CN114907266B - 一种二氢吡唑类化合物的制备方法 - Google Patents
一种二氢吡唑类化合物的制备方法 Download PDFInfo
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- CN114907266B CN114907266B CN202210534612.3A CN202210534612A CN114907266B CN 114907266 B CN114907266 B CN 114907266B CN 202210534612 A CN202210534612 A CN 202210534612A CN 114907266 B CN114907266 B CN 114907266B
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- -1 dihydropyrazole compound Chemical class 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 108
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 26
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- 239000003446 ligand Substances 0.000 claims abstract description 14
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 13
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 13
- KEQTWHPMSVAFDA-UHFFFAOYSA-N 2,3-dihydro-1h-pyrazole Chemical class C1NNC=C1 KEQTWHPMSVAFDA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 84
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 56
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 5
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 5
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 57
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 30
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 6
- 150000001336 alkenes Chemical group 0.000 abstract description 4
- 125000000524 functional group Chemical group 0.000 abstract description 4
- 150000001499 aryl bromides Chemical class 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 229930014626 natural product Natural products 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 239000000047 product Substances 0.000 description 45
- 150000007857 hydrazones Chemical class 0.000 description 35
- 238000004440 column chromatography Methods 0.000 description 28
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 238000012512 characterization method Methods 0.000 description 17
- 239000011734 sodium Substances 0.000 description 17
- PHMRPWPDDRGGGF-UHFFFAOYSA-N 2-bromoprop-1-ene Chemical compound CC(Br)=C PHMRPWPDDRGGGF-UHFFFAOYSA-N 0.000 description 14
- 239000007788 liquid Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 6
- 125000005394 methallyl group Chemical group 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 150000002576 ketones Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000005024 alkenyl aryl group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- MNSBHZNBVJAJND-UHFFFAOYSA-N 1-(2-bromoethenyl)-4-methoxybenzene Chemical group COC1=CC=C(C=CBr)C=C1 MNSBHZNBVJAJND-UHFFFAOYSA-N 0.000 description 1
- NHDODQWIKUYWMW-UHFFFAOYSA-N 1-bromo-4-chlorobenzene Chemical compound ClC1=CC=C(Br)C=C1 NHDODQWIKUYWMW-UHFFFAOYSA-N 0.000 description 1
- SRXJYTZCORKVNA-UHFFFAOYSA-N 1-bromoethenylbenzene Chemical compound BrC(=C)C1=CC=CC=C1 SRXJYTZCORKVNA-UHFFFAOYSA-N 0.000 description 1
- DLKQHBOKULLWDQ-UHFFFAOYSA-N 1-bromonaphthalene Chemical compound C1=CC=C2C(Br)=CC=CC2=C1 DLKQHBOKULLWDQ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- XMTQQYYKAHVGBJ-UHFFFAOYSA-N 3-(3,4-DICHLOROPHENYL)-1,1-DIMETHYLUREA Chemical compound CN(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XMTQQYYKAHVGBJ-UHFFFAOYSA-N 0.000 description 1
