CN107721869A - A kind of synthetic method of the cyanobenzaldehyde of 2 methoxyl group 4 - Google Patents
A kind of synthetic method of the cyanobenzaldehyde of 2 methoxyl group 4 Download PDFInfo
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C07—ORGANIC CHEMISTRY
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Abstract
The invention discloses a kind of synthetic method of the cyanobenzaldehyde of 2 methoxyl group 4, methods described comprises the steps of：Step 1：Using the methoxy benzoic acid of 4 methyl 3 as raw material, acyl chloride reaction, then ammonolysis obtain the methoxy benzamide of 4 methyl 3（Ⅰ）；Step 2：The methoxy benzamide of 4 methyl 3（Ⅰ）Carry out dehydration and obtain the methoxy benzonitrile of 4 methyl 3（Ⅱ）；Step 3：Bromine substitutes the methoxy benzonitrile of 4 methyl 3（Ⅱ）Methyl on hydrogen obtain the methoxy benzonitrile of 4 bromomethyl 3（Ⅲ）；Step 4：The methoxy benzonitrile of 4 bromomethyl 3（Ⅲ）Bromomethyl occur hydrolysis obtain the methoxy benzonitrile of 4 methylol 3（Ⅳ）；Step 5：The methoxy benzonitrile of 4 methylol 3（Ⅳ）Generation oxidation reaction obtains the cyanobenzaldehyde of 2 methoxyl group 4（Ⅴ）.The present invention has the advantages that Process Route Planning is reasonable, supplementary material is cheap and easy to get, easy to operate, cost is low, suitable for industrialized production.
Description
Technical field
The invention belongs to organic synthetic route design field, and in particular to a kind of 2- methoxy-4-cyano benzaldehydes
Synthetic method.
Background technology
2- methoxy-4-cyano benzaldehydes are a kind of very important pharmaceutical intermediates, are sought a kind of easy, cheap, easy
The synthetic method of industrialized production has great importance.
Some related documents of existing 2- methoxy-4-cyano benzaldehydes and patent report mainly have：
First, Chinese patent CN102020587A
This method using 3- methoxyl group -4- methyl benzoic acids as initiation material, by chloride, amidatioon, dehydration, bromo and
The multistep reactions such as hydrolysis, obtain 2- methoxy-4-cyano benzaldehydes.The drawbacks of this method is single bromo during bromo-reaction
Thing is difficult to be fully converted to two bromo-derivatives, causes hydrolysis impurity more, in addition bromo-reaction solvent for use carbon tetrachloride poison
Property is stronger, is unsuitable for industrialized production.
2nd, United States drug The Chemicals (Journal of Medicinal Chemistry), 2002,45 (12), 2388-
2409
This method is a similar structure, becomes aldehyde radical from methyl by bromo-reaction and hydrolysis.This method
Drawback is that the silver nitrate of costliness has been used in hydrolysis, with high costs, is unsuitable for industrialized production.
3rd, United States drug The Chemicals (Journal of Medicinal Chemistry), 2007,50 (10), 2468-
2485
Synthetic route one：
Synthetic route two：
Synthetic route three：
The several method of document report is mainly the construction for being absorbed in aldehyde radical.Route one passes through DMF-DMA (N, N- diformazans
Base formamide dimethylacetal) reacted with benzyl, then aoxidized by potassium metaperiodate, reach the purpose from methyl construction aldehyde radical.Should
The drawbacks of method, is that first step reaction temperature is higher, is unsuitable for industrialized production.Route two obtains single bromine by bromo-reaction
React to obtain target aldehyde compound for thing, then with caustic alcohol, ethanol, 2- nitropropanes.The drawbacks of this method, is to use poison
The larger 2- nitropropanes of property, are unsuitable for industrialized production.Route three obtains two bromo-derivatives by bromo-reaction, then hydrolyzes to obtain phase
The aldehyde answered.The drawbacks of this method is the silver nitrate that costliness has been used in hydrolysis, with high costs, is unsuitable for industrialized production.
The content of the invention
It is mentioned hereinbefore in order to overcome the shortcomings of, solve the above-mentioned problems in the prior art, the purpose of the present invention
It is to provide that a kind of processing step is simple, production cost is low, finished product purity is high and 2- methoxyl groups -4- suitable for industrialized production
The synthetic method of cyanobenzaldehyde.
