CN101503365A - Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol - Google Patents
Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol Download PDFInfo
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- CN101503365A CN101503365A CNA2009100582694A CN200910058269A CN101503365A CN 101503365 A CN101503365 A CN 101503365A CN A2009100582694 A CNA2009100582694 A CN A2009100582694A CN 200910058269 A CN200910058269 A CN 200910058269A CN 101503365 A CN101503365 A CN 101503365A
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Abstract
The invention discloses a method for preparing venlafaxine intermediate 1, (2- amino-1-(4- methoxyphenyl) ethide cyclohexanol. The method is characterized in that 1- cyano-((4- methoxyphenyl) methyl) cyclohexanol is deacidized by sodium borohydride or potassium borohydride under the catalysis of elemental iodine to obtain the 1, (2- amino-1-(4- methoxyphenyl) ethide cyclohexanol. The method has the advantages of mild reaction condition, simple post treatment, high yield, good product purity and low cost, and is suitable for commercial process.
Description
Technical field:
The invention belongs to medical technical field, be specifically related to Venlafaxine intermediate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin.
Technical background:
Venlafaxine (Venlafaxine) is a kind of non-tricyclic antidepressant thing, and its chemical name is: 1-[2-dimethylin-1-(4-p-methoxy-phenyl) ethyl] the hexalin hydrochloride, structural formula is:
Venlafaxine produces antidepressant effect by the recovery that suppresses serotonin and norepinephrine, have rapid-action, the advantage that untoward reaction is few, it mainly acts on except being used for anti depressant therapy, also be used for the anti-obesity medicine and anti-manic, be overexcited, epilepsy etc.
At present, among the preparation method of Venlafaxine, overwhelming majority method relates to intermediate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin, this compound can be described as the key intermediate in the Venlafaxine preparation, and this intermediate mainly is to obtain by 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin reduction.But at present disclosedly obtain 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl by 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin reduction] in the method for hexalin, relate to expensive and dangerous original reagent or the reducing catalyst gone back, as: world patent WO0250017 uses dangerous inflammable Raney Ni to be catalyzer, Chinese patent CN1640867 is a reductive agent with expensive red aluminium, and world patent WO2008062138 uses expensive palladium and platinic compound as catalyzer; The aftertreatment difficulty, as Chinese patent CN1504456 is reductive agent with the lithium aluminum hydride, with the aluminum chloride is catalyzer, oxidation products that reductive agent must be produced after reaction finishes and excessive reductive agent and catalyzer hydrolysis, cause producing a large amount of aluminium hydroxide flockss, make that the separatory step in the aftertreatment is difficult and slow; Yield is low, as: in the U.S. Pat 2004181093 under the multiple condition yield of reduction reaction all have only 60～70%.These drawbacks make Venlafaxine be difficult to realize the scale operation of economical and efficient.
Summary of the invention:
In view of present Venlafaxine intermediate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] defective on the process for preparing cyclohexanol, the invention provides a kind of reaction conditions gentleness, aftertreatment is easy, the yield height, good product purity, with low cost, be fit to Venlafaxine intermediate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl of suitability for industrialized production] preparation method of hexalin.
The present invention is achieved by the following technical solutions:
Join sodium hydroxide or potassium hydroxide and sodium borohydride or POTASSIUM BOROHYDRIDE in the reaction soln successively, reaction soln is: tetrahydrofuran (THF), ether, isopropyl ether, glycol dimethyl ether, drips of solution with iodine is added in the reaction system subsequently, the temperature that drips is-10 ℃～0 ℃, then reactant 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin is joined in the reaction system, in-10 ℃～25 ℃ reactions 1～10 hour, back flow reaction 0.5～2 hour again obtains target product 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl after aftertreatment at last] hexalin, reaction formula is as follows:
Reaction conditions gentleness of the present invention, aftertreatment is easy, the yield height, good product purity with low cost, is fit to Venlafaxine intermediate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] suitability for industrialized production of hexalin.
Below by preparation 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] the invention will be further described for the embodiment of hexalin, it should be noted that reaction conditions and raw material purpose that following examples are related are the present invention is done better explanation, rather than limitation of the present invention.
Embodiment
Embodiment 1
1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin synthetic
200 milliliters of anhydrous tetrahydro furans are joined in 1000 milliliters of there-necked flasks that are equipped with magnetic stirring bar, reflux condensing tube and drying tube, add 50 gram sodium hydrate solids and sodium borohydride 40 grams, stir 30 minutes postcooling to-10 ℃, drip 300 milliliters of anhydrous tetrahydrofuran solutions of 100 gram iodine, the control rate of addition remains between-10 ℃～0 ℃ temperature of reaction, dropwise, keep this temperature range reaction 30 minutes.100 gram 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin are dissolved in 300 milliliters of anhydrous tetrahydro furans, be added drop-wise in the reaction solution, the control rate of addition remains between-10 ℃～0 ℃ temperature of reaction, dropwise, keep this temperature range reaction 1 hour, the postheating reaction system makes and refluxed 30 minutes.The cooling reaction solution is to room temperature, and most of solvent is removed in underpressure distillation, and slow Dropwise 5 N hydrochloric acid is 300 milliliters under stirring, add the back and stirred 1 hour, add 1300 milliliters of pure water, drip sodium carbonate solution to pH8～9, with ethyl acetate extraction 3 times, each 300 milliliters, combined ethyl acetate, use anhydrous sodium sulfate drying after washing 3 times, being evaporated to driedly, obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter, 93.6 grams, molar yield 92.1%
1H-NMR (CDCl
3): 1.38～1.73 (m, 10H); 2.02 (s, 1H); 2.35 (m, 2H); 2.86～3.01 (m, 2H); 3.15 (s, 1H); 3.73 (s, 3H); 6.69 (d, 2H); 7.04 (d, 2H), HPLC purity: 95.5%.
