CN103275112A - Method for continuously synthesizing arylboronic acid ester by utilizing microreactor - Google Patents
Method for continuously synthesizing arylboronic acid ester by utilizing microreactor Download PDFInfo
- Publication number
- CN103275112A CN103275112A CN 201310171684 CN201310171684A CN103275112A CN 103275112 A CN103275112 A CN 103275112A CN 201310171684 CN201310171684 CN 201310171684 CN 201310171684 A CN201310171684 A CN 201310171684A CN 103275112 A CN103275112 A CN 103275112A
- Authority
- CN
- China
- Prior art keywords
- boric acid
- acid pinacol
- pinacol ester
- ester
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- -1 arylboronic acid ester Chemical class 0.000 title claims abstract description 154
- 238000000034 method Methods 0.000 title claims abstract description 42
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 146
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical class CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 141
- 239000000203 mixture Substances 0.000 claims abstract description 68
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 35
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 claims abstract description 7
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 claims description 114
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 claims description 62
- WGLLSSPDPJPLOR-UHFFFAOYSA-N tetramethylethylene Natural products CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 claims description 62
- 239000004327 boric acid Substances 0.000 claims description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000002994 raw material Substances 0.000 claims description 22
- 239000000047 product Substances 0.000 claims description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- IVDFJHOHABJVEH-UHFFFAOYSA-N HOCMe2CMe2OH Natural products CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- QHDRKFYEGYYIIK-UHFFFAOYSA-N isovaleronitrile Chemical compound CC(C)CC#N QHDRKFYEGYYIIK-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- ASDFSWMHZSWXPO-UHFFFAOYSA-N 2-(2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound COC1=CC=CC=C1B1OC(C)(C)C(C)(C)O1 ASDFSWMHZSWXPO-UHFFFAOYSA-N 0.000 claims description 4
- UIUHFOXVRLKIRL-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.B(O)(O)O.ClC=1C=CC=CC1 Chemical compound OC(C)(C)C(C)(C)O.B(O)(O)O.ClC=1C=CC=CC1 UIUHFOXVRLKIRL-UHFFFAOYSA-N 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 3
- WINSAMQIAMEZIK-UHFFFAOYSA-N 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Chemical compound C1=C(O)C(OC)=CC=C1B1OC(C)(C)C(C)(C)O1 WINSAMQIAMEZIK-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 3
- FIGQEPXOSAFKTA-UHFFFAOYSA-N 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(C#N)=C1 FIGQEPXOSAFKTA-UHFFFAOYSA-N 0.000 claims description 3
- HOPDTPGXBZCBNP-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(C#N)C=C1 HOPDTPGXBZCBNP-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- KWGACYZYFZTYRN-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.B(O)(O)O.BrCC1=CC=CC=C1 Chemical compound OC(C)(C)C(C)(C)O.B(O)(O)O.BrCC1=CC=CC=C1 KWGACYZYFZTYRN-UHFFFAOYSA-N 0.000 claims description 3
- MMSPHSKLNXQAOH-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.B(O)(O)O.NC1=CC=CC=C1 Chemical compound OC(C)(C)C(C)(C)O.B(O)(O)O.NC1=CC=CC=C1 MMSPHSKLNXQAOH-UHFFFAOYSA-N 0.000 claims description 3
- PBJADBUZJBFNON-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.S1C(=CC=C1)OB(O)O Chemical compound OC(C)(C)C(C)(C)O.S1C(=CC=C1)OB(O)O PBJADBUZJBFNON-UHFFFAOYSA-N 0.000 claims description 3
- 150000003927 aminopyridines Chemical class 0.000 claims description 3
- 150000005005 aminopyrimidines Chemical class 0.000 claims description 3
- DAJLHNABGVYSOO-UHFFFAOYSA-N boric acid;2,3-dimethylbutane-2,3-diol Chemical class OB(O)O.CC(C)(O)C(C)(C)O DAJLHNABGVYSOO-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229960001701 chloroform Drugs 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000004185 ester group Chemical group 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000002240 furans Chemical class 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 3
- APNSGVMLAYLYCT-UHFFFAOYSA-N isobutyl nitrite Chemical compound CC(C)CON=O APNSGVMLAYLYCT-UHFFFAOYSA-N 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 3
- 150000005002 naphthylamines Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000003217 pyrazoles Chemical class 0.000 claims description 3
- 150000003233 pyrroles Chemical class 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- KVZOCZPVDGYOTN-UHFFFAOYSA-N C(C)(C)(C)CC#N.N(=O)O Chemical compound C(C)(C)(C)CC#N.N(=O)O KVZOCZPVDGYOTN-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 abstract description 44
- 230000035484 reaction time Effects 0.000 abstract description 25
- 238000012546 transfer Methods 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 4
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical class CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 abstract 3
- 239000012414 tert-butyl nitrite Chemical class 0.000 abstract 3
- 239000007858 starting material Substances 0.000 abstract 1
- 238000005728 strengthening Methods 0.000 abstract 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- 230000005540 biological transmission Effects 0.000 description 16
- 230000002708 enhancing effect Effects 0.000 description 16
- 230000009466 transformation Effects 0.000 description 14
- 239000003921 oil Substances 0.000 description 11
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 238000004811 liquid chromatography Methods 0.000 description 10
- 230000005311 nuclear magnetism Effects 0.000 description 10
- 238000005086 pumping Methods 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- MDELYEBAXHZXLZ-UHFFFAOYSA-N 1h-indazol-4-amine Chemical compound NC1=CC=CC2=C1C=NN2 MDELYEBAXHZXLZ-UHFFFAOYSA-N 0.000 description 5
- UGUIBNHHDIEZJI-UHFFFAOYSA-N 2-fluoro-4-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=C(N)C(F)=C1 UGUIBNHHDIEZJI-UHFFFAOYSA-N 0.000 description 5
- WSARYNAINPBAEY-UHFFFAOYSA-N 3-fluoro-4-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=C(N)C=C1F WSARYNAINPBAEY-UHFFFAOYSA-N 0.000 description 5
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 5
- FVLAYJRLBLHIPV-UHFFFAOYSA-N pyrimidin-5-amine Chemical compound NC1=CN=CN=C1 FVLAYJRLBLHIPV-UHFFFAOYSA-N 0.000 description 5
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 4
- 239000004342 Benzoyl peroxide Substances 0.000 description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 4
- 235000019400 benzoyl peroxide Nutrition 0.000 description 4
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical group CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 2
- KQOIBXZRCYFZSO-UHFFFAOYSA-N 3,5-difluoroaniline Chemical compound NC1=CC(F)=CC(F)=C1 KQOIBXZRCYFZSO-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- FUJRFZKAWFSUHL-UHFFFAOYSA-N OC(C)(C)C(C)(C)O.B(O)(O)O.CC=1C=CC=C(C1)C Chemical compound OC(C)(C)C(C)(C)O.B(O)(O)O.CC=1C=CC=C(C1)C FUJRFZKAWFSUHL-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005112 continuous flow technique Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 229910001092 metal group alloy Inorganic materials 0.000 description 1
- KUDPGZONDFORKU-UHFFFAOYSA-N n-chloroaniline Chemical class ClNC1=CC=CC=C1 KUDPGZONDFORKU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for continuously synthesizing arylboronic acid ester by utilizing a microreactor, which belongs to the technical field of green organic synthesis application. The method comprises the following steps of: preheating substituted arylamine, tert-butyl nitrite, bisdiborane in a continuous-flow micro-channel reactor system by using substituted arylamine, acetonitrile, tert-butyl nitrite and bisdiborane as starting materials; and mixing the substituted arylamine with the bisdiborane and then reacting the obtained mixture with the tert-butyl nitrite, wherein in the reaction, the molar ratio of the substituted arylamine to the bisdiborane is (1:0.5)-(1:1.25), the molar ratio of the substituted arylamine to isoamyl nitrite is (1:1.1)-(1:1.5), the reaction temperature is 60 DEG C-120 DEG C, the reaction time is 50 seconds-3600 seconds, and the effective conversion ratio of the substituted arylamine is 50%-90%. The continuous-flow microreactor, which is capable of strengthening the mixing effect, the mass transfer effect and the heat transfer effect, is especially suitable for carrying out homogeneous reaction of the method. Moreover, the method has the characteristics of stable temperature control, safe process and less waste material.
