CN101407451A - Preparation method of 3,5-difluoroanisole - Google Patents
Preparation method of 3,5-difluoroanisole Download PDFInfo
- Publication number
- CN101407451A CN101407451A CNA2008100841622A CN200810084162A CN101407451A CN 101407451 A CN101407451 A CN 101407451A CN A2008100841622 A CNA2008100841622 A CN A2008100841622A CN 200810084162 A CN200810084162 A CN 200810084162A CN 101407451 A CN101407451 A CN 101407451A
- Authority
- CN
- China
- Prior art keywords
- difluoroanisole
- organic phase
- reaction
- water
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- OTGQPYSISUUHAF-UHFFFAOYSA-N 1,3-difluoro-5-methoxybenzene Chemical compound COC1=CC(F)=CC(F)=C1 OTGQPYSISUUHAF-UHFFFAOYSA-N 0.000 title abstract description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 72
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 27
- JXUKFFRPLNTYIV-UHFFFAOYSA-N 1,3,5-trifluorobenzene Chemical compound FC1=CC(F)=CC(F)=C1 JXUKFFRPLNTYIV-UHFFFAOYSA-N 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 90
- 239000012074 organic phase Substances 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- 238000004821 distillation Methods 0.000 claims description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 27
- 239000000706 filtrate Substances 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 238000000967 suction filtration Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000000638 solvent extraction Methods 0.000 claims description 5
- 125000001033 ether group Chemical group 0.000 claims description 3
- 239000000047 product Substances 0.000 abstract description 64
- 150000002894 organic compounds Chemical class 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 25
- 238000003756 stirring Methods 0.000 description 20
- 239000002994 raw material Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 238000001819 mass spectrum Methods 0.000 description 10
- 238000009833 condensation Methods 0.000 description 9
- 230000005494 condensation Effects 0.000 description 9
- 239000002253 acid Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000007086 side reaction Methods 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 238000006198 methoxylation reaction Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- -1 2,4 difluorobenzene amine Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- IMCCZKHIPVEUEI-UHFFFAOYSA-N n,n-difluoroaniline Chemical class FN(F)C1=CC=CC=C1 IMCCZKHIPVEUEI-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- RKWWASUTWAFKHA-UHFFFAOYSA-N 1-bromo-2,3-difluorobenzene Chemical class FC1=CC=CC(Br)=C1F RKWWASUTWAFKHA-UHFFFAOYSA-N 0.000 description 1
- UEMBNLWZFIWQFL-UHFFFAOYSA-N 3,5-dinitrophenol Chemical compound OC1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 UEMBNLWZFIWQFL-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- UKNLFGRCKMMVRB-UHFFFAOYSA-N bis(2-methylpropoxy)borinic acid Chemical class CC(C)COB(O)OCC(C)C UKNLFGRCKMMVRB-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Abstract
The invention relates to preparation of an organic compound, particularly to a method for preparing 3, 5-difluoro anisole, which belongs to the field of organic compound preparation technology. With the preparation of the organic compound, reaction products are obtained through a reaction between 1, 3, 5-trifluoro-benzene and sodium methoxide solution with the presence of solvent; then a post treatment is carried out to the reaction products to get 3, 5-difluoro anisole; the prepared product 3, 5-difluoro anisole has high purity and high product yield coefficient; in addition, the reaction steps are few and the production cycle of the product is short.
Description
Technical field
The present invention relates to a kind of preparation of organic compound, particularly a kind of 3, the preparation method of 5-difluoroanisole belongs to the preparing technical field of organic compound.
Background technology
3, the 5-difluoroanisole is a kind of important Minute Organic Synthesis intermediate, is mainly used in the synthetic of agricultural chemicals, medicine and liquid crystal material.
