CN105777461A - Method for synthesizing medical intermediate phenanthrene compound in sodium carbonate environment - Google Patents
Method for synthesizing medical intermediate phenanthrene compound in sodium carbonate environment Download PDFInfo
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- CN105777461A CN105777461A CN201610216498.4A CN201610216498A CN105777461A CN 105777461 A CN105777461 A CN 105777461A CN 201610216498 A CN201610216498 A CN 201610216498A CN 105777461 A CN105777461 A CN 105777461A
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- Prior art keywords
- compound
- formula
- synthesis
- phenanthrene
- catalyst
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- -1 phenanthrene compound Chemical class 0.000 title claims abstract description 32
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 title claims abstract description 16
- 229910000029 sodium carbonate Inorganic materials 0.000 title claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 239000003513 alkali Substances 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
- 239000012298 atmosphere Substances 0.000 claims abstract description 4
- 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 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- FGOSNANIQLJNSZ-UHFFFAOYSA-N acetonitrile copper Chemical compound [Cu].CC#N.CC#N.CC#N.CC#N FGOSNANIQLJNSZ-UHFFFAOYSA-N 0.000 claims description 15
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 9
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 7
- 150000002941 palladium compounds Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 15
- 238000011835 investigation Methods 0.000 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 description 13
- 239000012046 mixed solvent Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 101150003085 Pdcl gene Proteins 0.000 description 7
- 239000002131 composite material Substances 0.000 description 7
- ZYWUVGFIXPNBDL-UHFFFAOYSA-N n,n-diisopropylaminoethanol Chemical compound CC(C)N(C(C)C)CCO ZYWUVGFIXPNBDL-UHFFFAOYSA-N 0.000 description 7
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000010949 copper Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 239000005749 Copper compound Substances 0.000 description 3
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 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
- 230000003197 catalytic effect Effects 0.000 description 3
- 150000001880 copper compounds Chemical class 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 2
- 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
- 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
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 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 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-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
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 229910052802 copper Inorganic materials 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
- 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 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
- 229910052763 palladium Inorganic materials 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
- 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 2
- 150000002987 phenanthrenes Chemical class 0.000 description 2
- 238000012805 post-processing Methods 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 0 *c1cc2ccccc2c2ccccc12 Chemical compound *c1cc2ccccc2c2ccccc12 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-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
- AXNBHOOQHIIQFA-UHFFFAOYSA-N [S].C(F)(F)F Chemical compound [S].C(F)(F)F AXNBHOOQHIIQFA-UHFFFAOYSA-N 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 150000004074 biphenyls Chemical class 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
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 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
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 238000009510 drug design 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
- 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
- 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
- 150000002576 ketones Chemical class 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 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
- 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
- 230000008569 process Effects 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
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- C07C2/02—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by addition between unsaturated hydrocarbons
- C07C2/42—Preparation of hydrocarbons from hydrocarbons containing a smaller number of carbon atoms by addition between unsaturated hydrocarbons homo- or co-oligomerisation with ring formation, not being a Diels-Alder conversion
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2531/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- C07C2531/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- C07C2531/22—Organic complexes
Abstract
The invention relates to a method for synthesizing a medical intermediate phenanthrene compound as shown in a formula (I) in the description in a sodium carbonate environment.The method comprises the steps that in an inert atmosphere, in the presence of a catalyst, an organic ligand and sodium carbonate and in solvent, a compound of a formula (II) is reacted with a compound of a formula (III), and the compound of the formula (I) is obtained, wherein the formulas are shown in the description, R1 and R2 independently adopt H or C1-C6 alkyl groups or C1-C6 alkoxy groups or halogens, R3 adopts C6-C10 aryl groups or C5-C8 heteroaryl groups, the C6-C10 aryl groups or C4-C8 heteroaryl groups are optionally substituted with 1-3 substituent groups, and the substituent groups adopt the C1-C6 alkyl groups or halogens.According to the method for synthesizing the medical intermediate phenanthrene compound as shown in the formula (I) in the description in the sodium carbonate environment, by means of proper selection of the catalyst, the organic ligand, alkali and the solvent, the good effect is achieved, and a wide industrial application prospect is achieved.
