WO2010057406A1 - 一种3-溴-5-氯苯酚的制备方法 - Google Patents
一种3-溴-5-氯苯酚的制备方法 Download PDFInfo
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- WO2010057406A1 WO2010057406A1 PCT/CN2009/074490 CN2009074490W WO2010057406A1 WO 2010057406 A1 WO2010057406 A1 WO 2010057406A1 CN 2009074490 W CN2009074490 W CN 2009074490W WO 2010057406 A1 WO2010057406 A1 WO 2010057406A1
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- compound
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- bromo
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- 238000000034 method Methods 0.000 title claims abstract description 30
- GMGWXLPFRHYWAS-UHFFFAOYSA-N 3-bromo-5-chlorophenol Chemical compound OC1=CC(Cl)=CC(Br)=C1 GMGWXLPFRHYWAS-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 230000002378 acidificating effect Effects 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims description 39
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 34
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 26
- 229940125782 compound 2 Drugs 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 229940126214 compound 3 Drugs 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 235000010288 sodium nitrite Nutrition 0.000 claims description 13
- 239000012442 inert solvent Substances 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000006193 diazotization reaction Methods 0.000 claims description 4
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 3
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 claims description 2
- 239000004280 Sodium formate Substances 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- 235000019254 sodium formate Nutrition 0.000 claims description 2
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 claims description 2
- 239000007868 Raney catalyst Substances 0.000 claims 1
- 229910000564 Raney nickel Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000013341 scale-up Methods 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000012264 purified product Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000012954 diazonium Substances 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- 150000001989 diazonium salts Chemical class 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- CVXDZAQINLBEIC-UHFFFAOYSA-N 1-bromo-3-chloro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(Br)=C1 CVXDZAQINLBEIC-UHFFFAOYSA-N 0.000 description 12
- YYBRLVWWPRAQDX-UHFFFAOYSA-N 3-bromo-5-chloroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1 YYBRLVWWPRAQDX-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229910052688 Gadolinium Inorganic materials 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- GGMDFPMASIXEIR-UHFFFAOYSA-N 1-bromo-3-chloro-5-fluorobenzene Chemical compound FC1=CC(Cl)=CC(Br)=C1 GGMDFPMASIXEIR-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000006385 ozonation reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JRGGUPZKKTVKOV-UHFFFAOYSA-N 1-bromo-3-chlorobenzene Chemical compound ClC1=CC=CC(Br)=C1 JRGGUPZKKTVKOV-UHFFFAOYSA-N 0.000 description 1
- JOBPGDXYRPFRIV-UHFFFAOYSA-N 3-amino-5-chlorophenol Chemical compound NC1=CC(O)=CC(Cl)=C1 JOBPGDXYRPFRIV-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical class F* 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 208000027061 mild cognitive impairment Diseases 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
- C07C245/20—Diazonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
-
- 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
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/045—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by nitrogen
Definitions
- the invention relates to a preparation method of an organic synthesis intermediate, in particular to a preparation method of 3-bromo-5-chlorophenol. Background technique
- Patent WO 2006010545 describes a process for preparing 3-bromo-5-chlorophenol by using 3-chloro-5-fluorobromobenzene as a starting material, first performing a methoxy-substituted fluoro functional group, and then demethylating under acidic conditions.
- the method yield is low, and the synthesis of 3-chloro-5-fluorobromobenzene is cumbersome.
- the above three synthetic routes all have certain limitations, which brings certain difficulties to the industrial production of 3-bromo-5-chlorophenol. Summary of the invention
- the technical problem to be solved by the invention is to overcome the high cost, the side reaction, the complicated operation, the high energy consumption, the low raw material and the low yield of the existing 3-bromo-5-chlorophenol synthesis route.
- the defect provides a preparation method of 3-bromo-5-chlorophenol, which has the advantages of low cost, easy availability of raw materials, convenient operation, easy purification of products and easy scale-up production, and can also achieve relatively high yield.
- the present invention relates to a process for the preparation of 3-bromo-5-chlorophenol as shown in Formula 1, which comprises the following steps: Compound 3 is hydrolyzed in an acidic medium to obtain Compound 1;
- the method and conditions of the hydrolysis reaction may be the conventional methods and conditions for the hydrolysis reaction of the diazonium salt in the field, and the following conditions are particularly preferred in the present invention:
- the acid in the acidic medium is preferably used in an amount of from 1 to 20 times, more preferably from 8 to 12 times, the molar amount of the compound 3; the acidic medium may be selected from various ratios of sulfuric acid aqueous solution or sulfuric acid. a mixed solution of an aqueous solution and an organic inert solvent;
- the mass percentage of the aqueous sulfuric acid solution is preferably 5% to 90%, more preferably 30% to 60%; and the organic inert solvent is preferably selected from the group consisting of aromatic hydrocarbons, ethers and halogenated anthracene hydrocarbons.
- aromatic hydrocarbon is preferably toluene and/or xylene
- the ether is preferably one or more of tetrahydrofuran, ethylene glycol dimethyl ether and dioxan
- the halogenated hydrocarbon is preferably one or more of dichloromethane, chloroform and 1,2-dichloroacetam.
