CN108299506A - N- heterocycle carbine ruthenium complexs and its preparation method and application - Google Patents
N- heterocycle carbine ruthenium complexs and its preparation method and application Download PDFInfo
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- CN108299506A CN108299506A CN201810081473.7A CN201810081473A CN108299506A CN 108299506 A CN108299506 A CN 108299506A CN 201810081473 A CN201810081473 A CN 201810081473A CN 108299506 A CN108299506 A CN 108299506A
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- 229910052707 ruthenium Inorganic materials 0.000 title claims abstract description 28
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000005865 alkene metathesis reaction Methods 0.000 claims abstract description 25
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000460 chlorine Substances 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 239000011737 fluorine Substances 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000005864 Sulphur Chemical group 0.000 claims abstract description 3
- 125000003368 amide group Chemical group 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract 2
- 150000002431 hydrogen Chemical group 0.000 claims abstract 2
- 239000003054 catalyst Substances 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 239000002904 solvent Substances 0.000 claims description 26
- 239000012327 Ruthenium complex Substances 0.000 claims description 21
- ZVTDLPBHTSMEJZ-UPZRXNBOSA-N danoprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCC[C@H](C(N1C[C@@H](C[C@H]1C(=O)N2)OC(=O)N1CC2=C(F)C=CC=C2C1)=O)NC(=O)OC(C)(C)C)NS(=O)(=O)C1CC1 ZVTDLPBHTSMEJZ-UPZRXNBOSA-N 0.000 claims description 18
- 229950002891 danoprevir Drugs 0.000 claims description 18
- HWZVDMQWJBASSJ-UHFFFAOYSA-N 1-methoxycarbonylcyclopent-3-ene-1-carboxylic acid Chemical compound COC(=O)C1(CC=CC1)C(O)=O HWZVDMQWJBASSJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000005649 metathesis reaction Methods 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 4
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- JDIIGWSSTNUWGK-UHFFFAOYSA-N 1h-imidazol-3-ium;chloride Chemical compound [Cl-].[NH2+]1C=CN=C1 JDIIGWSSTNUWGK-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000010792 warming Methods 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 239000000843 powder Substances 0.000 description 20
- 239000003208 petroleum Substances 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000011986 second-generation catalyst Substances 0.000 description 6
- HECLRDQVFMWTQS-RGOKHQFPSA-N 1755-01-7 Chemical compound C1[C@H]2[C@@H]3CC=C[C@@H]3[C@@H]1C=C2 HECLRDQVFMWTQS-RGOKHQFPSA-N 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000005686 cross metathesis reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229910052750 molybdenum Inorganic materials 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 229910052721 tungsten Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
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- 238000010992 reflux Methods 0.000 description 3
- 238000007152 ring opening metathesis polymerisation reaction Methods 0.000 description 3
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000011733 molybdenum Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- -1 transition metal salt Chemical class 0.000 description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 2
- 239000010937 tungsten Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- WURBVZBTWMNKQT-UHFFFAOYSA-N 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-one Chemical compound C1=NC=NN1C(C(=O)C(C)(C)C)OC1=CC=C(Cl)C=C1 WURBVZBTWMNKQT-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920001153 Polydicyclopentadiene Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003426 co-catalyst Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000011985 first-generation catalyst Substances 0.000 description 1
- 229960002914 grazoprevir Drugs 0.000 description 1
- OBMNJSNZOWALQB-NCQNOWPTSA-N grazoprevir Chemical compound O=C([C@@H]1C[C@@H]2CN1C(=O)[C@@H](NC(=O)O[C@@H]1C[C@H]1CCCCCC1=NC3=CC=C(C=C3N=C1O2)OC)C(C)(C)C)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C OBMNJSNZOWALQB-NCQNOWPTSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 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
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ZYNMJJNWXVKJJV-UHFFFAOYSA-N propan-2-yloxybenzene Chemical class CC(C)OC1=CC=CC=C1 ZYNMJJNWXVKJJV-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 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
- 238000005872 self-metathesis reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- JTZZSQYMACOLNN-VDWJNHBNSA-N simeprevir Chemical compound O=C([C@@]12C[C@H]1\C=C/CCCCN(C)C(=O)[C@H]1[C@H](C(N2)=O)C[C@H](C1)OC=1C2=CC=C(C(=C2N=C(C=1)C=1SC=C(N=1)C(C)C)C)OC)NS(=O)(=O)C1CC1 JTZZSQYMACOLNN-VDWJNHBNSA-N 0.000 description 1
- 229960004608 simeprevir sodium Drugs 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2265—Carbenes or carbynes, i.e.(image)