For 3, the preparation method of 5-difluoroanisole, existing both at home and abroad many researchs, Hebei Weiyuan Biochemical Co., Ltd.'s technique center army scholar qin, Cai Cuiyu, " 3, the preparation method of 5-difluoroanisole " that Tian Junbo delivers disclose several preparations 3 in the prior art, the method for 5-difluoroanisole:
(1) with 3, the 5-difluoroaniline is a raw material, makes through diazotization, bromination, methoxylation;
(2) with 3, the 5-dinitrophenol(DNP) is a raw material, makes through high-temperature fluorination, methoxylation;
(3) be raw material with 2,4 difluorobenzene amine, make through bromination, diazotization, hydrolysis, methoxylation.
Simultaneously, on the basis of existing said synthesis route, be raw material with 2,4 difluorobenzene amine, opened up a new synthetic route, make through bromination, diazotization, metaphosphoric acid acidifying, methoxyl group reaction, concrete reaction process is as follows:
(5) be that raw material carries out grignard reaction earlier with 3,5 one difluoro bromobenzenes, again with boric acid three isobutyl esters react 3,5 one two fluorobenzoic boric acid diisobutyl esters then through oxidation, the methyl-sulfate methoxylation gets final product;
(6) at Chemistry Letters (1996), Naoto Takechi, Yasushi Fukai, Kazuyoshi Oka, reported 3, a kind of synthetic route of 5-difluoroanisole among the An Unexpected Route to FluorinatedAnisoles of andRolf Huisgend
Raw material 3,5 one difluoroanilines, 3,5-dinitrophenol(DNP) price comparison costliness, so the time mesosome 3 that synthesizes, 5-difluoroanisole cost is higher, so should not adopt preceding two kinds of synthesis routes.Article three, and the 4th raw materials used 2,4 one difluoroanilines of operational path be easy to get, feasible process, but its reaction times is longer, yield is lower.Article five, feasible process, but its reaction times is longer, and yield is lower.Though route reaction conditions gentleness the 6th, raw material become height and yield only 68%.
The present invention provides a kind of minimizing reactions steps, shortens production life cycle, reduces production costs, one-step synthesis 3 on the basis of existing technology, the method for 5-difluoroanisole.
Summary of the invention
The object of the present invention is to provide a kind of preparation 3, the method of 5-difluoroanisole, by 1,3,5-trifluoro-benzene and sodium methylate react, add follow-up suitable aftertreatment, make prepared product 3,5-difluoroanisole purity height, product yield height, and reactions steps is few, and life cycle of the product is short.
To achieve these goals, the technical solution used in the present invention is:
A kind of 3, the preparation method of 5-difluoroanisole, described method comprises:
(1) with 1,3,5-trifluoro-benzene and sodium methoxide solution react under the condition that solvent exists, and obtain reaction product;
(2) described reaction product is carried out aftertreatment, obtain described 3, the 5-difluoroanisole.
Of the present invention 1,3,5-trifluoro-benzene and sodium methylate are 60-100 ℃ in temperature and react; Preferred described temperature is 60-80 ℃.
In the step of the present invention (1), described solvent is one or more the combination in toluene, methyl alcohol, dimethyl formamide or the tetrahydrofuran (THF); Preferred described solvent is a methyl alcohol.
Aftertreatment of the present invention comprises:
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid is washed with described solvent; After pH value of filtrate transferred to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole;
2) get the resulting water of step 1), extract with organic solvent, separatory obtains water and organic phase; Water is continued to use organic solvent extraction, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs.
Distillation of the present invention is air distillation, and the cut of collection is 140-155 ℃ a cut; Preferred described cut is 144-150 ℃ a cut; More preferably described cut is 144-148 ℃.
Organic solvent of the present invention comprises: a kind of in ether, methylene dichloride, ethyl acetate or the ethanol, preferred described organic solvent is ether or methylene dichloride.
The concentration of sodium methoxide solution of the present invention is counted 20-80% with methyl alcohol; Preferred described concentration is 30-70%.
The time of reaction is 5-32 hour in the step of the present invention (1), and the preferred described time is 10-28 hour.
Among the present invention, 1,3, when 5-trifluoro-benzene and sodium methylate reacted, mol ratio was 1: 1-3: 1, and preferred described mol ratio is 1: 1-2: 1.
