CN103113243A - Synthetic method of 2-(7-methoxyl-1-naphthyl) ethylamine hydrochloride - Google Patents
Synthetic method of 2-(7-methoxyl-1-naphthyl) ethylamine hydrochloride Download PDFInfo
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- CN103113243A CN103113243A CN2013100743565A CN201310074356A CN103113243A CN 103113243 A CN103113243 A CN 103113243A CN 2013100743565 A CN2013100743565 A CN 2013100743565A CN 201310074356 A CN201310074356 A CN 201310074356A CN 103113243 A CN103113243 A CN 103113243A
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Abstract
The invention relates to a synthetic method of 2-(7-methoxyl-1-naphthyl) ethylamine hydrochloride. The method comprises the following steps of: reacting 7-methoxyl-1-naphthyl (a compound IV) with cyanoacetic acid to prepare (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile (a compound III); performing deep drawing quality (DDQ) dehydrogenation to prepare (7-methoxyl-1-naphthyl) acetonitrile; using sodium borohydride as a reducing agent and reacting sodium borohydride with calcium chloride in anhydrous tetrahydrofuran to react to obtain 2-(7-methoxyl-1-naphthyl) ethylamine; and satisfying with hydrochloric acid to obtain a compound I, wherein the compound is an important intermediate of synthetic agomelatine.
Description
Technical field
The present invention relates to a kind of 2-(7-methoxy-1-naphthyl) synthetic method of ethylamine hydrochloride, belong to technical field of medicine synthesis.
Background technology
Dysthymia disorders (Depression, DEP) is the common a kind of mood disorder of psychiatric department, and is low as main clinical characteristics take remarkable and lasting mental state, and mental state is low unbecoming with its situation.Mainly comprise clinically: the depression that dysthymia disorders (major depression), dysthymia, brain or physical disease Patients with Depression, psychoactive drug substance or non-habituation material caused by mental disorder occur together and post-schizophrenic depression etc.Its clinical manifestation is that depressed, bradyphrenia, speech action reduce, and work is lost interest etc.Maniac access appears at least 10% patients with depression afterwards different times, and should be diagnosed as the two-phase obstacle this moment.Dysthymia disorders has become global main spirits hygienic issues so far, is the harm universe's common disease, frequently-occurring disease, brings huge loss for individual, family and society.
Agomelatine is biological (electronics) isostere analogue of the naphthalene of melatonin, and it has replaced indole ring with naphthalene nuclear, makes it have more metabolic stability than melatonin.Agomelatine is selectivity and the specific agonist of a hypothalamus melatonin receptors, it is active to have again simultaneously weak 5-HT acceptor competitive antagonism concurrently, shows the novel pharmacological characteristics of a kind of MASSA (melatonin agonist and selectivity 5-HT antagonist).
A large amount of clinical trials show that Agomelatine is the novel effective thymoleptic that unique mechanism is arranged, and tolerance is good, and adverse reaction rate is lower.In clinical trial, surpass the treatment that 3900 routine patients with depression are accepted Agomelatine.It is slighter that untoward reaction usually occurs in two all symptoms for the treatment of.Agomelatine is used for adult's severe depression determined curative effect, and security is better than other thymoleptic, can not cause the clinical correlation body weight to increase, and has lower sexual dysfunction and the gastrointestinal reaction incidence of causing, and can not occur the symptom bounce-back after the drug withdrawal.In addition, clinical trial proof Agomelatine is improved the effect of sleep quality and shortening time for falling asleep.Therefore developing Agomelatine will have good social effect and economic benefit.
Agomelatine
Compound I is the Agomelatine important intermediate, the synthetic method of patent EP0447285 report: 7-methoxyl group-1-tetralone and ethyl bromoacetate reaction, sulphur dehydroaromatizationof make 7-methoxy-1-naphthyl ethyl acetate, through hydrolysis, chloride, ammonification, dehydration, reduction, obtain Compound I again.This method reactions steps is many, and has polystep reaction unstable, severe reaction conditions, and cost is high, does not meet industrial requirement.The used ethyl bromoacetate pungency of the first step is large, is unfavorable for labour protection, and solvent is benzene, and toxicity is large, easily causes environmental pollution.
The synthetic method of patent EP156420 report is as follows:
7-methoxyl group-1-tetralone and cyanoacetic acid reaction make (7-methoxyl group-3,4-dihydro-1-naphthyl) acetonitrile is then take allyl methacrylate(AMA) as Hydrogen acceptor, take Pd/C as catalyzer, make (7-methoxy-1-naphthyl) acetonitrile in reflux in toluene, again through reducing to get Compound I.When preparing (7-methoxy-1-naphthyl) acetonitrile in the method, used poisonous allyl methacrylate(AMA) to be dehydrogenating agent, easily caused environmental pollution, and it is extremely low to go on foot reaction yield.
