CN105732246B - It is a kind of to apply PdCl2(PPh3)2The method for synthesizing medicine intermediate phenanthrene compound - Google Patents
It is a kind of to apply PdCl2(PPh3)2The method for synthesizing medicine intermediate phenanthrene compound Download PDFInfo
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- CN105732246B CN105732246B CN201610216344.5A CN201610216344A CN105732246B CN 105732246 B CN105732246 B CN 105732246B CN 201610216344 A CN201610216344 A CN 201610216344A CN 105732246 B CN105732246 B CN 105732246B
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- phenanthrene
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- -1 phenanthrene compound Chemical class 0.000 title claims abstract description 29
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 19
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 title abstract description 12
- 239000003814 drug Substances 0.000 title description 11
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 title description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 title description 2
- 230000002194 synthesizing effect Effects 0.000 title description 2
- 229910002666 PdCl2 Inorganic materials 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 23
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- 239000003513 alkali Substances 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
- 239000013110 organic ligand Substances 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims abstract description 4
- 239000012298 atmosphere Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- FGOSNANIQLJNSZ-UHFFFAOYSA-N acetonitrile copper Chemical compound [Cu].CC#N.CC#N.CC#N.CC#N FGOSNANIQLJNSZ-UHFFFAOYSA-N 0.000 claims description 13
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 10
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 7
- ZYWUVGFIXPNBDL-UHFFFAOYSA-N n,n-diisopropylaminoethanol Chemical compound CC(C)N(C(C)C)CCO ZYWUVGFIXPNBDL-UHFFFAOYSA-N 0.000 claims description 6
- 150000002941 palladium compounds Chemical class 0.000 claims description 6
- WWVMHGUBIOZASN-UHFFFAOYSA-N 1-methyl-3-prop-2-enylimidazol-1-ium Chemical compound CN1C=C[N+](CC=C)=C1 WWVMHGUBIOZASN-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 2
- 101150003085 Pdcl gene Proteins 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 15
- 238000011835 investigation Methods 0.000 description 12
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000002131 composite material Substances 0.000 description 8
- 239000010949 copper Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000003446 ligand Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 230000010355 oscillation Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 235000010290 biphenyl Nutrition 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 150000002987 phenanthrenes Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 239000005749 Copper compound Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 150000001880 copper compounds Chemical class 0.000 description 3
- 229940031098 ethanolamine Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- PBIDWHVVZCGMAR-UHFFFAOYSA-N 1-methyl-3-prop-2-enyl-2h-imidazole Chemical compound CN1CN(CC=C)C=C1 PBIDWHVVZCGMAR-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- QNZRVYCYEMYQMD-UHFFFAOYSA-N copper;pentane-2,4-dione Chemical compound [Cu].CC(=O)CC(C)=O QNZRVYCYEMYQMD-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- RRHPTXZOMDSKRS-PHFPKPIQSA-L (1z,5z)-cycloocta-1,5-diene;dichloropalladium Chemical compound Cl[Pd]Cl.C\1C\C=C/CC\C=C/1 RRHPTXZOMDSKRS-PHFPKPIQSA-L 0.000 description 1
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- LCRCBXLHWTVPEQ-UHFFFAOYSA-N 2-phenylbenzaldehyde Chemical group O=CC1=CC=CC=C1C1=CC=CC=C1 LCRCBXLHWTVPEQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JNBBGHWQDWSEFZ-UHFFFAOYSA-N C1=CC=C(C=C1)C2=CC3=CC=CC=C3C4=C2C(=CC=C4)Cl Chemical compound C1=CC=C(C=C1)C2=CC3=CC=CC=C3C4=C2C(=CC=C4)Cl JNBBGHWQDWSEFZ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical class C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 238000010729 [4+2] benzannulation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 150000004074 biphenyls Chemical class 0.000 description 1
- 229910052796 boron Inorganic materials 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(II) bromide Substances [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- ZKXWKVVCCTZOLD-FDGPNNRMSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O ZKXWKVVCCTZOLD-FDGPNNRMSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 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 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- HNHHBKDPQPDTMD-UHFFFAOYSA-N furan thiophene Chemical compound O1C=CC=C1.O1C=CC=C1.S1C=CC=C1.S1C=CC=C1 HNHHBKDPQPDTMD-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/10—Cyclisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
- C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
- C07C17/266—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of hydrocarbons and halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2/00—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms
- C07C2/86—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon
- C07C2/861—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by condensation between a hydrocarbon and a non-hydrocarbon the non-hydrocarbon contains only halogen as hetero-atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
Abstract
PdCl is applied the present invention relates to a kind of2(PPh3)2The method of phenanthrene compound shown in the lower formula (I) of synthesis,The method includes：Under inert atmosphere, containing PdCl2(PPh3)2Catalyst, in the presence of organic ligand and alkali, in solvent, lower formula (II) compound reacts with formula (III) compound, to obtain formula (I) compound；Wherein, R1、R2It is each independently H, C1‑C6Alkyl, C1‑C6Alkoxy or halogen；R3 is C6‑C10Aryl or C5‑C8Heteroaryl, the C6‑C10Aryl or C4‑C8Heteroaryl is optionally replaced by 13 substituent groups, and the substituent group is C1‑C6Alkyl or halogen.The method achieves good effect by the selection of suitable catalyst, organic ligand, alkali and solvent, has extensive prospects for commercial application.
