CN108530241A - 一种具有苄位季碳中心的苯并环衍生物及氢溴酸依他佐辛的制备方法 - Google Patents
一种具有苄位季碳中心的苯并环衍生物及氢溴酸依他佐辛的制备方法 Download PDFInfo
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- CN108530241A CN108530241A CN201810299022.0A CN201810299022A CN108530241A CN 108530241 A CN108530241 A CN 108530241A CN 201810299022 A CN201810299022 A CN 201810299022A CN 108530241 A CN108530241 A CN 108530241A
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- compound
- nmr
- cdcl
- aryl
- eptazocine
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- 229950010920 eptazocine Drugs 0.000 title claims abstract description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title claims abstract description 19
- ZOWQTJXNFTWSCS-IAQYHMDHSA-N eptazocine Chemical compound C1N(C)CC[C@@]2(C)C3=CC(O)=CC=C3C[C@@H]1C2 ZOWQTJXNFTWSCS-IAQYHMDHSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 58
- 229910052799 carbon Inorganic materials 0.000 title abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 24
- -1 Eptazocine compound Chemical class 0.000 claims abstract description 22
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 16
- 239000000758 substrate Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 125000003518 norbornenyl group Chemical class C12(C=CC(CC1)C2)* 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 115
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 26
- 239000002585 base Substances 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 239000003638 chemical reducing agent Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- 125000004185 ester group Chemical group 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229910052710 silicon Inorganic materials 0.000 claims description 10
- 239000010703 silicon Substances 0.000 claims description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 9
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- CISNNLXXANUBPI-UHFFFAOYSA-N cyano(nitro)azanide Chemical group [O-][N+](=O)[N-]C#N CISNNLXXANUBPI-UHFFFAOYSA-N 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 229940126062 Compound A Drugs 0.000 claims description 7
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 150000001350 alkyl halides Chemical class 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- 238000006683 Mannich reaction Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 4
- 229940117975 chromium trioxide Drugs 0.000 claims description 4
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 125000002346 iodo group Chemical group I* 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- RBYGDVHOECIAFC-UHFFFAOYSA-L acetonitrile;palladium(2+);dichloride Chemical compound [Cl-].[Cl-].[Pd+2].CC#N.CC#N RBYGDVHOECIAFC-UHFFFAOYSA-L 0.000 claims description 2
- 238000005576 amination reaction Methods 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 claims description 2
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 239000010931 gold Substances 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 2
- 150000003003 phosphines Chemical class 0.000 claims description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- 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 2
- 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 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 229910010277 boron hydride Inorganic materials 0.000 claims 1
- DLIJPAHLBJIQHE-UHFFFAOYSA-N butylphosphane Chemical compound CCCCP DLIJPAHLBJIQHE-UHFFFAOYSA-N 0.000 claims 1
- 229910052792 caesium Inorganic materials 0.000 claims 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- KWZWNVAHEQHCTQ-UHFFFAOYSA-N diacetyloxyboranyl acetate Chemical compound CC(=O)OB(OC(C)=O)OC(C)=O KWZWNVAHEQHCTQ-UHFFFAOYSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 235000011056 potassium acetate Nutrition 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims 1
- 150000001503 aryl iodides Chemical class 0.000 abstract description 38
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 4
- 208000002193 Pain Diseases 0.000 abstract description 4
- 208000004550 Postoperative Pain Diseases 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 206010058019 Cancer Pain Diseases 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000002152 alkylating effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 208
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 52
- 239000007788 liquid Substances 0.000 description 47
- 239000003921 oil Substances 0.000 description 47
- 150000001347 alkyl bromides Chemical class 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 12
- 0 CC1(CC=O)c2cc(O*)ccc2CCC1 Chemical compound CC1(CC=O)c2cc(O*)ccc2CCC1 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- AUUNWLVVMHQXQM-UHFFFAOYSA-N 1-bromo-4-methylhept-3-ene Chemical compound CCCC(C)=CCCBr AUUNWLVVMHQXQM-UHFFFAOYSA-N 0.000 description 3