Description
Technical field
The present invention relates to utilize microreactor by substituted aromatic amines, acetonitrile, nitrite tert-butyl, duplex tetramethyl ethylene ketone base diboron hexahydride is starting raw material synthesizing aryl boric acid ester, particular content comprises that the channel module that utilization is made up of multiple miniature complete mixing flow structural unit is combined into enhancing mixed type micro passage reaction, utilizing the method for this reactor synthesizing aryl boric acid ester, is a kind of substituted aromatic amines of finishing in microreactor, nitrite tert-butyl, the preheating of three kinds of raw materials of duplex tetramethyl ethylene ketone base diboron hexahydride, after the mixing of substituted aromatic amines and duplex tetramethyl ethylene ketone base diboron hexahydride with the continuous flow process process of nitrite tert-butyl reaction.Present method can be under 60 ℃ ~ 120 ℃ reaction conditionss continous-stable synthesizing aryl boric acid ester safely.
Background technology
Microreactor generally refers to the small-sized reactive system through little processing and precision processing technology manufacturing.It comprises the needed mixing tank of chemical unit, interchanger, reactor, controller etc., and still, its line size is far smaller than conventional tubular reactor, and microminiaturized structure makes it have some new characteristics.
Aryl-boric acid ester is as an active intermediate, and is extremely important in organic synthesis.The coupled reaction of its derivative aryl boric acid and halogenated aryl hydrocarbon is the important channel that forms C-C key (Suzuki linked reaction), also is widely used in the reaction that forms C-O, C-N and C-S key.Aryl-boric acid ester is more stable in air, insensitive to moisture, can prolonged preservation and favored deeply.Simultaneously, aryl-boric acid ester is also more and more paid close attention to industrial, in the medicinal activity intermediate preparation, play the part of important role, having extensive use and vast market prospect at aspects such as softening agent, welding solubilizing agent, sanitas, polymeric additive, dyestuff, agricultural chemicals.
The production of aryl-boric acid ester at present mainly utilize halogenated aromatic compound under the metal palladium catalyst effect with two boron compound prepared in reaction, the bibliographical information yield mostly is 20%～80% greatly and does not wait, because reaction process is wayward, very easily produce the aryl compound of dehalogenation, and palladium catalysis method cost is higher, and aftertreatment waste water is too much.Also the active aryl intermediates of metal organic alkalis elder generation preparation such as useful lithium alkylide or Grignard reagent obtain aryl-boric acid ester with the boric acid ester reaction again.But this method conditional request harshness, general low temperature lithiation (70 ℃), esterification (70 ℃), conventional still reaction still unavoidably can produce because mixing the inhomogeneous problem such as local superheating that causes, and the transformation efficiency of reaction process is subjected to negative impact, and energy consumption is bigger.
Utilizing micro passage reaction to carry out the aryl-boric acid ester synthesising process research, is a breakthrough of common process.Micro passage reaction has the more not available characteristics of conventional tank reactor: the channel size microminiaturization; Bigger specific surface area; Good mass-and heat-transfer characteristic; Production is flexible and safety performance is high.Therefore utilize micro passage reaction to carry out synthetic this class reaction of aryl-boric acid ester incomparable advantage is arranged.
Disclose among the CN 102190676A in little a kind of method for preparing aryl boric acid in the device continuously of answering, this method utilizes aryl halide or aryl-heterocyclic and lithium alkylide to be made into mixture earlier at lesser temps (50 ℃), enters prepared in reaction aryl boric acid in the microreactor then with after boric acid ester mixes.Synthesizing aryl boric acid is compared the efficient that has improved reaction safety and production in this method and the traditional tank reactor, but because alkyl lithium reagents is active reagent, need anhydrous and oxygen-free to preserve, and mostly be hexane solution, so still there is the problem of certain safety problem and solvent waste in reaction.
Fanyang?mo（Angew.?Chem.?Int。Ed. 2010,49,1846-1849) wait researching and proposing of people to utilize substituted aromatic amines, nitrite tert-butyl, duplex tetramethyl ethylene ketone base diboron hexahydride as raw material, benzoyl peroxide (BPO) is as synthesizing aryl boric acid pinacol ester under the condition of catalyzer, show that through repeated experiments this method has certain feasibility in that microreactor is synthetic, have certain potentially dangerous but use benzoyl peroxide (BPO) in the reaction, need to be optimized.
By above publication and document as can be seen, the synthesizing aryl ester has feasibility in microreactor, has incomparable advantage with traditional still reaction.CN 102190676A is a kind of method of synthesizing aryl boric acid ester and has optimizable space, in conjunction with Fanyang mo(Angew. Chem. Int.Ed. 2010,49,1846-1849) wait people's research, proposed to utilize the compound that is easy to get more economically as raw material and reaction process more the controlled a kind of method of safety for the synthesis of aryl-boric acid ester.The present invention selects for use the micro passage reaction with enhancing mass transfer unit structure to utilize substituted aromatic amines, nitrite tert-butyl, duplex tetramethyl ethylene ketone base diboron hexahydride as raw material, the security that continous-stable synthesizing aryl boric acid ester under 60～120 ℃ of conditions, this method have improved mass transfer, rate of heat transfer, speed of reaction, temperature of reaction controllability and increased experimentation greatly.
Summary of the invention
The object of the present invention is to provide a kind of utilization to have the method that the micro passage reaction that strengthens the mass transfer unit structure carries out continuous synthesizing aryl boric acid ester, this method can be higher than under the reactor operating condition of normal temperature, rely on the kinetic energy of fluid own to finish mass-and heat-transfer, need not the mechanical stirring process, need not reaction channel and continue the Continuous Flow reaction method that reaction process just can obtain to be higher than popular response device transformation efficiency and weaken the side reaction generation outward.Utilization has the reaction yield that the micro passage reaction that strengthens the mass transfer unit structure can improve the synthesizing aryl boric acid ester, the formation that significantly improves speed of reaction and reduce by product, speed of reaction when improving simultaneously micro passage reaction empty greatly, avoid temperature and fluctuation of concentration in the reaction process, no temperature runaway and superheating phenomenon, reaction process safety.
For achieving the above object, the technical solution used in the present invention is:
A kind of method of utilizing the continuous synthesizing aryl boric acid ester of microreactor of the present invention, carry out according to following step:
1) in the reaction used substituted aromatic amines and duplex tetramethyl ethylene ketone base diboron hexahydride be blended in enhancing quality transmission type micro passage reaction modules A 1(Fig. 1) in finish and mix and preheating, the acetonitrile solution of the substituted aromatic amines that the desired mixt proportioning is calculated, two strands of materials of acetonitrile solution of duplex tetramethyl ethylene ketone base diboron hexahydride enter synchronously in this microreactor via volume pump (P1 and P2) separately and mix, mixing temperature is controlled by external heat exchanger, heat transferring medium is thermal oil, temperature is 60～120 ℃, and the module outlet is the mixture I that mixes;
2) go up step gained mixture I and directly enter mixing module A2(Fig. 1), mixing temperature is identical with temperature of reaction, nitrite tert-butyl enters the warm-up block C1(Fig. 1 that is in series with it through volume pump (P3) simultaneously) in, preheating temperature is identical with temperature of reaction, insert mixing module A2(Fig. 1 in parallel with it after preheating is finished again) in, the mol ratio by flow control substituted aromatic amines and nitrite tert-butyl is 1:1.1～1:1.5; Mix in the A2 module and reaction, (B1-B5 Fig. 1) and in the time-delay pipeline reacts, and after reaction process was finished, product flowed out from the outlet of reactor, enters the cooling last handling process to continue to insert a series of enhancing quality transmission types microchannel serial module structure; This reaction process is 50s～3600s in the microreactor internal reaction residence time, and temperature of reaction is 60～120 ℃; Reaction pressure is 0.1～1.5bar;
3) will concentrate from the product that microreactor outlet obtains, through column chromatography or other conventional purification process get final product the product aryl-boric acid ester.