Description
The present patent application is that application No. is 201510100568.5, (a kind of medicine intermediate is luxuriant and rich with fragrance filed in 6 days March in 2015
The synthetic method of class compound) patent application divisional application.
Technical field
The present invention relates to a kind of synthetic methods of fused ring compound, relate more specifically to a kind of medicine intermediate phenanthrene compound
Synthetic method, belong to organic synthesis and medicine intermediate synthesis field.
Background technology
The compounds such as fused ring compound such as naphthalene, anthracene, phenanthrene are researched and developed people due to the bioactivity of its generally existing by medicine
The attention and concern of member.Wherein, luxuriant and rich with fragrance and its derivative is a kind of important phenolic compound, has been widely used in medicine
Object designs and synthesis, material development field.
Just because of the such excellent in performance and potentiality of phenanthrene compound, thus study luxuriant and rich with fragrance and its derivative novel synthesis side
Method also be always organic chemical synthesis worker hot issue very deeply concerned.
Up to the present, the preparation process for having existed a variety of phenanthrene compounds in the prior art, from multiple angle researchs
The synthetic method that phenanthrene compound is suitble to.Such as：
(" Phenanthrene Synthesis by the Eosin Y-Catalyzed, Visible such as Xiao Tiebo
Light-Induced [4+2] Benzannulation of Biaryldiazonium Salts with Alkynes ",
Adv.Synth.Catal., 2012,354,3195-3199) report a kind of no metal catalytic, visible light-inducing diaryl
[4+2] benzo cyclization of diazo salt.Its equation is as follows：
(" the Expeditious Synthesis of Phenanthrenes via CuBr2-Catalyzed such as Ye Fei
Coupling of Terminal Alkynes and N-Tosylhydrazones Derived from O-Fo rmyl
Biphenyls ", Organic Letters, 2011,13,5020-5023) disclose a kind of coupling/ring of benzyl CuBr2 catalysis
Change reaction, the N- Tosylhydrazones derived from adjacent formyl biphenyl are raw material, and reaction equation is as follows：
(" Expedient Synthesis of Phenanthrenes via In (the III)-C such as Kwon Yongseok
Atalyzed 6-Exo-DigCycloisomerization ", Organic Letters, 2013,15,920-923) it reports
A kind of reaction for preparing phenanthrene compound of In (III) catalysis, has the advantages that react efficient, wide application range of substrates, anti-
Answer formula as follows：
As described above, although having been disclosed for the preparation method of various types of phenanthrene compounds in the prior art, these
Method still cannot meet medical, chemical industry synthesis field production requirement, this is because its intrinsic low production efficiency, raw material are not
It the problems such as can make full use of.
In view of this, the present inventor studies and has been intended to provide a kind of new catalytic of phenanthrene compound through a large number of experiments
Synthetic method has reached high income, willing purpose, has very extensive prospects for commercial application.
Invention content
For above-mentioned many defects, the present inventor is after having paid a large amount of creative work, by deeply grinding
Study carefully, and develop a kind of synthetic method for the phenanthrene compound can be used as pharmaceutical intermediate, and then completes the present invention.
