CN110078633B - Preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride - Google Patents
Preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride Download PDFInfo
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- XULVRLDLMHNCCX-UHFFFAOYSA-N 4-fluoro-3-methoxy-5-methylaniline;hydrochloride Chemical compound Cl.COC1=CC(N)=CC(C)=C1F XULVRLDLMHNCCX-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- VXKYOKPNAXNAFU-UHFFFAOYSA-N 4-bromo-1-fluoro-2-methylbenzene Chemical compound CC1=CC(Br)=CC=C1F VXKYOKPNAXNAFU-UHFFFAOYSA-N 0.000 claims abstract description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 20
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 18
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 16
- XRNNSKQHDNJRDJ-UHFFFAOYSA-N 5-bromo-2-fluoro-3-methylphenol Chemical compound CC1=CC(Br)=CC(O)=C1F XRNNSKQHDNJRDJ-UHFFFAOYSA-N 0.000 claims description 15
- BNLXSNQTRFKATL-UHFFFAOYSA-N 5-bromo-2-fluoro-1-methoxy-3-methylbenzene Chemical compound COC1=CC(Br)=CC(C)=C1F BNLXSNQTRFKATL-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- PQIYMNDFIMDJLN-UHFFFAOYSA-N 4-fluoro-3-methoxy-5-methylaniline Chemical compound COC1=CC(N)=CC(C)=C1F PQIYMNDFIMDJLN-UHFFFAOYSA-N 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- 238000010791 quenching Methods 0.000 claims description 12
- 230000000171 quenching effect Effects 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- HSHYZUINFUNPJO-UHFFFAOYSA-N 2-(bromomethyl)-1-methoxy-4-(trifluoromethoxy)benzene Chemical compound COC1=CC=C(OC(F)(F)F)C=C1CBr HSHYZUINFUNPJO-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 229940043279 diisopropylamine Drugs 0.000 claims description 6
- SURBAJYBTYLRMQ-UHFFFAOYSA-N dioxido(propan-2-yloxy)borane Chemical compound CC(C)OB([O-])[O-] SURBAJYBTYLRMQ-UHFFFAOYSA-N 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 claims description 5
- 229940087646 methanolamine Drugs 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 4
- VLFDXHTXMHURJH-UHFFFAOYSA-N (5-bromo-2-fluoro-3-methylphenyl)boronic acid Chemical compound CC1=CC(Br)=CC(B(O)O)=C1F VLFDXHTXMHURJH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 2
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000011112 process operation Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- IGBLRMMARKVIRO-UHFFFAOYSA-N 1-bromo-3-fluoro-4-methoxy-2-methylbenzene Chemical compound COC1=CC=C(Br)C(C)=C1F IGBLRMMARKVIRO-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QTCQBPOWSWCJLQ-UHFFFAOYSA-N 2-fluoro-3-methylphenol Chemical compound CC1=CC=CC(O)=C1F QTCQBPOWSWCJLQ-UHFFFAOYSA-N 0.000 description 1
- RWLJENRVVKIEMC-UHFFFAOYSA-N 4-bromo-2-fluoro-3-methylphenol Chemical compound CC1=C(F)C(O)=CC=C1Br RWLJENRVVKIEMC-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- -1 fluoro-3-methoxy-5-methylaniline Chemical compound 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/60—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by oxidation reactions introducing directly hydroxy groups on a =CH-group belonging to a six-membered aromatic ring with the aid of other oxidants than molecular oxygen or their mixtures with molecular oxygen
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/09—Preparation of ethers by dehydration of compounds containing hydroxy groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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Abstract
The invention discloses a preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride, belonging to the field of organic synthesis. A preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following synthetic route:
the preparation method of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride takes cheap and easily obtained 5-bromo-2-fluorotoluene as a starting material, obtains the 4-fluoro-3-methoxy-5-methylaniline hydrochloride through 5 steps of reaction, has convenient process operation, low cost, safety, high total yield and environmental friendliness, is suitable for industrial production, and has wide application prospect.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride.
