CN102249881A - Method for coproducing key intermediates of quinolone medicines by using o-dichlorobenzene as raw material - Google Patents
Method for coproducing key intermediates of quinolone medicines by using o-dichlorobenzene as raw material Download PDFInfo
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Abstract
The invention relates to the field of methods for preparing medicinal intermediates, in particular to the field of methods for preparing key intermediates of quinolone medicines, and develops a method for coproducing the key intermediates of the quinolone medicines by using o-dichlorobenzene as a raw material. The method comprises the following steps of: nitrifying the o-dichlorobenzene serving as the raw material, and performing distillation, purification and stepwise crystallization to obtain 2,3-dichloronitrobenzene and 3,4-dichloronitrobenzene; performing fluoridation on the 2,3-dichloronitrobenzene to obtain 3-chloro-2-fluoronitrobenzene, performing chlorination to obtain 2,6-dichlorofluorobenzene, performing nitration to obtain 1,3-dichloro-2-fluoro-4-nitrobenzene, and finally performing fluoridation to obtain 2,3,4-trifluoronitrobenzene; and performing fluoridation on the 2,3,4-trifluoronitrobenzene to obtain 3-chloro-4-fluoronitrobenzene, performing chlorination to obtain 1,3-dichloro-4-fluorobenzene, and finally performing acylation reaction on the 1,3-dichloro-4-fluorobenzene and acetylchloride to obtain 2,4-dichloro-5-fluoroacetophenone.
Description
Technical field
The present invention relates to the preparation method field of medicine intermediate, particularly relate to the preparation method field of quinolones key intermediate, having developed a kind of is the method for raw material coproduction quinolones key intermediate with the orthodichlorobenzene.
Background technology
2-fluoro-3-chloronitrobenzene, 4-fluoro-3-chloronitrobenzene, 2,6-dichlor fluorbenzene, 2,4 dichloro fluorobenzene, 2,3, the key intermediate of quinolones such as 4-trifluoronitrobenzene and 2,4-two chloro-5-fluoro acetophenones are preparation Ciprofloxacin and hydrochloric acid norfloxicin, Ofloxacine USP 23 and agricultural chemicals.
Chinese patent 92107812.9 has reported with the orthodichlorobenzene to be raw material, nitrated through concentrated nitric acid and vitriol oil mixing acid, dried organic layer carries out fluoridation under the effect of dimethyl sulfoxide (DMSO) and Potassium monofluoride, separate, the back content of purifying reaches 98% 4-fluoro-3-chloronitrobenzene, under its molten state, feed chlorine and generate 2,4 dichloro fluorobenzene.
Chinese patent 93110558.7 has reported that with orthodichlorobenzene and santochlor mixing chlorobenzene be starting raw material, through nitrated, fluoridize and makes 4-fluoro-3-chloronitrobenzene and 2-fluoro-5-chloronitrobenzene mixture, obtains 2,4 dichloro fluorobenzene through chlorination again.
Chinese patent 03150688.7 has reported with the orthodichlorobenzene to be raw material, through nitrated, to fluoridize again to separate and obtain 4-fluoro-3-chloronitrobenzene and 2-fluoro-3-chloronitrobenzene, 4-fluoro-3-chloronitrobenzene obtains 4-fluoro-3-chloroaniline through reduction, and 2-fluoro-3-chloronitrobenzene and chlorine reaction generate 2, the 6-dichlor fluorbenzene.
