CN111072697A - Preparation method of 4-phenoxyphenylboronic acid - Google Patents
Preparation method of 4-phenoxyphenylboronic acid Download PDFInfo
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- KFXUHRXGLWUOJT-UHFFFAOYSA-N (4-phenoxyphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1OC1=CC=CC=C1 KFXUHRXGLWUOJT-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 38
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims abstract description 28
- YAWIAFUBXXPJMQ-UHFFFAOYSA-N 1-bromo-4-(4-bromophenoxy)benzene Chemical compound C1=CC(Br)=CC=C1OC1=CC=C(Br)C=C1 YAWIAFUBXXPJMQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000004327 boric acid Substances 0.000 claims abstract description 17
- -1 boric acid ester Chemical class 0.000 claims abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 238000005893 bromination reaction Methods 0.000 claims abstract description 9
- 238000005580 one pot reaction Methods 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
- 230000031709 bromination Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 9
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical group COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- XUXNAKZDHHEHPC-UHFFFAOYSA-M sodium bromate Chemical compound [Na+].[O-]Br(=O)=O XUXNAKZDHHEHPC-UHFFFAOYSA-M 0.000 claims description 2
- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 claims description 2
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006138 lithiation reaction Methods 0.000 abstract description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 abstract description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000010791 quenching Methods 0.000 description 10
- 230000000171 quenching effect Effects 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- JDUYPUMQALQRCN-UHFFFAOYSA-N 4-bromophenyl phenyl ether Chemical compound C1=CC(Br)=CC=C1OC1=CC=CC=C1 JDUYPUMQALQRCN-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- WNHOMUCDFNTSEV-UHFFFAOYSA-N 1,1-diethoxyhexane Chemical compound CCCCCC(OCC)OCC WNHOMUCDFNTSEV-UHFFFAOYSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- SEJLPXCPMNSRAM-GOSISDBHSA-N 6-amino-9-[(3r)-1-but-2-ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one Chemical compound C1N(C(=O)C#CC)CC[C@H]1N1C(=O)N(C=2C=CC(OC=3C=CC=CC=3)=CC=2)C2=C(N)N=CN=C21 SEJLPXCPMNSRAM-GOSISDBHSA-N 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- QUIWHXQETADMGN-UHFFFAOYSA-N evobrutinib Chemical compound C=1C=C(OC=2C=CC=CC=2)C=CC=1C=1C(N)=NC=NC=1NCC1CCN(C(=O)C=C)CC1 QUIWHXQETADMGN-UHFFFAOYSA-N 0.000 description 1
- 229950003411 evobrutinib Drugs 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 229950009104 tirabrutinib Drugs 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a preparation method of 4-phenoxy phenylboronic acid, and belongs to the technical field of organic boric acid chemistry. Starting from diphenyl ether, reacting with NBS to generate 4,4' -dibromodiphenyl ether, then reacting with boric acid ester and butyl lithium in one pot, and hydrolyzing to obtain 4-phenoxy phenylboronic acid. In the invention, dibromo-compound which is easy to purify is generated during bromination, and mono-substituted product is generated by controlling the consumption of lithiation reagent and boric acid ester during lithiation.
Description
Technical Field
The invention relates to preparation of a medical intermediate organic boric acid, in particular to a preparation method of 4-phenoxyphenylboronic acid, belonging to the technical field of organic synthesis.
Background
4-phenoxyphenylboronic acid, white powdery or crystalline solid, CAS: 51067-38-0, is mainly used for synthesis of BTK target innovation drugs, tinib. Such as Evobrutinib, currently in the third clinical stage, is indicated for systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. Tirabrutinib, currently filed for NDA, is indicated for lymphoma. Ibrutinib, currently approved for marketing, is indicated in mantle cell lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, graft versus host disease, waldenstrom macroglobulinemia, and marginal zone lymphoma. From the above, it can be seen that the boric acid is a very important product of organoboronic acids, and the current synthetic routes mainly include the following three types:
the literature reports that 4-bromodiphenyl ether and magnesium metal are adopted to form a Grignard reagent, then the Grignard reagent reacts with trimethyl borate at low temperature, and acid is added for hydrolysis to obtain 4-phenoxyphenylboronic acid with the yield of 93%. Chem,2012, vol.10, #33,6693 and 6704.
