CN107108416A - 一种1,2‑二环丙基乙基苯酚及其光学异构体的制备方法 - Google Patents
一种1,2‑二环丙基乙基苯酚及其光学异构体的制备方法 Download PDFInfo
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- CN107108416A CN107108416A CN201680003434.4A CN201680003434A CN107108416A CN 107108416 A CN107108416 A CN 107108416A CN 201680003434 A CN201680003434 A CN 201680003434A CN 107108416 A CN107108416 A CN 107108416A
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- phenyl
- bis
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- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 230000003287 optical effect Effects 0.000 title claims abstract description 13
- -1 1,2 Bicyclopropyl ethyl -phenol Chemical compound 0.000 title claims description 106
- 150000001875 compounds Chemical class 0.000 claims abstract description 102
- 238000006243 chemical reaction Methods 0.000 claims abstract description 83
- 238000005859 coupling reaction Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 105
- 239000000460 chlorine Substances 0.000 claims description 73
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 47
- 239000002585 base Substances 0.000 claims description 43
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 41
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 38
- 239000003054 catalyst Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 31
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 25
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 150000004696 coordination complex Chemical group 0.000 claims description 19
- 229910052751 metal Inorganic materials 0.000 claims description 19
- 239000002184 metal Substances 0.000 claims description 19
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 17
- 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 16
- UWHWRJUMACAJPY-UHFFFAOYSA-N 5-methyl-2-phenyl-4,5-dihydro-1,3-oxazole Chemical compound O1C(C)CN=C1C1=CC=CC=C1 UWHWRJUMACAJPY-UHFFFAOYSA-N 0.000 claims description 16
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 16
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 229910052707 ruthenium Inorganic materials 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052741 iridium Inorganic materials 0.000 claims description 12
- 229910052763 palladium Inorganic materials 0.000 claims description 12
- 235000011009 potassium phosphates Nutrition 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- 229910052759 nickel Inorganic materials 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 11
- 229910052703 rhodium Inorganic materials 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 11
- 235000019441 ethanol Nutrition 0.000 claims description 10
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 10
- VYXHVRARDIDEHS-QGTKBVGQSA-N (1z,5z)-cycloocta-1,5-diene Chemical compound C\1C\C=C/CC\C=C/1 VYXHVRARDIDEHS-QGTKBVGQSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- JAZCEXBNIYKZDI-UHFFFAOYSA-N [Ir+] Chemical compound [Ir+] JAZCEXBNIYKZDI-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 150000002500 ions Chemical class 0.000 claims description 8
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 8
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 8
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 8
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 6
- 239000000758 substrate Substances 0.000 claims description 6
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 235000011056 potassium acetate Nutrition 0.000 claims description 5
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- 239000010703 silicon Substances 0.000 claims description 5
- MPAZTSPCGPGQNK-UHFFFAOYSA-N (1-diphenylphosphanylbenzo[d][1,3]benzodioxepin-11-yl)-diphenylphosphane Chemical compound C=12C(C(=CC=C3)P(C=4C=CC=CC=4)C=4C=CC=CC=4)=C3OCOC2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 MPAZTSPCGPGQNK-UHFFFAOYSA-N 0.000 claims description 4
- GTIXSUJKFAATAE-UHFFFAOYSA-N (r)-c3-tunephos Chemical compound C=12C(C(=CC=C3)P(C=4C=CC=CC=4)C=4C=CC=CC=4)=C3OCCCOC2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 GTIXSUJKFAATAE-UHFFFAOYSA-N 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 241000790917 Dioxys <bee> Species 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000006267 biphenyl group Chemical group 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- DPOGTJDEMBEUSH-UHFFFAOYSA-N dicyclohexyl(ethyl)phosphane Chemical compound C1CCCCC1P(CC)C1CCCCC1 DPOGTJDEMBEUSH-UHFFFAOYSA-N 0.000 claims description 4
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 150000008300 phosphoramidites Chemical class 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011698 potassium fluoride Substances 0.000 claims description 4
- 235000003270 potassium fluoride Nutrition 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- 235000011008 sodium phosphates Nutrition 0.000 claims description 4