Description
The present patent application is Application No. 201510100568.5 (a kind of medicine filed in 6 days March in 2015
The synthetic method of intermediate phenanthrene compounds) the divisional application of patent application.
Technical field
The present invention relates to the synthetic method of a kind of fused ring compound, relate more specifically to a kind of medicine intermediate luxuriant and rich with fragrance
The synthetic method of compound, belongs to organic synthesis and medicine intermediate synthesis field.
Background technology
The fused ring compound biological activity that such as compound such as naphthalene, anthracene, phenanthrene generally exists due to it and by medicine
The attention of research staff and concern.Wherein, luxuriant and rich with fragrance and derivant is the phenolic compound that a class is important,
Through being widely used in drug design and synthesis, material development field.
Just because of such excellent in performance and the potentiality of phenanthrene compound, thus research is luxuriant and rich with fragrance and derivant novel
Synthetic method also be always organic chemical synthesis worker hot issue the most deeply concerned.
Up to the present, there is the preparation technology of multiple phenanthrene compound in prior art, it is from multiple angles
Degree have studied the synthetic method that phenanthrene compound is suitable for.Such as:
(" Phenanthrene Synthesis by Eosin Y-Catalyzed, the Visible such as Xiao Tiebo
Light-Induced[4+2]Benzannulation of Biaryldiazonium Salts with
Alkynes ", Adv.Synth.Catal., 2012,354,3195-3199) report one without metal catalytic
, [4+2] benzo cyclization of the diaryl diazo salt of visible light-inducing.Its equation is as follows:
(" the Expeditious Synthesis of Phenanthrenes via such as Ye Fei
CuBr2-Catalyzed Coupling of Terminal Alkynes and N-Tosylhydrazones
Derived from O-Fo rmyl Biphenyls”,Organic Letters,2011,13,5020-5023)
Disclosing the coupling/cyclization of a kind of benzyl CuBr2 catalysis, it is derived from the N-of adjacent formyl biphenyl to toluene
Sulphonyl hydrazone is 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) report the reaction preparing phenanthrene compound that a kind of In (III) is catalyzed, its
Having and react efficient, the advantage of wide application range of substrates, its reaction equation is as follows:
Although as it has been described above, prior art has been disclosed for the preparation method of various types of phenanthrene compound,
But these methods still can not meet medicine, the Production requirement in chemical industry synthesis field, and this is intrinsic due to it
The problems such as production efficiency is low, raw material can not make full use of.
In view of this, the present inventor has aimed to provide the new of a kind of phenanthrene compound by substantial amounts of experimentation
Type process for catalytic synthesis, has reached yield purpose high, willing, has had quite varied commercial Application
Prospect.
Summary of the invention
For many defects of above-mentioned existence, the present inventor, after having paid substantial amounts of creative work, passes through
Further investigation, and develop the synthetic method of a kind of phenanthrene compound that can be used as pharmaceutical intermediate, and then complete
The present invention.
Specifically, the invention provides the synthetic method of phenanthrene compound shown in a kind of lower formula (I),
Described 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, thus obtains formula (I) compound；
Wherein, R1、R2It is each independently H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
R3For C6-C10Aryl or C5-C8Heteroaryl, described C6-C10Aryl or C4-C8Heteroaryl is optionally by 1-3
Individual substituent group replaces, such as, can be replaced by 1,2 or 3 substituent groups, and described substituent group is C1-C6
Alkyl or halogen.
In the described synthetic method of the present invention, C1-C6Alkyl refers to the alkyl with 1-6 carbon atom, example
As being methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, just
Amyl group, isopentyl, n-hexyl etc..
