CN106278841B - A kind of preparation method of 8- methoxyl groups -3,4- dihydro -1H-2- naphthalenones - Google Patents

A kind of preparation method of 8- methoxyl groups -3,4- dihydro -1H-2- naphthalenones Download PDF

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CN106278841B
CN106278841B CN201610573830.2A CN201610573830A CN106278841B CN 106278841 B CN106278841 B CN 106278841B CN 201610573830 A CN201610573830 A CN 201610573830A CN 106278841 B CN106278841 B CN 106278841B
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reducing agent
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王莺妹
金逸中
黄锦峰
涂文通
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ZHEJIANG YONGTAI PHARMACEUTICAL Co Ltd
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Abstract

The present invention relates to a kind of method preparing 83,4 dihydro 1H of methoxyl group, 2 naphthalenones, the present invention synthesizes 83,4 dihydro 1H of methoxyl group, 2 naphthalenones using 2 methoxy benzonitriles as starting material, by the reactions such as hydrolyzing, restoring.It has the following advantages that：1) 2 methoxy benzonitrile benzonitrile raw material, cheap and easily-available, 2) technological reaction mild condition, reaction time are short, high income, easy to operate, it is easy to accomplish industrialized production, 3) technique is avoided using expensive catalyst such as rhodium etc., and production cost is relatively low.4) there is the novel magnetic nanometer particle load lewis acid used good paramagnetism, separation and recovery only need to use simple externally-applied magnetic field that can recycle itself and reaction system quick separating, and process is simple, the three wastes are few, production cost is relatively low.

Description

A kind of preparation method of 8- methoxyl groups -3,4- dihydro -1H-2- naphthalenones
Technical field
The present invention relates to a kind of method preparing 8- methoxyl group -3,4- dihydro -1H-2- naphthalenones, it is specifically a kind of with 2- methoxy benzonitriles are the method that raw material prepares 8- methoxyl group -3,4- dihydro -1H-2- naphthalenones.
The present invention synthesizes 8- methoxyl groups -3,4- using 2- methoxy benzonitriles as starting material, by the reactions such as hydrolyzing, restoring Dihydro -1H-2- naphthalenones.
Background technology
8- methoxyl group -2- naphthalenones are synthesis dopamine (Dopamine) receptor stimulating agent and serotonin (Serotonin) The important starting material of acceptor inhibitor.
The existing preparation method of 8- methoxyl group -2- naphthalenones is：It is synthesis 2- methoxyphenylacetic acids, then 2- methoxyl groups first Phenylacetic acid cyclization under catalyst obtains 8- methoxyl group -3,4- dihydro -1H-2- naphthalenones.
Pertinent literature report about 2- methoxyphenylacetic acids mainly has：
Levine in 1948, Joseph etc. (Levine, Joseph et al.Preparation of ο- hydroxyphenylacetic acid.Journal of the American Chemical Society,70,1930； 1948) it reports using alpha-hydroxy-2-p-methoxybenzeneacetonitrile as Material synthesis 2- methoxyacetic acids.The raw material of the method is relatively high It is expensive.(Ghosh, Somnath et al.Studies the on oxygen such as subsequent Ghosh, Somnath heterocycles.Part 1.Acid catalyzed and photochemical reactions of some aryl diazo ketones.Tetrahedron,45(5),1441-6；1989) also with this Material synthesis 2- methoxyacetic acids, reaction Yield is 72% or so.
(Hey, the D.H.and Nagdy, K.A.Intermolecular such as nineteen fifty-three Hey, D.H. acylation.III.The preparation and ring closure of theα-(methoxyphenyl) glutaric acids.Journal of the Chemical Society,1894-9；1953) it reports with 2- methoxyl groups- α-oxygen-benzenpropanoic acid is Material synthesis 2- methoxyacetic acids.
(Shono, Tatsuya.Aryl the acetic acid such as nineteen eighty-two Shono, Tatsuya Derivatives.DE3207506,1982-09-16 it) discloses using 1- (2,2- dichloroethylenes) -2- methoxybenzenes as raw material 2- methoxyacetic acids are synthesized.(Huh, Dal Ho et al.An efficient method for one- such as Huh, Dal Ho carbon elongation of aryl aldehydes via their dibromoalkene derivatives.Tetrahedron,58(50),9925-9932；2002) it also discloses that with 1- (2,2- dibromo vinyls) -2- Methoxybenzene is raw material, under conditions of nafoxidine makees solvent, has synthesized 2- methoxyacetic acids.
