CN101503365B - 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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- CN101503365B CN101503365B CN2009100582694A CN200910058269A CN101503365B CN 101503365 B CN101503365 B CN 101503365B CN 2009100582694 A CN2009100582694 A CN 2009100582694A CN 200910058269 A CN200910058269 A CN 200910058269A CN 101503365 B CN101503365 B CN 101503365B
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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 the preparation method of Venlafaxine VEN midbody 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin.
Technical background:
Venlafaxine VEN (Venlafaxine) is a kind of non-tricyclic antidepressant thing, and its chemical name is: 1-[2-dimethylin-1-(4-p-methoxy-phenyl) ethyl] hexalin hydrochloride, and structural formula is:
Venlafaxine VEN produces antidepressant effect through the recovery that suppresses serotonin and sympathin; 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 obesity medicine and anti-manic, be overexcited, epilepsy etc.
At present; Among the preparation method of Venlafaxine VEN; Overwhelming majority method relates to midbody 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin; This compound can be described as the key intermediate in the Venlafaxine VEN preparation, and this midbody mainly is to obtain through 1-cyanic acid-[(4-p-methoxy-phenyl) methyl] hexalin reduction.But at present disclosed the reduction by 1-cyanic acid-[(4-p-methoxy-phenyl) methyl] hexalin obtains in the method for 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin; Relate to expensive with 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; Like Chinese patent CN1504456 is reductive agent with the lithium aluminum hydride; With the aluminum chloride is catalyzer; Must the oxidation products of reductive agent generation and excessive reductive agent and catalyzer hydrolysis be caused producing a large amount of white lake flockss after reaction finishes, 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 VEN be difficult to realize the scale operation of economical and efficient.
Summary of the invention:
In view of the defective on present Venlafaxine VEN midbody 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] process for preparing cyclohexanol; It is gentle to the invention provides a kind of reaction conditions; Aftertreatment is easy, and yield is high, good product purity; With low cost, the preparation method of Venlafaxine VEN midbody 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin of suitable suitability for industrialized production.
The present invention realizes through following technical scheme:
Sodium hydroxide or Pottasium Hydroxide and Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN are joined in the reaction soln successively, and reaction soln is: THF, ether; Isopropyl ether, glycol dimethyl ether, the drips of solution with iodine is added in the reaction system subsequently; The temperature that drips is-10 ℃～0 ℃; Then reactant 1-cyanic acid-[(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 more at last; After aftertreatment, obtain title product 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin, reaction formula is following:
Reaction conditions of the present invention is gentle, and aftertreatment is easy, and yield is high, and good product purity is with low cost, is fit to the suitability for industrialized production of Venlafaxine VEN midbody 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin.
Below the embodiment through preparation 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is described further the present invention; 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
Synthesizing of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin
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 Peng Qinghuana 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 TR reaction 30 minutes.100 gram 1-cyanic acid-[(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 TR reaction 1 hour, the postheating reaction system makes and refluxed 30 minutes.Cooling reaction liquid 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, and adds the back and stirs 1 hour; Add 1300 milliliters of pure water, drip sodium carbonate solution to pH 8～9, with ethyl acetate extraction 3 times, each 300 milliliters; Combined ethyl acetate is used anhydrous sodium sulfate drying after washing 3 times, is evaporated to driedly, and obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter; 93.6 gram, 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
Synthesizing of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin
20 liters of anhydrous tetrahydro furans are joined in 100 liters of reaction kettles of equipment reflux condensing tube and drying tube; Add 5 kilograms of sodium hydrate solids and 4 kilograms of Peng Qinghuanas; 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 TR reaction 30 minutes.10 kilograms of 1-cyanic acid-[(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 TR reaction 1 hour, the postheating reaction system makes and refluxed 30 minutes.Cooling reaction liquid is to room temperature, and most of solvent is removed in underpressure distillation, and slow Dropwise 5 N hydrochloric acid is 30 liters under stirring, and adds the back and stirs 1 hour; Change 500 liters of reaction kettles over to, add 130 kilograms of pure water, drip sodium carbonate solution to pH 8～9; With ethyl acetate extraction 3 times, each 30 liters, combined ethyl acetate; Use anhydrous sodium sulfate drying after washing 3 times, be evaporated to driedly, 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