The synthetic method of patent US20050182276 report is as follows: 7-methoxyl group-1-tetralone and cyanoacetic acid reaction make (7-methoxyl group-3,4-dihydro-1-naphthyl) acetonitrile, then carry at allyl methacrylate(AMA) and carbon that back flow reaction makes (7-methoxy-1-naphthyl) acetonitrile in the situation that palladium exists, (7-methoxy-1-naphthyl) acetonitrile hydro-reduction under the normal atmosphere of 30bar makes Compound I.This method is at preparation 2-(7-methoxy-1-naphthyl) during ethamine, hydro-reduction pressure is difficult to realize suitability for industrialized production up to 300 normal atmosphere.
Based on the pharmacy value of Agomelatine and good market outlook, comprehensive above several method, we have found a kind of good yield, the synthetic method of Compound I simple to operate.
Summary of the invention
The purpose of this invention is to provide a kind of simple to operately, yield is good, easily the synthetic method of the important intermediate of the Agomelatine of industrialization promotion.
This patent provides the preparation method of Compound I, may further comprise the steps:
I
A. 7-methoxyl group-1-tetralone (compound IV) makes (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile (compound III) with the cyanoacetic acid reaction
B. (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile makes (7-methoxy-1-naphthyl) acetonitrile through the DDQ dehydrogenation
C. (7-methoxy-1-naphthyl) acetonitrile is again take sodium borohydride as reductive agent, reacts in anhydrous tetrahydro furan with calcium chloride to obtain the 2-(7-methoxy-1-naphthyl) ethamine
D. filter, after filtrate is spin-dried for rear adding acetic acid ethyl dissolution, adds concentrated hydrochloric acid and transfer pH=2-3.
E. temperature control is separated out solid, and filtration drying obtains highly purified 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride (Compound I)
The invention provides the preparation method of Compound I, the Compound I I that step a obtains need not to be further purified, and is directly used in next step, can greatly reduce labour intensity, saves cost.
The invention provides the preparation method of Compound I, step c sodium borohydride is reductive agent, and reaction conditions is gentle, and is simple to operate.
The present invention also further provides the preparation method of Compound I, and wherein the mol ratio of Compound I I and sodium borohydride is 1:1.5-3, preferred 1:2.
The present invention also further provides the preparation method of Compound I, and wherein the mol ratio of sodium borohydride and calcium chloride is 1:1-5, preferred 1:1.
The present invention also further provides the preparation method of Compound I, and selected solvent is non-protonic solvent, preferred tetrahydrofuran (THF).
The present invention also further provides the preparation method of Compound I, it is characterized in that the steps d aftertreatment is simple, is fit to suitability for industrialized production.
The present invention also further provides the preparation method of Compound I, it is characterized in that step e, and recrystallization temperature is controlled at 0-10 ℃, preferred 5-7 ℃.
Step of the present invention is succinct, has avoided the severe condition such as toxic reagent, high pressure such as use allyl methacrylate(AMA).Reaction yield is high, and products obtained therefrom need not to be further purified, and easy-to-operate is beneficial to industrialization promotion.
Embodiment
Following embodiment is to describe in detail the present invention, and unrestricted the present invention.
Embodiment 1:(7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile is synthetic
Under the room temperature, successively 7-methoxyl group naphthane-1-ketone 176 g, cyanoacetic acid 128 g, toluene 1600 ml, benzylamine 27 g, enanthic acid 33 g are dropped in the 2L reaction flask, open and stir, heating, 114 ℃ of about 16h of reflux water-dividing, treat that the substrate total overall reaction disappears, stopped heating, naturally be cooled to room temperature after, ice-water bath is cooled to below 10 ℃ and separates out faint yellow solid, filter the filter cake toluene wash.Filtrate is washed with 500ml, 2mol/L sodium hydroxide solution, tell the toluene phase, again with 500ml purified water washing toluene phase, separatory, use again at last 500ml saturated common salt water washing toluene phase, separatory, toluene is evaporated under 70-75 ℃ dried, the residue brown oil be directly used in next step.
Embodiment 2:(7-methoxy-1-naphthyl) acetonitrile is synthetic
Under the room temperature, (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile 100 g are dissolved in the 500ml methylene dichloride, solution becomes sorrel.Successively DDQ 125 g, 1000ml methylene dichloride are added in the 2L reaction flask, the dichloromethane solution of 25-28 ℃ of lower dropping intermediate I of temperature is stirred, heats, controls in unlatching, drips to finish in 30 ± 2 ℃ to be incubated 1 hour.Insulation is finished, and filters, and filtrate is used 500ml saturated sodium bicarbonate solution repeated washing 3 times, tells dichloromethane layer, again uses the 500ml water washing, separatory; Use at last 500ml saturated common salt water washing methylene dichloride phase, separatory.Methylene dichloride is evaporated to dried under 30-35 ℃, and the residue yellow oil adds ethanol 260ml dissolving, and the ice-water bath crystallization that cools filters, and filter cake is off-white color, and 50 ℃ of lower oven dry 2 hours namely get (7-methoxy-1-naphthyl) acetonitrile.