Specifically, the present invention provides a kind of synthetic method of phenanthrene compound shown in lower formula (I),
The method includes：Under inert atmosphere, in the presence of catalyst, organic ligand and alkali, in solvent, lower formula (II)
Compound reacts with formula (III) compound, to obtain formula (I) compound；
Wherein, R1、R2It is each independently H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
R3For C6-C10Aryl or C5-C8Heteroaryl, the C6-C10Aryl or C4-C8Heteroaryl is optionally by 1-3 substituent group
Substitution, such as can be replaced by 1,2 or 3 substituent group, the substituent group is C1-C6Alkyl or halogen.
In the synthetic method of the present invention, C1-C6Alkyl refers to the alkyl for having 1-6 carbon atom, may be, for example, first
Base, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tertiary butyl, n-pentyl, isopentyl, n-hexyl etc..
In the synthetic method of the present invention, C1-C6Alkoxy refers to " C defined above1-C6Alkyl " and O atom
Group after being connected.
In the synthetic method of the present invention, the halogen may be, for example, fluorine, chlorine, bromine or iodine.
In the synthetic method of the present invention, the C6-C10Aryl refers to the aryl for having 6-10 carbon atom, such as
It can be phenyl or naphthyl.
In the synthetic method of the present invention, the C4-C8Heteroaryl refers to the heteroaryl for having 4-8 carbon atom, example
Such as can be pyridyl group, furan thiophene base or thienyl.
In the synthetic method of the present invention, the catalyst is the mixing of organic palladium compound and organocopper compound
The molar ratio of object, the two is 1:2-4 may be, for example, 1:2、1:3 or 1:4.
Wherein, organic palladium compound example is acid chloride (Pd (OAc)2), palladium bichloride (PdCl2), palladium acetylacetonate (Pd
(acac)2), (1,5- cyclo-octadiene) palladium bichloride (PdCl2(cod)), palladium trifluoroacetate (Pd (TFA)2), [1,1 '-bis- (hexichol
Base phosphino-) ferrocene] palladium chloride (PdCl2(dppf)), two (triphenylphosphine) palladium bichloride (PdCl2(PPh3)2) in it is any
A kind of or any a variety of mixture, most preferably PdCl2(dppf)。
Wherein, the organocopper compound is four acetonitrile copper ([(CH of hexafluorophosphoric acid3CN)4Cu]PF6), copper trifluoromethanesulfcomposite
(Cu(OTf)2), acetylacetone copper (Cu (acac)2), any one or more in copper acetate, most preferably hexafluorophosphoric acid tetrem
Nitrile copper ([(CH3CN)4Cu]PF6)。
The present invention the synthetic method in, the organic ligand be nitrogenous bidentate ligand, may be, for example, substitution or not
Substituted bipyridyl, substituted or unsubstituted Phen etc., may be, for example, following L1-L4：
Most preferably L1.
In the synthetic method of the present invention, the alkali is Na2CO3、K2CO3、NaOH、KOH、K3PO4、 Na3PO4、
NaHCO3、KHCO3, sodium acetate, sodium ethoxide, potassium tert-butoxide, diisopropylamine, any one of diisopropyl ethanolamine etc. or
Any a variety of mixture；Most preferably diisopropyl ethanolamine.
In the synthetic method of the present invention, the solvent is PEG-400 and 1- allyl -3- methylimidazole tetrafluoro boron
The mixture of hydrochlorate, the two volume ratio are 1:0.1-0.3 may be, for example, 1:0.1、1:0.2 or 1:0.3.
In the synthetic method of the present invention, the inert atmosphere may be, for example, nitrogen atmosphere or argon atmosphere.
In the synthetic method of the present invention, the molar ratio of formula (II) compound and formula (III) compound is 1:
2-4 may be, for example, 1:2、1:3 or 1:4.
In the synthetic method of the present invention, the molar ratio of formula (II) compound and catalyst is 1:0.08-
0.15, i.e., the ratio of the mole dosage and the sum of the mole dosage of two kinds of components of the composition catalyst of described formula (II) compound
It is 1:0.08-0.15 may be, for example, 1:0.08、1:0.1、1:0.12、1:0.14 or 1:0.15.
In the synthetic method of the present invention, the molar ratio of formula (II) compound and organic ligand is 1:0.1-
0.2, it may be, for example, 1:0.1、1:0.15 or 1:0.2.
In the synthetic method of the present invention, the molar ratio of formula (II) compound and alkali is 1:2-3 may be, for example,
1:2、1:2.5 or 1:3.