For at present domestic 2,3, the production of 4-trifluoronitrobenzene all adopts 2 basically, and the 6-dichlorphenamide bulk powder is through diazotization, and fluorine decomposes, and is nitrated, fluoridizes to make.Chinese patent 01127016.0 has reported that with 2 the 6-dibromo aniline is through diazotization, and fluorine decomposes generation 2, and 6-two bromofluoro benzenes are nitrated again, fluoridize at last to generate 2,3, the 4-trifluoronitrobenzene.And 2, the 6-dichlorphenamide bulk powder, 2, the prices of raw and semifnished materials such as 6-difluoro bromobenzene amine are higher, and the diazonium fluoride danger of decomposing, environment unfriendly.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, providing a kind of is the method for raw material coproduction quinolones key intermediate with the orthodichlorobenzene, and simple, the economic environmental protection of its technical process, reaction conditions gentleness, aftertreatment is easy and product purity good, yield significantly increases.For this reason, the present invention is by the following technical solutions: it may further comprise the steps:
(1), orthodichlorobenzene uses the nitration mixture of being made up of the vitriol oil and concentrated nitric acid to carry out nitration reaction, nitration reaction is after depickling removes water treatment, gives after the rectification under vacuum organic phase again that fractional crystallization obtains 2,3-dichloronitrobenzene and 3, the 4-dichloronitrobenzene,
(2), prepared 2, the 3-dichloronitrobenzene obtains 2,3 at last through following reactions steps, the 4-trifluoronitrobenzene:
2-a-1), 2,3, the 4-trifluoronitrobenzene obtains 2-fluoro-3-chloronitrobenzene through fluoridation,
2-a-2), 2-fluoro-3-chloronitrobenzene obtains 2 through chlorination reaction, the 6-dichlor fluorbenzene,
2-a-3), 2, the 6-dichlor fluorbenzene obtains 2 through nitration reaction, 4-two chloro-3-fluoronitrobenzenes,
2-a-4), 2,4-two chloro-3-fluoronitrobenzenes obtain 2,3 through fluoridation, the 4-trifluoronitrobenzene;
Prepared 3, the 4-dichloronitrobenzene obtains 2 at last through following reactions steps, 4-two chloro-5-fluoro acetophenones:
2-b-1), 3, the 4-dichloronitrobenzene obtains 4-fluoro-3-chloronitrobenzene through fluoridation,
2-b-2), 4-fluoro-3-chloronitrobenzene obtains 2,4 dichloro fluorobenzene through chlorination reaction,
2-b-3), 2,4 dichloro fluorobenzene and Acetyl Chloride 98Min. generation acylation reaction obtain 2,4-two chloro-5-fluoro acetophenones.
On the basis of adopting technical scheme of the present invention, the present invention also can adopt following further technical scheme:
The nitration reaction temperature of above-mentioned steps of the present invention (1) is 60～120 ℃, is preferably 90～100 ℃; And the method by recrystallize after the rectifying is to 2,3-dichloronitrobenzene and 3, and the 4-dichloronitrobenzene carries out Separation ﹠ Purification.The described nitration reaction temperature of step (2) is 0～60 ℃, is preferably 30～50 ℃.
Fluoridation described in the step of the present invention (2) is phase-transfer catalyst to be arranged and solvent is arranged or solvent-freely carrying out down, perhaps no phase-transfer catalyst with have solvent or solvent-free under carry out.
Phase-transfer catalyst of the present invention is tetramethyl ammonium chloride, etamon chloride, cetyl trimethylammonium bromide, palmityl trimethyl ammonium chloride or tetraphenylphosphonibromide bromide, is preferably tetramethyl ammonium chloride; Solvent is tetramethylene sulfone, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or 1, and 3-dimethyl-2-imidazolone (DMI) is preferably tetramethylene sulfone; Fluorizating agent is a Potassium monofluoride.
Step 2-a-1 of the present invention) in 2, the fluoridation of 3-dichloronitrobenzene have phase-transfer catalyst and solvent-free in the presence of carry out, temperature of reaction is 120～200 ℃, is preferably 160～170 ℃; 2, the mol ratio of 3-dichloronitrobenzene and Potassium monofluoride, phase-transfer catalyst is 1: (0.5～2.0): (0.01～0.04) is preferably 1: (0.9～1.0): (0.02～0.03).
Step 2-a-4 of the present invention) in 2, the fluoridation of 4-two chloro-3-fluoronitrobenzenes is at no phase-transfer catalyst and have and carry out in the presence of the solvent, and temperature of reaction is 140～230 ℃, is preferably 195～210 ℃; Described solvent is tetramethylene sulfone, DMF, DMSO or DMI.