In the described synthetic method of the present invention, C1-C6Alkoxyl refers to " C defined above1-C6Alkyl " with
Group after O atom is connected.
In the described synthetic method of the present invention, described halogen can be such as fluorine, chlorine, bromine or iodine.
In the described synthetic method of the present invention, described C6-C10Aryl refers to the virtue with 6-10 carbon atom
Base, such as, can be phenyl or naphthyl.
In the described synthetic method of the present invention, described C4-C8Heteroaryl refers to have the miscellaneous of 4-8 carbon atom
Aryl, such as, can be pyridine radicals, furan thiophene base or thienyl etc..
In the described synthetic method of the present invention, described catalyst is organic palladium compound and organocopper compound
Mixture, both mol ratios are 1:2-4, such as, can be 1:2,1:3 or 1:4.
Wherein, described organic palladium compound example is acid chloride (Pd (OAc)2), Palladous chloride. (PdCl2), levulinic
Ketone palladium (Pd (acac)2), (1,5-cyclo-octadiene) Palladous chloride. (PdCl2(cod)), palladium trifluoroacetate (Pd (TFA)2)、
[1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (PdCl2(dppf)), two (triphenylphosphine) Palladous chloride.
(PdCl2(PPh3)2) any one of or any multiple mixture, most preferably PdCl2(dppf)。
Wherein, described organocopper compound is hexafluorophosphoric acid four acetonitrile copper ([(CH3CN)4Cu]PF6), fluoroform sulphur
Acid copper (Cu (OTf)2), acetylacetone copper (Cu (acac)2), any one or more in copper acetate, optimum
Elect hexafluorophosphoric acid four acetonitrile copper ([(CH as3CN)4Cu]PF6)。
In the described synthetic method of the present invention, described organic ligand is nitrogenous bidentate ligand, such as, can be to take
Generation or unsubstituted bipyridyl, substituted or unsubstituted Phen etc., such as, can be following L1-L4:
Most preferably L1.
In the described synthetic method of the present invention, described alkali is Na2CO3、K2CO3、NaOH、KOH、K3PO4、
Na3PO4、NaHCO3、KHCO3, sodium acetate, Sodium ethylate, potassium tert-butoxide, diisopropylamine, diisopropyl second
Any one of hydramine etc. or any multiple mixture；Most preferably diisopropyl ethanolamine.
In the described synthetic method of the present invention, described solvent is PEG-400 Yu 1-pi-allyl-3-Methylimidazole.
The mixture of tetrafluoroborate, both volume ratios are 1:0.1-0.3, can be such as 1:0.1,1:0.2 or
1:0.3。
In the described synthetic method of the present invention, described inert atmosphere can be such as nitrogen atmosphere or argon atmosphere.
In the described synthetic method of the present invention, described formula (II) compound and the mol ratio of formula (III) compound
For 1:2-4, such as, can be 1:2,1:3 or 1:4.
In the described synthetic method of the present invention, described formula (II) compound with the mol ratio of catalyst is
1:0.08-0.15, two kinds of components of the mole dosage of the most described formula (II) compound and the described catalyst of composition
The ratio of mole dosage sum is 1:0.08-0.15, such as, can be 1:0.08,1:0.1,1:0.12,1:0.14
Or 1:0.15.
In the described synthetic method of the present invention, described formula (II) compound with the mol ratio of organic ligand is
1:0.1-0.2, such as, can be 1:0.1,1:0.15 or 1:0.2.
In the described synthetic method of the present invention, described formula (II) compound is 1:2-3 with the mol ratio of alkali, example
As being 1:2,1:2.5 or 1:3.
In the described synthetic method of the present invention, the consumption of described solvent does not has strict restriction, this area
Its consumption can suitably be selected by technical staff, such as, can be prone to carry out, be enough to according to making post processing
Reaction is smoothed out.