- the temperature of the hydrolysis reaction is preferably from 60 ° C to 150 ° C, more preferably from 80 ° C to 120 ° C.
- the reaction time is until the reaction is completed.
- the reactants are consumed by HPLC. until.
- pure compound 1 can be obtained by a simple post-treatment such as extraction, concentration, filtration, and drying.
- the compound 3 is a diazonium salt compound, and is generally used without isolation and purification according to a conventional operation method in the art, and therefore, in the preparation method of the above compound 1, the amount of the reagent related to the compound 3 is prepared by The amount of the raw material obtained after the complete conversion of the raw material is calculated.
- the starting material for preparing the compound 3 is preferably the following compound 2.
- the compound 3 can be obtained by the following method: Compound 2 can be subjected to diazotization reaction under acidic conditions;
- the method and conditions of the diazotization reaction can be a conventional method and condition for preparing a diazonium salt reaction in the art.
- the preferred methods and conditions are as follows:
- the compound 2 is subjected to a diazotization reaction with sodium nitrite or n-butyl nitrite to form a diazonium salt compound 3; wherein a method of reacting with sodium nitrite is a preferred method.
- the molar ratio of the compound 2 to the sodium nitrite is preferably 1:1 to 1:3, more preferably 1:1 to 1:2;
- the conditions are favorable for the progress of the reaction and ensure the stability of the diazonium salt.
- the strong acid is preferably one or more of hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid, preferably sulfuric acid;
- the molar amount of the compound 2 is from 1 to 100 times, more preferably from 8 to 20 times;
- the temperature of the reaction is preferably from -5 ° C to 50 ° C, preferably from 0 ° C to 10 °. C ;
- the reaction time is determined until the reaction is completed, and it is preferred to detect the consumption of the reactants by HPLC.
- the compound 2 can be obtained by the following method:
- the compound 4 can be subjected to a reduction reaction.
- the method and conditions of the reduction reaction may be the methods and conditions for the conventional nitro reduction reaction in the art, and the preferred methods and conditions are as follows:
- the reducing agent is preferably one or more of reduced iron powder, zinc powder, sodium dithionite, stannous chloride dihydrate, sodium borohydride and lithium aluminum hydride, and most preferably reduced iron powder
- the reducing agent is preferably used in an amount of from 1 to 20 times, more preferably from 5 to 10 times, the molar amount of the compound;
- the catalyst is preferably palladium carbon (Pd-C) or platinum carbon ( One or more of Pt-C) and Raney-Ni, preferably Raney-Ni; the amount of the catalyst is preferably 0.01 to 1 times the molar amount of the compound 4,
- the hydrogen source is preferably one or more of hydrogen, hydrazine hydrate, sodium formate, formic acid, ammonium formate and triethylamine formate, and most preferably hydrazine hydrate;
- the organic inert solvent is preferably a lower alcohol and/or a lower acid, more preferably a lower acid; the lower acid is preferably one or more of
- the temperature of the reduction reaction is preferably from 0 ° C to 80 ° C, more preferably from 10 ° C to 30 ° C; the time of the reduction reaction is detected until the reaction is completed, preferably by TLC. The reactants are consumed.
- the compound 4 can be synthesized by the method of Gazz. Chim. Ital., 1874, 4, 341.
- the positive effect of the invention is that: the preparation method of the invention can avoid expensive reagents or raw materials, thereby reducing the cost, and the raw materials are easy to obtain, the operation method is simple and convenient, the product is easy to be purified, and is not only suitable for laboratory preparation, but also suitable for industrialization. Mass production; it also achieves higher yields and purity. detailed description
- 3-bromo-5-chloronitrobenzene (23.6 g, 0.1 mol) was added to 200 mL of glacial acetic acid. After cooling to 0 ° C, reduced iron powder (33.6 g, 0.6 mol) was added. After stirring at 0 ° C for 2 h, the temperature was raised to room temperature. After stirring for 16 h, celite was filtered and washed with ethyl acetate (100 mL), and the filtrate was concentrated, and then filtered and evaporated to ethyl acetate (200 mL).
- 3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 10 mL of anhydrous acetonitrile and 5 mL of water, then sodium dithionite (6.96 g, 0.04 mol) was added and the mixture was warmed to 80 ° C for 2 h. After adding 10 mL of water and extracting with 3 X 15 mL of ethyl acetate, the organic layer was dried and concentrated to give 1.16 g of a tan solid.
- 3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 30 mL of absolute ethanol, then dihydrate was added.
- the stannous chloride (6.78 g, 0.03 mol) was heated to 80 ° C for 2 h, concentrated, and then added with ethyl acetate and refluxed for 30 min, filtered, and the filtrate was concentrated to give 1.63 g of a brownish brown liquid.
- 3-bromo-5-chloronitrobenzene (2.36 g, 0.01 mol) was added to 30 mL of ethyl acetate, and then added with 1% palladium carbon (0.03 mol), hydrogenated at room temperature for 1 h under normal pressure, filtered, and concentrated to give 2.06 g of a black liquid. , yield 99%.