- XCMISAPCWHTVNG-UHFFFAOYSA-N 3-bromothiophene Chemical compound BrC=1C=CSC=1 XCMISAPCWHTVNG-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 238000011910 5-exo-trig cyclization Methods 0.000 description 1
- LFCURAJBHDNUNG-UHFFFAOYSA-N 6-bromo-2,3-dihydro-1,4-benzodioxine Chemical compound O1CCOC2=CC(Br)=CC=C21 LFCURAJBHDNUNG-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- UXRZLDREKITWRO-UHFFFAOYSA-N P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 Chemical compound P(c1ccccc1)c1ccccc1.CC1(C)c2ccccc2Oc2ccccc12 UXRZLDREKITWRO-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000006254 arylation reaction Methods 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
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000005293 duran Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 239000011941 photocatalyst Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开了一种二氢吡唑类化合物的制备方法,包括:在经脱氧处理的氮气环境的封管中,式Ⅰ所示化合物和式Ⅱ‑1或式Ⅱ‑2所示化合物在碱、钯催化剂和膦配体的催化体系下反应,制备一系列含芳基和烯基取代的二氢吡唑类化合物。本发明中,反应体系所用到的原料,例如芳基溴化物和烯基溴化物原料易得,部分烯基溴化物经过简单的合成即可得到,并且二氢吡唑类化合物分子结构中烯烃基团的引入,为该类化合物转化为其它官能团化合物提供了便利条件,可以进一步转化成各种化学合成药物或天然产物。该制备方法高效、经济、绿色化、底物拓展范围广,反应条件温和,产率高,制备操作和后处理步骤简单。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种二氢吡唑类化合物的制备方法。
背景技术
氮杂环骨架具有独特药理活性,其结构广泛存在于天然产物和药物分子结构中。二氢吡唑类化合物是一类重要的五元氮杂环化合物,一系列治疗多种疾病的小分子药物都包含二氢吡唑骨架(1.C.J.Thomson,D.M.Barber,and D.J.Dixon.Angew.Chem.Int.Ed.2019,58,2469–2473;2.S.M.TK,A.Das,S.C.C,R.BC,S.K,S.KV.Journal of MolecularStructure 1255(2022)132415;3.B.N.Acharya,D.Saraswat,M.Tiwari,A.K.Shrivastava,R.Ghorpade,S.Bapna,M.P.Kaushik,European Journal of Medicinal Chemistry 45(2010)430–438;4.S.Luan,H.Zhong,X.Zhao,J.Yang,Y.Jing,D.Liu,L.Zhao.EuropeanJournal of Medicinal Chemistry 141(2017)584e595),因此发展高效的合成二氢吡唑类化合物的新方法显得格外重要。
早期基于β,γ-不饱和腙合成二氢吡唑类化合物主要有两种方法:一种是通过自由基5-exo-trig环化构建二氢吡唑环。首先利用合适的自由基前体,通过自由基的串联环化的途径实现一系列官能团化的二氢吡唑类化合物的合成。Han等人通过TEMPO氧化β,γ-不饱和腙实现双官能团环化合成二氢吡唑类化合物,其中包括使用无金属催化、过渡金属催化氧化环化和光催化自由基环化的策略(X.-Y.Duan,X.-L.Yang,R.Fang,X.-X.Peng,W.Yu,B.Han,J.Org.Chem.2013,78,10692–10704.)。Loh等人开发了一种自由基介导的烯烃与苯肼和偶氮二羧酸盐的二胺化反应,合成了含二胺取代的二氢吡唑类化合物(Zhu,M.-K.;Chen,Y.-C.;Loh,T.-P.Chem.Eur.J.2013,19,5250.)。肖文精等人利用β,γ-不饱和腙为起始底物,通过使Ru(bpy)3]Cl2.6H2O作为光催化剂,NaOH作为碱,氯仿作为溶剂,在3W波长450-460nm蓝光的照耀下,室温条件下反应12-16小时,以良好的产率得到相应的二氢吡唑类化合物(Hu,X.-Q.;Chen,J.-R.;Wei,Q.;Liu,F.-L.;Deng,Q.-H.;Beauchemin,A.M.;Xiao,W.-J.Angew.Chem.,Int.Ed.2014,53,12163)。之后,利用Umemoto’s作为三氟甲基化试剂实现了含三氟甲基取代的二氢吡唑类化合物的合成(Wei,Q.;Chen,J.-R.;Hu,X.-Q.;Yang,X.-C.;Lu,B.;Xiao,W.-J,.Org.Lett.2015,17,4464.)。Carreira等人通过锰和钴催化β,γ-不饱和腙的自由基历程的氨基环化反应实现了一系列二氢吡唑类衍生物的合成。(Balkenhohl,M.;S.;Georgiev,T.;Carreira,E.M.JACS Au 2021,1,919.)。
另一种方法是通过钯催化烯烃的碳胺化反应来实现。
肖文精等人通过无配体参与的钯催化β,γ-不饱和腙和芳基高价碘盐的胺芳化反应,合成含芳基取代二氢吡唑类化合物。之后,又进一步实现了插入一氧化碳,合成含有酮官能团的二氢吡唑类化合物(1.Yan,D.-M.;Zhao,Q.-Q.;Chen,J.-R.;Xiao,W.-J.Org.Lett.2017,19,5208;2.Chen J.,Yang,M.-N.;Chen,J.-R.;Xiao,W.-J.Org.Lett.,2018,20,3314.)。尽管该反应不需要使用额外的氧化剂,但是需要使用昂贵的高价碘试剂,同时高价碘盐的使用限制了底物的兼容性,并且当使用碘苯、溴苯为反应原料时,不能获得相应的二氢吡唑类目标产物。
因此,进一步发展高效的合成具有特殊官能团的二氢吡唑化合物的方法具有重要的应用价值,尤其是发展高效、经济、绿色化且底物拓展范围广的合成方法意义重大。
发明内容
目的:为解决现有技术的不足,本发明提供一种二氢吡唑类化合物的制备方法,利用简单的芳基溴化物为原料,高效制备二氢吡唑类化合物,在使用烯基溴化物时,可以在二氢吡唑分子骨架中引入碳碳双键官能团,为转化为其它化合物提供优异的转化位点,可以进一步转化成各种化学合成药物或天然产物。