Background
In 2012, Hui Li, Santa Clara, CA (US) et al used 2-fluoro-3-methylphenol as a starting material to prepare 4-fluoro-3-methoxy-5-methylaniline hydrochloride (see US 2012/28923; (2012); (A1) English) through 4 steps of reactions. Although the method has less process steps, the initial raw materials are not easy to synthesize, the price is high, the reaction conditions are harsh, and the three wastes are huge. Particularly, the first bromination, the third nitration and the fourth reaction are carried out in an autoclave, so that the reaction risk coefficient is high, the production discharge capacity is large, and the environmental pollution is easily caused.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride, which has the advantages of easily obtained raw materials, low cost, convenient and safe process operation, high total yield and environmental friendliness.
The technical scheme adopted by the invention is as follows:
a preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following synthetic route:
further, a preparation method of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following steps:
s1, sequentially adding 5-bromo-2-fluorotoluene and diisopropylamine into a three-necked bottle filled with an organic solvent, dropwise adding a cyclohexane solution dissolved with butyllithium into the three-necked bottle at 0 ℃, cooling the system to-50 to-80 ℃ after dropwise adding, reacting for 1-2 hours, dropwise adding a tetrahydrofuran solution of trimethyl borate or isopropyl borate into the reaction system, and continuing to react for 2-4 hours after dropwise adding; after the reaction is finished, carrying out water quenching reaction, separation, extraction and concentration to obtain 5-bromo-2-fluoro-3-methylphenylboronic acid;
s2, dissolving the 5-bromo-2-fluoro-3-methylphenylboronic acid in an organic solvent, cooling the system to 0-10 ℃, then dropwise adding an oxidant, heating the system to room temperature in a nitrogen atmosphere to react for 5-10 hours after dropwise adding is finished, and carrying out acid quenching reaction, separation, extraction and concentration after the reaction is finished to obtain 5-bromo-2-fluoro-3-methylphenol;
s3, dissolving the 5-bromo-2-fluoro-3-methylphenol in an organic solvent, then adding an alkali solution, dropwise adding dimethyl sulfate or methyl iodide or methanol in a nitrogen atmosphere, raising the temperature of the system to 60-80 ℃ after dropwise adding is finished, reacting for 1-2 hours, cooling the temperature of the system to room temperature after the reaction is finished, and then carrying out water quenching reaction, separation, extraction and concentration to obtain 5-bromo-2-fluoro-3-methyl anisole;
s4, dissolving the 5-bromo-2-fluoro-3-methylanisole in methanolamine, adding a catalyst, heating the system to 40-60 ℃ in a nitrogen atmosphere, reacting for 2-5 hours, cooling the system to room temperature after the reaction is finished, and performing water quenching reaction, separation, extraction and concentration to obtain 4-fluoro-3-methoxy-5-methylaniline;
s5, dissolving the 4-fluoro-3-methoxy-5-methylaniline in methanol or ethanol, then adding hydrogen chloride or a hydrogen chloride ethanol solution, heating the system to 60-80 ℃ under a nitrogen atmosphere, refluxing the reaction body for 1-2 h, cooling the system to room temperature after the reaction is finished, dropwise adding methyl tert-butyl ether into the system while stirring, and then filtering and drying to obtain the 4-fluoro-3-methoxy-5-methylaniline hydrochloride.
Further, the molar ratio of 5-bromo-2-fluoro-toluene, butyllithium, diisopropylamine, trimethyl borate, or isopropyl borate in S1 is 1: 1.0-1.5: 1.0-1.5: 1.0 to 1.5.
Further, in the S2, the oxidant is hydrogen peroxide, sodium hypochlorite or sodium hypobromite.
Further, the molar ratio of the 5-bromo-2-fluoro-3-methylbenzeneboronic acid to the oxidizing agent in the S2 is 1: 2.0 to 5.0.