- 3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 472 mL of propionic acid. After cooling to 0 ° C, reduced iron powder (0.5 mol) was added. After stirring at 0 ° C for 2 h, the temperature was raised to room temperature and stirred for 16 h. The celite was filtered and washed with ethyl acetate (100 mL), and the filtrate was concentrated and then filtered and evaporated to ethyl ether.
- 3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 200 mL of absolute ethanol, cooled to 0 ° C, then reduced Raney-Ni (O.lmol) was added, and 20 ml of formic acid was added with stirring at 0 ° C. After stirring at 0 ° C for 2 h, the temperature was raised to 80 ° C for 1 h, and the filtrate was concentrated to give a tan liquid, yield 95%.
- 3-bromo-5-chloronitrobenzene (23.6 g, Ol mol) was added to 200 mL of isopropyl acid, cooled to 0 ° C, then reduced iron powder (1 mol) was added, stirred at 0 ° C for 2 h, then warmed to room temperature and stirred for 16 h. Diatomaceous earth filtered After washing with 100 mL of ethyl acetate, the combined filtrate was concentrated and then filtered and evaporated to ethyl ether.
- the yellow diazonium salt solution obtained in Example 13 was slowly dropped into a mixed solution of 5% sulfuric acid (0.05 mol) and 200 mL of diethyl ether at 60 ° C, stirred at 60 ° C for 30 minutes, and allowed to stand for separation.
- the organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water.
- the combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL of diethyl ether, and dried and concentrated to 10 mL.
- the gadolinium was completely precipitated, filtered and washed with n-glycol to give a white solid, yield 72%.
- Compound 2 (10. 3 g, 0.05 mol) was added to 100 mL of 50% nitric acid, heated to 100 °C, stirred until dissolved, cooled to 0 ° C, controlled temperature below 10 ° C, and added sodium nitrite solid (4.14 g, 0.15 mol) The mixture was further stirred at 50 ° C for 30 minutes to obtain a yellow diazonium salt solution.
- the yellow diazonium salt solution obtained in Example 15 was slowly dropped into a mixed solution of 90% sulfuric acid (1 mol) and 200 mL of toluene at 150 ° C, stirred at 150 ° C for 30 minutes, and allowed to stand for separation, and the organic layer was added to 50.
- the mixture was stirred for 10 minutes with mL 4N sodium hydroxide, and the organic layer was separated and washed with 50 mL of water.
- the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 X 50 mL of toluene, and the organic layer was dried and concentrated to 10 mL. Add n-glum to all solids, filter and wash with n-glycol to dry a white solid, yield 70%
- the yellow diazonium salt solution obtained in Example 17 was slowly dropped into a mixed solution of 90% sulfuric acid (0.4 mol) and 200 mL of chloroform at 80 ° C, stirred at 80 ° C for 30 minutes, and allowed to stand for separation.
- the organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water.
- the combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL chloroform, and dried and concentrated to 10 mL.
- the gadolinium was completely precipitated, filtered and washed with n-glycol to give a white solid, yield 7.5%.
- Example 20 Preparation of 3-bromo-5-chlorophenol
- the yellow diazonium salt solution obtained in Example 19 was slowly dropped into a mixed solution of 40% sulfuric acid (0.6 mol) and 200 mL of chloroform at 120 ° C, stirred at 120 ° C for 30 minutes, and allowed to stand for separation.
- the organic layer was added to 50 mL of 4N. Stir the sodium hydroxide for 10 minutes, separate the layers and wash the organic layer with 50 mL of water.
- the combined aqueous layer was acidified with 4N hydrochloric acid to pH 4, extracted with 3 X 50 mL chloroform, and dried and concentrated to 10 mL.
- the gadolinium was completely precipitated from the solid, filtered and washed with n-heptane to give a white solid, yield 71%.
- the yellow diazonium salt solution obtained in Example 21 was slowly dropped into 50 ml of a mixed solution of 30% sulfuric acid and 200 mL of toluene at 90 ° C, stirred at 90 ° C for 30 minutes, and allowed to stand for separation.
- the organic layer was added with 50 mL of 4N sodium hydroxide. After stirring for 10 minutes, the organic layer was separated and washed with 50 mL of water.
- the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 ⁇ 50 mL of toluene, and dried and concentrated to 10 mL. The solid was all precipitated, filtered and washed with n-glycol to give a white solid 7.78 g, yield 75%.
- the yellow diazonium salt solution obtained in Example 21 was slowly dropped into 100 mL of 100 mL of 50% sulfuric acid, stirred at 90 ° C for 30 minutes, extracted with 2 X 50 mL of toluene, and the organic layer was added with 50 mL of 4 N oxyhydrogen.
- the sodium salt was stirred for 10 minutes, and the organic layer was separated and washed with 50 mL of water.