- RINOYHWVBUKAQE-UHFFFAOYSA-N 1-iodo-2-methylbenzene Chemical compound CC1=CC=CC=C1I RINOYHWVBUKAQE-UHFFFAOYSA-N 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 150000002848 norbornenes Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MSPXWJMFEVAKHQ-UHFFFAOYSA-N 1-fluoro-3-iodo-2-methylbenzene Chemical class CC1=C(F)C=CC=C1I MSPXWJMFEVAKHQ-UHFFFAOYSA-N 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 241000790917 Dioxys <bee> Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical compound Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种具有苄位季碳中心的苯并环衍生物及氢溴酸依他佐辛的制备方法。以芳基碘化物和烷基化试剂为起始原料,在钯催化剂、膦配体、降冰片烯衍生物、碱的作用下,在30℃到120℃下于有机溶剂中搅拌反应,即可得具有苄位季碳中心的苯并环衍生物。该方法所用的原料廉价易得,反应条件温和,底物普适性好,产率高,制备过程简单。同时,本发明还提供了一种合成氢溴酸依他佐辛化合物的方法,在本发明合成的具有苄位全碳季碳中心的1,2,3,4‑四氢化萘化合物的基础上只需要四步就可以合成具有治疗癌痛及手术后疼痛的药物氢溴酸依他佐辛,该方法合成步骤短,操作简单,总产率高。
Description
技术领域
本发明涉及一种具有苄位季碳中心的苯并环衍生物以及一种具有治疗癌痛及手术后疼痛的药物氢溴酸依他佐辛的制备方法,属于有机合成和药物化学领域。
背景技术
具有苄位季碳中心的1,2,3,4-四氢化萘或1,2-二氢化茚结构骨架是一类重要的结构单元,广泛存在于具有生物活性的天然产物和医药试剂中([1]D.M.Roll,P.J.Scheuer,J.Am.Chem.Soc.1983,105,6177.[2]P.W.Brian,J.C.McGowan,Nature 1945,156,144;[3]J.MacMillan,A.E.Vanstone,S.K.Yeboah,Chem.Commun.1968,613;c)J.R.Hanson,Nat.Prod.Rep.1995,12,381.[4]C.A.L.Bercht,J.P.C.M.Van Dongen,W.Heerma,R.J.J.C.Lousberg,F.J.E.M.Küppers,Tetrahedron 1976,32,2939.[5]L.Garrido,E.ZubHa,M.J.Ortega,J.Salva,J.Org.Chem.2003,68,293.[6]S.Shiotani,T.Kometani,K.Mitsuhashi,T.Nozawa,A.Kurobe,O.Futsukaichi,J.Med.Chem.1976,19,803.[7]P.W.Smethurst,W.H.Forrest,J.Hayden,Br.J.Anaesth.1971,43,1129.)。例如,具有1,2,3,4-四氢化萘结构的镇痛药物氢溴酸依他佐辛。目前,合成1,2,3,4-四氢化萘和1,2-二氢化茚化合物的方法主要有:(1)芳香化合物分子内的付克烷基化反应([1]D.Basavaiah,M.Bakthadoss,G.J.Reddy,Synthesis 2001,919;[2]Kurteva,V.B.;Santos,A.G.;Afonso,C.A.M.Org.Biomol.Chem.2004,2,514.);(2)过渡金属如铑催化的环加成反应(K.Tanaka,Y.Sawada,Y.Aida,M.Thammathevo,R.Tanaka,H.Sagae,Y.Otake,Tetrahedron 2010,66,1563);(3)过渡金属如金催化的环异构化反应([1]C.M.Grisé,Louis Barriault,Org.Lett.2006,8,905;[2]C.M.Grisé,Eric M.Rodrigue,LouisBarriault,Tetrahedron 2008,64,797);(4)分子内的Heck反应([1]T.Takemoto,M.Sodeoka,H.Sasai,M.Shibasaki,J.Am.Chem.Soc.1993,115,8477;[2]G.Hirai,Y.Koizumi,S.M.Moharram,H.Oguri,M.Hirama,Org.Lett.2002,4,1627;[3]S.Kesavan,J.S.Panek,J.A.Porco,Org.Lett.2007,9,5203);(5)自由基环化反应([1]C.-W.Kuo,J.-M.Fang,Synthetic Communications,2006,31,877;[2]W.Kong,N.Fuentes,A.Garca-Domnguez,E.Merino,C.Nevado,Angew.Chem.Int.Ed.2015,54,2487)。然而,这些方法大多需要预先合成特殊的官能团,极大地限制了这些方法的使用范围。因此发展高效、简洁的合成新方法显得尤为重要。本发明以芳基碘化物与烷基溴化物或烷基碘化物为起始原料,在催化剂、配体、降冰片烯衍生物、碱的作用下,在30℃到120℃下于有机溶剂中搅拌反应,即得到具有苄位全碳季碳中心的1,2,3,4-四氢化萘和1,2-二氢化茚化合物。该方法所用的原料廉价易得,反应条件温和,底物普适性好,产率高,制备过程简单。
临床药物氢溴酸依他佐辛,具有治疗癌痛及手术后疼痛的作用,现有的报道方法中需要7到20步才能完成合成([1]S.Shiotani,T.Kometani,K.Mitsuhashi,T.Nozawa,A.Kurobe,O.Futsukaichi,J.Med.Chem.1976,19,803;[2]T.Takemoto,M.Sodeoka,H.Sasai,M.Shibasaki,J.Am.Chem.Soc.1993,115,8477;[3]A.N.Hulme,S.S.Henry,A.I.Meyers,J.Org.Chem.1995,60,1265;[4]S.Shiotani,H.Okada,T.Yamamoto,K.Nakamata,J.Adachi,H.Nakamoto,Heterocycles 1996,43,113;[5]A.Fadel,P.Arzel,Tetrahedron:Asymmetry 1997,8,371;[6]S.K.Taylor,M.Ivanovic,L.J.Simons,M.M.Davis,Tetrahedron:Asymmetry 2003,14,743;[7]Y.Nakao,S.Ebata,A.Yada,T.Hiyama,M.Ikawa,S.Ogoshi,J.Am.Chem.Soc.2008,130,12874;[8]Q.Chen,X.Huo,Z.Yang,X.She,Chem.Asian J.2012,7,2543),合成路线较长,效率低下。
发明内容
为了解决现有技术中存在的不足,本发明提供一种具有苄位季碳中心的苯并环衍生物的合成方法。在我们发明的合成具有苄位全碳季碳中心的1,2,3,4-四氢化萘化合物的方法的基础上,我们发明了一种高效合成氢溴酸依他佐辛的方法,该方法只需要四步,大大减少了合成步骤,提高了合成效率。
本发明提供的技术方案具体如下:
具有通式I所示结构的化合物:
其中:
R1为与环L并环的芳环、杂芳环或取代环L上氢的取代基,取代基为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种或几种;n表示R1的个数,0≤n≤4;
R2选自氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种;
R3为m表示-CH2-的个数,0≤m≤10,
R3a选自氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种;
R3b选自芳基、杂环芳基、烷基中的一种;
R4为取代或未取代的C0-10碳链,取代基为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种或几种;
Y1为N或CH;
Y2为-O-、-NH-或-CH2-;
式I中的L、T用于描述不同位置的环,不表示任何化学含义。
一种合成通式I所示化合物的方法,包括以下步骤:在惰性气体保护下,将式II所示芳香碘代物、(i)式III所示烷基卤化物或(ii)式IV所示烷基卤化物、钯催化剂、膦配体、碱、式V所示降冰片烯衍生物于30~120℃的有机溶剂中搅拌反应,反应结束后分离提纯,分别得到(i)式I-a或(ii)式I-b所示的化合物;
其中:k表示-CH2-的个数,1≤k≤10;R1、R2、R3a、R3b、R4、Y1、Y2、m、n具有上述所限定的相同的含义;
式V中:
R6为五元环上的取代基,e代表取代基个数,1≤e≤8;
R6独立地选自金属离子M的羧酸盐、酯基、氰基、硝基、酰胺基、磺酰基、C1-10烷氧基、芳基、杂环芳基、C1-10烷基、卤素中的一种,M为Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+中的一种;e≥2时,各R6相同或不同。
本发明的方法优选使用钯催化剂来促进反应,可采用的钯催化剂包括零价或者二价的钯盐,例如:Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2等。可用商品化试剂,无需特殊处理。
本发明的方法优选使用膦配体来促进反应,三芳基膦(如苯基、呋喃基等)、三烷基膦(如环己基等)、XPhos(二环己基(2',4',6'-三异丙基-[1,1'-二苯基]-2-基)膦)、BrettPhos(二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-二苯基]-2-基)膦)、SPhos(二环己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦)、DavePhos(2'-(二环己基膦基)-N,N-二甲基-[1,1'-二苯基]-2-胺)、RuPhos(二环己基(2',6'-二异丙氧基-[1,1'-二苯基]-2-基)膦)、三(呋喃-2-基)膦、(3S,5S,7S)-金刚烷-1-基((1R,5S)-金刚烷-2-基)(丁基)膦等。可用商品化试剂,无需特殊处理。
本发明的方法优选使用碱来促进反应,可采用碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠等。可用商品化试剂,无需特殊处理。
本发明方法两种反应物的投料摩尔比为芳基碘代物:烷基溴化物=(1~10):1,优选为1.2:1。
本发明方法反应时间在48小时以内,反应温度为30~120℃。加热过程可采用油浴(例如硅油、石蜡油等)或者其它加热方式。
本发明优选在反应完成后对反应产物进行后处理,包括抽滤、浓缩和纯化。
所述抽滤过程可使用砂芯漏斗在减压的条件下过滤。
所述浓缩过程可采用常压蒸馏、减压蒸馏等方法,例如用旋转蒸发仪减压浓缩。
所述纯化过程是通过柱层析得到纯净的产物。
本发明还涉及一种氢溴酸依他佐辛的制备方法,其包含下列步骤:
(1)将化合物A中的醛基通过还原胺化的方法转化成二级胺,制得化合物B;
(2)将化合物B的苄位氧化成羰基,然后与甲醛发生Mannich反应,制得化合物C;
(3)化合物C在还原剂的作用下羰基被还原成亚甲基,同时脱掉氧上的保护基,制得依他佐辛;
(4)依他佐辛在氢溴酸的作用下制得依他佐辛的氢溴酸盐。
其中,R表示烷基、芳基、硅基、苄基等,这里优选苄基。
步骤(1)中,所述的还原胺化反应的方法和条件为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:将化合物A、甲胺和还原剂溶于有机溶剂,搅拌反应,即可。其中,所述的溶剂较佳的为二氯甲烷、1,2-二氯乙烷、四氢呋喃、甲醇和乙醇中的一种或多种,优选甲醇。所述的甲胺可以是甲胺盐酸盐或者甲胺的溶液。所述的还原剂较佳的是硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠,优选氰基硼氢化钠。所述的甲胺的用量较佳的为化合物A的摩尔量的1~10倍,优选5倍。所述的还原剂的用量较佳的为化合物A的摩尔量的1~5倍,优选2倍。所述的反应时间以监测反应完全为止,一般为5~12小时。所述的反应温度较佳的为0~50℃,优选30℃。