To achieve the above object, the present invention adopts the following technical scheme that：
A kind of synthetic method of 2- methoxy-4-cyano benzaldehydes, is comprised the steps of：
Step 1：Using 4- methyl -3- methoxy benzoic acids as raw material, sent out with chloride reagent in acyl chloride reaction solvent
After raw reaction, react with aminating agent to obtain 4- methyl -3- methoxy benzamides (I) in aminating reaction solvent；
Step 2：4- methyl -3- methoxy benzamides (I) react with dehydrated reagent in certain solvent, obtain 4- first
Base -3- methoxy benzonitriles (II)；
Step 3：In certain solvent, in the presence of bromating agent and catalyst, bromine substitution 4- methyl -3- methoxybenzene first
Hydrogen on the methyl of nitrile (II) obtains 4- bromomethyl -3- methoxy benzonitriles (III)；
Step 4：Participation of the bromomethyl of 4- bromomethyls -3- methoxy benzonitriles (III) in water-soluble alkali made from step 3
Under in water occur hydrolysis obtain 4- methylol -3- methoxy benzonitriles (IV)；
Step 5：4- methylol -3- methoxy benzonitriles (IV) occur in certain solvent in the presence of oxidising agent
Oxidation reaction obtains 2- methoxy-4-cyano benzaldehydes (V)；
Reaction scheme is as follows：
Wherein, the chloride reagent described in step 1 is thionyl chloride, and acyl chloride reaction solvent used is toluene, two
One kind in toluene, chlorobenzene；Described aminating agent is ammoniacal liquor, and described aminating reaction solvent is water.
Wherein, 4- methyl -3- methoxy benzoic acids, chloride reagent, the mole ratio of aminating agent are 1 in step 1:
1.0~5.0:2.0~5.0；Preferable mol ratio is 1:3.0:3.0；Acyl chloride reaction temperature is 60~110 DEG C；Preferable temperature
Spend for 80~90 DEG C；Aminating reaction temperature is 0~30 DEG C；Preferable temperature is 15~25 DEG C.
Wherein, the dehydrating agent described in step 2 is thionyl chloride, and solvent used is in toluene, chlorobenzene and dimethylbenzene
It is a kind of；4- methyl -3- methoxy benzamides (I), the mole ratio of dehydrating agent are 1:1.0~5.0；Preferable mol ratio is 1:
4.0；Reaction temperature is 45~110 DEG C；Preferable temperature is 100~110 DEG C.
Wherein, the bromating agent described in step 3 is N-bromosuccinimide, and described catalyst is benzoyl peroxide
(BPO), solvent used is one kind in chlorobenzene, carbon tetrachloride and 1,2- dichloroethanes；4- methyl -3- methoxy benzonitriles
(II), bromating agent, the mole ratio of catalyst are 1:1.0~2.0:0.01~0.03；Preferable mol ratio is 1:1.8:0.03；
Reaction temperature is 65~100 DEG C；Preferable temperature is 80~100 DEG C.
Wherein, the water-soluble alkali described in step 4 is one kind in sodium carbonate, cesium carbonate and potassium carbonate；4- bromomethyls -3-
Methoxy benzonitrile (III), the mole ratio of water-soluble alkali are 1:1.0~3.0；Preferable mol ratio is 1:2.7；Reaction temperature
For 65~105 DEG C；Preferable temperature is 90~100 DEG C.
Wherein, the oxidant described in step 5 is manganese dioxide, and described solvent is dichloromethane, chloroform and 1,2- bis-
One kind in chloroethanes；4- methylol -3- methoxy benzonitriles (IV), the mole ratio of oxidising agent are 1:3.0~10.0；It is excellent
The mol ratio of choosing is 1:4.0；Reaction temperature is 35~45 DEG C；Preferable temperature is 36~39 DEG C.