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- AQIHMSVIAGNIDM-UHFFFAOYSA-N benzoyl bromide Chemical compound BrC(=O)C1=CC=CC=C1 AQIHMSVIAGNIDM-UHFFFAOYSA-N 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 150000007942 carboxylates Chemical class 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- HCBRTCFUVLYSKU-URFUVCHWSA-N (1r)-2-tert-butyl-1-[(1r)-2-tert-butyl-1,3-dihydroisophosphindol-1-yl]-1,3-dihydroisophosphindole Chemical compound CC(C)(C)P1CC2=CC=CC=C2[C@@H]1[C@H]1C2=CC=CC=C2CP1C(C)(C)C HCBRTCFUVLYSKU-URFUVCHWSA-N 0.000 claims description 2
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 2
- RKWWASUTWAFKHA-UHFFFAOYSA-N 1-bromo-2,3-difluorobenzene Chemical compound FC1=CC=CC(Br)=C1F RKWWASUTWAFKHA-UHFFFAOYSA-N 0.000 claims description 2
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 150000001555 benzenes Chemical group 0.000 claims description 2
- QKZWXPLBVCKXNQ-ROJLCIKYSA-N dipamp Chemical compound COC1=CC=CC=C1[P@@](C=1C=CC=CC=1)CC[P@@](C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-ROJLCIKYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 20
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 3
- 150000002989 phenols Chemical class 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 150000001639 boron compounds Chemical class 0.000 abstract description 2
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 41
- 239000000243 solution Substances 0.000 description 28
- 239000007788 liquid Substances 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- 239000003208 petroleum Substances 0.000 description 21
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- ZYGAMJLTPLERBC-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid propan-2-ol Chemical compound B(O)(O)OC(C)(C)C(C)(C)O.C(C)(C)O ZYGAMJLTPLERBC-UHFFFAOYSA-N 0.000 description 1
- VUTGVRJAQQWHIX-UHFFFAOYSA-N 1,3-bis(1-cyclopropylethenyl)-2-phenylmethoxybenzene Chemical compound C(C1=CC=CC=C1)OC1=C(C=CC=C1C(=C)C1CC1)C(=C)C1CC1 VUTGVRJAQQWHIX-UHFFFAOYSA-N 0.000 description 1
- DREUXBUJNNMGEV-UHFFFAOYSA-N 1,3-dibromo-2-[(4-nitrophenyl)methoxy]benzene Chemical compound BrC1=C(C(=CC=C1)Br)OCC1=CC=C(C=C1)[N+](=O)[O-] DREUXBUJNNMGEV-UHFFFAOYSA-N 0.000 description 1
- FYTQDADUVFGKHG-UHFFFAOYSA-N 1,3-dibromo-2-phenylmethoxybenzene Chemical compound BrC1=CC=CC(Br)=C1OCC1=CC=CC=C1 FYTQDADUVFGKHG-UHFFFAOYSA-N 0.000 description 1
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- 208000026139 Memory disease Diseases 0.000 description 1
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- 101100109871 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) aro-8 gene Proteins 0.000 description 1
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- BEOKBUHJDGJDKO-UHFFFAOYSA-N [Cl].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 Chemical compound [Cl].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BEOKBUHJDGJDKO-UHFFFAOYSA-N 0.000 description 1
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- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000004645 aluminates Chemical class 0.000 description 1
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- 230000037005 anaesthesia Effects 0.000 description 1
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- 230000036506 anxiety Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000009739 binding Methods 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940045803 cuprous chloride Drugs 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
- ORBBTCHHNMWMCP-UHFFFAOYSA-K cycloocta-1,5-diene trichloroiridium Chemical class [Ir](Cl)(Cl)Cl.C1=CCCC=CCC1 ORBBTCHHNMWMCP-UHFFFAOYSA-K 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- VBXJWRFADSRGDI-UHFFFAOYSA-L dichloronickel propane Chemical class CCC.Cl[Ni]Cl VBXJWRFADSRGDI-UHFFFAOYSA-L 0.000 description 1
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
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- 238000003379 elimination reaction Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
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- 239000002024 ethyl acetate extract Substances 0.000 description 1
- NPTDXPDGUHAFKC-UHFFFAOYSA-N ethynylcyclopropane Chemical group C#CC1CC1 NPTDXPDGUHAFKC-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- ABCGFHPGHXSVKI-UHFFFAOYSA-O meso-tetrakis(n-methyl-4-pyridyl)porphine(4+) Chemical compound C1=C[N+](C)=CC=C1C(C1=CC=C(N1)C(C=1C=C[N+](C)=CC=1)=C1C=CC(=N1)C(C=1C=C[N+](C)=CC=1)=C1C=CC(N1)=C1C=2C=C[N+](C)=CC=2)=C2N=C1C=C2 ABCGFHPGHXSVKI-UHFFFAOYSA-O 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
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- 230000008506 pathogenesis Effects 0.000 description 1
- YHBDIEWMOMLKOO-UHFFFAOYSA-I pentachloroniobium Chemical compound Cl[Nb](Cl)(Cl)(Cl)Cl YHBDIEWMOMLKOO-UHFFFAOYSA-I 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- OSCBARYHPZZEIS-UHFFFAOYSA-N phenoxyboronic acid Chemical class OB(O)OC1=CC=CC=C1 OSCBARYHPZZEIS-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- RWRDJVNMSZYMDV-UHFFFAOYSA-L radium chloride Chemical class [Cl-].[Cl-].[Ra+2] RWRDJVNMSZYMDV-UHFFFAOYSA-L 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- ABTOQLMXBSRXSM-UHFFFAOYSA-N silicon tetrafluoride Chemical compound F[Si](F)(F)F ABTOQLMXBSRXSM-UHFFFAOYSA-N 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- OJUSBFWTJVFJMJ-UHFFFAOYSA-N tert-butyl (2,6-dibromophenyl) carbonate Chemical compound C(OC(C)(C)C)(OC1=C(C=CC=C1Br)Br)=O OJUSBFWTJVFJMJ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- CMLWFCUAXGSMBB-UHFFFAOYSA-N tris(2,6-dimethoxyphenyl)phosphane Chemical compound COC1=CC=CC(OC)=C1P(C=1C(=CC=CC=1OC)OC)C1=C(OC)C=CC=C1OC CMLWFCUAXGSMBB-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