- the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 ⁇ 50 mL of toluene, and then dried and concentrated to 10 mL. The solid was completely precipitated, filtered and washed with n-glycol to give a white solid, 6.73 g, yield 65%.
- the yellow diazonium salt solution obtained in Example 24 was slowly dropped into 200 mL of 50% sulfuric acid at 90 ° C, stirred at 90 ° C for 30 minutes, extracted with 2 X 50 mL of toluene, and the organic layer was added with 50 mL of 4N sodium hydroxide and stirred for 10 minutes.
- the organic layer was separated and washed with 50 mL of water, and the aqueous layer was combined and acidified to pH 4 with 4N hydrochloric acid, extracted with 3 ⁇ 50 mL of toluene, and dried and concentrated to 10 mL of organic layer. Filtered and washed with n-glycol to give a white solid 5.11 g, yield 49%.
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Description
一种 3-溴 -5-氯苯酚的制备方法 技术领域
本发明涉及一种有机合成中间体的制备方法, 具体的涉及一种 3-溴 -5- 氯苯酚的制备方法。 背景技术
3-溴 -5-氯苯酚, 英文名称为 3-Bromo-5-chlorophenol, CAS 为 56962-04-0, 其结构式如式 1所示。
1 化合物 1作为一种重要的有机合成中间体, 专利 US2006025462描述了 将其用于制备一种治疗由免疫缺陷病毒引起的疾病的药物,专利 2007078128 描述了将其用于制备一种非核苷类逆转录酶抑制剂,专利 WO2007145569描 述了将其用于制备治疗阿尔茨海默病轻度认知功能障碍疾病的一种药物, 市 场需求潜力非常大, 但其合成方法均存在一定的局限性。 目前, 3-溴 -5-氯苯 酚几条主要的合成路线如下:
1. 文献 J. Am. Chem. Soc, 2003, 125, 7792描述了以间氯溴苯为原料,经 过硼酸酯化再进行臭氧化反应得到 3-溴 -5-氯苯酚的方法,所用硼试剂价格昂 贵, 臭氧化反应的副反应较多, 且需投入新型设备, 耗能较高。
2. 文献 J. Chem. Soc, 1926, 2078描述了以 3-氨基 -5-氯苯酚为原料经桑 德迈耳反应合成 3-溴 -5-氯苯酚的方法, 但所用原料不易得, 且收率较低。
3. 专利 WO 2006010545描述了以 3-氯 -5-氟溴苯为原料, 先进行甲氧基 取代氟官能团,然后在酸性条件下脱甲基制备 3-溴 -5-氯苯酚的方法, 该方法 收率偏低, 且原料 3-氯 -5-氟溴苯合成繁琐。
上述三条合成路线,均存在一定的局限性,给 3-溴 -5-氯苯酚的工业化生 产带来一定的困难。 发明内容
本发明所要解决的技术问题是为了克服现有的 3-溴 -5-氯苯酚合成路线 中成本较高、 副反应较多、 操作复杂、 耗能较高、 原料不易得及收率较低的 缺陷, 提供了一种 3-溴 -5-氯苯酚的制备方法, 其成本较低、 原料易得、 操作 方便、 产物易纯化和易放大生产, 还可以达到比较高的产率。
3 1
其中, X—为 CI—、 Br 、 HS04—或 N03—。
其中,所述的水解反应的方法和条件可以为本领域重氮盐水解反应的常 规方法和条件, 本发明特别优选下述条件:
所述的酸性介质中的酸的用量较佳的为化合物 3的摩尔量的 1〜20倍, 更佳的为 8〜12倍; 所述的酸性介质可选用各种比例的硫酸水溶液、 或硫酸 水溶液与有机惰性溶剂形成的混合溶液;
其中, 所述的硫酸水溶液的质量百分比较佳的为 5%〜90%, 更佳的为 30%〜60%; 所述的有机惰性溶剂较佳的选自芳香烃、醚和卤代垸烃中的一种 或多种; 其中所述的芳香烃优选甲苯和 /或二甲苯, 所述的醚优选四氢呋喃、 乙二醇二甲醚和二恶垸中的一种或多种, 所述的卤代垸烃优选二氯甲垸、 氯 仿和 1,2-二氯乙垸中的一种或多种。
所述的水解反应的温度较佳的为 60°C〜150°C, 更佳的为 80°C〜120°C ; 反应的时间以检测反应完全为止, 较佳的以 HPLC检测反应物消耗完为止。