In the synthetic method of the present invention, there is no stringent restriction, people in the art for the dosage of the solvent
Member can suitably select its dosage, such as can be easy to carry out, be enough to react and be smoothed out according to post-process.
In the synthetic method of the present invention, reaction temperature is 60-80 DEG C, may be, for example, 60 DEG C, 70 DEG C or 80 DEG C.
In the synthetic method of the present invention, the reaction time is 8-12 hours, be may be, for example, 8 hours, 10 hours or 12
Hour.
In the synthetic method of the present invention, post-processing after reaction is specific as follows：After reaction, to reaction
Deionized water is added in system, fully oscillation, washing, separates organic layer, be washed with deionized again, separate organic layer；It will
Organic layer is concentrated under reduced pressure, and removes, silica gel column chromatography on gained residue, with volume ratio for 1:The n-hexyl alcohol of 2-4 and mixing for chloroform
Bonding solvent is eluted as eluting solvent, is detected through TLC, and same composition is merged, and is removed eluting solvent, is obtained target chemical combination
Object.
As described above, the present invention provides a kind of synthetic method of the phenanthrene compound as medicine intermediate, the method
It is right to obtain purpose product with high yield by selection/combination/collaboration of suitable catalyst, You Jipei, alkali and solvent
The actual production of the intermediates such as medicine, chemical industry is of great advantage, has extensive prospects for commercial application.
Specific implementation mode
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not constitutes any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Wherein, in all embodiments, unless otherwise prescribed, used ligand L 1 is matching of being referred to of above formula L1
Body.
Embodiment 1
The mixing being made of in right amount PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates is added into reactor
(the two volume ratio is 1 to solvent:0.1) it, is then replaced twice with nitrogen so that be nitrogen atmosphere in reactor；Then it is added
The bromo- 4 '-chlordiphenyls of the upper formula (II) compound 2- of 100mmol, the upper formula (III) compound styrene of 200mmol, by 3mmolPdCl2
(dppf) and four acetonitrile copper of 6mmol hexafluorophosphoric acids composition composite catalyst, 10mmol ligand Ls 1 and 200mmol diisopropyls
Ethanol amine is warming up to 60 DEG C, and reacts 12 hours at such a temperature under stirring.
After reaction, deionized water is added into reaction system, fully oscillation, washing, separates organic layer, spends again
Ion water washing, separates organic layer；Organic layer is concentrated under reduced pressure, is removed, silica gel column chromatography on gained residue is with volume ratio
1:2 n-hexyl alcohol and the mixed solvent of chloroform are eluted as eluting solvent, are detected through TLC, and same composition is merged, and removing is washed
Desolventizing obtains the chloro- 10- phenyl phenanthrene of target compound 2-, yield 95.3%.
1H-NMR (300MHz, CDCl3)δ:8.63 (d, J=8.9Hz, 1H), 8.49-8.44 (m, 2H), 7.84 (d, J=
2.2Hz, 1H), 7.71 (d, J=8.1Hz, 1H), 7.63 (s, 1H), 7.52 (dd, J=8.9,2.3Hz, 1H), 7.51-7.41
(m, 6H).
Embodiment 2
The mixing being made of in right amount PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates is added into reactor
(the two volume ratio is 1 to solvent:0.2) it, is then replaced twice with nitrogen so that be nitrogen atmosphere in reactor；Then it is added
The upper formula (II) compound 2- bromo biphenyls of 100mmol, the upper formula (III) compound 1- methyl -3- vinyl benzenes of 300mmol, by
3mmolPdCl2(dppf) and four acetonitrile copper of 9mmol hexafluorophosphoric acids composition composite catalyst, 15mmol ligand Ls 1 and 250mmol
Diisopropyl ethanolamine is warming up to 70 DEG C, and reacts 10 hours at such a temperature under stirring.
After reaction, deionized water is added into reaction system, fully oscillation, washing, separates organic layer, spends again
Ion water washing, separates organic layer；Organic layer is concentrated under reduced pressure, is removed, silica gel column chromatography on gained residue is with volume ratio
1:3 n-hexyl alcohol and the mixed solvent of chloroform are eluted as eluting solvent, are detected through TLC, and same composition is merged, and removing is washed
Desolventizing, tolyl is luxuriant and rich with fragrance between obtaining target compound 9-, yield 94.7%.