Zhao in 1998, Mangzhu etc. (Zhao, Mangzhu et al.A novel chromium trioxide catalyzed oxidation of primary alcohols to the carboxylic acids.Tetrahedron Letters,39(30),5323-5326；1998) it reports using 2- methoxybenzenes ethyl alcohol as Material synthesis 2- methoxyacetic acids, Yield is higher, is 98%, but catalyst chromium trioxide used is carcinogenic substance and more expensive；Tschane, David M. etc. (Tschane,David M.et al.Oxidation process of alcohols using periodic acid and Chromium catalyst.WO9952850,1999-10-21) disclosed in synthetic method similar to this document, catalysis used Agent is chromium trioxide.Zhao in 1999, Mangzhu etc. (Zhao, Mangzhu et al.Oxidation of Primary Alcohols to Carboxylic Acids with Sodium Chlorite Catalyzed by TEMPO and Bleach.Journal of Organic Chemistry,64(7),2564-2566；1999) it reports with 2- methoxybenzene second Alcohol is raw material, under the catalysis of 2,2,6,6- tetramethyl piperidine -1- oxygen radicals, has synthesized 2- methoxyphenylacetic acids；Li, Jing etc. (Li,Jing et al.Oxidation of primary alcohols in the presence of TEMPO.WO9952849,21Oct1999-10-21) disclosed in synthetic method similar to this document, catalyst used is 2,2, 6,6- tetramethyl piperidine -1- oxygen radicals；(Zhao, Matthew M.et the al.Oxidation of such as Zhao, Matthew M. primary alcohols to carboxylic acids with sodium chlorite catalyzed by tempo and bleach:4-methoxyphenylacetic acid.Organic Syntheses,81,195-203；2005) it is reported The method in road is also similar to this document, 2,2,6,6- tetramethyl piperidine -1- oxygen radicals of used catalyst.
Liu in 2011, Zhi-Qiang etc. (Liu, Zhi-Qiang et al.Gene Cloning, Expression, and Characterization of a Nitrilase from Alcaligenes faecalis ZJUTB10.Journal of Agricultural and Food Chemistry,59(21),11560-11570；2011) it reports with 2- methoxybenzene second Nitrile is Material synthesis 2- methoxyphenylacetic acids, and method used is biological enzyme enzyme process (nitrilase), although the method environment Close friend, but its nitrilase is more difficult is extracted from microorganism.
Yao Yi in 2012 etc. (the synthesising process research Chemical Manufactures and technology of the methoxyphenamine hydrochlorides such as Yao Yi, 19 (1), 7-9；2012) it reports and generates 2- methoxyphenylacetic acids by raw material and dimethyl suflfate reaction of o-hydroxy phenylacetic acid, yield exists 92% or so, but dimethyl suflfate used is more toxic.
About the synthetic method of methoxy substitution -3,4- dihydro -1H-2- naphthalenones, document and patent report mainly have：
(the James Leslie Charlton et such as James Leslie Charlton in 1980 al.Photoreactions ofα-sulfonyloxyketones.Can.J.Chem.58,458-462；1980) it reports Under conditions of illumination, 1- tolysulfonyl oxygroups -4- (3- methoxyphenyls) -2- butanone can generate 8- methoxyl group -2- naphthalenones, Reaction route is shown below.But its yield is relatively low, is 23%.
McKervery in 1984, M.Anthony etc. (McKervery, M.Anthony et al.Efficient synthesis of bicyclo[5.3.0]decatrienones and of 2-tetralones via rhodium(II) acetate-catalyzed cyclization ofα-diazoketones derived from 3-arylpropionic Acids) report by Buchner react based on synthesized 8- methoxyl group -2- naphthalenones, synthetic route is as shown in following formula 1.
Copinga in 1993, Swier etc. (Copinga, Swier et al.2-Amido-8-methoxytetralins: A series of nonindolic melatonin-like agents.Journal of Medicinal Chemistry, 36(20),2891-8；1993) a variety of method synthesis 8- methoxyl group -2- naphthalenones (8-methoxy-2-tetralone) are reported, Such as following formula 2, shown in formula 3.Dimethyl suflfate used be more toxic and rhodium catalyst costly.