此歩骤在反应完全之后, 只需要简单的后处理如萃取、 浓缩、 过滤、 干 燥等方法即可得到纯的化合物 1。
本发明中, 化合物 3是重氮盐类化合物, 根据本领域常规操作方法, 一 般不分离纯化而直接使用, 因此在上述化合物 1的制备方法中, 与化合物 3 相关的试剂的用量, 均以制备它的原料完全转化后得到的量来计算, 在本发 明中, 制备化合物 3的原料较佳的为下述的化合物 2。
2 3 其中, X 为 CI—、 Br 、 HS04—或 N03—。
其中,所述的重氮化反应的方法和条件可为本领域制备重氮盐反应的常 规方法和条件。 优选的方法和条件如下:
在强酸性水溶液中,化合物 2与亚硝酸钠或亚硝酸正丁酯进行重氮化反 应, 形成重氮盐化合物 3; 其中, 与亚硝酸钠反应的方法是较佳的方法。
在所述的化合物 2与亚硝酸钠的反应中,化合物 2与亚硝酸钠的摩尔比 较佳的为 1:1〜1:3, 更佳的为 1:1〜1:2; 反应在强酸酸性条件下有利于反应的 进行并保证重氮盐的稳定性, 所述的强酸较佳的为盐酸、 氢溴酸、 硝酸和硫 酸中的一种或多种, 优选硫酸; 所述的硫酸的用量较佳的为化合物 2的摩尔 量的 1〜100倍, 更佳的为 8〜20倍; 所述的反应的温度较佳的为 -5°C〜50°C, 优选 0°C〜10°C ; 所述的反应的时间以检测反应完全为止, 较佳的为以 HPLC 检测反应物消耗完为止。
4 2
将化合物 4进行还原反应即可。
其中,所述的还原反应的方法和条件可以为本领域常规的硝基还原反应 的方法和条件, 优选的方法和条件如下:
在有机惰性溶剂中, 在还原剂、 或者催化剂和氢源的作用下, 化合物 4
进行还原反应, 形成化合物 2。
其中, 所述的还原剂较佳的为还原铁粉、 锌粉、 连二亚硫酸钠、 二水合 氯化亚锡、 硼氢化钠和氢化铝锂的一种或多种, 最佳的为还原铁粉; 所述的 还原剂的用量较佳的为化合物 4摩尔量的 1〜20倍, 更佳的为 5〜10倍; 所述 的催化剂较佳的为钯碳(Pd-C)、 铂碳(Pt-C)和兰尼镍(Raney-Ni) 中的一 种或多种, 优选兰尼镍 (Raney-Ni); 催化剂的用量较佳的为化合物 4的摩 尔量的 0.01〜1倍, 更佳的为 0.1〜0.2倍; 所述的氢源较佳的为氢气、水合肼、 甲酸钠、 甲酸、 甲酸铵和甲酸三乙胺盐中的一种或多种, 最佳的为水合肼; 所述的有机惰性溶剂较佳的为低级醇和 /或低级酸,更佳的为低级酸;所述低 级酸优选甲酸、 乙酸、 丙酸、 异丙酸和正丁酸中的一种或多种, 更佳的为乙 酸; 所述的有机惰性溶剂与化合物 4的体积质量比较佳为 l〜100ml/g, 更佳 的为 8〜20ml/g。
所述的还原反应的温度较佳的为 0°C〜80°C, 更佳的为 10°C〜30°C ; 所述 的还原反应的时间以检测反应完全为止, 较佳的以 TLC检测反应物消耗完 为止。
本发明中, 所述的化合物 4可参照文献 Gazz. Chim. Ital., 1874, 4, 341 的方法合成获得。
除特殊说明外, 本发明涉及的试剂和原料均市售可得。
本发明的积极进歩效果在于: 本发明的制备方法可避免昂贵的试剂或原 料, 从而降低成本, 且原料易得、 操作方法简单方便、 产物易纯化, 不仅适 合实验室少量制备, 也适合工业化大规模生产; 其还可以达到较高的产率和 纯度。 具体实施方式
下面用实施例来进一歩说明本发明, 但本发明并不受其限制。
其中所述的常温为 20〜40°C, 常压为 0.8atm〜1.2atm。
实施例 1 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (23.6 g, 0.1 mol) 加入 200 mL冰醋酸, 冷却到 0°C后 加入还原铁粉 (33.6 g, 0.6 mol), 0°C搅拌 2h后升温至室温搅拌 16h, 硅藻 土过滤并以 100 mL乙酸乙酯洗涤,合并滤液浓缩后再以 200 mL乙酸乙酯溶 解过滤, 滤液浓缩得褐色液体 19.2 g, 收率 93 %。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 91.5%
实施例 2 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (23.6 g, 0.1 mol) 加入 200 mL无水乙醇, 冷却到 0°C 后加入还原 Raney-Ni (0.59 g, 0.01 mol), 0°C搅拌下滴入水合肼 23 mL, 0°C 搅拌 2h后升温至 80°C反应 lh, 过滤滤液浓缩后得 20.9 g黄褐色液体, 收率 98%。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 93.2%
实施例 3 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (2.36 g, 0.01 mol) 加入 10 mL无水乙腈和 5 mL水, 再加入连二亚硫酸钠 (6.96 g, 0.04 mol) 升温至 80°C反应 2h, 浓缩后加入 10 mL水, 以 3 X 15 mL乙酸乙酯萃取, 有机层干燥浓缩后得 1.16 g黄褐色 固体, 收率 56%。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 86.4%