1H-NMR (300MHz, CDCl3) δ:8.72 (dd, J=8.3,1.2Hz, 1H), 8.51 (d, J=1.6Hz, 1H),
7.96 (dd, J=8.3,1.4Hz, 1H), 7.83 (d, J=8.0Hz, 1H), 7.68-7.61 (m, 2H), 7.52 (ddd, J=
8.2,6.9,1.3Hz, 1H), 7.45-7.31 (m, 4H), 7.27-7.22 (m, 2H), 2.63 (s, 3H).
Embodiment 3
The mixing being made of in right amount PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates is added into reactor
(the two volume ratio is 1 to solvent:0.3) it, is then replaced twice with nitrogen so that be nitrogen atmosphere in reactor；Then it is added
The upper formula (II) compound 2- bromo biphenyls of 100mmol, the upper formula (III) compound 1- vinyl naphthalenes of 400mmol, by 3mmolPdCl2
(dppf) and four acetonitrile copper of 12mmol hexafluorophosphoric acids composition composite catalyst, 20mmol ligand Ls 1 and 300mmol diisopropyls
Ethanol amine is warming up to 80 DEG C, and reacts 8 hours at such a temperature under stirring.
After reaction, deionized water is added into reaction system, fully oscillation, washing, separates organic layer, spends again
Ion water washing, separates organic layer；Organic layer is concentrated under reduced pressure, is removed, silica gel column chromatography on gained residue is with volume ratio
1:4 n-hexyl alcohol and the mixed solvent of chloroform are eluted as eluting solvent, are detected through TLC, and same composition is merged, and removing is washed
Desolventizing obtains target compound 9- (naphthalene -1- bases) phenanthrene, yield 95.7%.
1H-NMR (300MHz, CDCl3)δ:8.82 (d, J=8.2Hz, 2H), 8.61 (s, 1H), 8.02-7.95 (m, 2H),
7.83 (d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.65-7.31 (m, 9H).
Embodiment 4
The mixing being made of in right amount PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates is added into reactor
(the two volume ratio is 1 to solvent:0.2) it, is then replaced twice with nitrogen so that be nitrogen atmosphere in reactor；Then it is added
The upper formula (II) compound 2- bromo biphenyls of 100mmol, the upper formula (III) compound 2- vinylpyridines of 300mmol, by 2mmolPdCl2
(dppf) and four acetonitrile copper of 6mmol hexafluorophosphoric acids composition composite catalyst, 20mmol ligand Ls 1 and 200mmol diisopropyls
Ethanol amine is warming up to 70 DEG C, and reacts 12 hours at such a temperature under stirring.
After reaction, deionized water is added into reaction system, fully oscillation, washing, separates organic layer, spends again
Ion water washing, separates organic layer；Organic layer is concentrated under reduced pressure, is removed, silica gel column chromatography on gained residue is with volume ratio
1:3 n-hexyl alcohol and the mixed solvent of chloroform are eluted as eluting solvent, are detected through TLC, and same composition is merged, and removing is washed
Desolventizing obtains target compound 9- (pyridine -2- bases) phenanthrene, yield 94.9%.
1H-NMR (300MHz, CDCl3)δ:8.83 (d, J=4.9Hz, 1H), 8.76 (dd, J=8.3,1.3Hz, 1H),
8.57-8.51 (m, 1H), 8.07 (dd, J=8.2,1.4Hz, 1H), 7.89-7.83 (m, 3H), 7.71-7.62 (m, 2H),
7.58-7.52 (m, 1H), 7.45 (dd, J=8.1Hz, 1.6Hz, 1H), 7.41-7.35 (m, 2H).
Embodiment 5-28：The investigation of palladium catalyst compound component
Embodiment 5-8：Except respectively by PdCl therein2(dppf) acid chloride (Pd (OAc) 2) is replaced with outside, other operations
It is constant, embodiment 5-8 is implemented with the same way with embodiment 1-4.
Embodiment 9-12：Except respectively by PdCl therein2(dppf) palladium bichloride (PdCl2) is replaced with outside, other operations are equal
It is constant, embodiment 9-12 is implemented with the same way with embodiment 1-4.
Embodiment 13-16：Except respectively by PdCl therein2(dppf) palladium acetylacetonate (Pd (acac) is replaced with2) outside,
Its operation is constant, and embodiment 13-16 is implemented with the same way with embodiment 1-4.
Embodiment 17-20：Except respectively by PdCl therein2(dppf) (1,5- cyclo-octadiene) palladium bichloride (PdCl is replaced with2
(cod)) outside, other operations are constant, and embodiment 17-20 is implemented with the same way with embodiment 1-4.
Embodiment 21-24：Except respectively by PdCl therein2(dppf) palladium trifluoroacetate (Pd (TFA) is replaced with2) outside, it is other
Operation is constant, and embodiment 21-24 is implemented with the same way with embodiment 1-4.
Embodiment 25-28：Except respectively by PdCl therein2(dppf) two (triphenylphosphine) palladium bichloride (PdCl2 are replaced with
(PPh3)2) outside, other operations are constant, and embodiment 25-28 is implemented with the same way with embodiment 1-4.
The yield of products therefrom is as shown in table 1 below：
Table 1：The investigation of palladium compound component
It can be seen that working as the PdCl in composite catalyst2(dppf) when replacing with other palladium compounds, lead to yield
It is greatly lowered, this demonstrate that PdCl2(dppf) there can be best catalytic effect together with four acetonitrile copper of hexafluorophosphoric acid.
Embodiment 29-40：The investigation of catalyst copper compound component
Embodiment 29-32：Except four acetonitrile copper of hexafluorophosphoric acid therein is replaced with copper trifluoromethanesulfcomposite (Cu respectively
(OTf)2) outside, other operations are constant, and embodiment 29-32 is implemented with the same way with embodiment 1-4.
Embodiment 33-36：Except four acetonitrile copper of hexafluorophosphoric acid therein is replaced with acetylacetone copper (Cu respectively
(acac)2) outside, other operations are constant, and embodiment 33-36 is implemented with the same way with embodiment 1-4.
Embodiment 37-40：In addition to four acetonitrile copper of hexafluorophosphoric acid therein is replaced with copper acetate respectively, other operations are not
Become, embodiment 37-40 is implemented with the same way with embodiment 1-4.
The yield of products therefrom is as shown in table 2 below：
Table 2：The investigation of copper compound component
It can be seen that when the four acetonitrile copper of hexafluorophosphoric acid in composite catalyst is replaced with other copper compounds, lead
Yield is caused to be greatly lowered, this demonstrate that four acetonitrile copper of hexafluorophosphoric acid can be with PdCl2(dppf) best catalysis is played together
Effect.
Embodiment 41-52：The investigation of organic ligand
Embodiment 41-44：In addition to organic ligand therein is replaced with L2 by L1 respectively, it is other operation it is constant, with
The same way of embodiment 1-4 implements embodiment 41-44.
Embodiment 45-48：In addition to organic ligand therein is replaced with L3 by L1 respectively, it is other operation it is constant, with
The same way of embodiment 1-4 implements embodiment 45-48.
Embodiment 49-52：In addition to organic ligand therein is replaced with L4 by L1 respectively, it is other operation it is constant, with
The same way of embodiment 1-4 implements embodiment 49-52.
The yield of products therefrom is as shown in table 3 below：
Table 3：The investigation of organic ligand
It can be seen that in all ligands, L1 has best reaction effect, even very similar with L1 structures
L2, yield also have comparable reduction.
Embodiment 53-64：The investigation of alkali
In addition to alkali therein is replaced with other alkali by diisopropyl ethanolamine, it is other constant and with embodiment 1-4's
Same way implements embodiment 53-64, and institute see the table below 4 using alkali, correspondence and products collection efficiency：
Table 4：The investigation of alkali
It can be seen that when using other alkali when, yield is caused to be greatly lowered, even with institute in embodiment 1-4
Using the very similar diisopropylamine of diisopropyl ethanolamine, yield also has significant decrease.
Embodiment 65-72：The investigation of solvent
Embodiment 65-68：The mixed solvent in embodiment 1-4 is replaced with into PEG-400 respectively, it is other constant, and obtain
Embodiment 65-68 is arrived.
Embodiment 69-72：The mixed solvent in embodiment 1-4 is replaced with into 1- allyl -3- methylimidazole tetrafluoros respectively
Borate, it is other constant, and obtained embodiment 69-72.
The yield of products therefrom is as shown in table 5 below：
Table 5：The investigation of solvent
It can be seen that when using the solvent of one-component, yield has comparable reduction, only uses the composition of the two
When, the excellent effect of the present invention could be obtained.