Step 2-b-1 of the present invention) in 3, the fluoridation of 4-dichloronitrobenzene have phase-transfer catalyst and solvent-free in the presence of carry out, temperature of reaction is 120～230 ℃, is preferably 160～180 ℃.
The chlorination reaction and the 2-b-2 of 2-fluoro-3-chloronitrobenzene step 2-a-2 of the present invention)) 4-fluoro-3-chloronitrobenzene chlorination reaction solvent-free down with the chlorine direct reaction, the mode of employing reactive distillation is reacted.Step 2-a-2 of the present invention) chlorination reaction temperature of 2-fluoro-3-chloronitrobenzene is 150～230 ℃ in, step 2-b-2) in the temperature of chlorination reaction of 4-fluoro-3-chloronitrobenzene be 150～220 ℃.
2-b-3 of the present invention) aftertreatment of the acylation reaction of 2,4 dichloro fluorobenzene and Acetyl Chloride 98Min. is that the method for recrystallize is purified behind the employing second distillation purifying in.Described Lewis acid is an aluminum chloride, zinc chloride, and boron trifluoride is preferably aluminum chloride; Described 2,4 dichlor fluorbenzenes and Lewis acid, the mol ratio of Acetyl Chloride 98Min. are 1: (0.5～2.5): (1～3) is preferably 1: (1.5～2.0): (1～1.2); Described acylation reaction temperature is 10～150 ℃, is preferably 40～120 ℃.
The present invention is with 2, and the 6-dichlor fluorbenzene is a raw material, fluoridizes preparation 2 after nitrated again, 3, the method for 4-trifluoronitrobenzene produces 2 with the principle that continuity is produced, 3,4-trifluoronitrobenzene and 2,4-two chloro-5-fluoro acetophenones, obtained the key intermediate of quinolones thus: 2-fluoro-3-chloronitrobenzene, 4-fluoro-3-chloronitrobenzene, 2,6-dichlor fluorbenzene, 2,4 dichloro fluorobenzene, 2,3,4-trifluoronitrobenzene and 2,4-two chloro-5-fluoro acetophenones.Not only solved the production cost problem of higher,, reduced to pollute playing an important role more to cleaning ambient.
No matter be from the angle of production security or the angle that reduces production costs, with the orthodichlorobenzene is starting raw material, nitrated back is comparatively rational by carrying out fluoridation behind the rectifying separation recrystallize, not only avoid loss of material to cause increasing substantially of production cost, more solved great difficult problems such as environmental pollution and potential safety hazard.
Embodiment
Following type reaction is used for illustrating the present invention.Within the technical scheme that those skilled in that art all belong to the present invention to the simple replacement done of invention or improvement etc. and protected.
One, step (1), nitration reaction
Embodiment 1
Drop into the 210g orthodichlorobenzene in the 500ml four-hole boiling flask, be warming up to 90 ℃ and drip 340g nitration mixture (nitric acid of 100g69% and the sulfuric acid of 240g98%), control is reflected at 95～100 ℃, finish back insulation 2h, cooling back layering, reclaim(ed) sulfuric acid, organic phase washing, neutralization, recrystallize obtains 210g3 after the rectifying separation of dry back, 4-dichloronitrobenzene (content 〉=99.5%), and 53g 2,3-dichloronitrobenzene (content 〉=99.6%), total recovery is 95.8%.
Two, step (2)
1,2, the 3-dichloronitrobenzene obtains 2-fluoro-3-chloronitrobenzene through fluoridation, and chlorination obtains 2 then, and the 6-dichlor fluorbenzene nitratedly obtains 2, and 4-two chloro-3-fluoronitrobenzenes are fluoridized at last and obtained 2,3, the 4-trifluoronitrobenzene,
1.1, fluoridation
Embodiment 2
In the 500ml four-hole boiling flask, drop into 400g (2.08mol) 2, the 3-dichloronitrobenzene, be warming up to 140 ℃ and drop into 112g (1.93mol) KF, carry out decompression dehydration, at 140～150 ℃ of insulation 3h, dehydration is warmed up to 140 ℃ after finishing, and between 150～160 ℃ 6.6g (0.06mol) tetramethyl ammonium chloride is joined in the reactor, finish the back at 165 ± 5 ℃ of insulation 8h, stopped reaction, cooling, washing, organic phase distillation back rectifying earlier after the layering, reclaim 2,3-dichloronitrobenzene 100g generates 2-fluoro-3-chloronitrobenzene 240g, content 99.6%, yield 87.6%.
