CN104177268B - A kind of preparation method of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin - Google Patents
A kind of preparation method of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin Download PDFInfo
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- CN104177268B CN104177268B CN201410483328.3A CN201410483328A CN104177268B CN 104177268 B CN104177268 B CN 104177268B CN 201410483328 A CN201410483328 A CN 201410483328A CN 104177268 B CN104177268 B CN 104177268B
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Abstract
The present invention relates to the preparation method of a kind of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin, it is characterized by and the hydroborate of Raney's nickel and metal is joined in reaction solvent, then 1-[cyano group (p-methoxyphenyl) methyl] hexalin is added, carry out hydrogenation reaction, 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.The present invention has that yield is high, purity good, with low cost, waste water produces less and the advantage of applicable suitability for industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin, particularly relate to the preparation method of a kind of VENLAFAXINE HCL intermediate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] 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] cyclohexanol HCI, and its structural formula is:
Venlafaxine is serotonin, the reuptake inhibitor of norepinephrine and Dopamine HCL, has 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 reports the method that one prepares 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin, the method is raw material catalytic hydrogenation preparation under catalyst rhodium-aluminium sesquioxide effect with 1-[cyano group (p-methoxyphenyl) methyl] hexalin, but catalyst rhodium is expensive. improper large-scale industrial production;
2, Chinese Journal of Pharmaceuticals 2004,35 (10) titles are report in the synthesis of VENLAFAXINE HCL to prepare 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin by red aluminium and nickelous chloride/POTASSIUM BOROHYDRIDE as raw material reductive agent reduction 1-[cyano group (p-methoxyphenyl) methyl] hexalin, the red aluminium of raw material and the nickelous chloride price comparison high flow rate amount of these two kinds of methods uses are larger, and aftertreatment produces a large amount of waste water.
3, CN1847219A title is " synthetic method of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin formate ", reports and uses Lithium Aluminium Hydride to reduce as reductive agent; CN101503365B title is that " preparation method of Venlafaxine intermediate 1-［ 2-amino-1-(4-p-methoxy-phenyl) ethyl ］ hexalin " to report under iodine catalysis with POTASSIUM BOROHYDRIDE or sodium borohydride is that raw material carries out reduction reaction, 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 be A process for the preparation of venlafaxine hydrochloride etc. mention 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 preparation method of the 1-of applicable suitability for industrialized production [2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin.
Technology contents of the present invention is: the preparation method of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin, it is characterized by and the hydroborate of Raney's nickel and metal is joined in reaction solvent, then 1-[cyano group (p-methoxyphenyl) methyl] hexalin is added, nitrogen replacement three times, hydrogen exchange three times, hydrogenation to 0.5 ~ 5Mpa, in 10 ~ 40 DEG C of reactions, detect 1-[cyano group (p-methoxyphenyl) methyl] hexalin without namely reacting end by HPLC; 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 20% ~ 200% of 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight, hydroborate consumption is 1% ~ 10% of 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight, solvent load be 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 is 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,
400 grams of methyl alcohol are added successively in 1L hydriding reactor, 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 about 5 hours, HPLC detects raw material 1-[cyano group (p-methoxyphenyl) methyl] hexalin without namely reacting complete, nitrogen replacement, feed liquid is through filtering, faint yellow dope and 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin 50 grams is obtained after concentrating under reduced pressure is dry, molar yield 98.4%, purity 97.8%.
Example 2
400 grams of ethanol are added successively in 1L hydriding reactor, 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 about 5 hours, HPLC detects raw material 1-[cyano group (p-methoxyphenyl) methyl] hexalin without namely reacting complete, nitrogen replacement, feed liquid is through filtering, faint yellow dope and 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin 50.5 grams is obtained after concentrating under reduced pressure is dry, molar yield 99.3%, purity 98.1%.
Claims (1)
1. the preparation method of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin, it is characterized by and the hydroborate of Raney's nickel and metal is joined in reaction solvent, then 1-[cyano group (p-methoxyphenyl) methyl] hexalin is added, 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] hexalin without namely reacting end by HPLC; 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 20% ~ 200% of 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight, hydroborate consumption is 1% ~ 10% of 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight, and solvent load is 4 ~ 20 times of 1-[cyano group (p-methoxyphenyl) methyl] hexalin weight.
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Citations (2)
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010046808A2 (en) * | 2008-10-21 | 2010-04-29 | Alembic Limited | A process for the preparation of venlafaxine hydrochloride |
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| 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 |
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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. |