(Lee, Sunkyung et al.A new, simple the procedure for such as nineteen ninety-five Lee, Sunkyung the preparation of8-methoxy-2-tetralone.Synthetic Communications,25(18),2775- 80；1995) method for reporting synthesis 8- methoxyl group -2- naphthalenones, synthetic route are shown below.For Fu Ke acyl groups therein It is relatively low that change-cycloalkylation reacts its yield, is 68% or so.
(the Claudio C.Silveira et al.Synthetic such as Claudio C.Silveira in 2004 approaches to 2-tetralones.Tetrahedron,2004,60:8295-8328) 2- naphthalene ketone derivants are reviewed Synthetic method, the synthesis for 8- methoxyl group -2- naphthalenones are to be reacted by Buchner under conditions of rhodium catalyst, then exist In the presence of trifluoroacetic acid, target product, wherein rhodium catalyst are generated costly.Rammohan Devulapally in 2009 (Rammohan Devulapally.An efficient and Versatile Methodology for the Synthesis of 2-Tetralones,9-Phenanthrol Derivatives and their Application in The Total Synthesis of Zenkequinone B) synthetic method that reports 2- naphthalene ketone derivants, it uses Rieke Mg、TiCl4Etc. expensive reagents.
(Bin YAO et al.Design, the Synthesis and Biological such as Bin YAO in 2006 Evaluation of Non-azole Inhibitors of Lanosterol 14α-Demethylase of Fungi.Chinese Chemical Letters 17 (9), 1189-1192,2006) report the conjunctions of 8- methoxyl group -2- naphthalenones The method reported similar to Copinga, Swier etc. at route, method.Subsequent 2007, (such as Yao Bin are novel by Yao Bin etc. Tetralin quasi-compound synthesizes and extracorporeal antifungal activity studies chemistry journals, 65 (3):257-264；2007) in chemical journal On report the method.
There are many deficiencies by 8- methoxyl group -3,4- dihydro -1H-2- naphthalenones preparation process disclosed in above-mentioned patent, such as Side reaction is more, using expensive catalyst, reaction time consumption is long, production cost is high, post-processing wastewater flow rate is big, to the corrosivity of equipment and The problems such as pollution level of environment is serious.
The present invention prepares 8- first using 2- methoxy benzonitriles as starting material, through the reactions such as hydrolysis, reduction, halogenated, substitution The method of oxygroup -3,4- dihydro -1H-2- naphthalenones is there is not yet pertinent literature and patent report.
Invention content
It is an object of the invention to use 2- methoxy benzonitriles for Material synthesis intermediate 2- methoxyphenylacetic acids first, Then target product 8- methoxyl groups -2- is obtained by the reaction by chlorination reaction, friedel-crafts acylation-cycloalkylation by 2- methoxyphenylacetic acids Naphthalenone.
The technical solution adopted by the present invention is：
According to the application embodiment, this application provides 8- methoxyl groups -3,4- bis- shown in a kind of formula (I) The preparation method of hydrogen -1H-2- naphthalenones,
It is characterized in that the described method comprises the following steps：
(1) the 2- methoxy benzonitriles of formula (VIII) are hydrolyzed to the O-Anisic Acid of formula (VII) in the presence of acid； The O-Anisic Acid of formula (VII) restores the 2- methoxy benzyl alcohols for generating formula (VI) in the presence of a reducing agent；Formula (VI) 2- methoxy benzyl alcohols and thionyl chloride occur chlorination reaction generate formula (V) 2- methoxyl group benzyl chlorides；The 2- methoxyl groups of formula (V) Benzyl chloride reacts the 2- p-methoxybenzeneacetonitriles for generating formula (IV) with Cymag；2- p-methoxybenzeneacetonitriles the depositing in mixed acid of formula (IV) The 2- methoxyphenylacetic acids of intermediate formula (III) are hydrolyzed under；
The 2- first of the 2- methoxy benzonitriles of the wherein described formula (VIII), the O-Anisic Acid of formula (VII), formula (VI) The 2- methoxyphenylacetic acids of oxygroup benzyl alcohol, the 2- methoxyl groups benzyl chloride of formula (V), the 2- p-methoxybenzeneacetonitriles of formula (IV), formula (III) Structure difference it is as follows：
(2) it is as follows to react generation with chlorination reagent under the action of catalyst for the 2- methoxyphenylacetic acids of intermediate formula (III) The 2- methoxyphenylacetyl chlorides of shown formula (II).：
(3) the 2- methoxyphenylacetyl chlorides of aforementioned formula (II) react under conditions of support type lewis acid with ethylene Generate the 8- methoxyl group -3,4- dihydro -1H-2- naphthalenones of target product formula (I).
