CN102115458A - Synthesis method of 3-methoxy-2-aryl(methyl)acrylate compounds - Google Patents
Synthesis method of 3-methoxy-2-aryl(methyl)acrylate compounds Download PDFInfo
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- CN102115458A CN102115458A CN201010561323XA CN201010561323A CN102115458A CN 102115458 A CN102115458 A CN 102115458A CN 201010561323X A CN201010561323X A CN 201010561323XA CN 201010561323 A CN201010561323 A CN 201010561323A CN 102115458 A CN102115458 A CN 102115458A
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Abstract
The invention relates to a synthesis method of 3-methoxy-2-aryl(methyl)acrylate compounds, which comprises the following steps: by using phenylmethyl acetate with or without substituting groups as a raw material, carrying out formylation reaction at -20-100 DEG C for 4-6 hours in a nitrogen atmosphere in the presence of Lewis acid in an aprotic solvent neutralized formylation reagent, dissociating with an organic base, hydrolyzing with hydrochloric acid, and stratifying, wherein the organic layer is an intermediate; carrying out methylation reaction on the intermediate, benzyltriethylammonium chloride, a methylation reagent and an inorganic base at 20-100 DEG C for 1-3 hours; after the reaction finishes, washing with water, desolventizing, and recrystallizing or distilling while depressurizing to obtain the product. The invention has the advantages of fewer processing steps (the methylation reaction can be directly carried out without purifying and separating the intermediate product), favorable selectivity, higher yield and low cost; and the reaction process is easy to control, and is safe and easy to amplify.
Description
Technical field
The invention belongs to the synthetic method technical field of the oxygen methyl compound that has acrylate-based, halogenic substituent and fragrance or heterocyclic substituent in the aromatic nucleus, relate to the preparation method of a kind of synthetic 3-methoxyl group-2-aromatic base acrylic compound.
Background technology
Methoxy acrylic bactericide is a class mechanism of action uniqueness, has the novel agricultural sterilant of development potentiality and bright market prospects that its active group has (E)-'beta '-methoxy acrylic acid methyl esters or similar modular construction.
And this series products synthetic core technology is a methoxy methylene technology, promptly how to introduce a methoxy methene (CH at the ortho position of carboxylicesters
3OCH=) technology.
Present ordinary method (Pest Management Science 58:649-662 (online:2002)) is to introduce the hydroxyl methene by sodium hydride and formylation reagent earlier at the ortho position of substrate carboxylicesters, and separation methylates after purifying again.Because formylation reaction is to react under the effect of highly basic sodium hydrogen, so by product is many, yield is low, and must cause total recovery low, cost up to just carrying out next step methylation reaction after the formylation purification of products.On the other hand, sodium hydride has determined can have some security hidden danger in amplification production to characteristics such as water vapor sensitives owing to inflammable in the air.
And methoxy methylene technology of the present invention has replaced the use of dangerous sodium hydride with relatively cheap and safe Lewis acid, makes reaction process be easy to control, and is easy to operate and safe, is more conducive to amplify and produces; The formylation reaction selectivity is good, and transformation efficiency height, formylation intermediate product need not purifying and directly enter methylation reaction with separating.Make the yield and the selectivity of total reaction improve like this, cost significantly reduces.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of structural formula (I) and compound (II) and derivative thereof:
R wherein
1Be the aromatic base (comprising heterocycle and non-heterocyclic aromatic base) of band substituted radical, X is halogen (fluorine, chlorine, bromine or iodine), C
1-6Alkyl, C
2-6Thiazolinyl, nitro or cyano group, and n is 0 or 1.
Described: non-heterocyclic aromatic base comprises phenyl or naphthyl; Heterocyclic aromatic base comprises five yuan or the hexa-member heterocycle group that contains one or more heteroatoms O, S and N, as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,3-, 1,2,4-and 1,3,5-triazinyl, 1,2,4,5-tetrazine base, thienyl, quinolyl, isoquinolyl, quinoxalinyl or benzothienyl etc.;
Described aromatic base with substituted radical comprise 1～2 kind of following radicals: halogen, hydroxyl, C
1-6Alkyl (especially methyl is or/and ethyl), styryl, C
2-6Thiazolinyl (especially allyl group), C
1-4Alkoxyl group (especially methoxyl group), halo C
1-6Alkyl (especially chlorine or bromine is for methyl, trifluoromethyl or trichloromethyl), halo C
1-4Alkoxyl group (especially trifluoromethoxy).
