CN104230754A - Synthetic method for 7-methoxy-1-naphthylacetonitrile - Google Patents
Synthetic method for 7-methoxy-1-naphthylacetonitrile Download PDFInfo
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Abstract
The invention discloses a synthetic method for 7-methoxy-1-naphthylacetonitrile. By means of the method, 7-methoxy-1-tetralone is taken as the main starting material and subjected to a dehydration cyanation reaction and a dehydrogenation aromatization reaction sequentially for preparation, wherein the dehydration cyanation adopts single amine catalyst; the same reaction solvent is adopted in the dehydration cyanation reaction and the dehydrogenation aromatization reaction, a one-pot method reaction process is adopted for direct preparation, an intermediate product of the dehydration cyanation reaction is not required to be subjected to separation and purification treatment, and a produced solution of the dehydration cyanation reaction is directly applied to the dehydrogenation aromatization reaction. The final product yield is increased and the product quality is improved by increasing the reaction temperature and optimizing the technical conditions; and the synthetic method has the advantages that the reaction conditions is mild, the technical operation is simple and convenient, and the total yield can reach 97%.
Description
Technical field
The present invention relates to a kind of chemical preparation process, specifically, is a kind of new preparation process of (7-methoxy-1-naphthyl) acetonitrile.
Background technology
(7-methoxy-1-naphthyl) acetonitrile, No. CAS is [138113-08-3], and molecular formula is as follows.
(7-methoxy-1-naphthyl) acetonitrile is the key intermediate of synthesis Agomelatine.Agomelatine (agomelatine), chemistry N-[2-(7-methoxy-1-naphthyl) ethyl] ethanamide by name, trade(brand)name Valdoxan is a kind of melatonin agonists, has antagonism 5HT concurrently
2C, it is first melatonin class thymoleptic, can effectively Cure of depression, improving water flood parameter and retentivity function.
(7-methoxy-1-naphthyl) acetonitrile synthetic method is generally divided into following a few class:
Synthetic Communications (31 (4), 621-629; 2001) report with 7-methoxyl group naphthane-1-ketone as raw material, first occur to replace with acetonitrile under butyllithium effect and occur, further by 2, under chloro-5,6-dicyan para benzoquinone (DDQ) dehydrogenation reactions of 3-bis-and acid catalysis, dehydration reaction prepares (7-methoxy-1-naphthyl) acetonitrile.Overall yield of reaction is 76%.But reaction raw materials used is as comparatively dangerous in butyllithium, is unfavorable for industrialization.
Archiv der Pharmazie (Weinheim, Germany) (326 (2), 119-20; 1993) report with 7-methoxynaphthalene-1-acetic acid for raw material, eliminate obtained (7-methoxy-1-naphthyl) acetonitrile through chloride, ammonification, dehydration.Total recovery is 79%.But the more difficult acquisition of this route Raw.
EP0447285 reports and Reformatsky is occurred for 7-methoxyl group naphthane-1-ketone and ethyl bromoacetate reacts, and then by obtained (7-methoxy-1-naphthyl) ethyl acetate of sulphur dehydroaromatizationof, then eliminate obtained (7-methoxy-1-naphthyl) acetonitrile through hydrolysis, chloride, ammonification, dehydration.Reaction scheme reaches 6 steps, and total recovery is lower, only has 30%.
WO2009053545 reports with 7-methoxynaphthalene-1-formic acid as raw material, first 7-methoxynaphthalene-1-methyl alcohol is reduced into through BH3, further with sulfur oxychloride generation chlorination, there is substitution reaction and generate (7-methoxy-1-naphthyl) acetonitrile in last and KCN.Reaction raw materials is comparatively active, dangerous, is unfavorable for industrialization.Overall yield of reaction is 76%.
EP1564202 reports with 7-methoxyl group naphthane-1-ketone as raw material, first obtained (7-methoxyl group-3 is reacted with cyanoacetic acid, 4-dihydro-1-naphthyl) acetonitrile, then be Hydrogen acceptor with allyl methacrylate(AMA), take Pd/C as catalyzer, at obtained (7-methoxy-1-naphthyl) acetonitrile of reflux in toluene.Overall yield of reaction is 82%.Allyl methacrylate(AMA) and Pd/C cost intensive in this route, yield is medium, is unfavorable for industrialization.