The second document reports that 4-bromodiphenyl ether is reacted with n-butyllithium, then reacted with triisopropyl borate at low temperature, and hydrolyzed with acid to obtain 4-phenoxyphenylboronic acid with a yield of 84% by adopting a continuous flow reaction mode. Refer to org.ProcesssDev, 2018, vol.22, #6, 741-746.
The third report of the document reports that diphenyl ether and boron trichloride are reacted at high temperature under the catalysis of metal aluminum, methyl iodide and the like, and then hydrolyzed to obtain 4-phenoxyphenylboronic acid, and the yield of the first step of the method is only 4%, so that the method is only suitable for quickly preparing samples and is not suitable for being used as a process of the method. Reference is made to J.Am.chem.Soc,1960, vol.82, 4163-4166.
From the above methods, except that the third method is not suitable for process amplification, the former two methods have high yield of boric acid after 4-phenoxybromobenzene forms active species and reacts with boric acid ester.
In the existing 4-phenoxybromobenzene raw material synthesis method, except for adopting 4-bromophenol to react with iodobenzene, the yield of the reaction with bromobenzene is not high, and the most effective, economical and effective mode is to adopt diphenyl ether to react with NBS to generate 4-phenoxybromobenzene. Therefore, there is a need for an improvement of the existing synthesis method to meet the need of industrial scale-up and to meet the high purity product supply in the market.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a preparation method of 4-phenoxyphenylboronic acid. Starting from diphenyl ether, reacting with a brominating reagent to generate 4,4' -dibromodiphenyl ether, then reacting with boric acid ester and butyl lithium, and hydrolyzing to obtain 4-phenoxy phenylboronic acid. In the invention, a dibromo-compound which is easy to purify is generated during bromination, and a mono-substituted product is generated by controlling the dosage of a lithiation reagent and boric acid ester during lithiation.
The invention relates to a preparation method of 4-phenoxyphenylboronic acid, which comprises the following steps:
reacting diphenyl ether with a brominating reagent to generate 4,4' -dibromo diphenyl ether, reacting the intermediate with boric acid ester and n-butyl lithium, and hydrolyzing and purifying to obtain the 4-phenoxy phenylboronic acid.
The reaction equation is expressed as:
further, in the technical scheme, NBS and bromine are adopted as the brominating reagent, wherein when the bromine reacts, the reaction can be accelerated in the presence of Lewis acid and sodium bromate. From an industrial scale-up perspective, NBS brominating reagents are preferred.
Further, in the above technical scheme, the bromination reaction can be realized in common organic solvents. Preferred reaction solvents are common solvents such as tetrahydrofuran, water, methanol, ethanol, dichloromethane, 1, 2-dichloroethane, acetonitrile, acetone, ethyl acetate, and the like.
Further, in the above technical scheme, the molar ratio of the brominating agent to the diphenyl ether during the bromination reaction is 2-3:1, and the preferred equivalent ratio is 2.2: 1.
Further, in the above technical scheme, the reaction temperature is-10 ℃ to 50 ℃ during the bromination reaction.
In the actual reaction, after the bromination reaction treatment, the purity of the obtained crude product can reach about 99.0 percent, and after one-time pulping and purification, the purity can reach more than 99.8 percent.
Further, in the above technical scheme, the 4,4 '-dibromodiphenyl ether, the borate and the n-butyllithium are preferably carried out under one-pot conditions, that is, a mode of mixing the 4,4' -dibromodiphenyl ether and the borate in a solvent and dropwise adding the n-butyllithium.
Further, in the above technical solution, the borate is selected from trimethyl borate, triethyl borate, triisopropyl borate and n-butyl borate, and preferably triisopropyl borate.
Furthermore, in the technical scheme, the equivalent ratio of the 4,4' -dibromodiphenyl ether, the boric acid ester and the n-butyllithium is 1:1-1.1: 2-2.5.
Further, in the technical scheme, when the method is reacted with n-butyl lithium in a one-pot method, the reaction temperature is controlled to be-40 ℃ to-10 ℃.