The support type lewis acid structure is：
The support type lewis acid is selected from AlCl3-IL-SiO2@γ-Fe2O3、FeCl3-IL-SiO2@γ-Fe2O3、BF3- IL-SiO2@γ-Fe2O3、TiCl4-IL-SiO2@γ-Fe2O3、SnCl4-IL-SiO2@γ-Fe2O3、ZnCl2-IL-SiO2@γ- Fe2O3, preferably AlCl3-IL-SiO2@γ-Fe2O3；
IL=1- methyl -3- described in support type lewis acid (trimethoxy-silylpropyl) imidazolitm chloride.
According to the application embodiment, acid described in step (1) is sulfuric acid, and the 2- methoxyl groups of formula (VIII) The molar ratio of benzonitrile and acid is 1:0.8-1.2, preferably 1:1；Reaction temperature is 120-150 DEG C in step (1), preferably 125- 130℃。
According to the application embodiment, reducing agent described in step (1) is NaBH4, and the 2- first of formula (VII) The molar ratio of p-methoxybenzoic acid and reducing agent is 1:1-3, preferably 1:2；Step (2) is reacted 4 hours at 100 DEG C.
According to the application embodiment, step successively adds reducing agent and solvent in (1) under the conditions of ice-water bath The O-Anisic Acid of tetrahydrofuran and formula (VII), the diethyl ether solution that sulfuric acid is then added dropwise are reacted at room temperature, and And the O-Anisic Acid of formula (VII) and the molar ratio of reducing agent are 1:1-3, preferably 1:2.5.It carries out in this way The reduction reaction of the O-Anisic Acid of formula (VII), can improve the yield of product.
According to the application embodiment, acid described in step (1) is sulfuric acid or mixed acid, and mixed acid is sulfuric acid With the mixture of acetic acid；The molar ratio of sulfuric acid and acetic acid is 3-8 in mixed acid:1, preferably 5:1.Present inventor is unexpected Ground is found, without wishing to be bound by any theory, and the yield of 2- methoxyphenylacetic acids can be significantly improved using mixed acid.
According to the application embodiment, catalyst described in step (2) is DMF, TMEDA, triethylamine or diformazan Yl pyridines amine, preferably DMF；Chlorination reagent is oxalyl chloride or thionyl chloride, preferably thionyl chloride.
According to the application embodiment, step (2) is reacted 5~8 hours at a reflux temperature, preferably in reflux temperature The lower reaction of degree 6 hours.
According to the application embodiment, step (3) the support type lewis acid is AlCl3-IL-SiO2@γ- Fe2O3。
According to the application embodiment, reaction temperature is room temperature in step (3)；Reaction time is 1.5~2 small When.
According to the application embodiment, the molar ratio of ethylene and 2- methoxyphenylacetic acids is 1 in step (3):1~ 1.5:1, preferably 9:7.
According to the application embodiment, the molar ratio of ethylene and 2- methoxyphenylacetyl chlorides is 1 in step (3):1 ~1.5:1.
The present invention prepares 8- first using 2- methoxy benzonitriles as starting material, through the reactions such as hydrolysis, reduction, halogenated, substitution Oxygroup -3,4- dihydro -1H-2- naphthalenones, the technique have the following advantages that compared with prior art：1) 2- methoxy benzonitriles benzonitrile is former Material, it is cheap and easily-available；2) technological reaction mild condition, reaction time are short, high income, easy to operate, it is easy to accomplish industrialized production； 3) technique is avoided using expensive catalyst such as rhodium etc., and production cost is relatively low；4) friedel-crafts acylation-cycloalkylation reaction uses New Magnetic Field Controlled Property nanometer particle load lewis acid AlCl3-IL-SiO2@γ-Fe2O3For catalyst, novel magnetic nano load lewis acid There is catalyst good paramagnetism, separation and recovery only can need to quickly be divided it with reaction system using simple externally-applied magnetic field From recycling, process is simple, the three wastes are few, production cost is relatively low.
Specific implementation mode
In order to make the purpose , technical scheme and advantage of the present invention be clearer, present invention following specific examples It illustrates, but the present invention is limited to absolutely not these examples.It is as described below to be only the preferred embodiment of the present invention, it is used only for explaining The present invention, it cannot be construed as a limitation to the scope of the present invention.It should be pointed out that all spirit in the present invention All any modification, equivalent and improvement etc. with being done within principle, should all be included in the protection scope of the present invention.