Embodiment 3
Press embodiment 2, the phase-transfer catalyst tetramethyl ammonium chloride reduces to 3.3g (0.03mol) direct reaction, reclaims 2, and 3-dichloronitrobenzene 230g generates 2-fluoro-3-chloronitrobenzene 108g, content 97.8%, yield 69.5%.
Embodiment 4
Press embodiment 2, replace the tetramethyl ammonium chloride reaction with 25.2g tetraphenylphosphonibromide bromide (0.06mol), reclaim 2,3-dichloronitrobenzene 105g generates 2-fluoro-3-chloronitrobenzene 229.2g, content 99.4%, yield 85%.
Embodiment 5
Press embodiment 2, the amount of KF reduces to 96.7g (1.67mol), reclaims 2, and 3-dichloronitrobenzene 120g generates 2-fluoro-3-chloronitrobenzene 212g, content 99.1%, yield 82.8%.
Embodiment 6
Press embodiment 2, temperature of reaction rises to 170～180 ℃, reclaims 2, and 3-dichloronitrobenzene 150g generates 2-fluoro-3-chloronitrobenzene 165.2g, content 98.1%, yield 72.3%.
1.2, chlorination reaction
Embodiment 7
In the 250ml four-hole boiling flask, drop into 240g (1.368mol) 2-fluoro-3-chloronitrobenzene, heat up 180 ℃, feed dried chlorine, control still temperature is at 180～190 ℃, mode with reactive distillation is reacted 8h～10h, collect distillate, washing, alkali cleaning is to weakly alkaline, the organic phase underpressure distillation gets 2 after the layering, 6-dichlor fluorbenzene 210g, content 99.7%, yield 93%.
Embodiment 8
Press embodiment 7, directly react 8h in the mode that refluxes, reaction obtains 2,6-dichlor fluorbenzene 140g, content 98.9%, yield 62%.
Embodiment 9
Press embodiment 7, control still temperature is at 210～230 ℃, and reaction obtains 2,6-dichlor fluorbenzene 170g, content 98.0%, yield 75.3%.
1.3, nitrated and fluoridation
Embodiment 10
Drop into the vitriol oil and the 100g (0.606mol) 2 of 64g 98% in the 250ml four-hole boiling flask, the 6-dichlor fluorbenzene stirs, the vitriol oil of the 33g98% that has prepared 20～25 ℃ of following droppings and the mixing acid of 39g98% concentrated nitric acid, and 2.5h dropwises.Be warming up at 40～45 ℃ after finishing and be incubated 1.5 hours.Insulation finishes after washing is extremely neutral, and organic phase underpressure distillation dehydration back is stand-by.
Drop into 285g tetramethylene sulfone and 87g (1.5mol) KF in the 250ml four-hole boiling flask, the dehydration back adds the previous step nitration product, and at 195 ± 5 ℃ of insulation 5h, removing under reduced pressure behind the solvent again, rectifying obtains 2,3,4-trifluoronitrobenzene 91.7g, content 99.8%, yield 85.5%.
Embodiment 11
Press embodiment 10, the amount of KF reduces to 66g (1.138mol), and reaction obtains 2,3,4-trifluoronitrobenzene 81g, content 99.1%, yield 75.5%.
Embodiment 12
Press embodiment 10, fluorination reaction temperature is raised to 210～220 ℃, and reaction obtains 2,3,4-trifluoronitrobenzene 85g, content 98.5%, yield 79.3%.
2, prepared 3, the 4-dichloronitrobenzene obtains 4-fluoro-3-chloronitrobenzene through fluoridation, and chlorination obtains 2,4 dichloro fluorobenzene then, and last and Acetyl Chloride 98Min. generation acylation reaction obtains 2,4-two chloro-5-fluoro acetophenones.