步骤(2)中,所述的苄位氧化和Mannich反应的方法和条件为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:将化合物B和氧化剂于溶剂中搅拌反应一段时间后加入甲醛,继续搅拌反应,即可。其中,所述的氧化剂较佳的为二氧化锡、二氧化锰、三氧化铬、高锰酸钾等,优选三氧化铬。所述的氧化剂的用量较佳的为化合物B的摩尔量的1~5倍,优选2.5倍。所述的溶剂较佳的为二氯甲烷、1,2-二氯乙烷、四氢呋喃、1,4-二氧六环、丙酮、醋酸和水中的一种或多种,优选醋酸和水的混合物,其体积比为1:1~10:1,优选4:1。所述的反应时间以监测反应完全为止,一般为1~5小时。所述的反应温度较佳的为0~40℃,优选30℃。在后续的Mannich反应中,所述的甲醛可以是多聚甲醛或者甲醛的溶液。所述的甲醛的用量较佳的为化合物B的摩尔量的1~5倍,优选1.1倍。所述的反应时间以监测反应完全为止,一般为10~24小时。所述的反应温度较佳的为40~100℃,优选55℃。所述的苄位氧化和Mannich反应可以分步进行或者一锅法进行。
步骤(3)中,所述的还原羰基和脱保护的方法和条件为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:将化合物C、还原剂和催化量的酸于有机溶剂中混合,氢气氛围下搅拌反应,即可。其中,所述的还原剂较佳的是钯/碳、氢氧化钯/碳。所述的还原剂的用量较佳的为化合物C的质量的5%~100%倍,优选30%倍。所述的溶剂较佳的甲醇和乙醇中的一种或多种。所述的酸较佳的为醋酸、硫酸、盐酸和高氯酸,优选高氯酸。所述的氢气压力为常压或者加压,优选40个大气压的压力。所述的反应时间以监测反应完全为止,一般为10~24小时。所述的反应温度较佳的为50~100℃,优选65℃。
步骤(4)中,所述的酸化成盐的方法和条件为本领域此类反应的常规方法和条件,本发明特别优选下述方法和条件:将化合物依他佐辛与氢溴酸搅拌反应,即可。其中,所述的氢溴酸百分比浓度为10%~48%,优选40%。所述的反应时间一般为10~60分钟。所述的反应温度较佳的为0~40℃,优选25℃。
本发明的方法可以高效地制备具有苄位季碳中心的1,2,3,4-四氢化萘或1,2-二氢化茚衍生物,和现有技术相比,本发明具有下列优势:
1、本发明所涉及的主要原料为芳基碘代物和烷基溴化物,此原料可用商品化试剂,无需特殊处理,且价格低廉,种类繁多;
2、本发明方法所涉及的反应使用的催化剂为廉价的金属钯盐,相比于之前的反应使用的催化剂或者络合物等是一个重要的补充;
3、本发明方法所涉及的反应使用的催化量的降冰片烯衍生物,相比于之前的反应使用的降冰片烯的用量大大减少;
4、本发明方法所涉及的反应对官能团具有很好的容忍性和普适性,取代基可以为烷基、烷氧基、氰基、酯基、硝基、卤原子(F、Cl、Br)等。
5、本发明方法可以大量(克级)制备1,2,3,4-四氢化萘和1,2-二氢化茚化合物,为工业化生产奠定了良好的基础。
6、本发明方法制备的1,2,3,4-四氢化萘衍生物可以高效、快捷(只需要四步)地转化成具有治疗癌痛及手术后疼痛的药物氢溴酸依他佐辛。
具体实施方式
下面通过实例对本发明给予进一步说明,值得注意的是,本发明不仅限于下述的实施例。
实施例1:化合物I-1的制备
在氩气体保护下,向干燥并装有磁力搅拌子的反应管中加入催化剂烯丙基氯化钯二聚体(3.7mg,0.01mmol)、配体XPhos(10.5mg,0.022mmol)、碳酸钾(69.1mg,0.5mmol)和干燥的乙腈(1.0mL),该混合物在室温下搅拌反应15分钟。将溶有芳基碘化物[1-碘萘(61mg,0.24mmol)]、烷基溴化物[反式6-溴-3-甲基-2-己烯-1-醇(38.6mg,0.2mmol)]和5-降冰片烯-2-羧酸(5.5mg,0.04mmol)的干燥乙腈(1.0mL)溶液加入到上述反应管中,然后加热至70℃在氩气保护氛围下反应24小时。反应冷却至室温后,混合物用硅藻土过滤,乙酸乙酯洗涤,减压除去溶剂,柱层析提纯得化合物I-1(无色油状液体,产率81%)。1H NMR(400MHz,CDCl3):δ9.36(dd,J=3.5,2.4Hz,1H),8.32(d,J=8.7Hz,1H),7.81(dd,J=8.1,1.5Hz,1H),7.63(d,J=8.3Hz,1H),7.51–7.47(m,1H),7.43–7.39(m,1H),7.19(d,J=8.3Hz,1H),3.44(dd,J=16.0,2.4Hz,1H),3.03–2.91(m,2H),2.87(dd,J=16.0,3.6Hz,1H),2.05–1.94(m,1H),1.93–1.85(m,3H),1.80(s,3H);13C NMR(100MHz,CDCl3):δ203.4,136.4,136.3,133.9,131.6,129.9,128.8,127.7,125.8,125.5,124.4,54.8,42.2,37.1,32.8,28.7,18.8;HRMS(ESI-TOF):理论计算值:C17H18NaO[M+Na+]261.1250,实测值:261.1254。
实施例2:化合物I-2的制备
所用的烷基溴化物为反式7-溴-4-甲基-3-庚烯-1-醇(41.4mg,0.2mmol),其他条件同实施例1,得化合物I-2(无色油状液体,产率68%)。1H NMR(400MHz,CDCl3):δ9.58(t,J=1.6Hz,1H),8.34(d,J=8.7Hz,1H),7.79(dd,J=8.0,1.7Hz,1H),7.60(d,J=8.3Hz,1H),7.46–7.36(m,2H),7.17(d,J=8.4Hz,1H),2.98–2.87(m,2H),2.78–2.71(m,1H),2.31–2.22(m,1H),2.13–2.06(m,1H),1.95–1.81(m,4H),1.73–1.67(m,4H);13C NMR(100MHz,CDCl3):δ202.7,137.2,136.6,133.7,132.4,129.6,128.8,127.2,125.5,125.3,124.3,40.7,40.3,38.0,34.0,33.1,28.6,19.1;HRMS(ESI-TOF):理论计算值:C18H20NaO[M+Na+]275.1406,实测值:275.1406。
实施例3:化合物I-3的制备
所用的芳基碘化物为2-甲基碘苯(52.3mg,0.24mmol),其他条件同实施例1,得化合物I-3(无色油状液体,产率65%)。1H NMR(400MHz,CDCl3):δ9.50(t,J=3.0Hz,1H),7.04–7.01(m,1H),6.96–6.94(m,2H),3.15(dd,J=16.2,3.2Hz,1H),2.85–2.82(m,2H),2.53(dd,J=16.2,2.8Hz,1H),2.49(s,3H),2.04–1.94(m,1H),1.86–1.76(m,3H),1.50(s,3H);13CNMR(100MHz,CDCl3):δ203.4,140.0,138.0,136.3,131.2,128.4,126.3,54.1,41.7,37.0,32.3,27.9,23.8,19.3;HRMS(ESI-TOF):理论计算值:C14H18NaO[M+Na+]225.1250,实测值:225.1247。
实施例4:化合物I-4的制备
所用的芳基碘化物为2-甲基碘苯(52.3mg,0.24mmol),烷基溴化物为反式7-溴-4-甲基-3-庚烯-1-醇(41.4mg,0.2mmol),其他条件同实施例1,得化合物I-4(无色油状液体,产率75%)。1H NMR(400MHz,CDCl3):δ9.74(t,J=1.6Hz,1H),7.02–6.98(m,1H),6.94–6.92(m,2H),2.80–2.77(m,2H),2.49–2.32(m,2H),2.45(s,3H),2.15–2.07(m,1H),1.82–1.72(m,4H),1.57–1.53(m,1H),1.41(s,3H);13C NMR(100MHz,CDCl3):δ202.8,140.8,138.5,136.8,130.9,128.3,125.8,40.3,39.8,38.0,32.6(2C),27.8,23.5,19.4;HRMS(ESI-TOF):理论计算值:C15H20NaO[M+Na+]239.1406,实测值:239.1410。
实施例5:化合物I-5的制备
所用的芳基碘化物为2-乙基碘苯(55.7mg,0.24mmol),其他条件同实施例1,得化合物I-5(无色油状液体,产率73%)。1H NMR(400MHz,CDCl3):δ9.52(t,J=3.0Hz,1H),7.12–7.06(m,2H),6.96–6.93(m,1H),3.08(dd,J=16.1,2.7Hz,1H),2.93–2.77(m,4H),2.62(dd,J=16.1,3.2Hz,1H),1.96–1.88(m,1H),1.81–1.74(m,3H),1.55(s,3H),1.26(t,J=7.5Hz,3H);13C NMR(100MHz,CDCl3):δ203.7,143.1,139.5,137.9,129.4,128.0,126.4,55.0,42.0,37.0,32.7,29.0,27.4,19.2,16.7;HRMS(ESI-TOF):理论计算值:C15H20NaO[M+Na+]239.1406,实测值:239.1412。
实施例6:化合物I-6的制备
所用的芳基碘化物为2-异丙基碘苯(59.1mg,0.24mmol),其他条件同实施例1,得化合物I-6(无色油状液体,产率60%)。1H NMR(400MHz,CDCl3):δ9.53(dd,J=3.3,2.5Hz,1H),7.18(dd,J=7.8,1.7Hz,1H),7.12(t,J=7.5Hz,1H),6.95–6.92(m,1H),3.54–3.47(m,1H),3.08(dd,J=16.2,2.5Hz,1H),2.83(t,J=6.2Hz,2H),2.64(dd,J=16.2,3.3Hz,1H),1.94–1.86(m,1H),1.80–1.75(m,3H),1.57(s,3H),1.26(t,J=6.6Hz,6H);13C NMR(100MHz,CDCl3):δ203.8,148.4,138.7,137.8,128.0,126.5,126.2,55.1,42.3,36.8,32.9,30.3,29.1,25.2,24.3,19.2;HRMS(ESI-TOF):理论计算值:C16H22NaO[M+Na+]253.1563,实测值:253.1564。
实施例7:化合物I-7的制备
所用的芳基碘化物为2-碘-1,1’-联苯(67.2mg,0.24mmol),其他条件同实施例1,得化合物I-7(无色油状液体,产率63%)。1H NMR(400MHz,CDCl3):δ9.48(dd,J=3.0,2.1Hz,1H),7.36–7.30(m,4H),7.17–7.09(m,3H),6.84(dd,J=6.8,2.3Hz,1H),2.97–2.93(m,2H),2.51(dd,J=16.8,2.1Hz,1H),2.17(dd,J=16.8,3.0Hz,1H),1.95–1.77(m,3H),1.64–1.56(m,1H),1.33(s,3H);13C NMR(100MHz,CDCl3):δ203.9,144.8,142.4,139.8,137.7,130.9,130.4,129.8,129.6,128.0,127.4,127.1,125.4,54.8,40.7,37.2,32.0,30.8,18.9;HRMS(ESI-TOF):理论计算值:C19H20NaO[M+Na+]287.1406,实测值:287.1409。
实施例8:化合物I-8的制备