Embodiment 1
The addition 2- methoxy benzonitriles (13.3g, 0.1mol) in 100mL round-bottomed flasks, dropwise addition sulfuric acid (9.8g, 0.1mol) solution, after completion of dropwise addition, 125-130 DEG C of insulation reaction 2 hours, reaction terminates, be cooled to 100 DEG C hereinafter, plus water it is dilute It releases, is cooled to 50 DEG C hereinafter, layering, remove raw material, acquired solution decompression dehydration 1-1.5 hours when original solution half (about) is cold But crystallization obtains O-Anisic Acid 13.98g, yield 92%.
Embodiment 2
Sodium borohydride 7.57g (0.2mol) is dissolved in the tetrahydrofuran solution of 283mL in 500mL three-necked bottles, is stirred. Then O-Anisic Acid 15.2g (0.1mol) is added, is reacted 4 hours under the conditions of 100 DEG C.It is cooling, add water 100mL, stirs Filtering after mixing uniformly, filtrate decompression recycling, there is a Precipitation, dry white granular solid 2- methoxy benzyl alcohols 13.13 G, yield 95% detect reaction process with TLC.
Embodiment 3
In 250mL three-necked bottles, under the conditions of ice-water bath, sodium borohydride (19g, 0.5mol) addition tetrahydrofuran (100mL, Do not purify) in, it is subsequently added into O-Anisic Acid 30.4g (0.2mol), new H is then added dropwise2SO4(13.2mL, 0.5mol) second Ethereal solution (total amount 40mL).It is stirred at room temperature after dripping 12 hours.Methanol (40mL) is added dropwise, is concentrated into half, is subsequently added into 20%NaOH (200mL), rotary evaporation falls solvent.Obtained mixture flows back 3 hours.It is cooling, filtering, and it is diluted to 400mL, It is extracted 4 times with dichloromethane (150mL), saturated sodium-chloride (200mL) is washed, and anhydrous sodium sulfate drying, filtering is evaporated under reduced pressure out two Chloromethanes, product are recrystallized with ethyl acetate (40mL)/n-hexane (120mL), and filtering is dried in vacuo to obtain white granular solid 2- methoxy benzyl alcohol 27.09g, yield 98% detect reaction process with TLC.
Embodiment 4
In 100mL round-bottomed flasks be added 2- methoxy benzyl alcohols (13.8g, 0.1mol) and dichloromethane (30mL) and Thionyl chloride (11.9g, 0.1mol) is then added in DMF (1mL), and temperature rising reflux is stirred to react 3h, is cooled to room temperature, detaches institute Organic phase is obtained, 2- methoxyl group benzyl chloride 14.41g, yield 92% are distilled to obtain.
2- methoxyl groups benzyl chloride (15.7g, 0.1mol) and ethyl alcohol (30mL) and water are added in 100mL round-bottomed flasks (5mL) is then added Cymag (4.9g, 0.1mol), is stirred to react, after reaction, separating obtained organic phase distills to obtain 2- P-methoxybenzeneacetonitrile 13.38g, yield 91%.
Embodiment 5
In 100mL round-bottomed flasks be added 2- p-methoxybenzeneacetonitriles (14.7g, 0.1mol), then by 70% sulfuric acid (14g, 100 DEG C 0.143mol) are heated to, is added drop-wise in flask within 1-1.5 hours, after completion of dropwise addition, 125-130 DEG C of insulation reaction 2 hours, Reaction terminates, and is cooled to 100 DEG C hereinafter, be diluted with water, and is cooled to 50 DEG C hereinafter, layering, removes raw material, acquired solution decompression is de- Water 1-1.5 hours, cooling crystallization obtain 2- methoxyphenylacetic acid 14.61g, yield 88%.
Embodiment 6
In 100mL round-bottomed flasks be added 2- p-methoxybenzeneacetonitriles (14.7g, 0.1mol), then by sulfuric acid (9.8g, 0.1mol) and acetic acid (1.2g, 0.02mol) mixed acid is heated to 100 DEG C, is added drop-wise in flask within 1-1.5 hours, completion of dropwise addition Afterwards, 125-130 DEG C of insulation reaction 2 hours, reaction terminates, and is cooled to 100 DEG C hereinafter, be diluted with water, be cooled to 50 DEG C hereinafter, point Layer, removes Ammonium hydrogen sulfate, decompression dehydration 1-1.5 hours, and cooling crystallization obtains 2- methoxyphenylacetic acid 15.44g, yield 93%.