- C07C37/18—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving halogen atoms of halogenated compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明涉及一种通式(A)所述化合物及其光学异构体的制备方法,该制备方法包括将卤代苯酚衍生物与硼化合物偶联后再催化氢化得到通式(A)化合物,该方法具有反应路线短,原料价廉易得,适合工业化生产等优点。通式(A)化合物结构如下所示,R的定义与说明书定义一致。
Description
本发明涉及一种通式(A)所述化合物及其光学异构体的制备方法,该制备方法包括将卤代苯酚衍生物与硼化合物偶联后再催化氢化得到通式(A)化合物。
GABAA受体是中枢神经系统中主要的抑制性神经递质受体。GABAA受体由跨膜多肽亚基的五聚体构成,19种不同的亚基组成了多种不同的GABAA受体亚型。GABAA受体涉及麻醉、抑郁、焦虑、癫痫、记忆障碍、药物依赖等多种疾病的发病机制和诊断治疗。
WO2014180305描述了一类苯酚衍生物及其制备方法和在中枢神经领域的用途,并具有良好的GABAA受体激动活性,有些化合物具有比市售丙泊酚更强的GABAA激动活性,尤其是一些环丙基乙基苯酚衍生物及其异构体在动物实验上显示更大治疗指数、更高安全指数、更宽的治疗窗或对应制剂中水相的游离浓度低,可预测有避免注射痛的效果,具有良好的临床应用前景,其通式结构如下:
同时也公开了1,2-二环丙基乙基苯酚衍生物的制备方法,涉及手性化合物得均采用色谱柱的方法来制备其手性化合物,例如:
该方法路线长,反应苛刻,使用色谱柱来手性拆分,不利于工业生产。
本发明的目的在于解决其不足之处,提供一种新的手性分离方法,通过对新中间体的不对称催化氢化得到通式(I)化合物。
发明内容
本发明涉及一种通式(A)化合物及其光学异构体的制备方法,其中通过通式(II)化合物进行还原反应制得,其中
R选自H或羟基保护基。
本发明优选方案,一种通式(A)化合物及其光学异构体的制备方法,其中通式(A)化合物选自其光学异构体即通式(I)化合物,其中
反应中使用还原剂为氢气,所使用的催化剂选自金属配合物,所述金属选自Co、Ni、Ru、Pd、Ir或Rh。
本发明优选方案,一种通式(I)化合物的制备方法,其中:
所述金属配合物的配体各自独立的选自(S)-二氢二苯磷苯基-4-异丙基恶唑、(R)-二氢二苯磷苯基-4-异丙基恶唑、(S)-(+)-2-[2-(二苯基膦)苯基]-4-苯基-2-噁唑啉、(R)-(-)-2-[2-(二苯基膦)苯基]-4-苯基-2-噁唑啉、(1S,1S',2R,2R')-Tangphos、(1R,1R’,2S,2S’)-Tangphos、(-)-1,2-双((2R,5R)-2,5-二甲基磷)苯、(+)-1,2-双((2S,5S)-2,5-二甲基磷)苯、(R,R)-DIPAMP((1R,2R)-二[(2-甲氧基苯基)苯基磷]乙烷)、(S,S)-DIPAMP、(1R,1'R,2S,2'S)-DuanPhos、(1S,1'S,2R,2R)-DuanPhos、(+)-异丙烯-2,3-二羟-1,4-双二丙基膦丁烷、(-)-异丙烯-2,3-二羟-1,4-双二丙基膦丁烷、N-二甲基-[(S)-1,1'-螺二氢茚-7,7'-二基]亚磷酰胺、N-二甲基-[(R)-1,1'-螺二氢茚-7,7'-二基]亚磷酰胺、(R)-(+)-(6,6'-二甲氧基联苯-2,2'-基)双(二苯基膦)、(S)-(+)-(6,6'-二甲氧基联苯-2,2'-基)双(二苯基膦)、((4S,5S)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基]二环己基膦、((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯
基-4,5-二氢恶唑-4-基)-2-苯基乙基]二环己基膦、(S)-8-[(二苯基膦基)氧基]-2-苯基-5.6.7.8-四氢喹啉、(R)-8-[(二苯基膦基)氧基]-2-苯基-5.6.7.8-四氢喹啉、(R)-(-)-1-[(S)-2-二苯基磷]二茂铁乙基二环己基磷、(S)-(+)-1-[(R)-2-二苯基磷]二茂铁乙基二环己基磷、R-(+)-1,1'-联萘-2,2'-双二苯膦、S-(-)-1,1'-联萘-2,2'-双二苯膦、(S)-7,7'-双[二(3,5-二甲基苯基羟亚磷基))-1,1'-螺二氢茚、(R)-7,7'-双[二(3,5-二甲基苯基羟亚磷基))-1,1'-螺二氢茚、((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基]二苯基膦、((4S,5S)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基]二苯基膦、(R)-C3-TUNEPHOS、(R)-C4-TUNEPHOS、(S)-C3-TUNEPHOS、(R)-C4-TUNEPHOS、(S)-7,7'-双[二(3,5-二甲基苯基)膦基]-1,1'-螺二氢茚、(R)-7,7'-双[二(3,5-二甲基苯基)膦基]-1,1'-螺二氢茚、(R)-7,7'-双[二(对甲基苯基)膦基]-1,1'-螺二氢茚、(S)-7,7'-双[二(对甲基苯基)膦基]-1,1'-螺二氢茚、(R)-7,7'-双(二苯基膦基)-1,1'-螺二氢茚、(S)-7,7'-双(二苯基膦基)-1,1'-螺二氢茚、(R)-4-叔丁基-2-(2-[(二苯基膦基)氧基]-2-丙基)-4,5-二氢恶唑、(S)-4-叔丁基-2-(2-[(二苯基膦基)氧基]-2-丙基)-4,5-二氢恶唑、(1S,5S,6S)-1,6-双(联苯基膦氧基)螺旋[4.4]壬烷、(1R,5R,6R)-1,6-双(联苯基膦氧基)螺旋[4.4]壬烷、(R,R)-N-甲磺酰-1,2-二苯基乙烷二胺、(S,S)-N-甲磺酰-1,2-二苯基乙烷二胺、(-)-MENO,(+)-MENO、(S)-[2,2]-PhanePhos、(R)-[2,2]-PhanePhos、(R,S,R,S)-Me-PennPhos、(S,R,S,R)-Me-PennPhos、(R)-Bdpab、(S)-Bdpab、(S)-(+)-(3,5-二氧-4-磷环己基[2,1-a;3,4-a']4-二萘基)哌啶、(R)-(-)-(3,5-二氧-4-磷环己基[2,1-a;3,4-a']4-二萘基)哌啶、对伞花烃、1,5-COD中的一种或多种;
所述金属配合物的简单离子可以不存在,或选自K+、OAc-、Cl-、BF4 -、PF6 -、CF3SO3 -、B(C6H5)4 -、Al(OC(CF3)3)4 -或[B[3,5-(CF3)2C6H3]4]-。
本发明优选方案,一种通式(I)化合物的制备方法,其中:
通式(I)化合物选自
所述金属配合物选自((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐、(R)-Ru(OAc)2BINAP、(R)-(+)-[Ru(C3-TUNEPHOS)(C6H6)Cl]Cl、(R)-(+)-[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、(R)-(+)-[Ru(BIPHEP)(C6H6)Cl]Cl、(R)-Ir(Tol-SDP)(COD)Cl、(R)-(+)-Ir(MeO-BIPHEP)(COD)Cl、((4S,5S)-(+)-O-[1-苯甲基
-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐、(S)-Ru(OAc)2BINAP、(S)-(+)-[Ru(C3-TUNEPHOS)(C6H6)Cl]Cl、(S)-(+)-[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、(S)-(+)-[Ru(BIPHEP)(C6H6)Cl]Cl、(S)-Ir(Tol-SDP)(COD)Cl、(S)-(+)-Ir(MeO-BIPHEP)(COD)Cl。
本发明优选方案,一种通式(I)化合物的制备方法,其中:
反应中所使用的溶剂选自水、二甲基亚砜、乙腈、N,N-二甲基甲酰胺、含有1至6个碳原子的醇、含有1至6个碳原子的酮、含有1至6个碳原子的羧酸、含有1至6个碳原子的羧酸酯、含有1至6个碳原子的醚、5至6元环或C1-6烷烃中的任一种或任几种任意比例的混合物;所述的环含有0至4个选自N、O、S的杂原子,所述的醇、酮、羧酸、羧酸酯、醚、环或烷烃任选进一步被0至6个选自H、F、Cl、Br、I、(=O)、甲基、乙基、异丙基或三氟甲基的取代基所取代;
反应中所使用的溶剂优选水、甲醇、六氟异丙醇、三氟乙醇、乙醇、异丙醇、二氧六环、氯仿、丙酮、乙酸、二甲基亚砜、二氯甲烷、二氯乙烷、四氢呋喃、乙腈、乙酸乙酯、甲基四氢呋喃、甲基叔丁基醚、乙醚、N,N-二甲基甲酰胺、苯、甲苯、氟化苯、1,2-二氟苯、对溴氟苯、2,3-二氟溴苯、六氟苯、溴五氟苯、二甲苯、三甲苯、二(三氟甲基)苯、三(三氟甲基)苯或三氟甲基苯中的任一种或任几种任意比例的混合物。
本发明优选方案,一种通式(I)化合物的制备方法,其中:
R选自H、甲基、苄基、硝基苄基、对甲氧基苄基、甲氧基甲醚、甲氧乙氧基甲基、叔丁基羰基、苯甲酰基、乙酰基、氯甲基羰基、对甲苯磺酰基、甲磺酰基、苯磺酰基、对硝基苯磺酰基、邻硝基苯磺酰基、三甲基硅基、三乙基硅基、对硝基苯甲酰基、对溴苯甲酰基、烯丙基、苄氧基羰基、叔丁氧基羰基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基。
本发明优选方案,一种通式(I)化合物的制备方法,其中:
反应压力选自2atm~50atm;优选2atm~30atm;
反应温度选自0~60℃;优选0~40℃。
本发明涉及一种通式(II)化合物的制备方法,其中进一步包括通过式(III)与式(IV)或式(IV`)化合物反应制备得到:
X选自Cl、Br或I;优选Br;
M选自Na、K或Li;
R各自独立的选自H或羟基保护基;
R1、R2和R3各自独立的选自H、OH、F、Cl、Br、C1-6烷氧基,或者R1和R2可以与其相连的原子一起形成4至10元环,所述环除含有杂原子B外,还含有0至4个选自O、N或S的杂原子,所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代。
本发明优选方案,一种通式(II)化合物的制备方法,其中:
X选自Br;
式(IV)化合物选自
式(IV`)化合物选自
本发明优选方案,一种通式(II)化合物的制备方法,其中:
反应中所使用的催化剂选自负载型金属催化剂或金属配合物,所述的金属选自Pd、Ru、Ir、Rh或Ni;
反应中所使用的溶剂选自甲苯、二氧六环、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺、水、乙二醇二甲醚、二氯甲烷或二氯乙烷中的任一种或任几种任意比例的混合物;
所述的反应加入碱性试剂,所述的碱性试剂选自碳酸钠、碳酸氢钠、醋酸钠、磷酸钠、碳酸铯、碳酸钾、碳酸氢钾、醋酸钾、磷酸钾、三乙胺、氟化钾、叔丁基胺、N,N-二异丙基乙胺、三丁胺、吡啶中的任一种或任几种的混合物。