Further, the mole ratio of the 5-bromo-2-fluoro-3-methylphenol, the dimethyl sulfate or the methyl iodide or the methanol in the S3 is 1: 1.0 to 2.
Further, the mass ratio of the 5-bromo-2-fluoro-3-methylanisole to the catalyst in the S4 is 1: 0.01 to 0.1.
Further, the organic solvent in S1 is at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and toluene; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-toluene is 5-10: 1.
Further, the organic solvent in S2 is at least one of tetrahydrofuran, dichloromethane, dioxane, and methyl tert-butyl ether; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-3-methylbenzeneboronic acid is 5-10: 1.
Further, the organic solvent in S3 is at least one of tetrahydrofuran, dioxane, and DMF; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-3-methylphenol is 5-10: 1.
Specifically, the extracting agent used for extraction is one or two of methyl tert-butyl ether, ethyl acetate and dichloromethane; the alkali solution in the S3 is at least one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide solution; the catalyst in the S4 is manganese, iron, nickel, zinc, copper, palladium, rhodium, cesium, platinum, ruthenium or cobalt and a complex compound or a complex compound thereof; the mass ratio of methanolamine or ethanol to 5-bromo-2-fluoro-3-methylanisole in S4 is 0.6-1: 1; the mass ratio of the methanol or the ethanol to the 4-fluoro-3-methoxy-5-methylaniline in the S5 is 5-10: 1.
The invention has the beneficial effects that: the preparation method of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride takes cheap and easily obtained 5-bromo-2-fluorotoluene as a starting material, obtains the 4-fluoro-3-methoxy-5-methylaniline hydrochloride through 5 steps of reaction, has convenient process operation, low cost, safety, high total yield and environmental friendliness, is suitable for industrial production, and has wide application prospect.
Drawings
FIG. 15 nuclear magnetic resonance spectrum of bromo-2-fluoro-3-methylphenol;
FIG. 25 shows the nuclear magnetic resonance spectrum of bromo-2-fluoro-3-methylanisole;
FIG. 34 nuclear magnetic resonance spectrum of fluoro-3-methoxy-5-methylaniline;
FIG. 44-fluoro-3-methoxy-5-methylaniline hydrochloride.
Detailed Description
The embodiments of the present invention can be obtained by different substitutions in specific ranges based on the above technical solutions, and therefore, the following embodiments are only preferred embodiments of the embodiments, and any technical substitutions made by the above technical solutions are within the protection scope of the present invention.
Example 1
A preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following steps:
preparation of S1.5-bromo-2-fluoro-3-methylphenylboronic acid
Sequentially adding 5-bromo-2-fluorotoluene (50g, 1.0eq) and diisopropylamine (26.7g, 1eq) into a three-neck flask containing tetrahydrofuran (500g), dropwise adding a cyclohexane (100g) solution of butyllithium (16.92g, 1eq) at 0 ℃, cooling the system to-65 ℃ after dropwise adding, reacting for 2 hours, dropwise adding a tetrahydrofuran (100g) solution of isopropyl borate (49.77g, 1.3eq) into the reaction system, and continuing to react for 3 hours after dropwise adding. After the reaction was completed, water was slowly added to the reaction system, the organic phase was separated, the product was extracted from the aqueous phase with methyl tert-butyl ether (500g), the organic phase was concentrated to dryness, and column chromatography (PE: MTBE ═ 20:1) was performed to obtain 5-bromo-2-fluoro-3-methylphenylboronic acid in yield: 85 percent.
Preparation of S2.5-bromo-2-fluoro-3-methylphenol
Dissolving 5-bromo-2-fluoro-3-methylphenylboronic acid (50g, 1.0eq) in tetrahydrofuran (500g), cooling to 5 ℃, slowly adding hydrogen peroxide (45g, 3.0eq) dropwise into the reaction system, after dropwise addition, heating the system to room temperature under a nitrogen atmosphere to react for 7 hours, after the reaction is finished, slowly adding hydrochloric acid into the reaction system, then extracting an organic phase with methyl tert-butyl ether (250g), concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 5-bromo-2-fluoro-3-methylphenol, wherein the yield is as follows: 80 percent.