In the described synthetic method of the present invention, reaction temperature is 60-80 DEG C, such as, can be 60 DEG C, 70 DEG C
Or 80 DEG C.
In the described synthetic method of the present invention, the response time is 8-12 hour, such as, can be 8 hours, 10
Hour or 12 hours.
In the described synthetic method of the present invention, the post processing after reaction terminates is specific as follows: after reaction terminates,
In reaction system, add deionized water, fully vibration, washing, separate organic layer, again use deionized water
Washing, separates organic layer；By organic layer concentrating under reduced pressure, remove, silica gel column chromatography on gained residue, with
Volume ratio is that the hexanol of 1:2-4 carries out eluting with the mixed solvent of chloroform as eluting solvent, examines through TLC
Survey, merge same composition, remove eluting solvent, obtain target compound.
As it has been described above, the invention provides the synthetic method of a kind of phenanthrene compound as medicine intermediate, institute
Method of stating is by suitable catalyst, You Jipei, the selection/combination/work in coordination with of alkali and solvent, thus with high yield
Having obtained purpose product, the actual production to intermediate such as medicine, chemical industry is of great advantage, has work widely
Industry application prospect.
Detailed description of the invention
Below by specific embodiment, the present invention is described in detail, but these exemplary embodiments
Purposes and purpose are only used for enumerating the present invention, not constitute any type of to the real protection scope of the present invention
Any restriction, more non-is confined to this by protection scope of the present invention.
Wherein, in all embodiments, unless otherwise prescribed, the ligand L 1 used is above formula L1 institute
The part referred to.
Embodiment 1
In reactor, addition is made up of PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount
Mixed solvent (both volume ratios are 1:0.1), then replaces twice with nitrogen so that be blanket of nitrogen in reactor
Enclose；It is subsequently adding the bromo-4 '-chlordiphenyl of formula (II) compound 2-on 100mmol, 200mmol upper formula (III) chemical combination
Thing styrene, by 3mmolPdCl2(dppf) and 6mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst,
10mmol ligand L 1 and 200mmol diisopropyl ethanolamine, is warming up to 60 DEG C under stirring, and in this temperature
Lower reaction 12 hours.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer,
Again it is washed with deionized, separates organic layer；By organic layer concentrating under reduced pressure, remove, on gained residue
Silica gel column chromatography, the mixed solvent of the hexanol using volume ratio as 1:2 and chloroform is washed as eluting solvent
De-, detect through TLC, merge same composition, remove eluting solvent, obtain target compound 2-chloro-10-benzene
Ji Fei, productivity is 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
In reactor, addition is made up of PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount
Mixed solvent (both volume ratios are 1:0.2), then replaces twice with nitrogen so that be blanket of nitrogen in reactor
Enclose；It is subsequently adding formula (II) compound 2-bromo biphenyl on 100mmol, 300mmol upper formula (III) compound 1-first
Base-3-vinyl benzene, by 3mmolPdCl2And compound the urging of 9mmol hexafluorophosphoric acid four acetonitrile copper composition (dppf)
Agent, 15mmol ligand L 1 and 250mmol diisopropyl ethanolamine, be warming up to 70 DEG C under stirring, and
React 10 hours at a temperature of Gai.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer,
Again it is washed with deionized, separates organic layer；By organic layer concentrating under reduced pressure, remove, on gained residue
Silica gel column chromatography, the mixed solvent of the hexanol using volume ratio as 1:3 and chloroform is washed as eluting solvent
De-, detect through TLC, merge same composition, remove eluting solvent, obtain tolyl between target compound 9-
Phenanthrene, productivity is 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
In reactor, addition is made up of PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount
Mixed solvent (both volume ratios are 1:0.3), then replaces twice with nitrogen so that be blanket of nitrogen in reactor
Enclose；It is subsequently adding formula (II) compound 2-bromo biphenyl on 100mmol, 400mmol upper formula (III) compound 1-second
Thiazolinyl naphthalene, by 3mmolPdCl2(dppf) and 12mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst,
20mmol ligand L 1 and 300mmol diisopropyl ethanolamine, is warming up to 80 DEG C under stirring, and in this temperature
Lower reaction 8 hours.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer,
Again it is washed with deionized, separates organic layer；By organic layer concentrating under reduced pressure, remove, on gained residue
Silica gel column chromatography, the mixed solvent of the hexanol using volume ratio as 1:4 and chloroform is washed as eluting solvent
De-, detect through TLC, merge same composition, remove eluting solvent, obtain target compound 9-(naphthalene-1-base)
Phenanthrene, productivity is 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
In reactor, addition is made up of PEG-400 with 1-pi-allyl-3-methyl imidazolium tetrafluoroborate in right amount
Mixed solvent (both volume ratios are 1:0.2), then replaces twice with nitrogen so that be blanket of nitrogen in reactor
Enclose；It is subsequently adding formula (II) compound 2-bromo biphenyl on 100mmol, 300mmol upper formula (III) compound 2-second
Thiazolinyl pyridine, by 2mmolPdCl2(dppf) and 6mmol hexafluorophosphoric acid four acetonitrile copper composition composite catalyst,
20mmol ligand L 1 and 200mmol diisopropyl ethanolamine, is warming up to 70 DEG C under stirring, and in this temperature
Lower reaction 12 hours.
After reaction terminates, in reaction system, add deionized water, fully vibration, washing, separate organic layer,
Again it is washed with deionized, separates organic layer；By organic layer concentrating under reduced pressure, remove, on gained residue
Silica gel column chromatography, the mixed solvent of the hexanol using volume ratio as 1:3 and chloroform is washed as eluting solvent
De-, detect through TLC, merge same composition, remove eluting solvent, obtain target compound 9-(pyridine-2-
Base) luxuriant and rich with fragrance, productivity is 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 outward, other
Operate the most constant, implement embodiment 5-8 with the same way with embodiment 1-4.
Embodiment 9-12: except respectively by PdCl therein2(dppf) Palladous chloride. (PdCl2) is replaced with outward, other behaviour
Make the most constant, implement embodiment 9-12 with the same way with embodiment 1-4.
Embodiment 13-16: except respectively by PdCl therein2(dppf) palladium acetylacetonate (Pd (acac) is replaced with2) outward,
Other operation is the most constant, implements embodiment 13-16 with the same way with embodiment 1-4.
Embodiment 17-20: except respectively by PdCl therein2(dppf) (1,5-cyclo-octadiene) Palladous chloride. is replaced with
(PdCl2(cod)) outward, other operation is the most constant, implements embodiment with the same way with embodiment 1-4
17-20。
Embodiment 21-24: except respectively by PdCl therein2(dppf) palladium trifluoroacetate (Pd (TFA) is replaced with2) outward,
Other operation is the most constant, implements embodiment 21-24 with the same way with embodiment 1-4.
Embodiment 25-28: except respectively by PdCl therein2(dppf) two (triphenylphosphine) Palladous chloride. is replaced with
(PdCl2(PPh3)2) outward, other operation is the most constant, implements embodiment with the same way with embodiment 1-4
25-28。
The productivity of products therefrom is as shown in table 1 below:
Table 1: the investigation of palladium compound component
As can be seen here, when by the PdCl in composite catalyst2(dppf), when replacing with other palladium compound, all lead
Cause productivity to be greatly lowered, this demonstrate that PdCl2(dppf) can have together with hexafluorophosphoric acid four acetonitrile copper
Good catalytic effect.
Embodiment 29-40: the investigation of catalyst copper compound component
Embodiment 29-32: except respectively hexafluorophosphoric acid four acetonitrile copper therein being replaced with copper trifluoromethanesulfcomposite
(Cu(OTf)2) outward, other operation is the most constant, implements embodiment 29-32 with the same way with embodiment 1-4.