Embodiment 2
1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin synthetic
20 liters of anhydrous tetrahydro furans are joined in 100 liters of reactors of equipment reflux condensing tube and drying tube, add 5 kilograms of sodium hydrate solids and 4 kilograms of sodium borohydrides, stir 30 minutes postcooling to-10 ℃, drip 30 liters of anhydrous tetrahydrofuran solutions of 10 kilograms of iodine, the control rate of addition remains between-10 ℃～0 ℃ temperature of reaction, dropwise, keep this temperature range reaction 30 minutes.10 kilograms of 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin is dissolved in 30 liters of anhydrous tetrahydro furans, be added drop-wise in the reaction solution, the control rate of addition remains between-10 ℃～0 ℃ temperature of reaction, dropwise, keep this temperature range reaction 1 hour, the postheating reaction system makes and refluxed 30 minutes.The cooling reaction solution is to room temperature, most of solvent is removed in underpressure distillation, slow Dropwise 5 N hydrochloric acid is 30 liters under stirring, adding the back stirred 1 hour, change 500 liters of reactors over to, add 130 kilograms of pure water, drip sodium carbonate solution, use ethyl acetate extraction 3 times to pH8～9, each 30 liters, combined ethyl acetate is used anhydrous sodium sulfate drying after washing 3 times, is evaporated to dried, obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter, 9.44 kilogram, molar yield 92.9%, HPLC purity: 94.8%.
Embodiment 3
1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin synthetic
200 milliliters of anhydrous tetrahydro furans are joined in 1000 milliliters of there-necked flasks that are equipped with magnetic stirring bar, reflux condensing tube and drying tube, add 50 gram sodium hydrate solids and 55 gram POTASSIUM BOROHYDRIDE, stir 30 minutes postcooling to-10 ℃, drip 300 milliliters of anhydrous tetrahydrofuran solutions of 100 gram iodine, the control rate of addition remains between-10 ℃～0 ℃ temperature of reaction, dropwise, keep this temperature range reaction 30 minutes.100 gram 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin are dissolved in 300 milliliters of anhydrous tetrahydro furans, be added drop-wise in the reaction solution, the control rate of addition remains between 20 ℃～25 ℃ temperature of reaction, dropwise, keep this temperature range reaction 10 hours, the postheating reaction system makes and refluxed 2 hours.The cooling reaction solution is to room temperature, and most of solvent is removed in underpressure distillation, and slow Dropwise 5 N hydrochloric acid is 300 milliliters under stirring, add the back and stirred 1 hour, add 1300 milliliters of pure water, drip sodium carbonate solution to pH8～9, with ethyl acetate extraction 3 times, each 300 milliliters, combined ethyl acetate, use anhydrous sodium sulfate drying after washing 3 times, being evaporated to driedly, obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter, 87.1 grams, molar yield 85.7%
1H-NMR (CDCl
3): 1.35～1.69 (m, 10H); 2.01 (s, 1H); 2.29 (m, 2H); 2.82～2.94 (m, 2H); 3.09 (s, 1H); 3.71 (s, 3H); 6.64 (d, 2H); 7.03 (d, 2H), HPLC purity: 94.4%.
Embodiment 4
1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin synthetic
200 milliliters of anhydrous glycol dimethyl ethers are joined in 1000 milliliters of there-necked flasks that are equipped with magnetic stirring bar, reflux condensing tube and drying tube, add 50 gram sodium hydrate solids and sodium borohydride 40 grams, stir 30 minutes postcooling to-10 ℃, drip 300 milliliters of anhydrous ethylene glycol dimethyl ether solutions of 100 gram iodine, the control rate of addition remains between-10 ℃～0 ℃ temperature of reaction, dropwise, keep this temperature range reaction 30 minutes.In 100 gram 1-cyano group-[(4-p-methoxy-phenyl) methyl] 300 milliliters of anhydrous glycol dimethyl ethers of hexalin, be added drop-wise in the reaction solution, the control rate of addition remains between 0 ℃～5 ℃ temperature of reaction, dropwise, keep this temperature range reaction 6 hours, the postheating reaction system makes and refluxed 1 hour.The cooling reaction solution is to room temperature, and most of solvent is removed in underpressure distillation, and slow Dropwise 5 N hydrochloric acid is 300 milliliters under stirring, add the back and stirred 1 hour, add 1300 milliliters of pure water, drip sodium carbonate solution to pH8～9, with ethyl acetate extraction 3 times, each 300 milliliters, combined ethyl acetate, use anhydrous sodium sulfate drying after washing 3 times, being evaporated to driedly, obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter, 83.3 grams, molar yield 82.0%
1H-NMR (CDCl
3): 1.37～1.74 (m, 10H); 2.01 (s, 1H); 2.33 (m, 2H); 2.81～3.01 (m, 2H); 3.12 (s, 1H); 3.68 (s, 3H); 6.71 (d, 2H); 7.04 (d, 2H), HPLC purity: 92.3%.