In the above-mentioned reaction of the present invention, the bromo of step 3 and the hydrolysis of step 4 are committed steps of the invention.Text
The bromo-reaction of report is offered, is to obtain single bromo-derivative after purification or double bromo-derivatives after purification, then reaction is hydrolyzed, is used
Method provided by the invention, the bromo-reaction of step 3 is available based on single bromo-derivative, the mixing containing a small amount of double bromo-derivatives
Thing, it can be directly used for next step hydrolysis.The hydrolysising condition of document report, using carbonate (such as calcium carbonate, carbon of microsolubility
Sour barium etc.), after hydrolysis is complete, slightly soluble acid carbonate is removed by the method for filtering, the present invention is replaced micro- with water-soluble alkali
Soluble carbonate (such as calcium carbonate, barium carbonate) is hydrolyzed, and after reaction completely, is not required to filter, directly uses solvent extraction product,
Operating procedure is simplified, single bromo-derivative hydrolyzes to obtain 4- methylol -3- methoxy benzonitriles (IV), and double bromo-derivative hydrolysis directly obtain
To 2- methoxy-4-cyano benzaldehydes (V), this one-step hydrolysis reacts to obtain 4- methylol -3- methoxy benzonitriles (IV) and 2-
The mixture of methoxy-4-cyano benzaldehyde (V), without purifying, the oxidation reaction of next step is directly carried out, and ensure cyanogen
Base is stable, unaffected.
The preparation method that the present invention is reported, have technique simple in actual production, simple to operate, high income, be easy to
The advantages that industrialized production.
With specific embodiment, the present invention is described further below.
Embodiment
Embodiment 1：
The synthesis of step 1,4- methyl -3- methoxy benzamides (I)
150 grams of 4- methyl -3- methoxy benzoic acids (0.903mol) of addition, 500 grams of toluene and 215 grams in four mouthfuls of reaction bulbs
Thionyl chloride (1.81mol), it is heated to 110 DEG C and reacts 6 hours, is evaporated under reduced pressure recovery toluene and the thionyl chloride of excess, it is past residual
150 grams of toluene of addition in thing are stayed, is stirred, is evaporated under reduced pressure is steamed until solvent-free again, 100 grams of dilution in acetonitrile of residue
Acetonitrile solution is obtained, it is standby；
316 gram of 25% ammoniacal liquor (2.25mol) and 316 grams of water are added in four mouthfuls of reaction bulbs, 15 DEG C are cooled to, by above-mentioned gained
Acetonitrile solution dropwise is into reaction bulb, and drop finishes, insulation reaction 3 hours, and filtering, filter cake is fully washed with water, 80 DEG C of gained solid
Drying, obtains 141 grams of 4- methyl -3- methoxy benzamides (I), yield 95%, purity ＞ 98%.
The synthesis of step 2,4- methyl -3- methoxy benzonitriles (II)
In four mouthfuls of reaction bulbs add 100 grams of 4- methyl -3- methoxy benzamides (I) (0.605mol), 400 grams of toluene and
108 grams of thionyl chlorides (0.908mol), are heated to 110 DEG C of back flow reactions 4 hours, and point plate tracks to raw material disappearance, cools, decompression
The thionyl chloride of concentrated solvent and excess, crude product is obtained, crude product is beaten 2 hours with 200 grams of petroleum ethers, filtering, filter cake oil
Ether washs, and drains, and drying obtains 85 grams of 4- methyl -3- methoxy benzonitriles (II), yield 95%, purity ＞ 97%.
The synthesis of step 3,4- bromomethyl -3- methoxy benzonitriles (III)
50 grams of 4- methyl -3- methoxy benzonitriles (II) (0.34mol), 79 grams of N- bromos fourths two are added in four mouthfuls of reaction bulbs
Acid imide (NBS) (0.444mol), 0.9 gram of benzoyl peroxide (BPO) (3.72mmol) and 500 grams of carbon tetrachloride, are heated to
80 DEG C are reacted 5 hours, and point plate tracks to raw material disappearance, is cooled to room temperature, adds 300 gram of 5% sodium thiosulfate solution and is quenched
Reaction, organic layer is separated, 100 grams of carbon tetrachloride extractions of water layer, merges organic layer, anhydrous sodium sulfate drying filters, and filtrate is dense
Contracting obtains crude product, and crude product is beaten with 50 grams of ethyl acetate and 500 grams of petroleum ethers, obtains 53 grams of 4- bromomethyl -3- methoxybenzene first
Nitrile (III), yield 69%, purity ＞ 95%.
