CN102731269B - Synthesis method of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol - Google Patents
Synthesis method of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol Download PDFInfo
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Abstract
The invention discloses a synthesis method of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol. The method comprises the following reaction steps of: 1, reacting 2,3,5,6-tetrafluorobenzyl alcohol with hydrogen halide in a solvent for 2-20h at 40-120 DEG C to obtain 3-halomethyl-1,2,4,5-tetrafluorobenzene; 2, reacting the 3-halomethyl-1,2,4,5-tetrafluorobenzene in methanol for 1-20h at 0-65 DEG C under the action of an inorganic alkali to obtain 3-methoxymethyl-1,2,4,5-tetrafluorobenzene; 3, dissolving the 3-methoxymethyl-1,2,4,5-tetrafluorobenzene into an inert solvent, dripping an organic lithium reagent at 0-78 DEG C to react for 0.5-5h, inputting formaldehyde gas into the reaction system to continuously react for 0.5-5h, and carrying out the quenching reaction by a protonic solvent to obtain the 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol. The synthesis method provided by the invention has the advantages of good reaction selectivity, cheap and available reagents, and high reaction yield and high purity of the product.
Description
Technical field:
The present invention relates to a kind of 4-methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, specifically, relate to a kind of with 2,3,5,6-tetrafluorobenzyl alcohol for raw material, synthetic 4-methoxymethyl-2, the method for 3,5,6-tetrafluorobenzyl alcohol.
Background technology:
4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol is the key intermediate of synthetic tetra fluoro benzene.Tetra fluoro benzene is the health pyrethroid insecticides of a kind of high-efficiency low-toxicity of SUMITOMO CHEMICAL chemical industry Co., Ltd. exploitation, is mainly used in the control of sanitary insect pest, and market outlook are wide.
4-methoxymethyl-2 that have at present bibliographical information, 3,5,6-tetrafluorobenzyl alcohol synthetic method mainly contains following several:
1, take tetrafluoro terephthalyl alcohol as raw material, under methylating reagent effect, through selective methylation reaction, obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol.
As the patent of invention CN1297875 of SUMITOMO CHEMICAL chemical industry Co., Ltd. application, adopt methyl-sulfate as methylating reagent, the patent of invention CN101913997 of Guizhou cypress silk specialization work application adopts methyl chloride as methylating reagent.Although the method step is the shortest, only need single step reaction to get final product to obtain target compound, because two hydroxyls all exist methylated possibility, therefore inevitably generate dme by product, increased the difficulty of product purification, affect the raising of product purity.In addition, methylating reagent is Shortcomings also, and methyl-sulfate toxicity is too high, and methyl chloride is gas, uses more inconvenient.
2, take tetrafluoro terephthalyl alcohol as raw material, through halo, methoxylation, obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol.
As the patent of invention JP2000344703 of SUMITOMO CHEMICAL chemical industry Co., Ltd. application.The method be take tetrafluoro terephthalyl alcohol equally as raw material, therefore, when halogenating reaction, inevitably generates dihalo thing, and when methoxylation, also have the even possibility of poly of dimerization, thereby make product purity lower, impurity forms complicated, purification difficult.
3, at document J.Fluo. Chem. 130 (2009), in 938-941, reported with 2,3,5,6-tetrafluorobenzyl alcohol is raw material, first under methyl-sulfate effect, obtains methoxymethyl tetra fluoro benzene, then under highly basic effect, obtains methoxymethyl tetrafluorobenzoic aid with carbon dioxide reaction, through reduction reaction, obtain 4-methoxymethyl-2 again, 3,5,6-tetrafluorobenzyl alcohol.
This method is with 2,3,5,6-tetrafluorobenzyl alcohol is raw material, has avoided the problem of reaction preference, and weak point is to use hypertoxic methyl-sulfate as methylating reagent, do not meet green synthetic requirement, simultaneous reactions need be reduced into the step of alcohol through acid, reductive agent used is expensive, and reaction conditions is harsher.
Summary of the invention:
The object of the present invention is to provide a kind of 4-methoxymethyl-2 of novelty, the advantage such as the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, has good reaction selectivity, and reagent is cheap and easy to get and environmentally friendly, and reaction yield is high, good product purity.
