CN1310163A - 2,4-dichloro-5-fluoro-3-methoxy acetophenone and its preparation - Google Patents
2,4-dichloro-5-fluoro-3-methoxy acetophenone and its preparation Download PDFInfo
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Abstract
The present invention provides one preparation process of 2,4-dichloro-5-fluoro-methoxy acetophenone as one new intermediate compound for preparing mocicarboxylic acid. The process includes the reaction between acetylation reagent and 2,4-dichloro-5-fluoro-3-methoxy brombenzene.
Description
The present invention relates to acetophenone derivs and preparation method thereof, particularly phenyl polyhalide ethyl ketone and preparation method thereof.
The phenyl polyhalide ethyl ketone is widely used as the starting raw material of the various carbostyril family antibacterial drugs of preparation and other compound, (chemical name is 1-cyclopropyl-7-chloro-6-fluoro-8-methoxyl group-1 to Moses's carboxylic acid, 4-dihydro-4-Oxoquinoline-3-carboxylic acid) for making the precursor of Moxifloxacin, present reported Moses's carboxylic acid is basically from 2,4, the beginning of 5-three fluoro-trimethoxybenzoic acids (or Benzoyl chloride), concrete document is the EP 421668 of Pfizer for example openly, the EP230 of Kyorin company, 295.
Yet, 2,4,5-three fluoro-3-methoxybenzoic acids usually will be from the raw material penta fluoro benzene formonitrile HCN or 2,3,5 of costliness, and reaction obtains (seeing also JP83/74667, JP85/72885) 6-tetrafluoro-4-methoxy nitrobenzene through the number step.
For solving problems of the prior art, the applicant looks for another way, and has prepared a kind of intermediate of synthetic Moses's carboxylic acid newly, and its preparation is from the 2,4 dichloro fluorobenzene of cheapness, for synthetic Moses's carboxylic acid opens up a new way.Certainly, new compound provided by the invention also can be used as the synthetic of other compound.
Therefore, one of purpose of the present invention provides the new intermediate 2 of a kind of Moses's of preparation carboxylic acid, 4-two chloro-5-fluoro-3-methoxyacetophenones, and its chemical structural formula is:
Another purpose of the present invention provides the method for the above-mentioned intermediate of preparation, and its synthetic route is as follows;
Wherein, X is selected from halogen atom, comprises fluorine, chlorine, bromine, iodine; Preferably X is selected from chlorine atom or bromine atoms, and X is preferably the chlorine atom.
The nitration reaction of preparation 2 can be used under the nitration reaction condition known in the art and carries out.In the present invention, the nitrating agent nitration mixture that uses the concentrated nitric acid and the vitriol oil to be made into carries out.React completely for making, the amount of concentrated nitric acid is greater than the amount of 2,4 dichloro fluorobenzene, and the ratio of its usage quantity and 2,4 dichloro fluorobenzene is 1～6: 1 usually, is preferably 2～4: 1.Reaction can be carried out below normal temperature to 70 ℃, preferably, is reflected under 50-60 ℃ and carries out.
The bromination reaction of preparation 3, method conventional in the available prior art is carried out.Then use bromine and potassium bromate in the present invention, be reflected at about 40 ℃ and carry out.
The methoxylation of preparation 4 then carries out under alkaline condition, uses sodium methylate as methoxylation reagent.The amount of sodium methylate is a bit larger tham 3-bromo-2, the amount of 4-two chloro-5-fluoronitrobenzenes, and both are preferably 1.2-1.5: 1 than being 1～2: 1 usually.In the present invention, methyl alcohol yes preferred solvent, alkali can use mineral alkali NaOH or KOH.
Reaction can be carried out under the temperature of solvent refluxing at 40 ℃, preferably, is reflected at about 60 ℃ and carries out.
The hydrogenation of preparation 5 can carry out with the hydrogenation way of routine, preferably uses palladium-Pd/carbon catalyst hydrogenation to finish.
The preparation of compound 6 is finished by diazotization and bromination step, and the reactant between two-step reaction does not separate, and its reaction conditions can be selected with reference to the similar reaction of routine.