技术方案:为解决上述技术问题,本发明采用的技术方案为:
一种二氢吡唑类化合物的制备方法,包括:在碱、钯催化剂、膦配体的催化体系下,式Ⅰ所示化合物、式Ⅱ-1或式Ⅱ-2所示化合物在有机溶剂中进行反应,得到式III-1或式III-2所示的二氢吡唑类化合物;
其中,R1取代基选自H、F、Cl、Me、OMe、tBu、CF3,或为/>
Z为单键或者-CH=CH-;
R2取代基选自H、Me、Ph;
R3取代基选自H、Me、CF3、Ph,R4取代基选自H、Me、Ph;
环A为苯基、
R5取代基选自H、F、Cl、Me、OMe、tBu、CF3、CO2Me。
在一些实施例中,式Ⅰ所示化合物:式Ⅱ-1或式Ⅱ-2所示化合物:碱:钯催化剂:膦配体的投料摩尔比为1:2:1:0.05:0.15。
在一些实施例中,所述碱选自叔丁醇钠、叔丁醇钾、叔丁基锂、碳酸钾、碳酸钠、碳酸铯中的一种或几种,优选碱为叔丁醇钠。
在一些实施例中,钯催化剂为氯化烯丙基钯二聚物、三(二亚苄基丙酮)二钯、醋酸钯、二(乙酰丙酮)钯(Ⅱ)、氯化钯、醋酸钯中的一种或几种,优选钯催化剂为三(二亚苄基丙酮)二钯。
在一些实施例中,膦配体为三苯基膦、1,1’-双(二苯基膦)二茂铁、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽、双(2-二苯基膦)苯醚、2-双环己基膦-2’,6’-二异丙氧基联苯、2-二环己基膦-2,4,6-三异丙基联苯中的一种或几种,优选膦配体为2-二环己基膦-2,4,6-三异丙基联苯。
在一些实施例中,反应的有机溶剂选自四氢呋喃、甲苯、1,4-二氧六环、乙腈、1,2-二氯乙烷、乙醇的一种或几种,优选为甲苯。
在一些实施例中,反应的投料顺序为先加入钯催化剂、膦配体和有机溶剂,再加入式Ⅰ所示化合物、式Ⅱ-1或式Ⅱ-2所示化合物以及碱,然后在经脱氧处理的氮气环境中进行反应。
在一些实施例中,反应的温度是60-100℃,反应的时间是10-50h;进一步的,反应的温度优选为80℃,反应的时间优选为24h。
在一些实施例中,有机溶剂的加入量为(0.2~0.3)0.25mol式Ⅰ所示化合物使用1L有机溶剂。
在一些实施例中,式Ⅰ所示化合物(β,γ-不饱和腙)的制备方法,包括:
步骤1烯基醇的合成
相应的醛1.0equiv加入无水四氢呋喃溶剂中,在0℃下滴加烯丙基化镁1.5equiv反应半个小时,然后恢复至室温反应4-8小时。通过TLC监控反应进程,饱和氯化铵溶液淬灭。接着再用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥后,浓缩得到相应的醇的粗品,不需要进一步分离直接用于下一步反应。
步骤2烯基酮的制备
在0℃下向含有烯基醇的乙醚溶液中滴加琼斯试剂2.0-3.0equiv,待反应完全后,用分液漏斗分离有机相,再用乙酸乙酯萃取二至三次,合并有机相用无水硫酸钠干燥,浓缩萃取液,柱层析分离得到相应的酮。
步骤3烯基腙的制备
无水乙醇中加入相应的酮1.0eqiuv乙酰肼1.5eqiuv加入反应体系中,并加入乙酸0.2eqiuv作为催化剂。用TLC监控至反应完全,最后用旋转蒸发仪去除乙醇进行柱层析或重结晶,从而得到相应的腙。
在一些实施例中,利用碱、钯催化剂和膦配体组成的催化体系,催化β,γ-不饱和腙与烯基/芳基溴化物的反应,具体包括以下步骤:
步骤1在经脱氧脱水处理过的封管(一种带有聚四氟乙烯旋盖的可密封的耐高压的玻璃反应管)中,加入的各反应原料的量以摩尔比计:β,γ-不饱和腙:烯基/芳基溴化物:碱:钯催化剂:含膦配体=1:2:1:0.05:0.15,加入的溶剂量应满足β,γ-不饱和腙的摩尔浓度为0.25mol/L,然后将上述封管置于油浴锅中加热10-50h;
步骤2反应结束,通过柱层析技术分离提纯产物,得到二氢吡唑类化合物。
其中,所述步骤(1)中的反应温度设置为60-100℃;碱为:叔丁醇钠、叔丁醇钾、碳酸钾、碳酸钠、碳酸铯中的一种;钯催化剂为氯化烯丙基钯二聚物、三(二亚苄基丙酮)二钯、醋酸钯、二(乙酰丙酮)钯(Ⅱ)中的一种;含膦配体为三苯基膦、1,1’-双(二苯基膦)二茂铁、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽、双(2-二苯基膦)苯醚、2-双环己基膦-2,6’-二异丙氧基联苯、2-二环己基膦-2,4,6-三异丙基联苯中的一种;所用溶剂为四氢呋喃、甲苯、1,4-二氧六环、乙腈、二氯乙烷中的一种。
制备二氢吡唑类化合物的反应式如下:
有益效果:本发明提供的一种二氢吡唑类化合物的制备方法,具有以下优点:由β,γ-不饱和腙与烯基/芳基溴化物,通过钯催化碳胺化反应制备二氢吡唑类衍生物的方法,该方法利用烯基腙和芳基烯基溴化物通过一步同时形成碳碳键和碳氮键的偶联反应,实现了二氢吡唑类化合物的合成,具有首创性。本发明公开的制备方法中,反应体系所用到的原料反应活性高,例如烯基溴化物和芳基溴化物原料易得,均为商业化产品,部分烯基溴化物经过简单的合成即可得到,并且二氢吡唑类化合物分子结构中烯烃基团的引入,为该类化合物转化为其它官能团化合物提供了便利条件。该制备方法高效、经济、绿色化、底物拓展范围广,反应条件温和,产率高,制备操作和后处理步骤简单。无需额外加入氧化剂或高价碘试剂。
具体实施方式
下面结合实施例对本发明作进一步描述。以下实施例只是用于更加清楚地说明本发明的性能,而不能仅局限于下面的实施例。
实施例一
制备:1-(5-甲基-5-(2-甲基烯丙基)-3-对甲苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
方法1:在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.01mmol,9.2mg),2-二环己基膦-2,4,6-三异丙基联苯(0.03mmol,14.3mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),叔丁醇钠(0.2mmol,19.2mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色固体46.1mg,熔点53-55℃,产率85%。产物结构表征数据如下:1H NMR(CDCl3,400MHz)δ7.58(d,J=8.0Hz,2H),7.20(d,J=8.0Hz,2H),4.84(s,1H),4.71(s,1H),3.47(d,J=17.6Hz,1H),3.22(d,J=14.4Hz,1H),2.90(d,J=17.2Hz,1H),2.43(d,J=14.0Hz,1H),2.38(s,3H),2.34(s,3H),1.69(s,3H),1.67(s,3H);
13C NMR(CDCl3,100MHz)δ169.8,152.7,142.2,140.2,129.3,129.0,126.2,115.3,65.9,45.2,44.9,26.8,23.5,23.1,21.4;
IR(KBr)υ:3285,3071,2971,2920,2303,1901,1810,1653,1422,1363,1327,1264,1226,1182,1118,1033,958,928,900,847,810,745,710,623,563,534,488,463,431cm-1;
HRMS Calcd(ESI)m/z for C17H22N2NaO[M+Na]+:293.1624,found:293.1625.