Embodiment 5
1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin synthetic
200 milliliters of anhydrous glycol dimethyl ethers are joined in 1000 milliliters of there-necked flasks that are equipped with magnetic stirring bar, reflux condensing tube and drying tube, add 50 gram sodium hydrate solids and 55 gram POTASSIUM BOROHYDRIDE, stir 30 minutes postcooling to-10 ℃, drip 300 milliliters of anhydrous ethylene glycol dimethyl ether solutions of 100 gram iodine, the control rate of addition remains between-10 ℃～0 ℃ temperature of reaction, dropwise, keep this temperature range reaction 30 minutes.100 gram 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin are dissolved in 300 milliliters of anhydrous glycol dimethyl ethers, be added drop-wise in the reaction solution, the control rate of addition remains between 20 ℃～25 ℃ temperature of reaction, dropwise, keep this temperature range reaction 10 hours, the postheating reaction system makes and refluxed 2 hours.The cooling reaction solution is to room temperature, and most of solvent is removed in underpressure distillation, and slow Dropwise 5 N hydrochloric acid is 300 milliliters under stirring, add the back and stirred 1 hour, add 1300 milliliters of pure water, drip sodium carbonate solution to pH8～9, with ethyl acetate extraction 3 times, each 300 milliliters, combined ethyl acetate, use anhydrous sodium sulfate drying after washing 3 times, being evaporated to driedly, obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter, 82.0 grams, molar yield 80.7%
1H-NMR (CDCl
3): 1.36～1.69 (m, 10H); 2.02 (s, 1H); 2.30 (m, 2H); 2.82～2.92 (m, 2H); 3.11 (s, 1H); 3.72 (s, 3H); 6.63 (d, 2H); 7.03 (d, 2H), HPLC purity: 96.2%.
Claims (8)
1. Venlafaxine intermediate 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized in that under iodine catalysis, obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl with sodium borohydride or potassium borohydride reduction 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin] hexalin.
2. preparation according to claim 1 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized in that having added sodium hydroxide or potassium hydroxide in the reaction.
3. preparation according to claim 1 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized in that reaction solvent is: tetrahydrofuran (THF), ether, isopropyl ether, glycol dimethyl ether.
4. preparation according to claim 1 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized in that the temperature that the drips of solution with iodine is added in the reaction system is-10 ℃～0 ℃.
5. preparation according to claim 1 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized in that adding after 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin, react at-10 ℃～25 ℃.
6. preparation according to claim 1 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized in that adding after 1-cyano group-[(4-p-methoxy-phenyl) methyl] hexalin, is 1～10 hour in the time of-10 ℃～25 ℃ of reactions.
7. preparation according to claim 1 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, it is characterized in that the reflux temperature that temperature of reaction is risen to reaction system after-10 ℃～25 ℃ reaction for some time reacts.
8. preparation according to claim 1 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] preparation method of hexalin, the time that it is characterized in that back flow reaction is 0.5～2 hour.
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| CN2009100582694A CN101503365B (en) | 2009-02-04 | 2009-02-04 | Preparation of venlafaxine intermediate 1-[2-amino-1-(4-methoxy phenyl)ethyl] cyclohexanol |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177268A (en) * | 2014-09-22 | 2014-12-03 | 山东华生化学股份有限公司 | Preparation method of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol |
| CN111072505A (en) * | 2019-12-27 | 2020-04-28 | 合肥华方医药科技有限公司 | Preparation method of venlafaxine impurity |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1824815A2 (en) * | 2005-10-19 | 2007-08-29 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of highly pure 1-[2-dimethylamino-(4-methoxyphenyl) ethyl]cyclohexanol hydrochloride |
| CN100404497C (en) * | 2006-01-04 | 2008-07-23 | 四川大学 | Nitrile reducing process to prepare amine |
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2009
- 2009-02-04 CN CN2009100582694A patent/CN101503365B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104177268A (en) * | 2014-09-22 | 2014-12-03 | 山东华生化学股份有限公司 | Preparation method of 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol |
| CN104177268B (en) * | 2014-09-22 | 2015-10-28 | 山东华生化学股份有限公司 | A kind of preparation method of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin |
| CN111072505A (en) * | 2019-12-27 | 2020-04-28 | 合肥华方医药科技有限公司 | Preparation method of venlafaxine impurity |
| 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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