The used microreactor of the present invention is enhancing quality transmission type microreactor, and this reactive system is assembled by the polylith module.Intermodule can be assembled or the series connection assembling in parallel connection, and module is with the heat exchange path and react the integrated and one of path, or only contains the reaction path, and is immersed in the temperature control heat-conducting medium.In heat exchange path or heat-conducting medium, be furnished with thermopair, can be used for measuring the actual temperature of heat transferring medium in the heat exchange path or extraneous heat-conducting medium.The material of this module is silicon single crystal, special glass, pottery, the stainless steel that scribbles the corrosion resistant coating or metal alloy, tetrafluoroethylene etc.Reactive system can be anticorrosion withstand voltage, and voltage endurance capability is looked the material difference and different, and reaction maximum safety pressure power is 0.1～20bar in the system.Micro Channel Architecture is divided the once-through type channel architecture and is strengthened two kinds of mixed type channel architectures in the module.
Mix and reaction process two portions with nitrite tert-butyl after the mixing of the preheating, substituted aromatic amines that the enhancing quality transmission type microreactor system that the present invention carries out continuous synthesizing aryl boric acid ester comprises substituted aromatic amines, nitrite tert-butyl, three kinds of raw materials of duplex tetramethyl ethylene ketone base diboron hexahydride and duplex tetramethyl ethylene ketone base diboron hexahydride, therefore the preheating and mixing module, the warm-up block of nitrite tert-butyl, the reaction module of some amount and the time-delay pipeline of respective length that need substituted aromatic amines and duplex tetramethyl ethylene ketone base diboron hexahydride, concrete quantity and length are determined by flow velocity, reaction time.Mode of connection is: substituted aromatic amines is connected with the mixing module (A2) of nitrite tert-butyl with preheating, the mixing module (A1) of duplex tetramethyl ethylene ketone base diboron hexahydride, nitrite tert-butyl warm-up block (C1) is in parallel with mixture I mixing module (A2) with nitrite tert-butyl, and (B1-B5) and time-delay pipeline are connected with the reaction module group then.
The aromatic amine of indication of the present invention comprises six element heterocycles and 5-membered heterocycles aromatic amine such as naphthylamines and derivative, aminopyridine and derivative thereof, aminopyrimidine and the derivative thereof etc. that aniline and derivative thereof, heteroatoms replace, can be as synthetic as structural formula (I), (II), (III), (IV) with the aryl-boric acid ester (V):
X=CH or N wherein; Y=CH, CR1 or N; Z=CH or N; W=NH, O or S are preferably O or S; Wherein n=0, various 3-7 unit's cycloaliphatic ring, the aromatic nucleus that does not replace or replace or contain heteroatomic aromatic nucleus; Be preferably nothing, phenyl ring, pyridine ring, pyrazoles, thiophene, pyrroles, furans, tetrahydrofuran (THF), tetramethylene, pentamethylene or hexanaphthene; R
1, R2, R3 can be in the following substituting group any one: H, methyl, ethyl, propyl group, sec.-propyl, isobutyl-, cyclopropyl, cyclobutyl, trifluoromethyl, aromatic base, halogen, first sulfydryl, methylsulfonyl, ester group, cyano group, carboxyl, formamido-, methylsulfonyl amido, methoxycarbonyl or ethoxy carbonyl, is preferably H, methyl, sec.-propyl, isobutyl-, cyclopropyl, chlorine, bromine, first sulfydryl, methylsulfonyl, trifluoromethyl, cyano group.
The boric acid ester that the present invention synthesized comprises 2-fluoro-4-methylsulfonyl phenylo boric acid pinacol ester; 3-fluoro-4-methylsulfonyl phenylo boric acid pinacol ester; 2-chlorobenzene boric acid pinacol ester; 4-fluorobenzoic boric acid pinacol ester; 2-methoxyphenylboronic acid pinacol ester; 2; 6-dimethyl benzene boric acid pinacol ester; 3; 5-two fluorobenzoic boric acid pinacol esters; between methoxycarbonyl phenylo boric acid pinacol ester; to carboxyl phenylo boric acid pinacol ester; to methoxycarbonyl phenylo boric acid pinacol ester; 4-benzyloxycarbonyl phenylo boric acid pinacol ester; 4-benzyloxy phenylo boric acid pinacol ester; 4-(methanesulfonamido) phenylo boric acid pinacol ester; 4-(4-morpholinyl) phenylo boric acid pinacol ester; 4-(4-methyl isophthalic acid-piperazinyl) phenylo boric acid pinacol ester; 3-carboxyl phenylo boric acid pinacol ester; 3-hydroxybenzene boric acid pinacol ester; N-Boc-3-fluoro-4-amino-benzene boric acid pinacol ester; 4-bromomethyl benzene boric acid pinacol ester; 4-(methylamino formyl radical) phenylo boric acid pinacol ester; 4-(4-ethyl-1-piperazinyl) phenylo boric acid pinacol ester; 4-(4-Boc-1-piperazinyl) phenylo boric acid pinacol ester; 4-(3-methyl trimethylene oxide-3-yl) phenylo boric acid pinacol ester; 4-(4-THP trtrahydropyranyl) phenylo boric acid pinacol ester; 4-(4-morpholinyl methyl) phenylo boric acid pinacol ester; 4-(4-fluoro-piperidino) phenylo boric acid pinacol ester; 4-(3; 3-two fluoro-piperidino) phenylo boric acid pinacol ester; 4-(1-pyrrolidyl alkylsulfonyl) phenylo boric acid pinacol ester; 3-cyanophenylboronic acid pinacol ester; 3-hydroxyl-4-methoxyphenylboronic acid pinacol ester; 4-cyanophenylboronic acid pinacol ester; 4-amino-benzene boric acid pinacol ester; 4-[3-(2-chloro-3; 6-two fluorophenoxies) propyl group] the phenylo boric acid pinacol ester; naphthalene-2-boric acid pinacol ester; imidazo [1; 2-a] pyridine-6-boric acid pinacol ester; 7-azaindole-5-boric acid pinacol ester; 4-1H-indazole boric acid pinacol ester; 5-methoxyl group-3-pyridine boric acid pinacol ester; 3-pyridine boric acid pinacol ester; 2-nitro-5-pyridine boric acid pinacol ester; 5-pyrimidine boric acid pinacol ester; 2,4-, two chloro-5-pyrimidine boric acid pinacol esters; 2-thienyl boric acid pinacol ester; 5-chloro-2-thienyl boric acid pinacol ester; thiazole-5-boric acid pinacol ester; 2-pyrroles's boric acid pinacol ester; 1-methyl-3-pyrroles's boric acid pinacol ester; indoles-4-boric acid pinacol ester; 5-indoles boric acid pinacol ester; 3-pyridazine boric acid pinacol ester; 2-pyrazine boric acid pinacol ester; 4-pyrazoles boric acid pinacol ester; 1-methyl-4-pyrazoles boric acid pinacol ester; 1-ethyl-4-pyrazoles boric acid pinacol ester; 1-benzyl-4-pyrazoles boric acid pinacol ester; 1-Boc-4-pyrazoles boric acid pinacol ester etc.