The inventive method synthetic compound contains a carbon-to-carbon double bond at least, so there is cis-trans isomerism, the form with two kinds of isomer mixtures exists usually.Different synthetic methods, the ratio difference of the cis-trans-isomer of generation product.And as the sterilant that fungicidal activity is arranged, the fungicidal activity height of trans usually (E-type) ratios of the isomers Cis formula (Z-type) isomer, the inventive method synthetic compound is a primary product with E-type isomer.
Processing method of the present invention may further comprise the steps:
(1) under nitrogen protection, in the aprotic solvent,-20～100 ℃, body material is that general formula (III) or compound (IV) and formylation reagent in the presence of lewis acidic formylation reaction take place, and dissociates back dilute hydrochloric acid hydrolysis then through organic bases, reaction times is 4～6h, add water, layering, getting organic layer is intermediate;
(2) under 20 ℃ to 100 ℃ conditions, step (1) gained intermediate and benzyltriethylammoinium chloride, methylating reagent and mineral alkali are carried out methylation reaction 1～3h, reaction finish washes with water, precipitation, recrystallization or underpressure distillation obtain general formula (I) or compound (II).Its reaction equation is as follows:
The related formylation reagent of the inventive method comprises manthanoate and ortho-formiate.As be selected from a kind of in methyl-formiate, ethyl formate, trimethyl orthoformate, the triethyl orthoformate etc.The preferred trimethyl orthoformate of the present invention.The consumption of formylation reagent is substrate (III) or 1.0-6.0 molar equivalent (IV), the preferred 1.2-3.0 molar equivalent of the present invention.
The related Lewis acid bag of the inventive method is selected from a kind of in titanium tetrachloride, zinc chloride, boron trifluoride, aluminum chloride, alkyl aluminum chloride, phosphorus pentafluoride, antimony pentafluoride, tindichloride and the tin tetrachloride etc.The preferred titanium tetrachloride of the present invention.Lewis acidic consumption is substrate (III) or 1.0-6.0 molar equivalent (IV), the preferred 1.2-3.0 molar equivalent of the present invention.
The organic bases that the inventive method adopted is a tertiary amine, is selected from a kind of in Trimethylamine 99, triethylamine, Tributylamine, diisopropylethylamine, the pyridine etc.The preferred triethylamine of the present invention.The consumption of organic bases is substrate (III) or 1.0-10.0 molar equivalent (IV), the preferred 2.0-6.0 molar equivalent of the present invention.
The described methylating reagent of the inventive method is selected from a kind of in trimethyl orthoformate, methyl-sulfate, methylcarbonate, methyl chloride, monobromethane, methyl iodide and the trifluoromethane sulfonic acid methyl esters etc.Preferably sulfuric acid dimethyl ester of the present invention.The consumption of methylating reagent is substrate (III) or 1.0-5.0 molar equivalent (IV), the preferred 1.0-3.0 molar equivalent of the present invention.
The mineral alkali that the inventive method adopted is a kind of in yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide and the potassium hydroxide etc.The consumption of mineral alkali is substrate (III) or 0.1-5.0 molar equivalent (IV), and the preferred 0.5-3.0 molar equivalent of the present invention is the aqueous solution of 5～50wt% during use.
Reaction involved in the present invention suits to carry out in aprotic solvent.Aprotic solvent is selected from chlorobenzene, dichlorobenzene, chloroform, methylene dichloride, 1, a kind of in the 2-ethylene dichloride, and consumption is 500～1500ml/ mole substrate (III) or (IV).
Described chemical reaction the 1st, the 2 Buwen's degree conditions of the inventive method are generally-20～100 ℃.Preferably-10～60 ℃.Total reaction time is 5-20h.
In practice, with following processing step better effects if:
(1) under the exsiccant nitrogen protection, in reaction flask, add methylene dichloride and titanium tetrachloride successively, be cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate, behind the stirring at room 1h, cooling reaction solution to 0 ℃, drip (III) or (IV), behind the stirring at room 2h, cooling reaction solution to 5 ℃, stirring at room 1h behind the adding triethylamine, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid 10min after, add water washing, separatory, getting organic layer is intermediate;
(2) under the room temperature, in the organic phase of above-mentioned gained, add benzyltriethylammoinium chloride successively, 20% aqueous sodium hydroxide solution and methyl-sulfate.Add water washing after stirring 2h under the room temperature, the decompression precipitation gets product.
Compared with prior art, the advantage that the present invention gives prominence to is: the invention provides a kind of method of novel methoxy methyleneization, step is few, and intermediate product need not purifying and directly enters methylation reaction with separating, and selectivity is good, and yield is higher relatively, and is with low cost; Reaction process is easy to control, and safety is easy to amplify.
Below with embodiment concrete synthetic operation of the present invention is further described.