所用的芳基碘化物为2-氟碘苯(53.3mg,0.24mmol),其他条件同实施例1,得化合物I-8(无色油状液体,产率78%)。1H NMR(400MHz,CDCl3):δ9.57–9.56(m,1H),7.11–7.06(m,1H),6.90–6.1(m,2H),3.13(ddd,J=15.6,2.3,1.2Hz,1H),2.82–2.71(m,2H),2.61(ddd,J=15.6,3.4,1.4Hz,1H),1.91–1.85(m,1H),1.81–1.71(m,3H),1.47(d,J=1.1Hz,3H);13C NMR(100MHz,CDCl3):δ203.3,161.9(d,J=246.1Hz),140.1(d,J=4.9Hz),129.2(d,J=11.7Hz),127.4(d,J=9.9Hz),125.5(d,J=2.7Hz),113.9(d,J=24.5Hz),54.3(d,J=6.2Hz),38.7,35.4(d,J=1.9Hz),30.9(d,J=2.7Hz),28.2(d,J=3.7Hz),19.4;19F NMR(377MHz,CDCl3)δ–110.3;HRMS(ESI-TOF):理论计算值:C13H15FNaO[M+Na+]229.0999,实测值:229.1006。
实施例9:化合物I-9的制备
所用的芳基碘化物为2-氯碘苯(57.2mg,0.24mmol),其他条件同实施例1,得化合物I-9(无色油状液体,产率64%)。1H NMR(400MHz,CDCl3):δ9.51(dd,J=3.2,2.2Hz,1H),7.20–7.17(m,1H),7.06–6.99(m,2H),3.65(dd,J=16.2,2.2Hz,1H),2.84–2.80(m,2H),2.65(dd,J=16.2,3.2Hz,1H),1.97–1.88(m,1H),1.80–1.71(m,3H),1.58(s,3H);13C NMR(100MHz,CDCl3):δ203.1,140.7,138.7,133.8,130.0,129.1,127.2,53.3,40.9,37.2,32.4,26.9,19.1;HRMS(ESI-TOF):理论计算值:C13H15ClNaO[M+Na+]245.0704,实测值:245.0710。
实施例10:化合物I-10的制备
所用的芳基碘化物为2-苄氧基碘苯(74.4mg,0.24mmol),其他条件同实施例1,得化合物I-10(无色油状液体,产率71%)。1H NMR(400MHz,CDCl3):δ9.47(dd,J=3.6,2.3Hz,1H),7.45–7.35(m,5H),7.09(t,J=7.9Hz,1H),6.79–6.74(m,2H),5.07(s,2H),3.34(dd,J=15.5,2.4Hz,1H),2.78(t,J=6.1Hz,2H),2.46(dd,J=15.5,3.6Hz,1H),1.85–1.68(m,4H),1.47(s,3H);13C NMR(100MHz,CDCl3):δ204.7,157.4,139.6,137.0,130.0,128.8,128.2,127.8,127.0,122.8,109.9,70.4,54.1,40.4,35.9,31.7,27.4,19.4;HRMS(ESI-TOF):理论计算值:C20H22NaO2[M+Na+]317.1512,实测值:317.1514。
实施例11:化合物I-11的制备
所用的芳基碘化物为叔丁基(2-碘苄氧基)二甲基硅(83.6mg,0.24mmol),其他条件同实施例1,得化合物I-11(无色油状液体,产率51%)。1H NMR(400MHz,CDCl3):δ9.45(dd,J=3.6,2.1Hz,1H),7.30(dd,J=7.6,1.6Hz,1H),7.14(t,J=7.5Hz,1H),7.04(dd,J=7.3,1.5Hz,1H),4.93(d,J=12.2Hz,1H),4.77(d,J=12.2Hz,1H),3.17(dd,J=16.1,2.1Hz,1H),2.84(t,J=6.4Hz,2H),2.51(dd,J=16.2,3.5Hz,1H),1.93–1.86(m,1H),1.85–1.76(m,2H),1.75–1.69(m,1H),1.49(s,3H),0.91(s,9H),0.13(s,3H),0.11(s,3H);13C NMR(100MHz,CDCl3):δ204.0,139.5,139.3,137.8,129.9,129.3,126.4,64.4,55.4,41.5,36.9,32.2,29.3,26.1,19.1,18.5,-4.9,-5.0;HRMS(ESI-TOF):理论计算值:C20H32NaO2Si[M+Na+]355.2064,实测值:355.2060。
实施例12:化合物I-12的制备
所用的芳基碘化物为N-Boc保护的3-氯-4-碘苯胺(84.9mg,0.24mmol),其他条件同实施例1,得化合物I-12(无色油状液体,产率61%)。1H NMR(400MHz,CDCl3):δ9.50(dd,J=3.3,2.2Hz,1H),7.05(s,1H),6.40(s,1H),3.60(dd,J=16.1,2.2Hz,1H),2.77(t,J=6.4Hz,2H),2.59(dd,J=16.1,3.3Hz,1H),1.93–1.84(m,1H),1.78–1.68(m,3H),1.54(s,3H),1.50(s,9H);13C NMR(100MHz,CDCl3):δ203.3,152.6,141.2,137.0,134.1,133.1,119.8,118.3,53.4,40.9,36.8,32.7,28.4,28.1,27.1,19.2;HRMS(ESI-TOF):理论计算值:C18H24ClNNaO3[M+Na+]360.1337,实测值:360.1335。
实施例13:化合物I-13的制备
所用的芳基碘化物为3-氟-2-甲基碘苯(56.6mg,0.24mmol),其他条件同实施例1,得化合物I-13(无色油状液体,产率72%)。1H NMR(400MHz,CDCl3):δ9.49(t,J=2.9Hz,1H),6.93–6.89(m,1H),6.85–6.80(m,1H),3.15(dd,J=16.3,3.1Hz,1H),2.78(t,J=6.0Hz,2H),2.56(dd,J=16.3,2.8Hz,1H),2.36(d,J=3.2Hz,3H),1.98–1.89(m,1H),1.82–1.72(m,3H),1.50(s,3H);13C NMR(100MHz,CDCl3):δ202.8,160.6(d,J=240.3Hz),141.8(d,J=1.9Hz),133.2(d,J=3.4Hz),128.7(d,J=9.1Hz),123.1(d,J=14.6Hz),113.2(d,J=24.5Hz),54.1,41.5,37.3(d,J=2.1Hz),31.8,27.9,19.3,13.8(d,J=9.6Hz);9F NMR(377MHz,CDCl3)δ–115.5;HRMS(ESI-TOF):理论计算值:C14H17FNaO[M+Na+]243.1156,实测值:243.1160。
实施例14:化合物I-14的制备
所用的芳基碘化物为4-氟-2-甲基碘苯(56.6mg,0.24mmol),其他条件同实施例1,得化合物I-14(无色油状液体,产率70%)。1H NMR(400MHz,CDCl3):δ9.49(t,J=3.0Hz,1H),6.68–6.64(m,2H),3.12(dd,J=16.3,3.3Hz,1H),2.83–2.79(m,2H),2.51(dd,J=16.3,2.7Hz,1H),2.47(s,3H),2.00–1.95(m,1H),1.83–1.73(m,3H),1.46(s,3H);13C NMR(100MHz,CDCl3):δ203.0,160.4(d,J=244.9Hz),140.4(d,J=7.3Hz),138.8(d,J=7.5Hz),135.7(d,J=3.1Hz),117.6(d,J=20.4Hz),114.1(d,J=19.3Hz),54.1,41.6,36.6,32.6(d,J=1.6Hz),28.0,23.8(d,J=1.5Hz),19.0;19F NMR(377MHz,CDCl3)δ–118.8.HRMS(ESI-TOF):理论计算值:C14H17FNaO[M+Na+]243.1156,实测值:243.1161。
实施例15:化合物I-15的制备
所用的芳基碘化物为4-溴-2-甲基碘苯(71.3mg,0.24mmol),其他条件同实施例1,得化合物I-15(无色油状液体,产率59%)。1H NMR(400MHz,CDCl3):δ9.50(t,J=2.9Hz,1H),7.09(brs,2H),3.11(dd,J=16.3,3.2Hz,1H),2.82–2.79(m,2H),2.52(dd,J=16.3,2.6Hz,1H),2.45(s,3H),2.02–1.92(m,1H),1.82–1.72(m,3H),1.46(s,3H);13C NMR(100MHz,CDCl3):δ202.7,140.3,139.1,138.6,133.6,130.9,119.9,53.9,41.3,36.8,32.2,27.8,23.5,19.0;HRMS(ESI-TOF):理论计算值:C14H17BrNaO[M+Na+]303.0355,实测值:303.0354。
实施例16:化合物I-16的制备
所用的芳基碘化物为4-硝基-2-甲基碘苯(63.1mg,0.24mmol),其他条件同实施例1,得化合物I-16(无色油状液体,产率85%)。1H NMR(400MHz,CDCl3):δ9.53(t,J=2.6Hz,1H),7.80–7.77(m,2H),3.22(dd,J=16.8,2.9Hz,1H),2.93(t,J=6.4Hz,2H),2.62(dd,J=16.8,2.2Hz,1H),2.57(s,3H),2.07–2.02(m,1H),1.87–1.76(m,3H),1.49(s,3H);13C NMR(100MHz,CDCl3):δ201.3,148.0,145.5,139.9,138.2,125.2,122.8,53.9,41.0,37.4,32.5,27.5,24.0,18.8;HRMS(ESI-TOF):理论计算值:C14H17NNaO3[M+Na+]270.1101,实测值:270.1105。
实施例17:化合物I-17的制备
所用的芳基碘化物为4-碘-3-甲基苯甲酸甲酯(66.3mg,0.24mmol),其他条件同实施例1,得化合物I-17(无色油状液体,产率83%)。1H NMR(400MHz,CDCl3):δ9.48(t,J=2.8Hz,1H),7.61–7.59(m,2H),3.88(s,3H),3.17(dd,J=16.4,3.0Hz,1H),2.88(t,J=6.3Hz,2H),2.58–2.53(m,4H),2.05–1.95(m,1H),1.85–1.74(m,3H),1.49(s,3H);13C NMR(100MHz,CDCl3):δ202.4,167.2,145.4,138.4,136.6,131.9,129.4,127.7,53.9,52.1,41.4,37.3,32.3,27.7,23.8,19.1;HRMS(ESI-TOF):理论计算值:C16H20NaO3[M+Na+]283.1305,实测值:283.1306。
实施例18:化合物I-18的制备
所用的芳基碘化物为1-溴-4-碘萘(79.9mg,0.24mmol),其他条件同实施例1,得化合物I-18(无色油状液体,产率60%)。1H NMR(400MHz,CDCl3):δ9.37(dd,J=3.4,2.4Hz,1H),8.33–8.27(m,2H),7.56–7.49(m,3H),3.40(dd,J=16.1,2.5Hz,1H),3.01–2.91(m,2H),2.87(dd,J=16.1,3.4Hz,1H),2.05–1.98(m,1H),1.92–1.84(m,3H),1.78(s,3H);13CNMR(100MHz,CDCl3):δ202.7,137.2,136.7,133.1,132.6,131.9,128.9,126.3,126.0,125.8,122.3,54.8,42.1,37.0,32.5,28.8,18.6;HRMS(ESI-TOF):理论计算值:C17H17BrNaO[M+Na+]339.0355,实测值:339.0359。
