CN113692401A - 芳香族氨基酸衍生物的制备方法 - Google Patents
芳香族氨基酸衍生物的制备方法 Download PDFInfo
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- CN113692401A CN113692401A CN202080028840.2A CN202080028840A CN113692401A CN 113692401 A CN113692401 A CN 113692401A CN 202080028840 A CN202080028840 A CN 202080028840A CN 113692401 A CN113692401 A CN 113692401A
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- amino
- methoxy
- carbonyl
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- -1 aromatic amino acid derivative Chemical class 0.000 title claims abstract description 1121
- 238000000034 method Methods 0.000 title claims abstract description 109
- 230000008569 process Effects 0.000 title claims description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 64
- 239000000654 additive Substances 0.000 claims abstract description 33
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 230000000996 additive effect Effects 0.000 claims abstract description 25
- 239000011701 zinc Substances 0.000 claims abstract description 10
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 333
- 150000001875 compounds Chemical class 0.000 claims description 300
- 150000003839 salts Chemical class 0.000 claims description 123
- 229910052739 hydrogen Inorganic materials 0.000 claims description 114
- 239000001257 hydrogen Substances 0.000 claims description 114
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 86
- 125000006239 protecting group Chemical group 0.000 claims description 76
- 239000012453 solvate Substances 0.000 claims description 66
- 125000003118 aryl group Chemical group 0.000 claims description 62
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 61
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 52
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 229910052751 metal Inorganic materials 0.000 claims description 44
- 239000002184 metal Substances 0.000 claims description 44
- 239000002904 solvent Substances 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 37
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical group 0.000 claims description 33
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 29
- 239000003446 ligand Substances 0.000 claims description 28
- 238000002156 mixing Methods 0.000 claims description 28
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 239000003638 chemical reducing agent Substances 0.000 claims description 25
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 24
- 150000002739 metals Chemical class 0.000 claims description 24
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 17
- 125000003277 amino group Chemical group 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 229910052742 iron Inorganic materials 0.000 claims description 10
- 229910052759 nickel Inorganic materials 0.000 claims description 8
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 7
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 6
- 229910052804 chromium Inorganic materials 0.000 claims description 6
- 239000011651 chromium Substances 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- 239000010949 copper Substances 0.000 claims description 6
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 6
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 5
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 5
- 229910052794 bromium Chemical group 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 5
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 4
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 claims description 4
- KFBKRCXOTTUAFS-UHFFFAOYSA-N nickel;triphenylphosphane Chemical compound [Ni].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 KFBKRCXOTTUAFS-UHFFFAOYSA-N 0.000 claims description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- QDZGLKRYQGDOFS-UHFFFAOYSA-N C1=CCCCCC([Ni]C=2CCCCC=CC=2)=C1 Chemical compound C1=CCCCCC([Ni]C=2CCCCC=CC=2)=C1 QDZGLKRYQGDOFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 claims description 3