- B01J31/2269—Heterocyclic carbenes
- B01J31/2273—Heterocyclic carbenes with only nitrogen as heteroatomic ring members, e.g. 1,3-diarylimidazoline-2-ylidenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F132/00—Homopolymers of cyclic compounds containing no unsaturated aliphatic radicals in a side chain, and having one or more carbon-to-carbon double bonds in a carbocyclic ring system
- C08F132/08—Homopolymers of cyclic compounds containing no unsaturated aliphatic radicals in a side chain, and having one or more carbon-to-carbon double bonds in a carbocyclic ring system having condensed rings
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F4/00—Polymerisation catalysts
- C08F4/42—Metals; Metal hydrides; Metallo-organic compounds; Use thereof as catalyst precursors
- C08F4/72—Metals; Metal hydrides; Metallo-organic compounds; Use thereof as catalyst precursors selected from metals not provided for in group C08F4/44
- C08F4/80—Metals; Metal hydrides; Metallo-organic compounds; Use thereof as catalyst precursors selected from metals not provided for in group C08F4/44 selected from iron group metals or platinum group metals
-
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- B01J2231/50—Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds
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Abstract
The present invention provides one kind N heterocycle carbine ruthenium complexs as shown in formula (I):Wherein, X is oxygen or sulphur;L is selected fromR1、R2Separately it is selected from fluorine, chlorine, bromine, iodine, RCOO, R C1‑C8Alkyl;R3Selected from C1‑C8Alkyl, C1‑C8Alkoxy, substituted or unsubstituted C3‑C8Naphthenic base, substituted or unsubstituted C3‑C8Heterocycle, substituted or unsubstituted C6‑C15Aryl, substituted or unsubstituted C6‑C15Heteroaryl;R4、R5、R6、R7Separately it is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1‑C8Alkyl, C1‑C8Alkoxy, substituted or unsubstituted C3‑C8Naphthenic base, substituted or unsubstituted C3‑C8Heterocycle, substituted or unsubstituted C6‑C15Aryl, substituted or unsubstituted C6‑C15Heteroaryl, amide groups, sulfoamido.The complex compound of the present invention is used for olefin metathesis reaction, has many advantages, such as that dosage is low, easy to operate, high income, at low cost, has a vast market application prospect.
Description
Technical field
The present invention relates to the technical fields of catalyst preparation in olefin metathesis reaction, and it is miscellaneous to relate more specifically to a kind of N-
Ring Cabbeen ruthenium complex and its preparation method and application.
Background technology
Olefin metathesis reaction refers to by the unsaturated carbon-carbon double bond of metal olefin complex compound (also known as metal carbene) catalysis
Or the three carbon skeleton rearrangement reactions between key, the reaction are broadly divided into following 4 major class:(1) ring opening metathesis polymerzation
(Ring-opening metathesis polymerization, ROMP);(2) cultural care (Ring-closing
Metathesis, RCM);(3) cross-metathesis (Cross metathesis, CM);(4) ring opening cross-metathesis reaction
(Ring-opening cross metathesis, ROCM).
As the catalyst of olefin metathesis reaction key factor, development is broadly divided into two stages:First stage is
20th century, the 50's to middle 1960s, the structural formula of the olefin metathesis catalyst of this period is indefinite, main
To be mixed by transition metal salt and main group alkyl reagent or solid support substrate, the advantages of this kind of catalyst be it is at low cost,
It is easily-synthesized, is convenient for commercial Application, the disadvantage is that short life, being also easy to produce side reaction, being especially quick to the impurity in air, steam and system
Sense, generally requires the compounds such as strong lewis acid as co-catalyst;Second stage be middle 1960s so far, this section
The structure of the olefin metathesis catalyst of time is specific, and the research of this section of period catalyst is concentrated mainly on transition metal
On the complex compound of Ti, Ta, W, Mo, Ru, Os etc., main catalyst system and catalyzing is W, Mo, Ru, wherein the most prominent with Ru.This be because
Although very high for tungsten carbone catalyst catalytic activity, stability is poor, to air, water sensitive, and it is simultaneous with substrate functional group
Capacitive is very poor;The catalytic activity of molybdenum carbone catalyst is very high, sensitive to functional groups such as carbonyl, hydroxyls in empty gas and water and substrate;
And the oxytropism of ruthenium is low, and good stability is shown to a large amount of polarized functional groups, and ruthenium carbone catalyst to empty gas and water,
Functional group in substrate has preferable compatibility, therefore the application of ruthenium carbone catalyst is more extensive compared with tungsten, molybdenum.