2.1, fluoridation
Embodiment 13
In the 500ml four-hole boiling flask, drop into 400g (2.08mol) 3, the 4-dichloronitrobenzene, be warming up to 150 ℃ and drop into 116g (2.0mol) KF, carry out decompression dehydration, at 140～150 ℃ of insulation 3h, be warmed up to 160～165 ℃ after dehydration finishes 8.3g (0.08mol) tetramethyl ammonium chloride joined in the reactor, the still temperature control is at 165～170 ℃, finish the back at 165 ± 5 ℃ of insulation 7h, stopped reaction, cooling, washing, organic phase distillation back rectifying earlier after the layering, reclaim 3,4-dichloronitrobenzene 85g generates 4-fluoro-3-chloronitrobenzene 250.5g, content 99.7%, yield 87%.
Embodiment 14
Press embodiment 13, the phase-transfer catalyst tetramethyl ammonium chloride reduces to 5.7g (0.052mol), reclaims 3.4-dichloronitrobenzene 120g, generates 4-fluoro-3-chloronitrobenzene 184.3g, content 97.0%, yield 72%.
Embodiment 15
Press embodiment 13, the amount of KF reduces to 96g (1.655mol), reclaims 3, and 4-dichloronitrobenzene 98g generates 4-fluoro-3-chloronitrobenzene 230.2g, content 99.0%, yield 83.4%.
Embodiment 16
Press embodiment 13, temperature of reaction is elevated to 180～190 ℃, reclaims 3,4-dichloronitrobenzene 100g, and reaction obtains 4-fluoro-3-chloronitrobenzene 202g, content 98.7%, yield 73.7%.
2.2, chlorination reaction
Embodiment 17
In the 250ml four-hole boiling flask, drop into 240g (1.37mol) 4-fluoro-3-chloronitrobenzene, heat up 170 ℃, feed dried chlorine, control still temperature is at 170～180 ℃, mode with reactive distillation is reacted 8h, collect distillate, washing, alkali cleaning is to weakly alkaline, after the layering after the organic phase distillation again rectifying obtain 2,4-dichlor fluorbenzene 207g, content 99.8%, yield 91.7%.
Embodiment 18
Press embodiment 17, directly react 8h in the mode that refluxes, reaction obtains 2,4 dichloro fluorobenzene 150g, content 98.2%, yield 66.4%.
Embodiment 19
Press embodiment 17, temperature of reaction rises to 200 ℃, obtains 2,4 dichloro fluorobenzene 198g, content 98.5%, yield 87.6%.
2.3, acylation reaction
Embodiment 20
Drop into 2,4 dichloro fluorobenzene 150g (0.91mol) in the 1000ml four-hole boiling flask, be cooled to 20 ℃ and add aluminum chloride 200.2g (1.5mol), at 20～30 ℃ of dripping acetyl chloride 78.5g (1.0mol), 2～3h adds.Slowly be warming up to 40 ℃ and be incubated 30min, slowly be warming up to 70 ℃ again, and be incubated 1～2h, slowly be warming up to 110 ℃ at last, at 110 ± 2 ℃ of insulation 3～4h, cooling, the hydrochloric acid of adding 500g 5%, at 80～90 ℃ of hydrolysis 2～3h, finish after washing to neutral, organic phase obtains 2 through the second distillation recrystallize, 4-two chloro-5-fluoro acetophenone 168g, content 99.8%, yield 89.3%.
Embodiment 21
Press embodiment 20, replace aluminum chloride, obtain 2,4-two chloro-5-fluoro acetophenone 135g, content 99.0%, yield 71.8% with 204g (1.5mol) zinc chloride.
Embodiment 22
Press embodiment 20, replace aluminum chloride, obtain 2 with 102g (1.5mol) boron trifluoride, 4-two chloro-5-fluoro acetophenone 167g, content 99.5%, yield 88.8%, yield is higher, but the boron trifluoride chemical reactivity is very high, meets the decomposition of blasting property of water.Might generate with copper and alloy thereof and to have volatile chloroacetylene.Be exposed to when meeting moisture in the air and be hydrolyzed into fluoroboric acid and boric acid rapidly, produce white smoke, corrodibility is very strong.