Synthesizing of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin
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 97MINs; 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 TR reaction 30 minutes.100 gram 1-cyanic acid-[(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 TR reaction 10 hours, the postheating reaction system makes and refluxed 2 hours.Cooling reaction liquid 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, and adds the back and stirs 1 hour; Add 1300 milliliters of pure water, drip sodium carbonate solution to pH 8～9, with ethyl acetate extraction 3 times, each 300 milliliters; Combined ethyl acetate is used anhydrous sodium sulfate drying after washing 3 times, is evaporated to driedly, and obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter; 87.1 gram, 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
Synthesizing of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin
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 Peng Qinghuana 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 TR reaction 30 minutes.In 100 gram 1-cyanic acid-[(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 TR reaction 6 hours, the postheating reaction system makes and refluxed 1 hour.Cooling reaction liquid 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, and adds the back and stirs 1 hour; Add 1300 milliliters of pure water, drip sodium carbonate solution to pH 8～9, with ethyl acetate extraction 3 times, each 300 milliliters; Combined ethyl acetate is used anhydrous sodium sulfate drying after washing 3 times, is evaporated to driedly, and obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter; 83.3 gram, 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
Synthesizing of 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin
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 97MINs; 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 TR reaction 30 minutes.100 gram 1-cyanic acid-[(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 TR reaction 10 hours, the postheating reaction system makes and refluxed 2 hours.Cooling reaction liquid 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, and adds the back and stirs 1 hour; Add 1300 milliliters of pure water, drip sodium carbonate solution to pH 8～9, with ethyl acetate extraction 3 times, each 300 milliliters; Combined ethyl acetate is used anhydrous sodium sulfate drying after washing 3 times, is evaporated to driedly, and obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is light yellow thickness oily matter; 82.0 gram, 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 (7)
1. the preparation method of Venlafaxine VEN midbody 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is characterized in that under iodine catalysis, obtaining 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin with Peng Qinghuana or potassium borohydride reduction 1-cyanic acid-[(4-p-methoxy-phenyl) methyl] hexalin.
2. the preparation method of preparation 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin according to claim 1 is characterized in that having added sodium hydroxide or Pottasium Hydroxide in the reaction.
3. the preparation method of preparation 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin according to claim 1 is characterized in that reaction solvent is: THF, ether, isopropyl ether or glycol dimethyl ether.
4. the preparation method of preparation according to claim 1 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin is characterized in that the temperature that the drips of solution with iodine is added in the reaction system is-10 ℃～0 ℃.
5. the preparation method of preparation 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin according to claim 1 is characterized in that adding after 1-cyanic acid-[(4-p-methoxy-phenyl) methyl] hexalin, reacts at-10 ℃～25 ℃.
6. the preparation method of preparation 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin according to claim 1; It is characterized in that adding after 1-cyanic acid-[(4-p-methoxy-phenyl) methyl] hexalin, is 1～10 hour in the time of-10 ℃～25 ℃ of reactions.
7. the preparation method of preparation 1-[2-amino-1-(4-p-methoxy-phenyl) ethyl] hexalin according to claim 1; It is characterized in that adding after 1-cyanic acid-[(4-p-methoxy-phenyl) methyl] hexalin;-10 ℃～25 ℃ reactions 1～10 hour, back flow reaction 0.5～2 hour more at last.
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| 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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| 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 |
| WO2007047972A2 (en) * | 2005-10-19 | 2007-04-26 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of highly pure 1-[2-dimethylamino-(4-methoxyphenyl) ethyl]cyclohexanol hydrochloride |
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| WO2007047972A2 (en) * | 2005-10-19 | 2007-04-26 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of highly pure 1-[2-dimethylamino-(4-methoxyphenyl) ethyl]cyclohexanol hydrochloride |
| CN1810766A (en) * | 2006-01-04 | 2006-08-02 | 四川大学 | Nitrile reducing process to prepare amine |
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