Among the present invention, the described number of times that water is continued with organic solvent extraction is 2-5 time.
Specifically, with 1,3,5-trifluoro-benzene and sodium methylate are raw material among the present invention, synthesize 3, the 5-difluoroanisole, its
The main reaction reaction formula is as follows:
The side reaction reaction formula is as follows:
In above-mentioned reaction formula, though there is certain side reaction to take place, it is few that but above-mentioned two side reactions take place, therefore, content of by-products is very low in the reaction product that obtains, because the speed of response difference of main reaction and side reaction is very big, react even experimental results show that the longer time, surpass 36 hours such as time of reaction, by-product B content is also little in the product that obtains, the content of by-product A is very little especially, and, because the boiling point of principal product and by product is widely different, very easily separate, therefore the principal product of preparing by method of the present invention 3, the yield of 5-difluoroanisole and content are all very high.
Method of the present invention may further comprise the steps:
In reactor, add sodium methoxide solution under the normal temperature, wherein the concentration of sodium methoxide solution is counted 20-80% with methyl alcohol, preferred described concentration is 30-70%, slowly be added to solvent in the reactor then, stir at a slow speed, described solvent is one or more the combination in toluene, methyl alcohol, dimethyl formamide or the tetrahydrofuran (THF), and preferred described solvent is a methyl alcohol; With 1,3, the 5-trifluoro-benzene adds in the reaction flask under stirring condition, 1,3, the mol ratio of 5-trifluoro-benzene and sodium methylate is 1: 1-3: 1, preferred described mol ratio is 1: 1-2: 1, and heating, make that preferred described temperature is 60-80 ℃ under the condition that is reflected at 60-100 ℃, by TCL monitoring reaction progress, react after 5-32 hour, reaction product is carried out naturally cooling, carry out aftertreatment then.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises:
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid is washed with described solvent; Filtrate is diluted with hydrochloric acid or water, regulate the pH value to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-155 ℃ cut;
2) get the resulting water of step 1), extract with organic solvent, separatory obtains water and organic phase; Water is continued to use organic solvent extraction, merge organic phase afterwards, and organic phase distilled, obtain 3, the 5-difluoroanisole, described organic solvent comprises: a kind of in ether, methylene dichloride, ethyl acetate or the ethanol, and preferred described organic solvent is ether or methylene dichloride, described distillation is identical with step 1).
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs.
Product after weighing, through gas chromatographic detection, its purity 〉=99.5%, product yield is more than 95%.
With 1,3,5-trifluoro-benzene and sodium methylate react among the present invention, and solvent for use is one of following or more than one arbitrary combination toluene, methyl alcohol, DMF, THF all can be made solvent or solvent-free, particular methanol in the reaction.Temperature of reaction is controlled at 60 ℃～100 ℃, preferred 60 ℃～80 ℃.Sodium methylate concentration is control 20%～80% (CH
3Na is in methyl alcohol), preferred 30%～70%.With TCL monitoring reaction progress, the reaction times was controlled at 5～32 hours in the reaction process.
The invention has the beneficial effects as follows:
One, this synthetic route adopts 1,3, and the 5-trifluoro-benzene is made raw material.Because in the prior art, also not open with 1,3, the 5-trifluoro-benzene is that raw material is synthetic 3, the method for 5-difluoroanisole, and therefore, the present invention has opened up a kind of new synthetic 3, the method for 5-difluoroanisole.And from existing research, prior art generally believes with 1,3,5-trifluoro-benzene and sodium methylate reaction synthesize 3, in the process of 5-difluoroanisole, because 1,3, three fluorine atoms in the 5-trifluoro-benzene are in the position of equity, think to cause a large amount of side reactions to take place, the present invention has then overcome this technology prejudice, with 1,3, the 5-trifluoro-benzene is a raw material, in preparation 3, be surprised to find that in the process of 5-difluoroanisole that by method of the present invention, it is few to make side reaction take place, by product thereby prepare 3, the 5-difluoroanisole.