The synthesis of step 4,4- methylol -3- methoxy benzonitriles (IV)
277 grams of 4- bromomethyl -3- methoxy benzonitriles (III) (1.23mol), 260 grams of sodium carbonate are added in four mouthfuls of reaction bulbs
(2.45mol) and 2500 grams of water, are heated to 90 DEG C of back flow reactions 2 hours, put plate, and reaction finishes, and is cooled to room temperature, adds 1000
The extraction of gram dichloromethane, water layer are extracted twice with 800 grams and 500 grams of dichloromethane again, merging organic layer, successively with 150 gram 1%
Watery hydrochloric acid and 150 grams of saturated aqueous common salts respectively washed once, organic layer anhydrous sodium sulfate drying, be concentrated to give crude product 4- hydroxyl first
(IV) 128.7 gram of base -3- methoxy benzonitriles.
The synthesis of step 5,2- methoxy-4-cyano benzaldehydes (V)
In four mouthfuls of reaction bulbs add 128.7 grams of 4- methylol -3- methoxy benzonitriles (IV) (0.788mol), 205.6 grams
Manganese dioxide (2.364mol) and 1600 grams of dichloromethane, are heated to 39 DEG C of back flow reactions about 8 hours, put plate, and reaction finishes, and drops
Warm to room temperature, filter, filter cake fully washs with dichloromethane, and filtrate is concentrated to give crude product, crude product with 80 grams of dichloromethane, 80 grams
Ethanol and 240 grams of petroleum ether mixed solvent recrystallizations, obtain 53 grams of 2- methoxy-4-cyano benzaldehydes (V), yield 42%.
1H-NMR(400MHz,CDCl3)δ(ppm):3.970(3H,s,CH3),7.251(1H,s,ArH),7.299-7.318
(1H, d, J=7.6Hz, ArH), 7.872-7.891 (1H, d, J=7.6Hz, ArH), 10.465 (1H, s, CHO).
Embodiment 2
The synthesis of step 1,4- methyl -3- methoxy benzamides (I)
0.9mol 4- methyl -3- methoxy benzoic acids, xylene solvent and 0.9mol protochlorides are added in four mouthfuls of reaction bulbs
Sulfone, it is heated to 60 DEG C and reacts 6 hours, the thionyl chloride of vacuum distillation recovered solvent and excess, add toluene into residue, stir
Mix uniformly, be evaporated under reduced pressure steamed until solvent-free again, residue obtains acetonitrile solution with dilution in acetonitrile, standby；
630 gram of 25% ammoniacal liquor (4.5mol) is added in four mouthfuls of reaction bulbs, is cooled to 0 DEG C, above-mentioned gained acetonitrile solution is dripped
It is added in reaction bulb, drop finishes, insulation reaction 3 hours, and filtering, filter cake is fully washed with water, dries, obtains 4- methyl -3- methoxies
Yl-benzamide (I).
The synthesis of step 2,4- methyl -3- methoxy benzonitriles (II)
0.6mol 4- methyl -3- methoxy benzamides (I), xylene solvent and 0.6mol are added in four mouthfuls of reaction bulbs
Thionyl chloride, is heated to 45 DEG C of back flow reactions 4 hours, and point plate tracks to raw material disappearance, cooling, be concentrated under reduced pressure solvent and excess
Thionyl chloride, crude product is obtained, crude product is beaten 2 hours with petroleum ether, filtering, filter cake petroleum ether, is drained, and drying obtains 4-
Methyl -3- methoxy benzonitriles (II).
The synthesis of step 3,4- bromomethyl -3- methoxy benzonitriles (III)
0.3mol 4- methyl -3- methoxy benzonitriles (II), 0.3mol N- bromo succinyl are added in four mouthfuls of reaction bulbs
Imines (NBS), 9mmol benzoyl peroxides (BPO) and chlorobenzene solvent, it is heated to 65 DEG C and reacts 5 hours, point plate tracks to raw material
Disappear, be cooled to room temperature, add 5% sodium thiosulfate solution and reaction is quenched, separate organic layer, water layer is extracted with chlorobenzene, is closed
And organic layer, anhydrous sodium sulfate drying, filtering, filtrate are concentrated to give crude product, crude product ethyl acetate and petroleum ether mashing, obtained
4- bromomethyl -3- methoxy benzonitriles (III).