Embodiment 3:2-(7-methoxy-1-naphthyl) ethylamine hydrochloride is synthetic
Under the room temperature, (7-methoxy-1-naphthyl) acetonitrile 80 g are dissolved in the 800 ml anhydrous tetrahydro furans, add calcium chloride 90 g, temperature control 0-5 ℃, add sodium borohydride 31 g in batches, finish, rise to room temperature reaction 5h.Filtration is finished in reaction, filtrate is evaporated to dried under 50 ℃, the residue yellow oil, add ethyl acetate 320ml dissolving, heat filtering adds the about 30ml of hydrochloric acid and transfers pH=2-3, the cooling crystallization, 10 ℃ of lower 1-2h that stir filter, and 50 ℃ of lower oven dry of filter cake namely get the 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride.
Claims (8)
1. the 2-(7-methoxy-1-naphthyl) preparation method of ethylamine hydrochloride (Compound I), its feature may further comprise the steps:
I
A.7-methoxyl group-1-tetralone (compound IV) makes (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile (compound III) with the cyanoacetic acid reaction
B. (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile makes (7-methoxy-1-naphthyl) acetonitrile through the DDQ dehydrogenation
The c.(7-methoxy-1-naphthyl) acetonitrile (Compound I I) is again take sodium borohydride as reductive agent, reacts in anhydrous tetrahydro furan with calcium chloride to obtain the 2-(7-methoxy-1-naphthyl) ethamine
D. filter, after filtrate is spin-dried for rear adding acetic acid ethyl dissolution, adds concentrated hydrochloric acid and transfer pH=2-3.
E. temperature control is separated out solid, and filtration drying obtains highly purified 2-(7-methoxy-1-naphthyl) ethylamine hydrochloride (Compound I).
2. a kind of 2-(7-methoxy-1-naphthyl according to claim 1) preparation method of ethylamine hydrochloride (Compound I), the compound III that it is characterized in that step a gained need not purifying, reaction solution is through after simply extracting, and organic phase directly is spin-dried for, and is used for next step dehydrogenation reaction.
3. a kind of 2-(7-methoxy-1-naphthyl according to claim 1) preparation method of ethylamine hydrochloride (Compound I) is characterized in that step c sodium borohydride is reductive agent, and reaction conditions is gentle.
4. a kind of 2-(7-methoxy-1-naphthyl according to claim 1) preparation method of ethylamine hydrochloride (Compound I), the mol ratio that it is characterized in that step c Compound I I and sodium borohydride is 1:1.5-3, preferred 1:2.
5. a kind of 2-(7-methoxy-1-naphthyl according to claim 1) preparation method of ethylamine hydrochloride (Compound I), the mol ratio that it is characterized in that step c sodium borohydride and calcium chloride is 1:1-5, preferred 1:1.
6. a kind of 2-(7-methoxy-1-naphthyl according to claim 1) preparation method of ethylamine hydrochloride (Compound I) is characterized in that step c selects non-protonic solvent, preferred tetrahydrofuran (THF).
7. a kind of 2-(7-methoxy-1-naphthyl according to claim 1) preparation method of ethylamine hydrochloride (Compound I) is characterized in that the steps d aftertreatment is simple, is fit to suitability for industrialized production.
8. a kind of 2-(7-methoxy-1-naphthyl according to claim 1) preparation method of ethylamine hydrochloride (Compound I) is characterized in that step e, and recrystallization temperature is controlled at 0-10 ℃, preferred 5-7 ℃.
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Cited By (4)
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|---|---|---|---|---|
| CN104230754A (en) * | 2014-09-17 | 2014-12-24 | 浙江科技学院 | Synthetic method for 7-methoxy-1-naphthylacetonitrile |
| CN104230754B (en) * | 2014-09-17 | 2017-01-04 | 浙江科技学院 | A kind of synthetic method of (7-methoxy-1-naphthyl) acetonitrile |
| CN107353229A (en) * | 2017-08-08 | 2017-11-17 | 许昌恒生制药有限公司 | A kind of preparation method of agomelatine intermediate body |
| CN112574066A (en) * | 2019-09-27 | 2021-03-30 | 江苏豪森药业集团有限公司 | Preparation method of agomelatine intermediate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230754A (en) * | 2014-09-17 | 2014-12-24 | 浙江科技学院 | Synthetic method for 7-methoxy-1-naphthylacetonitrile |
| CN104230754B (en) * | 2014-09-17 | 2017-01-04 | 浙江科技学院 | A kind of synthetic method of (7-methoxy-1-naphthyl) acetonitrile |
| CN107353229A (en) * | 2017-08-08 | 2017-11-17 | 许昌恒生制药有限公司 | A kind of preparation method of agomelatine intermediate body |
| CN112574066A (en) * | 2019-09-27 | 2021-03-30 | 江苏豪森药业集团有限公司 | Preparation method of agomelatine intermediate |
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Application publication date: 20130522 |