方法2:在10mL的封管中,首先加入氯化烯丙基钯二聚物(0.01mmol,3.65mg),2-二环己基膦-2,4,6-三异丙基联苯(0.03mmol,14.3mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),叔丁醇钠(0.2mmol,19.2mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色固体39.8mg,熔点53-55℃,产率73%。
方法3:在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.01mmol,9.2mg),2-双环己基膦-2’,6’-二异丙氧基联苯(0.03mmol,14.0mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),叔丁醇钠(0.2mmol,19.2mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色固体44.9mg,熔点53-55℃,产率83%。
方法4:在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.01mmol,9.2mg),2-二环己基膦-2,4,6-三异丙基联苯(0.03mmol,14.3mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),碳酸铯(0.2mmol,65.16mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色固体36.4mg,熔点53-55℃,产率67%。
方法5:在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.01mmol,9.2mg),2-二环己基膦-2,4,6-三异丙基联苯(0.03mmol,14.3mg),乙腈(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),叔丁醇钠(0.2mmol,19.2mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色固体38.5mg,熔点53-55℃,产率71%。
方法6:在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.01mmol,9.2mg),2-二环己基膦-2,4,6-三异丙基联苯(0.03mmol,14.3mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),叔丁醇钠(0.2mmol,19.2mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌10小时后。通过柱层析分离提纯产物得到黄色固体46.1mg,熔点53-55℃,产率31%。
方法7:在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.01mmol,9.2mg),2-二环己基膦-2,4,6-三异丙基联苯(0.03mmol,14.3mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),叔丁醇钠(0.2mmol,19.2mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌50小时后。通过柱层析分离提纯产物得到黄色固体46.1mg,熔点53-55℃,产率83%。
方法8:在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.01mmol,9.2mg),2-二环己基膦-2,4,6-三异丙基联苯(0.03mmol,14.3mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),叔丁醇钠(0.2mmol,19.2mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于60℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色固体46.1mg,熔点53-55℃,产率47%。
方法9:在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.01mmol,9.2mg),2-二环己基膦-2,4,6-三异丙基联苯(0.03mmol,14.3mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.2mmol,46.1mg),2-溴丙烯(0.4mmol,48.4mg),叔丁醇钠(0.2mmol,19.2mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于100℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色固体46.1mg,熔点53-55℃,产率53%。
实施例二
制备:1-(5-甲基-5-(2-甲基烯丙基)-3-苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,108.1mg),2-溴丙烯(1.0mmol,121.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色油状液体107.6mg,产率83%。
产物结构表征数据如下:1H NMR(CDCl3,400MHz)δ7.70-7.68(m,2H),7.41-7.39(m,3H),4.85(s,1H),4.71(s,1H),3.50(d,J=17.6Hz,1H),3.23(d,J=14.0Hz,1H),2.93(d,J=17.6Hz,1H),2.44(d,J=14.0Hz,1H),2.35(s,3H),1.70(s,3H),1.67(s,3H);
13C NMR(CDCl3,100MHz)δ169.9,152.6,142.2,131.8,129.9,128.6,126.3,115.3,66.1,45.1,44.9,26.8,23.5,23.1;
IR(KBr)υ:2926,2382,2349,2315,1661,1411,1363,1328,1261,1133,1033,930,896,841,759,692,611,538,426cm-1.
HRMS Calcd(ESI)m/z for C16H20N2NaO[M+Na]+:279.1468,found:279.1468.
实施例三
制备:1-(5-甲基-5-(2-甲基烯丙基)-3-(4-氯苯基)-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,125.4mg),2-溴丙烯(1.0mmol,121.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色油状液体99.2mg,产率68%。
产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.60(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),4.84(s,1H),4.70(s,1H),3.45(d,J=17.2Hz,1H),3.21(d,J=14.4Hz,1H),2.89(d,J=17.6Hz,1H),2.42(d,J=14.0Hz,1H),2.33(s,3H),1.68(s,3H),1.66(s,3H);
13C NMR(CDCl3,100MHz)δ169.9,151.4,142.1,135.8,130.3,128.8,127.5,115.4,66.4,45.0,44.9,26.8,23.5,23.1;
IR(KBr)υ:3074,2931,2841,2381,2315,1659,1608,1518,1410,1364,1328,1254,1176,1114,1036,931,898,833,630,578,545,457cm-1;
HRMS Calcd(ESI)m/z for C16H19ClN2NaO[M+Na]+:313.1078,found:313.1080.