Embodiment 7
Thionyl chloride (41.65g, 350mmol) is slowly added to 2- methoxyphenylacetic acids (23.24g, 140mmol) and dichloro In the mixed solution of methane (90mL) (stirring while adding), and the dry dimethylformamide of several drip-dry is added, in the protection of nitrogen Under, temperature rising reflux is stirred to react 6 hours, is cooled to room temperature in a water bath.The condition of solvent and excessive thionyl chloride in decompression Under steam removal, obtain grease formula (II), need not purify and be used for the next step.
AlCl is added in the reaction vessel3-IL-SiO2@γ-Fe2O3(37.8g) and dichloromethane (450mL), and Strong stirring at room temperature.Formula (II) crude product is dissolved in dichloromethane (120mL), and is added dropwise by dropping funel, is subsequently passed ethylene (180mmol), duration 1 hour.It is stirred for 1 hour, reaction terminates, and isolates organic layer.Organic layer is moistened by saturated sodium-chloride It washes, is layered, magnesium sulfate drying concentrates in a vacuum.Distillation, is recrystallized to give formula (I) solid 20.94g in petroleum ether (m.p.55~58 DEG C), yield 85%.
Embodiment 8
Thionyl chloride (41.65g, 350mmol) is slowly added to 2- methoxyphenylacetic acids (23.24g, 140mmol) and dichloro In the mixed solution of methane (90mL) (stirring while adding), and the dry triethylamine of several drip-dry is added, under the protection of nitrogen, heating Return stirring reacts 6 hours, is cooled to room temperature in a water bath.Solvent and excessive thionyl chloride steam shifting at reduced pressure It removes, obtains grease formula (II), need not purify and be used for the next step.
AlCl is added in the reaction vessel3-IL-SiO2@γ-Fe2O3(47.25g) and dichloromethane (450mL), and Strong stirring at room temperature.Formula (II) crude product is dissolved in dichloromethane (120mL), and is added dropwise by dropping funel, is subsequently passed ethylene (180mmol), duration 1 hour.It is stirred for 1 hour, reaction terminates, and isolates organic layer.Organic layer is moistened by saturated sodium-chloride It washes, is layered, magnesium sulfate drying concentrates in a vacuum.Distillation, is recrystallized to give formula (I) solid 17.99g in petroleum ether (m.p.55~58 DEG C), yield 73%.
Embodiment 9
Thionyl chloride (41.65g, 350mmol) is slowly added to 2- methoxyphenylacetic acids (23.24g, 140mmol) and dichloro In the mixed solution of methane (90mL) (stirring while adding), and the dry tetramethylethylenediamine of several drip-dry is added, in the protection of nitrogen Under, temperature rising reflux is stirred to react 6 hours, is cooled to room temperature in a water bath.The condition of solvent and excessive thionyl chloride in decompression Under steam removal, obtain grease formula (II), need not purify and be used for the next step.
AlCl is added in the reaction vessel3-IL-SiO2@γ-Fe2O3(28.35g) and dichloromethane (450mL), and Strong stirring at room temperature.Formula (II) crude product is dissolved in dichloromethane (120mL), and is added dropwise by dropping funel, is subsequently passed ethylene (180mmol), duration 1 hour.It is stirred for 1 hour, reaction terminates, and isolates organic layer.Organic layer is moistened by saturated sodium-chloride It washes, is layered, magnesium sulfate drying concentrates in a vacuum.Distillation, is recrystallized to give formula (I) solid 17.49g in petroleum ether (m.p.55~58 DEG C), yield 71%.
Embodiment 10
Thionyl chloride (41.65g, 350mmol) is slowly added to 2- methoxyphenylacetic acids (23.24g, 140mmol) and dichloro In the mixed solution of methane (90mL) (stirring while adding), and the dry lutidines amine of several drip-dry is added, in the protection of nitrogen Under, temperature rising reflux is stirred to react 6 hours, is cooled to room temperature in a water bath.The condition of solvent and excessive thionyl chloride in decompression Under steam removal, obtain grease formula (II), need not purify and be used for the next step.