But current ruthenium catalyst promoting olefin metathesis reaction has the following problems:
(1) target product low yield can not make full use of raw material when preparing target product, cause the wave in resource
Take;
(2) dosage of ruthenium catalyst is big, is easy to cause overrun metal content in target product, on the one hand increases succeeding target
The processing work of product influences the production efficiency of target product;Another aspect catalyst amount is big, the longer increasing of product process cycle
Production cost is added.
For example, 2010011566 A1 of WO are disclosed prepares anti-hepatitis drug lattice drawing using the catalysis of zhan 1B ruthenium catalysts
The intermediate of Rui Wei (Grazoprevir Hydrate), yield 25%;2007014926 A1 of WO are disclosed using H-G first
The intermediate of anti-hepatitis drug Xi Meiruiwei (Simeprevir Sodium), yield 60% are prepared for catalyst;
US8299021B2 is disclosed prepares anti-hepatitis drug Dan Nuoruiwei sodium (Danoprevir using H-G second generation catalysts
Sodium intermediate), yield 52%;Document Org.Lett., 1999,1,953-956 is reported to be urged using the Grubbs second generations
Reaction prepares 3- cyclopentene -1,1- dicarboxylic acid methyl esters to agent under 45 degrees Celsius in methylene chloride, and catalyst amount is up to 5% and rubs
You, be easy to cause metal Ru too high levels in product;CN1571791A discloses a kind of new catalyst ruthenium complex, uses
Dosage when promoting olefin metathesis reacts is up to 1% mole;CN102643175 discloses a kind of solid carrying ruthenium complex and urges
Agent, dosage when being reacted for catalyzed alkene intramolecular metathesis cyclization are up to 2% mole.
Invention content
In view of problems of the prior art, the first object of the present invention is to propose a kind of N- heterocycle carbine ruthenium networks
Object is closed, can effectively solve the problem that in current ruthenium catalyst promoting olefin metathesis reaction that target yield is low, ruthenium catalyst dosage
Big the problem of leading to overrun metal content in target product.
In order to reach the above-mentioned purpose of the present invention, the present invention proposes a kind of preparation method of N- heterocycle carbines ruthenium complex,
It is with N- heterocycle carbine ruthenium complexs simple for process, can efficiently obtaining stable structure.
Another object of the present invention is to provide N- heterocycle carbine ruthenium complexs to make catalyst in olefin metathesis reaction
Purposes, specifically, the olefin metathesis double decomposition in the molecule in the olefin metathesis metathesis reaction, polymerisation of cyclization is anti-
The purposes of Ying Zhongzuo catalyst;More specifically, 3- cyclopentene -1,1- dicarboxylic acid methyl ester, HCV inhibitor are being prepared
Make the purposes of catalyst in the key intermediate of Danoprevir.
In order to reach the above-mentioned purpose of the present invention, the present invention provides N- heterocycle carbine ruthenium complexs as catalyst preparation
3- cyclopentene -1,1- dicarboxylic acid methyl esters, HCV inhibitor Danoprevir key intermediate method.
One kind N- heterocycle carbine ruthenium complexs as shown in formula (I):
Wherein, X is oxygen or sulphur;L is selected fromR1、R2Separately be selected from fluorine, chlorine, bromine,
Iodine, RCOO-, R C1-C8Alkyl;R3Selected from C1-C8Alkyl, C1-C8Alkoxy, substituted or unsubstituted C3-C8Naphthenic base takes
Generation or unsubstituted C3-C8Heterocycle, substituted or unsubstituted C6-C15Aryl, substituted or unsubstituted C6-C15Heteroaryl;R4、
R5、R6、R7Separately it is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C8Alkyl, C1-C8Alkoxy, substitution do not take
The C in generation3-C8Naphthenic base, substituted or unsubstituted C3-C8Heterocycle, substituted or unsubstituted C6-C15Aryl, substitution or unsubstituted
C6-C15Heteroaryl, amide groups, sulfoamido.