Embodiment 33-36: except respectively hexafluorophosphoric acid four acetonitrile copper therein being replaced with acetylacetone copper
(Cu(acac)2) outward, other operation is the most constant, implements embodiment 33-36 with the same way with embodiment 1-4.
Embodiment 37-40: in addition to respectively hexafluorophosphoric acid four acetonitrile copper therein being replaced with copper acetate, other behaviour
Make the most constant, implement embodiment 37-40 with the same way with embodiment 1-4.
The productivity of products therefrom is as shown in table 2 below:
Table 2: the investigation of copper compound component
As can be seen here, when the hexafluorophosphoric acid four acetonitrile copper in composite catalyst is replaced with other copper compound,
All cause productivity to be greatly lowered, this demonstrate that hexafluorophosphoric acid four acetonitrile copper can be with PdCl2(dppf) one rise
Wave best catalytic effect.
Embodiment 41-52: the investigation of organic ligand
Embodiment 41-44: in addition to respectively organic ligand therein being replaced with L2 by L1, other operation is the most not
Become, implement embodiment 41-44 with the same way with embodiment 1-4.
Embodiment 45-48: in addition to respectively organic ligand therein being replaced with L3 by L1, other operation is the most not
Become, implement embodiment 45-48 with the same way with embodiment 1-4.
Embodiment 49-52: in addition to respectively organic ligand therein being replaced with L4 by L1, other operation is the most not
Become, implement embodiment 49-52 with the same way with embodiment 1-4.
The productivity of products therefrom is as shown in table 3 below:
Table 3: the investigation of organic ligand
As can be seen here, in all of part, L1 has best reaction effect, even if with L1 structure
Very similar L2, its productivity also has suitable reduction.
Embodiment 53-64: the investigation of alkali
In addition to alkali therein is replaced with other alkali by diisopropyl ethanolamine, other the most constant and and embodiment
The same way of 1-4 implements embodiment 53-64, and used alkali, corresponding relation and products collection efficiency see table 4:
Table 4: the investigation of alkali
As can be seen here, when using other alkali, productivity is all caused to be greatly lowered, even and if embodiment
The diisopropylamine that used in 1-4, diisopropyl ethanolamine is similar to very much, its productivity also significantly reduces.
Embodiment 65-72: the investigation of solvent
Embodiment 65-68: respectively the mixed solvent in embodiment 1-4 is replaced with PEG-400, other is the most not
Become, and obtained embodiment 65-68.
Embodiment 69-72: respectively the mixed solvent in embodiment 1-4 is replaced with 1-pi-allyl-3-Methylimidazole.
Tetrafluoroborate, other is the most constant, and has obtained embodiment 69-72.
The productivity of products therefrom is as shown in table 5 below:
Table 5: the investigation of solvent
As can be seen here, when using the solvent of one-component, productivity has suitable reduction, only uses both
Compositions time, the excellent effect of the present invention could be obtained.
Embodiment 73-80: the investigation of single catalyst component
Embodiment 73-76: respectively the composite catalyst in embodiment 1-4 is replaced with same amount
PdCl2(dppf), i.e. PdCl2(dppf) consumption is total consumption of original two kinds of components, and has obtained embodiment
73-76。
Embodiment 77-80: respectively the composite catalyst in embodiment 1-4 is replaced with the hexafluoro phosphorus of same amount
Acid four acetonitrile copper, the i.e. consumption of hexafluorophosphoric acid four acetonitrile copper are total consumption of original two kinds of components, and obtain
Embodiment 77-80.
The productivity of products therefrom is as shown in table 6 below:
Table 6: the investigation of single catalyst component
As can be seen here, when using one-component catalyst, productivity has suitable reduction, only uses both
During mixture, play the synergism of uniqueness each other, thus achieved the excellent catalysis effect of the present invention
Really, this is non-obvious.