- 229910021587 Nickel(II) fluoride Inorganic materials 0.000 claims description 3
- 229910021588 Nickel(II) iodide Inorganic materials 0.000 claims description 3
- JEZFASCUIZYYEV-UHFFFAOYSA-N chloro(triethoxy)silane Chemical compound CCO[Si](Cl)(OCC)OCC JEZFASCUIZYYEV-UHFFFAOYSA-N 0.000 claims description 3
- RQKPFSQDBAZFJV-UHFFFAOYSA-N cyclopenta-1,3-diene;nickel(2+) Chemical compound [Ni+2].C1C=CC=[C-]1.C1C=CC=[C-]1 RQKPFSQDBAZFJV-UHFFFAOYSA-N 0.000 claims description 3
- XXECWTBMGGXMKP-UHFFFAOYSA-L dichloronickel;2-diphenylphosphanylethyl(diphenyl)phosphane Chemical compound Cl[Ni]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 XXECWTBMGGXMKP-UHFFFAOYSA-L 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 3
- LGQLOGILCSXPEA-UHFFFAOYSA-L nickel sulfate Chemical compound [Ni+2].[O-]S([O-])(=O)=O LGQLOGILCSXPEA-UHFFFAOYSA-L 0.000 claims description 3
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 3
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 claims description 3
- YOCBOYPGZVFUCQ-UHFFFAOYSA-L nickel(2+);tricyclohexylphosphane;dichloride Chemical compound Cl[Ni]Cl.C1CCCCC1P(C1CCCCC1)C1CCCCC1.C1CCCCC1P(C1CCCCC1)C1CCCCC1 YOCBOYPGZVFUCQ-UHFFFAOYSA-L 0.000 claims description 3
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 3
- QEKXARSPUFVXIX-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dibromide Chemical compound [Ni+2].[Br-].[Br-].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 QEKXARSPUFVXIX-UHFFFAOYSA-L 0.000 claims description 3
- KBJMLQFLOWQJNF-UHFFFAOYSA-N nickel(II) nitrate Inorganic materials [Ni+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O KBJMLQFLOWQJNF-UHFFFAOYSA-N 0.000 claims description 3
- 229910000363 nickel(II) sulfate Inorganic materials 0.000 claims description 3
- DBJLJFTWODWSOF-UHFFFAOYSA-L nickel(ii) fluoride Chemical compound F[Ni]F DBJLJFTWODWSOF-UHFFFAOYSA-L 0.000 claims description 3
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 claims description 3
- 229910000008 nickel(II) carbonate Inorganic materials 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 11
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 claims 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims 1
- 150000003862 amino acid derivatives Chemical class 0.000 abstract description 38
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 560
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 275
- 239000000243 solution Substances 0.000 description 120
- 238000006243 chemical reaction Methods 0.000 description 72
- 125000005336 allyloxy group Chemical group 0.000 description 64
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 61
- 238000004128 high performance liquid chromatography Methods 0.000 description 57
- 239000000203 mixture Substances 0.000 description 55
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 48
- 150000003254 radicals Chemical class 0.000 description 39
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 38
- 229940024606 amino acid Drugs 0.000 description 38
- 235000001014 amino acid Nutrition 0.000 description 38
- 238000002360 preparation method Methods 0.000 description 37
- 150000001413 amino acids Chemical class 0.000 description 32
- 230000014759 maintenance of location Effects 0.000 description 32
- 239000007858 starting material Substances 0.000 description 32
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 31
- 150000002500 ions Chemical class 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- 125000003710 aryl alkyl group Chemical group 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- 229910052796 boron Inorganic materials 0.000 description 22
- 238000004587 chromatography analysis Methods 0.000 description 22
- 125000000753 cycloalkyl group Chemical group 0.000 description 21
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 125000003342 alkenyl group Chemical group 0.000 description 20
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 20