Further, X is oxygen.
Further, R1、R2Selected from chlorine.
Further, R3Selected from isopropyl.
Further, R4、R5、R6、R7Selected from hydrogen.
Further, the N- heterocycle carbines ruthenium complex is following compound:
The present invention also provides a kind of preparation methods of above-mentioned N- heterocycle carbines ruthenium complex, include the following steps:
(1) ruthenium complex shown in modus ponens 3 and N- heterocycle carbines imidazole hydrochloride (LHCl), in a solvent, in 40~100
DEG C reaction to get compound shown in formula 4;
(2) compound shown in modus ponens 4 is reacted with compound shown in formula 2, in a solvent, in 40~100 DEG C of reactions to get formula
(I) ruthenium complexs of N- heterocycle carbines shown in.
Further, in step (1), the solvent is non-protonic solvent;Preferably n-hexane, normal heptane, toluene;More
Preferably n-hexane;The reaction temperature is 60 DEG C;
In step (2), the solvent is non-protonic solvent;Preferably n-hexane, normal heptane, toluene, dichloromethane;More
Preferably n-hexane;The reaction temperature is 40 DEG C.
The present invention also provides a kind of preparation methods of 3- cyclopentene -1,1- dicarboxylic acid methyl ester, it includes the following steps:
Solvent is added in compound shown in modus ponens 6 and above-mentioned N- heterocycle carbines ruthenium complex, react 60 in 60~110 DEG C~
120 minutes to get compound shown in formula 7.
Further, the solvent is non-protonic solvent;Preferably tetrahydrofuran, toluene, n-hexane, normal heptane;More
Preferably normal heptane;
The reaction temperature is 100 DEG C;The reaction time is 120 minutes.
Further, 6 compound of formula and the molar ratio of N- heterocycle carbine ruthenium complexs shown in formula (I) are 1:0.0001~
0.0005;Preferably 1:0.0002.
The present invention also provides a kind of preparation method of the key intermediate of HCV inhibitor Danoprevir, it include with
Lower step:
Compound shown in modus ponens 8 and claim 1-5 any one of them N- heterocycle carbine ruthenium complexs, are added solvent,
8~12 hours are reacted in 40~110 DEG C to get compound shown in formula 9.
Further, the solvent is non-protonic solvent;Preferably tetrahydrofuran, toluene, dichloromethane;More preferably
Toluene;
The reaction temperature is 70 DEG C;The reaction time is 10 hours.
The present invention also provides the purposes that above-mentioned N- heterocycle carbines ruthenium complex makees catalyst in olefin metathesis reaction.
Further, the olefin metathesis reaction is the olefin metathesis metathesis reaction of intramolecular cyclization, polymerize instead
Olefin metathesis metathesis reaction in answering.
Further, above-mentioned N- heterocycle carbines ruthenium complex generates dicyclopentadiene in catalysis dicyclopentadiene ring-opening polymerisation
(Polydicyclopentadiene) during, relatively good activity is also shown.
For the above it should be noted that in the present invention, " substitution " refer to hydrogen atom in molecule by it is other not
Same atom or molecule is replaced.
The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix (Ca~Cb) alkyl
Show any alkyl containing " a " to " b " a carbon atom.For example, (C1~C4) alkyl refers to the alkyl for including 1~4 carbon atom.
The C1~C8Alkyl refers to C1、C2、C3、C4、C5、C6、C7、C8Alkyl, i.e., with 1~8 carbon atom straight chain
Or the alkyl of branch, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, sec-butyl, amyl, hexyl, heptan
Base, octyl etc..C1-C8Alkoxy, C3-C8Naphthenic base, C3-C8Heterocycle, C6-C15Aryl, C6-C15Heteroaryl also has and it
The corresponding meaning of group.For example, the C3-C8Naphthenic base refers to C3、C4、C5、C6、C7、C8Naphthenic base, such as cyclopropyl, ring fourth
Base, cyclopenta, cyclohexyl, suberyl, cyclooctyl etc..
Abbreviation and abbreviation:
The advantageous effect that the present invention reaches:The present invention provides a kind of efficient N- heterocycle carbine ruthenium complex catalysts,
It has the advantages that structural stability is high, is readily synthesized;It can be widely applied to the olefin metathesis reaction of intramolecular cyclization, gathers
Reaction etc. is closed, there is extensive market application value;In addition, its when preparing target product with the spy that high income, dosage are low
Point also can guarantee that tenor is within standard level in product, simplify product while improving target product output
Subsequent processing work, to reduce the input cost of associated products production.