AlCl is added in the reaction vessel3-IL-SiO2@γ-Fe2O3(18.9g) and dichloromethane (450mL), and Strong stirring at room temperature.Formula (II) crude product is dissolved in dichloromethane (120mL), and is added dropwise by dropping funel, is subsequently passed ethylene (180mmol), duration 1 hour.It is stirred for 1 hour, reaction terminates, and isolates organic layer.Organic layer is moistened by saturated sodium-chloride It washes, magnesium sulfate drying concentrates in a vacuum.Distillation, be recrystallized to give in petroleum ether formula (I) solid 17.25g (m.p.55~ 58 DEG C), yield 70%.
Embodiment 11
Oxalyl chloride (41.65g, 350mmol) is slowly added to 2- methoxyphenylacetic acids (23.24g, 140mmol) and dichloromethane In the mixed solution of alkane (90mL) (stirring while adding), and the dry dimethylformamide of several drip-dry is added, under the protection of nitrogen, Temperature rising reflux is stirred to react 6 hours, is cooled to room temperature in a water bath.Solvent and excessive thionyl chloride steam at reduced pressure Go out to remove, obtain grease formula (II), need not purify and is used for the next step.
AlCl is added in the reaction vessel3-IL-SiO2@γ-Fe2O3(37.8g) and dichloromethane (450mL), and Strong stirring at room temperature.Formula (II) crude product is dissolved in dichloromethane (120mL), and is added dropwise by dropping funel, is subsequently passed ethylene (180mmol), duration 0.5 hour.It is stirred for 1 hour, reaction terminates, and isolates organic layer.Organic layer passes through saturated sodium-chloride Rinse, layering, magnesium sulfate drying concentrate in a vacuum.Distillation, is recrystallized to give formula (I) solid 16.76g in petroleum ether (m.p.55~58 DEG C), yield 68%.
Embodiment 12
Thionyl chloride (41.65g, 350mmol) is slowly added to 2- methoxyphenylacetic acids (23.24g, 140mmol) and dichloro In the mixed solution of methane (90mL) (stirring while adding), and the dry dimethylformamide of several drip-dry is added, in the protection of nitrogen Under, temperature rising reflux is stirred to react 6 hours, is cooled to room temperature in a water bath.The condition of solvent and excessive thionyl chloride in decompression Under steam removal, obtain grease formula (II), need not purify and be used for the next step.
AlCl is added in the reaction vessel3-IL-SiO2@γ-Fe2O3(28.35g) and dichloromethane (450mL), and Strong stirring at room temperature.Formula (II) crude product is dissolved in dichloromethane (120mL), and is added dropwise by dropping funel, is subsequently passed ethylene (180mmol), duration 0.5 hour.It is stirred for 1 hour, reaction terminates, and isolates organic layer.Organic layer passes through saturated sodium-chloride Rinse, layering, magnesium sulfate drying concentrate in a vacuum.Distillation, is recrystallized to give formula (I) solid 16.02g in petroleum ether (m.p.55~58 DEG C), yield 65%.

Claims (18)

1. the preparation method of 8- methoxyl groups -3,4- dihydro -1H-2- naphthalenones shown in a kind of formula (I),
It is characterized in that the described method comprises the following steps：
(1) the 2- methoxy benzonitriles of formula (VIII) are hydrolyzed to the O-Anisic Acid of formula (VII) in the presence of acid；Formula (VII) O-Anisic Acid restores the 2- methoxy benzyl alcohols for generating formula (VI) in the presence of a reducing agent；Formula (VI) The 2- methoxyl group benzyl chlorides that chlorination reaction generates formula (V) occur for 2- methoxy benzyl alcohols and thionyl chloride；The 2- methoxybenzyls of formula (V) Chlorine reacts the 2- p-methoxybenzeneacetonitriles for generating formula (IV) with Cymag；The 2- p-methoxybenzeneacetonitriles of formula (IV) water in the presence of acid Solution is the 2- methoxyphenylacetic acids of intermediate formula (III)；
The 2- methoxyl groups of the 2- methoxy benzonitriles of the wherein described formula (VIII), the O-Anisic Acid of formula (VII), formula (VI) Benzyl alcohol, the 2- methoxyl groups benzyl chloride of formula (V), the 2- p-methoxybenzeneacetonitriles of formula (IV), formula (III) 2- methoxyphenylacetic acids knot Structure difference is as follows：
(2) it is as follows to react generation with chlorination reagent under the action of catalyst for the 2- methoxyphenylacetic acids of intermediate formula (III) The 2- methoxyphenylacetyl chlorides of formula (II)：
(3) the 2- methoxyphenylacetyl chlorides of aforementioned formula (II) react generation under conditions of support type lewis acid with ethylene 8- methoxyl group -3,4- dihydro -1H-2- naphthalenones of target product formula (I),
The support type lewis acid is selected from AlCl3-IL-SiO2@γ-Fe2O3、FeCl3-IL-SiO2@γ-Fe2O3、BF3-IL- SiO2@γ-Fe2O3、TiCl4-IL-SiO2@γ-Fe2O3、SnCl4-IL-SiO2@γ-Fe2O3、ZnCl2-IL-SiO2@γ- Fe2O3；
IL described in support type lewis acid is 1- methyl -3- (trimethoxy-silylpropyl) imidazolitm chloride.