Embodiment
Below all embodiment relate to the reaction of the reagent of water sensitive all carried out under the drying nitrogen protection, and solvent will carry out drying before using.
Embodiment 1
(E)-and 3-methoxyl group-2{2-[6-(trifluoromethyl)-2-pyridine oxygen methyl] phenyl } preparation of methyl acrylate.
Under the exsiccant nitrogen protection, in reaction flask, add successively methylene dichloride (350ml) and titanium tetrachloride (58.1g 0.3mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (31.9g, 0.3mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃ drips 2-[6-(trifluoromethyl)-2-pyridine oxygen methyl] and the phenylacetic acid methyl esters (97.6g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (61.9g, 0.6mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (219.2g, 0.6mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (60g, 0.3mol) and methyl-sulfate (35.6g, 0.3mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.Gained yellow solid normal hexane recrystallization gets Off-white solid 60.6g, and yield is 55.2%.Fusing point 73-75 ℃.
Embodiment 2
(E)-and 3-methoxyl group-2{2-[6-(trifluoromethyl)-2-pyridine oxygen methyl] phenyl } preparation of methyl acrylate.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.8g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃ drips 2-[6-(trifluoromethyl)-2-pyridine oxygen methyl] and the phenylacetic acid methyl esters (97.6g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.Gained yellow solid normal hexane recrystallization gets Off-white solid 93.4g, and yield is 85.1%.Fusing point 73-75 ℃.
Embodiment 3～10
(E)-3-methoxyl group-2{2-[6-(trifluoromethyl) under the differential responses condition-2-pyridine oxygen methyl] phenyl } preparation of methyl acrylate.
According to the method for embodiment 2, preparation (E)-3-methoxyl group-2{2-[6-(trifluoromethyl)-2-pyridine oxygen methyl under following different reaction reagent condition] phenyl } methyl acrylate, gained the results are shown in table 1:
Preparation (E)-3-methoxyl group-2{2-[6-(trifluoromethyl)-2-pyridine oxygen methyl under the table 1 differential responses reagent condition] phenyl } methyl acrylate
According to the method for embodiment 2, preparation (E)-3-methoxyl group-2{2-[6-(trifluoromethyl)-2-pyridine oxygen methyl under following different temperature of reaction] phenyl } methyl acrylate, gained the results are shown in table 2:
Preparation (E)-3-methoxyl group-2{2-[6-(trifluoromethyl)-2-pyridine oxygen methyl under the different temperature of reaction of table 2] phenyl } methyl acrylate
Embodiment 11
(E)-and 3-methoxyl group-2[2-(6-chloro-2-pyridine oxygen methyl) phenyl] preparation of methyl acrylate:
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.1g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃, drip 2-(6-chloro-2-pyridine oxygen methyl) phenylacetic acid methyl esters (87.5g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.Gained yellow solid normal hexane recrystallization gets Off-white solid 80.1g, and yield is 80.0%.Fusing point 91-92 ℃.
Embodiment 12
(E)-and 3-methoxyl group-2-{2-[(3-oxyethyl group-4-methoxyl group phenoxy group) methyl] phenyl } preparation of methyl acrylate.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.1g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃ drips 2-[(3-oxyethyl group-4-methoxyl group phenoxy group) methyl] the phenylacetic acid methyl esters (99.1g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.Gained yellow solid normal hexane recrystallization gets white solid 96.2g, and yield is 86.2%.98 ℃ of fusing points.
Embodiment 13
(E)-and 3-methoxyl group-2-{2-[(2, the 5-dimethyl phenoxy) methyl] phenyl } preparation of methyl acrylate.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.1g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃ drips 2-[(2, the 5-dimethyl phenoxy) methyl] the phenylacetic acid methyl esters (85.3g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.Gained yellow solid normal hexane recrystallization gets white solid 82.0g, and yield is 83.7%.Fusing point 108-110 ℃.
Embodiment 14
(E)-and 3-methoxyl group-2-{2-[(3-(E)-styryl phenoxy group) methyl] phenyl } preparation of methyl acrylate.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.1g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃ drips 2-[(3-(E)-styryl phenoxy group) methyl] the phenylacetic acid methyl esters (107.5g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.The underpressure distillation under 110-115 ℃/2-3mm Hg of gained oily crude product gets the 90.1g colorless oil, and yield is 75.1%.
Embodiment 15:
(E)-preparation of 3-methoxyl group-2-(2-methyl)-phenylacrylic acid methyl esters.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.8g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃, drip 2-methylphenyl acetic acid methyl esters (50.2g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.The underpressure distillation under 90-95 ℃/2-3mm Hg of gained oily crude product gets the 40.6g colorless oil, and yield is 65.7%.