In addition to this, the preparation method provided by the invention for preparing the catalyst its with easy to operate, high income, input
Advantage at low cost.
In addition, application of the N- heterocycle carbines ruthenium complex provided by the invention in olefin metathesis reaction, for preparationization
The fields such as work new material and pharmaceutical synthesis provide a kind of new preparation method, with easy to operate, high income, input cost
Low advantage.
Specific implementation mode
The specific implementation mode of form by the following examples remakes further specifically the above of the present invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
The preparation route of L:
Compound L is prepared by above-mentioned route.Grubbs first generation catalyst (compound A) is bought from Suzhou Xin Nuoke.
Solvent for use is reacted to buy from Chengdu Ke Long chemical reagents factory.N-hexane, dichloromethane pass through under nitrogen atmosphere
CaH2The 10h that flows back removes water deoxygenation.Nuclear-magnetism instrument is that (CDCl3 is solvent to 300 type Nuclear Magnetic Resonance of Bruker AVANCE, and TMS is
Internal standard);Mass spectrometer is Bruker microTOF-Q high-resolution mass spectrometers.
Embodiment 1
The preparation of the ruthenium complexs of N- heterocycle carbines shown in 5a:Under the conditions of anhydrous and oxygen-free, in 50 milliliters schlenk bottles successively
1000 mg (1.22mmol) compounds A, 1320mg (2.46mmol) compound 3a and 205mg (1.83mmol) tert-butyl alcohol is added
40mL toluene is added in potassium.It is reacted 5 hours at 70 DEG C under stirring.It is spin-dried for solvent, uses petroleum ether:Ethyl acetate=20:1 does and flows
Phase, column chromatography obtain red brown solid powder intermediate 4a, 637mg, yield 50.2%;
Under the conditions of anhydrous and oxygen-free, 637mg complexs 4a (0.61mmol) intermediate obtained in the previous step is dissolved in 30mL
In dichloromethane, 72mg (0.73mmol) stannous chloride is added and stirs 5 minutes, then by 99mg (0.61mmol) 2- isopropoxy benzenes
Ethylene is added into reaction, is warming up to 40 DEG C, reacts 1 hour, stops reaction, (whether is mobile phase by the direct column chromatography of reaction solution
For petroleum ether:Ethyl acetate=20:1) brown solid powder 5a, 355mg, yield 71.0%, are obtained.1H NMR(300MHz,
CDCl3) δ 16.71 (s, 1H), 7.55 (t, J=7.7Hz, 2H), 7.42 (t, J=7.8Hz, 1H), 7.32 (d, J=7.7Hz,
4H), 7.13 (s, 2H), 6.94 (d, J=7.3Hz, 1H), 6.80 (dd, J=11.1,8.0Hz, 2H), 4.97-4.81 (m,
1H), 2.88-2.71 (m, 4H), 1.61 (dddd, J=32.7,21.0,13.4,6.6Hz, 18H), 1.35 (d, J=6.0Hz,
6H), 0.77 (dt, J=14.3,7.3Hz, 25H) .13C NMR (75MHz, CDCl3) δ 178.23,152.55,146.21,
144.22,137.05,128.80,128.23,125.90,125.43,122.06,121.71,112.84,75.00, 40.76,
28.11,25.36,21.51,11.89,10.31.;HR-MS(ESI)m/z:Calcd for C45H64Cl2N2ORu{[M-Cl]
+} 820.3439,found 785.3877。
Embodiment 2
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters:1g diallyl dimethyl malenates are weighed, 2mL positive heptan is added
Alkane is passed through nitrogen stirring at normal temperature 20 minutes;0.78mg catalyst 5a are weighed, is dissolved and is added into reactor with 1mL normal heptanes,
It is warming up to 100 DEG C, reacts 90 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, 0.85 gram, yield:
98.5%.
Embodiment 3
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters:10g diallyl dimethyl malenates are weighed, 25mL is being added just
Heptane is passed through nitrogen stirring at normal temperature 20 minutes;7.80mg catalyst 5a are weighed, dissolved with 5mL normal heptanes and are added to reactor
In, it is warming up to 100 DEG C, reacts 100 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, 8.52 grams, yield:
98.5%.