Further, in the above technical scheme, when reacting with n-butyllithium in one pot, the reaction solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, cyclopentylmethyl ether, tert-butylmethyl ether and the like, or a mixture of the above solvent and toluene.
Advantageous effects of the invention
In the invention, two sides of diphenyl ether are brominated simultaneously to generate symmetrical di-p-bromophenyl ether, the intermediate is easy to purify, and the mono-substituted product is generated only by controlling the dosage of a lithiation reagent and boric acid ester during lithiation.
The method overcomes the defects that when the 4-phenoxybromobenzene needs to be purified in the prior art, the boiling point is too high during direct rectification, heat conduction oil needs to be rectified at high temperature, and when recrystallization purification is adopted, multiple crystallization is needed, the process is complicated, and the recovery rate is not high.
The method has been verified on a hundred kilogram scale and has the prospect of an industrial method.
Detailed Description
Example 1
Diphenyl ether (17.2g,0.1mol) was dissolved in 140mL of dichloroethane, NBS (39.2g, 0.22mol) was added portionwise with stirring, after the addition was complete, the mixture was stirred at room temperature for 1 hour, then heated to reflux overnight, HPLC showed complete reaction, the temperature was reduced to below 35 ℃, and the solvent was evaporated off under reduced pressure. Pouring the system into ice water, stirring vigorously for half an hour, adding ethyl acetate for extraction twice, evaporating the solvent by rotation, and recrystallizing the crude product by using an ethanol/toluene (1/5) mixed solvent to obtain 31.2 g of off-white solid 4,4' -dibromodiphenyl ether with the purity of 99.8 percent and the yield of 95.0 percent.
Under nitrogen, the above 4,4' -dibromodiphenyl ether (16.4g,0.05mol), diethoxymethane (160mL) and triisopropyl borate (9.4g,0.05mol) were mixed, cooled to-70 ℃ to-60 ℃, and 40mL of a 2.5M n-butyllithium hexane solution was added dropwise. After the dropwise addition, stirring was carried out for 1 hour under heat preservation. Then naturally raising the temperature to room temperature for reaction overnight, cooling and adding 1M hydrochloric acid for quenching, wherein the temperature is not higher than 0 ℃ in the quenching process. Diethoxyhexane (60mL) was extracted twice, the oil layers were combined, evaporated to dryness under reduced pressure, added with ethyl acetate to redissolve, filtered and evaporated to dryness again, and n-heptane was slurried to give an off-white solid 8.2 g, yield 77%, HPLC: 99.8%, HNMR structure.
Example 2
Diphenyl ether (17.2g,0.1mol) was dissolved in 80mL dioxane, NBS (39.2g, 0.22mol) was added portionwise with stirring, and after the addition was complete, the mixture was stirred at room temperature for 1 hour, then heated to 50 ℃ for 3 hours, HPLC showed completion, and the solvent was evaporated off under reduced pressure. Pouring the system into ice water, stirring vigorously for half an hour, adding ethyl acetate for extraction, evaporating the solvent to dryness by rotation, and recrystallizing the crude product by using an ethanol/toluene (1/5) mixed solvent to obtain 30.6 g of off-white solid 4,4' -dibromodiphenyl ether with the purity of 99.7 percent and the yield of 93.3 percent.
Under nitrogen, the above 4,4' -dibromodiphenyl ether (16.4g,0.05mol), diethoxymethane (160mL) and triisopropyl borate (9.4g,0.05mol) were mixed, cooled to-70 ℃ to-60 ℃, and 40mL of a 2.5M n-butyllithium hexane solution was added dropwise. After the dropwise addition, stirring was carried out for 1 hour under heat preservation. Then naturally raising the temperature to room temperature for reaction overnight, cooling and adding 1M hydrochloric acid for quenching, wherein the temperature is not higher than 0 ℃ in the quenching process. Diethoxyhexane (60mL) was extracted twice, the oil layers were combined, evaporated to dryness under reduced pressure, added with ethyl acetate to redissolve, filtered and evaporated to dryness again, and n-heptane was slurried to give an off-white solid 8.2 g, yield 77%, HPLC: 99.8%, HNMR structure.