People's (Chinese Journal of Pharmaceuticals such as man of Tang Deng, 2008,39 (3): 161-162) report with 7-methoxyl group naphthane-1-ketone as raw material, first (7-methoxyl group-3 is obtained with cyanoacetic acid in reflux in toluene dehydration reaction, 4-dihydro-1-naphthyl) acetonitrile, reflux water-dividing 24h, be cooled to room temperature, reaction solution is successively with the washing of 2mol/L sodium hydroxide solution, water and saturated brine, with anhydrous magnesium sulfate drying, filter, then filtrate steamed and obtained oily intermediate product except after toluene.Again chloro-for 2,3-bis-5,6-dicyan para benzoquinone (DDQ) are dissolved in methylene dichloride, the dichloromethane solution of above-mentioned oily intermediate product is dripped at 20 DEG C, drip complete insulated and stirred lh, reacting liquid filtering, filtrate is successively with the washing of saturated sodium bicarbonate solution, water and saturated brine, with anhydrous magnesium sulfate drying, filter, filtrate steaming removal solvent methylene dichloride, residuum ethanol: water (5:3) recrystallization, dry, obtain pale powder (7-methoxy-1-naphthyl) acetonitrile.Overall yield of reaction is 91%.Operate comparatively loaded down with trivial details in this route, and have employed different reaction solvents in two-step reaction, intermediate product needs separation, precipitation, and gained oily intermediate product impurity is many, and color is dark, makes final product shade and quality deviation.Solvent for use methylene dichloride toxicity is large, boiling point is low, and environment friendly difference is also difficult to reclaim.
Patent of invention CN101723855B: a kind of synthetic method of (7-methoxy-1-naphthyl) acetonitrile.This patent have employed with 7-methoxyl group naphthane-1-ketone for predominant starting material, makes (7-methoxy-1-naphthyl) acetonitrile successively through dehydration acetonitrile, dehydrogenation and aromatization.In second of dewatering in this patent cyanation and people's (Chinese Journal of Pharmaceuticals such as man of Tang Deng, 2008,39 (3): 161-162) all have employed enanthic acid and benzylamine acting in conjunction in dehydration second cyanation, in a salt form as catalyzer, promote that cyanoacetic acid and 7-methoxyl group naphthane-1-ketone carry out dehydration reaction.Because catalyzer is in a salt form as catalyzer, when being reacted by reflux dewatering in reaction, there is catalyzer and constantly taken out of reaction system, need constantly to add catalyzer, and cause the transformation efficiency of product to decline, the reaction times extends, and yield reduces.
To sum up, all there is various defect in existing various synthetic method, or yield is lower, or raw material not easily obtains, or raw materials used too danger is unfavorable for industrial production, or raw materials cost costly, or operating procedure is loaded down with trivial details, the defects such as solvent for use toxicity is large, boiling point is low, and quality product is poor.Existing technological line all needs to improve in environment friendly and cost.
Summary of the invention
The present invention, just for the various weak points existed in prior art, provides a kind of preparation method of simple to operate, (7-methoxy-1-naphthyl) acetonitrile that cost is low.
The present invention, for achieving the above object, is realized by such technical scheme:
The invention discloses the synthetic method of one (7-methoxy-1-naphthyl) acetonitrile, with 7-methoxyl group naphthane-1-ketone for predominant starting material, make through dehydration acetonitrile, dehydrogenation and aromatization successively, chemical equation is as follows:
Single amines catalyst is adopted in dehydration acetonitrile; Same reaction solvent is adopted in the reaction of dehydration acetonitrile and dehydroaromatizationof, one pot reaction technique is adopted directly to prepare, without the need to carrying out separation and purification treatment to the intermediate product of dehydration second cyanation, directly dehydration acetonitrile reaction product solution is used for dehydrogenation and aromatization.
As improving further, the concrete preparation process of synthetic method of the present invention is as follows:
(1) dewater acetonitrile: 7-methoxyl group naphthane-1-ketone carries out dehydration second cyanation with cyanoacetic acid under single amines catalyst catalysis, temperature of reaction is reflux temperature, reaction times 3 ~ 20h, (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile solution is obtained after cooling;
(2) dehydroaromatizationof: by product (the 7-methoxyl group-3 of gained in step (1), 4-dihydro-1-naphthyl) acetonitrile solution and 2,3-bis-chloro-5,6-dicyan para benzoquinone carries out reaction dehydrogenation, adopt and same reaction solvent in reactions steps (1), temperature of reaction is 30-80 DEG C, and the reaction times is 0.5 ~ 2h; Reacting liquid filtering, filtrate carries out alkali cleaning, saturated common salt water washing successively, and after removing solvent under reduced pressure, residuum ethanol: water recrystallization, obtains (7-methoxy-1-naphthyl) acetonitrile.
As improving further, ethanol of the present invention: the volume ratio of water is V/V=3:7 ~ 7:3.
As improving further, amines catalyst of the present invention is one or more mixtures of benzylamine, O-Phenylene Diamine, mphenylenediamine or Ursol D.
As improving further, same reaction solvent of the present invention is benzene or toluene.