Preparation of S3.5-bromo-2-fluoro-3-methylanisole
Dissolving 5-bromo-2-fluoro-3-methylphenol (50g, 1.0eq) in DMF (250g), then adding potassium hydroxide solution (27.3g, 2.0eq), under nitrogen atmosphere, further adding methyl iodide (32.5g, 1.0eq) dropwise, after the dropwise addition is finished, raising the temperature of the system to 70 ℃, reacting for 2h, after the reaction of the raw materials is finished, cooling the system to room temperature, adding water into the system for quenching reaction, extracting an organic phase with methyl tert-butyl ether (500g), separating the organic phase, concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 5-bromo-2-fluoro-3-methyl anisole, wherein the yield is: 75 percent.
S4.4-fluoro-3-methoxy-5-methylaniline preparation
Dissolving 5-bromo-2-fluoro-3-methylanisole (50g, 1.0eq) in methanolamine solution (30g, 2.0eq), adding catalyst rhodium (2.5g), raising the temperature of the system to 50 ℃ under nitrogen atmosphere, reacting for 2 hours, cooling the system to room temperature after the reaction is finished, adding water into the system for quenching reaction, extracting an organic phase with methyl tert-butyl ether (100g), concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 4-fluoro-3-methoxy-5-methylaniline, wherein the yield is as follows: 90 percent.
S5.4-fluoro-3-methoxy-5-methylanilide hydrochloride
Dissolving 4-fluoro-3-methoxy-5-methylaniline (50g, 1.0eq) in ethanol (250g), then adding a hydrogen chloride ethanol solution (40g, 2.0eq), raising the temperature of the system to 70 ℃ under a nitrogen atmosphere, carrying out reflux reaction for 2h, cooling the system to room temperature after the reaction is finished, adding methyl tert-butyl ether (250g) into the system while stirring, separating out a large amount of solid, stirring for a plurality of minutes, filtering, and drying to obtain 4-fluoro-3-methoxy-5-methylaniline hydrochloride, wherein the yield is as follows: 89 percent.
Example 2
A preparation method of 4-fluoro-3-methoxy-5-methylaniline hydrochloride comprises the following steps:
preparation of S1.5-bromo-2-fluoro-3-methylphenylboronic acid
Adding 5-bromo-2-fluorotoluene (50g, 1.0eq) and diisopropylamine (40.15g, 1.5eq) into a three-neck flask containing tetrahydrofuran (500g) in sequence, dropwise adding a cyclohexane (100g) solution of butyllithium (25.38g, 1.5eq) at 0 ℃, cooling the system to-65 ℃ after dropwise adding, reacting for 2h, dropwise adding a tetrahydrofuran (100g) solution of isopropyl borate (74.65g, 1.5eq) into the reaction system, and continuing to react for 3h after dropwise adding. After the reaction was completed, water was slowly added to the reaction system, the organic phase was separated, the product was extracted from the aqueous phase with methyl tert-butyl ether (500g), the organic phase was concentrated to dryness, and column chromatography (PE: MTBE ═ 20:1) was performed to obtain 5-bromo-2-fluoro-3-methylphenylboronic acid in yield: 75 percent.
Preparation of S2.5-bromo-2-fluoro-3-methylphenol
Dissolving 5-bromo-2-fluoro-3-methylphenylboronic acid (50g, 1.0eq) in tetrahydrofuran (500g), cooling to 5 ℃, slowly adding hydrogen peroxide (75g, 5.0eq) dropwise into the reaction system, after dropwise addition, heating the system to room temperature under a nitrogen atmosphere to react for 7 hours, after the reaction is finished, slowly adding hydrochloric acid into the reaction system, then extracting an organic phase with methyl tert-butyl ether (250g), concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 5-bromo-2-fluoro-3-methylphenol, wherein the yield is as follows: 80 percent.