The synthesis of step 4,4- methylol -3- methoxy benzonitriles (IV)
0.1mol 4- bromomethyl -3- methoxy benzonitriles (III), 0.1mol cesium carbonates and water are added in four mouthfuls of reaction bulbs,
It is heated to 65 DEG C of back flow reactions 2 hours, puts plate, reaction finishes, and is cooled to room temperature, adds dichloromethane extraction, water layer is again with two
Chloromethanes is extracted twice, and is merged organic layer, respectively be washed once with 1% watery hydrochloric acid and saturated aqueous common salt successively, and organic layer is with anhydrous
Sodium sulphate is dried, and is concentrated to give crude product 4- methylol -3- methoxy benzonitriles (IV).
The synthesis of step 5,2- methoxy-4-cyano benzaldehydes (V)
0.05mol 4- methylol -3- methoxy benzonitriles (IV), 5mol manganese dioxide and chlorine are added in four mouthfuls of reaction bulbs
Imitative solvent, is heated to 35 DEG C of back flow reactions about 8 hours, puts plate, reaction finishes, and is cooled to room temperature, filters, filter cake dichloromethane
Fully washing, filtrate are concentrated to give crude product, crude product dichloromethane, ethanol and petroleum ether mixed solvent recrystallization, obtain 2- first
Epoxide -4- cyanobenzaldehydes (V).
Embodiment 3
The synthesis of step 1,4- methyl -3- methoxy benzamides (I)
0.9mol 4- methyl -3- methoxy benzoic acids, chlorobenzene solvent and 4.5mol protochlorides are added in four mouthfuls of reaction bulbs
Sulfone, it is heated to 80 DEG C and reacts 6 hours, the thionyl chloride of vacuum distillation recovered solvent and excess, add toluene into residue, stir
Mix uniformly, be evaporated under reduced pressure steamed until solvent-free again, residue obtains acetonitrile solution with dilution in acetonitrile, standby；
252 gram of 25% ammoniacal liquor (1.8mol) is added in four mouthfuls of reaction bulbs, it is 30 DEG C to control temperature, and above-mentioned gained acetonitrile is molten
Drop is added in reaction bulb, and drop finishes, insulation reaction 3 hours, and filtering, filter cake is fully washed with water, is dried, is obtained 4- methyl -3-
Methoxy benzamide (I).
The synthesis of step 2,4- methyl -3- methoxy benzonitriles (II)
0.6mol 4- methyl -3- methoxy benzamides (I), chlorobenzene solvent and 3mol chlorinations are added in four mouthfuls of reaction bulbs
Sulfoxide, is heated to 100 DEG C of back flow reactions 4 hours, and point plate tracks to raw material disappearance, and cooling, be concentrated under reduced pressure solvent and the chlorine of excess
Change sulfoxide, obtain crude product, crude product is beaten 2 hours with petroleum ether, filtering, filter cake petroleum ether, is drained, and drying obtains 4- first
Base -3- methoxy benzonitriles (II).
The synthesis of step 3,4- bromomethyl -3- methoxy benzonitriles (III)
It is sub- that 0.5mol 4- methyl -3- methoxy benzonitriles (II), 1mol N- bromos succinyl are added in four mouthfuls of reaction bulbs
Amine (NBS), 10mmol benzoyl peroxides (BPO) and 1,2- dichloroethane solvent, be heated to 100 DEG C react 5 hours, point plate with
Track to raw material is disappeared, and is cooled to room temperature, adds 5% sodium thiosulfate solution and reaction is quenched, be layered, and water layer is extracted with chlorobenzene,
Merge organic layer, with anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give crude product 4- bromomethyl -3- methoxy benzonitriles (III).
The synthesis of step 4,4- methylol -3- methoxy benzonitriles (IV)
0.1mol 4- bromomethyl -3- methoxy benzonitriles (III), 0.27mol potassium carbonate and water are added in four mouthfuls of reaction bulbs,
It is heated to 100 DEG C of back flow reactions 2 hours, puts plate, reaction finishes, and is cooled to room temperature, adds dichloromethane extraction, water layer is again with two
Chloromethanes is extracted twice, and is merged organic layer, respectively be washed once with 1% watery hydrochloric acid and saturated aqueous common salt successively, and organic layer is with anhydrous
Sodium sulphate is dried, and is concentrated to give crude product 4- methylol -3- methoxy benzonitriles (IV).