As improving further, in dehydration second cyanation of the present invention, 7-methoxyl group naphthane-1-ketone: cyanoacetic acid: amines catalyst: the weight ratio of reaction solvent is: 1:0.58 ~ 1.21:0.05 ~ 0.30:5.23 ~ 10.45.
Synthetic method of the present invention is with 7-methoxyl group naphthane-1-ketone for predominant starting material, makes successively, adopt same reaction solvent through dehydration acetonitrile, dehydrogenation and aromatization, and two-step reaction step adopts one kettle way technique directly to prepare.The catalyzer adopted in reactions steps (1) is single amines catalyst, catalytic effect and good reaction selectivity, not easily reaction system is taken in distillation out of, without the need to adding, thus significantly reduce the usage quantity of catalyzer and use kind, not only reduce production cost, and simplify technological operation step.The catalyzer adopted in reactions steps (1) is single amines catalyst, due to catalytic effect and good reaction selectivity, is significantly shortened in the reaction times, shortens to 3-20h, significantly reduce energy consumption from original 40h.Simultaneously because the reaction times shortens, decrease side reaction, improve product yield, reduce cost.The use of this catalyzer substantially increases the space-time yield of this technique, improves production efficiency, reduces production cost, improves quality product.
Reactions steps (1) adopts benzene or toluene as reaction solvent, and after reflux water-dividing has reacted, cooling obtains (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile solution, directly carries out second step reaction, without the need to separation and purification intermediate product.The literature method comparing man of Tang Deng report decreases operation steps, improves production efficiency, and steams owing to decreasing high temperature the process desolventized, decrease the introducing of impurity, improve quality product.In reactions steps (2), still adopt the solvent of previous step as reaction solvent, avoid the use of the height lower boiling solvent of poison (as methylene dichloride, chloroform class) used in bibliographical information.And underpressure distillation reclaim the reaction solvent obtained still can be used for the first step reaction in.In reactions steps (2), by improving temperature of reaction, Optimizing Technical, improves the finished product yield, improves quality product.Use synthetic method of the present invention, reaction conditions is gentle, and technological operation is simple and convenient, and total recovery can reach 97%.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but scope of the present invention is not limited to embodiment.
Embodiment 1
(1) dewater acetonitrile: 7-methoxyl group naphthane-1-ketone 100kg, cyanoacetic acid 100kg, benzylamine 10kg, toluene 600kg are put in 1000L reactor.Be warmed up to 116 DEG C of backflows, back flow reaction divides water 8h.(7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile solution is obtained after cooling.
(2) DDQ of dehydroaromatizationof: 150kg is dissolved in 200kg toluene solution, is added drop-wise to by this solution in the reaction solution obtained in step (1), temperature of reaction 50 DEG C, stirring reaction 0.5h.Reacting liquid filtering, filtrate is again through alkali cleaning, saturated common salt washing.After underpressure distillation is steamed and desolventized, residuum is through ethanol: water (V/V=7:3) recrystallization obtains 108.5kg white to pale yellow crystals solid (7-methoxy-1-naphthyl) acetonitrile, yield 97%.Measure fusing point 81.8-83 DEG C.
Embodiment 2
(1) dewater acetonitrile: 7-methoxyl group naphthane-1-ketone 200kg, cyanoacetic acid 150kg, benzylamine 10kg, benzene 1500kg are put in 3000L reactor.Be warmed up to 86 DEG C of backflows, back flow reaction divides water 20h.(7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile solution is obtained after cooling.
(2) DDQ of dehydroaromatizationof: 270kg is dissolved in 400kg benzole soln, is added drop-wise to by this solution in the reaction solution obtained in step (1), temperature of reaction 30 DEG C, reaction times 2.0h.Reacting liquid filtering, filtrate is again through alkali cleaning, saturated common salt washing.After underpressure distillation is steamed and desolventized, residuum is through ethanol: water (V/V=5:5) recrystallization obtains 208kg white to pale yellow crystals solid (7-methoxy-1-naphthyl) acetonitrile, yield 93%.Measure fusing point 82.5-83.4 DEG C.
Embodiment 3
(1) dewater acetonitrile: 7-methoxyl group naphthane-1-ketone 250kg, cyanoacetic acid 300kg, benzylamine 75kg, toluene 2000kg are put in 3000L reactor.Be warmed up to 115 DEG C of backflows, back flow reaction divides water 3h.(7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile solution is obtained after cooling.