The technical solution used in the present invention, a kind of 4-methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, is characterized in that:
Comprise following reactions steps:
(1) 2,3,5,6-tetrafluorobenzyl alcohol (I) in solvent, with hydrogen halide in 40~120
oc reaction 2~20 hours, obtains 3-monochloromethyl-1,2,4,5-tetra fluoro benzene (II);
(2) 3-monochloromethyl-1,2,4,5-tetra fluoro benzene (II) is in methyl alcohol, under mineral alkali effect, in 0~65
oc reaction 1~20 hour, obtains 3-methoxymethyl-1,2,4,5-tetra fluoro benzene (III);
(3) 3-methoxymethyl-1,2,4,5-tetra fluoro benzene (III) is dissolved in inert solvent, in 0~-78
ounder C, drip organolithium reagent, react 0.5~5 hour, pass into dry formaldehyde gas, continue reaction 0.5~5 hour, through protic solvent cancellation reaction, obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol (IV).
The synthetic route that the present invention adopts can be with shown in following reaction formula:
。
Further arrange as follows:
A kind of 4-of the present invention methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, in synthesis step 1, hydrogen halide used is selected from one or both in hydrogenchloride, hydrogen bromide; Hydrogen halide add mode without particular restriction, can disposablely add enough hydrogen halide, also can in reaction process, add hydrogen halide in batches; The existence form of hydrogen halide can be hydrogen halide, can be also hydrogen halide solution, if solution, the aqueous solution of preferred corresponding hydrogen halide; The consumption of hydrogen halide with guarantee compound (I) fully reaction be as the criterion, 1~10 times of the amount of substance that preferred hydrogen halide consumption is compound (I).
A kind of 4-of the present invention methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, in synthesis step 1, solvent used can be single solvent, can be also mixed solvent, preferred solvent composition is mixed solvent.In mixed solvent, wherein a kind of solvent is preferably water, and other solvent is organic solvent, is selected from following one or more mixing: the alkane solvents such as normal hexane, hexanaphthene, normal heptane, octane, the aromatic hydrocarbon solvents such as benzene,toluene,xylene; In mixed solvent, the volume ratio of organic solvent and water is 5:1~1:5; Solvent load is 1~20 times of compound (I) quality.
A kind of 4-of the present invention methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, in synthesis step 1, temperature of reaction is 40~120
oc.It should be noted that, reaction can be carried out under system reflux state, but because system refluxes, will speed up hydrogen halide and volatilize from reaction system, thereby need more hydrogen halide just can react fully and carry out, therefore preferred temperature of reaction should be lower than the reflux temperature of practical systems.
A kind of 4-of the present invention methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, in synthesis step 1, reaction can be carried out under normal pressure (or being uncovered system) condition, also can under pressurization (or being enclosed system) condition, carry out.Under normal pressure (or being uncovered system), react, easily cause the volatilization loss of hydrogen halide, hydrogen halide consumption is increased and reaction times prolongation, but lower to the requirement of conversion unit.Under pressurization (or being enclosed system), carry out, can avoid hydrogen halide volatilization loss, simultaneous reactions temperature can obtain suitable raising (along with system pressure raises, system reflux temperature is corresponding rising also), thereby can reduce consumption the Reaction time shorten of hydrogen halide, but to also corresponding raising of the requirement of conversion unit.Under pressurization (or being enclosed system), react, reaction system pressure is preferably 0.1-0.5 MPa.
A kind of 4-of the present invention methoxymethyl-2,3,5, the synthetic method of 6-tetrafluorobenzyl alcohol, in synthesis step 1, the reaction times is 2~20 hours, the concrete reaction times, by HPLC or GC Analysis deterrmination, is reaction end when compound (I) content (area normalization method) is less than 2 %.
A kind of 4-of the present invention methoxymethyl-2,3,5, the synthetic method of 6-tetrafluorobenzyl alcohol, in synthesis step 2, mineral alkali used, is selected from following one or more mixing: lithium hydroxide, sodium hydroxide, potassium hydroxide, Quilonum Retard, sodium carbonate, salt of wormwood, lithium bicarbonate, sodium bicarbonate, saleratus; The consumption of alkali is 1~3 times of compound (II) amount of substance.Except above-mentioned mineral alkali, also can adopt sodium methylate to use as alkali, when using sodium methylate to make alkali, solvent can be used methyl alcohol, also can use inert solvent, as tetrahydrofuran (THF), 2-methyltetrahydrofuran, toluene etc., but because its cost is relatively high, therefore do not there is economically competitive power.