Embodiment 73-80：The investigation of single catalyst component
Embodiment 73-76：Composite catalyst in embodiment 1-4 is replaced with to the PdCl of same amount respectively2
(dppf), i.e. PdCl2(dppf) dosage is total dosage of original two kinds of components, and has obtained embodiment 73-76.
Embodiment 77-80：Composite catalyst in embodiment 1-4 is replaced with to the hexafluorophosphoric acid tetrem of same amount respectively
Nitrile copper, the i.e. dosage of four acetonitrile copper of hexafluorophosphoric acid are total dosage of original two kinds of components, and have obtained embodiment 77-80.
The yield of products therefrom is as shown in table 6 below：
Table 6：The investigation of single catalyst component
It can be seen that when using one-component catalyst, yield has comparable reduction, only uses the two mixture
When, unique synergistic effect has been played between each other, and to achieve the excellent catalytic effect of the present invention, this is non-obvious
's.
In conclusion the present invention provides a kind of synthetic methods of medicine intermediate phenanthrene compound to pass through in the method
Comprehensive selection and/or the collaboration of catalyst, organic ligand, alkali and solvent to obtain purpose product with high yield, and are worked as and are changed
When becoming any type component or being omitted, products collection efficiency is caused to have significant decrease.It can be seen that the method tool of the present invention
There is good, extensive commercial application potentiality, can be applied to the synthesis field of medicine intermediate.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention
It encloses.In addition, it should also be understood that, after reading the technical contents of the present invention, those skilled in the art can make the present invention each
Kind change, modification and/or variation, all these equivalent forms equally fall within and are protected defined by the application the appended claims
Within the scope of shield.
Claims (6)
1. a kind of applying PdCl2(PPh3)2The method of phenanthrene compound shown in the lower formula (I) of synthesis,
The method includes：Under inert atmosphere, in the presence of catalyst, organic ligand and alkali, in solvent, lower formula (II) chemical combination
Object reacts with formula (III) compound, to obtain formula (I) compound；
Wherein, R1、R2It is each independently H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
R3For C6-C10Aryl or C5-C8Heteroaryl, the C6-C10Aryl or C5-C8Heteroaryl is optionally replaced by 1-3 substituent group,
The substituent group is C1-C6Alkyl or halogen；
The catalyst is the mixture of organic palladium compound and organocopper compound, and the molar ratio of the two is 1:2-4, wherein
Organic palladium compound is PdCl2(PPh3)2, the organocopper compound is four acetonitrile copper of hexafluorophosphoric acid；
The organic ligand is following L1：
The alkali is diisopropyl ethanolamine；
The solvent is the mixture of PEG-400 and 1- allyl -3- methyl imidazolium tetrafluoroborates, and the two volume ratio is 1:
0.1-0.3。
2. the method for the synthesis according to claim 1 phenanthrene compound, which is characterized in that formula (II) compound with
The molar ratio of formula (III) compound is 1:2-4.
3. the method for the synthesis according to claim 1 phenanthrene compound, which is characterized in that formula (II) compound with
The molar ratio of catalyst is 1:0.08-0.15.
4. the method for the synthesis according to claim 1 phenanthrene compound, which is characterized in that formula (II) compound with
The molar ratio of organic ligand is 1:0.1-0.2.
5. the method for the synthesis according to claim 1 phenanthrene compound, which is characterized in that formula (II) compound with
The molar ratio of alkali is 1:2-3.
6. the method for the synthesis phenanthrene compound according to claim 1, which is characterized in that reaction temperature is 60-80 DEG C；
Reaction time is 8-12 hours.
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| Title |
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| 2,3-Dichloro-5,6-dicyano-para-benzoquinone (DDQ)/ Methanesulfonic Acid (MsOH)-Mediated Intramolecular Arene-Alkene Oxidative Coupling;Ko Hoon Kim等;《Advanced Synthesis & Catalysis》;20140220;第356卷(第4期);第701页左栏倒数第2行至右栏第3行以及Scheme5 * |
| Ligand-Free Heck Reaction: Pd(OAc)2 as an Active Catalyst Revisited;Qingwei Yao等;《The Journal of Organic Chemistry》;20030816;第68卷;第7529-7531页表1-4 * |
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