本发明优选方案,一种通式(II)化合物的制备方法,其中:
X选自Br;
式(IV)化合物选自
式(IV`)化合物选自
反应中所使用的催化剂选自负载型金属催化剂或金属配合物,所述的金属选自Pd、Ru、Ir、Rh或Ni;
反应中所使用的溶剂选自甲苯、二氧六环、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺、水、乙二醇二甲醚、二氯甲烷或二氯乙烷中的任一种或任几种任意比例的混合物;
所述的反应加入碱性试剂,所述的碱性试剂选自碳酸钠、碳酸氢钠、醋酸钠、磷酸钠、碳酸铯、碳酸钾、碳酸氢钾、醋酸钾、磷酸钾、三乙胺、氟化钾、叔丁基胺、N,N-二异丙基乙胺、三丁胺、吡啶中的任一种或任几种的混合物。
本发明优选方案,一种通式(II)化合物的制备方法,其中:
R为H、叔丁基羰基、叔丁氧基羰基、烯丙基、苄基、对硝基苄基、对硝基苯甲酰基、苯甲酰基、对甲苯磺酰基、对硝基苯磺酰基、邻硝基苯磺酰基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基;
反应中所使用的催化剂选自Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/Ru-Phos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P或Pd2(dba)3/t-Bu3P。
本发明优选方案,一种通式(II)化合物的制备方法,其中:
R为H、对硝基苯磺酰基、邻硝基苯磺酰基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基;
反应中所使用的催化剂选自负载型金属催化剂或金属配合物,所述的金属选自Pd、Ru、Ir、Rh或Ni;
反应中所使用的溶剂选自甲苯、二氧六环、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺、水、乙二醇二甲醚、二氯甲烷或二氯乙烷中的任一种或任几种任意比例的混合物;
所述的反应加入碱性试剂,所述的碱性试剂选自碳酸钠、碳酸氢钠、醋酸钠、磷酸钠、碳酸铯、碳酸钾、碳酸氢钾、醋酸钾、磷酸钾、三乙胺、氟化钾、叔丁基胺、N,N-
二异丙基乙胺、三丁胺、吡啶中的任一种或任几种的混合物。
反应中所使用的催化剂选自Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/Ru-Phos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P或Pd2(dba)3/t-Bu3P。
本发明优选方案,一种通式(I)化合物的制备方法,其中:
a)通过式(III)化合物和式(IV)或式(IV`)化合物偶联反应制备得到式(II)化合物,反应中所使用的催化剂选自负载型金属催化剂或金属配合物,所述的金属选自Pd、Ru、Ir、Rh或Ni,
作为选择,R为羟基保护基时,式(II)化合物可以进一步脱去保护,
作为选择,R为H时,式(II)化合物可以进一步用羟基保护基保护,
b)通式(II)化合物被还原后得到通式(I)化合物,其中反应中使用还原剂为氢气,所使用的催化剂选自金属配合物,所述金属选自Co、Ni、Ru、Pd、Ir或Rh,
作为选择,R为羟基保护基时,通式(I)化合物可以进一步脱去保护,
作为选择,R为H时,通式(I)化合物可以进一步用羟基保护基保护,
X选自Cl、Br或I;M选自Na、K或Li;
R为H或羟基保护基;
R1、R2和R3各自独立的选自H、OH、F、Cl、Br、C1-6烷氧基,或者R1和R2可以与其相连的原子一起形成4至10元环,所述环除含有杂原子B外,还含有0至4个选自O、N或S的杂原子,所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代。
本发明优选方案,一种通式(I)化合物的制备方法,其中
通式(I)化合物选自
a)反应中所使用的催化剂选自Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/Ru-Phos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P或Pd2(dba)3/t-Bu3P;
b)反应中所述的催化剂选自((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐、(R)-Ru(OAc)2BINAP、(R)-(+)-[Ru(C3-TUNEPHOS)(C6H6)Cl]Cl、(R)-(+)-[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、(R)-(+)-[Ru(BIPHEP)(C6H6)Cl]Cl、(R)-Ir(Tol-SDP)(COD)Cl、(R)-(+)-Ir(MeO-BIPHEP)(COD)Cl。
本发明涉及一种式(II)所示的化合物,其中
R选自H或羟基保护基;优选H、叔丁基羰基、叔丁氧基羰基、烯丙基、苄基、对硝基苄基、对硝基苯甲酰基、苯甲酰基、对甲苯磺酰基、对硝基苯磺酰基、邻硝基苯磺酰基、R-(1-苯基)乙基氨基羰基或S-(1-苯基)乙基氨基羰基。
本发明涉及一种式(A)所示的化合物或者其光学异构体,其中所述的光学异构体为式(I-a)、(I-b)或者(I-c)所示的化合物,其中:
R选自羟基保护基;优选叔丁基羰基、叔丁氧基羰基、烯丙基、苄基、对硝基苄基、对硝基苯甲酰基、苯甲酰基、对甲苯磺酰基、对硝基苯磺酰基、邻硝基苯磺酰基、R-(1-苯基)乙基氨基羰基或S-(1-苯基)乙基氨基羰基;优选R-(1-苯基)乙基氨基羰基或S-(1-苯基)乙基氨基羰基。
本发明涉及的羟基保护基选自烷基醚类保护基、酯类保护基或硅醚类保护基,羟基
保护基包括但不限于H、甲基、苄基、硝基苄基、对甲氧基苄基、甲氧基甲醚、甲氧乙氧基甲基、叔丁基羰基、苯甲酰基、乙酰基、氯甲基羰基、对甲苯磺酰基、甲磺酰基、苯磺酰基、对硝基苯磺酰基、邻硝基苯磺酰基、三甲基硅基、三乙基硅基、对硝基苯甲酰基、对溴苯甲酰基、烯丙基、苄氧基羰基、叔丁氧基羰基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基;羟基保护基的的保护和脱除反应,均按常规方法制备;其脱除方法包括但不限于:
1)烷基醚类保护基可以在碱性或酸性条件下脱除,所述碱或酸包括但不限于氢化钠、甲醇钠、碳酸钾、氢氧化钾、氢氧化钠、吡啶、三氟乙酸、盐酸、甲酸或乙酸;
2)酯类保护基可以在碱性条件下脱除,所述碱包括但不限于甲醇钠、碳酸钾、氢氧化钾、氢氧化钠、氢化铝锂、吡啶或氨;
3)硅醚类保护基可以在氟化氢、四丁基氟化氨等条件下脱除。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明涉及到被多个取代基取代时,各取代基可以相同或不相同。
本发明涉及到含有多个杂原子时,各杂原子可以相同或不相同。
本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫、氮或卤素均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫或氮任选进一步被1至5个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“路易斯酸”是指能作为电子对接受体的原子,分子,离子或原子团,包括但不限于AlCl3、ZnCl2、SnCl4、TiCl4、FeCl3、BF3、NbCl5、SiF4、SbF5、CF3COOH、CuCl2、FeBr3、BCl3或AlBr3等。
“配合物”也称络合物,是指含有配位单元的化合物。由中心原子或离子与几个配体分子或离子以配位键相结合而形成的复杂分子或离子,通常称为配位单元。
“金属配合物”是指配位单元是由金属和配体构成,当金属与多个配体结合时,配体可以相同,也可以不相同。所述金属选自过渡金属非限制性实例包括Co、Ni、Ru、Pd、Ir或Rh;所述配体的非限制性实例包括Cl-、OAc-、CN-、COD、PPh3、P(i-Pr)3、P(环己基)3、P(o-MeOPh)3、P(p-MeOPh)3、Ph2P(CH2)3PPh2、Ph2P(CH2)2PPh2、Ph2P(CH2)4PPh2、Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp)、dppp、dppb、dppe、dba、BINAP、TDMPP、
TMPP、TMSPP、P(O-邻甲氧基苯基)3、P(O-对甲氧基苯基)3、吡啶、Bu3P、n-Bu3P、(MeO)3P、AsPh3\P(OEt)3。除配位单元外金属配合物可以含有简单离子,也可以缺省,所述的简单离子选自Cl-、BF4 -、PF6 -、CF3SO3 -、B(C6F5)4 -、B(C6H5)4 -、Al(OC(CF3)3)4 -或[B[3,5-(CF3)2C6H3]4]-。金属配合物的非限制性实例包括Pd(OAc)2、PdCl2(PPh3)2、Pd(PPh3)4、PdCl2(dppf)、Pd(dba)2、(dppp)NiCl2、(R)-Ru(OAc)2BINAP、(Ph3P)3·RuClH、[(Ph)3P]3RuCl2、[(Ph)3P]3Ru(CO)H2、Ph3P)3·IrH、Ir(dppe)2、Ph3P)3·RhCl、((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐、(R)-Ru(OAc)2BINAP、(R)-(+)-[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、(R)-(+)-[Ru(BIPHEP)(C6H6)Cl]Cl、(R)-Ir(Tol-SDP)(COD)Cl、(R)-(+)-Ir(MeO-BIPHEP)(COD)Cl或由Pd(OAc)2、PdCl2与AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe)、Ph2P(CH2)3PPh2(dppp)组成的催化体系。
图1为实施例7的化合物5-1X-射线单晶衍射图谱。
以下结合附图及实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(BrukerAvance III 400和BrukerAvance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),氘代乙腈(CD3CN),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
(Ph3P)3·RhCl:三(三苯基膦)氯化铑
(Ph3P)3·RuClH:三(三苯基膦)氯氢化钌
(Ph3P)3·IrH:三(三苯基膦)氢化合铱
(R)-Ru(OAc)2BINAP:二乙酸根[(R)-(+)-2,2'-二(二苯基膦基)-1,1'-联萘基]钌
[(Ph)3P]3RuCl2:三(三苯基膦)二氯化钌
[(Ph)3P]3Ru(CO)H2:三(三苯基膦)羰基二氢钌
PdCl2:二氯化钯
Pd(OAc)2:二醋酸钯
PdCl2(PPh3)2:三(三苯基膦)二氯化钯
Pd(PPh3)4:四(三苯基膦)钯
PdCl2(dppf):[1,1'-双(二苯基膦基)二茂铁]二氯化钯
Pd(dba)2:三(二亚苄基丙酮)二钯
(dppp)NiCl2:1,3-双(二苯基膦)丙烷氯化镍
[Ir(COD)Cl]2:1,5-环辛二烯氯化铱二聚体
[Ru(C6H6)Cl2]2:二氯苯基钌(II)二聚体
(R)-(+)-MeO-BIPHEP:(R)-(+)-(6,6'-二甲氧基联苯-2,2'-基)双(二苯基膦)
(R)-(+)-BINAP:(R)-(+)-1,1'-联萘-2,2'-双二苯膦