Embodiment 16
(E)-preparation of 3-methoxyl group-2-phenylacrylic acid methyl esters.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.8g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃, drip methyl phenylacetate (45.0g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.The underpressure distillation under 90-95 ℃/2-3mm Hg of gained oily crude product gets the 35.3g colorless oil, and yield is 61.2%.
Embodiment 17
(E)-preparation of 3-methoxyl group-2-(4-tert-butyl-phenyl) methyl acrylate.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.1g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃, drip 4-tert.-butylbenzene methyl acetate (61.8g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.The underpressure distillation under 113-118 ℃/2-3mm Hg of gained oily crude product gets the faint yellow oily thing of 57.7g, and yield is 77.5%.
Embodiment 18
(E)-preparation of 3-methoxyl group-2-(3-chloro-phenyl-) methyl acrylate.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.1g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃, drip the 3-chlorophenyl acetate (55.4g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.The underpressure distillation under 113-118 ℃/2-3mm Hg of gained oily crude product gets the faint yellow oily thing of 44.9g, and yield is 66.0%.
Embodiment 19
(E)-and 3-methoxyl group-2-{2-[(5-trifluoromethyl pyrazine oxygen base) methyl] phenyl } preparation of methyl acrylate.
Under the exsiccant nitrogen protection, in reaction flask, add 1 successively, 2-ethylene dichloride (350ml) and titanium tetrachloride (87.1g 0.45mol), is cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate (47.1g, 0.45mol).Behind the stirring at room 1h, cooling reaction solution to 0 ℃ drips 2-[(5-trifluoromethyl pyrazine oxygen base) methyl] the phenylacetic acid methyl esters (97.9g, 0.3mol).Behind the stirring at room 2h, cooling reaction solution to 5 ℃, add triethylamine (74.3g, 0.72mol).Behind the stirring at room 1h, cooling reaction solution to 10 ℃, drip 10% dilute hydrochloric acid (263g, 0.72mol).Behind the 10min, add the 200mL water washing, separatory, getting organic layer is intermediate.
Under the room temperature, in the organic phase of above-mentioned gained, add successively benzyltriethylammoinium chloride (2.8g, 0.012mol), 20% aqueous sodium hydroxide solution (72g, 0.36mol) and methyl-sulfate (46.3g, 0.36mol).Add water washing after stirring 2h under the room temperature, the decompression precipitation.Gained yellow solid recrystallizing methanol gets faint yellow solid 79.8g, and yield is 72.2%.
Claims (13)
1.3-the synthetic method of methoxyl group-2-aromatic base methyl acrylate compound is characterized in that the synthetic method of following structural compounds:
R wherein
1Be the heterocyclic aromatic base or the non-heterocyclic aromatic base of band substituted radical, X is fluorine, chlorine, bromine or iodine, C
1-6Alkyl, C
2-6Thiazolinyl, nitro or cyano group, and n is 0 or 1;
Described: non-heterocyclic aromatic base comprises phenyl or naphthyl; Heterocyclic aromatic base comprises five yuan or the hexa-member heterocycle group that contains one or more heteroatoms O, S and N, as pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,3-, 1,2,4-and 1,3,5-triazinyl, 1,2,4,5-tetrazine base, thienyl, quinolyl, isoquinolyl, quinoxalinyl or benzothienyl;
Substituted radical in the aromatic base is 1～2 following radicals: halogen, hydroxyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-4Alkoxyl group, halo C
1-6Alkyl, halo C
1-4Alkoxyl group, styryl;
The synthesis technique step is:
(1) formylation: used following body material:
Under-20～100 ℃ of nitrogen protection, aprotic solvent neutralizations, formylation reaction takes place in general formula (III) or compound (IV) and formylation reagent in the presence of lewis acidic, dissociate through organic bases then, the dilute hydrochloric acid hydrolysis, reaction times is 4～6h, add water, layering, getting organic layer is intermediate;
Wherein: formylation reagent is selected from a kind of in methyl-formiate, ethyl formate, trimethyl orthoformate, the triethyl orthoformate, and consumption is substrate (III) or 1.0-6.0 molar equivalent (IV); Lewis acid is selected from a kind of in titanium tetrachloride, zinc chloride, boron trifluoride, aluminum chloride, alkyl aluminum chloride, phosphorus pentafluoride, antimony pentafluoride, tindichloride and the tin tetrachloride, and consumption is substrate (III) or 1.0-6.0 molar equivalent (IV); Organic bases is selected from a kind of in Trimethylamine 99, triethylamine, Tributylamine, diisopropylethylamine, the pyridine, and consumption is substrate (III) or 1.0-10.0 molar equivalent (IV); Aprotic solvent is selected from chlorobenzene, dichlorobenzene, chloroform, methylene dichloride, 1, a kind of in the 2-ethylene dichloride, and consumption is 500～1500ml/ mole substrate (III) or (IV);
(2) methylate: under-20～100 ℃ of conditions, step (1) gained intermediate and benzyltriethylammoinium chloride, methylating reagent and mineral alkali are carried out methylation reaction 1～3h, reaction finishes and washes with water, gets product through precipitation, recrystallization or underpressure distillation;
Wherein: methylating reagent is selected from a kind of in trimethyl orthoformate, methyl-sulfate, methylcarbonate, methyl chloride, monobromethane, methyl iodide and the trifluoromethane sulfonic acid methyl esters, and consumption is substrate (III) or 1.0-5.0 molar equivalent (IV); Mineral alkali is a kind of in yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide and the potassium hydroxide, and consumption is substrate (III) or 0.1-5.0 molar equivalent (IV), is the aqueous solution of 5～50wt% during use.
2. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound, it is characterized in that the substituted radical C in the described aromatic base
1-6Alkyl be that methyl is or/and ethyl.
3. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound, it is characterized in that the substituted radical C in the described aromatic base
1-4Alkoxyl group be that methoxyl group is or/and oxyethyl group.
4. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound, it is characterized in that the substituted radical halo C in the described aromatic base
1-6Alkyl is that chlorine or bromine is for methyl, trifluoromethyl or trichloromethyl.
5. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound, it is characterized in that the substituted radical halo C in the described aromatic base
1-4Alkoxyl group is a trifluoromethoxy.
6. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound; it is characterized in that formylation reagent is a trimethyl orthoformate described in synthesis technique step (1) formylation, consumption is substrate (III) or 1.2-3.0 molar equivalent (IV).
7. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound; it is characterized in that Lewis acid is a titanium tetrachloride described in synthesis technique step (1) formylation, consumption is substrate (III) or 1.2-3.0 molar equivalent (IV).
8. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound; it is characterized in that organic bases is a triethylamine described in synthesis technique step (1) formylation, consumption is substrate (III) or 2.0-6.0 molar equivalent (IV).
9. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound, it is characterized in that aprotic solvent is methylene dichloride or 1 described in synthesis technique step (1) formylation, the 2-ethylene dichloride.
10. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound, it is characterized in that synthesis technique step (2) methylate described in methylating reagent be methyl-sulfate, consumption is substrate (III) or 1.0-3.0 molar equivalent (IV).
11. according to the synthetic method of the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound, it is characterized in that synthesis technique step (2) methylate described in the mineral alkali consumption be substrate (III) or 0.5-3.0 molar equivalent (IV).
12. synthetic method according to the described 3-methoxyl group of claim 1-2-aromatic base methyl acrylate compound, it is characterized in that formylation reagent is a trimethyl orthoformate described in described synthesis technique step (1) formylation, consumption is substrate (III) or 1.2-3.0 molar equivalent (IV); Described Lewis acid is a titanium tetrachloride, and consumption is substrate (III) or 1.2-3.0 molar equivalent (IV); Described organic bases is a triethylamine, and consumption is substrate (III) or 2.0-6.0 molar equivalent (IV); Described aprotic solvent is methylene dichloride or 1, the 2-ethylene dichloride; Methylating reagent was a methyl-sulfate described in synthesis technique step (2) methylated, and consumption is substrate (III) or 1.0-3.0 molar equivalent (IV); Described mineral alkali consumption is substrate (III) or 0.5-3.0 molar equivalent (IV).
13. the synthetic method according to any described 3-methoxyl group-2-phenylacrylic acid methyl esters compounds in the claim 1～12 is characterized in that the synthesis technique step is:
(1) under the exsiccant nitrogen protection, in reaction flask, add methylene dichloride and titanium tetrachloride successively, be cooled to 10 ℃, under vigorous stirring, drip trimethyl orthoformate, behind the stirring at room 1h, cooling reaction solution to 0 ℃, drip (III) or (IV), behind the stirring at room 2h, cooling reaction solution to 5 ℃ adds stirring at room 1h behind the triethylamine, cooling reaction solution to 10 ℃, behind the dilute hydrochloric acid 10min of dropping 10%, add water washing, separatory;
(2) under the room temperature, in the organic phase of above-mentioned gained, add benzyltriethylammoinium chloride successively, 20% aqueous sodium hydroxide solution and methyl-sulfate.Add water washing after stirring 2h under the room temperature, the decompression precipitation gets product.
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