实施例19:化合物I-19的制备
所用的芳基碘化物为4-碘-2,3-二氢化茚(58.6mg,0.24mmol),其他条件同实施例1,得化合物I-19(无色油状液体,产率58%)。1H NMR(400MHz,CDCl3):δ9.51(t,J=3.0Hz,1H),7.04(d,J=7.6Hz,1H),6.92(d,J=7.6Hz,1H),3.13–3.03(m,2H),2.96–2.89(m,1H),2.83–2.79(m,4H),2.52(dd,J=15.9,2.9Hz,1H),2.12–1.91(m,3H),1.85–1.74(m,3H),1.45(s,3H);13C NMR(100MHz,CDCl3):δ203.7,143.7,141.5,138.3,135.1,128.5,122.8,53.9,40.0,36.8,35.2,32.4,31.5,27.9,26.2,19.6;HRMS(ESI-TOF):理论计算值:C16H20NaO[M+Na+]251.1406,实测值:251.1407。
实施例20:化合物I-20的制备
所用的芳基碘化物为5-碘-1,2,3,4,-四氢化萘(61.9mg,0.24mmol),其他条件同实施例1,得化合物I-20(无色油状液体,产率53%)。1H NMR(400MHz,CDCl3):δ9.49(t,J=3.0Hz,1H),6.90(s,2H),3.16(dd,J=16.3,3.1Hz,1H),2.96(dt,J=14.6,5.0Hz,1H),2.83–2.65(m,5H),2.55(dd,J=16.4,2.8Hz,1H),1.98–1.93(m,1H),1.87–1.68(m,7H),1.53(s,3H);13C NMR(100MHz,CDCl3):δ203.7,139.3,137.3,137.1,135.2,127.9,127.6,54.6,42.5,36.9,32.3,30.1,29.2,28.3,22.8,21.9,19.3;HRMS(ESI-TOF):理论计算值:C17H22NaO[M+Na+]265.1563,实测值:265.1566。
实施例21:化合物I-21的制备
所用的芳基碘化物为6-氯-5-碘-2,3-二氢螺(茚-1,2’-(1,3)二氧戊烷)(80.8mg,0.24mmol),其他条件同实施例1,得化合物I-21(无色油状液体,产率75%)。1H NMR(400MHz,CDCl3):δ9.48(dd,J=3.4,2.2Hz,1H),7.21(s,1H),4.20–4.14(m,2H),4.12–4.04(m,2H),3.63(dd,J=16.1,2.3Hz,1H),2.82–2.54(m,5H),2.31–2.28(m,2H),1.94–1.87(m,1H),1.81–1.70(m,3H),1.57(s,3H);13C NMR(100MHz,CDCl3):δ203.2,141.8,140.9,139.5,137.0,132.7,124.3,116.9,65.5,65.3,53.1,40.6,37.3,36.9,28.7,27.4,26.8,18.5;HRMS(ESI-TOF):理论计算值:C18H21ClNaO3[M+Na+]343.1071,实测值:343.1073。
实施例22:化合物I-22的制备
所用的芳基碘化物为3-苄氧基碘苯(74.4mg,0.24mmol),烷基碘化物为反式6-碘-3-甲基-2-己烯-1-醇(48mg,0.2mmol),催化剂烯丙基氯化钯二聚体(3.7mg,0.01mmol)、配体XPhos(10.5mg,0.022mmol),其他条件同实施例1,得化合物I-22(无色油状液体,产率53%)。1H NMR(400MHz,CDCl3):δ9.54(dd,J=3.6,2.4Hz,1H),7.45–7.37(m,4H),7.34–7.30(m,1H),7.01(d,J=8.4Hz,1H),6.89(d,J=2.6Hz,1H),6.77(dd,J=8.4,2.6Hz,1H),5.03(s,2H),2.77(dd,J=15.2,2.5Hz,1H),2.72(t,J=6.1Hz,2H),2.53(dd,J=15.2,3.5Hz,1H),1.88–1.71(m,3H),1.75–1.70(m,1H),1.38(s,3H);13C NMR(100MHz,CDCl3):δ203.5,157.2,143.7,137.2,130.5,129.2,128.7,128.1,127.7,113.4,112.7,70.3,56.2,36.8,36.6,30.8,29.6,19.6;HRMS(ESI-TOF):理论计算值:C20H22NaO2[M+Na+]317.1512,实测值:317.1503。
实施例23:化合物I-23的制备
所用的芳基碘化物为叔丁基(3-碘苯氧基)二苯基硅烷(110mg,0.24mmol),烷基碘化物为反式6-碘-3-甲基-2-己烯-1-醇(48mg,0.2mmol),其他条件同实施例1,得化合物I-23(无色油状液体,产率48%)。1H NMR(400MHz,CDCl3):δ9.16(dd,J=4.0,2.0Hz,1H),7.71(td,J=8.1,1.5Hz,4H),7.45–7.33(m,6H),6.86(d,J=8.1Hz,1H),6.67(dd,J=8.3,2.5Hz,1H),6.52(d,J=2.5Hz,1H),2.66–2.56(m,2H),2.32(dd,J=15.0,2.1Hz,1H),2.15(dd,J=15.1,4.0Hz,1H),1.74–1.63(m,3H),1.61–1.55(m,1H),1.12(s,9H),1.07(s,3H);13C NMR(100MHz,CDCl3):δ203.7,153.9,142.9,135.6,133.2,133.1,130.3,130.1,130.0,129.1,127.9,118.1,117.6,56.1,36.6,36.2,30.6,29.6,26.7,19.6,19.6;HRMS(ESI-TOF):理论计算值:C29H34NaO2Si[M+Na+]465.2220,实测值:465.2215。
实施例24:化合物I-24的制备
所用的芳基碘化物为3-碘-2-甲氧基吡啶(56.4mg,0.24mmol),其他条件同实施例1,得化合物I-24(无色油状液体,产率62%)。1H NMR(400MHz,CDCl3):δ9.52(dd,J=3.6,2.1Hz,1H),7.87(d,J=5.1Hz,1H),6.62(d,J=5.2Hz,1H),3.93(s,3H),3.22(dd,J=15.5,2.2Hz,1H),2.69(t,J=6.2Hz,2H),2.56(dd,J=15.6,3.6Hz,1H),1.88–1.82(m,1H),1.79–1.69(m,3H),1.42(s,3H);13C NMR(100MHz,CDCl3):δ203.6,161.9,149.0,143.5,124.4,118.8,53.6,53.1,39.2,34.8,30.8,26.6,18.7;HRMS(ESI-TOF):理论计算值:C13H17NNaO2[M+Na+]242.1151,实测值:242.1151。
实施例25:化合物I-25的制备
所用的芳基碘化物为4-碘-喹啉(61.2mg,0.24mmol),其他条件同实施例1,得化合物I-25(无色油状液体,产率65%)。1H NMR(400MHz,CDCl3):δ9.43(dd,J=3.2,2.5Hz,1H),9.05(s,1H),8.24(dd,J=8.9,1.1Hz,1H),7.94(dd,J=8.1,1.5Hz,1H),7.70–7.66(m,1H),7.52(t,J=7.5Hz,1H),3.32(dd,J=16.0,2.5Hz,1H),3.16–3.13(m,2H),2.92(dd,J=16.1,3.3Hz,1H),2.09–2.03(m,1H),1.98–1.88(m,3H),1.76(s,3H);13C NMR(100MHz,CDCl3):δ202.4,151.7,151.6,134.5,130.0,129.6(2C),128.4,125.7,124.7,54.4,41.1,37.0,34.9,28.4,18.7;HRMS(ESI-TOF):理论计算值:C16H18NO[M+H+]240.1383,实测值:240.1386。
实施例26:化合物I-26的制备
所用的芳基碘化物为2,6-二苄氧基-3-碘苯甲酸甲酯(113.8mg,0.24mmol),其他条件同
实施例1,得化合物I-26(淡黄色固体,产率88%)。熔点:120–122℃,1H NMR(400MHz,CDCl3):δ9.49(dd,J=3.5,2.3Hz,1H),7.43–7.29(m,10H),6.48(s,1H),5.10–5.13(m,4H),3.75(s,3H),3.18(dd,J=15.5,2.3Hz,1H),2.74(t,J=6.0Hz,2H),2.46(dd,J=15.5,3.5Hz,1H),1.82–1.70(m,3H),1.68–1.61(m,1H),1.40(s,3H);13C NMR(100MHz,CDCl3):δ204.4,167.6,156.3,154.7,141.8,136.8,128.7,128.6,128.2,127.9,127.6,127.4,127.0,115.8,108.6,75.7,70.5,54.4,52.6,40.1,35.8,32.4,28.7,19.1;HRMS(ESI-TOF):理论计算值:C29H30NaO5[M+Na+]481.1985,实测值:481.1990。
实施例27:化合物I-27的制备
所用的芳基碘化物为2,6-二苄氧基-3-碘苯甲酸甲酯(113.8mg,0.24mmol),烷基溴化物为反式7-溴-4-甲基-3-庚烯-1-醇(41.4mg,0.2mmol),其他条件同实施例1,得化合物I-27(无色油状液体,产率61%)。1H NMR(400MHz,CDCl3):δ9.59(t,J=2.0Hz,1H),7.42–7.31(m,10H),6.46(s,1H),5.07(s,2H),5.04(s,2H),3.73(s,3H),2.71(t,J=5.7Hz,2H),2.41–2.33(m,1H),2.21–2.15(m,2H),1.78–1.61(m,4H),1.51–1.45(m,1H),1.33(s,3H);13CNMR(100MHz,CDCl3):δ203.3,167.7,156.6,154.4,142.1,137.1,136.9,128.6,128.5,128.1,127.9,127.5,127.0,115.8,108.5,75.8,70.5,52.6,40.4,38.5,36.9,32.9,32.6,28.4,19.2;HRMS(ESI-TOF):理论计算值:C30H32NaO5[M+Na+]495.2142,实测值:495.2147。
实施例28:化合物I-28的制备
所用的芳基碘化物为5-苄氧基-6-碘-2,2-二甲基苯并[1,3]二氧-4-酮(98.4mg,0.24mmol),其他条件同实施例1,得化合物I-28(无色油状液体,产率76%)。1H NMR(400MHz,CDCl3):δ9.47(dd,J=3.1,2.1Hz,1H),7.56–7.54(m,2H),7.42–7.33(m,3H),6.49(t,J=1.0Hz,1H),5.16(d,J=10.2Hz,1H),5.02(d,J=10.2Hz,1H),3.27(dd,J=15.9,2.2Hz,1H),2.77(t,J=6.2Hz,2H),2.50(dd,J=15.9,3.1Hz,1H),1.82–1.70(m,8H),1.66–1.60(m,2H),1.41(s,3H);13C NMR(100MHz,CDCl3):δ203.6,160.7,158.9,155.1,149.0,136.4,129.9,128.7(2C),128.5,112.4,105.3,105.1,54.3,39.7,35.9,32.7,28.3,26.1,25.2,18.8;HRMS(ESI-TOF):理论计算值:C24H26NaO5[M+Na+]417.1672,实测值:417.1670。