Embodiment 4
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters:50g diallyl dimethyl malenates are weighed, 135mL is being added just
Heptane is passed through nitrogen stirring at normal temperature 20 minutes;39.0mg catalyst 5a are weighed, dissolved with 15mL normal heptanes and are added to reactor
In, it is warming up to 100 DEG C, reacts 120 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, 42.8 grams, yield:
98.7%.
Embodiment 5
The preparation of Danoprevir intermediates:50mg compounds 8 are weighed, the dissolving of 5mL toluene is added.Nitrogen room temperature is passed through to stir
It mixes 20 minutes, weighs 0.3mg catalyst 5a and be added in reactor, be warming up to 70 DEG C, react 10 hours, the reaction was complete, column layer
Analyse (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 36.1mg, yield 75.3%.
Embodiment 6
The preparation of Danoprevir intermediates:500mg compounds 8 are weighed, the dissolving of 50mL toluene is added.It is passed through nitrogen room temperature
Stirring 20 minutes, weighs 3.0mg catalyst 5a and is added in reactor, is warming up to 70 DEG C, reacts 10 hours, the reaction was complete, column
Chromatograph (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 362.0mg, yield 75.5%.
Embodiment 7
The preparation of Danoprevir intermediates:500mg compounds 8 are weighed, the dissolving of 50mL toluene is added.It is passed through nitrogen room temperature
Stirring 20 minutes, weighs 3.0mg catalyst 5a and is added in reactor, is warming up to 90 DEG C, reacts 8 hours, the reaction was complete, column
Chromatograph (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 350.0mg, yield 73.0%.
Embodiment 8
The preparation of Danoprevir intermediates:500mg compounds 8 are weighed, the dissolving of 50mL toluene is added.It is passed through nitrogen room temperature
Stirring 20 minutes, weighs 3.0mg catalyst 5a and is added in reactor, is warming up to 110 DEG C, reacts 7 hours, the reaction was complete, column
Chromatograph (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 335.6mg, yield 70.0%.
Embodiment 9
The preparation of Danoprevir intermediates:500mg compounds 8 are weighed, the dissolving of 50mL toluene is added.It is passed through nitrogen room temperature
Stirring 20 minutes, weighs 3.0mg catalyst 5a and is added in reactor, is warming up to 50 DEG C, reacts 12 hours, the reaction was complete, column
Chromatograph (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 341.4mg, yield 71.2%.
Embodiment 10
The preparation of Danoprevir intermediates:5.0g compounds 8 are weighed, the dissolving of 500mL toluene is added.It is passed through nitrogen room temperature
Stirring 20 minutes, weighs 30.0mg catalyst 5a and is added in reactor, is warming up to 70 DEG C, reacts 10 hours, and the reaction was complete,
Column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 3.65g, yield 76.1%.
Embodiment 11
The preparation of dicyclopentadiene:It weighs 1.000g dicyclopentadienes to be added into reaction bulb, 19mL is added at 35 DEG C
Under nitrogen protection, 0.20mg (monomers are added in toluene stirring and dissolving:Catalyst=32000:1) catalyst 5a is warming up to 50 DEG C and stirs
It mixes 30 minutes, methanol is added, polymer is precipitated, polymer is crushed, it is small to be placed in 110 DEG C of dryings 24 in vacuum drying chamber by filtering
When, conversion ratio 97.1%.
Embodiment 12
The preparation of dicyclopentadiene:It weighs 10.000g dicyclopentadienes to be added into reaction bulb, be added at 35 DEG C
Under nitrogen protection, 1.94mg (monomers are added in 190mL toluene stirring and dissolvings:Catalyst=32000:1) catalyst 5a is warming up to
50 DEG C are stirred 30 minutes, methanol are added, polymer is precipitated, polymer is crushed, is placed in 110 DEG C of dryings in vacuum drying chamber by filtering
24 hours, conversion ratio 97.5%.
Comparative example 1
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters:1g diallyl dimethyl malenates are weighed, 2mL positive heptan is added
Alkane is passed through nitrogen stirring at normal temperature 20 minutes;Weigh 5.9mgGrubbs second generation catalyst, dissolved with 1mL normal heptanes and be added to
In reactor, it is warming up to 100 DEG C, reacts 90 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, 0.52 gram,
Yield:60.0%.