Example 3
Diphenyl ether (17.2g,0.1mol) was dissolved in 120mL acetonitrile, NBS (39.2g, 0.22mol) was added portionwise with stirring, and after completion of the addition, the mixture was stirred at room temperature for 1 hour, then heated to 50 ℃ to react for 3 hours, HPLC showed completion of the reaction, and then the solvent was distilled off under reduced pressure. Pouring the system into ice water, stirring vigorously for half an hour, adding ethyl acetate for extraction, evaporating the solvent to dryness by rotation, and recrystallizing the crude product by using an ethanol/toluene (1/5) mixed solvent to obtain 30.9 g of off-white solid 4,4' -dibromodiphenyl ether with the purity of 99.7 percent and the yield of 94.1 percent.
The above 4,4' -dibromodiphenyl ether (16.4g,0.05mol), tetrahydrofuran (160mL) and triisopropyl borate (9.4g,0.05mol) were mixed under nitrogen atmosphere, cooled to-70 ℃ to-60 ℃ and 40mL of a 2.5M n-butyllithium hexane solution was added dropwise. After the dropwise addition, stirring was carried out for 1 hour under heat preservation. Then naturally raising the temperature to room temperature for reaction overnight, cooling and adding 1M hydrochloric acid for quenching, wherein the temperature is not higher than 0 ℃ in the quenching process. Tetrahydrofuran (60mL) was extracted twice, the oil layers were combined, evaporated to dryness under reduced pressure, added ethyl acetate to redissolve, filtered and evaporated again to dryness, and n-heptane/methyl tert-butyl ether (10/1) slurried to give 7.9 g of an off-white solid with a yield of 74%, HPLC: 99.9%, and the HNMR structure is consistent.
Example 4
Diphenyl ether (17.2g,0.1mol) was dissolved in 120mL acetonitrile, NBS (39.2g, 0.22mol) was added portionwise with stirring, and after completion of the addition, the mixture was stirred at room temperature for 1 hour, then heated to 50 ℃ to react for 3 hours, HPLC showed completion of the reaction, and then the solvent was distilled off under reduced pressure. Pouring the system into ice water, stirring vigorously for half an hour, adding ethyl acetate for extraction, evaporating the solvent to dryness by rotation, and recrystallizing the crude product by using an ethanol/toluene (1/5) mixed solvent to obtain 30.9 g of off-white solid 4,4' -dibromodiphenyl ether with the purity of 99.7 percent and the yield of 94.1 percent.
The above 4,4' -dibromodiphenyl ether (16.4g,0.05mol), tetrahydrofuran (160mL) and triisopropyl borate (10.3g,0.055mol) were mixed under nitrogen, cooled to-70 ℃ to-60 ℃, and 44mL of a 2.5M n-butyllithium hexane solution was added dropwise. After the dropwise addition, stirring was carried out for 1 hour under heat preservation. Then naturally raising the temperature to room temperature for reaction overnight, cooling and adding 1M hydrochloric acid for quenching, wherein the temperature is not higher than 0 ℃ in the quenching process. Tetrahydrofuran (60mL) was extracted twice, the oil layers were combined, evaporated to dryness under reduced pressure, added ethyl acetate to redissolve, filtered and evaporated again to dryness, and n-heptane/methyl tert-butyl ether (10/1) slurried to give 9.7 g of an off-white solid in 91% yield, HPLC: 99.9%, and the HNMR structure is consistent.
Example 5
Diphenyl ether (17.2g,0.1mol) was dissolved in 120mL acetonitrile, NBS (39.2g, 0.22mol) was added portionwise with stirring, and after completion of the addition, the mixture was stirred at room temperature for 1 hour, then heated to 50 ℃ to react for 3 hours, HPLC showed completion of the reaction, and then the solvent was distilled off under reduced pressure. Pouring the system into ice water, stirring vigorously for half an hour, adding ethyl acetate for extraction, evaporating the solvent to dryness by rotation, and recrystallizing the crude product by using an ethanol/toluene (1/5) mixed solvent to obtain 30.9 g of off-white solid 4,4' -dibromodiphenyl ether with the purity of 99.7 percent and the yield of 94.1 percent.