Being reflected in the organic solvent of synthesizing aryl boric acid ester of the present invention carried out, used organic solvent is selected from common non-protonic solvent, toluene for example, dimethylbenzene, sym-trimethylbenzene, methylene dichloride, trichloromethane, tetracol phenixin, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, ethylene dichloride, dimethyl sulfoxide (DMSO), N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, methane amide, ethyl acetate, isopropyl acetate, ether, isopropyl ether, methyl tertiary butyl ether, normal hexane, acetonitrile, isovaleronitrile, N-Methyl pyrrolidone etc., preferred acetonitrile, isovaleronitrile, N,N-dimethylacetamide, N-Methyl pyrrolidone or their any mixture.
A used raw material nitrite tert-butyl of the present invention is interpreted as optimal selection, and other raw material comprises that similar nitrous acid alkane esters compounds such as Isopentyl nitrite, isobutyl nitrite can be used as its surrogate.
The purification of the separation of product and solvent (acetonitrile) concentrates and applies mechanically and can be undertaken by ordinary method and equipment.
The present invention utilize strengthen quality transmission type microreactor synthesizing aryl boric acid ester technology compared with prior art, have following advantage:
1. this synthesizing aryl boric acid ester technology is the continuous flowing reaction, and the reaction times shortens to several minutes, significantly improves reaction efficiency and production efficiency, has weakened the degree that side reaction takes place;
2. entire reaction course is finished in the microreactor that assembles, and need not extra after-treatment devices such as transfer, has avoided leakage and the risk of pollution of raw material (substituted aromatic amines, solvent and nitrite tert-butyl);
3. various substrates can be finished mixing, reaction process in the microreactor module, need not mechanical stirring, mix fast evenly reaction process reaction safety;
4. strengthen the quality transmission type passage in the conversion unit micro passage reaction that adopts and to strengthen mass transfer, heat transfer property, keep temperature of reaction constant, avoid the temperature runaway phenomenon, reduce production of by-products;
5. present method raw material is easy to get, cost is low, reaction temperature and, be easy to control, handle simple, the yield height, be easy to amplify continuously and stably production, and be fit to the nearly all substituted aryl aniline of preparation, include but not limited to contain substituted aromatic aniline and heterocyclic aniline, the waste material that produces is few, and solvent can be recycled.
Description of drawings:
Fig. 1 is example microreactor system and device figure for the used microreactor module of the present invention;
Fig. 2 is the method flow synoptic diagram according to the continuous synthesizing aryl boric acid ester of a case study on implementation of the present invention.
The present invention is by reducing the reaction times significantly, the synthesis technique that will have the aryl-boric acid ester under two-step approach in the technology (will reacting with boric acid ester again after the aryl halides lithiumation earlier) or the palladium catalyst effect now is simplified greatly, improve productive rate, improved the transformation efficiency of target product.The residence time of reactant has been shortened in the use of mixing module and reaction module effectively in the microreactor, and makes the technology serialization of synthesizing aryl boric acid ester.
Fig. 2 is the method flow synoptic diagram according to the continuous synthesizing aryl boric acid ester of a case study on implementation of the present invention.Step 1 is with the acetonitrile solution mixing of substituted aromatic amines and duplex tetramethyl ethylene ketone base diboron hexahydride and is preheated to 80 ℃, obtains the mixture I after the mixing.Step 2 is that nitrite tert-butyl is preheated to 80 ℃, step 3 is to mix through the nitrite tert-butyl of preheating and mixture I and to begin to react, step 4 is continuation reaction process of reaction solution, outlet collect reaction solution through aftertreatment get final product the product aryl boric acid.
Fig. 1 is that the reactor used module of the present invention is example microreactor system and device figure, at first substituted aryl and duplex tetramethyl ethylene ketone base diboron hexahydride are mixed by step 1 and be preheated to 80 ℃, obtain the mixture I after the mixing, mixes through step 3 with the mixture I after the acetonitrile solution of nitrite tert-butyl is preheated to 80 ℃ through step 2 and react, pass through step 4 again and finish reaction process.Mixture I of the present invention is the acetonitrile solution mixture of substituted aryl and duplex tetramethyl ethylene ketone base diboron hexahydride, 80 ℃ of mixture temperatures.Mixture I residence time in mixing module A1 is 19-28s, the residence time of nitrite tert-butyl in warm-up block C1 is 40s, mix in mixing module A2 with the mixture I and continue that (B1-B5) and time-delay pipeline, the total residence time of reaction is 50～3600s by the reaction module group through the nitrite tert-butyl after the preheating.
More than described the present invention, the illustrative explanation of following examples implementation result of the present invention can not be interpreted as it is limiting the scope of the invention.
The following example system carries out in microreactor according to the requirement of the inventive method.
Embodiment 1
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: the acetonitrile solution (0.5mol/ L) of pre-configured 2-fluoro-4-methylsulfonyl aniline, the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is 2-fluoro-4-methylsulfonyl aniline: duplex tetramethyl ethylene ketone base diboron hexahydride=1.0:0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment 2-fluoro-4-methylsulfonyl aniline: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment 2-fluoro-4-methylsulfonyl aniline: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 800s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (100-200 order silica gel), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 2-fluoro-4-methylsulfonyl aniline transformation efficiency is that 100%, 2-fluoro-4-methylsulfonyl phenylo boric acid pinacol ester yield is 48.0%.
Embodiment 2
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: the acetonitrile solution (0.5mol/ L) of pre-configured 3-fluoro-4-methylsulfonyl aniline, the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is 3-fluoro-4-methylsulfonyl aniline: duplex tetramethyl ethylene ketone base diboron hexahydride=1.0: 0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment 3-fluoro-4-methylsulfonyl aniline: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment 3-fluoro-4-methylsulfonyl aniline: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 780s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (100-200 order silica gel), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 3-fluoro-4-methylsulfonyl aniline transformation efficiency is that 100%, 3-fluoro-4-methylsulfonyl phenylo boric acid pinacol ester yield is 62.0%.
Embodiment 3
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: the acetonitrile solution of pre-configured 2-chloroaniline (1.0mol/ L), the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is 2 chloroanilines: duplex tetramethyl ethylene ketone base diboron hexahydride=0.5:0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment the 2-chloroaniline: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment the 2-chloroaniline: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 500s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (100-200 order silica gel), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 2-chloroaniline transformation efficiency is that 100%, 2-chlorobenzene boric acid pinacol ester yield is 66.2%.
Embodiment 4
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: the acetonitrile solution of pre-configured 4-fluoroaniline (1.0mol/ L), the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is the 4-fluoroaniline: duplex tetramethyl ethylene ketone base diboron hexahydride=0.5:0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment the 4-fluoroaniline: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment the 4-fluoroaniline: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 600s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (100-200 order silica gel), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 4-fluoroaniline transformation efficiency is that 100%, 4-fluorobenzoic boric acid pinacol ester yield is 82.1%.
Embodiment 5
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: the acetonitrile solution (1.0mol/ L) of pre-configured 2-methoxyl group base aniline, the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is the 2-anisidine: duplex tetramethyl ethylene ketone base diboron hexahydride=0.5: 0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment the 2-anisidine: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment the 2-anisidine: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 1100s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (silica gel 100-200 order), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (silica gel 300-400 order) purifying, at this moment, 2-anisidine transformation efficiency is that 100%, 2-methoxyphenylboronic acid pinacol ester yield is 56.3%.
Embodiment 6
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: pre-configured 2, the acetonitrile solution of 6-xylidine (1.0mol/ L), the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is 2,6-xylidine: duplex tetramethyl ethylene ketone base diboron hexahydride=0.5:0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment 2, the 6-xylidine: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment 2, the 6-xylidine: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 1400s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (100-200 order silica gel), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 2,6-xylidine transformation efficiency is that 100%, 2,6-dimethyl benzene boric acid pinacol ester yield is 53.8%.
Embodiment 7
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: pre-configured 3, the acetonitrile solution of 5-difluoroaniline (1.0mol/ L), the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is 3,5-difluoroaniline: duplex tetramethyl ethylene ketone base diboron hexahydride=0.5:0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment 3, the 5-difluoroaniline: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment 3, the 5-difluoroaniline: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 600s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is mixed sample (100-200 order silica gel) through concentrating, and usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 3,5-difluoroaniline transformation efficiency is 100%, 3,5-, two fluorobenzoic boric acid pinacol ester yields are 61.2%.
Embodiment 8
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: the acetonitrile solution of pre-configured 3-aminopyridine (1.0mol/ L), the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is the 3-aminopyridine: duplex tetramethyl ethylene ketone base diboron hexahydride=0.5:0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment the 3-aminopyridine: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment the 3-aminopyridine: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 900s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (100-200 order silica gel), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 3-aminopyridine transformation efficiency is that 100%, 3-pyridine boric acid pinacol ester yield is 72%.
Embodiment 9
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: the acetonitrile solution of pre-configured 5-aminopyrimidine (0.5mol/ L), the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is the 5-aminopyrimidine: duplex tetramethyl ethylene ketone base diboron hexahydride=1.0:0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment the 5-aminopyrimidine: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment the 5-aminopyrimidine: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 780s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (100-200 order silica gel), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 5-aminopyrimidine transformation efficiency is that 100%, 5-pyrimidine boric acid pinacol ester yield is 62.1%.
Embodiment 10
(1) equipment therefor: a kind of serialization micro passage reaction, determine microreactor module connection mode with reference to Fig. 1 system and device figure, hybrid reaction number of modules and time-delay length of pipeline determine that according to flow velocity and reaction time heat transferring medium is thermal oil;
(2) mixture I configuration: the acetonitrile solution (0.5mol/ L) of pre-configured 4-amino-1H-indazole, the acetonitrile solution (1.0mol/ L) of duplex tetramethyl ethylene ketone base diboron hexahydride, the velocity ratio of setting volume pump P1, pump P2 is 4-amino-1H-indazole: duplex tetramethyl ethylene ketone base diboron hexahydride=1.0:0.55, pump into simultaneously among the mixing module A1, setting this section heat exchange temperature is 80 ℃, i.e. the configurable mixture I that mixes.This moment 4-amino-1H-indazole: the mol ratio of duplex tetramethyl ethylene ketone base diboron hexahydride is 1:1.1;
(3) acetonitrile solution of pre-configured nitrite tert-butyl (1.0mol/ L), pumping among the warm-up block C1 preheating through pump P3 flows into then and mixes with the mixture I among the mixing module A2 and react, a series of enhancing quality transmission type hybrid reaction modules (B1-B5) finish with time-delay pipeline hybrid reaction to reaction continues to flow through, this moment 4-amino-1H-indazole: duplex tetramethyl ethylene ketone base diboron hexahydride: the mol ratio of nitrite tert-butyl is 1:1.1:1.5, reaction time is 850s, and reaction solution enters collection container at the even outflow reactor of outlet;
(4) thick product is through concentrating, mix sample (100-200 order silica gel), usable highly effective liquid chromatography and nuclear-magnetism (hydrogen spectrum) detect behind column chromatography (300-400 order silica gel) purifying, at this moment, 4-amino-1H-indazole transformation efficiency is that 100%, 4-1H-indazole boric acid pinacol ester yield is 56.4%.
Claims
1, a kind of method of utilizing the continuous synthesizing aryl boric acid ester of microreactor is characterized in that carrying out according to following step:
1) raw material preheating all is to finish in microreactor, and temperature is 60 ℃ ~ 120 ℃, and the module outlet is each raw material after the accurate temperature controlling preheating;
2) substituted aromatic amines after the last step gained preheating and two strands of raw materials of acetonitrile solution of duplex tetramethyl ethylene ketone base diboron hexahydride insert the microchannel module entrance, through mix the mixture I, after the mixture I is mixed in another microreactor with nitrite tert-butyl acetonitrile solution through preheating and is reacted, continue by microreactor (containing pipeline) after reaction process is finished, to enter collector; This reaction process residence time in microreactor is 50s ~ 3600s, and temperature of reaction is 60 ℃ ~ 120 ℃, reaction pressure 0.1 ~ 1.5bar;
3) reaction solution that will obtain from microreactor outlet is through concentrating, through column chromatography or other conventional purification process get final product the product aryl-boric acid ester.
2, a kind of method of utilizing the continuous synthesizing aryl boric acid ester of microreactor according to claim 1, it is characterized in that wherein the mol ratio of substituted aromatic amines and duplex tetramethyl ethylene ketone base diboron hexahydride is 1:0.5 ~ 1:1.25, the mol ratio of substituted aromatic amines and Isopentyl nitrite is 1:1.1 ~ 1:1.5, and temperature of reaction is 60 ℃ ~ 120 ℃.
3, comprise six element heterocycles and 5-membered heterocycles aromatic amine such as naphthylamines and derivative, aminopyridine and derivative thereof, aminopyrimidine and the derivative thereof etc. that aniline and derivative thereof, heteroatoms replace according to the aromatic amine of the described indication of the present invention of claim 1, can be as synthetic as structural formula (I), (II), (III), (IV) with the aryl-boric acid ester (V):
X=CH or N wherein; Y=CH, CR1 or N; Z=CH or N; W=NH, O or S are preferably O or S; Wherein n=0, various 3-7 unit's cycloaliphatic ring, the aromatic nucleus that does not replace or replace or contain heteroatomic aromatic nucleus; Be preferably nothing, phenyl ring, pyridine ring, pyrazoles, thiophene, pyrroles, furans, tetrahydrofuran (THF), tetramethylene, pentamethylene or hexanaphthene; R
1, R
2, R
3Can be in the following substituting group any one: H, methyl, ethyl, propyl group, sec.-propyl, isobutyl-, cyclopropyl, cyclobutyl, trifluoromethyl, aromatic base, halogen, first sulfydryl, methylsulfonyl, ester group, cyano group, carboxyl, formamido-, methylsulfonyl amido, methoxycarbonyl or ethoxy carbonyl, be preferably H, methyl, sec.-propyl, isobutyl-, cyclopropyl, chlorine, bromine, first sulfydryl, methylsulfonyl, trifluoromethyl, cyano group.
4; the boric acid ester that described the present invention is synthesized according to claim 1 comprises 2-fluoro-4-methylsulfonyl phenylo boric acid pinacol ester; 3-fluoro-4-methylsulfonyl phenylo boric acid pinacol ester; 2-chlorobenzene boric acid pinacol ester; 4-fluorobenzoic boric acid pinacol ester; 2-methoxyphenylboronic acid pinacol ester; 2; 6-dimethyl benzene boric acid pinacol ester; 3; 5-two fluorobenzoic boric acid pinacol esters; between methoxycarbonyl phenylo boric acid pinacol ester; to carboxyl phenylo boric acid pinacol ester; to methoxycarbonyl phenylo boric acid pinacol ester; 4-benzyloxycarbonyl phenylo boric acid pinacol ester; 4-benzyloxy phenylo boric acid pinacol ester; 4-(methanesulfonamido) phenylo boric acid pinacol ester; 4-(4-morpholinyl) phenylo boric acid pinacol ester; 4-(4-methyl isophthalic acid-piperazinyl) phenylo boric acid pinacol ester; 3-carboxyl phenylo boric acid pinacol ester; 3-hydroxybenzene boric acid pinacol ester; N-Boc-3-fluoro-4-amino-benzene boric acid pinacol ester; 4-bromomethyl benzene boric acid pinacol ester; 4-(methylamino formyl radical) phenylo boric acid pinacol ester; 4-(4-ethyl-1-piperazinyl) phenylo boric acid pinacol ester; 4-(4-Boc-1-piperazinyl) phenylo boric acid pinacol ester; 4-(3-methyl trimethylene oxide-3-yl) phenylo boric acid pinacol ester; 4-(4-THP trtrahydropyranyl) phenylo boric acid pinacol ester; 4-(4-morpholinyl methyl) phenylo boric acid pinacol ester; 4-(4-fluoro-piperidino) phenylo boric acid pinacol ester; 4-(3; 3-two fluoro-piperidino) phenylo boric acid pinacol ester; 4-(1-pyrrolidyl alkylsulfonyl) phenylo boric acid pinacol ester; 3-cyanophenylboronic acid pinacol ester; 3-hydroxyl-4-methoxyphenylboronic acid pinacol ester; 4-cyanophenylboronic acid pinacol ester; 4-amino-benzene boric acid pinacol ester; 4-[3-(2-chloro-3; 6-two fluorophenoxies) propyl group] the phenylo boric acid pinacol ester; naphthalene-2-boric acid pinacol ester; imidazo [1; 2-a] pyridine-6-boric acid pinacol ester; 7-azaindole-5-boric acid pinacol ester; 4-1H-indazole boric acid pinacol ester; 5-methoxyl group-3-pyridine boric acid pinacol ester; 3-pyridine boric acid pinacol ester; 2-nitro-5-pyridine boric acid pinacol ester; 5-pyrimidine boric acid pinacol ester; 2,4-, two chloro-5-pyrimidine boric acid pinacol esters; 2-thienyl boric acid pinacol ester; 5-chloro-2-thienyl boric acid pinacol ester; thiazole-5-boric acid pinacol ester; 2-pyrroles's boric acid pinacol ester; 1-methyl-3-pyrroles's boric acid pinacol ester; indoles-4-boric acid pinacol ester; 5-indoles boric acid pinacol ester; 3-pyridazine boric acid pinacol ester; 2-pyrazine boric acid pinacol ester; 4-pyrazoles boric acid pinacol ester; 1-methyl-4-pyrazoles boric acid pinacol ester; 1-ethyl-4-pyrazoles boric acid pinacol ester; 1-benzyl-4-pyrazoles boric acid pinacol ester; 1-Boc-4-pyrazoles boric acid pinacol ester etc.
5, carry out according to being reflected in the organic solvent of the described synthesizing aryl boric acid ester of the present invention of claim 1, used organic solvent is selected from common non-protonic solvent, toluene for example, dimethylbenzene, sym-trimethylbenzene, methylene dichloride, trichloromethane, tetracol phenixin, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, ethylene dichloride, dimethyl sulfoxide (DMSO), N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, methane amide, ethyl acetate, isopropyl acetate, ether, isopropyl ether, methyl tertiary butyl ether, normal hexane, acetonitrile, isovaleronitrile, N-Methyl pyrrolidone etc., preferred acetonitrile, isovaleronitrile, N,N-dimethylacetamide, N-Methyl pyrrolidone or their any mixture.
6, be interpreted as optimal selection according to a used raw material nitrite tert-butyl of the described the present invention of claim 1, other raw material comprises that similar nitrous acid alkane esters compounds such as Isopentyl nitrite, isobutyl nitrite can be used as its surrogate.
V. brief summary
The present invention relates to a kind of method of utilizing the continuous synthesizing aryl boric acid ester of microreactor, belong to green organic synthesis applied technical field.This method is starting raw material with substituted aromatic amines, acetonitrile, nitrite tert-butyl, duplex tetramethyl ethylene ketone base diboron hexahydride, after the mixing of the preheating, substituted aromatic amines of in the Continuous Flow micro channel reactor system, finishing substituted aromatic amines, nitrite tert-butyl, three kinds of raw materials of duplex tetramethyl ethylene ketone base diboron hexahydride and duplex tetramethyl ethylene ketone base diboron hexahydride with the processes such as reaction of nitrite tert-butyl.The mol ratio of substituted aromatic amines and duplex tetramethyl ethylene ketone base diboron hexahydride is 1:0.5 ~ 1:1.25 in the reaction, the mol ratio of substituted aromatic amines and Isopentyl nitrite is 1:1.1 ~ 1:1.5, temperature of reaction is 60 ~ 120 ℃, and the reaction times is 50s ~ 3600s, and the effective transformation efficiency of substituted aromatic amines can reach 50% ~ 90%.Reinforcement mixing, mass transfer, the heat-transfer effect type continuous current micro-reactor that the present invention adopts is particularly suitable for carrying out the homogeneous reaction of this method, has that temperature control is stable, process safety, characteristics that waste material is few.
Claims (6)
1. method of utilizing the continuous synthesizing aryl boric acid ester of microreactor is characterized in that carrying out according to following step:
Raw material preheating all is to finish in microreactor, and temperature is 60 ℃ ~ 120 ℃, and the module outlet is each raw material after the accurate temperature controlling preheating;
Substituted aromatic amines after the last step gained preheating and two strands of raw materials of acetonitrile solution of duplex tetramethyl ethylene ketone base diboron hexahydride insert the microchannel module entrance, through mix the mixture I, after the mixture I is mixed in another microreactor with nitrite tert-butyl acetonitrile solution through preheating and is reacted, continue by microreactor (containing pipeline) after reaction process is finished, to enter collector; This reaction process residence time in microreactor is 50s ~ 3600s, and temperature of reaction is 60 ℃ ~ 120 ℃, reaction pressure 0.1 ~ 1.5bar;
The reaction solution that will obtain from microreactor outlet is through concentrating, through column chromatography or other conventional purification process get final product the product aryl-boric acid ester.
2. a kind of method of utilizing the continuous synthesizing aryl boric acid ester of microreactor according to claim 1, it is characterized in that wherein the mol ratio of substituted aromatic amines and duplex tetramethyl ethylene ketone base diboron hexahydride is 1:0.5 ~ 1:1.25, the mol ratio of substituted aromatic amines and Isopentyl nitrite is 1:1.1 ~ 1:1.5, and temperature of reaction is 60 ℃ ~ 120 ℃.
3. comprise six element heterocycles and 5-membered heterocycles aromatic amine such as naphthylamines and derivative, aminopyridine and derivative thereof, aminopyrimidine and the derivative thereof etc. that aniline and derivative thereof, heteroatoms replace according to the aromatic amine of the described indication of the present invention of claim 1, can be as synthetic as structural formula (I), (II), (III), (IV) with the aryl-boric acid ester (V):
X=CH or N wherein; Y=CH, CR1 or N; Z=CH or N; W=NH, O or S are preferably O or S; Wherein n=0, various 3-7 unit's cycloaliphatic ring, the aromatic nucleus that does not replace or replace or contain heteroatomic aromatic nucleus; Be preferably nothing, phenyl ring, pyridine ring, pyrazoles, thiophene, pyrroles, furans, tetrahydrofuran (THF), tetramethylene, pentamethylene or hexanaphthene; R
1, R
2, R
3Can be in the following substituting group any one: H, methyl, ethyl, propyl group, sec.-propyl, isobutyl-, cyclopropyl, cyclobutyl, trifluoromethyl, aromatic base, halogen, first sulfydryl, methylsulfonyl, ester group, cyano group, carboxyl, formamido-, methylsulfonyl amido, methoxycarbonyl or ethoxy carbonyl, be preferably H, methyl, sec.-propyl, isobutyl-, cyclopropyl, chlorine, bromine, first sulfydryl, methylsulfonyl, trifluoromethyl, cyano group.
4. the boric acid ester that described the present invention is synthesized according to claim 1 comprises 2-fluoro-4-methylsulfonyl phenylo boric acid pinacol ester; 3-fluoro-4-methylsulfonyl phenylo boric acid pinacol ester; 2-chlorobenzene boric acid pinacol ester; 4-fluorobenzoic boric acid pinacol ester; 2-methoxyphenylboronic acid pinacol ester; 2; 6-dimethyl benzene boric acid pinacol ester; 3; 5-two fluorobenzoic boric acid pinacol esters; between methoxycarbonyl phenylo boric acid pinacol ester; to carboxyl phenylo boric acid pinacol ester; to methoxycarbonyl phenylo boric acid pinacol ester; 4-benzyloxycarbonyl phenylo boric acid pinacol ester; 4-benzyloxy phenylo boric acid pinacol ester; 4-(methanesulfonamido) phenylo boric acid pinacol ester; 4-(4-morpholinyl) phenylo boric acid pinacol ester; 4-(4-methyl isophthalic acid-piperazinyl) phenylo boric acid pinacol ester; 3-carboxyl phenylo boric acid pinacol ester; 3-hydroxybenzene boric acid pinacol ester; N-Boc-3-fluoro-4-amino-benzene boric acid pinacol ester; 4-bromomethyl benzene boric acid pinacol ester; 4-(methylamino formyl radical) phenylo boric acid pinacol ester; 4-(4-ethyl-1-piperazinyl) phenylo boric acid pinacol ester; 4-(4-Boc-1-piperazinyl) phenylo boric acid pinacol ester; 4-(3-methyl trimethylene oxide-3-yl) phenylo boric acid pinacol ester; 4-(4-THP trtrahydropyranyl) phenylo boric acid pinacol ester; 4-(4-morpholinyl methyl) phenylo boric acid pinacol ester; 4-(4-fluoro-piperidino) phenylo boric acid pinacol ester; 4-(3; 3-two fluoro-piperidino) phenylo boric acid pinacol ester; 4-(1-pyrrolidyl alkylsulfonyl) phenylo boric acid pinacol ester; 3-cyanophenylboronic acid pinacol ester; 3-hydroxyl-4-methoxyphenylboronic acid pinacol ester; 4-cyanophenylboronic acid pinacol ester; 4-amino-benzene boric acid pinacol ester; 4-[3-(2-chloro-3; 6-two fluorophenoxies) propyl group] the phenylo boric acid pinacol ester; naphthalene-2-boric acid pinacol ester; imidazo [1; 2-a] pyridine-6-boric acid pinacol ester; 7-azaindole-5-boric acid pinacol ester; 4-1H-indazole boric acid pinacol ester; 5-methoxyl group-3-pyridine boric acid pinacol ester; 3-pyridine boric acid pinacol ester; 2-nitro-5-pyridine boric acid pinacol ester; 5-pyrimidine boric acid pinacol ester; 2,4-, two chloro-5-pyrimidine boric acid pinacol esters; 2-thienyl boric acid pinacol ester; 5-chloro-2-thienyl boric acid pinacol ester; thiazole-5-boric acid pinacol ester; 2-pyrroles's boric acid pinacol ester; 1-methyl-3-pyrroles's boric acid pinacol ester; indoles-4-boric acid pinacol ester; 5-indoles boric acid pinacol ester; 3-pyridazine boric acid pinacol ester; 2-pyrazine boric acid pinacol ester; 4-pyrazoles boric acid pinacol ester; 1-methyl-4-pyrazoles boric acid pinacol ester; 1-ethyl-4-pyrazoles boric acid pinacol ester; 1-benzyl-4-pyrazoles boric acid pinacol ester; 1-Boc-4-pyrazoles boric acid pinacol ester etc.
5. carry out according to being reflected in the organic solvent of the described synthesizing aryl boric acid ester of the present invention of claim 1, used organic solvent is selected from common non-protonic solvent, toluene for example, dimethylbenzene, sym-trimethylbenzene, methylene dichloride, trichloromethane, tetracol phenixin, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, ethylene dichloride, dimethyl sulfoxide (DMSO), N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, methane amide, ethyl acetate, isopropyl acetate, ether, isopropyl ether, methyl tertiary butyl ether, normal hexane, acetonitrile, isovaleronitrile, N-Methyl pyrrolidone etc., preferred acetonitrile, isovaleronitrile, N,N-dimethylacetamide, N-Methyl pyrrolidone or their any mixture.
6. be interpreted as optimal selection according to a used raw material nitrite tert-butyl of the described the present invention of claim 1, other raw material comprises that similar nitrous acid alkane esters compounds such as Isopentyl nitrite, isobutyl nitrite can be used as its surrogate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310171684 CN103275112A (en) | 2013-05-11 | 2013-05-11 | Method for continuously synthesizing arylboronic acid ester by utilizing microreactor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310171684 CN103275112A (en) | 2013-05-11 | 2013-05-11 | Method for continuously synthesizing arylboronic acid ester by utilizing microreactor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103275112A true CN103275112A (en) | 2013-09-04 |
Family
ID=49057756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201310171684 Withdrawn CN103275112A (en) | 2013-05-11 | 2013-05-11 | Method for continuously synthesizing arylboronic acid ester by utilizing microreactor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103275112A (en) |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104045661A (en) * | 2014-05-07 | 2014-09-17 | 陕西师范大学 | Method for preparation of aryl boronic acid and aryl borate by alcohol-promoted boronation reaction of aromatic amine |
| CN105418548A (en) * | 2015-12-11 | 2016-03-23 | 大连世慕化学有限公司 | Microreactor used for alpha-position hydrogen atom chlorination of alpha-dicarbonyl compound and synthesis method |
| CN105601652A (en) * | 2014-10-28 | 2016-05-25 | 中国石油化工股份有限公司 | Method for preparing metal organic framework material |
| CN105601661A (en) * | 2016-03-22 | 2016-05-25 | 南京曙光精细化工有限公司 | Method for preparing mercaptosilane coupling agent by using channel reactor |
| CN105753762A (en) * | 2016-04-21 | 2016-07-13 | 南京工业大学 | Indole C3 derivative and preparation method thereof |
| CN105906656A (en) * | 2016-05-17 | 2016-08-31 | 凯莱英医药集团（天津）股份有限公司 | Synthetic method of crizotinib intermediate |
| WO2016140884A1 (en) | 2015-03-02 | 2016-09-09 | Rigel Pharmaceuticals, Inc. | TGF-β INHIBITORS |
| CN106311108A (en) * | 2016-09-23 | 2017-01-11 | 中国科学院上海高等研究院 | Microreactor with replaceable bed layer and application of microreactor |
| WO2018017633A1 (en) | 2016-07-21 | 2018-01-25 | Bristol-Myers Squibb Company | TGF Beta RECEPTOR ANTAGONISTS |
| CN110407870A (en) * | 2019-08-13 | 2019-11-05 | 南通江山农药化工股份有限公司 | The preparation method and its micro passage reaction of glyphosate |
| CN110498798A (en) * | 2019-08-28 | 2019-11-26 | 复旦大学 | A microreactor tandem synthesis method for indole anticancer drug molecules |
| CN112225722A (en) * | 2020-11-12 | 2021-01-15 | 张家港威胜生物医药有限公司 | Method for preparing crizotinib intermediate by using microchannel reactor |
| CN113444116A (en) * | 2021-06-04 | 2021-09-28 | 华东师范大学 | System and method for continuous chemical reactions for arylboronic acid ester synthesis under flow via microfluidic chip |
| TWI759165B (en) * | 2020-04-03 | 2022-03-21 | 大陸商常州強力先端電子材料有限公司 | Method for synthesizing oxetane compound by using microreactor |
| CN114345255A (en) * | 2021-12-27 | 2022-04-15 | 沈阳化工研究院有限公司 | Device for continuously preparing 3,3, 3-trifluoro-2, 2-dichloropropanal |
| CN115838378A (en) * | 2023-02-24 | 2023-03-24 | 研峰科技(北京)有限公司 | Continuous flow synthesis process of pyridine boric acid compound |
-
2013
- 2013-05-11 CN CN 201310171684 patent/CN103275112A/en not_active Withdrawn
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104045661A (en) * | 2014-05-07 | 2014-09-17 | 陕西师范大学 | Method for preparation of aryl boronic acid and aryl borate by alcohol-promoted boronation reaction of aromatic amine |
| CN105601652A (en) * | 2014-10-28 | 2016-05-25 | 中国石油化工股份有限公司 | Method for preparing metal organic framework material |
| CN105601652B (en) * | 2014-10-28 | 2018-06-19 | 中国石油化工股份有限公司 | A kind of method for preparing metal-organic framework materials |
| WO2016140884A1 (en) | 2015-03-02 | 2016-09-09 | Rigel Pharmaceuticals, Inc. | TGF-β INHIBITORS |
| CN105418548B (en) * | 2015-12-11 | 2018-06-19 | 大连科铎环境科技有限公司 | For the microreactor and synthetic method of α-hydrogen atom chlorination of dicarbonyl compound α |
| CN105418548A (en) * | 2015-12-11 | 2016-03-23 | 大连世慕化学有限公司 | Microreactor used for alpha-position hydrogen atom chlorination of alpha-dicarbonyl compound and synthesis method |
| CN105601661A (en) * | 2016-03-22 | 2016-05-25 | 南京曙光精细化工有限公司 | Method for preparing mercaptosilane coupling agent by using channel reactor |
| CN105753762A (en) * | 2016-04-21 | 2016-07-13 | 南京工业大学 | Indole C3 derivative and preparation method thereof |
| CN105906656A (en) * | 2016-05-17 | 2016-08-31 | 凯莱英医药集团（天津）股份有限公司 | Synthetic method of crizotinib intermediate |
| CN105906656B (en) * | 2016-05-17 | 2018-01-23 | 凯莱英医药集团（天津）股份有限公司 | A kind of gram of azoles replaces the synthetic method of Buddhist nun's intermediate |
| WO2018017633A1 (en) | 2016-07-21 | 2018-01-25 | Bristol-Myers Squibb Company | TGF Beta RECEPTOR ANTAGONISTS |
| CN106311108A (en) * | 2016-09-23 | 2017-01-11 | 中国科学院上海高等研究院 | Microreactor with replaceable bed layer and application of microreactor |
| CN110407870A (en) * | 2019-08-13 | 2019-11-05 | 南通江山农药化工股份有限公司 | The preparation method and its micro passage reaction of glyphosate |
| CN110407870B (en) * | 2019-08-13 | 2024-03-29 | 南通江山农药化工股份有限公司 | Preparation method of glyphosate and microchannel reactor thereof |
| CN110498798A (en) * | 2019-08-28 | 2019-11-26 | 复旦大学 | A microreactor tandem synthesis method for indole anticancer drug molecules |
| CN110498798B (en) * | 2019-08-28 | 2020-09-29 | 复旦大学 | Microreactor series synthesis method of indole anticancer drug molecules |
| TWI759165B (en) * | 2020-04-03 | 2022-03-21 | 大陸商常州強力先端電子材料有限公司 | Method for synthesizing oxetane compound by using microreactor |
| CN112225722A (en) * | 2020-11-12 | 2021-01-15 | 张家港威胜生物医药有限公司 | Method for preparing crizotinib intermediate by using microchannel reactor |
| CN113444116A (en) * | 2021-06-04 | 2021-09-28 | 华东师范大学 | System and method for continuous chemical reactions for arylboronic acid ester synthesis under flow via microfluidic chip |
| CN114345255A (en) * | 2021-12-27 | 2022-04-15 | 沈阳化工研究院有限公司 | Device for continuously preparing 3,3, 3-trifluoro-2, 2-dichloropropanal |
| CN114345255B (en) * | 2021-12-27 | 2023-09-12 | 沈阳化工研究院有限公司 | Device for continuously preparing 3, 3-trifluoro-2, 2-dichloropropionaldehyde |
| CN115838378A (en) * | 2023-02-24 | 2023-03-24 | 研峰科技(北京)有限公司 | Continuous flow synthesis process of pyridine boric acid compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103275112A (en) | Method for continuously synthesizing arylboronic acid ester by utilizing microreactor | |
| CN103183620B (en) | The nitrated method preparing nitroguanidine of guanidine sulfate in Continuous Flow micro passage reaction | |
| Roberge et al. | Development of an industrial multi‐injection microreactor for fast and exothermic reactions–part II | |
| CN101450300A (en) | Continuous current micro-reactor and preparation method and use thereof | |
| CN104478728B (en) | A method for synthesizing 1,5-dinitronaphthalene and 1,8-dinitronaphthalene by microchannel reaction | |
| CN103172545A (en) | Method for preparing nitroguanidine through micro-channel reactor | |
| CN101973940B (en) | Continuously synthesizing method of sulfonic acid alkyl group ionic liquid | |
| CN108863760A (en) | A method of utilizing micro passage reaction continuous production glyoxalic acid | |
| CN103193682B (en) | In Continuous Flow micro passage reaction, Guanidinium nitrate acidifying Dehydration is for the method for nitroguanidine | |
| CN103172546B (en) | Method for preparing nitroguanidine by adopting micro-channel reactor | |
| CN101225045A (en) | Micro-wave synthetic method for preparing methyl salicylate | |
| CN102617479A (en) | Method for synthesizing dihydropyrimidine ketone compounds using micro reactors | |
| CN113121585A (en) | Micro-reaction system and method for continuously preparing gamma-chloropropyltrichlorosilane | |
| CN103694169B (en) | Micro passage reaction is utilized to synthesize the method for 2,2,4-trimethylammonium-1,2-dihydroquinoline and polymkeric substance thereof | |
| CN110117216A (en) | A kind of continuous flow preparation method of 2,6- diethyl -4- methyl bromobenzene | |
| CN110156560A (en) | A method of preparing 2,6- diethyl -4- methyl bromobenzene | |
| CN109867605A (en) | The method of 1,2,4- butanetriol trinitrate is prepared in continuous flow micro passage reaction | |
| CN109369498A (en) | A kind of method that microreactor continuously synthesizes the bromo- 2- rubigan -5- trifluoromethyl pyrpole -3- nitrile of 4- | |
| CN110272346B (en) | Method for continuously producing ethyl trifluoroacetate | |
| Zhou et al. | Facile preparation of N-Alkyl-2-pyrrolidones in a continuous-flow microreactor | |
| CN110498798B (en) | Microreactor series synthesis method of indole anticancer drug molecules | |
| CN104558025A (en) | Method for continuously synthesizing O,S-dimethyl phosphoroamidothioate based on pipe type reaction device | |
| CN103028356A (en) | Device and method for performing aromatic heterocyclic lithium halide exchange reaction at room temperature | |
| CN102229576B (en) | Method for synthesizing 1,2,4-triazine compound by using micro-reactor | |
| CN114409671A (en) | A kind of full continuous flow preparation method of (+)-biotin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C04 | Withdrawal of patent application after publication (patent law 2001) | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20130904 |