A kind of 4-of the present invention methoxymethyl-2,3,5, the synthetic method of 6-tetrafluorobenzyl alcohol, in synthesis step 2, reaction times is 1~20 hour, and the concrete reaction times, by HPLC or GC Analysis deterrmination, is reaction end when compound (II) content (area normalization method) is less than 1 %.
A kind of 4-of the present invention methoxymethyl-2,3,5, the synthetic method of 6-tetrafluorobenzyl alcohol, in synthesis step 3, inert solvent used, be selected from following one or more mixing: tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1, the ether solvents such as 4-dioxane, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, the alkane solvents such as normal hexane, hexanaphthene, normal heptane, octane, the aromatic hydrocarbon solvents such as benzene,toluene,xylene; Solvent load is 1~10 times of compound (III) quality.
A kind of 4-of the present invention methoxymethyl-2,3,5, the synthetic method of 6-tetrafluorobenzyl alcohol, in synthesis step 3, organolithium reagent used, is selected from following one or more mixing: n-Butyl Lithium, isobutyl-lithium, s-butyl lithium, tert-butyl lithium, n-propyl lithium, isopropyl lithium, lithium methide, diisopropylamine lithium (LDA), LHMDS (LHMDS); The effective concentration of organolithium reagent is pressed commodity marks concentration and is calculated, during use without carrying out any dilution or concentrated; The ratio of the amount of substance of organolithium reagent and compound (III) is: 1:1~1.5:1; The rate of addition of organolithium reagent so that reaction system in temperature control in the range of reaction temperature requiring, determine.
A kind of 4-of the present invention methoxymethyl-2,3,5, the synthetic method of 6-tetrafluorobenzyl alcohol, in synthesis step 3, dry formaldehyde gas used, can prepare in the following way: heating paraformaldehyde, trioxymethylene, formalin produce, and obtain after drying; Formaldehyde gas can directly pass into reaction system, and the mode that also can carry by rare gas element enters reaction system; If adopted carrying mode, rare gas element used is selected from following one or both mixing: nitrogen, helium; The ratio of the amount of substance of formaldehyde and compound (III) is: 1:1~3:1; Formaldehyde gas pass into speed so that reaction system in temperature control in the range of reaction temperature requiring, determine.
A kind of 4-of the present invention methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, in synthesis step 3, temperature of reaction is 0~-78
oc, preferred temperature of reaction is-30~-70
oc.
A kind of 4-of the present invention methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, in synthesis step 3, for the protic solvent of cancellation reaction system, is selected from following one or more mixing: water, methyl alcohol, ethanol, formic acid, acetic acid.
Compared with prior art, its useful effect is embodied in the present invention:
(1) fundamentally solve the selective problems of reaction, reduced the generation of by product, reduced product purification difficulty, improved product purity;
(2) avoided the use of poisonous reagent methyl-sulfate, agents useful for same is cheap and easy to get and environmentally friendly;
(3) compound (II), under highly basic effect, reacts and obtains product with formaldehyde gas, has avoided first generating in prior art carboxylic acid, then by operations such as carboxylic acid reduction, has shortened reactions steps, has improved the economy of reaction;
(4) to have reaction yield high for this synthetic method, the advantages such as good product purity.
Embodiment:
With specific embodiment, further illustrate technical scheme of the present invention below, but protection scope of the present invention is not limited to this:
Embodiment mono-:
In 500 milliliters of four-hole boiling flasks that mechanical stirring, thermometer, prolong are housed, add 50 grams of compounds (I), 150 grams of concentrated hydrochloric acids, 200 grams of toluene, stir and are warming up to 70
oc reaction 10 hours, reaction system is cooled to room temperature, separates organic phase, and drying, precipitation obtain 49.8 grams of compounds (II, X=Cl), purity 98.3 %.
Embodiment bis-:
In 500 milliliters of four-hole boiling flasks that mechanical stirring, thermometer, prolong are housed, add 54 grams of compounds (I), 130 grams of concentrated hydrochloric acids, 250 grams of normal heptanes, stir and are warming up to 75
oc reaction 8 hours, reaction system separates organic phase, and cooling crystallization filters, and obtains 50.3 grams of compounds (II, X=Cl), purity 99.2 %.