Two, single step reaction, the product yield height.Because the present invention adopts 1,3, the 5-trifluoro-benzene makes raw material and sodium methylate reacts, only need single step reaction can obtain 3, the 5-difluoroanisole, and in the method for prior art, usually will be through two step or three-step reactions, even it is more, just can obtain 3, the product of 5-difluoroanisole, the carrying out of a plurality of steps, the loss of each step etc. causes the yield of the finished product not high in the operating process, and by single step reaction of the present invention, make that the yield of the finished product is very high, its yield is more than 95%.
Three, the purity height of product.By reaction product is carried out aftertreatment, selected appropriate post processing mode among the present invention, made that the purity of resulting product is very high, the purity of common product 〉=99.5%.
Four, among the present invention, no matter be to need the solvent used in the reaction process, problem the such as still organic solvent of using in last handling process can use repeatedly, thereby fundamentally eliminate post-reaction treatment complexity in the traditional technology, and is seriously polluted.
Therefore, preparation 3 provided by the invention, the method for 5-difluoroanisole has safety simple to operate, the reaction yield height, advantage such as production cost is low, and three wastes discharge amount is few has bigger implementary value and economic results in society.
Description of drawings
Fig. 1 is the mass spectrum of the product of use preparation method's preparation of the present invention.
Embodiment
The present invention further specifies with reference to the following example, executes example but the present invention is not limited to these.
Embodiment 1
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 10.72mol (578.8g) solution, the concentration of sodium methoxide solution counts 20% with methyl alcohol, then the solvent methanol of 938mL slowly is added in the there-necked flask, stirs at a slow speed.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 70-80 ℃, after reaction is carried out 5 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid methanol wash 2 times; With filtrate with the salt acid for adjusting pH value of 0.1mol/L to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-148 ℃ cut;
2) get the resulting water of step 1), extract with ether, separatory obtains water and organic phase; Water is continued to use extracted with diethyl ether 2 times, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-148 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 737.2g.
3, the yield 95.5% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.6%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Embodiment 2
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 5.36mol (289.44g) solution, the concentration of sodium methoxide solution counts 30% with methyl alcohol, then the solvent toluene of 1000mL slowly is added in the there-necked flask, stirs at a slow speed.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 60-80 ℃, after reaction is carried out 10 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid methanol wash 2 times; With filtrate with the salt acid for adjusting pH value of 0.1mol/L to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-148 ℃ cut;
2) get the resulting water of step 1), extract with methylene dichloride, separatory obtains water and organic phase; Water is continued to use dichloromethane extraction 4 times, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-150 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 733.2g.
3, the yield 95.0% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.6%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Embodiment 3
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 8.04mol (434.16g) solution, the concentration of sodium methoxide solution counts 40% with methyl alcohol, then the solvent dimethyl formamide of 950mL slowly is added in the there-necked flask, stirs at a slow speed.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 60-100 ℃, after reaction is carried out 18 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid methanol wash 2 times; With filtrate with the salt acid for adjusting pH value of 0.1mol/L to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-148 ℃ cut;
2) get the resulting water of step 1), extract with ether, separatory obtains water and organic phase; Water is continued to use extracted with diethyl ether 2 times, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-148 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 740.19g.
3, the yield 95.9% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.7%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Embodiment 4
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 13.4mol (723.6g) solution, the concentration of sodium methoxide solution counts 40% with methyl alcohol, then the solvents tetrahydrofurane of 880mL slowly is added in the there-necked flask, stirs at a slow speed.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 70-80 ℃, after reaction is carried out 5 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid is washed 2 times with tetrahydrofuran (THF); With filtrate with the salt acid for adjusting pH value of 0.1mol/L to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 144-148 ℃ cut;
2) get the resulting water of step 1), extract with ethyl acetate, separatory obtains water and organic phase; Water is continued to use ethyl acetate extraction 3 times, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 144-148 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 739.42g.