实施例四
制备:1-(5-甲基-5-(2-甲基烯丙基)-3-(2,3-二氢苯并[b]二噁英-6-基)-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,137.2mg),2-溴丙烯(1.0mmol,121.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色油状液体123.3mg,产率78%。
产物结构表征数据如下:1H NMR(CDCl3,400MHz)δ7.20-7.16(m,2H),6.87(d,J=8.0Hz,1H),4.83(s,1H),4.69(s,1H),4.27(s,4H),3.42(d,J=17.2Hz,1H),3.20(d,J=14.0Hz,1H),2.85(d,J=17.6Hz,1H),2.40(d,J=14.0Hz,1H),2.31(s,3H),1.68(s,3H),1.65(s,3H);
13C NMR(CDCl3,100MHz)δ169.7,152.2,145.3,143.5,142.2,125.4,119.9,117.4,115.3(2C),66.0,64.5,64.2,45.3,44.9,26.8,23.5,23.1;
IR(KBr)υ:3072,2930,2312,1659,1574,1513,1411,1363,1317,1284,1246,1183,1124,1066,890,817,747,625,457cm-1;
HRMS Calcd(ESI)m/z for C18H22N2NaO3[M+Na]+:337.1523,found:337.1524.
实施例五
制备:1-(5-甲基-5-(2-甲基烯丙基)-3-(萘-2-基)-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,133.2mg),2-溴丙烯(1.0mmol,121.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色油状液体126.8mg,产率83%。
产物结构表征数据如下:1H NMR(CDCl3,400MHz)δ8.01(d,J=8.4Hz,1H),7.90-7.83(m,4H),7.53-7.51(m,2H),4.87(s,1H),4.76(s,1H),3.62(d,J=17.2Hz,1H),3.27(d,J=14.0Hz,1H),3.06(d,J=17.6Hz,1H),2.49(d,J=14.0Hz,1H),2.41(s,3H),1.73(s,6H(3H*2));
13C NMR(CDCl3,100MHz)δ169.9,152.6,142.1,134.0,133.0,129.4,128.3(2C),127.8,127.0,126.6(2C),123.1,115.4,66.3,45.1,45.0,26.9,23.6,23.2;
IR(KBr)υ:3060,2966,2927,1662,1603,1477,1413,1366,1321,1264,1178,1130,1018,930,897,858,818,747,632,558,475cm-1;
HRMS Calcd(ESI)m/z for C20H22N2NaO[M+Na]+:329.1624,found:329.1622.
实施例六
制备:1-(5-甲基-5-(2-甲基烯丙基)-3-(4-甲氧基苯基)-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,123.2mg),2-溴丙烯(1.0mmol,121.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到淡黄色固体114.4mg,产率80%。熔点:94–97℃。产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.62(d,J=9.2Hz,2H),6.91(d,J=8.8Hz,2H),4.83(s,1H),4.70(s,1H),3.83(s,3H),3.45(d,J=17.6Hz,1H),3.21(d,J=14.0Hz,1H),2.89(d,J=17.6Hz,1H),2.42(d,J=14.0Hz,1H),2.33(s,3H),1.69(s,3H),1.66(s,3H);
13C NMR(CDCl3,100MHz)δ169.6,161.0,152.4,142.2,127.8,124.4,115.2,114.0,65.9,55.3,45.3,44.8,26.8,23.5,23.1;
IR(KBr)υ:3071,2974,2916,2316,1652,1598,1420,1398,1362,1324,1263,1185,1137,1090,1016,957,928,905,822,756,621,533,489,448cm-1;
HRMS Calcd(ESI)m/z for C17H22N2NaO2[M+Na]+:309.1573,found:309.1576.
实施例七
制备:1-(5-甲基-5-((氢-茚-2-基)甲基)-3-对甲苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),2-溴化茚(1.0mmol,195.1mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到淡黄色固体155.9mg,产率91%。熔点:101–103℃。产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.55(d,J=8.4Hz,2H),7.36(d,J=7.6Hz,1H),7.29-7.27(m,1H),7.23-7.18(m,3H),7.14-7.10(m,1H),6.61(s,1H),3.67(d,J=14.8Hz,1H),3.45(d,J=17.2Hz,1H),3.33(s,2H),3.06-2.98(m,2H),2.43(s,3H),2.38(s,3H),1.73(s,3H);
13C NMR(CDCl3,100MHz)δ169.9,152.5,145.2,144.7,143.5,140.3,130.4,129.2,128.7,126.2,126.1,124.0,123.3,120.2,66.2,45.8,41.6,39.1,26.3,23.6,21.4;
IR(KBr)υ:3059,3016,2958,2924,1648,1603,1406,1361,1326,1262,1174,1117,1092,1029,930,907,842,816,753,715,629,594,550,503,465,422cm-1;
HRMS Calcd(ESI)m/z for C23H24N2NaO[M+Na]+:367.1781,found:367.1784.