Embodiment tri-:
In 500 milliliters of withstand voltage reactors, add 30 grams of compounds (I), 40 grams of concentrated hydrochloric acids, 120 grams of normal heptanes, confined reaction system, stirs and is warming up to 90
oc reaction 6 hours, reaction system is cooled to room temperature, filters, and obtains 31.0 grams of compounds (II, X=Cl), purity 98.8 %.
Embodiment tetra-:
In 250 milliliters of there-necked flasks that mechanical stirring, thermometer, reflux water-dividing device are housed, add 30 grams of compounds (I), 48 50 grams of % hydrobromic acid solutions, 200 grams of toluene, stir and heat up, reflux water-dividing is to anhydrous separating, and reaction system desolvation, obtains compound (II, X=Br) 36.4 grams, purity 98.5 %.
Embodiment five:
In 500 milliliters of four-hole boiling flasks that mechanical stirring, thermometer, bubbling pipe, prolong are housed, add 50 grams of compounds (I), 120 grams, water, 250 grams of toluene, stir and are warming up to 80
oc, through bubbling pipe, in the mode of bubbling, lead to hydrogen chloride gas 1 hour, insulation reaction, every 1 hour, logical hydrogen chloride gas 15 minutes, HPLC detects to little 2 % of compound (I) content, and reaction system is cooled to room temperature, separates organic phase, drying, precipitation, obtain 48.5 grams of compounds (II, X=Cl), purity 98.6 %.
Embodiment six:
In being housed, 250 milliliters of there-necked flasks of mechanical stirring, thermometer add 30 grams of compounds (II, X=Cl), 100 grams of methyl alcohol, and 23 grams of Anhydrous potassium carbonates, stir and are warming up to 50
oc reaction 4 hours, reaction system desolvation, adds 100 grams, water, stirs, and by 50 grams of extracting twice of ethyl acetate, merges organic phase, drying, precipitation, obtains 27.1 grams of compounds (III), purity 99.2 %.
Embodiment seven:
In being housed, 250 milliliters of there-necked flasks of mechanical stirring, thermometer add 50 grams of compounds (II, X=Cl), 150 grams of methyl alcohol, 20 grams, sodium hydroxide, stirring at room reaction 8 hours, reaction system desolvation, add 100 grams, water, stir, by 70 grams of extracting twice of ethyl acetate, merge organic phase, drying, precipitation, obtains 44.8 grams of compounds (III), purity 98.4 %.
Embodiment eight:
In being housed, 100 milliliters of there-necked flasks of mechanical stirring, thermometer add 10 grams of compounds (II, X=Cl), 50 grams of anhydrous methanols, 15 grams of saleratus, temperature rising reflux reaction 7 hours, reaction system desolvation, add 50 grams, water, stir, by 20 grams of extracting twice of ethyl acetate, merge organic phase, drying, precipitation, obtains 8.8 grams of compounds (III), purity 98.1 %.
Embodiment nine:
In being housed, 500 milliliters of four-hole boiling flasks of mechanical stirring, thermometer add 50 grams of compounds (II, X=Br), 300 grams of anhydrous methanols, and 33 grams, sodium carbonate, stirs and is warming up to 40
oc reaction 6 hours, reaction system desolvation, adds 100 grams, water, stirs, and by 70 grams of extracting twice of ethyl acetate, merges organic phase, drying, precipitation, obtains 37.5 grams of compounds (III), purity 99.0 %.
Embodiment ten:
In 500 milliliters of four-hole boiling flasks that mechanical stirring, thermometer, bubbling pipe, constant pressure funnel are housed, add 40 grams of compounds (III), 120 grams of anhydrous glycol dimethyl ethers stir and are cooled to-40 under nitrogen protection
oc, 140 milliliters of the hexane solutions (1.6 mol/L) of dropping n-Butyl Lithium, after dropwising, continue to stir 0.5 hour, in system, pass into formaldehyde gas (generated after adding thermal depolymerization by 12.5 grams of paraformaldehydes, and slowly brought into by nitrogen gas stream), after logical finishing, continue to stir 0.5 hour.Reaction system is warming up to 0
oc, drips 100 grams of water, filters, and removes insolubles, and filtrate, with 50 grams of extractions of ethyl acetate 2 times, merges organic phase, drying, precipitation, distills to obtain 41.3 grams of compounds (IV), purity 99.3 %.
Embodiment 11:
In 500 milliliters of four-hole boiling flasks that mechanical stirring, thermometer, bubbling pipe, constant pressure funnel are housed, add 30 grams of compounds (III), 70 grams of anhydrous tetrahydro furans stir and are cooled to-40 under nitrogen protection
oc, drips diisopropylamine lithium solution (2.0 mol/L) 100 milliliters, after dropwising, continue to stir 1 hour, in system, pass into formaldehyde gas (generated after adding thermal depolymerization by 12 grams of paraformaldehydes, and slowly brought into by nitrogen gas stream), after logical finishing, continue to stir 1 hour.Reaction system is warming up to 10
oc, drips 80 grams of water, filters, and removes insolubles, and filtrate, with 40 grams of extractions of ethyl acetate 2 times, merges organic phase, drying, precipitation, distills to obtain 31.8 grams of compounds (IV), purity 99.2 %.
Embodiment 12:
In 500 milliliters of there-necked flasks that mechanical stirring, thermometer, bubbling pipe, constant pressure funnel are housed, add 30 grams of compounds (III), 70 grams of anhydrous tetrahydro furans stir and are cooled to-70 under nitrogen protection
oc, 105 milliliters of the hexane solutions (1.6 mol/L) of dropping n-Butyl Lithium, after dropwising, continue to stir 1 hour, in system, pass into formaldehyde gas (generated after adding thermal depolymerization by 12 grams of paraformaldehydes, and slowly brought into by nitrogen gas stream), after logical finishing, continue to stir 1 hour.Reaction system is warming up to 10
oc, drips 70 grams of water, filters, and removes insolubles, and filtrate, with 40 grams of extractions of ethyl acetate 2 times, merges organic phase, drying, precipitation, distills to obtain 32.2 grams of compounds (IV), purity 99.1 %.
Embodiment 13:
In 500 milliliters of four-hole boiling flasks that mechanical stirring, thermometer, bubbling pipe, constant pressure funnel are housed, add 25 grams of compounds (III), 70 grams of anhydrous tetrahydro furans stir and are cooled to-50 under nitrogen protection
oc, 90 milliliters of the hexane solutions (1.6 mol/L) of dropping n-Butyl Lithium, after dropwising, continue to stir 0.5 hour, in system, pass into formaldehyde gas (generated after adding thermal depolymerization by 11 grams of trioxymethylenes, and slowly brought into by nitrogen gas stream), after logical finishing, continue to stir 1 hour.Reaction system is warming up to 10
oc, drips 50 grams of water, filters, and removes insolubles, and filtrate, with 40 grams of extractions of ethyl acetate 2 times, merges organic phase, drying, precipitation, distills to obtain 25.9 grams of compounds (IV), purity 99.0 %.
Embodiment 14:
In 500 milliliters of four-hole boiling flasks that mechanical stirring, thermometer, bubbling pipe, constant pressure funnel are housed, add 35 grams of compounds (III), 105 grams of anhydrous 2-methyltetrahydrofurans stir and are cooled to-60 under nitrogen protection
oc, 135 milliliters of the hexane solutions (1.6 mol/L) of dropping isobutyl-lithium, after dropwising, continue to stir 1 hour, in system, pass into formaldehyde gas (generated after adding thermal depolymerization by 11 grams of paraformaldehydes, and slowly brought into by nitrogen gas stream), after logical finishing, continue to stir 0.5 hour.Reaction system is warming up to 5
oc, drips 90 grams of water, filters, and removes insolubles, and filtrate, with 30 grams of extractions of 2-methyltetrahydrofuran 2 times, merges organic phase, drying, precipitation, distills to obtain 37.2 grams of compounds (IV), purity 99.3 %.
Embodiment 15:
In 250 milliliters of there-necked flasks that mechanical stirring, thermometer, bubbling pipe, constant pressure funnel are housed, add 20 grams of compounds (III), 50 grams of anhydrous 2-methyltetrahydrofurans stir and are cooled to-60 under nitrogen protection
oc, 70 milliliters of the hexane solutions (1.6 mol/L) of dropping n-Butyl Lithium, after dropwising, continue to stir 0.5 hour, in system, pass into formaldehyde gas (generated after adding thermal depolymerization by 7 grams of paraformaldehydes, and slowly brought into by nitrogen gas stream), after logical finishing, continue to stir 0.5 hour.Reaction system is warming up to 5
oc, drips 50 grams of water, filters, and removes insolubles, and filtrate, with 30 grams of extractions of 2-methyltetrahydrofuran 2 times, merges organic phase, drying, concentrates, distills and to obtain 20.1 grams of compounds (IV), purity 99.4 %.
Claims (2)
1. 4-methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, is characterized in that, comprises following reactions steps:
(1) 2,3,5,6-tetrafluorobenzyl alcohol in solvent, with hydrogen halide in 40~120
oc reaction 2~20 hours, obtains 3-monochloromethyl-1,2,4,5-tetra fluoro benzene;
In synthesis step 1, hydrogen halide used is selected from one or both in hydrogenchloride, hydrogen bromide; Hydrogen halide consumption is 1~10 times of 2,3,5,6-tetrafluorobenzyl alcohol amount of substance;
In synthesis step 1, solvent used is mixed solvent, and solvent load is 2,3,1~20 times of 5,6-tetrafluorobenzyl alcohol quality, in mixed solvent, wherein solvent is a water, and other solvent is organic solvent, and the volume ratio of organic solvent and water is 5:1~1:5; Described organic solvent is selected from following one or more mixing: normal hexane, hexanaphthene, normal heptane, octane, benzene,toluene,xylene;
(2) 3-monochloromethyl-1,2,4,5-tetra fluoro benzene is in methyl alcohol, under mineral alkali effect, in 0~65
oc reaction 1~20 hour, obtains 3-methoxymethyl-1,2,4,5-tetra fluoro benzene;
In synthesis step 2, mineral alkali used, be selected from following one or more: lithium hydroxide, sodium hydroxide, potassium hydroxide, Quilonum Retard, sodium carbonate, salt of wormwood, lithium bicarbonate, sodium bicarbonate, saleratus; The consumption of alkali is 3-monochloromethyl-1,1~3 times of 2,4,5-tetra fluoro benzene amount of substance;
(3) 3-methoxymethyl-1,2,4,5-tetra fluoro benzene is dissolved in inert solvent, in 0~-78
ounder C, drip organolithium reagent, react 0.5~5 hour, pass into dry formaldehyde gas, continue reaction 0.5~5 hour, through protic solvent cancellation reaction, obtain 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol;
In synthesis step 3, inert solvent used, be selected from following one or more: tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, isopropyl ether, methyl tertiary butyl ether, glycol dimethyl ether, diethylene glycol dimethyl ether, normal hexane, hexanaphthene, normal heptane, octane, benzene,toluene,xylene; Solvent load is 3-methoxymethyl-1,1~10 times of 2,4,5-tetra fluoro benzene quality;
In synthesis step 3, organolithium reagent used, be selected from following one or more: n-Butyl Lithium, isobutyl-lithium, s-butyl lithium, tert-butyl lithium, n-propyl lithium, isopropyl lithium, lithium methide, diisopropylamine lithium, LHMDS; Organolithium reagent and 3-methoxymethyl-1, the ratio of the amount of substance of 2,4,5-tetra fluoro benzene is: 1:1~1.5:1;
In synthesis step 3, for the protic solvent of cancellation reaction system, be selected from following one or more: water, methyl alcohol, ethanol, formic acid, acetic acid.
2. a kind of 4-according to claim 1 methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, is characterized in that: in synthesis step 1, reaction is carried out under normal pressure or pressurized conditions; System pressure under pressurized conditions is 0.1-0.5 MPa.
3. a kind of 4-according to claim 1 methoxymethyl-2,3,5, the synthetic method of 6-tetrafluorobenzyl alcohol, it is characterized in that: in synthesis step 3, dry formaldehyde gas used, in the following way preparation: heating paraformaldehyde, trioxymethylene or formalin produce, and obtain after drying; Formaldehyde and 3-methoxymethyl-1, the ratio of the amount of substance of 2,4,5-tetra fluoro benzene is: 1:1~3:1; Dried formaldehyde gas directly passes into reaction system or the mode of carrying by rare gas element enters reaction system; If adopted carrying mode, rare gas element used is selected from following one or both mixing: nitrogen, helium.
4. a kind of 4-according to claim 1 methoxymethyl-2, the synthetic method of 3,5,6-tetrafluorobenzyl alcohol, is characterized in that: in synthesis step 3, temperature of reaction is 0~-78
oc.
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