3, the yield 95.8% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.5%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Embodiment 5
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 15mol (810g) solution, the concentration of sodium methoxide solution counts 50% with methyl alcohol, then the solvent methanol of 560mL slowly is added in the there-necked flask, stirs at a slow speed.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 70-80 ℃, after reaction is carried out 5 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid methanol wash 2 times; With filtrate with the salt acid for adjusting pH value of 0.1mol/L to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 144-150 ℃ cut;
2) get the resulting water of step 1), extract with ethanol, separatory obtains water and organic phase; Water is continued to use alcohol extraction 5 times, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 144-150 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 733.24g.
3, the yield 95.0% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.6%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Embodiment 6
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 16.08mol (868.32g) solution, the concentration of sodium methoxide solution counts 80% with methyl alcohol, slowly be added in the there-necked flask then the solvent of 450mL, stir at a slow speed, described solvent is that the volume ratio of dimethyl formamide and tetrahydrofuran (THF) is 1: 1 a mixing solutions.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 70-80 ℃, after reaction is carried out 5 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid is washed 2 times with above-mentioned reaction solvent; With the filtrate water dilution, make the pH value to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 144-150 ℃ cut;
2) get the resulting water of step 1), extract with ether, separatory obtains water and organic phase; Water is continued to use extracted with diethyl ether 3 times, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 144-150 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 738.65g.
3, the yield 95.7% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.6%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Embodiment 7
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 10.72mol (578.8g) solution, the concentration of sodium methoxide solution counts 20% with methyl alcohol, then the solvent methanol of 938mL slowly is added to the there-necked flask kind, stirs at a slow speed.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 70-80 ℃, after reaction is carried out 5 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid methanol wash 2 times; With the filtrate water dilution, make after the pH value neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 144-148 ℃ cut;
2) get the resulting water of step 1), extract with ethyl acetate, separatory obtains water and organic phase; Water is continued to use ethyl acetate extraction 5 times, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 144-148 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 737.2g.
3, the yield 95.5% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.8%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Embodiment 8
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 9.64mol (520.56g) solution, the concentration of sodium methoxide solution counts 30% with methyl alcohol, then the solvent of 780mL slowly is added to the there-necked flask kind, stir at a slow speed, described solvent is toluene and 1: 4 mixing solutions of tetrahydrofuran (THF) volume ratio.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 60-80 ℃, after reaction is carried out 10 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid methanol wash 2 times; With filtrate with the salt acid for adjusting pH value of 0.2mol/L to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-155 ℃ cut;
2) get the resulting water of step 1), extract with ether, separatory obtains water and organic phase; Water is continued to merge organic phase afterwards, and organic phase is distilled with extraction 2 times, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-155 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 744.82g.
3, the yield 96.5% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.57%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Embodiment 9
In the 5L there-necked flask of thermometer, spherical condensation tube and mechanical stirrer is housed, add at normal temperatures and contain sodium methylate 5.36mol (289.44g) solution, the concentration of sodium methoxide solution counts 40% with methyl alcohol, then the solvent dimethyl formamide of 950mL slowly is added to the there-necked flask kind, stirs at a slow speed.
Under stirring condition, with 5.36mol (708g) 1,3, the 5-trifluoro-benzene drops in the reaction flask, and heat temperature raising, makes to carry out under the condition be reflected at 60-100 ℃, after reaction is carried out 18 hours, stops heating, and with the reaction product naturally cooling.
Cooled reaction product is carried out aftertreatment, and described aftertreatment comprises
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid is washed 3 times with dimethyl formamide; With the filtrate water dilution, make the pH value to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-148 ℃ cut;
2) get the resulting water of step 1), extract with ether, separatory obtains water and organic phase; Water is continued to use extracted with diethyl ether 2 times, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole, described distillation is air distillation, collects 140-148 ℃ cut;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs, and product heavily is 742.51g.
3, the yield 96.2% of 5-difluoroanisole product, through gas chromatographic detection, its purity is 99.5%, the mass spectrum of products therefrom confirms that products therefrom is the purpose product as shown in Figure 1, promptly 3, the 5-difluoroanisole.