实施例 4 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯(2.36 g, 0.01 mol)加入 30 mL无水乙醇, 再加入二水
合氯化亚锡 (6.78 g, 0.03 mol) 升温至 80°C反应 2h, 浓缩后加入乙酸乙酯 回流 30分钟过滤, 滤液浓缩后得 1.63 g黄褐色液体, 收率 79 %。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 90.2%
实施例 5 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (2.36 g, 0.01 mol) 加入 30 mL乙酸乙酯, 再加入 1% 钯碳 0.03 mol, 室温下常压氢化 lh, 过滤, 滤液浓缩后得 2.06 g黑色液体, 收率 99%。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 83.9%
实施例 6 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (2.36 g, 0.01 mol) 加入 2.36mL无水乙醇, 再加入硼 氢化钠(O.Olmol)升温至 30°C反应 2h, 浓缩后加入 lO mL水, 以 3 X 15 mL 乙酸乙酯萃取, 有机层干燥浓缩后得黄褐色固体, 收率 53 %。 HPLC: 90% 实施例 7 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (2.36 g, 0.01 mol) 加入 236mL无水乙醇, 再加入硼 氢化钠(0.2mol)在 10°C反应 2h, 浓缩后加入 lO mL水, 以 3 X 15 mL乙酸 乙酯萃取, 有机层干燥浓缩后得黄褐色固体, 收率 50%。 HPLC: 90.2%
实施例 8 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (23.6 g, 0.1 mol) 加入 189mL无水乙醇, 冷却到 0°C 后加入还原 Raney-Ni ( 0.001 mol) , 0°C搅拌下加入甲酸铵 0.3mol, 0°C搅拌 2h后升温至 80°C反应 lh, 过滤滤液浓缩后得黄褐色液体, 收率 93 %。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 93.2%
实施例 9 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (23.6 g, O.l mol) 加入 472mL丙酸, 冷却到 0°C后加 入还原铁粉(0.5mol), 0°C搅拌 2h后升温至室温搅拌 16h, 硅藻土过滤并以 100 mL乙酸乙酯洗涤, 合并滤液浓缩后再以 200 mL乙酸乙酯溶解过滤, 滤 液浓缩得褐色液体, 收率 90%。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 92.2%
实施例 10 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (23.6 g, O.l mol) 加入 200 mL无水乙醇, 冷却到 0°C 后加入还原 Raney-Ni (O.lmol), 0°C搅拌下加入甲酸 20ml, 0°C搅拌 2h后升 温至 80°C反应 lh, 过滤滤液浓缩后得黄褐色液体, 收率 95 %。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 93.2%
实施例 11 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (23.6 g, O.l mol) 加入 200 mL无水乙醇, 冷却到 0°C 后加入还原 Raney-Ni (0.02mol), 0°C搅拌下加入水合肼 23ml, 0°C搅拌 2h 后升温至 80°C反应 lh, 过滤滤液浓缩后得黄褐色液体, 收率 95 %。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 93.2%
实施例 12 3-溴 -5-氯苯胺的制备
3-溴 -5-氯硝基苯 (23.6 g, O.l mol) 加入 200 mL异丙酸, 冷却到 0°C后 加入还原铁粉 (lmol), 0°C搅拌 2h后升温至室温搅拌 16h, 硅藻土过滤并
以 100 mL乙酸乙酯洗涤, 合并滤液浓缩后再以 200 mL乙酸乙酯溶解过滤, 滤液浓缩得褐色液体, 收率 90%。
¾ NMR (300MHz, CDC13) δ: 3.80 (br, 2H, NH2), 6.60 (t, J=1.40Hz, 1H, Ph), 6.72 (t, J= 1.40Hz, 1H, Ph), 6.89 (t, J=1.40Hz, 1H, Ph).