The synthesis of step 5,2- methoxy-4-cyano benzaldehydes (V)
0.05mol 4- methylol -3- methoxy benzonitriles (IV), 3mol manganese dioxide and 1 are added in four mouthfuls of reaction bulbs,
2- dichloroethane solvents, are heated to 36 DEG C of back flow reactions about 8 hours, put plate, and reaction is finished, and is cooled to room temperature, filters, and filter cake is used
Dichloromethane fully washs, and filtrate is concentrated to give crude product, and crude product dichloromethane, ethanol and petroleum ether mixed solvent recrystallize,
Obtain 2- methoxy-4-cyano benzaldehydes (V).
Embodiment 4
The synthesis of step 1,4- methyl -3- methoxy benzamides (I)
0.9mol 4- methyl -3- methoxy benzoic acids, toluene solvant and 2.7mol protochlorides are added in four mouthfuls of reaction bulbs
Sulfone, it is heated to 90 DEG C and reacts 6 hours, the thionyl chloride of vacuum distillation recovered solvent and excess, add toluene into residue, stir
Mix uniformly, be evaporated under reduced pressure steamed until solvent-free again, residue obtains acetonitrile solution with dilution in acetonitrile, standby；
378 gram of 25% ammoniacal liquor (2.7mol) is added in four mouthfuls of reaction bulbs, it is 25 DEG C to control temperature, and above-mentioned gained acetonitrile is molten
Drop is added in reaction bulb, and drop finishes, insulation reaction 3 hours, and filtering, filter cake is fully washed with water, is dried, is obtained 4- methyl -3-
Methoxy benzamide (I).
The synthesis of step 2,4- methyl -3- methoxy benzonitriles (II)
0.6mol 4- methyl -3- methoxy benzamides (I), toluene solvant and 1.8mol chlorine are added in four mouthfuls of reaction bulbs
Change sulfoxide, be heated to 100 DEG C of back flow reactions 4 hours, point plate tracks to raw material disappearance, cooling, be concentrated under reduced pressure solvent and excess
Thionyl chloride, crude product is obtained, crude product is beaten 2 hours with petroleum ether, filtering, filter cake petroleum ether, is drained, and drying obtains 4-
Methyl -3- methoxy benzonitriles (II).
The synthesis of step 3,4- bromomethyl -3- methoxy benzonitriles (III)
0.5mol 4- methyl -3- methoxy benzonitriles (II), 0.9mol N- bromo succinyl are added in four mouthfuls of reaction bulbs
Imines (NBS), 15mmol benzoyl peroxides (BPO) and chlorobenzene solvent, it is heated to 80 DEG C and reacts 5 hours, point plate tracks to original
Material disappears, and is cooled to room temperature, adds 5% sodium thiosulfate solution and reaction is quenched, be layered, water layer is extracted with chlorobenzene, is associated with
Machine layer, with anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give crude product 4- bromomethyl -3- methoxy benzonitriles (III).
The synthesis of step 4,4- methylol -3- methoxy benzonitriles (IV)
0.1mol 4- bromomethyl -3- methoxy benzonitriles (III), 0.3mol sodium carbonate and water are added in four mouthfuls of reaction bulbs,
It is heated to 105 DEG C of back flow reactions 2 hours, puts plate, reaction finishes, and is cooled to room temperature, adds dichloromethane extraction, water layer is again with two
Chloromethanes is extracted twice, and is merged organic layer, respectively be washed once with 1% watery hydrochloric acid and saturated aqueous common salt successively, and organic layer is with anhydrous
Sodium sulphate is dried, and is concentrated to give crude product 4- methylol -3- methoxy benzonitriles (IV).
The synthesis of step 5,2- methoxy-4-cyano benzaldehydes (V)
0.05mol 4- methylol -3- methoxy benzonitriles (IV), 4mol manganese dioxide and two are added in four mouthfuls of reaction bulbs
Chloromethane alkane solvents, are heated to 45 DEG C of back flow reactions about 8 hours, put plate, and reaction finishes, and is cooled to room temperature, filters, filter cake dichloro
Methane fully washs, and filtrate is concentrated to give crude product, crude product dichloromethane, ethanol and petroleum ether mixed solvent recrystallization, obtains
2- methoxy-4-cyano benzaldehydes (V).