实施例29:化合物I-29的制备
所用的烷基溴化物为反式6-溴-1-甲氧基-3-甲基-2-己烯(41.4mg,0.2mmol),其他条件同实施例1,得化合物I-29(无色油状液体,顺反异构体的总产率81%,比率为顺式:反式=1:1.8)。化合物I-29反式构型的核磁和质谱数据为:1H NMR(400MHz,CDCl3):δ8.44–8.41(m,1H),7.76–7.72(m,1H),7.59(d,J=9.0Hz,1H),7.39–7.32(m,2H),7.17(d,J=8.4Hz,1H),6.14(d,J=13.0Hz,1H),5.16(d,J=13.0Hz,1H),3.47(s,3H),2.92(t,J=6.2Hz,2H),1.91–1.73(m,4H),1.66(s,3H);13C NMR(100MHz,CDCl3):δ147.5,138.0,135.5,133.7,132.1,128.8,128.5,128.1,127.0,124.4,124.2,115.4,56.2,44.2,38.2,32.5,28.8,18.7;HRMS(ESI-TOF):理论计算值:C18H20NaO[M+Na+]275.1406,实测值:275.1411.化合物I-29顺式构型的核磁和质谱数据为:1H NMR(400MHz,CDCl3):δ8.49–8.46(m,1H),7.77–7.74(m,1H),7.57(d,J=8.3Hz,1H),7.41–7.33(m,2H),7.16(d,J=8.3Hz,1H),5.76(d,J=6.8Hz,1H),4.81(d,J=6.8Hz,1H),3.43(s,3H),3.01–2.85(m,2H),2.12–1.99(m,2H),1.88–1.80(m,2H),1.79(s,3H);13C NMR(100MHz,CDCl3):δ144.1,140.3,134.2,133.6,131.9,128.9,128.6,127.3,126.4,124.2,124.1,118.8,59.7,40.7,38.7,32.4,28.5,19.3;HRMS(ESI-TOF):理论计算值:C18H20NaO[M+Na+]275.1406,实测值:275.1411。
实施例30:化合物I-30的制备
所用的烷基溴化物为反式7-溴-4-甲基-3-庚烯-2-醇(41.4mg,0.2mmol),其他条件同实施例1,得化合物I-30(无色油状液体,产率71%)。1H NMR(400MHz,CDCl3):δ8.35(d,J=8.8Hz,1H),7.80(dd,J=8.1,1.6Hz,1H),7.60(d,J=8.3Hz,1H),7.49–7.45(m,1H),7.41–7.37(m,1H),7.18(d,J=8.4Hz,1H),3.45(d,J=15.4Hz,1H),3.10(d,J=15.4Hz,1H),3.01–2.89(m,2H),2.20–2.15(m,1H),1.88–1.80(m,3H),1.85(s,3H),1.78(s,3H);13CNMR(100MHz,CDCl3):δ208.6,137.8,136.1,133.9,131.9,129.8,128.9,127.2,125.8,125.1,124.2,54.4,40.7,37.8,32.9,32.0,28.7,19.0;HRMS(ESI-TOF):理论计算值:C18H20NaO[M+Na+]275.1406,实测值:275.1409。
实施例31:化合物I-31的制备
所用的烷基溴化物为反式10-溴-7-甲基-6-癸烯-5-醇(49.8mg,0.2mmol),其他条件同实施例1,得化合物I-31(无色油状液体,产率45%)。1H NMR(400MHz,CDCl3):δ8.35(d,J=8.7Hz,1H),7.79(dd,J=8.0,1.6Hz,1H),7.59(d,J=8.3Hz,1H),7.48–7.43(m,1H),7.40–7.36(m,1H),7.18(d,J=8.3Hz,1H),3.39(d,J=15.7Hz,1H),3.10(d,J=15.7Hz,1H),3.01–2.88(m,2H),2.22–2.08(m,3H),1.87–1.77(m,3H),1.77(s,3H),1.38–1.31(m,2H),1.14–1.04(m,2H),0.77(t,J=7.3Hz,3H);13C NMR(100MHz,CDCl3):δ210.7,138.0,136.0,133.9,131.8,129.8,128.9,127.1,125.9,125.0,124.1,53.3,44.4,40.7,37.8,32.9,28.6,25.7,22.3,19.0,13.9;HRMS(ESI-TOF):理论计算值:C21H26NaO[M+Na+]317.1876,实测值:317.1879。
实施例32:化合物I-32的制备
所用的烷基溴化物为反式9-溴-6-甲基壬烷-1,5-二烯-4-醇(46.6mg,0.2mmol),其他条件同实施例1,得化合物I-31(无色油状液体,产率53%)。1H NMR(400MHz,CDCl3):δ8.41(d,J=8.7Hz,1H),7.80(dd,J=8.0,1.6Hz,1H),7.60(d,J=8.3Hz,1H),7.49–7.44(m,1H),7.40–7.36(m,1H),7.18(d,J=8.4Hz,1H),6.76–6.67(m,1H),5.98(dd,J=15.5,1.7Hz,1H),3.32(s,2H),3.00–2.89(m,2H),2.19–2.14(m,1H),1.86–1.77(m,9H);13C NMR(100MHz,CDCl3):δ199.8,142.1,138.5,135.8,133.9,133.1,131.8,129.7,128.8,127.2,126.1,125.0,124.1,50.4,40.6,38.0,32.9,28.5,18.9,18.3;HRMS(ESI-TOF):理论计算值:C20H22NaO[M+Na+]301.1563,实测值:301.1564。
实施例33:化合物I-33的制备
所用的烷基溴化物为反式6-溴-3-乙基-2-己烯-1-醇(41.4mg,0.2mmol),其他条件同实施例1,得化合物I-33(无色油状液体,产率72%)。1H NMR(400MHz,CDCl3)δ9.42(dd,J=3.7,2.4Hz,1H),8.30(d,J=8.2Hz,1H),7.80(dd,J=8.0,1.6Hz,1H),7.62(d,J=8.3Hz,1H),7.49–7.45(m,1H),7.42–7.38(m,1H),7.19(d,J=8.3Hz,1H),3.42(dd,J=15.7,2.5Hz,1H),2.96(t,J=6.3Hz,2H),2.84(dd,J=15.7,3.7Hz,1H),2.45–2.36(m,1H),2.21–2.09(m,2H),1.94–1.78(m,3H),0.78(t,J=7.5Hz,3H);13C NMR(100MHz,CDCl3)δ203.8,137.2,135.4,133.8,132.0,129.9,128.8,127.7,125.6,125.3,124.4,53.2,40.8,37.5,32.8,32.7,18.8,8.9;HRMS(ESI-TOF):理论计算值:C18H20NaO[M+Na+]275.1406,实测值:275.1414。
实施例34:化合物I-34的制备
所用的烷基溴化物为反式6-溴-3-苯基-2-己烯-1-醇(41.4mg,0.2mmol),其他条件同实施例1,得化合物I-34(无色油状液体,产率67%)。1H NMR(400MHz,CDCl3)δ8.98(dd,J=3.8,1.8Hz,1H),7.78(dd,J=8.1,1.4Hz,1H),7.71(d,J=8.4Hz,1H),7.39–7.14(m,9H),3.82(dd,J=15.3,1.8Hz,1H),3.26(dd,J=15.3,3.8Hz,1H),3.11–2.98(m,2H),2.25–2.18(m,1H),2.14–2.09(m,1H),1.80–1.71(m,2H);13C NMR(100MHz,CDCl3)δ202.9,149.3,138.2,133.9,133.4,131.3,129.2,128.6,128.4,128.1,127.0,126.2,125.4,124.6,53.5,45.0,44.0,32.3,18.1;HRMS(ESI-TOF):理论计算值:C22H20NaO[M+Na+]323.1406,实测值:323.1406。
实施例35:化合物I-35的制备
所用的烷基溴化物为反式6-溴-2-己烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-35(无色油状液体,产率81%)。1H NMR(400MHz,CDCl3)δ9.92(dd,J=2.0,0.9Hz,1H),7.88(d,J=8.4Hz,1H),7.82(dd,J=8.1,1.4Hz,1H),7.64(d,J=8.3Hz,1H),7.53–7.49(m,1H),7.46–7.42(m,1H),7.20(d,J=8.4Hz,1H),4.25–4.20(m,1H),2.96–2.93(m,2H),2.89–2.81(m,2H),1.99–1.86(m,4H);13C NMR(100MHz,CDCl3)δ201.9,134.5,133.5,132.7,131.3,129.1,128.3,126.7,126.4,124.9,122.4,49.7,30.0,27.4,27.2,17.7;HRMS(ESI-TOF):理论计算值:C16H16NaO[M+Na+]247.1093,实测值:247.1094。
实施例36:化合物I-36的制备
所用的烷基溴化物为反式6-溴-3-甲基-2-己烯-1,5-二醇(41.8mg,0.2mmol),其他条件同实施例1,得化合物I-36(无色油状液体,产率47%)。1H NMR(400MHz,CDCl3):δ9.76(t,J=3.0Hz,1H),8.33(d,J=8.7Hz,1H),7.83(d,J=8.0,1H),7.68(d,J=8.4Hz,1H),7.52–7.48(m,1H),7.45–7.41(m,1H),7.19(d,J=8.4Hz,1H),4.28–4.21(m,1H),3.26–3.22(m,2H),3.14(dd,J=15.6,2.7Hz,1H),2.99(dd,J=16.2,9.5Hz,1H),2.34(dt,J=13.2,2.8Hz,1H),1.94–1.90(m,1H),1.88(s,3H);13C NMR(100MHz,CDCl3):δ202.8,136.3,134.3,132.8,131.2,129.9,128.7,128.5,125.9,125.7,124.8,63.8,53.7,50.0,41.6,39.4,30.2;HRMS(ESI-TOF):理论计算值:C17H18NaO2[M+Na+]277.1199,实测值:277.1206。
实施例37:化合物I-37的制备
所用的烷基溴化物为反式7-溴-2-庚烯-1-醇(38.6mg,0.2mmol),其他条件同实施例1,得化合物I-37(无色油状液体,产率76%)。1H NMR(400MHz,CDCl3)δ9.80(dd,J=2.7,1.3Hz,1H),8.18(d,J=8.7Hz,1H),7.81(dd,J=8.1,1.4Hz,1H),7.64(d,J=8.3Hz,1H),7.52–7.48(m,1H),7.44–7.40(m,1H),7.25–7.22(m,1H),4.71–4.65(m,1H),3.20–3.07(m,2H),2.90–2.80(m,2H),2.06–1.96(m,2H),1.90–1.77(m,3H),1.56–1.53(m,1H);13C NMR(100MHz,CDCl3)δ202.1,139.6,138.1,132.9,131.9,130.2,129.0,127.3,126.5,124.8,123.0,46.4,36.3,32.3,30.5,27.6,25.1;HRMS(ESI-TOF):理论计算值:C17H18NaO[M+Na+]261.1250,实测值:261.1255。