The above 4,4' -dibromodiphenyl ether (16.4g,0.05mol), 2-methyltetrahydrofuran (160mL) and triisopropyl borate (10.3g,0.055mol) were mixed under nitrogen, cooled to-70 ℃ to-60 ℃, and 44mL of a 2.5M n-butyllithium hexane solution was started dropwise. After the dropwise addition, stirring was carried out for 1 hour under heat preservation. Then naturally raising the temperature to room temperature for reaction overnight, cooling and adding 1M hydrochloric acid for quenching, wherein the temperature is not higher than 0 ℃ in the quenching process. 2-methyltetrahydrofuran (60mL) was extracted twice, the oil layers were combined, evaporated to dryness under reduced pressure, added ethyl acetate to redissolve and filtered, evaporated again to dryness, and n-heptane/methyl tert-butyl ether (10/1) slurried to give 9.6 g of an off-white solid in 90% yield, HPLC: 99.8%, HNMR structure.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (9)
1. The preparation method of the 4-phenoxyphenylboronic acid is characterized by comprising the following steps:
reacting diphenyl ether with a brominating reagent to generate 4,4' -dibromo diphenyl ether, reacting the intermediate with boric acid ester and n-butyl lithium, and hydrolyzing and purifying to obtain the 4-phenoxy phenylboronic acid.
2. The method for producing 4-phenoxyphenylboronic acid according to claim 1, wherein: NBS or bromine is used as a brominating reagent, wherein when the bromine is used, the reaction can be accelerated in the presence of Lewis acid and sodium bromate.
3. The method for producing 4-phenoxyphenylboronic acid according to claim 1, wherein: the reaction solvent is selected from tetrahydrofuran, water, methanol, ethanol, dichloromethane, 1, 2-dichloroethane, acetonitrile, acetone or ethyl acetate.
4. The method for producing 4-phenoxyphenylboronic acid according to claim 1, wherein: when in bromination reaction, the mol ratio of the bromination reagent to the diphenyl ether is 2-3: 1; the reaction temperature is-10 ℃ to 50 ℃.
5. The method for producing 4-phenoxyphenylboronic acid according to any one of claims 1 to 4, wherein: after bromination reaction, the purity of the obtained crude product can reach about 99.0 percent, and after one-time pulping and purification, the purity can reach more than 99.8 percent.
6. The method for producing 4-phenoxyphenylboronic acid according to claim 1, wherein: the 4,4 '-dibromodiphenyl ether, the boric acid ester and the n-butyllithium are carried out under the condition of a one-pot method, namely the 4,4' -dibromodiphenyl ether and the boric acid ester are mixed in a solvent, and the n-butyllithium is dripped.
7. The method for producing 4-phenoxyphenylboronic acid according to claim 1, wherein: the boric acid ester is selected from trimethyl borate, triethyl borate, triisopropyl borate or n-butyl borate.
8. The method for producing 4-phenoxyphenylboronic acid according to claim 1, wherein: the equivalent ratio of the 4,4' -dibromodiphenyl ether, the boric acid ester and the n-butyllithium is 1:1-1.1: 2-2.5.
9. The method for producing 4-phenoxyphenylboronic acid according to claim 1 or 6, wherein: when reacting with n-butyllithium, the reaction solvent is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, diethoxymethane, cyclopentylmethyl ether, tert-butylmethyl ether and the like, or a mixture of the above solvents and toluene; the reaction temperature is controlled between-40 ℃ and-10 ℃.
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| CN114874102A (en) * | 2021-12-20 | 2022-08-09 | 青岛科技大学 | A kind of method for preparing 4,4-diaminodiphenyl ether |
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| CN112321622A (en) * | 2020-11-28 | 2021-02-05 | 沧州普瑞东方科技有限公司 | Preparation method of N-aryl carbazole-3-boric acid |
| CN114874102A (en) * | 2021-12-20 | 2022-08-09 | 青岛科技大学 | A kind of method for preparing 4,4-diaminodiphenyl ether |
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