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 19
- 125000000304 alkynyl group Chemical group 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- 125000003545 alkoxy group Chemical group 0.000 description 16
- 229960002989 glutamic acid Drugs 0.000 description 15
- 235000019260 propionic acid Nutrition 0.000 description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 15
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 14
- 125000005842 heteroatom Chemical group 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 125000004429 atom Chemical group 0.000 description 13
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 13
- 125000005843 halogen group Chemical group 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 13
- 125000004043 oxo group Chemical group O=* 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000010828 elution Methods 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- XDELKSRGBLWMBA-UHFFFAOYSA-N 3-iodopyridine Chemical compound IC1=CC=CN=C1 XDELKSRGBLWMBA-UHFFFAOYSA-N 0.000 description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 125000001153 fluoro group Chemical group F* 0.000 description 11
- 125000003709 fluoroalkyl group Chemical group 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- GRJHONXDTNBDTC-UHFFFAOYSA-N phenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=CC=C1 GRJHONXDTNBDTC-UHFFFAOYSA-N 0.000 description 11
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 229960005261 aspartic acid Drugs 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 9
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 9
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 8
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 125000004430 oxygen atom Chemical group O* 0.000 description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000006297 dehydration reaction Methods 0.000 description 7
- 230000008034 disappearance Effects 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 6
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- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000010422 internal standard material Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
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- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
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- ACJOIWBNYDPODS-UHFFFAOYSA-N n-(oxan-2-yl)benzamide Chemical compound C=1C=CC=CC=1C(=O)NC1CCCCO1 ACJOIWBNYDPODS-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
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- DMTATAJEGAYCRV-UHFFFAOYSA-N n-methylsulfonylbenzamide Chemical compound CS(=O)(=O)NC(=O)C1=CC=CC=C1 DMTATAJEGAYCRV-UHFFFAOYSA-N 0.000 description 1
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- NQVPSGXLCXZSTB-UHFFFAOYSA-N n-tert-butyl-2-chloroacetamide Chemical compound CC(C)(C)NC(=O)CCl NQVPSGXLCXZSTB-UHFFFAOYSA-N 0.000 description 1
- IYRGXJIJGHOCFS-UHFFFAOYSA-N neocuproine Chemical compound C1=C(C)N=C2C3=NC(C)=CC=C3C=CC2=C1 IYRGXJIJGHOCFS-UHFFFAOYSA-N 0.000 description 1
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- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000004288 oxazolidin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC1([H])* 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 description 1
- 229960003868 paraldehyde Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- ZQBVUULQVWCGDQ-UHFFFAOYSA-N propan-1-ol;propan-2-ol Chemical compound CCCO.CC(C)O ZQBVUULQVWCGDQ-UHFFFAOYSA-N 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- COLRMVLTWJTLFJ-UHFFFAOYSA-N pyridin-2-yl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=CC=N1 COLRMVLTWJTLFJ-UHFFFAOYSA-N 0.000 description 1
- ZRNDSLLIAOLRJS-UHFFFAOYSA-N pyridin-3-yl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=CN=C1 ZRNDSLLIAOLRJS-UHFFFAOYSA-N 0.000 description 1
