in reaction solvent, then add 1-[cyano group (p-methoxyphenyl) methyl] hexalin, nitrogen replacement three times, hydrogen exchange three times, hydrogenation to 0.5～5Mpa, in 10～40 DEG C of reactions, detects 1-[cyano group (p-methoxyphenyl) methyl by HPLC] hexalin is without reacting end; Nitrogen replacement, reaction solution, through filtering, obtains faint yellow dope after concentrating under reduced pressure is dry and is reaction product 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin;
Wherein reaction solvent is methyl alcohol or ethanol or Virahol, and the hydroborate of metal is sodium borohydride or POTASSIUM BOROHYDRIDE;
Raney's nickel consumption is 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight 20%～200%, hydroborate consumption is 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight 1%～10%, solvent load is 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight 4～20 times.
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| CN201410483328.3A CN104177268B (en) | 2014-09-22 | 2014-09-22 | A kind of preparation method of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin |
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| CN201410483328.3A CN104177268B (en) | 2014-09-22 | 2014-09-22 | A kind of preparation method of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159330A (en) * | 2020-09-28 | 2021-01-01 | 苏州第四制药厂有限公司 | Preparation method of venlafaxine hydrochloride intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1810766A (en) * | 2006-01-04 | 2006-08-02 | 四川大学 | Nitrile reducing process to prepare amine |
| CN101503365A (en) * | 2009-02-04 | 2009-08-12 | 成都樵枫科技发展有限公司 | Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol |
| WO2010046808A2 (en) * | 2008-10-21 | 2010-04-29 | Alembic Limited | A process for the preparation of venlafaxine hydrochloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1810766A (en) * | 2006-01-04 | 2006-08-02 | 四川大学 | Nitrile reducing process to prepare amine |
| WO2010046808A2 (en) * | 2008-10-21 | 2010-04-29 | Alembic Limited | A process for the preparation of venlafaxine hydrochloride |
| CN101503365A (en) * | 2009-02-04 | 2009-08-12 | 成都樵枫科技发展有限公司 | Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159330A (en) * | 2020-09-28 | 2021-01-01 | 苏州第四制药厂有限公司 | Preparation method of venlafaxine hydrochloride intermediate |
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Effective date of registration: 20161208 Address after: 2188 No. 213012 Jiangsu province Zhonglou District of Changzhou City Avenue Patentee after: Changzhou wintop Chemical Technology Co Ltd Address before: 272200 Jining chemical industry economic and Technological Development Zone, Shandong Patentee before: SHANDONG HUASHENG CHEMICAL CO., LTD. |