HPLC: 92.2%
实施例 13 化合物 3 (X—为 Br ) 的制备
化合物 2 ( 10.3 g, 0.05 mol)加入 100 mL 50%氢溴酸升温至 100°C搅拌 至溶解, 冷却至 0°C, 控制温度 10°C以下, 分批加入亚硝酸钠固体(4.14 g, 0.05mol) , -5°C继续搅拌 30分钟, 得黄色重氮盐溶液。
实施例 14 3-溴 -5-氯苯酚的制备
将实施例 13所得黄色重氮盐溶液缓慢滴入 60°C的 5 %硫酸 (0.05mol) 和 200 mL乙醚混合溶液中, 60°C搅拌 30分钟,静至分液,有机层加入 50 mL 4N氢氧化钠搅拌 10分钟, 分液并以 50 mL水洗涤有机层, 合并水层并以 4N盐酸酸化至 pH为 4左右, 以 3 X 50 mL乙醚萃取, 有机层干燥浓缩至 10 mL滴加正庚垸至固体全部析出, 过滤并以正庚垸洗涤干燥得白色固体, 收 率 72%。
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph), 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 99.1%
实施例 15 化合物 3 (X—为 N03— ) 的制备
化合物 2 ( 10.3 g, 0.05 mol)加入 100 mL 50%硝酸升温至 100 °C搅拌至 溶解, 冷却至 0°C, 控制温度 10°C以下, 分批加入亚硝酸钠固体 (4.14 g, 0.15mol) , 50°C继续搅拌 30分钟, 得黄色重氮盐溶液。
实施例 16 3-溴 -5-氯苯酚的制备
将实施例 15所得黄色重氮盐溶液缓慢滴入 150°C的 90%硫酸 (lmol) 和 200 mL甲苯混合溶液中, 150°C搅拌 30分钟, 静至分液, 有机层加入 50
mL 4N氢氧化钠搅拌 10分钟, 分液并以 50 mL水洗涤有机层, 合并水层并 以 4N盐酸酸化至 pH为 4左右, 以 3 X 50 mL甲苯萃取, 有机层干燥浓缩至 10 mL滴加正庚垸至固体全部析出, 过滤并以正庚垸洗涤干燥得白色固体, 收率 70%
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph), 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 99.1%
实施例 17 化合物 3 (X—为 N03— ) 的制备
化合物 2 ( 10.3 g, 0.05 mol)加入 100 mL 50%硝酸升温至 100 °C搅拌至 溶解, 冷却至 0°C, 控制温度 10°C以下, 分批加入亚硝酸钠固体 (4.14 g, 0.15mol) , 30°C继续搅拌 30分钟, 得黄色重氮盐溶液。
实施例 18 3-溴 -5-氯苯酚的制备
将实施例 17所得黄色重氮盐溶液缓慢滴入 80°C的 90%硫酸 (0.4mol) 和 200 mL氯仿混合溶液中, 80°C搅拌 30分钟,静至分液,有机层加入 50 mL 4N氢氧化钠搅拌 10分钟, 分液并以 50 mL水洗涤有机层, 合并水层并以 4N盐酸酸化至 pH为 4左右, 以 3 X 50 mL氯仿萃取, 有机层干燥浓缩至 10 mL滴加正庚垸至固体全部析出, 过滤并以正庚垸洗涤干燥得白色固体, 收 率 70.5 %。
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph), 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 99.1%
实施例 19 化合物 3 (X—为 N03— ) 的制备
化合物 2 ( 10.3 g, 0.05 mol)加入 100 mL 50%硝酸升温至 100 °C搅拌至 溶解, 冷却至 0°C, 控制温度 10°C以下, 分批加入亚硝酸钠固体 (4.14 g, 0.15mol) , 30°C继续搅拌 30分钟, 得黄色重氮盐溶液。
实施例 20 3-溴 -5-氯苯酚的制备
将实施例 19所得黄色重氮盐溶液缓慢滴入 120 °C的 40%硫酸 (0.6mol) 和 200 mL氯仿混合溶液中, 120°C搅拌 30分钟, 静至分液, 有机层加入 50 mL 4N氢氧化钠搅拌 10分钟, 分液并以 50 mL水洗涤有机层, 合并水层并 以 4N盐酸酸化至 pH为 4左右, 以 3 X 50 mL氯仿萃取, 有机层干燥浓缩至 10 mL滴加正庚垸至固体全部析出, 过滤并以正庚垸洗涤干燥得白色固体, 收率 71 %。
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph): 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 99.1%
实施例 21 化合物 3 (X—为 HS04— ) 的制备
化合物 2 ( 10.3 g, 0.05 mol)加入 100 mL 50%硫酸升温至 100 °C搅拌至 溶解, 冷却至 0°C, 控制温度 10°C以下, 分批加入亚硝酸钠固体 (4.14 g, 0.06 mol), 0°C继续搅拌 30分钟, 得黄色重氮盐溶液。
实施例 22 3-溴 -5-氯苯酚的制备
将实施例 21所得黄色重氮盐溶液缓慢滴入 90°C50 mL的 30%硫酸和 200 mL甲苯混合溶液中, 90°C搅拌 30分钟,静至分液,有机层加入 50 mL 4N 氢氧化钠搅拌 10分钟, 分液并以 50 mL水洗涤有机层, 合并水层并以 4N 盐酸酸化至 pH为 4左右, 以 3 X 50 mL甲苯萃取,有机层干燥浓缩至 10 mL 滴加正庚垸至固体全部析出, 过滤并以正庚垸洗涤干燥得白色固体 7.78 g, 收率 75 %。
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph): 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 99.1%
实施例 23 3-溴 -5-氯苯酚的制备
将实施例 21所得黄色重氮盐溶液缓慢滴入 100°C 100 mL的 50%硫酸 中, 90°C搅拌 30分钟, 以 2 X 50 mL甲苯萃取, 有机层加入 50 mL 4N氢氧
化钠搅拌 10分钟, 分液并以 50 mL水洗涤有机层, 合并水层并以 4N盐酸 酸化至 pH为 4左右, 以 3 X 50 mL甲苯萃取, 有机层干燥浓缩至 10 mL滴 加正庚垸至固体全部析出, 过滤并以正庚垸洗涤干燥得白色固体 6.73 g, 收 率 65 %。
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph) 6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 98.6%
实施例 24 化合物 3 (X—为 CD 的制备
化合物 2 ( 10.3 g, 0.05 mol) 加入 80 mL浓盐酸, 冷却至 0°C, 控制温 度 10°C以下, 分批加入亚硝酸钠固体 (4.14 g, 0.06 mol), 0°C继续搅拌 30 分钟, 得黄色重氮盐溶液。
实施例 25 3-溴 -5-氯苯酚的制备
将实施例 24所得黄色重氮盐溶液缓慢滴入 90°C 200 mL的 50%硫酸, 90°C搅拌 30分钟, 以 2 X 50 mL甲苯萃取, 有机层加入 50 mL 4N氢氧化钠 搅拌 10分钟, 分液并以 50 mL水洗涤有机层, 合并水层并以 4N盐酸酸化 至 pH为 4左右, 以 3 X 50 mL甲苯萃取, 有机层干燥浓缩至 10 mL滴加正 庚垸至固体全部析出, 过滤并以正庚垸洗涤干燥得白色固体 5.11 g, 收率 49%。
¾ NMR (300MHz, CDC13) δ: 5.16 (br, 1H, OH), 6.82 (t, J=1.46Hz, 1H, Ph)
6.93 (t, J= 1.46Hz, 1H, Ph), 7.12 (t, J=1.46Hz, 1H, Ph).