实施例八
制备:1-(5-甲基-5-(2-苯基烯丙基)-3-对甲苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
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在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),1-溴苯乙烯(1.0mmol,183.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到淡黄色固体125.8mg,产率76%。熔点:88-91℃。
产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.40(d,J=8.0Hz,2H),7.20-7.16(m,7H),5.15(s,1H),5.09(s,1H),3.71(d,J=13.6Hz,1H),3.31(d,J=17.6Hz,1H),2.82(d,J=17.2Hz,1H),2.71(d,J=14.0Hz,1H),2.38(s,3H),1.91(s,3H),1.72(s,3H);
13C NMR(CDCl3,100MHz)δ169.9,152.1,146.2,141.6,139.9,129.1,128.9,127.8,127.2,126.7,126.1,118.0,66.1,45.2,42.4,27.0,23.0,21.4;
IR(KBr)υ:2983,2927,2305,1651,1596,1494,1439,1413,1362,1328,1238,1179,1129,1100,1033,938,845,813,781,737,697,629,589,545,518,429cm-1;
HRMS Calcd(ESI)m/z for C22H24N2NaO[M+Na]+:355.1781,found:355.1783.
实施例九
制备:1-(5-甲基-5-(环己-1-烯-1-基甲基)-3-对甲苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),环基基溴(1.0mmol,161.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到淡黄色固体107.9mg,产率70%。熔点:74-76℃。
产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.57(d,J=8.0Hz,2H),7.19(d,J=8.0Hz,2H),5.43(s,1H),3.43(d,J=17.6Hz,1H),3.07(d,J=14.0Hz,1H),2.87(d,J=17.2Hz,1H),2.38(s,3H),2.33(s,3H),2.30(d,J=14.0Hz,1H),1.93-1.88(m,4H),1.65(s,3H),1.50-1.33(m,4H);
13C NMR(CDCl3,100MHz)δ169.7,152.7,140.0,134.4,129.2,129.1,126.5,126.2,66.5,45.6,45.4,29.2,26.7,25.4,23.5,23.0,22.1,21.4;
IR(KBr)υ:3066,3034,2992,2928,2855,2389,2303,1931,1656,1410,1362,1327,1259,1229,1184,1137,1099,1031,940,884,822,707,625,601,540,458,421cm-1.
HRMS Calcd(ESI)m/z for C20H26N2NaO[M+Na]+:333.1937,found:333.1936.
实施例十
制备:E-1-(5-甲基-5-(3-(4-甲氧基苯基)烯丙基)-3-对甲苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),1-溴-2-(4’-甲氧基苯基)乙烯(1.0mmol,213.1mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色油状液体121.2mg,产率67%。产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.57(d,J=8.0Hz,2H),7.22(d,J=8.8Hz,2H),7.19(d,J=8.0Hz,2H),6.80(d,J=8.8Hz,2H),6.44(d,J=15.6Hz,1H),5.95-5.87(m,1H),3.78(s,3H),3.32(d,J=17.2Hz,1H),3.12(dd,J1=14.0,J2=7.2Hz,1H),2.95(d,J=17.2Hz,1H),2.74(dd,J1=14.0,J2=7.6Hz,1H),2.38(s,3H*2),1.70(s,3H);
13C NMR(CDCl3,100MHz)δ169.7,158.9,152.3,140.2,133.4,130.1,129.2,128.9,127.2,126.2,122.4,113.8,66.6,55.2,45.8,41.3,25.4,23.3,21.4;
IR(KBr)υ:2929,2838,2389,2314,1660,1606,1511,1417,1362,1326,1300,1249,1176,1110,1033,969,933,816,631,550,516cm-1;
HRMS Calcd(ESI)m/z for C23H26N2NaO2[M+Na]+:385.1886,found:385.1886.
实施例十一
制备:1-(5-甲基-5-苄基-3-对甲苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入相对应是我β,γ-不饱和腙(0.5mmol,115.2mg),溴苯(1.0mmol,157.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄淡黄色固体154.2mg,产率98%。熔点:88-92℃。
产物结构表征数据如下:1H NMR(CDCl3,400MHz)δ7.44(d,J=8.0Hz,2H),7.24-7.20(m,2H),7.17-7.12(m,5H),3.55(d,J=13.6Hz,1H),3.37(d,J=17.6Hz,1H),3.11(d,J=13.2Hz,1H),2.83(d,J=17.6Hz,1H),2.38(s,3H),2.34(s,3H),1.74(s,3H);
13C NMR(CDCl3,100MHz)δ170.0,152.2,140.1,136.9,130.1,129.1,128.8,128.2,126.6,126.1,67.1,45.0,42.7,25.8,23.6,21.4;
IR(KBr)υ:3068,3026,2962,2921,2310,1933,1653,1603,1494,1430,1362,1328,1263,1228,1176,1115,1072,1029,965,931,889,822,757,704,622,589,544,513,482,427cm-1;
HRMS Calcd(ESI)m/z for C20H22N2NaO[M+Na]+:329.1624,found:329.1631.