Comparative example 2
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters:1g diallyl dimethyl malenates are weighed, 40mL dichloros are added
Methane is passed through nitrogen stirring at normal temperature 20 minutes;147.6mg Grubbs second generation catalyst is weighed, simultaneously with the dissolving of 6mL normal heptanes
It is added into reactor, is warming up to reflux, react 30 minutes, the reaction was complete, is spin-dried for dichloromethane, obtains white solid powder,
0.85 gram, yield:97%.
Comparative example 3
The preparation of 3- cyclopentene -1,1- dicarboxylic acid methyl esters:1g diallyl dimethyl malenates are weighed, 45mL positive heptan is added
Alkane is passed through nitrogen stirring at normal temperature 20 minutes;14.7mg Grubbs second generation catalyst is weighed, is dissolved and is added with 5mL normal heptanes
Into reactor, it is warming up to reflux, reacts 150 minutes, the reaction was complete, is spin-dried for normal heptane, obtains white solid powder, and 0.77
Gram, yield:89%.
Comparative example 4
The preparation of Danoprevir intermediates:50mg compounds 8 are weighed, the dissolving of 5mL toluene is added.Nitrogen room temperature is passed through to stir
It mixes 20 minutes, weighs 1.15mg catalyst Hoveyda-Grubbs second generation catalyst and be added in reactor, be warming up to 70
DEG C, it reacts 10 hours, the reaction was complete, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder
24.0mg, yield 50.1%.
Comparative example 5
The preparation of Danoprevir intermediates:50mg compounds 8 are weighed, the dissolving of 5mL toluene is added.Nitrogen room temperature is passed through to stir
It mixes 20 minutes, weighs 2.31mg Hoveyda-Grubbs second generation catalyst and be added in reactor, be warming up to 70 DEG C, reaction
10 hours, the reaction was complete, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) white solid powder 18.3mg is obtained, it receives
Rate 38.1%.
Comparative example 6
The preparation of Danoprevir intermediates:50mg compounds 8 are weighed, the dissolving of 15mL dichloromethane is added.It is passed through nitrogen
Stirring at normal temperature 20 minutes weighs 2.68mg catalyst Z han-1B catalyst and is added in reactor, is warming up to reflux, reaction 10
Hour, the reaction was complete, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 27.8mg, yield
58%.
Comparative example 7
The preparation of Danoprevir intermediates:50mg compounds 8 are weighed, the dissolving of 5mL toluene is added.Nitrogen room temperature is passed through to stir
It mixes 20 minutes, weighs 0.27mg Zhan-1B catalyst and be added in reactor, be warming up to 70 DEG C, react 10 hours, column chromatography
(petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 14.4mg, yield 30%.
Comparative example 8
Since amide H has acidity in compound 8, the activity of cyclization metathesis catalyst can be influenced, and be easy to cause
Impurity generates, therefore obtains compound 8a, then pass through cyclization using the amino in benzoyl protection compound 8 in building-up process
Double decomposition obtains intermediate 9, to advanced optimize the preparation process of compound 9.
The preparation of Danoprevir intermediates:50mg compound 8a are weighed, the dissolving of 5mL toluene is added.It is passed through nitrogen room temperature
Stirring 20 minutes, weighs 0.23mg catalyst Z han-1B catalyst and is added in reactor, is warming up to 70 DEG C, reaction 10 is small
When, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 30.4mg, yield 63%.
Comparative example 9
The preparation of Danoprevir intermediates:500mg compound 8a are weighed, the dissolving of 50mL toluene is added.It is normal to be passed through nitrogen
Temperature stirring 20 minutes, weighs 2.3mg catalyst Z han-1B catalyst and is added in reactor, is warming up to 70 DEG C, reaction 10 is small
When, column chromatography (petroleum ether:Ethyl acetate=1:1 is mobile phase) obtain white solid powder 313mg, yield 65%.
Catalyst 5a has in preparing 3- cyclopentene -1,1- dicarboxylic acid methyl esters, Danoprevir intermediates preferably to be urged
Change effect, and the correlated response of the two is the olefin metathesis metathesis reaction of intramolecular cyclization;In addition prepared by catalyst 5a
Has preferable catalytic effect during dicyclopentadiene, this reaction is the olefin metathesis metathesis reaction in polymerisation.