(R)-Tol-SDP:(R)-7,7'-双(二(对甲基苯基)膦基]-1,1'-螺二氢茚
COD:1,5-环辛二烯
B(C6F5)4 -:四(五氟苯基)硼酸根
B(C6H5)4 -:四(苯基)硼酸根
Al(OC(CF3)3)4 -:四(三(三氟甲基)甲氧基)铝酸根
[B[3,5-(CF3)2C6H3]4]-:四(3,5-二(三氟甲基)苯基)硼酸根
DIPAMP:双[(2-甲氧基苯基)苯基磷]乙烷
实施例1
2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)
2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
方法一:
氮气保护下,向反应瓶中加入无水氯化锂(4.66g,110mmol)、氯化亚酮(10.89g,110mmol)和干燥的N,N-二甲基甲酰胺(300mL),室温下搅拌1小时后,依次加入醋酸钾(10.80g,110mmol)、联硼酸片那醇硼酯(27.93g,110mmol)和环丙基乙炔(1A)(6.61g,100mmol),室温下继续搅拌20小时,加入饱和食盐水(200mL)搅拌10分钟,抽滤,滤饼用乙酸乙酯洗(50mL),滤液用乙酸乙酯(150mL×3)萃取,收集有机层用饱和食盐水(150mL×3)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(10.80g,产率:55.67%)。
方法二:
氮气保护下,向两口瓶中加入无水四氢呋喃(30mL),用水泵置换氮气10min,滴加二异丁基氢化铝(DIBAL-H)(1.5M in toluene,17.3mL,26.0mmol),加毕于冰水浴中冷却至0℃后,滴加环丙基乙炔(1A)(1.322g,20.0mmol),升至室温搅拌2小时后,却至0℃,加入异丙醇频哪醇硼酸酯(11.116g,60.0mmol),加毕升至80℃搅拌4小时后,冷却至室温,加入水(30mL)搅拌30min,乙酸乙酯萃取(30mL×2),合并有机相用无水硫酸钠干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(530mg,产率:14%)。
方法三:
将溴苯(1.87g,10.0mmol),联硼酸片那醇酯(2.78g,11.0mmol),三环己基膦(280mg,1.0mmol),醋酸钯(40mg,0.5mmol)和环丙乙炔(1A)(0.66g,10mmol)溶于甲苯(20mL)中,加入三氟乙醇(2.0g,20.0mmol),氮气置换3次.加热至80℃搅拌7h.,冷却至室温,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(230mg,产率:12%)。
1H NMR(400MHz,CDCl3):δ5.64(d,1H),5.49(d,1H),1.54-1.48(m,1H),
1.26(s,12H)δ0.70-0.65(m,2H),0.60-0.57(m,2H)。
实施例2
2,6-二(1-环丙基乙烯基)苯酚(化合物2)
2,6-bis(1-cyclopropylvinyl)phenol
方法一:
第一步:(R)-2,6-二溴苯基(1-苯乙基)氨基甲酸酯(2B)
(R)-2,6-dibromophenyl(1-phenylethyl)carbamate
向250mL单口瓶中加入2,6-二溴苯酚(2A)(5.0g,19.85mmol)和四氢呋喃(50mL),搅拌下加入三乙胺(4.02g,39.70mmol),(R)-1-苯基乙基异氰酸酯(4.38g,29.77mmol),氮气保护,室温反应5小时,反应液直接拌硅胶,柱层析分离纯化得白色固体状的(R)-2,6-二溴苯基(1-苯乙基)氨基甲酸酯(2B)(5.6g,产率77.8%)。
1H NMR(400MHz,CDCl3)δ7.55(d,2H),7.45-7.38(m,3H),7.34-7.30(m,2H),6.99(t,1H),5.48(s,1H),5.02-4.96(m,1H),1.64(d,3H)。
第二步:(R)-2,6-二(1-环丙基乙烯基)苯基(1-苯乙基)氨基甲酸酯(2C)
(R)-2,6-bis(1-cyclopropylvinyl)phenyl(1-phenylethyl)carbamate
将(R)-2,6-二溴苯基(1-苯乙基)氨基甲酸酯(2B)(0.5g,1.25mmol)、2-(1-环己基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(0.73g,3.76mmol)和碳酸钾水溶液(4mol/L,12mL,5.01mmol)加入到甲苯(10mL)中,然后加入催化剂[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.091g,0.125mmol),置换氮气三次,氮气保护,90℃反应5个小时,旋除溶剂,直接柱层析(石油醚:乙酸乙酯(v/v)=100:1-50:1)纯化得黄色固体状(R)-2,6-二(1-环丙基乙烯基)苯基(1-苯乙基)氨基甲酸酯(2C)(0.2g,产率42.7%)。
1H NMR(400MHz,CDCl3)δ7.36-7.34(m,4H),7.29-7.27(m,1H),7.20-7.12(m,3H),5.19(d,1H),4.96(d,4H),4.90-4.86(m,1H),1.61-1.59(m,2H),1.53(d,3H),0.69(d,4H),0.51(d,4H)。
第三步:2,6-二(1-环丙基乙烯基)苯酚(化合物2)
2,6-bis(1-cyclopropylvinyl)phenol
向100mL单口瓶中加入(R)-2,6-二(1-环丙基乙烯基)苯基(1-苯乙基)氨基甲酸酯(2C)(3.0g,8.03mmol)和四氢呋喃(50mL),搅拌下加入水(10mL)和氢氧化钠(0.642g,16.06mmol),氮气保护,70℃反应5小时,反应完毕后,分液,有机相用盐酸水溶液(1mol/L)(20mL×3)洗至中性,无水硫酸钠干燥,过滤,将滤液减压浓缩得黄色油状物,湿法柱层析分离纯化得黄色油状的2,6-二(1-环丙基乙烯基)苯酚(化合物2)(0.9g,产率50%)
1H NMR(400MHz,CDCl3)δ7.06(d,2H),6.83(t,1H),7.34-7.30(m,2H),5.77(s,1H),5.23(d,2H),5.06(d,2H),1.75-1.68(m,2H),0.78-0.73(m,4H),0.54-0.50(m,4H)。
方法二:
将2,6二溴苯(2A)(1.0g,4.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.55g,8.0mmol)和七水磷酸钾(5.41g,16.0mmol)溶于甲苯/水(v/v=3/1,8mL)混合溶剂中,N2置换空气,边搅拌边置换空气约30分钟。加入催化剂醋酸钯(0.018g,0.08mmol)和2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(Ruphos)(0.075g,0.16mmol),继续N2置换空气3次后,置于100℃油浴中反应3小时。将反应液自然冷至室温,分离有机相,水相用乙酸乙酯(10mL×2)萃取,合并有机相,有机相用水(5mL×2)洗涤,无水硫酸钠干燥,浓缩得深色粘稠液体,HPLC显示目标产物含量64.1%(210nm)。
方法三:
将2,6二溴苯(2A)(20.2g,80.0mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(31.06g,160.0mmol)和七水磷酸钾(108.3g,320.0mmol)溶于甲苯/水(v/v=1/1,80mL)混合溶剂中,N2置换空气,边搅拌边置换空气约30分钟。加入催化剂醋酸钯(0.18g,0.8mmol)和2-二环己基膦-2',6'-二甲氧基-联苯(S-phos)(0.656g,1.6mmol),继续N2置换空气3次后,置于106℃油浴中回流反应6小时。将反应液自然冷至室温,分离有机相,水相用乙酸乙酯萃取(50mL×2),合并有机相,有机相用水洗涤(3mL×2),无水硫酸钠干燥,浓缩得深色粘稠液体,HPLC显示目标产物含量68.0%(210nm)。
方法四:
将2,6二溴苯(2A)(1.0g,4.0mmol),2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.55g,8.0mmol),七水磷酸钾(5.41g,16.0mmol)溶于4mL(THF/H2O=1/1)混合溶剂中,N2置换空气,边搅拌边置换空气约30分钟。加入催化剂醋酸钯(0.036g,0.16mmol)和2-二环己基膦-2',6'-二甲氧基-联苯(S-phos)(0.13g,0.32mmol),继续N2置换空气3次后,置于90℃油浴中回流反应6小时。将反应液自然冷至室温,分离有机相,水相用乙酸乙酯萃取(10mL×2),合并有机相,有机相用水(5mL×2)洗涤,无水硫酸钠干燥,浓缩得深色粘稠液体,HPLC显示目标产物含量77.0%(210nm)。
方法五:
反应瓶中加入2,6-二溴苯酚(2A)(0.252g,1mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(0.485g,2.5mmol)、磷酸钾(0.637g,3mmol)以及甲苯/水(3mL/1mL)混合溶剂,室温下用水泵抽气10分钟后,加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)[PdCl2(dppf)](0.073g,0.1mmol),加毕再次抽气15分钟后,置于已预热到90℃油浴中搅拌反应,3小时后停止反应,冷却至室温,反应液用乙酸乙酯(20mL×2)萃取,收集的有机层用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2,6-二(1-环丙基烯基)苯酚(化合物2)(0.114g,产率:50%)。
方法六:反应瓶中加入2,6-二溴苯酚(2A)(1.0g,4mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.69g,2.2mmol)、氯化钯(0.073g,0.4mmol),三叔丁基膦的溶液(1.4mL,1mol/L,1.4mmol)磷酸钾(2.53g,12mmol)以及甲苯/水(10mL/3mL)混合溶剂,室温下用水泵抽气10分钟后,置于已预热到90℃油浴中搅拌反应,3小时后停止反应,冷却至室温,反应液用乙酸乙酯(20mL×2)萃取,收集的有机层用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物2,6-二(1-环丙基烯基)苯酚(化合物2)(0.5g,产率60%)。
MS m/z(ESI):227.1(M+1)。
1H NMR(400MHz,CDCl3)δ7.07(d,2H),6.84(t,1H),5.78(s,1H),5.26–5.20(m,2H),5.06(d,2H),1.76–1.69(m,2H),0.79–0.74(m,4H),0.55–0.51(m,4H)。
实施例3
[2,6-二(1-环丙基乙烯基)苯基]乙酸酯(化合物3)
2,6-bis(1-cyclopropylvinyl)phenyl acetate
反应瓶中加入(2,6-二溴苯基)乙酸酯(3A)(0.5g,1.7mmol)、2-(1-环丙基乙烯基)