Embodiment 23
Press embodiment 20, the amount of aluminum chloride reduces to 145.8g (1.03mol), obtains 2,4-two chloro-5-fluoro acetophenone 147g, content 99.6%, yield 78.1%.
Embodiment 24
Press embodiment 20, the amount of Acetyl Chloride 98Min. is increased to 92.8g (1.18mol), obtains 2,4-two chloro-5-fluoro acetophenone 165g, content 95.8%, yield 87.7%.
Embodiment 25
Press embodiment 20, temperature of reaction rises to 130 ℃, obtains 2,4-two chloro-5-fluoro acetophenone 130g, content 942%, yield 69.1%.
Claims (10)
1. one kind is the method for raw material coproduction quinolones key intermediate with the orthodichlorobenzene, it is characterized in that it may further comprise the steps:
(1), orthodichlorobenzene uses the nitration mixture of being made up of the vitriol oil and concentrated nitric acid to carry out nitration reaction, nitration reaction is after depickling removes water treatment, gives after the rectification under vacuum organic phase again that fractional crystallization obtains 2,3-dichloronitrobenzene and 3, the 4-dichloronitrobenzene,
(2), prepared 2, the 3-dichloronitrobenzene obtains 2,3 at last through following reactions steps, the 4-trifluoronitrobenzene:
2-a-1), 2,3, the 4-trifluoronitrobenzene obtains 2-fluoro-3-chloronitrobenzene through fluoridation,
2-a-2), 2-fluoro-3-chloronitrobenzene obtains 2 through chlorination reaction, the 6-dichlor fluorbenzene,
2-a-3), 2, the 6-dichlor fluorbenzene obtains 2 through nitration reaction, 4-two chloro-3-fluoronitrobenzenes,
2-a-4), 2,4-two chloro-3-fluoronitrobenzenes obtain 2,3 through fluoridation, the 4-trifluoronitrobenzene;
Prepared 3, the 4-dichloronitrobenzene obtains 2 at last through following reactions steps, 4-two chloro-5-fluoro acetophenones:
2-b-1), 3, the 4-dichloronitrobenzene obtains 4-fluoro-3-chloronitrobenzene through fluoridation,
2-b-2), 4-fluoro-3-chloronitrobenzene obtains 2,4 dichloro fluorobenzene through chlorination reaction,
2-b-3), 2,4 dichloro fluorobenzene and Acetyl Chloride 98Min. generation acylation reaction obtain 2,4-two chloro-5-fluoro acetophenones.
2. method according to claim 1 is characterized in that the nitration reaction temperature is 60～120 ℃ in the step (1), preferred 90～100 ℃; The nitration reaction temperature is 0～60 ℃ in the step (2), is preferably 30～50 ℃.
3. method according to claim 1 is characterized in that step 2-a-1) in 2, the fluoridation of 3-dichloronitrobenzene have phase-transfer catalyst and solvent-free in the presence of carry out, temperature of reaction is 120～200 ℃, be preferably 160～170 ℃; 2, the mol ratio of 3-dichloronitrobenzene and Potassium monofluoride, phase-transfer catalyst is 1: (0.5～2.0): (0.01～0.04) is preferably 1: (0.9～1.0): (0.02～0.03).
4. method according to claim 1 is characterized in that step 2-a-4) in 2, the fluoridation of 4-two chloro-3-fluoronitrobenzenes is carried out in the presence of the solvent at no phase-transfer catalyst and having, temperature of reaction is 140～230 ℃, is preferably 195～210 ℃; Described solvent is tetramethylene sulfone, DMF, DMSO or DMI.
5. method according to claim 1 is characterized in that step 2-b-1) in 3, the fluoridation of 4-dichloronitrobenzene have phase-transfer catalyst and solvent-free in the presence of carry out, temperature of reaction is 120～230 ℃, be preferably 160～180 ℃.
6. according to claim 3 or 5 described methods, it is characterized in that used phase-transfer catalyst is selected from tetramethyl ammonium chloride, etamon chloride, cetyl trimethylammonium bromide, palmityl trimethyl ammonium chloride, tetraphenylphosphonibromide bromide.
7. method according to claim 1, it is characterized in that step 2-a-2) the chlorination reaction and the 2-b-2 of 2-fluoro-3-chloronitrobenzene) 4-fluoro-3-chloronitrobenzene chlorination reaction solvent-free down with the chlorine direct reaction, the mode of employing reactive distillation is reacted.
8. method according to claim 1 is characterized in that step 2-a-2) in the chlorination reaction temperature of 2-fluoro-3-chloronitrobenzene be 150～230 ℃, step 2-b-2) in the temperature of chlorination reaction of 4-fluoro-3-chloronitrobenzene be 150～220 ℃.
9. method according to claim 1; it is characterized in that 2-b-3) in the acylation reaction temperature of 2,4 dichloro fluorobenzene and Acetyl Chloride 98Min. be 10～150 ℃, be preferably 40～120 ℃; acylation reaction is used Lewis acid, and described Lewis acid is selected from aluminum chloride, zinc chloride, boron trifluoride.
10. method according to claim 9, the mol ratio that it is characterized in that 2,4 dichloro fluorobenzene and Lewis acid, Acetyl Chloride 98Min. is 1: (0.5～2.5): (1～3) is preferably 1: (1.5～2.0): (1～1.2).
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| CN201410610959.7A CN104496824B (en) | 2011-05-09 | 2011-05-09 | A kind of method using o-dichlorohenzene as raw material coproduction QNS key intermediate |
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| CN113248353A (en) * | 2021-07-01 | 2021-08-13 | 山东国邦药业有限公司 | Preparation method of 2, 4-dichloro-5-fluoro acetophenone |
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| CN115650831A (en) * | 2022-12-26 | 2023-01-31 | 山东国邦药业有限公司 | Synthetic method of 2, 4-dichloro-5-fluoro acetophenone |
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| CN102675120A (en) * | 2012-05-24 | 2012-09-19 | 江苏隆昌化工有限公司 | Preparation method of 3, 4-dichloronitrobenzene by solid acid catalyst |
| CN103420842A (en) * | 2013-08-01 | 2013-12-04 | 上虞市临江化工有限公司 | Preparation method for 2,3,4-trifluoronitrobenzene |
| CN103483145A (en) * | 2013-09-09 | 2014-01-01 | 江苏德峰药业有限公司 | Improved synthesis method of dichlorofluorobenzene |
| CN104587810A (en) * | 2014-12-26 | 2015-05-06 | 浙江林江化工股份有限公司 | Comprehensive utilization method of chlorination tail gas of nitrides |
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| CN110642720A (en) * | 2019-10-12 | 2020-01-03 | 浙江林江化工股份有限公司 | Preparation method of 2, 4-difluoro-3, 5-dichloronitrobenzene |
| CN110642720B (en) * | 2019-10-12 | 2022-09-27 | 浙江吉泰新材料股份有限公司 | Preparation method of 2, 4-difluoro-3, 5-dichloronitrobenzene |
| CN113582805A (en) * | 2020-04-30 | 2021-11-02 | 浙江省常山长盛化工有限公司 | Production process for producing high-purity 2, 4-dichlorofluorobenzene by taking o-dichlorobenzene as raw material |
| CN113248353A (en) * | 2021-07-01 | 2021-08-13 | 山东国邦药业有限公司 | Preparation method of 2, 4-dichloro-5-fluoro acetophenone |
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| CN115650831A (en) * | 2022-12-26 | 2023-01-31 | 山东国邦药业有限公司 | Synthetic method of 2, 4-dichloro-5-fluoro acetophenone |
| CN116589359A (en) * | 2023-06-06 | 2023-08-15 | 云南云天化股份有限公司 | Method for preparing 3, 4-dichloronitrobenzene at low temperature |
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