2. according to the method described in claim 1, it is characterized in that the support type lewis acid is AlCl3-IL-SiO2@γ- Fe2O3。
3. according to the method described in claim 1, it is characterized in that acid described in step (1) is sulfuric acid, and formula (VIII) The molar ratio of 2- methoxy benzonitriles and acid is 1:0.8-1.2；Reaction temperature is 120-150 DEG C in step (1).
4. according to the method described in claim 1, it is characterized in that acid described in step (1) is sulfuric acid, and formula (VIII) The molar ratio of 2- methoxy benzonitriles and acid is 1:1；Reaction temperature is 125-130 DEG C in step (1).
5. according to the method described in claim 1, it is characterized in that reducing agent described in step (1) is NaBH4, and formula (VII) O-Anisic Acid and reducing agent molar ratio be 1:1-3；Step (2) is reacted 4 hours at 100 DEG C.
6. according to the method described in claim 1, it is characterized in that reducing agent described in step (1) is NaBH4, and formula (VII) O-Anisic Acid and reducing agent molar ratio be 1:2；Step (2) is reacted 4 hours at 100 DEG C.
7. according to the method described in claim 1, it is characterized in that successively adding reducing agent and solvent four under the conditions of ice-water bath The O-Anisic Acid of hydrogen furans and formula (VII), the diethyl ether solution that sulfuric acid is then added dropwise are reacted at room temperature, and The O-Anisic Acid of formula (VII) and the molar ratio of reducing agent are 1:1-3.
8. according to the method described in claim 1, it is characterized in that successively adding reducing agent and solvent four under the conditions of ice-water bath The O-Anisic Acid of hydrogen furans and formula (VII), the diethyl ether solution that sulfuric acid is then added dropwise are reacted at room temperature, and The O-Anisic Acid of formula (VII) and the molar ratio of reducing agent are 1:2.5.
9. according to the method described in claim 1, it is characterized in that sour described in step (1) is sulfuric acid or mixed acid, mixing Acid is the mixture of sulfuric acid and acetic acid；The molar ratio of sulfuric acid and acetic acid is 3-8 in mixed acid:1.
10. according to the method described in claim 1, it is characterized in that sour described in step (1) is sulfuric acid or mixed acid, mixing Acid is the mixture of sulfuric acid and acetic acid；The molar ratio of sulfuric acid and acetic acid is 5 in mixed acid:1.
11. according to the method described in claim 1, it is characterized in that catalyst described in step (2) is DMF, TMEDA, three second Amine or lutidines amine；Chlorination reagent is oxalyl chloride or thionyl chloride.
12. according to the method described in claim 1, it is characterized in that catalyst described in step (2) is DMF；Chlorination reagent is Thionyl chloride.
13. according to the method described in claim 1, it is characterized in that step (2) is reacted 5~8 hours at a reflux temperature.
14. according to the method described in claim 1, it is characterized in that step (2) is reacted 6 hours at a reflux temperature.
15. according to the method described in claim 1, it is characterized in that reaction temperature is room temperature in step (3)；Reaction time is 1.5~2 hours.
16. according to the method described in claim 1, it is characterized in that in step (3) ethylene and 2- methoxyphenylacetic acids mole Than being 1:1~1.5:1.
17. according to the method described in claim 1, it is characterized in that in step (3) ethylene and 2- methoxyphenylacetic acids mole Than being 9:7.
18. according to the method described in claim 1, it is characterized in that ethylene and 2- methoxyphenylacetyl chlorides rub in step (3) You are than being 1:1~1.5:1.
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