Thus summarize and show that catalyst 5a i.e. N- heterocycle carbines ruthenium complex can be applied to olefin metathesis reaction.
The above, only presently preferred embodiments of the present invention, are not intended to limit the invention, patent protection model of the invention
It encloses and is subject to claims, equivalent structure variation made by every description with the present invention should all include similarly
Within the scope of the present invention.
Claims (15)
1. a kind of N- heterocycle carbine ruthenium complexs as shown in formula (I):
Wherein, X is oxygen or sulphur;
L is selected from
R1、R2Separately it is selected from fluorine, chlorine, bromine, iodine, RCOO-, R C1-C8Alkyl;
R3Selected from C1-C8Alkyl, C1-C8Alkoxy, substituted or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C3-C8It is miscellaneous
Ring group, substituted or unsubstituted C6-C15Aryl, substituted or unsubstituted C6-C15Heteroaryl;
R4、R5、R6、R7Separately it is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C8Alkyl, C1-C8Alkoxy, substitution
Or unsubstituted C3-C8Naphthenic base, substituted or unsubstituted C3-C8Heterocycle, substituted or unsubstituted C6-C15Aryl, substitution or
Unsubstituted C6-C15Heteroaryl, amide groups, sulfoamido.
2. N- heterocycle carbines ruthenium complex according to claim 1, it is characterised in that:X is oxygen.
3. N- heterocycle carbines ruthenium complex according to claim 1, it is characterised in that:R1、R2Selected from chlorine.
4. N- heterocycle carbines ruthenium complex according to claim 1, it is characterised in that:R3Selected from isopropyl.
5. N- heterocycle carbines ruthenium complex according to claim 1, it is characterised in that:R4、R5、R6、R7Selected from hydrogen.
6. according to claim 1-5 any one of them N- heterocycle carbine ruthenium complexs, it is characterised in that:The N- heterocycle carbines
Ruthenium complex is following compound:
7. the preparation method of claim 1-6 any one of them N- heterocycle carbine ruthenium complexs, it is characterised in that:The preparation
Method includes the following steps:
(1) ruthenium complex shown in modus ponens 3 and N- heterocycle carbines imidazole hydrochloride (LHCl), it is in a solvent, anti-in 40~100 DEG C
It should be to get compound shown in formula 4;
(2) compound shown in modus ponens 4 is reacted with compound shown in formula 2, in a solvent, in 40~100 DEG C of reactions to get formula (I)
Shown N- heterocycle carbines ruthenium complex.
8. preparation method according to claim 7, it is characterised in that:In step (1), the solvent is that aprotic is molten
Agent, the reaction temperature are 60 DEG C;
In step (2), the solvent is non-protonic solvent, and the reaction temperature is 40 DEG C.
9. a kind of preparation method of 3- cyclopentene -1,1- dicarboxylic acid methyl ester, it is characterised in that:The preparation method includes following step
Suddenly:
Compound shown in modus ponens 6 and claim 1-6 any one of them N- heterocycle carbine ruthenium complexs, are added solvent, in 60
~110 DEG C are reacted 60~120 minutes to get compound shown in formula 7.
10. preparation method according to claim 9, it is characterised in that:The solvent is non-protonic solvent, the reaction
Temperature is 100 DEG C;The reaction time is 120 minutes.
11. preparation method according to claim 9 or 10, it is characterised in that:6 compound of formula and N- heterocycles shown in formula (I)
The molar ratio of Cabbeen ruthenium complex is 1:0.0001~0.0005.
12. a kind of preparation method of the key intermediate of HCV inhibitor Danoprevir, it is characterised in that:The preparation method
Include the following steps:
Compound shown in modus ponens 8 and claim 1-6 any one of them N- heterocycle carbine ruthenium complexs, are added solvent, in 40
~110 DEG C are reacted 8~12 hours to get compound shown in formula 9.
13. preparation method according to claim 12, it is characterised in that:The solvent is non-protonic solvent, described anti-
It is 70 DEG C to answer temperature;The reaction time is 10 hours.
14. the N- heterocycle carbine ruthenium complexs described in claim 1-6 make the purposes of catalyst in olefin metathesis reaction.
15. purposes according to claim 14, it is characterised in that:The olefin metathesis reaction is intramolecular cyclization
Olefin metathesis metathesis reaction in olefin metathesis metathesis reaction, polymerisation.
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