Preparation of S3.5-bromo-2-fluoro-3-methylanisole
Dissolving 5-bromo-2-fluoro-3-methylphenol (50g, 1.0eq) in DMF (250g), then adding potassium hydroxide solution (27.3g, 2.0eq), under a nitrogen atmosphere, further adding methyl iodide (48.75g, 1.5eq) dropwise, after the dropwise addition is finished, raising the temperature of the system to 70 ℃, reacting for 2 hours, after the reaction of the raw materials is finished, cooling the system to room temperature, adding water into the system for quenching reaction, extracting an organic phase with methyl tert-butyl ether (500g), separating the organic phase, concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 5-bromo-2-fluoro-3-methyl anisole, wherein the yield is as follows: 89 percent.
S4.4-fluoro-3-methoxy-5-methylaniline preparation
Dissolving 5-bromo-2-fluoro-3-methylanisole (50g, 1.0eq) in methanolamine solution (30g, 2.0eq), adding palladium catalyst (0.5g), raising the temperature of the system to 50 ℃ under nitrogen atmosphere, reacting for 2 hours, cooling the system to room temperature after the reaction is finished, adding water into the system for quenching reaction, extracting an organic phase with methyl tert-butyl ether (100g), concentrating the organic phase to dryness, and performing column chromatography (PE: MTBE 20:1) to obtain 4-fluoro-3-methoxy-5-methylaniline, wherein the yield is as follows: 80 percent.
S5.4-fluoro-3-methoxy-5-methylanilide hydrochloride
Dissolving 4-fluoro-3-methoxy-5-methylaniline (50g, 1.0eq) in ethanol (250g), then adding a hydrogen chloride ethanol solution (40g, 2.0eq), raising the temperature of the system to 70 ℃ under a nitrogen atmosphere, carrying out reflux reaction for 2h, cooling the system to room temperature after the reaction is finished, adding methyl tert-butyl ether (250g) into the system while stirring, separating out a large amount of solid, stirring for a plurality of minutes, filtering, and drying to obtain 4-fluoro-3-methoxy-5-methylaniline hydrochloride, wherein the yield is as follows: 82 percent.
The nuclear magnetic detection result of the 5-bromo-2-fluoro-3-methylphenol is as follows:1h NMR (400MHz, (CD3)2SO): δ 6.91(1H, s),6.86(1H, s),2.17(3H, s), as shown in fig. 1.
The nuclear magnetic detection result of the 5-bromo-2-fluoro-3-methylanisole is as follows:1h NMR (400MHz, (CD3)2 SO). delta.7.15 (1H, s),7.03(1H, s),3.82(3H, s),2.19(3H, s) as shown in FIG. 2.
The nuclear magnetic detection result of the 4-fluoro-3-methoxy-5-methylaniline is as follows: the nuclear magnetic detection result of the 4-fluoro-3-methoxy-5-methylaniline is as follows: 1H NMR (400MHz, (CD3)2 SO). delta.7.00 (1H, s),6.82(1H, s),3.82(3H, s),2.23(3H, s), as shown in FIG. 3.
The nuclear magnetic detection result of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride is as follows:1h NMR (400MHz, (CD3)2 SO). delta.7.00 (1H, s),6.82(1H, s),3.82(3H, s),2.23(3H, s) as shown in FIG. 4.