HPLC: 98.2%
Claims
1、 一种如式 1所示的 3-溴 -5-氯苯酚的制备方法, 其特征在于包含下列 歩骤: 将化合物 3在酸性介质中进行水解反应即可制得化合物 1 ;
2、 如权利要求 1所述的制备方法, 其特征在于: 所述的酸性介质中酸 的用量为化合物 3的摩尔量的 1〜20倍; 所述的酸性介质为硫酸水溶液、 或 硫酸水溶液与有机惰性溶剂形成的混合溶液; 所述的水解反应的温度为 60°C〜150°C ; 所述的反应的时间以检测反应完全为止。
3、 如权利要求 2所述的制备方法, 其特征在于: 所述的酸性介质中的 酸的用量为化合物 3摩尔量的 8〜12倍; 所述的硫酸水溶液的质量百分比为 5%〜90%;所述的有机惰性溶剂选自芳香烃、醚和卤代垸烃中的一种或多种; 所述的水解反应的温度为 80°C〜120°C。
4、 如权利要求 1所述的制备方法, 其特征在于: 所述的化合物 3由下 列方法制得: 化合物 2在酸性条件下进行重氮化反应即可;
5、 如权利要求 4所述的制备方法, 其特征在于: 所述的化合物 3由下
列方法制得: 在强酸性水溶液中, 化合物 2与亚硝酸钠或亚硝酸正丁酯进行 重氮化反应, 形成化合物 3。
6、 如权利要求 5所述的制备方法, 其特征在于: 在所述的化合物 2与 亚硝酸钠的反应中: 所述的化合物 2与亚硝酸钠的摩尔比为 1:1〜1:3; 所述 的强酸性水溶液中的强酸为盐酸、 氢溴酸、 硝酸和硫酸中的一种或多种; 所 述的反应的温度为 -5°C〜50°C ; 所述的反应的时间以检测反应完全为止。
7、 如权利要求 4所述的制备方法, 其特征在于: 所述的化合物 2由下 列方法制得:
4 2
将化合物 4进行还原反应即可。
8、 如权利要求 7所述的制备方法, 其特征在于: 所述的化合物 2由下 列方法制得: 在有机惰性溶剂中, 在还原剂、 或者催化剂和氢源的作用下, 化合物 4进行还原反应, 形成化合物 2。
9、 如权利要求 8所述的制备方法, 其特征在于: 所述的还原剂为还原 铁粉、 锌粉、 连二亚硫酸钠、 二水合氯化亚锡、 硼氢化钠和氢化铝锂的一种 或多种; 所述的还原剂的用量为化合物 4摩尔量的 1〜20倍; 所述的催化剂 为钯碳、 铂碳和兰尼镍中的一种或多种; 所述的催化剂的用量为化合物 4的 摩尔量的 0.01〜1倍; 所述的氢源为氢气、 水合肼、 甲酸钠、 甲酸、 甲酸铵和 甲酸三乙胺盐中的一种或多种; 所述的有机惰性溶剂为低级醇和 /或低级酸; 所述的有机惰性溶剂与化合物 4的体积质量比为 l〜100ml/g; 所述的还原反 应的温度为 0°C〜80°C ; 所述的反应的时间以检测反应完全为止。
10、 如权利要求 9所述的制备方法, 其特征在于: 所述的还原剂的用量 为化合物 4的摩尔量的 5〜10倍; 所述的催化剂的用量为化合物 4的摩尔量
的 0.1〜0.2倍; 所述的低级酸为甲酸、 乙酸、 丙酸、 异丙酸和正丁酸中的 种或多种; 所述的有机惰性溶剂与化合物 4的体积质量比为 8〜20ml/g; 所 的还原反应的温度为 10°C〜30°C。
4 2
将化合物 4进行还原反应即可。
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