-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(1.0g,5.1mmol)、磷酸钾(1.8g,8.5mmol)以及甲苯/水(10mL/5mL)混合溶剂,室温下用水泵抽气10分钟后,加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)[PdCl2(dppf)](0.25g,0.34mmol),加毕再次抽气15分钟后,置于已预热到90℃油浴中搅拌反应,3小时后停止反应,冷却至室温,反应液用乙酸乙酯(20mL×2)萃取,收集的有机层用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物[2,6-二(1-环丙基乙烯基)苯基]乙酸酯(化合物3)(0.24g,产率50%)。
MS m/z(ESI):269.3(M+1)。
1H NMR(400MHz,CDCl3)δ:7.22–7.15(m,3H),5.03(s,2H),4.94(d,J=1.2Hz,2H),2.20(s,3H),1.61–1.56(m,2H),0.75–0.72(m,4H),0.55–0.51(m,4H)。
实施例4
[2,6-二(1-环丙基烯基)苯基]特戊酸酯(化合物4)
2,6-bis(1-cyclopropylvinyl)phenyl pivalate
向反应瓶中加入2,6-二溴苯基特戊酸酯(4A)(0.5g,1.5mmol)、2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(0.86g,4.5mmol)、磷酸钾(1.58g,7.5mmol)以及甲苯/水(10mL/5mL)混合溶剂,室温下用水泵抽气10分钟后,加入1,1'-二(二苯膦基)二茂铁二氯化钯(II)[PdCl2(dppf)](0.22g,3.0mmol),加毕再次抽气15分钟后,置于已预热到90℃油浴中搅拌反应,3小时后停止反应,冷却至室温,反应液用乙酸乙酯(20mL×2)萃取,收集的有机层用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,过滤,将滤液减压浓缩,残留物用硅胶柱色谱分离提纯(石油醚)得到黄色液体状的目标产物[2,6-二(1-环丙基烯基)苯基]特戊酸酯(化合物4)(0.17g,产率35%)。
MS m/z(ESI):311.1(M+1)。
1H NMR(400MHz,CDCl3)δ7.15–7.11(m,3H),5.07(dd,2H),4.87(d,2H),1.66–1.59(m,2H),1.28(s,9H),0.75–0.61(m,4H),0.53–0.35(m,4H)。
实施例5
2,6-二((R)-1-环丙基乙基)苯酚(化合物5)
2,6-bis((R)-1-cyclopropylethyl)phenol
向250mL高压釜中加入2,6-二(1-环丙基乙烯基)苯酚(化合物2)(0.228g,1.007mmol)和二氯甲烷(5mL),加入催化剂((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐(17mg,0.01mmol),氢气置换三次,20atm下反应5小时,浓缩,快速柱层析(石油醚/乙酸乙酯(v/v)=10:1)得到白色固体状的2,6-二((R)-1-环丙基乙基)苯酚(化合物5)(0.18g,产率88%,手性HPLC:88%)。
Rt=15.7min,分离条件:手性柱CHIRALPAK OZ-H,流动相:正己烷/异丙醇(v/v)=100:0,流速:1.0mL/分钟,UV=214nm,柱温:35℃。
MS m/z(ESI):229.2(M-1)。
1H NMR:(400MHz,CDCl3):δ7.13(d,2H,ArH),6.90(t,1H,),5.06(s,1H,ArOH),2.52-2.48(m,2H),1.29(d,6H),1.06-1.02(m,2H),0.55-0.42(m.4H),0.22-0.16(m,4H)。
实施例6
[2,6-二[(1R)-1-环丙基乙基]苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物5-1)
[2,6-bis[(1R)-1-cyclopropylethyl]phenyl]N-[(1R)-1-phenylethyl]carbamate
向反应瓶中加入[2,6-二[(1R)-1-环丙基乙基]苯酚(化合物5)(1.00g,4.34mmol)和四氢呋喃(10mL),滴加三乙胺(0.44g,4.34mmol),搅拌均匀后加入(1R)-1-苯乙基异氰酸酯(0.83g,5.64mmol),加热至63℃搅拌过夜,减压浓缩,用乙酸乙酯(5mL)溶解,减压抽滤除去不溶物,将滤液减压浓缩,得到白色固体状的[2,6-二[(1R)-1-环丙基乙基]苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物5-1)(1.2g,HPLC:97.4%,chiral-HPLC:99.88%)。
MS m/z(ESI):378.5[M+1]。
实施例7
[2,6-二[(1R)-1-环丙基乙基]苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物5-1)的X-射线单晶衍射测试
取上述制备得到的[2,6-二[(1R)-1-环丙基乙基]苯基]N-[(1R)-1-苯乙基]氨基甲酸酯(化合物5-1,10mg)溶于异丙醇中,加热溶清后,静置数天,有单晶晶体析出,抽滤洗涤,干燥后单晶检测。
化合物5-1的18位碳原子的绝对构型由已知的(R)-(+)-1-苯乙基异氰酸酯引入,故化合物5-1的18位碳原子的绝对构型为R构型,根据X-射线单晶衍射图谱(图1)显示:C-7、C-12的绝对构型与18-C的绝对构型一致,故为R构型,从而确证化合物5的C-7、C-12的绝对构型均为R构型。
实施例8
化合物5的手性保持实验
化合物5-1需经过碱性水解反应后获得产物化合物5。通过进行手性保持实验,证实在碱性水解过程中化合物5-1未发生C-7、C-12处的绝对构型转变。
方法:化合物5(手性纯度为99.88%)与氢氧化钠水溶液和1,4-二氧六环在85℃加热2小时后(此条件比化合物5-1水解条件更剧烈),再次进行手性纯度测试,证实化合物5的手性纯度仍为99.88%,与实验前手性纯度一致。实验结果证实化合物5-1中C-7、C-12的绝对构型与水解终产物化合物5中C-7、C-12的绝对构型一致。
实施例9
2,6-二((S)-1-环丙基乙基)苯酚(化合物6)
2,6-bis((S)-1-cyclopropylethyl)phenol
向250mL高压釜中加入2,6-二(1-环丙基乙烯基)苯酚(化合物2)(0.228g,1.007mmol)和二氯甲烷(5mL),加入催化剂((4S,5S)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐(17mg,0.01mmol),氢气置换三次,20atm下反应5小时,浓缩,快速柱层析(石油醚/乙酸乙酯(v/v)=10:1)得到白色固体状的2,6-二((S)-1-环丙基乙基)苯酚(化合物6)(0.18g,产率:88%,手性HPLC:77%)。
MS m/z(ESI):229.2(M-1)。
1H NMR:(400MHz,CDCl3):δ7.13(d,2H),6.90(t,1H),5.06(s,1H),2.52-2.48(m,2H),1.29(d,6H),1.06-1.02(m,2H),0.55-0.42(m,4H),0.22-0.16(m,4H)。
实施例10
二(1-环丙基乙基)苯酚(化合物7)
bis(1-cyclopropylethyl)phenol
方法一:
室温下在25mL的圆底烧瓶中加入2,6-二(1-环丙基乙烯基)苯酚(化合物2)(226
mg,1mmol)和二氯甲烷(2mL),然后加入催化剂Raney-Ni(5.8mg,0.1mmol),加完后加上氢气球,水泵减压下置换氢气3次,然后在氢气球的氛围下,室温反应5小时,旋干溶剂,残留物柱层析纯化(石油醚:乙酸乙酯=10:1)得标题化合物二(1-环丙基乙基)苯酚(化合物7),淡黄色液体(69mg,产率30%)。
方法二:
室温下在10mL的西林瓶中加入2,6-二(1-环丙基乙烯基)苯酚(化合物2)(113mg,0.5mmol)和二氯甲烷(2mL),然后加入催化剂Raney-Ni(5.8mg,0.1mmol),加完将西林瓶置于将高压釜中,密闭拧紧,水泵抽气并用钢瓶中的氢气置换氢气3次,充入氢气,高压釜上的压力表氢气压力显示为20atm,室温下反应20小时;旋干溶剂,残留物柱层析纯化(石油醚:乙酸乙酯=10:1),得标题化合物二(1-环丙基乙基)苯酚(化合物7),淡黄色液体(77mg,产率67%)。
方法三:
室温下在10mL的西林瓶中加入2,6-二(1-环丙基乙烯基)苯酚(化合物2)(113mg,0.5mmol)和二氯甲烷(2mL),然后加入催化剂Rh(COD)2BF4(4.1mg,0.01mmol),加完将西林瓶置于将高压釜中,密闭拧紧,水泵抽气并用钢瓶中的氢气置换氢气3次.充入氢气,高压釜上的压力表氢气压力显示为20atm,室温下反应20小时;旋干溶剂,残留物柱层析纯化(石油醚:乙酸乙酯=10:1),得标题化合物二(1-环丙基乙基)苯酚(化合物7),淡黄色液体(80mg,产率69%)。
实施例11
2,6-二((R,S)-1-环丙基乙基)苯酚(化合物8)
2,6-bis((R,S)-1-cyclopropylethyl)phenol
室温下在10mL的西林瓶中加入2,6-二(1-环丙基乙烯基)苯酚(化合物2)(113mg,0.5mmol)和二氯甲烷(2mL),然后加入催化剂(R)-RuBINAP(8.4mg,0.01mmol),加完将西林瓶置于将高压釜中,密闭拧紧,水泵抽气并用钢瓶中的氢气置换氢气3次.充入氢气,高压釜上的压力表氢气压力显示为20atm,室温下反应20小时,旋干溶剂,残留物柱层析纯化(石油醚:乙酸乙酯=10:1)得淡黄色液体2,6-二((R)-1-环丙基乙基)苯酚(化合物5),2,6-二((R,S)-1-环丙基乙基)苯酚(化合物8)和2,6-二((S)-1-环丙基乙基)苯酚(化合物6)的混合物(100mg,总产率87%,手性纯度比为:33.5:57.6:8.8)。
实施例12
2,6-二(1-环丙基乙烯基)苯酚(化合物2)
2,6-bis(1-cyclopropylvinyl)phenol
第一步:2,6-二溴苯基4-硝基苯磺酸酯(9B)
2,6-dibromophenyl 4-nitrobenzenesulfonate
将2,6-二溴苯酚(2A)(10g,39.7mmol),氢氧化钠(1.75g,43.8mmol),THF(50mL)加入反应瓶,60℃加热反应2小时,冰浴冷却,加入对硝基苯磺酰氯(9.65g,43.5mmol)的四氢呋喃(20ml)溶液,加完升至室温反应3小时,停止反应;加入100mL水稀释,分液,水层用乙酸乙酯(100mL×2)萃取,合并有机相,用饱和食盐水(200mL×2)洗涤,无水硫酸钠干燥,浓缩,乙酸乙酯重结晶得黄色晶体2,6-二溴苯基4-硝基苯磺酸酯(9B),(11.1g,产率64%);
1H NMR(400MHz,CDCl3)δ8.43(2H,d),8.25(2H,d),7.57(2H,d),7.05(2H,t).LC-MS:495(+23)。
第二步:2,6-二(1-环丙级乙烯基)苯基4-硝基苯磺酸酯(9C)
2,6-bis(1-cyclopropylvinyl)phenyl 4-nitrobenzenesulfonate
将(2,6-二溴苯基)4-硝基苯磺酸酯(9B)(8g,18.30mmol),2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(10.7g,55.1mmol),磷酸钾(15.5g,73.0