Claims (10)
1, a kind of 3, the preparation method of 5-difluoroanisole is characterized in that, described method comprises:
(1) with 1,3,5-trifluoro-benzene and sodium methoxide solution react under the condition that solvent exists, and obtain reaction product;
(2) described reaction product is carried out aftertreatment, obtain described 3, the 5-difluoroanisole.
2, method according to claim 1 is characterized in that, and is described 1,3, and 5-trifluoro-benzene and sodium methylate are 60-100 ℃ in temperature and react; Preferred described temperature is 60-80 ℃.
3, method according to claim 1 is characterized in that, in step (1), described solvent is one or more the combination in toluene, methyl alcohol, dimethyl formamide or the tetrahydrofuran (THF); Preferred described solvent is a methyl alcohol.
4, method according to claim 1 is characterized in that, described aftertreatment comprises:
1) reaction product is carried out suction filtration, obtain solid and filtrate, solid is washed with described solvent; After pH value of filtrate transferred to neutrality, leave standstill separatory, obtain water and organic phase; Get organic phase and distill, obtain 3, the 5-difluoroanisole;
2) get the resulting water of step 1), extract with organic solvent, separatory obtains water and organic phase; Water is continued to use organic solvent extraction, merge organic phase afterwards, and organic phase is distilled, obtain 3, the 5-difluoroanisole;
3) with step 1) and step 2) resulting 3, the 5-difluoroanisole merges, and weighs.
5, method according to claim 4 is characterized in that, described distillation is air distillation, and the cut of collection is 140-155 ℃ a cut; Preferred described cut is 144-150 ℃ a cut; More preferably described cut is 144-148 ℃.
6, method according to claim 4 is characterized in that, described organic solvent comprises: a kind of in ether, methylene dichloride, ethyl acetate or the ethanol, preferred described organic solvent is ether or methylene dichloride.
7, method according to claim 1 is characterized in that, the concentration of sodium methoxide solution is counted 20-80% with methyl alcohol; Preferred described concentration is 30-70%, and described concentration is mass volume ratio.
8, method according to claim 1 is characterized in that, the time of reaction is 5-32 hour in the described step (1), and the preferred described time is 10-28 hour.
9, method according to claim 1 is characterized in that, sodium methylate and 1,3, and when the 5-trifluoro-benzene reacted, mol ratio was 1: 1-3: 1, preferred described mol ratio is 1: 1-2: 1.
10, method according to claim 4 is characterized in that, the described number of times that water is continued with organic solvent extraction is 2-5 time.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100841622A CN101407451B (en) | 2008-03-27 | 2008-03-27 | Preparation method of 3,5-difluoroanisole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100841622A CN101407451B (en) | 2008-03-27 | 2008-03-27 | Preparation method of 3,5-difluoroanisole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101407451A true CN101407451A (en) | 2009-04-15 |
| CN101407451B CN101407451B (en) | 2012-05-02 |
Family
ID=40570693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100841622A Active CN101407451B (en) | 2008-03-27 | 2008-03-27 | Preparation method of 3,5-difluoroanisole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101407451B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012081A (en) * | 2011-09-20 | 2013-04-03 | 烟台九目化学制品有限公司 | 4-iodophenylether derivative preparation method |
| CN106478377A (en) * | 2016-08-28 | 2017-03-08 | 浙江林江化工股份有限公司 | A kind of synthetic method of 2,3 difluoro 5 bromophenol |
| GB2489890B (en) * | 2010-01-14 | 2017-08-30 | Commissariat L Energie Atomique Et Aux Energies Alternatives | Method for synthesizing 3,5-dichloroanisole from 1,3,5-trichlorobenzene |