Preparation purpose product I is finished as acylating agent with acetyl halide in the presence of magnesium and cuprous halide.The reaction of magnesium and cuprous halide and compound 6 at room temperature causes by stirring, and reaction should keep carrying out at low temperatures, can be preferably at-50 ℃～-10 ℃ and carry out at-80 ℃～-5 ℃ usually.The acylations step can be carried out under normal temperature at-50 ℃.
Described cuprous halide is generally and uses cuprous chloride or cuprous bromide, preferably uses cuprous chloride.
Below further specify the present invention with specific embodiment.
The embodiment the first step is nitrated
Preparation 2,4-two chloro-5-fluoronitrobenzenes
With 60 milliliters of concentrated nitric acids (1.41 moles), the vitriol oil 93 milliliters (1.75 moles) and water are made into nitration mixture for 16.5 milliliters.Dripping 58.3 milliliters of 2,4 dichloro fluorobenzenes (0.50 mole) below 40 ℃, 50-60 ℃ of reaction 2 hours.Material is poured in the trash ice, filtered, be washed to neutrality, dry faint yellow crystallization 2,4-two chloro-5-fluoronitrobenzenes 99.9 grams (0.476 mole), the yield 95.1% of getting.mp39-42℃。The second step bromination
Preparation 3-bromo-2,4-two chloro-5-fluoronitrobenzenes
With 2,4-two chloro-5-fluoronitrobenzenes, 96.6 grams (0.46 mole) and 1150 milliliters of Glacial acetic acid that contain 9.7 milliliters of bromines mix, and slowly add the solution that 690 milliliters of vitriol oils and 464 ml waters are made into again.Under 40 ℃, 67.5 gram potassium bromates are divided and add (each 9.65 grams) in the reaction solution for seven times, added in about 2 hours.Stopped reaction after 8 hours.Slowly material is poured in 3, the 000 ml water solution that are dissolved with 46.0 gram sodium bisulfites, placement is spent the night.Filter, with warm water (about 30 ℃) washing 3-4 time, oven dry gets faint yellow 3-bromo-2,4-two chloro-5-fluoronitrobenzenes 122.1 grams (0.423 mole), yield 91.9%.mp51-53.5℃。The 3rd step methoxylation
Preparation 2,4-two chloro-5-fluoro-3-methoxy nitrobenzenes
With 3-bromo-2, fluorine-based nitre benzene 120 grams (0.415 mole) of 4-two chloro-5-, 500 milliliters of methyl alcohol, sodium hydroxide 1.66g (0.042 mole) and sodium methylate 26.9 grams (0.498 mole) mixed, 60 ℃ of reactions 4 hours.Use the extracted with diethyl ether reaction product, at water successively, anhydrous sodium sulfate drying is used in dilute hydrochloric acid and water washing.Steam solvent, resistates is recrystallization in ethanol, gets 2,4-two chloro-5-fluoro-3-methoxy nitrobenzenes 73.5 grams (0.306 mole), yield 73.8%.The 4th step hydrogenation
Preparation 2,4-two chloro-5-fluoro-3-anisidines
With 2,4-two chloro-5-fluoro-3-methoxy nitrobenzenes 72.0 grams (0.3 mole), 500 ml methanol and 2.65 gram palladium-Pd/carbon catalysts are under the 3MPa at hydrogen pressure, 60 ℃ were reacted 3 hours.Reaction mass is as cold as room temperature, leaches catalyzer, steams solvent, gets 2,4-two chloro-5-fluoro-3-anisidines 58.5 grams (0.279 mole), yield 92.9%.The 5th step diazotization and bromo
Preparation 2,4-two chloro-5-fluoro-3-methoxyl group bromobenzenes