mmol),PdCl2(dppf)(1.33g,1.82mmol)溶解于甲苯/水(40/40ml)中,排气30分钟,N2保护,100℃反应4h,停止反应;硅藻土过滤,滤渣用乙酸乙酯(50mL×1)洗涤,滤液分液,水层用乙酸乙酯(50mL×2)萃取,合并有机相,饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,快速硅胶柱层析,石油醚:乙酸乙酯=40:1得褐色液体粗品5.5g,乙醇打浆得黄色固体2.8g(产率37%)。
1H NMR(400MHz,CDCl3)δ8.33(2H,d),8.07(2H,d),4.92(2H,s),4.82(2H,s),1.54-1.47(m,4H),0.72-0.67(m,4H),0.44-0.40(m,4H);
LC-MS:433(M+23);
第三步:2,6-二(1-环丙基乙烯基)苯酚(化合物2)
2,6-bis(1-cyclopropylvinyl)phenol
将[2,6-二(1-环丙基乙烯基)苯基]4-硝基苯磺酸酯(9C)(0.5g,1.2mmol),氢氧化钠(0.146g,3.6mmol)及乙醇(5ml)加入到反应瓶中,60℃反应3小时停止反应,浓缩,硅胶柱层析得淡黄色液体2,6-二(1-环丙基乙烯基)苯酚(化合物2)0.2g(产率72%);
LC-MS:227(M+1)。
实施例13
2,6-二溴苯基4-甲基苯磺酸酯(化合物10)
2,6-dibromophenyl 4-methylbenzenesulfonate
将2,6-二溴苯酚2A(1g,4mmol),氢氧化钠(0.175g,4.4mmol),5ml乙氰加入到反应瓶中,60℃搅拌0.5h;加入对甲苯磺酰氯(0.833g,44mmol),继续60℃搅拌2h,反应完全,停止反应。浓缩,柱层析(石油醚:乙酸乙酯=100:1)得2,6-二溴苯基4-甲基苯磺酸酯(化合物10),白色固体(1.33g,产率82.5%)。
1H NMR(400MHz,CDCl3):δ7.91(2H,d),7.53(2H,d),7.35(2H,d),6.99(2H,t),2.47(3H,s)。
LC-MS:407.1(+1)。
实施例14
1,3-二溴-2-((4-硝基苄基)氧基)苯(化合物11)
1,3-dibromo-2-((4-nitrobenzyl)oxy)benzene
将2,6-二溴苯酚2A(10g,40mmol),对硝基苄溴(8.58g,40mmol),碳酸钾(8.23g,60mmol),乙氰(50ml)加入到反应瓶中,80℃反应5h,停止反应。过滤,滤液浓缩,石油醚重结晶得1,3-二溴-2-((4-硝基苄基)氧基)苯(化合物11),灰色粉末固体(9g,产率65%)。
1H NMR(400MHz,CDCl3):δ8.27(2H,d),7.76(2H,d,),7.56(2H,d),6.99(2H,t),5.14(2H,s)。
LC-MS:409.8(+23)。
实施例15
1,3-二溴-2-(苄基氧基)苯(化合物12)
1,3-dibromo-2-(benzyloxy)benzene
将化合物2,6-二溴苯酚(5.0g,19.85mmol)溶于50ml乙腈中,加入碳酸钾(4.11g,29.77mmol),加热到60度下滴加溴化苄(3.73g,21.83mmol),加完后,60度继续搅拌反应3小时。反应液浓缩干,加入200ml EA(乙酸乙酯),水洗(50ml×3),饱和氯化钠洗(50ml×3),硫酸钠干燥,过滤,浓缩干,过柱纯化(乙酸乙酯:石油醚=1:100)得1,3-二溴-2-(苄基氧基)苯(化合物12),黄色油状(11.2g,产率80%)。
1H NMR(400MHz,CDCl3)δ7.75-7.33(m,7H),6.63(t,1H),5.16(s,2H)。
实施例16
2-(苄氧基)-1,3-双(1-环丙基乙烯基)苯(化合物13)
2-(benzyloxy)-1,3-bis(1-cyclopropylvinyl)benzene
往反应瓶中加入溶剂甲苯/水(2.5L/2.5L),搅拌,加入2,6-二溴苯基(化合物12)甲基苯(4g,11.7mmol),2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(6.8g,35mmol),碳酸钾(6.6g,48mmol),PdCl2(dppf)(0.9g,1.23mmol),排气0.5h,N2保护,90℃反应6小时,停止反应;过滤,分液,水层用乙酸乙酯(40ml×1)萃取,合并有机相,无水硫酸钠干燥,浓缩,柱层析,石油醚洗脱得2-(苄氧基)-1,3-双(1-环丙基乙烯基)苯(化合物13),无色液体(1.9g,产率51%)。
1H NMR(400MHz,CDCl3)δ7.38(2H,d),7.36-7.26(3H,m)7.17(2H,d),7.06(1H,d),5.08(4H,s),4.89(2H,s),1.87-1.80(2H,m),0.76-0.71(m,4H),0.58-0.54(m,4H)。
LC-MS:317.0(+1)。
实施例17
叔丁基(2,6-二溴苯基)碳酸脂(化合物14)
tert-butyl(2,6-dibromophenyl)carbonate
将2,6-二溴苯酚2A(10.0g,39.70mmol)溶于100ml乙腈中,加入化合物三乙胺(8.03g,79.40mmol),4-二甲氨基吡啶(DMAP)(0.485g,3.97mmol),室温下滴加二碳酸二叔丁酯(13.0g,59.55mmol),加完后,室温下继续搅拌反应3小时。反应液浓缩干,加入200ml乙酸乙酯,用盐酸(1N)水溶液洗(50ml×3),水洗(50ml×3),饱和氯化钠洗(50ml×3),硫酸钠干燥,过滤,浓缩得叔丁基(2,6-二溴苯基)碳酸脂(化合物14),固体(11.2g,产率80%)。
1H NMR(400MHz,CDCl3)δ7.55(d,2H),6.76(t,1H),1.58(s,9H)。
实施例18
2-(烯丙氧基)-1,3-二溴苯(化合物15)
2-(allyloxy)-1,3-dibromobenzene
将原料(2,6-二溴苯基)甲基苯(5g,19.8mmol)、烯丙基溴(2.88g,23.8mmol)、碳酸钾(3.29g,23.8mmol),加入到60ml丙酮中,60℃加热搅拌反应2小时,原料消失,停止反应;过滤,滤液浓缩,柱层析,纯石油醚洗脱得2-(烯丙氧基)-1,3-二溴苯(化合物15),无色液体(5.68g,产率98%)。
1H NMR(400MHz,CDCl3):δ7.50(2H,d,),6.86(1H,t,),6.19-6.14(1H,m),5.31(2H,d),4.56(2H,d)。
实施例19
2,6-二(1-环丙级乙烯基)苯基苯甲酸酯(化合物16)
2,6-bis(1-cyclopropylvinyl)phenyl benzoate
第一步:2,6-二溴苯基4-苯甲酸酯(16B)
2,6-dibromophenyl benzoate
在250mL的单口烧瓶中加入2,6-二溴苯酚(2A)(10g,39.7mmol),二氯甲烷(100mL)溶解,依次加入苯甲酸(5.3g,43.7mmol)、DCC(9.0g,43.7mmol)、4-二甲氨基吡
啶(DMAP)(0.48g,4.0mmol),室温反应3小时,减压抽滤除去不溶物,浓缩,残留物柱层析纯化(石油醚:乙酸乙酯=30:1)得2,6-二溴苯基4-苯甲酸酯(16B),(12.0g,产率85.7%)。
1H NMR(400MHz,CDCl3)δ8.28-8.26(m,2H),7.68-7.56(m,5H),7.05(t,1H)。
第二步:2,6-二(1-环丙级乙烯基)苯基苯甲酸酯(化合物16)
2,6-bis(1-cyclopropylvinyl)phenyl benzoate
在50mL的圆底烧瓶中加入2,6-二溴苯基4-苯甲酸酯(16B)(0.5g,1.4mmol),二氧六环(6mL)溶解,依次加入2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(0.82g,3.7mmol)、Pd(dppf)Cl2(0.1g,0.14mmol)、K2CO3(4M,2mL),N2保护中,90℃反应7h,滤液分液,水层用乙酸乙酯(10mL×2)萃取,合并有机相,饱和食盐水(10mL)洗涤,无水硫酸钠干燥,浓缩,制备板分离(石油醚:乙酸乙酯=60:1)得无色油状物2,6-二(1-环丙级乙烯基)苯基苯甲酸酯(化合物16)(0.15g,产率33%)。
1H NMR(400MHz,CDCl3)δ8.13-8.11(m,2H),7.61-7.58(m,1H),7.47(t,2H),7.25-7.19(m,3H),4.97-4.94(m,4H),1.61-1.56(m,2H),0.67-0.65(m,4H),0.48-0.45(m,4H)。
实施例20
第二步:2,6-二(1-环丙级乙烯基)苯基4-硝基苯甲酸酯(化合物17)
2,6-bis(1-cyclopropylvinyl)phenyl 4-nitrobenzoate
第一步:2,6-二溴苯基4-硝基苯甲酸酯(17B)
2,6-dibromophenyl 4-nitrobenzoate
在250mL的单口烧瓶中加入2,6-二溴苯酚(2A)(10g,39.7mmol),二氯甲烷(50mL)溶解,依次加入TEA(三乙胺)(6.0g,59.6mmol)、4-二甲氨基吡啶(DMAP)(0.48g,4.0mmol),冰浴中滴加对硝基苯甲酰氯(8.1g,43.7mmol)的DCM(二氯甲烷)(50mL)溶液,加完后升至室温反应2小时,依次用水(100mL×1)、HCl(2M,100mL×1)、饱和食盐水(100mL×1)洗涤,无水硫酸钠干燥0.5h,浓缩得淡黄色固体2,6-二溴苯基4-硝基苯甲酸酯(17B)(13.0g,产率81.8%)。
1H NMR(400MHz,CDCl3)δ8.46-8.38(m,4H),7.63(d,2H),7.10(t,1H)。
第二步:2,6-二(1-环丙级乙烯基)苯基4-硝基苯甲酸酯(化合物17)
2,6-bis(1-cyclopropylvinyl)phenyl 4-nitrobenzoate
在50mL的圆底烧瓶中加入2,6-二溴苯基4-硝基苯甲酸酯(17B)(0.5g,1.25mmol),甲苯(6mL)和水(3mL)溶解,依次加入2-(1-环丙基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(化合物1)(0.73g,3.7mmol)、Pd(dppf)Cl2(0.1g,0.13mmol)、磷酸钾(K3PO4)
(0.66g,3.12mmol),N2保护中,90℃反应7h,滤液分液,水层用乙酸乙酯(10mL×2)萃取,合并有机相,饱和食盐水(10mL)洗涤,无水硫酸钠干燥,浓缩,制备板分离(石油醚:乙酸乙酯=60:1)得黄色油状物2,6-二(1-环丙级乙烯基)苯基4-硝基苯甲酸酯(化合物17)(0.12g,产率25%)。
Claims (18)
- 一种通式(A)化合物及其光学异构体的制备方法,其特征在于通过通式(II)化合物进行还原反应制得,其中R选自H或羟基保护基。
- 根据权利要求1所述的制备方法,其特征在于通式(A)化合物选自其光学异构体即通式(I)化合物,其中反应中使用还原剂为氢气,所使用的催化剂选自金属配合物,所述金属选自Co、Ni、Ru、Pd、Ir或Rh。