实施例38:化合物I-38的制备
所用的烷基溴化物为反式3-(3-溴丙烷)-2-丙烯-1-醇(39mg,0.2mmol),其他条件同实施例1,得化合物I-38(无色油状液体,产率21%)。1H NMR(400MHz,CDCl3):δ9.99(dd,J=2.8,1.6Hz,1H),7.86–7.83(m,2H),7.73(d,J=8.3Hz,1H),7.54–7.50(m,1H),7.47–7.43(m,1H),7.24(d,J=8.4Hz,1H),6.22(dd,J=9.7,2.5Hz,1H),4.03–3.98(m,1H),3.66–3.58(m,2H),3.16–3.10(m,1H),2.87–2.83(m,1H),2.65–2.60(m,1H),2.28–2.18(m,1H),1.83–1.74(m,1H).13C NMR(100MHz,CDCl3)δ201.3,136.0,133.0,132.5,130.4,129.6,129.2,128.6,126.8,125.1,122.1,77.0,64.4,49.8,30.3,28.5;HRMS(ESI-TOF):理论计算值:C16H16NaO2[M+Na+]263.1043,实测值:263.1039。
实施例39:化合物I-39的制备
所用的烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-39(无色油状液体,产率56%)。1H NMR(600MHz,CDCl3):δ9.60(t,J=3.0Hz,1H),8.08(d,J=8.5Hz,1H),7.88(d,J=8.2Hz,1H),7.72(d,J=8.2Hz,1H),7.50(t,J=7.5Hz,1H),7.43(t,J=7.6Hz,1H),7.35(d,J=8.2Hz,1H),3.10–3.02(m,3H),2.95(dd,J=15.1,3.5Hz,1H),2.39–2.35(m,1H),2.19–2.14(m,1H),1.70(s,3H);13C NMR(100MHz,CDCl3):δ203.3,142.1,141.2,133.9,129.8,129.7,128.7,126.2,124.7,123.7,123.2,53.9,48.0,40.1,30.9,27.8;HRMS(ESI-TOF):理论计算值:C16H16NaO[M+Na+]247.1093,实测值:247.1096。
实施例40:化合物I-40的制备
所用的烷基溴化物为反式6-溴-4-甲基-3-己烯-1-醇(38.6mg,0.2mmol),其他条件同实施例1,得化合物I-40(无色油状液体,产率60%)。1H NMR(400MHz,CDCl3):δ9.64(t,J=1.4Hz,1H),8.07(d,J=8.3Hz,1H),7.86(d,J=7.9Hz,1H),7.70(d,J=8.2Hz,1H),7.48–7.39(m,2H),7.34(d,J=8.2Hz,1H),3.10–2.96(m,2H),2.48–2.41(m,2H),2.27–2.13(m,3H),2.05–1.98(m,1H),1.61(s,3H);13C NMR(100MHz,CDCl3):δ202.7,142.4,141.6,133.7,130.3,129.5,128.3,126.0,124.6,123.7,123.2,49.4,40.6,39.3,33.2,31.1,28.1;HRMS(ESI-TOF):理论计算值:C17H18NaO[M+Na+]261.1250,实测值:261.1256。
实施例41:化合物I-41的制备
所用的芳基碘化物为2-甲基碘苯(52.3mg,0.24mmol),烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-41(无色油状液体,产率46%)。1H NMR(400MHz,CDCl3):δ9.67(t,J=3.0Hz,1H),7.11–7.05(m,2H),6.95(d,J=7.0Hz,1H),2.97–2.83(m,2H),2.82–2.71(m,2H),2.39(s,3H),2.24–2.17(m,1H),2.03–1.96(m,1H),1.46(s,3H);13C NMR(100MHz,CDCl3):δ203.3,146.0,143.5,133.5,129.7,127.4,122.9,52.9,47.2,39.8,30.2,26.2,19.7;HRMS(ESI-TOF):理论计算值:C13H16NaO[M+Na+]211.1093,实测值:211.1098。
实施例42:化合物I-42的制备
所用的芳基碘化物为2-乙基碘苯(55.7mg,0.24mmol),烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-42(无色油状液体,产率50%)。1H NMR(400MHz,CDCl3):δ9.67(t,J=3.0Hz,1H),7.18–7.04(m,1H),7.07–7.04(m,2H),2.97–2.84(m,2H),2.82–2.68(m,4H),2.23–2.17(m,1H),2.04–1.96(m,1H),1.50(s,3H),1.27(t,J=7.5Hz,3H);13C NMR(100MHz,CDCl3):δ203.3,145.5,143.6,140.1,127.6,127.5,122.6,53.7,47.3,40.0,30.2,27.2,25.0,15.6;HRMS(ESI-TOF):理论计算值:C14H18NaO[M+Na+]225.1250,实测值:225.1252。
实施例43:化合物I-43的制备
所用的芳基碘化物为2-氟碘苯(53.3mg,0.24mmol),烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-43(无色油状液体,产率50%)。1H NMR(400MHz,CDCl3):δ9.71(t,J=3.0Hz,1H),7.18–7.13(m,1H),6.99(d,J=7.4Hz,1H),6.84(t,J=9.5Hz,1H),3.04–2.89(m,2H),2.86–2.78(m,2H),2.21–2.13(m,1H),2.08–2.00(m,1H),1.47(s,3H);13C NMR(100MHz,CDCl3):δ202.8,159.7(d,J=245.2Hz),146.4(d,J=6.1Hz),134.6(d,J=14.6Hz),129.3(d,J=7.6Hz),120.8(d,J=3.3Hz),113.9(d,J=21.2Hz),53.3(d,J=2.1Hz),46.1(d,J=2.4Hz),39.3,31.0(d,J=1.6Hz),26.5(d,J=1.7Hz);19F NMR(377MHz,CDCl3):δ–121.1;HRMS(ESI-TOF):理论计算值:C12H13FNaO[M+Na+]215.0843,实测值:215.0854。
实施例44:化合物I-44的制备
所用的芳基碘化物为2-氯碘苯(57.2mg,0.24mmol),烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-44(无色油状液体,产率42%)。1H NMR(400MHz,CDCl3):δ9.66(dd,J=3.3,2.1Hz,1H),7.15–7.10(m,3H),3.09(dd,J=15.6,2.1Hz,1H),3.00–2.89(m,2H),2.85(dd,J=15.6,3.3Hz,1H),2.23–2.16(m,1H),2.05–1.98(m,1H),1.49(s,3H);13C NMR(100MHz,CDCl3):δ202.8,146.0,144.5,130.5,128.8,128.5,123.7,52.4,47.7,39.2,30.4,25.8;HRMS(ESI-TOF):理论计算值:C12H13ClNaO[M+Na+]231.0547,实测值:231.0555。
实施例45:化合物I-45的制备
所用的芳基碘化物为2-甲氧基碘苯(56.2mg,0.24mmol),烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-45(无色油状液体,产率45%)。1H NMR(400MHz,CDCl3):δ9.65(dd,J=3.8,2.2Hz,1H),7.18–7.13(m,1H),6.82(d,J=8.0Hz,1H),6.69(d,J=8.1Hz,1H),3.81(s,3H),2.99–2.83(m,3H),2.75(dd,J=15.0,3.8Hz,1H),2.13–2.06(m,1H),2.01–1.94(m,1H),1.43(s,3H);13C NMR(100MHz,CDCl3):δ204.4,156.4,145.1,135.3,128.8,117.5,108.8,55.1,53.1,46.4,39.6,30.6,26.0;HRMS(ESI-TOF):理论计算值:C13H16NaO[M+Na+]227.1043,实测值:227.1049。
实施例46:化合物I-46的制备
所用的芳基碘化物为2,6-二苄氧基-3-碘苯甲酸甲酯(113.8mg,0.24mmol),烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-46(无色油状液体,产率55%)。1H NMR(400MHz,CDCl3):δ9.61(dd,J=3.4,2.2Hz,1H),7.44–7.33(m,10H),6.62(s,1H),5.10–5.04(m,4H),3.82(s,3H),2.96–2.81(m,2H),2.79–2.65(m,2H),2.13–2.05(m,1H),1.99–1.93(m,1H),1.39(s,3H);13C NMR(100MHz,CDCl3):δ203.6,167.7,156.9,153.4,147.6,136.8(2C),132.7,128.7,128.6,128.3,127.9,127.8,126.9,116.0,104.8,76.1,70.8,53.3,52.7,46.3,39.4,31.2,27.1;HRMS(ESI-TOF):理论计算值:C28H28NaO5[M+Na+]467.1829,实测值:467.1834。
实施例47:化合物I-47的制备
所用的芳基碘化物为5-苄氧基-6-碘-2,2-二甲基苯并[1,3]二氧-4-酮(98.4mg,0.24mmol),烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg,0.2mmol),其他条件同实施例1,得化合物I-47(无色油状液体,产率55%)。1H NMR(400MHz,CDCl3):δ9.57(dd,J=3.0,2.1Hz,1H),7.53–7.50(m,2H),7.41–7.34(m,3H),6.58(s,1H),5.18(d,J=10.3Hz,1H),5.02(d,J=10.4Hz,1H),2.93–2.86(m,2H),2.81–2.67(m,2H),2.12–2.04(m,1H),1.98–1.91(m,1H),1.74(s,6H),1.36(s,3H);13C NMR(100MHz,CDCl3):δ202.9,159.0,157.6,157.5,154.6,136.6,135.2,128.9,128.7,128.5,108.7,105.3,105.2,53.2,46.3,38.8,31.4,26.9,25.9,25.4;HRMS(ESI-TOF):理论计算值:C23H24NaO5[M+Na+]403.1516,实测值:403.1518。
实施例48:化合物D的制备