In sum, the invention provides the synthetic method of a kind of medicine intermediate phenanthrene compound, in the method
In, by the combined selection of catalyst, organic ligand, alkali and solvent and/or collaborative, thus obtain with high yield
Arrive purpose product, and when changing any component or being omitted, all cause products collection efficiency to have aobvious
Write and reduce.As can be seen here, the method for the present invention has good, commercial Application potentiality widely, can apply
Synthesis field in medicine intermediate.
Should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the guarantor of the present invention
Protect scope.Additionally, it will also be appreciated that after the technology contents having read the present invention, those skilled in the art
The present invention can make various change, amendment and/or modification, and all these equivalent form of value falls within this Shen equally
Please be within the protection domain that limited of appended claims.
Claims (7)
1. a method for phenanthrene compound shown in the lower formula (I) of synthesis under sodium carbonate environment,
Described 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, thus obtains formula (I) compound；
Wherein, R1、R2It is each independently H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
R3 is C6-C10Aryl or C5-C8Heteroaryl, described C6-C10Aryl or C4-C8Heteroaryl is optionally by 1-3
Individual substituent group replaces, and described substituent group is C1-C6Alkyl or halogen；
Described catalyst is the mixture of organic palladium compound and organocopper compound, and both mol ratios are
1:2-4, wherein, described organic palladium compound is PdCl2(dppf), described organocopper compound is hexafluoro phosphorus
Acid four acetonitrile copper；
Described organic ligand is the one in following L1-L4:
Described alkali is Na2CO3；
Described solvent is the mixture of PEG-400 Yu 1-pi-allyl-3-methyl imidazolium tetrafluoroborate, Liang Zheti
Long-pending ratio is 1:0.1-0.3.
The method of the described phenanthrene compound of synthesis the most according to claim 1, it is characterised in that described in have
Machine part is L1.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that institute
The mol ratio stating formula (II) compound and formula (III) compound is 1:2-4.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that institute
The mol ratio stating formula (II) compound and catalyst is 1:0.08-0.15.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that institute
The mol ratio stating formula (II) compound and organic ligand is 1:0.1-0.2.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that institute
The mol ratio stating formula (II) compound and alkali is 1:2-3.
The method of the described phenanthrene compound of synthesis the most according to claim 1 and 2, it is characterised in that anti-
Temperature is answered to be 60-80 DEG C；Response time is 8-12 hour.
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Non-Patent Citations (2)
| Title |
|---|
| MASAKI SHIMIZU等: "Palladium-catalyzed double cross-coupling reaction of 1,2-bis(pinacolatoboryl)alkenes and –arenes with 2,2’-dibromobiaryls: annulative approach to functionalized polycyclic aromatic hydrocarbons", 《TETRAHEDRON》 * |
| RONG ZHU等: "Copper-Catalyzed Oxytrifluoromethylation of Unactivated Alkenes", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
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| Publication number | Publication date |
|---|---|
| CN105777461B (en) | 2018-09-25 |
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Effective date of registration: 20200519 Address after: 314113 room 505, building A2, No. 555, Chuangye Road, Dayun Town, Jiashan County, Jiaxing City, Zhejiang Province (application for residence) Patentee after: Zhejiang aolanding Biotechnology Co., Ltd Address before: No. 300, South Rehe Road, Xiaguan street, Gulou District, Nanjing City, Jiangsu Province Co-patentee before: Hu Shuting Patentee before: Huang Zhemin |
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Correction item: Patentee|Address Correct: Zhejiang aolanding Biotechnology Co., Ltd.|314113 505, building A2, No. 555, Chuangye Road, Dayun Town, Jiashan County, Jiaxing City, Zhejiang Province False: Zhejiang aolanding Biotechnology Co., Ltd.|314113 505, building A2, No. 555, Chuangye Road, Dayun Town, Jiashan County, Jiaxing City, Zhejiang Province Number: 23-02 Volume: 36 |
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