| CN108586204A (en) * | 2018-05-28 | 2018-09-28 | 朱晓萍 | A kind of synthesis technology of 2,3- difluorophenols |
| CN114835562A (en) * | 2022-06-27 | 2022-08-02 | 山东华安新材料有限公司 | Preparation method of methoxyflurane |
-
2008
- 2008-03-27 CN CN2008100841622A patent/CN101407451B/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2489890B (en) * | 2010-01-14 | 2017-08-30 | Commissariat L Energie Atomique Et Aux Energies Alternatives | Method for synthesizing 3,5-dichloroanisole from 1,3,5-trichlorobenzene |
| CN103012081A (en) * | 2011-09-20 | 2013-04-03 | 烟台九目化学制品有限公司 | 4-iodophenylether derivative preparation method |
| CN103012081B (en) * | 2011-09-20 | 2015-01-28 | 烟台九目化学制品有限公司 | 4-iodophenylether derivative preparation method |
| CN106478377A (en) * | 2016-08-28 | 2017-03-08 | 浙江林江化工股份有限公司 | A kind of synthetic method of 2,3 difluoro 5 bromophenol |
| CN106478377B (en) * | 2016-08-28 | 2019-10-01 | 浙江林江化工股份有限公司 | A kind of synthetic method of 2,3- Difluoro-5-Bromophenol |
| CN108586204A (en) * | 2018-05-28 | 2018-09-28 | 朱晓萍 | A kind of synthesis technology of 2,3- difluorophenols |
| CN114835562A (en) * | 2022-06-27 | 2022-08-02 | 山东华安新材料有限公司 | Preparation method of methoxyflurane |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101407451B (en) | 2012-05-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106242971B (en) | A kind of chloracetate synthesis in water technology and its new method for preparing 2,4-D ester | |
| CN101407451B (en) | Preparation method of 3,5-difluoroanisole | |
| CN102924301A (en) | Preparation method of N,N-bis(2-hydroxyethyl)isopropanolamine | |
| CN115785032A (en) | Synthesis method of intermediate alpha-chloroacetyl-gamma-butyrolactone and synthesis method of thiathiazole | |
| CN107935921A (en) | A kind of preparation method of 2,3 dichloropyridine | |
| CN106478381B (en) | A method of bis ether fluorenes is prepared by catalyzing epoxyethane | |
| CN109678698B (en) | Preparation method of 2, 4-dichlorobenzoyl chloride | |
| CN103694119A (en) | Preparation method of ethyl 4,4,4-trifluoroacetoacetate | |
| CN114805019A (en) | Method for synthesizing 2-aryl-1-cyclohexanol based on continuous flow reaction technology | |
| CN104030922A (en) | Method for preparing dimethyl n-butyl malonate | |
| CN103058984A (en) | Synthesis method of watermelon ketone | |
| CN102775311B (en) | Preparation method of isooctyl salicylate | |
| Frost | Preparation and Properties of Some Negatively-substituted Organosilanes | |
| CN108752205A (en) | The industrialized production modified technique of one kind (R) -2- (4- chloro-2-methyl benzene oxygen) octyl propionate root resistance agent | |
| CN102276426A (en) | Novel synthetic method of 3, 4, 5-trihydroxystilbene | |
| CN111393869B (en) | Fluorescent dye containing phenylethynyl naphthalene, preparation method and application thereof | |
| CN103145554A (en) | Preparation method of 1-decanoyl-rac-glycerol compound | |
| CN105622350A (en) | Synthesis method of resveratrol | |
| CN104003850B (en) | A kind of preparation method of 2-chloroethoxy-2-oxyethyl group di-alcohol | |
| CN100532423C (en) | Plastic of polyester ketone containing fluorin, and preparation method | |
| JPS62108839A (en) | Production of 3-fluorobenzoic acid compound | |
| CN108752218A (en) | A kind of variation route prepared by Du Lutewei key intermediates 2,4- difluorobenzylamines | |
| CN110981756A (en) | Hexafluoroisopropyl acrylate monomer and preparation method thereof | |
| CN104529726A (en) | Preparation method of hydroxyacetophenone | |
| CN113788754B (en) | Preparation method of bifenthrin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of 3,5-difluorobenzyl ether Granted publication date: 20120502 Pledgee: Bank of China Limited Xingtang Branch Pledgor: HEBEI MILESTONE ELECTRONIC MATERIAL Co.,Ltd. Registration number: Y2024130000004 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |