CN102796003B - Preparation method of 2-fluoro-4,5-dichloronitrobenzene - Google Patents

Preparation method of 2-fluoro-4,5-dichloronitrobenzene Download PDF

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CN102796003B
CN102796003B CN201210238247.8A CN201210238247A CN102796003B CN 102796003 B CN102796003 B CN 102796003B CN 201210238247 A CN201210238247 A CN 201210238247A CN 102796003 B CN102796003 B CN 102796003B
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fluoroaniline
chloro
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CN102796003A (en
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陈兴权
蒋锐
董燕敏
郝永兵
王林
殷杰
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Jining Xinruida Information Technology Co ltd
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Changzhou University
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Abstract

The invention discloses a preparation method of 2-fluoro-4,5-dichloronitrobenzene, relating to the technical field of preparation of medicine and pesticide intermediates. The industrialized preparation method of the 2-fluoro-4,5-dichloronitrobenzene comprises the following steps: by using 4-fluoroaniline as an initial raw material, carrying out acetylation, chlorination, hydrolysis, diazotization-Sandmeyer reaction and nitrification to synthesize the 2-fluoro-4,5-dichloronitrobenzene. The 2-fluoro-4,5-dichloronitrobenzene prepared by the method disclosed by the invention is a light yellow solid, and the purity is 98.5%; the raw material conversion rate for each reaction step reaches 100%; and the total yield of the whole process is up to 27.1%.

Description

2-is fluoro-4, the preparation method of 5-dichloronitrobenzene
Technical field
The present invention relates to the preparing technical field of medicine, pesticide intermediate, specifically, the present invention is that a kind of 2-is fluoro-4, the preparation method of 5-dichloronitrobenzene.
Background technology
2-is fluoro-4, and 5-dichloronitrobenzene is as a kind of important medicine, pesticide intermediate, and purposes is very extensive, as synthesized 1) dibenzocycloheptene derivative, this compounds can be treated nervous disorders.(Ek Fredyik, Olsson Roger, Ohlsson Jorgen. Amino-substituted diaryl[a, d] cycloheptene analogs as for preparing them, and their use as muscarinic agonists[P]. WO 2008021463 A2,2008-02-21); 2) there is benzsulfamide and the benzimidizole derivatives of anti-microbial property.(Brooks Carl, Goodman Krista B, Cleary Pamela A, et al. Benzenesulfonamide inhibitor of CCR2 chemokine receptor[P]. WO 2007014054 A2,2007-02-01); 3) quinazoline derivant, the activity of arrestin matter Tyrosylprotein kinase effectively, reduces the occurrence probability of cancer, diabetes.(Ahn Young Gil, Kim Jong Woo, Bang Chant, et al. Quinazoline derivatives as a multiplex inhibitor and method for the preparation thereof[P]. WO 2007055514 A1,2007-05-18); 4) pyrimidine carboxylic acid derivatives, they are a kind of wide spectrum, efficient weedicide.（Epp?Jeffrey,?Lo?William,?Schmitzer?Paul.?2-(2-Fluoro-substitutedphenyl)-6-amino-5-choloro-4-pyrimidinecarboxylates?and?their?use?as?herbicides[P].?WO?2009023438?A2,?2009-02-19）。But there are no the report of its synthetic method, therefore, develop a synthetic route very necessary at present.
Summary of the invention
The object of this invention is to provide synthetic 2-fluoro-4, the method for 5-dichloronitrobenzene and technique, to meet industrial production needs.
The inventive method is take para-fluoroaniline as raw material, is synthesized into 2-fluoro-4,5-dichloronitrobenzene through acetylize, chloro, hydrolysis, diazotization-Sang Demaier, nitrated five step precision work.Present method comprises following reaction equation:
Figure 2012102382478100002DEST_PATH_IMAGE001
2-of the present invention is fluoro-4, and the preparation method of 5-dichloronitrobenzene carries out according to following step:
(1) acetylization reaction: to the para-fluoroaniline and the organic solvent that add new steaming in reaction vessel, be heated to 30～70 ℃, preferably 30～60 ℃ of temperature, 40～50 ℃ of optimum tempss.Stir lower drip acetylation reagent diacetyl oxide or CH 3cOCl, preferably diacetyl oxide, wherein the amount of substance ratio range of acetylation reagent and para-fluoroaniline is 1.0～1.5:1, preferably 1.1～1.3:1, optimum range 1.1～1.2:1, when dropping, temperature is controlled at 40～100 ℃, preferably 40～60 ℃, be then warming up to 60～100 ℃, 70～90 ℃ of optimum tempss, insulation reaction 1～3 h, makes intermediate product 4-fluoroacetanilide;
Wherein in step (1), organic solvent used is mainly ClCH 2cH 2cl, CH 2cl 2, CH 3cOOH etc., preferably CH 3cOOH.Wherein the ratio of para-fluoroaniline and organic solvent is 1 mol:200～800 mL, preferably 1 mol:200～400 mL, most preferably 1 mol:300～400 mL.
(2) chlorination: above-mentioned reaction is cooled at 40～60 ℃ and passes into chlorine, insulation reaction is to finishing.After reaction finishes, product is poured in frozen water, product is separated out with solid, suction filtration, and mother liquor modulation neutrality refilters, dry, then through aqueous ethanolic solution recrystallization, obtains the chloro-4-fluoroacetanilide of 2-finished product.
Wherein in step (2), what recrystallization adopted is ethanol-water solution, and the amount of substance ratio range of thick product and ethanol is 1:2.0～6.0, with the amount of substance ratio range of water be 1:0.10～2.0, the mass concentration of aqueous ethanolic solution is 60%～95%.
(3) hydrolysis reaction: add the chloro-4-fluoroacetanilide of 2-in reaction vessel, slowly add aqueous sodium hydroxide solution and phase-transfer catalyst CH under stirring 3cH 2oH, is warming up to backflow, and insulation to reaction finishes, and after reaction finishes, pours product into H 2in O, under stirring, add NH 4cl, regulates pH to 8～9, is cooled to room temperature, leave standstill, and suction filtration, filtrate separates organic layer, water layer CH 2cl 2extraction, merges organic layer.Washing organic layer, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains the chloro-4-fluoroaniline of colourless transparent liquid 2-.
Wherein the amount of substance ratio range of step (3) NaOH and the chloro-4-fluoroacetanilide of 2-is 2.0～3.0:1, and optimum range is 2.4～2.6:1, and the mass concentration scope of aqueous sodium hydroxide solution is 5%～15%, and optimum concn is 10%,
(4) diazotization-Sang Demaier reaction: add dense HCl, CH in reaction vessel 3cOOH, adds the chloro-4-fluoroaniline of 2-of new steaming lentamente under stirring, be warming up to 40～90 ℃, 40～70 ℃ of preferred range, 50～70 ℃ of optimum temperature ranges.After temperature arrives optimum temperature range, insulation reaction 0.5～1 h, is cooled to 40～60 ℃, under stirring, adds CuCl, insulation reaction 0.5～1.0 h.Under said temperature, drip NaNO again 2the aqueous solution, wherein NaNO 2with the amount of substance ratio range of the chloro-4-fluoroaniline of 2-be 1.0～1.5:1, optimum range is 1.0～1.3:1, drips rear insulation reaction to finishing.After reaction finishes, be down to room temperature, under stirring, pour product into H 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride extraction for water layer, merges organic layer.Washing organic layer, then use NaHCO 3the aqueous solution is washed till pH value for neutral, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene.
Wherein the ratio range of the chloro-4-fluoroaniline of step (4) 2-and dense HCl is 1 mol:200～400 mL, and optimum range is 1 mol:250～350 mL, CH 3the amount of substance ratio range of the chloro-4-fluoroaniline of COOH and 2-is 2.5～4.5:1, and optimum range is 3.0～4.0:1, and wherein the amount of substance ratio range of step (4) CuCl and the chloro-4-fluoroaniline of 2-is 0.50～0.65:1.
(5) nitration reaction: add successively solvent and 3,4-dichlor fluorbenzene in reactor, control temperature at-5～15 ℃, preferred range is 5～15 ℃, and optimum temperature range is 10～15 ℃.Stir the lower dense HNO of nitrating agent that drips 3, the HNO of being fuming 3or add nitrate in batches, and controlling temperature range is-5～15 ℃, preferably 5～15 ℃ of temperature, and optimum temperature range is 10～15 ℃, after nitrating agent adds, insulation reaction is to finishing.After reaction finishes, under stirring, product is poured in trash ice, product is separated out with solid, suction filtration.Gained filter cake CH 2cl 2dissolve anhydrous Na 2sO 4dry, rotation is steamed and is desolventized, and obtains faint yellow solid 2-fluoro-4,5-dichloronitrobenzene.
The solvent that wherein step (5) adds is mainly diacetyl oxide, dense H 2sO 4, preferred dense H 2sO 4solvent and 3,4-dichlor fluorbenzene material ratio range 400～1000 mL:1 mol, preferably 500～900 mL:1 mol, optimum range is 700～800 mL:1 mol, and wherein added nitrating agent and 3,4-dichlor fluorbenzene amount of substance ratio range are 0.95～1.1:1, preferable range is 1.00～1.05:1, and optimum ratio is 1:1.
advantage of the present invention
2-is fluoro-4, and 5-dichloronitrobenzene is a kind of important fine-chemical intermediate, has purposes widely at medicine, pesticide industry, at present there are no the report of its related methods of synthesis.The present invention relates to a kind of 2-fluoro-4, the preparation method of 5-dichloronitrobenzene.This method is take para-fluoroaniline as raw material, synthesizes 2-fluoro-4 through acetylize, chloro, hydrolysis, diazotization-Sang Demaier, nitrated five steps, 5-dichloronitrobenzene, and process total recovery reaches 27.1%.The transformation efficiency of every step raw material can reach 100%, and the raw material using in whole technique and reagent are all cheap and easy to get, and reaction conditions is easy to control, and production cost is lower, is that synthetic 2-is fluoro-4, preferably technique of 5-dichloronitrobenzene.
Embodiment
Embodiment mono-:
(1) acetylize, chloro are treated different things alike: to para-fluoroaniline 22.2 g that add new steaming in reaction vessel, Glacial acetic acid 60 mL, are warming up to 30 ℃, dropwise drip 20.4 g diacetyl oxides under stirring.Diacetyl oxide drips off post-heating to 60～70 ℃, and insulation reaction is to finishing.Slightly be cooled to 40 ℃, slowly import Cl 2, maintain temperature of reaction at 40～50 ℃, insulation reaction 12 h, reaction finishes.Product is poured in 500 mL frozen water, separated out solid, suction filtration, mother liquor Na 2cO 3furnishing neutrality refilters, and obtains crude product.Through 60% aqueous ethanolic solution recrystallization, obtain chloro-4-fluoroacetanilide 29.8 g of white needles solid 2-again, yield is 79.1%.
(2) hydrolysis reaction: add the chloro-4-fluoroacetanilide of 28.1 g2-in reaction vessel, slowly add 12.0 gNaOH and 108 gH under stirring 2the aqueous solution that O is mixed into and 1.5 gCH 3cH 2oH, is slowly warming up to backflow, insulation reaction 6 h, and reaction finishes.Pour product into 200 mLH 2in O, under stirring, add NH 4cl, regulates pH to 8～9.Leave standstill, suction filtration, filtrate separates organic layer, water layer CH 2cl 2(40 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains chloro-4-fluoroaniline 14.9 g of colourless transparent liquid 2-, yield 67.7%.
(3) diazotization-Sang Demaier reaction: add the dense HCl of 20 mL, 15 g CH in reaction vessel 3cOOH, slowly adds the new chloro-4-fluoroaniline of 2-steaming of 14.5 g under stirring.Be warming up to 40～50 ℃, insulation reaction 0.5 h.After insulation finishes, under equality of temperature, add 4.95 gCuCl, stir 0.5 h, at this temperature, drip by 6.90 g NaNO 2with 20.7 g H 2the aqueous solution that O is made into, controls rate of addition and is advisable not produce a large amount of reddish-brown nitrogen dioxide gas.After dropwising, insulation reaction is to finishing.After reaction finishes, be down to room temperature, under stirring, product poured into 150 mLH 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride for water layer (30 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, then uses 5%NaHCO 3the aqueous solution is washed till neutrality, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene 6.7 g, yield 40.5%.
(4) nitration reaction: under cryosel is bathed, add the dense H of 20 mL in reactor 2sO 4with 8.25 g3,4-dichlor fluorbenzene, treats that temperature is down to-5 ℃, adds 4.80 gKNO in batches 3, in adition process, control temperature of reaction and be no more than 0 ℃.After adding, insulation reaction is to finishing, and being reacted to the later stage has solid to separate out.After reaction finishes, under stirring, product is poured in 200 mL trash ices, separated out solid, suction filtration.Filter cake 60 mLCH 2cl 2dissolve anhydrous Na 2sO 4dry, rotation is steamed and is desolventized, and obtains faint yellow solid 2-fluoro-4,5-dichloronitrobenzene 5.9 g, yield 55.5%.
Embodiment bis-:
(1) acetylize, chloro are treated different things alike: to para-fluoroaniline 22.2 g that add new steaming in reaction vessel, Glacial acetic acid 60 mL, are warming up to 70 ℃, dropwise drip 30.6 g diacetyl oxides under stirring.Diacetyl oxide drips off post-heating to 90～100 ℃, and insulation reaction is to finishing.Slightly be cooled to 60 ℃, slowly import Cl 2, maintain temperature of reaction at 50～60 ℃, insulation reaction 10 h, reaction finishes.Product is poured in 500 mL frozen water, separated out solid, suction filtration, mother liquor Na 2cO 3furnishing neutrality refilters, and obtains crude product.Through 80% aqueous ethanolic solution recrystallization, obtain chloro-4-fluoroacetanilide 30.0 g of white needles solid 2-again, yield is 79.7%.
(2) hydrolysis reaction: add the chloro-4-fluoroacetanilide of 28.1 g2-in reaction vessel, slowly add 18.0 gNaOH and 162 gH under stirring 2the aqueous solution that O is mixed into and 1.5 gCH 3cH 2oH, is slowly warming up to backflow, insulation reaction 4.5 h, and reaction finishes.Pour product into 200 mLH 2in O, under stirring, add NH 4cl, regulates pH to 8～9.Leave standstill, suction filtration, filtrate separates organic layer, water layer CH 2cl 2(40 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains chloro-4-fluoroaniline 15.3 g of colourless transparent liquid 2-, yield 69.5%.
(3) diazotization-Sang Demaier reaction: add the dense HCl of 30 mL, 20 gCH in reaction vessel 3cOOH, slowly adds the new chloro-4-fluoroaniline of 2-steaming of 14.5 g under stirring.Be warming up to 60～65 ℃, insulation reaction 0.5 h.After insulation finishes, be cooled to 50 ℃, add 4.95 gCuCl, stir 0.5 h, at this temperature, drip by 8.97 g NaNO 2with 27 gH 2the aqueous solution that O is made into, controls rate of addition and is advisable not produce a large amount of reddish-brown nitrogen dioxide gas.After dropwising, insulation reaction is to finishing.After reaction finishes, be down to room temperature, under stirring, product poured into 150 mLH 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride for water layer (30 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, then uses 5%NaHCO 3the aqueous solution is washed till pH value for neutral, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene 8.5 g, yield 51.3%.
(4) nitration reaction: under ice-water bath, add the dense H of 30 mL in reactor 2sO 4with 8.25 g3,4-dichlor fluorbenzene, treats that temperature is down to 0 ℃, adds 5.56 gKNO in batches 3, control temperature of reaction and be no more than 5 ℃.KNO 3after adding, insulation reaction is to finishing.After reaction finishes, under stirring, product is poured in 200 mL trash ices, separated out solid, suction filtration.Filter cake 60 mLCH 2cl 2dissolve anhydrous Na 2sO 4dry, rotation is steamed and is desolventized, and obtains faint yellow solid 2-fluoro-4,5-dichloronitrobenzene 8.6 g, yield 80.7%.
Embodiment tri-:
(1) acetylize, chloro are treated different things alike: to para-fluoroaniline 55.5 g that add new steaming in reaction vessel, Glacial acetic acid 160 mL, are warming up to 40 ℃, dropwise drip 59.2 g diacetyl oxides under stirring.Diacetyl oxide drips off post-heating to 70～80 ℃, and insulation reaction is to finishing.Slightly be cooled to 40 ℃, slowly import Cl 2, maintain temperature of reaction at 40～50 ℃, insulation reaction 13.5 h, reaction finishes.Product is poured in 1500 mL frozen water, separated out solid, suction filtration, mother liquor Na 2cO 3furnishing neutrality refilters, and obtains crude product.Through 70% aqueous ethanolic solution recrystallization, obtain chloro-4-fluoroacetanilide 78.8 g of white needles solid 2-again, yield is 83.5%.
(2) hydrolysis reaction: add the chloro-4-fluoroacetanilide of 28.1 g2-in reaction vessel, slowly add 14.4 gNaOH and 129.6 gH under stirring 2the aqueous solution that O is mixed into and 1.5 gCH 3cH 2oH, is slowly warming up to backflow, and insulation reaction 5 h, after reaction finishes.Pour product into 200 mLH 2in O, under stirring, add NH 4cl, regulates pH to 8～9.Leave standstill, suction filtration, filtrate separates organic layer, water layer CH 2cl 2(40 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains chloro-4-fluoroaniline 16.0 g of colourless transparent liquid 2-, yield 72.6%.
(3) diazotization-Sang Demaier reaction: add the dense HCl of 35 mL, 18 gCH in reaction vessel 3cOOH, slowly adds the new chloro-4-fluoroaniline of 2-steaming of 14.5 g under stirring.Be warming up to 60～65 ℃, insulation reaction 0.5 h.After insulation finishes, be cooled to 60 ℃, add 4.95 gCuCl, stir 0.5 h, at this temperature, drip by 8.97 g NaNO 2with 27 gH 2the aqueous solution that O is made into, controls rate of addition and is advisable not produce a large amount of reddish-brown nitrogen dioxide gas.After dropwising, insulation reaction is to finishing.After reaction finishes, be down to room temperature, under stirring, product poured into 150 mLH 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride for water layer (30 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, then uses 5%NaHCO 3the aqueous solution is washed till pH value for neutral, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene 8.3 g, yield 50.1%.
(4) nitration reaction: under ice-water bath, add the dense H of 40 mL in reactor 2sO 4with 8.25 g3,4-dichlor fluorbenzene, treats that temperature is down to 10 ℃, adds 5.05 gKNO in batches 3, control temperature of reaction and be no more than 15 ℃.KNO 3after adding, insulation reaction 30 min, reaction finishes, and under stirring, product is poured in 200 mL trash ices, separates out solid, suction filtration.Filter cake 60 mLCH 2cl 2dissolve anhydrous Na 2sO 4dry, rotation is steamed and is desolventized, and obtains faint yellow solid 2-fluoro-4,5-dichloronitrobenzene 8.6 g, yield 80.7%.
Embodiment tetra-:
(1) acetylize, chloro are treated different things alike: to para-fluoroaniline 55.5 g that add new steaming in reaction vessel, Glacial acetic acid 160 mL, are warming up to 40 ℃, dropwise drip 59.2 g diacetyl oxides under stirring.Diacetyl oxide drips off post-heating to 80～90 ℃, and insulation reaction is to finishing.Slightly be cooled to 50 ℃, slowly import Cl 2, maintain temperature of reaction at 50～60 ℃, insulation reaction 10.5 h, reaction finishes.Product is poured in 1500 mL frozen water, separated out solid, suction filtration, mother liquor Na 2cO 3furnishing neutrality refilters, and obtains crude product.Through 80% aqueous ethanolic solution recrystallization, obtain chloro-4-fluoroacetanilide 78.2 g of white needles solid 2-again, yield is 83.0%.
(2) hydrolysis reaction: add the chloro-4-fluoroacetanilide of 28.1 g2-in reaction vessel, slowly add 14.4 gNaOH and 129.6 gH under stirring 2the aqueous solution that O is mixed into and 1.5 gCH 3cH 2oH, is slowly warming up to backflow, insulation reaction 3.5 h, and reaction finishes.Pour product into 200 mLH 2in O, under stirring, add NH 4cl, regulates pH to 8～9.Leave standstill, suction filtration, filtrate separates organic layer, water layer CH 2cl 2(40 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains chloro-4-fluoroaniline 16.1 g of colourless transparent liquid 2-, yield 73.1%.
(3) diazotization-Sang Demaier reaction: add the dense HCl of 40 mL, 27 gCH in reaction vessel 3cOOH, slowly adds the new chloro-4-fluoroaniline of 2-steaming of 14.5 g under stirring.Be warming up to 80～90 ℃, insulation reaction 0.5 h.After insulation finishes, be cooled to 60 ℃, add 6.44 gCuCl, stir 0.5 h, at this temperature, drip by 7.59 g NaNO 2with 22 gH 2the aqueous solution that O is made into, controls rate of addition and is advisable not produce a large amount of reddish-brown nitrogen dioxide gas.After dropwising, be down to room temperature, under stirring, product poured into 150 mLH 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride for water layer (30 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, then uses 5%NaHCO 3the aqueous solution is washed till pH value for neutral, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene 6.2 g, yield 37.4%.
(4) nitration reaction: under cryosel is bathed, add the dense H of 40 mL in reactor 2sO 4with 8.25 g3,4-dichlor fluorbenzene, treats that temperature is down to-7 ℃, drips the 3.48 g HNO of being fuming 3, control temperature of reaction and be no more than 0 ℃.The HNO of being fuming 3after adding, insulation reaction is to finishing.After reaction finishes, under stirring, product is poured in 250 mL trash ices, separated out solid, suction filtration.Filter cake 60 mLCH 2cl 2dissolve anhydrous Na 2sO 4dry, rotation is steamed and is desolventized, and obtains faint yellow solid 2-fluoro-4,5-dichloronitrobenzene 8.5 g, yield 79.3%.
Embodiment five:
(1) acetylize, chloro are treated different things alike: to para-fluoroaniline 55.5 g that add new steaming in reaction vessel, Glacial acetic acid 160 mL, are warming up to 40 ℃, dropwise drip 61.2 g diacetyl oxides under stirring.Diacetyl oxide drips off post-heating to 70～80 ℃, and insulation reaction is to finishing.Slightly be cooled to 40 ℃, slowly import Cl 2, maintain temperature of reaction at 40～50 ℃, insulation reaction 10 h, reaction finishes.Product is poured in 1500 mL frozen water, separated out solid, suction filtration, mother liquor Na 2cO 3furnishing neutrality refilters, and obtains crude product.Through 80% aqueous ethanolic solution recrystallization, obtain chloro-4-fluoroacetanilide 78.5 g of white needles solid 2-again, yield is 83.2%.
(2) hydrolysis reaction: add the chloro-4-fluoroacetanilide of 28.1 g2-in reaction vessel, slowly add 15.0 gNaOH and 135 gH under stirring 2the aqueous solution that O is mixed into and 1.5 gCH 3cH 2oH, is slowly warming up to backflow, insulation reaction 3.5 h, and reaction finishes.Pour product into 200 mLH 2in O, under stirring, add NH 4cl, regulates pH to 8～9.Leave standstill, suction filtration, filtrate separates organic layer, water layer CH 2cl 2(40 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains chloro-4-fluoroaniline 16.3 g of colourless transparent liquid 2-, yield 74.0%.
(3) diazotization-Sang Demaier reaction: add the dense HCl of 30 mL, 20 gCH in reaction vessel 3cOOH, slowly adds the new chloro-4-fluoroaniline of 2-steaming of 14.5 g under stirring.Be warming up to 60～65 ℃, insulation reaction 0.5 h.After insulation finishes, be cooled to 50 ℃, add 5.44 gCuCl, stir 0.5 h, at this temperature, drip by 8.97 g NaNO 2with 27 gH 2the aqueous solution that O is made into, controls rate of addition and is advisable not produce a large amount of reddish-brown nitrogen dioxide gas.After dropwising, insulation reaction is to finishing.After reaction finishes, be down to room temperature, under stirring, product poured into 150 mLH 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride for water layer (30 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, then uses 5%NaHCO 3the aqueous solution is washed till pH value for neutral, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene 8.8 g, yield 53.1%.
(4) nitration reaction: under cryosel is bathed, add the dense H of 40 mL in reactor 2sO 4with 8.25 g3,4-dichlor fluorbenzene, treats that temperature is down to-5 ℃, drips the HNO of 4.84 g 65% 3, control temperature of reaction and be no more than 0 ℃.After dropwising, insulation reaction is to finishing.After reaction finishes, under stirring, product is poured in 250 mL trash ices, separated out solid, suction filtration.Filter cake 60 mLCH 2cl 2dissolve anhydrous Na 2sO 4dry, rotation is steamed and is desolventized, and obtains faint yellow solid 2-fluoro-4,5-dichloronitrobenzene 8.8 g, yield 82.6%.
Embodiment six:
(1) acetylize, chloro are treated different things alike: to para-fluoroaniline 111 g that add new steaming in reaction vessel, Glacial acetic acid 320 mL, are warming up to 40 ℃, dropwise drip 122.4 g diacetyl oxides under stirring.Diacetyl oxide drips off post-heating to 70～80 ℃, and insulation reaction is to finishing.Slightly be cooled to 40 ℃, slowly import Cl 2, maintain temperature of reaction at 40～50 ℃, insulation reaction 10h, reaction finishes.Product is poured in 3000 mL frozen water, separated out solid, suction filtration, mother liquor Na 2cO 3furnishing neutrality refilters, and obtains crude product.Through 95% aqueous ethanolic solution recrystallization, obtain chloro-4-fluoroacetanilide 157.1 g of white needles solid 2-again, yield is 83.2%.
(2) hydrolysis reaction: add the chloro-4-fluoroacetanilide of 28.1 g2-in reaction vessel, slowly add 15.0 gNaOH and 135 gLH under stirring 2the aqueous solution that O is mixed into and 1.5 gCH 3cH 2oH, is slowly warming up to backflow, insulation reaction 3.5 h, and reaction finishes.Pour product into 200 mLH 2in O, under stirring, add NH 4cl, regulates pH to 8～9.Leave standstill, suction filtration, filtrate separates organic layer, water layer CH 2cl 2(40 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains chloro-4-fluoroaniline 16.3 g of colourless transparent liquid 2-, yield 74.0%.
(3) diazotization-Sang Demaier reaction: add the dense HCl of 35 mL, 20 gCH in reaction vessel 3cOOH, slowly adds the new chloro-4-fluoroaniline of 2-steaming of 14.5 g under stirring.Be warming up to 60～65 ℃, insulation reaction 0.5 h.After insulation finishes, be cooled to 50 ℃, add 5.94 gCuCl, stir 0.5 h, at this temperature, drip by 10.35 g NaNO 2with 31.0 gH 2the aqueous solution that O is made into, controls rate of addition and is advisable not produce a large amount of reddish-brown nitrogen dioxide gas.After dropwising, be down to room temperature, under stirring, product poured into 150 mLH 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride for water layer (30 mL × 3) extraction, merges organic layer.Water (30 mL × 3) is washed organic layer, then uses 5%NaHCO 3the aqueous solution is washed till pH value for neutral, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized.Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene 7.0 g, yield 42.3%.
(4) nitration reaction: under cryosel is bathed, add 30 mL diacetyl oxides and 8.25 g3 in reactor, 4-dichlor fluorbenzene, treats that temperature is down to-5 ℃, drips the HNO of 4.84 g65% 3, in dropping process, control temperature and be no more than 5 ℃.Gas-chromatography tracing display nitration reaction does not occur.

Claims (4)

1.2-is fluoro-4, and the preparation method of 5-dichloronitrobenzene, is characterized in that carrying out according to following step:
(1) acetylization reaction: to the para-fluoroaniline and the organic solvent that add new steaming in reaction vessel, be heated to 30～70 ℃, stir lower acetylation reagent diacetyl oxide or the CH of dripping 3cOCl, wherein the amount of substance ratio range of acetylation reagent and para-fluoroaniline is 1.0～1.5:1, and when dropping, temperature is controlled at 40～100 ℃, is then warming up to 60～100 ℃, and insulation reaction 1～3 h makes intermediate product 4-fluoroacetanilide;
(2) chlorination: above-mentioned reaction is cooled at 40～60 ℃ and passes into chlorine, insulation reaction is to finishing; After reaction finishes, product is poured in frozen water, product is separated out with solid, suction filtration, and mother liquor modulation neutrality refilters, dry, then through aqueous ethanolic solution recrystallization, obtains the chloro-4-fluoroacetanilide of 2-finished product;
(3) hydrolysis reaction: add the chloro-4-fluoroacetanilide of 2-in reaction vessel, slowly add aqueous sodium hydroxide solution and phase-transfer catalyst CH under stirring 3cH 2oH, is warming up to backflow, and insulation to reaction finishes, and after reaction finishes, pours product into H 2in O, under stirring, add NH 4cl, regulates pH to 8～9, is cooled to room temperature, leave standstill, and suction filtration, filtrate separates organic layer, water layer CH 2cl 2extraction, merges organic layer;
Washing organic layer, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized; Underpressure distillation, obtains the chloro-4-fluoroaniline of colourless transparent liquid 2-;
(4) diazotization-Sang Demaier reaction: add dense HCl, CH in reaction vessel 3cOOH, adds the chloro-4-fluoroaniline of 2-of new steaming lentamente under stirring, be warming up to 40～90 ℃, and after temperature arrives temperature range, insulation reaction 0.5～1 h, is cooled to 40～60 ℃, under stirring, adds CuCl, insulation reaction 0.5～1.0 h; Under said temperature, drip NaNO again 2the aqueous solution, wherein NaNO 2with the amount of substance ratio range of the chloro-4-fluoroaniline of 2-be 1.0～1.5:1, drip rear insulation reaction to finishing; After reaction finishes, be down to room temperature, under stirring, pour product into H 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride extraction for water layer, merges organic layer;
Washing organic layer, then use NaHCO 3the aqueous solution is washed till pH value for neutral, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized;
Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene;
(5) nitration reaction: add successively solvent and 3,4-dichlor fluorbenzene in reactor, control temperature at-5～15 ℃, stir the lower dense HNO of nitrating agent that drips 3, the HNO of being fuming 3or add nitrate in batches, and controlling temperature range is-5～15 ℃, after nitrating agent adds, insulation reaction is to finishing; After reaction finishes, under stirring, product is poured in trash ice, product is separated out with solid, suction filtration; Gained filter cake CH 2cl 2dissolve anhydrous Na 2sO 4dry, rotation is steamed and is desolventized, and obtains faint yellow solid 2-fluoro-4,5-dichloronitrobenzene.
2. 2-according to claim 1 is fluoro-4, and the preparation method of 5-dichloronitrobenzene is characterized in that wherein in step (1), organic solvent used is mainly ClCH 2cH 2cl, CH 2cl 2, CH 3the COOH wherein ratio of para-fluoroaniline and organic solvent is 1:200～800 (mol/mL),
Wherein in step (2), what recrystallization adopted is ethanol-water solution, and the amount of substance ratio range of thick product and ethanol is 1:2.0～6.0, with the amount of substance ratio range of water be 1:0.10～2.0, the mass concentration of aqueous ethanolic solution is 60%～95%;
Wherein the amount of substance ratio range of step (3) NaOH and the chloro-4-fluoroacetanilide of 2-is 2.0～3.0:1, and the mass concentration scope of aqueous sodium hydroxide solution is 5%～15%,
Wherein the ratio range of the chloro-4-fluoroaniline of step (4) 2-and dense HCl is 1:200～400(mol/mL), CH 3the amount of substance ratio range of the chloro-4-fluoroaniline of COOH and 2-is 2.5～4.5:1, and wherein the amount of substance ratio range of step (4) CuCl and the chloro-4-fluoroaniline of 2-is 0.50～0.65:1;
The solvent that wherein step (5) adds is mainly diacetyl oxide, dense H 2sO 4, solvent and 3,4-dichlor fluorbenzene material ratio range 400～1000:1 (mL/mol), wherein added nitrating agent and 3,4-dichlor fluorbenzene amount of substance ratio range are 0.95～1.1:1.
3. 2-according to claim 1 is fluoro-4, and the preparation method of 5-dichloronitrobenzene, is characterized in that
Wherein step (1) acetylization reaction: to the para-fluoroaniline and the organic solvent that add new steaming in reaction vessel, be heated to 40～50 ℃; Stir the lower acetylation reagent diacetyl oxide that drips, wherein the amount of substance ratio range of acetylation reagent and para-fluoroaniline is 1.1～1.2:1, and when dropping, temperature is controlled at 40～60 ℃, is then warming up to 70～90 ℃, insulation reaction 1～3 h, makes intermediate product 4-fluoroacetanilide;
Wherein (4) diazotization-Sang Demaier reaction: add dense HCl, CH in reaction vessel 3cOOH, adds the chloro-4-fluoroaniline of 2-of new steaming lentamente under stirring, be warming up to 50～70 ℃;
After temperature arrives temperature range, insulation reaction 0.5～1 h, is cooled to 40～60 ℃, under stirring, adds CuCl, insulation reaction 0.5～1.0 h;
Under said temperature, drip NaNO again 2the aqueous solution, wherein NaNO 2with the amount of substance ratio range of the chloro-4-fluoroaniline of 2-be 1.0～1.3:1, drip rear insulation reaction to finishing; After reaction finishes, be down to room temperature, under stirring, pour product into H 2in O, leave standstill, separate organic layer, 1,2-ethylene dichloride extraction for water layer, merges organic layer;
Washing organic layer, then use NaHCO 3the aqueous solution is washed till pH value for neutral, anhydrous Na 2sO 4dry, suction filtration, rotation is steamed and is desolventized;
Underpressure distillation, obtains colourless transparent liquid 3,4-dichlor fluorbenzene;
Wherein (5) nitration reaction: add successively solvent and 3,4-dichlor fluorbenzene in reactor, controlling temperature is 10～15 ℃; Stir the lower dense HNO of nitrating agent that drips 3, the HNO of being fuming 3or add nitrate in batches, and controlling temperature range is 10～15 ℃, after nitrating agent adds, insulation reaction is to finishing; After reaction finishes, under stirring, product is poured in trash ice, product is separated out with solid, suction filtration; Gained filter cake CH 2cl 2dissolve anhydrous Na 2sO 4dry, rotation is steamed and is desolventized, and obtains faint yellow solid 2-fluoro-4,5-dichloronitrobenzene.
4. 2-according to claim 2 is fluoro-4, and the preparation method of 5-dichloronitrobenzene is characterized in that wherein in step (1), organic solvent used is CH 3cOOH; Wherein the ratio of para-fluoroaniline and organic solvent is 1:300～400(mol/mL);
Wherein the amount of substance ratio range of step (3) NaOH and the chloro-4-fluoroacetanilide of 2-is 2.4～2.6:1, and the mass concentration of aqueous sodium hydroxide solution is 10%,
Wherein the ratio range of the chloro-4-fluoroaniline of step (4) 2-and dense HCl is 1:250～350 (mol/mL); CH 3the amount of substance ratio range of the chloro-4-fluoroaniline of COOH and 2-is 3.0～4.0:1, and wherein the amount of substance ratio range of step (4) CuCl and the chloro-4-fluoroaniline of 2-is 0.50～0.65:1;
The solvent that wherein step (5) adds is dense H 2sO 4, solvent and 3,4-dichlor fluorbenzene material ratio range are 700～800: 1 (mL/mol), wherein added nitrating agent and 3,4-dichlor fluorbenzene amount of substance ratio are 1:1.
CN201210238247.8A 2012-07-11 2012-07-11 Preparation method of 2-fluoro-4,5-dichloronitrobenzene Expired - Fee Related CN102796003B (en)

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