Claims (11)
1. a kind of synthetic method of 2- methoxy-4-cyano benzaldehydes, it is characterised in that comprise the steps of：
Step 1：Using 4- methyl -3- methoxy benzoic acids as raw material, occur instead in acyl chloride reaction solvent with chloride reagent
Ying Hou, react with aminating agent to obtain 4- methyl -3- methoxy benzamides (I) in aminating reaction solvent；
Step 2：4- methyl -3- methoxy benzamides (I) react with dehydrated reagent in certain solvent, obtain 4- methyl -3-
Methoxy benzonitrile (II)；
Step 3：In certain solvent, in the presence of bromating agent and catalyst, bromine substitution 4- methyl -3- methoxy benzonitriles
(II) the hydrogen on methyl obtains 4- bromomethyl -3- methoxy benzonitriles (III)；
Step 4：The bromomethyl of 4- bromomethyls -3- methoxy benzonitriles (III) made from step 3 in the presence of water-soluble alkali in
Hydrolysis occurs in water and obtains 4- methylol -3- methoxy benzonitriles (IV)；
Step 5：4- methylol -3- methoxy benzonitriles (IV) aoxidize in certain solvent in the presence of oxidising agent
Reaction obtains 2- methoxy-4-cyano benzaldehydes (V)；
Reaction scheme is as follows：
2. synthetic method according to claim 1, it is characterised in that the chloride reagent described in step 1 is thionyl chloride,
Described acyl chloride reaction solvent is one kind in toluene, dimethylbenzene, chlorobenzene；Described aminating agent is ammoniacal liquor, described ammonia
Change reaction dissolvent is water.
3. preparation method according to claim 1 or 2, it is characterised in that 4- methyl -3- methoxy benzoic acids in step 1,
Chloride reagent, the mole ratio of aminating agent are 1:1.0~5.0:2.0~5.0；Preferable mol ratio is 1:3.0:3.0；Acyl
Chlorination reaction temperature is 60~110 DEG C；Preferable temperature is 80~90 DEG C；Aminating reaction temperature is 0~30 DEG C；Preferable temperature
For 15~25 DEG C.
4. synthetic method according to claim 1, it is characterised in that the dehydrating agent described in step 2 is thionyl chloride, described
Solvent be toluene, chlorobenzene, one kind in dimethylbenzene.
5. the preparation method according to claim 1 or 4, it is characterised in that the 4- methyl -3- methoxybenzenes described in step 2
Formamide (I), the mole ratio of dehydrating agent are 1:1.0~5.0；Preferable mol ratio is 1:4.0；Reaction temperature is 45~110
℃；Preferable temperature is 100~110 DEG C.
6. synthetic method according to claim 1, it is characterised in that the bromating agent described in step 3 is N- bromo ambers
Acid imide, described catalyst are benzoyl peroxide, and described solvent is in chlorobenzene, carbon tetrachloride, 1,2- dichloroethanes
It is a kind of.
7. the preparation method according to claim 1 or 6, it is characterised in that 4- methyl -3- methoxy benzonitriles in step 3
(II), bromating agent, the mole ratio of catalyst are 1:1.0~2.0:0.01~0.03；Preferable mol ratio is 1:1.8:0.03；
Reaction temperature is 65~100 DEG C；Preferable temperature is 80~100 DEG C.
8. synthetic method according to claim 1, it is characterised in that the water-soluble alkali described in step 4 is sodium carbonate, carbon
One kind in sour caesium and potassium carbonate.
9. the preparation method according to claim 1 or 8, it is characterised in that 4- bromomethyls -3- methoxybenzene first in step 4
Nitrile (III), the mole ratio of water-soluble alkali are 1:1.0~3.0；Preferable mol ratio is 1:2.7；Reaction temperature is 65~105
℃；Preferable temperature is 90~100 DEG C.
10. synthetic method according to claim 1, it is characterised in that the oxidising agent described in step 5 is titanium dioxide
Manganese, described solvent are one kind in dichloromethane, chloroform, 1,2- dichloroethanes.
11. the synthetic method according to claim 1 or 10, it is characterised in that 4- methylols -3- methoxybenzenes in step 5
Formonitrile HCN (IV), the mole ratio of oxidising agent are 1:3.0~10.0；Preferable mol ratio is 1:4.0；Reaction temperature is 35~45
℃；Preferable temperature is 36~39 DEG C.
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