实施例十二
制备:4-((5-甲基-3-对甲苯基-1-乙酰基-4,5,-二氢-1H-吡唑-5-基)甲基)苯甲酸甲酯
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),4-溴苯甲酸甲酯(1.0mmol,215.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到淡黄色固体152.8mg,产率84%。熔点:145–147℃。
产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.88(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),3.83(s,3H),3.69(d,J=13.6Hz,1H),3.31(d,J=17.6Hz,1H),3.08(d,J=13.6Hz,1H),2.87(d,J=17.6Hz,1H),2.35(s,3H),2.31(s,3H),1.74(s,3H);
13C NMR(CDCl3,100MHz)δ170.0,166.7,152.0,142.3,140.1,130.0,129.4,129.1,128.4,126.0,66.8,51.8,45.1,42.6,26.0,23.5,21.3;
IR(KBr)υ:2937,1715,1650,1605,1441,1408,1361,1323,1284,1179,1108,1027,968,934,843,810,765,713,628,539,488,427cm-1;
HRMS Calcd(ESI)m/z for C22H24N2NaO3[M+Na]+:387.1679,found:387.1679.
实施例十三
制备:1-(5-甲基-5-(4-氯苯基)-3-对甲苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),4-溴氯苯(1.0mmol,191.5mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到淡黄色固体170.2mg,产率85%。熔点:121–123℃。产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.44(d,J=8.0Hz,2H),7.20(d,J=8.4Hz,2H),7.15(d,J=8.0Hz,2H),7.10(d,J=8.4Hz,2H),3.60(d,J=13.6Hz,1H),3.31(d,J=17.2Hz,1H),3.03(d,J=13.6Hz,1H),2.88(d,J=17.2Hz,1H),2.37(s,3H),2.35(s,3H),1.74(s,3H);
13C NMR(CDCl3,100MHz)δ170.1,152.1,140.2,135.4,132.5,131.4,129.2,128.6,128.4,126.1,66.9,45.1,42.0,25.9,23.6,21.4;
IR(KBr)υ:2965,2927,2863,1903,1645,1494,1407,1324,1254,1158,1089,1027,933,805,626,551,512,446cm-1;
HRMS Calcd(ESI)m/z for C20H21ClN2NaO[M+Na]+:363.1235,found:363.1235.
实施例十四
制备:1-(5-甲基-5-((萘-1-基)甲基)-3-对甲苯基-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),1-溴代萘(1.0mmol,207.1mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到淡黄色固体177.3mg,产率99%。熔点:114–116℃。
产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ8.23(d,J=8.4Hz,1H),7.82(d,J=7.6Hz,1H),7.75-7.71(m,1H),7.53-7.44(m,2H),7.42-7.38(m,4H),7.13(d,J=8.0Hz,2H),4.04(d,J=14.0Hz,1H),3.74(d,J=14.0Hz,1H),3.44(d,J=17.2Hz,1H),2.76(d,J=17.6Hz,1H),2.45(s,3H),2.35(s,3H),1.76(s,3H).
13C NMR(CDCl3,100MHz)δ170.3,152.5,140.1,133.9,133.5,133.1,129.1,128.7,128.4,127.5,126.1,125.9,125.4,125.2,124.4,68.1,45.4,37.6,25.5,23.7,21.4.IR(KBr)υ;3687,3034,2926,1816,1652,1601,1511,1410,1363,1323,1262,1223,1181,1126,1028,964,924,785,621,586,546,510,432cm-1;
HRMS Calcd(ESI)m/z for C24H24N2NaO[M+Na]+:379.1781,found:379.1781.
实施例十五
制备:1-(5-甲基--3-对甲苯基-5-((噻吩-3-基)甲基)-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),3-溴噻吩(1.0mmol,163.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到淡黄色固体136.4mg,产率87%。熔点:93–94℃。
产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.48(d,J=8.4Hz,2H),7.19-7.15(m,3H),6.99(d,J=3.2Hz,1H),6.91(d,J=4.8Hz,1H),3.64(d,J=14.4Hz,1H),3.35(d,J=17.2Hz,1H),3.13(d,J=14.0Hz,1H),2.91(d,J=17.2Hz,1H),2.37(s,3H),2.36(s,3H),1.73(s,3H);
13C NMR(100MHz,CDCl3)δ169.9,152.2,140.1,137.1,129.2,129.0,128.8,126.1,125.2,122.9,66.7,45.7,37.6,25.7,23.5,21.4;
IR(KBr)υ:3097,2977,1637,1435,1412,1362,1329,1270,1240,1161,1114,1031,935,859,810,736,699,628,591,550,500,446cm-1;
HRMS Calcd(ESI)m/z for C18H20N2NaOS[M+Na]+:335.1189,found:335.1188.
实施例十六
制备:1-(5-甲基-3-对甲苯基-5-((2,3-二氢苯并[b][1,4]二噁英-6-基)甲基)-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,115.2mg),6-溴-1,4-苯并二噁烷(1.0mmol,215.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色油状液体178.6mg,产率98%。
产物结构表征数据如下:1H NMR(CDCl3,400MHz)δ7.48(d,J=8.4Hz,2H),7.16(d,J=8.0Hz,2H),6.73-6.62(m,3H),4.18(s,4H),3.44(d,J=13.6Hz,1H),3.36(d,J=17.6Hz,1H),3.02(d,J=13.6Hz,1H),2.82(d,J=17.2Hz,1H),2.38(s,3H),2.36(s,3H),1.70(s,3H).
13C NMR(CDCl3,100MHz)δ170.0,152.2,143.1,142.2,140.1,130.2,129.2,128.9,126.2,123.2,118.9,116.9,67.2,64.2,45.0,41.9,25.7,23.6,21.4.
IR(KBr)υ:3873,3805,3748,3449,2927,2381,2349,2315,1656,1506,1411,1363,1326,1288,1259,1209,1126,1067,922,886,815,770,683,623,422cm-1;
HRMS Calcd(ESI)m/z for C22H24N2NaO3[M+Na]+:387.1679,found:387.1680.
实施例十七
制备:1-(5-甲基-5-苄基-3-(4-叔丁基苯基)-4,5-二氢-1H-吡唑-1-基)-1-乙酮
在10mL的封管中,首先加入三(二亚苄基丙酮)二钯(0.025mmol,22.9mg),2-二环己基膦-2,4,6-三异丙基联苯(0.075mmol,35.7mg),甲苯(2.0mL),然后在室温下,搅拌10min,接下来加入β,γ-不饱和腙(0.5mmol,136.2mg),溴苯(1.0mmol,157.0mg),叔丁醇钠(0.5mmol,48.0mg)。最后对反应体系进行抽换气,充入氮气,将反应管密封好放置于80℃油浴锅中,加热搅拌24小时后。通过柱层析分离提纯产物得到黄色油状液体146.4mg,产率84%。
产物结构表征数据如下:
1H NMR(CDCl3,400MHz)δ7.50(d,J=8.4Hz,2H),7.37(d,J=8.8Hz,2H),7.25-7.22(m,2H),7.19-7.17(m,3H),3.58(d,J=13.6Hz,1H),3.39(d,J=17.6Hz,1H),3.13(d,J=13.6Hz,1H),2.85(d,J=17.2Hz,1H),2.39(s,3H),1.74(s,3H),1.31(s,9H);
13C NMR(CDCl3,100MHz)δ170.1,153.2,152.1,137.0,130.2,128.8,128.2,126.6,126.0,125.4,67.1,45.0,42.7,34.7,31.1,25.9,23.6;
IR(KBr)υ:2962,2384,2312,1660,1603,1411,1362,1326,1266,1169,1117,1030,932,834,740,704,622,568,421cm-1;
HRMS Calcd(ESI)m/z for C23H28N2NaO[M+Na]+:371.2094,found:371.2095.
由上述提供的实例表明,本发明提供了一种二氢吡唑类化合物的方法,该方法高效、经济、绿色化、底物拓展范围广,反应条件温和,产率高,制备操作和后处理步骤简单。
以上已以较佳实施例公开了本发明,然其并非用以限制本发明,凡采用等同替换或者等效变换方式所获得的技术方案,均落在本发明的保护范围之内。
Claims (7)
1.一种二氢吡唑类化合物的制备方法,其特征在于,包括:在碱、钯催化剂、膦配体的催化体系下,式Ⅰ所示化合物、式Ⅱ-1或式Ⅱ-2所示化合物在有机溶剂中进行反应,得到式III-1或式III-2所示的二氢吡唑类化合物;
其中,R1取代基选自H、F、Cl、Me、OMe、tBu、CF3,或为/>
Z为单键或者-CH=CH-;
R2取代基选自H、Me、Ph;
R3取代基选自H、Me、CF3、Ph,R4取代基选自H、Me、Ph;
环A为苯基、
R5取代基选自H、F、Cl、Me、OMe、tBu、CF3、CO2Me;
钯催化剂为氯化烯丙基钯二聚物、三(二亚苄基丙酮)二钯、醋酸钯、二(乙酰丙酮)钯(Ⅱ)、氯化钯、醋酸钯中的一种或几种;
膦配体为三苯基膦、1,1’-双(二苯基膦)二茂铁、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽、双(2-二苯基膦)苯醚、2-双环己基膦-2’,6’-二异丙氧基联苯、2-二环己基膦-2,4,6-三异丙基联苯中的一种或几种。
2.根据权利要求1所述的二氢吡唑类化合物的制备方法,其特征在于,式Ⅰ所示化合物:式Ⅱ-1或式Ⅱ-2所示化合物:碱:钯催化剂:膦配体的投料摩尔比为1:2:1:0.05:0.15。
3.根据权利要求1所述的二氢吡唑类化合物的制备方法,其特征在于,所述碱选自叔丁醇钠、叔丁醇钾、叔丁基锂、碳酸钾、碳酸钠、碳酸铯中的一种或几种。
4.根据权利要求1所述的二氢吡唑类化合物的制备方法,其特征在于,反应的有机溶剂选自四氢呋喃、甲苯、1,4-二氧六环、乙腈、1,2-二氯乙烷、乙醇的一种或几种。
5.根据权利要求1所述的二氢吡唑类化合物的制备方法,其特征在于,反应的投料顺序为先加入钯催化剂、膦配体和有机溶剂,再加入式Ⅰ所示化合物、式Ⅱ-1或式Ⅱ-2所示化合物以及碱,然后在经脱氧处理的氮气环境中进行反应。
6.根据权利要求1所述的二氢吡唑类化合物的制备方法,其特征在于,反应的温度是60-100℃,反应的时间是10-50h。
7.根据权利要求1所述的二氢吡唑类化合物的制备方法,其特征在于,有机溶剂的加入量为0.2~0.3mol式Ⅰ所示化合物使用1L有机溶剂。
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