- 根据权利要求2所述的制备方法,其特征在于:所述金属配合物的配体各自独立的选自(S)-二氢二苯磷苯基-4-异丙基恶唑、(R)-二氢二苯磷苯基-4-异丙基恶唑、(S)-(+)-2-[2-(二苯基膦)苯基]-4-苯基-2-噁唑啉、(R)-(-)-2-[2-(二苯基膦)苯基]-4-苯基-2-噁唑啉、(1S,1S',2R,2R')-Tangphos、(1R,1R’,2S,2S’)-Tangphos、(-)-1,2-双((2R,5R)-2,5-二甲基磷)苯、(+)-1,2-双((2S,5S)-2,5-二甲基磷)苯、(R,R)-DIPAMP、(S,S)-DIPAMP、(1R,1'R,2S,2'S)-DuanPhos、(1S,1'S,2R,2R)-DuanPhos、(+)-异丙烯-2,3-二羟-1,4-双二丙基膦丁烷、(-)-异丙烯-2,3-二羟-1,4-双二丙基膦丁烷、N-二甲基-[(S)-1,1'-螺二氢茚-7,7'-二基]亚磷酰胺、N-二甲基-[(R)-1,1'-螺二氢茚-7,7'-二基]亚磷酰胺、(R)-(+)-(6,6'-二甲氧基联苯-2,2'-基)双(二苯基膦)、(S)-(+)-(6,6'-二甲氧基联苯-2,2'-基)双(二苯基膦)、((4S,5S)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基]二环己基膦、((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基]二环己基膦、(S)-8-[(二苯基膦基)氧基]-2-苯基-5.6.7.8-四氢喹啉、(R)-8-[(二苯基膦基)氧基]-2-苯基-5.6.7.8-四氢喹啉、(R)-(-)-1-[(S)-2-二苯基磷]二茂铁乙基二环己基磷、(S)-(+)-1-[(R)-2-二苯基磷]二茂铁乙基二环己基磷、R-(+)-1,1'-联萘-2,2'-双二苯膦、S-(-)-1,1'-联萘-2,2'-双二 苯膦、(S)-7,7'-双[二(3,5-二甲基苯基羟亚磷基))-1,1'-螺二氢茚、(R)-7,7'-双[二(3,5-二甲基苯基羟亚磷基))-1,1'-螺二氢茚、((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基]二苯基膦、((4S,5S)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基]二苯基膦、(R)-C3-TUNEPHOS、(R)-C4-TUNEPHOS、(S)-C3-TUNEPHOS、(R)-C4-TUNEPHOS、(S)-7,7'-双[二(3,5-二甲基苯基)膦基]-1,1'-螺二氢茚、(R)-7,7'-双[二(3,5-二甲基苯基)膦基]-1,1'-螺二氢茚、(R)-7,7'-双[二(对甲基苯基)膦基]-1,1'-螺二氢茚、(S)-7,7'-双[二(对甲基苯基)膦基]-1,1'-螺二氢茚、(R)-7,7'-双(二苯基膦基)-1,1'-螺二氢茚、(S)-7,7'-双(二苯基膦基)-1,1'-螺二氢茚、(R)-4-叔丁基-2-(2-[(二苯基膦基)氧基]-2-丙基)-4,5-二氢恶唑、(S)-4-叔丁基-2-(2-[(二苯基膦基)氧基]-2-丙基)-4,5-二氢恶唑、(1S,5S,6S)-1,6-双(联苯基膦氧基)螺旋[4.4]壬烷、(1R,5R,6R)-1,6-双(联苯基膦氧基)螺旋[4.4]壬烷、(R,R)-N-甲磺酰-1,2-二苯基乙烷二胺、(S,S)-N-甲磺酰-1,2-二苯基乙烷二胺、(-)-MENO,(+)-MENO、(S)-[2,2]-PhanePhos、(R)-[2,2]-PhanePhos、(R,S,R,S)-Me-PennPhos、(S,R,S,R)-Me-PennPhos、(R)-Bdpab、(S)-Bdpab、(S)-(+)-(3,5-二氧-4-磷环己基[2,1-a;3,4-a']4-二萘基)哌啶、(R)-(-)-(3,5-二氧-4-磷环己基[2,1-a;3,4-a']4-二萘基)哌啶、对伞花烃、1,5-COD中的一种或多种;所述金属配合物的简单离子可以不存在,或选自K+、OAc-、Cl-、BF4 -、PF6 -、CF3SO3 -、B(C6H5)4 -、Al(OC(CF3)3)4 -或[B[3,5-(CF3)2C6H3]4]-。
- 根据权利要求3所述的制备方法,其特征在于:通式(I)化合物选自所述金属配合物选自((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐、(R)-Ru(OAc)2BINAP、(R)-(+)-[Ru(C3-TUNEPHOS)(C6H6)Cl]Cl、(R)-(+)-[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、(R)-(+)-[Ru(BIPHEP)(C6H6)Cl]Cl、(R)-Ir(Tol-SDP)(COD)Cl、(R)-(+)-Ir(MeO-BIPHEP)(COD)Cl、((4S,5S)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐、(S)-Ru(OAc)2BINAP、(S)-(+)-[Ru(C3-TUNEPHOS)(C6H6)Cl]Cl、(S)-(+)-[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、(S)-(+)-[Ru(BIPHEP)(C6H6)Cl]Cl、(S)-Ir(Tol-SDP)(COD)Cl、(S)-(+)-Ir(MeO-BIPHEP) (COD)Cl。
- 根据权利要求4所述的制备方法,其特征在于:反应中所使用的溶剂选自水、二甲基亚砜、乙腈、N,N-二甲基甲酰胺、含有1至6个碳原子的醇、含有1至6个碳原子的酮、含有1至6个碳原子的羧酸、含有1至6个碳原子的羧酸酯、含有1至6个碳原子的醚、5至6元环或C1-6烷烃中的任一种或任几种任意比例的混合物;所述的环含有0至4个选自N、O、S的杂原子,所述的醇、酮、酸、酯、醚、环或烷烃任选进一步被0至6个选自H、F、Cl、Br、I、(=O)、甲基、乙基、异丙基或三氟甲基的取代基所取代。
- 根据权利要求5所述的制备方法,其特征在于:反应中所使用的溶剂选自水、甲醇、六氟异丙醇、三氟乙醇、乙醇、异丙醇、二氧六环、氯仿、丙酮、乙酸、二甲基亚砜、二氯甲烷、二氯乙烷、四氢呋喃、乙腈、乙酸乙酯、甲基四氢呋喃、甲基叔丁基醚、乙醚、N,N-二甲基甲酰胺、苯、甲苯、氟化苯、1,2-二氟苯、对溴氟苯、2,3-二氟溴苯、六氟苯、溴五氟苯、二甲苯、三甲苯、二(三氟甲基)苯、三(三氟甲基)苯或三氟甲基苯中的任一种或任几种任意比例的混合物。
- 根据权利要求1~6任意一项所述的制备方法,其特征在于:R选自H、甲基、苄基、硝基苄基、对甲氧基苄基、甲氧基甲醚、甲氧乙氧基甲基、叔丁基羰基、苯甲酰基、乙酰基、氯甲基羰基、对甲苯磺酰基、甲磺酰基、苯磺酰基、对硝基苯磺酰基、邻硝基苯磺酰基、三甲基硅基、三乙基硅基、对硝基苯甲酰基、对溴苯甲酰基、烯丙基、苄氧基羰基、叔丁氧基羰基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基。
- 根据权利要求1~6任意一项所述的制备方法,其特征在于:压力选自2atm~50atm;反应温度选自0~60℃。
- 根据权利要求1~6任意一项所述的制备方法,其特征在于:压力选自2atm~30atm;反应温度选自0~40℃。
- 一种通式(II)化合物的制备方法,其特征在于包括通过式(III)与式(IV)或式(IV`)化合物反应制备得到;X选自Cl、Br或I;M选自Na、K或Li;R各自独立的选自H或羟基保护基;R1、R2和R3各自独立的选自H、OH、F、Cl、Br、C1-6烷氧基,或者R1和R2可以与其相连的原子一起形成4至10元环,所述环除含有杂原子B外,还含有0至4个选自O、N或S的杂原子,所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取代基所取代。
- 根据权利要求10所述的制备方法,其特征在于:X选自Br;式(IV)化合物选自式(IV`)化合物选自
- 根据权利要求11所述的制备方法,其特征在于:所述的反应加入催化剂,反应中所使用的催化剂选自负载型金属催化剂或金属配合物,所述的金属选自Pd、Ru、Ir、Rh或Ni;所述的反应加入溶剂,反应中所使用的溶剂选自甲苯、二氧六环、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺、水、乙二醇二甲醚、二氯甲烷或二氯乙烷中的任一种或任几种任意比例的混合物;所述的反应加入碱性试剂,所述的碱性试剂选自碳酸钠、碳酸氢钠、醋酸钠、磷酸钠、碳酸铯、碳酸钾、碳酸氢钾、醋酸钾、磷酸钾、三乙胺、氟化钾、叔丁基胺、N,N-二异丙基乙胺、三丁胺、吡啶中的任一种或任几种的混合物。
- 根据权利要求12所述的制备方法,其特征在于:R为H、叔丁基羰基、叔丁氧基羰基、烯丙基、苄基、对硝基苄基、对硝基苯甲酰基、苯甲酰基、对甲苯磺酰基、对硝基苯磺酰基、邻硝基苯磺酰基、S-(1-苯基)乙基氨基羰基或R-(1-苯基)乙基氨基羰基;反应中所使用的催化剂选自Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/Ru-Phos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P或Pd2(dba)3/t-Bu3P。
- 一种通式(I)化合物的制备方法,其特在在于:a)通过式(III)化合物和式(IV)或式(IV`)化合物偶联反应制备得到式(II)化合物,反应中所使用的催化剂选自负载型金属催化剂或金属配合物,所述的金属选自Pd、Ru、Ir、Rh或Ni,作为选择,R为羟基保护基时,通式(II)化合物可以进一步脱去保护,作为选择,R为H时,通式(II)化合物可以进一步用羟基保护基保护,b)通式(II)化合物被还原后得到通式(I)化合物,其中反应中使用还原剂为氢气,所使用的催化剂选自金属配合物,所述金属选自Co、Ni、Ru、Pd、Ir或Rh,作为选择,R为羟基保护基时,通式(I)化合物可以进一步脱去保护,作为选择,R为H时,通式(I)化合物可以进一步用羟基保护基保护,X选自Cl、Br或I;M选自Na、K或Li;R为H或羟基保护基;R1、R2和R3各自独立的选自H、OH、F、Cl、Br、C1-6烷氧基,或者R2和R3可以与其相连的原子一起形成4至10元环,所述环除含有杂原子B外,还含有0至4个选自O、N或S的杂原子,所述的环可以任选被0至4个选自H、C1-6烷基或C1-6烷氧基的取 代基所取代。
- 根据权利要求14所述的制备方法,其特在于通式(I)化合物选自a)反应中所使用的催化剂选自Pd(OAc)2、Pd(OAc)2/S-Phos、Pd(OAc)2/Ru-Phos、(PhCN)2PdCl2、Ni(cod)2、NiCl2-diglyme、PdCl2-PEPPSI-iPr、PdCl2/t-Bu3P、PdCl2/(Cy)3P、Pd(dppf)Cl2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd(OAc)2/t-Bu3P、Pd(OAc)2/(Cy)3P或Pd2(dba)3/t-Bu3P;b)反应中所述的催化剂选自((4R,5R)-(+)-O-[1-苯甲基-1-(5-甲基-2-苯基-4,5-二氢恶唑-4-基)-2-苯基乙基](二环己基膦亚盐)(1,5-COD)铱(I)四(3,5-二(三氟甲基)苯基硼酸盐、(R)-Ru(OAc)2BINAP、(R)-(+)-[Ru(C3-TUNEPHOS)(C6H6)Cl]Cl、(R)-(+)-[Ru(MeO-BIPHEP)(C6H6)Cl]Cl、(R)-(+)-[Ru(BIPHEP)(C6H6)Cl]Cl、(R)-Ir(Tol-SDP)(COD)Cl、(R)-(+)-Ir(MeO-BIPHEP)(COD)Cl。
- 一种式(II)所示的化合物,其中R选自H或羟基保护基。
- 根据权利要求16所述化合物,其中R选自H、叔丁基羰基、叔丁氧基羰基、烯丙基、苄基、对硝基苄基、对硝基苯甲酰基、苯甲酰基、对甲苯磺酰基、对硝基苯磺酰基、邻硝基苯磺酰基、R-(1-苯基)乙基氨基羰基或S-(1-苯基)乙基氨基羰基。
- 一种式(A)所示的化合物或者其光学异构体,其中所述的光学异构体为式(I-a)、(I-b)或者(I-c)所示的化合物,其中:R选自羟基保护基。
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