With 2,4-two chloro-5-fluoro-3-anisidines 52.5 grams (0.25 mole) are added in 165 milliliters of hydrochloric acid-water (1: 1) solution of 70 ℃, stir into pasty state, are as cold as 0-5 ℃.In 30 minutes, drip the solution that Sodium Nitrite 18.2 grams (0.263 mole) and 50 ml waters are made into.The diazonium solution of gained slowly is added in the solution that cuprous bromide (0.299 mole) and 160 milliliters of Hydrogen bromides (HBr) are made into, stirred 2 hours, placement is spent the night.Steam distillation, distillate extracts with toluene.Oil reservoir is used 10% aqueous sodium hydroxide solution successively, the vitriol oil and water washing, anhydrous sodium sulfate drying.Steam solvent, resistates is with the silica gel phase that fixes, and normal hexane-methylene dichloride is made moving phase, carries out column chromatography, 2,4-two chloro-5-fluoro-3-methoxyl group bromobenzenes 58.1 grams (0.212 mole), yield 84.9%.The 6th step acetylize
Preparation 2,4-two chloro-5-fluoro-3-methoxyacetophenones
With 2,0.20 mole of 4-two chloro-5-fluoro-3-methoxyl group bromobenzene, 0.22 mole in magnesium powder, 0.24 mole of cuprous chloride and tetrahydrofuran (THF) at room temperature stir for 240 milliliters and cause, and cooling fast makes to be reflected under-30 ± 10 ℃ and carries out then.TLC follows the tracks of and reacts completely.Dropping was dissolved in 50 milliliters of Acetyl Chloride 98Min.s (0.3 mole) in the toluene again ,-30 ± 10 ℃ of reactions 8 hours.Make reaction be raised to room temperature, stirred 3 hours.Pour material into 170 and restrain in the vitriolic trash ice that contains 75 milliliter 25%, stirred 5 minutes.Tell organic phase, water layer extracts with toluene.Merge organic layer, use sodium chloride aqueous solution successively, the aqueous solution of sodium bicarbonate and water washing, anhydrous sodium sulfate drying.Decompression steams solvent, and resistates is recrystallization in ethanol, gets 2,4-two chloro-5-fluoro-3-methoxyacetophenones 38.7 grams (0.163 mole), yield 81.6%.mp36.7-39.4℃。
Claims (5)
1. formula I compound (2,4-two chloro-5-fluoro-3-methoxyacetophenones).
2. the preparation method of formula I compound
Comprise following formula: compound
React with following formula: compound
CH
3COX
Wherein X is selected from halogen atom.
3. according to the method for claim 2, wherein be reflected under the Mg+CuY existence and carry out, wherein Y is selected from the chlorine or bromine atom.
4. according to the method for claim 2, wherein X is for being selected from chlorine atom and bromine atoms.
5. according to claim 4 method, wherein X is selected from the chlorine atom.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402920A (en) * | 2014-11-27 | 2015-03-11 | 薛峰 | Method for synthesizing 2-halogenated-3-pinacol borate-5-chloroaniline |
| CN105646140A (en) * | 2016-03-28 | 2016-06-08 | 浙江工业大学 | Preparation method of 1,2,4,5-tetrafluorobenzene |
| CN116693375A (en) * | 2023-08-08 | 2023-09-05 | 山东国邦药业有限公司 | Synthesis method of 2, 4-dichloro-5-fluoro acetophenone |
-
2000
- 2000-02-24 CN CN 00103100 patent/CN1310163A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402920A (en) * | 2014-11-27 | 2015-03-11 | 薛峰 | Method for synthesizing 2-halogenated-3-pinacol borate-5-chloroaniline |
| CN105646140A (en) * | 2016-03-28 | 2016-06-08 | 浙江工业大学 | Preparation method of 1,2,4,5-tetrafluorobenzene |
| CN105646140B (en) * | 2016-03-28 | 2018-06-29 | 浙江工业大学 | A kind of preparation method of 1,2,4,5- phenyl tetrafluorides |
| CN116693375A (en) * | 2023-08-08 | 2023-09-05 | 山东国邦药业有限公司 | Synthesis method of 2, 4-dichloro-5-fluoro acetophenone |
| CN116693375B (en) * | 2023-08-08 | 2023-11-24 | 山东国邦药业有限公司 | Synthesis method of 2, 4-dichloro-5-fluoro acetophenone |
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