向干燥并装有磁力搅拌子的反应管中加入甲胺盐酸盐(40.1mg,0.59mmol)、氰基硼氢化钠(14.9mg,0.24mmol)和甲醇(0.5mL),搅拌下缓慢加入化合物I-22(35mg,0.12mmol)的甲醇(2.0mL)溶液,然后于室温下搅拌12小时。加入饱和的碳酸氢钠溶液,二氯甲烷萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压除去溶剂,柱层析提纯得化合物D(白色固体,产率94%),熔点188–190℃。1H NMR(400MHz,CDCl3):δ9.39(s,1H),7.46–7.44(m,2H),7.37–7.33(m,2H),7.30–7.27(m,1H),6.95(d,J=8.4Hz,1H),6.86(d,J=2.6Hz,1H),6.74(dd,J=8.4,2.6Hz,1H),5.08(m,2H),2.83(td,J=12.4,4.3Hz,1H),2.68–2.56(m,3H),2.51(s,3H),2.34(td,J=12.9,4.5Hz,1H),2.04(td,J=12.8,4.3Hz,1H),1.77–1.65(m,3H),1.61–1.55(m,1H),1.26(s,3H).13C NMR(100MHz,CDCl3):δ157.3,143.1,137.4,130.4,129.4,128.6,127.9,127.7,113.3,112.3,70.0,46.0,38.3,36.5,35.4,32.7,31.2,29.7,19.6.HRMS(ESI-TOF):理论计算值:C21H28NO[M+H+]310.2165,实测值:310.2167。
实施例49:化合物E的制备
向装有磁力搅拌子的反应管中加入化合物D(44mg,0.142mmol)和冰醋酸(3mL),搅拌下缓慢加入三氧化铬(35.5mg,0.355mmol)的水/冰醋酸(1/4,1mL)溶液,然后于室温搅拌2小时。化合物D消失后,向反应体系中加入甲醇(0.5mL),在室温下继续搅拌一小时。然后加入质量分数为37%的甲醛水溶液(0.155mmol),反应体系升温至55℃,并在此温度下搅拌16小时。反应结束后恢复至室温,减压除去醋酸,粗产物加入水(3mL),然后用10%的氢氧化钠水溶液中和至碱性,乙醚萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压除去溶剂,柱层析提纯得化合物E(白色固体,产率71%),熔点175–177℃。1H NMR(400MHz,CDCl3):δ8.02(d,J=8.5Hz,1H),7.43–7.32(m,5H),6.96–6.92(m,2H),5.11(s,2H),3.54(dd,J=12.7,8.4Hz,1H),3.13(d,J=12.7Hz,1H),2.87–2.82(m,1H),2.70–2.60(m,2H),2.56(s,3H),2.52–2.36(m,2H),2.27–2.21(m,1H),1.68–1.63(m,1H),1.48(s,3H);13C NMR(100MHz,CDCl3):δ199.1,164.0,152.6,135.9,130.1,128.8,128.5,127.7,125.8,113.5,111.5,70.3,60.5,53.2,47.0,44.0,42.3,36.2,36.0,29.9;HRMS(ESI-TOF):理论计算值:C22H26NO2[M+H+]336.1958,实测值:336.1961。
实施例50:化合物(±)-eptazocine的制备
向装有磁力搅拌子的反应瓶中加入化合物E(30mg,0.09mmol)、钯/碳(9mg)、70%的高氯酸(2μL)和乙醇(2mL),然后于40atm的氢气压力下65℃反应24小时。过滤除去钯/碳,减压蒸馏除去溶剂,粗产物加入水(3mL),然后用10%的氢氧化钠水溶液中和至中性,乙醚萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压除去溶剂,柱层析提纯得化合物(±)-eptazocine(无色油状液体,产率90%)。1H NMR(600MHz,Methanol-d4):δ6.88(d,J=8.2Hz,1H),6.69(d,J=2.5Hz,1H),6.56(dd,J=8.3,2.5Hz,1H),3.08(t,J=12.1Hz,1H),2.77(dd,J=15.4,4.4Hz,1H),2.67(d,J=13.1Hz,1H),2.45(td,J=8.0,4.4Hz,1H),2.36(d,J=15.4Hz,1H),2.24(s,3H),2.21(dd,J=13.8,3.3Hz,1H),1.86(dd,J=13.5,7.2Hz,1H),1.80–1.68(m,4H),1.23(s,3H);13C NMR(100MHz,Methanol-d4):δ156.8,145.4,132.2,127.4,114.4,113.6,64.9,60.1,46.5,41.6,37.8,37.3,33.9,30.8;HRMS(ESI-TOF):理论计算值:C15H22NO[M+H+]232.1696,实测值:232.1697。
实施例51:化合物氢溴酸依他佐辛的制备
向装有磁力搅拌子的反应管中加入化合物(±)-eptazocine(18mg,0.08mmol)和40%的氢溴酸溶液(1mL),室温下搅拌10分钟,减压蒸馏除去溶剂,即可得化合物氢溴酸依他佐辛(白色固体,产率91%),熔点267–269℃。1H NMR(400MHz,Methanol-d4):δ6.97(d,J=8.3Hz,1H),6.75(d,J=2.6Hz,1H),6.64(dd,J=8.3,2.5Hz,1H),3.71–3.63(m,1H),3.37–3.30(m,1H),2.92–2.87(m,1H),2.82(s,3H),2.73–2.62(m,3H),2.51(d,J=16.2Hz,1H),2.17–2.11(m,1H),2.10–2.05(m,1H),1.99–1.92(m,2H),1.34(s,3H);13C NMR(100MHz,Methanol-d4):δ157.7,143.4,132.7,125.8,115.5,113.6,63.6,59.8,47.6,43.4,40.8,37.2,36.4,33.1,28.7。
Claims (9)
1.具有通式I所示结构的化合物:
其中:
R1为与环L并环的芳环、杂芳环或取代环L上氢的取代基,取代基为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种或几种;n表示R1的个数,0≤n≤4;
R2选自氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种;
R3为m表示-CH2-的个数,0≤m≤10,
R3a选自氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种;
R3b选自芳基、杂环芳基、烷基中的一种;
R4为取代或未取代的C0-10碳链,取代基为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种或几种;
Y1为N或CH;
Y2为-O-、-NH-或-CH2-;
式I中的L、T用于描述不同位置的环,不表示任何化学含义。
2.一种合成权利要求1中通式I所示化合物的方法,其特征在于,包括以下步骤:在惰性气体保护下,将式II所示芳香碘代物、(i)式III所示烷基卤化物或(ii)式IV所示烷基卤化物、钯催化剂、膦配体、碱、式V所示降冰片烯衍生物于30~120℃的有机溶剂中搅拌反应,反应结束后分离提纯,分别得到(i)式I-a或(ii)式I-b所示的化合物;
其中:k表示-CH2-的个数,1≤k≤10;R1、R2、R3a、R3b、R4、Y1、Y2、m、n具有与权利要求1中所限定的相同的含义;
式V中:
R6为五元环上的取代基,e代表取代基个数,1≤e≤8;
R6独立地选自金属离子M的羧酸盐、酯基、氰基、硝基、酰胺基、磺酰基、C1-10烷氧基、芳基、杂环芳基、C1-10烷基、卤素中的一种,M为Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+中的一种;e≥2时,各R6相同或不同。
3.根据权利要求2所述的方法,其特征在于:所述的钯催化剂为Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2中的一种,所述的膦配体为三苯基膦、三环己基膦、二环己基(2',4',6'-三异丙基-[1,1'-二苯基]-2-基)膦、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-二苯基]-2-基)膦、二环己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦、2'-(二环己基膦基)-N,N-二甲基-[1,1'-二苯基]-2-胺、二环己基(2',6'-二异丙氧基-[1,1'-二苯基]-2-基)膦、三(呋喃-2-基)膦、(3S,5S,7S)-金刚烷-1-基((1R,5S)-金刚烷-2-基)(丁基)膦中的一种,所述的碱为碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠中的一种或几种。
4.根据权利要求2或3所述的方法,其特征在于:式II所示芳香碘代物与(i)式III所示烷基卤化物或(ii)式IV所示烷基卤化物的投料摩尔比为(1~10):1。
5.一种由权利要求1所述的通式I所示化合物制备氢溴酸依他佐辛的方法,其特征在于,包括以下步骤:
(1)将具有通式I所示结构的化合物A中的醛基通过还原胺化的方法转化成二级胺,制得化合物B;
(2)将化合物B的苄位氧化成羰基,然后与甲醛发生Mannich反应,制得化合物C;
(3)化合物C在还原剂的作用下羰基被还原成亚甲基,同时脱掉氧上的保护基,制得依他佐辛;
(4)依他佐辛在氢溴酸的作用下制得依他佐辛的氢溴酸盐。
其中,R为烷基、芳基、硅基、苄基中的一种。
6.如权利要求5所述的方法,其特征在于:步骤(1)具体为:将化合物A、甲胺和还原剂溶于有机溶剂,搅拌反应,即可;所述的还原剂为硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠中的一种或几种,甲胺的用量为化合物A摩尔量的1~10倍,还原剂的用量为化合物A摩尔量的1~5倍,反应温度为0~50℃。
7.如权利要求5所述的方法,其特征在于:步骤(2)具体为:将化合物B和氧化剂于溶剂中搅拌反应,然后加入甲醛,继续搅拌进行Mannich反应,即可;所述的氧化剂为二氧化锡、二氧化锰、三氧化铬、高锰酸钾中的一种或几种,所述的氧化剂的用量为化合物B摩尔量的1~5倍,溶剂为二氯甲烷、1,2-二氯乙烷、四氢呋喃、1,4-二氧六环、丙酮、醋酸、水中的一种或多种,苄位氧化成羰基的反应温度为0~40℃,所述的甲醛的用量为化合物B摩尔量的1~5倍,Mannich反应的温度为40~100℃。
8.如权利要求5所述的方法,其特征在于:步骤(3)具体为:将化合物C、还原剂和催化量的酸于有机溶剂中混合,氢气氛围下搅拌反应,即可;其中,所述的还原剂为钯/碳、氢氧化钯/碳中的一种,还原剂的用量为化合物C的质量的5%~100%倍,反应温度为50~100℃。
9.如权利要求5所述的方法,其特征在于:步骤(4)具体为:将化合物依他佐辛与氢溴酸搅拌反应,即可;其中,氢溴酸百分比浓度为10%~48%,反应时间为10~60分钟,反应温度为0~40℃。
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CN112574107A (zh) * | 2020-12-18 | 2021-03-30 | 浙江工业大学 | 一种阻转异构1-芳基异喹啉n-氧化物及其衍生物的合成方法 |
CN112574107B (zh) * | 2020-12-18 | 2023-04-07 | 浙江工业大学 | 一种阻转异构1-芳基异喹啉n-氧化物及其衍生物的合成方法 |
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