(2) DDQ of dehydroaromatizationof: 350kg is dissolved in 550kg toluene solution, is added drop-wise to by this solution in the reaction solution obtained in step (1), temperature of reaction 80 DEG C, reaction times 0.5h.Reacting liquid filtering, filtrate is again through alkali cleaning, saturated common salt washing.After underpressure distillation is steamed and desolventized, residuum is through ethanol: water (V/V=3:7) recrystallization obtains 251kg white to pale yellow crystals solid (7-methoxy-1-naphthyl) acetonitrile, yield 90%.Measure fusing point 81-83 DEG C.
Finally, it is also to be noted that enumerate above be only specific embodiments of the invention son.Obviously, the invention is not restricted to above examples of implementation, many distortion can also be had.All distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.
Claims (6)
1. the synthetic method of (7-methoxy-1-naphthyl) acetonitrile, with 7-methoxyl group naphthane-1-ketone for predominant starting material, make through dehydration acetonitrile, dehydrogenation and aromatization successively, chemical equation is as follows:
it is characterized in that, in described dehydration acetonitrile, adopt single amines catalyst; Same reaction solvent is adopted in the reaction of dehydration acetonitrile and dehydroaromatizationof, one pot reaction technique is adopted directly to prepare, without the need to carrying out separation and purification treatment to the intermediate product of dehydration second cyanation, directly dehydration acetonitrile reaction product solution is used for dehydrogenation and aromatization.
2. the synthetic method of (7-methoxy-1-naphthyl) acetonitrile according to claim 1, it is characterized in that, the concrete preparation process of described synthetic method is as follows:
(1) dewater acetonitrile: 7-methoxyl group naphthane-1-ketone carries out dehydration second cyanation with cyanoacetic acid under single amines catalyst catalysis, temperature of reaction is reflux temperature, reaction times 3 ~ 20h, (7-methoxyl-3,4-dihydro-1-naphthyl) acetonitrile solution is obtained after cooling;
(2) dehydroaromatizationof: by product (the 7-methoxyl group-3 of gained in step (1), 4-dihydro-1-naphthyl) acetonitrile solution and 2,3-bis-chloro-5,6-dicyan para benzoquinone carries out reaction dehydrogenation, adopt and same reaction solvent in reactions steps (1), temperature of reaction is 30-80 DEG C, and the reaction times is 0.5 ~ 2h; Reacting liquid filtering, filtrate carries out alkali cleaning, saturated common salt water washing successively, and after removing solvent under reduced pressure, residuum ethanol: water recrystallization, obtains (7-methoxy-1-naphthyl) acetonitrile.
3. the synthetic method of (7-methoxy-1-naphthyl) acetonitrile according to claim 1 and 2, is characterized in that, described ethanol: the volume ratio of water is V/V=3:7 ~ 7:3.
4. the synthetic method of (7-methoxy-1-naphthyl) acetonitrile according to claim 1 and 2, is characterized in that: described amines catalyst is one or more mixtures of benzylamine, O-Phenylene Diamine, mphenylenediamine or Ursol D.
5. the synthetic method of (7-methoxy-1-naphthyl) acetonitrile according to claim 1 and 2, is characterized in that: described same reaction solvent is benzene or toluene.
6. the synthetic method of (7-methoxy-1-naphthyl) acetonitrile according to claim 1 and 2, it is characterized in that: in described dehydration second cyanation, 7-methoxyl group naphthane-1-ketone: cyanoacetic acid: amines catalyst: the weight ratio of reaction solvent is: 1:0.58 ~ 1.21:0.05 ~ 0.30:5.23 ~ 10.45.
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| CN104725270A (en) * | 2015-03-02 | 2015-06-24 | 江西吉翔医药化工有限公司 | Method for preparing butylphenylacetonitrile |
| CN105601537A (en) * | 2016-01-25 | 2016-05-25 | 江西同和药业股份有限公司 | Preparation method of 2-(7-methoxyl-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 |
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Cited By (3)
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| 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 |
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Address after: 310023 Hangzhou Province, Zhejiang Province, and road, No. 318 Co-patentee after: RUIFUXIN JIANGSU PHARMACEUTICAL CO.,LTD. Patentee after: ZHEJIANG University OF SCIENCE AND TECHNOLOGY Address before: 310023 Hangzhou Province, Zhejiang Province, and road, No. 318 Co-patentee before: JIANGSU YUXIANG CHEMICAL Co.,Ltd. Patentee before: Zhejiang University of Science and Technology |
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Effective date of registration: 20180117 Address after: 224555 Jiangsu province Yancheng City Binhai Economic Development Zone Chemical Industry Park Ninghai Patentee after: RUIFUXIN JIANGSU PHARMACEUTICAL CO.,LTD. Address before: 310023 Hangzhou Province, Zhejiang Province, and road, No. 318 Co-patentee before: RUIFUXIN JIANGSU PHARMACEUTICAL CO.,LTD. Patentee before: Zhejiang University of Science and Technology |