Claims (10)
1. The preparation method of the 4-fluoro-3-methoxy-5-methylaniline hydrochloride is characterized in that the synthetic route is as follows:
2. the process for producing 4-fluoro-3-methoxy-5-methylaniline hydrochloride according to claim 1, comprising the steps of:
s1, sequentially adding 5-bromo-2-fluorotoluene and diisopropylamine into a three-necked bottle filled with an organic solvent, dropwise adding a cyclohexane solution dissolved with butyllithium into the three-necked bottle at 0 ℃, cooling the system to-50 to-80 ℃ after dropwise adding, reacting for 1-2 hours, dropwise adding a tetrahydrofuran solution of trimethyl borate or isopropyl borate into the reaction system, and continuing to react for 2-4 hours after dropwise adding; after the reaction is finished, carrying out water quenching reaction, separation, extraction and concentration to obtain 5-bromo-2-fluoro-3-methylphenylboronic acid;
s2, dissolving the 5-bromo-2-fluoro-3-methylphenylboronic acid in an organic solvent, cooling the system to 0-10 ℃, then dropwise adding an oxidant, heating the system to room temperature in a nitrogen atmosphere to react for 5-10 hours after dropwise adding is finished, and carrying out acid quenching reaction, separation, extraction and concentration after the reaction is finished to obtain 5-bromo-2-fluoro-3-methylphenol;
s3, dissolving the 5-bromo-2-fluoro-3-methylphenol in an organic solvent, then adding an alkali solution, dropwise adding dimethyl sulfate or methyl iodide or methanol in a nitrogen atmosphere, raising the temperature of the system to 60-80 ℃ after dropwise adding is finished, reacting for 1-2 hours, cooling the temperature of the system to room temperature after the reaction is finished, and then carrying out water quenching reaction, separation, extraction and concentration to obtain 5-bromo-2-fluoro-3-methyl anisole;
s4, dissolving the 5-bromo-2-fluoro-3-methylanisole in methanolamine, adding a catalyst, heating the system to 40-60 ℃ in a nitrogen atmosphere, reacting for 2-5 hours, cooling the system to room temperature after the reaction is finished, and performing water quenching reaction, separation, extraction and concentration to obtain 4-fluoro-3-methoxy-5-methylaniline;
s5, dissolving the 4-fluoro-3-methoxy-5-methylaniline in methanol or ethanol, then adding hydrogen chloride or a hydrogen chloride ethanol solution, heating the system to 60-80 ℃ under a nitrogen atmosphere, refluxing the reaction body for 1-2 h, cooling the system to room temperature after the reaction is finished, dropwise adding methyl tert-butyl ether into the system while stirring, and then filtering and drying to obtain the 4-fluoro-3-methoxy-5-methylaniline hydrochloride.
3. The method of claim 2, wherein the molar ratio of 5-bromo-2-fluoro-toluene, butyllithium, diisopropylamine, trimethyl borate, or isopropyl borate in S1 is 1: 1.0-1.5: 1.0-1.5: 1.0 to 1.5.
4. The method for preparing 4-fluoro-3-methoxy-5-methylaniline hydrochloride as in claim 2, wherein the oxidant in S2 is hydrogen peroxide, sodium hypochlorite or sodium hypobromite.
5. The method of claim 2, wherein the molar ratio of 5-bromo-2-fluoro-3-methylphenylboronic acid to oxidant in S2 is 1: 2.0 to 5.0.
6. The method of claim 2, wherein the molar ratio of 5-bromo-2-fluoro-3-methylphenol, dimethyl sulfate, methyl iodide or methanol in S3 is 1: 1.0 to 2.
7. The method for preparing 4-fluoro-3-methoxy-5-methylaniline hydrochloride according to claim 2, wherein the mass ratio of 5-bromo-2-fluoro-3-methylanisole to the catalyst in S4 is 1: 0.01 to 0.1.
8. The method for preparing 4-fluoro-3-methoxy-5-methylaniline hydrochloride according to claim 2, wherein the organic solvent in S1 is at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether and toluene; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-toluene is 5-10: 1.
9. The method for preparing 4-fluoro-3-methoxy-5-methylaniline hydrochloride according to claim 2 wherein said organic solvent in S2 is at least one of tetrahydrofuran, dichloromethane, dioxane and methyl tert-butyl ether; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-3-methylbenzeneboronic acid is 5-10: 1.
10. The method of claim 2, wherein the organic solvent of S3 is at least one of tetrahydrofuran, dioxane, and DMF; the mass ratio of the organic solvent to the 5-bromo-2-fluoro-3-methylphenol is 5-10: 1.
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