- CTEFYDWUNZVMNS-UHFFFAOYSA-N pyridin-4-yl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=NC=C1 CTEFYDWUNZVMNS-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- NPTLNLQAOVMCHI-UHFFFAOYSA-N pyrimidin-5-yl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CN=CN=C1 NPTLNLQAOVMCHI-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
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- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000012070 reactive reagent Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 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
- ZJMWRROPUADPEA-UHFFFAOYSA-N sec-butylbenzene Chemical compound CCC(C)C1=CC=CC=C1 ZJMWRROPUADPEA-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QOISWWBTZMFUEL-NSHDSACASA-N tert-butyl (2s)-2-amino-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 QOISWWBTZMFUEL-NSHDSACASA-N 0.000 description 1
- OTEKOKRQIUDVON-UHFFFAOYSA-N tert-butyl 2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-phenylbutanoate Chemical compound CC(C)(C)OC(=O)C(CCC1=CC=CC=C1)NC(=O)OCC2C3=CC=CC=C3C4=CC=CC=C24 OTEKOKRQIUDVON-UHFFFAOYSA-N 0.000 description 1
- MOEBHWABQQBBFU-UHFFFAOYSA-N tert-butyl 2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-phenylbutanoate Chemical compound CC(C)(C)OC(=O)C(CCC1=CC=CC=C1)N(C)C(=O)OCC2C3=CC=CC=C3C4=CC=CC=C24 MOEBHWABQQBBFU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
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- 150000003549 thiazolines Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- OHSJPLSEQNCRLW-UHFFFAOYSA-N triphenylmethyl radical Chemical compound C1=CC=CC=C1[C](C=1C=CC=CC=1)C1=CC=CC=C1 OHSJPLSEQNCRLW-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
- C07B37/04—Substitution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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Abstract
本发明提供通过使用添加剂使特定酯化合物与芳香族卤化物和锌在催化剂存在下反应来高效制备各种光学活性芳香族氨基酸衍生物的方法。本发明还提供了可以通过所述方法制备的氨基酸衍生物。
Description
技术领域
本发明涉及用作药物中间体的芳香族氨基酸衍生物及其制备方法。
背景技术
中等分子量化合物(分子量:500至2000)比低分子量化合物更容易接近以抑制蛋白质-蛋白质相互作用为代表的艰难目标。此外,中等分子量的化合物可能优于抗体,因为它们可以转移到细胞中。在具有生理活性的中等分子量化合物中,肽类药物是有价值的分子种类,已有40种或更多肽类药物上市(非专利文献1)。这样的肽类药物的代表性例子包括环孢菌素A和多粘菌素B。从它们的结构来看,可以发现它们是含有几种非天然氨基酸的肽化合物。非天然氨基酸是指非天然编码在mRNA上的氨基酸,非常有趣的是,天然存在的环孢菌素A和多粘菌素B中含有非天然氨基酸,此外,它们的药理活性是通过这样的非天然氨基酸的结构位点和体内作用位点之间的相互作用来表达的。与体内作用位点相互作用的非天然氨基酸的例子包括以地拉普利为代表的血管紧张素转换酶抑制剂的高苯丙氨酸部分结构(非专利文献2)。
综上所述,对于药物发现研究和药物制造而言,建立以高苯丙氨酸衍生物为代表的芳香族氨基酸衍生物的高效且通用的制备方法具有重要意义。
已知有以下光学活性芳香族氨基酸的制备方法。
以下(1)至(5)是通过从前手性起始材料诱导不对称中心获得光学活性芳香族氨基酸的方法或光学拆分芳香族氨基酸的DL-混合物的方法:
(1)以溴化苄为代表的高反应性卤代芳烷基化合物,通过使用光学活性相关转移催化剂对映选择性加成到甘氨酸衍生物或丙氨酸衍生物的方法(专利文献1);
(2)以溴化苄为代表的高反应性卤代芳烷基化合物非对映选择性地加成到衍生自甘氨酸的光学活性噁唑烷酮的方法(专利文献2);
(3)通过酶法从α-酮酸制备α-氨基酸的方法(专利文献3);
(4)光学拆分方法,其中N-乙酰芳香族氨基酸的DL-混合物以L-芳香族氨基酸选择性方式通过酰基转移酶脱乙酰化(专利文献4);和
(5)通过苯乙烯基乙醛酸衍生物的不对称还原得到的光学活性醇类制备高苯丙氨酸衍生物的方法,苯乙烯基乙醛酸衍生物的不对称还原是关键反应(非专利文献3)。
以下(6)至(9)是通过将官能团引入起始的光学活性氨基酸来制备目标光学活性芳香族氨基酸的方法:
(6)在钯催化剂的存在下,从衍生自光学活性丝氨酸的芳香族卤化物和锌试剂的制备方法(专利文献5);
(7)在镍催化剂的存在下,从衍生自天冬氨酸或谷氨酸的芳香族碘化物和N-羟基邻苯二甲酰亚胺酯的制备方法(非专利文献4);
(8)在镍催化剂的存在下,从衍生自天冬氨酸或谷氨酸芳香族锌试剂和的N-羟基邻苯二甲酰亚胺酯的制备方法(非专利文献5);和
(9)通过弗里德尔-克拉夫茨反应将天冬氨酸的侧链芳基化,制备高苯丙氨酸衍生物的方法(非专利文献6)。
引用列表
专利文献
[专利文献1]日本专利申请公开(JP-A)2001-48866
[专利文献2]JP-A 2009-96791
[专利文献3]JP-A S62-000289
[专利文献4]JP-A S60-169451
[专利文献5]日本专利申请公开(JP-A)2012-506909
非专利文献
[非专利文献1]Future Med.Chem.2009,1,1289-1310。
[非专利文献2]Chem.Pharm.Bull.,1986,34(7),2852-2858。
[非专利文献3]Synlett,2018,29,2203-2207。
[非专利文献4]J.Am.Chem.Soc.,2016,138,5016-5019。
[非专利文献5]J.Am.Chem.Soc.,2016,138,2174-2177。
[非专利文献6]Tetrahedron Lett.,2008,49,6566-6568。
发明内容
技术问题
本发明提供了制备芳香族氨基酸衍生物的高效且通用的方法。
在专利文献1或专利文献2的方法中,用作亲电试剂的卤代芳烷基化合物需要在碱性条件下稳定。其中所使用的亲电试剂必须是高反应性试剂,从而高效地形成碳-碳键,这限制了能够经受这种反应条件的试剂。因此,该方法不能说是作为通用的芳香族氨基酸衍生物的制备方法。
专利文献3中描述的方法需要稳定地供应进行酶促方法的α-酮羧酸,并且应该针对每种预期的芳族氨基酸衍生物制备适合α-酮羧酸的具有高底物特异性的酶,因此该方法不适合作为制备芳香族氨基酸衍生物的通用方法。
在专利文献4记载的方法中,在制备每种具有不同氨基酸侧链的多种芳香族氨基酸衍生物时,需要使用与待制备的各芳香族氨基酸衍生物对应的外消旋酰化芳香族氨基酸衍生物作为原料。此外,还需要制备能够选择性水解每种具有不同侧链结构的芳香族氨基酸衍生物的水解酶。更具体地,需要与芳香族氨基酸衍生物的种类对应的外消旋原料和水解酶,这使得作为制备方法的通用性变差。
专利文献5中描述的方法效率不高,因为从原料丝氨酸制备锌试剂需要多步反应。
非专利文献3中描述的方法作为工业反应存在问题,因为作为关键反应的不对称还原反应需要20atm的氢气流。此外,不对称还原反应中使用的苯乙烯基乙醛酸衍生物仅限于酰胺形式,需要转化为羧酸形式或酯形式,以用作药物中间体,因此该方法效率不高。
在非专利文献4记载的方法中,所用原料为芳香族碘化物和N-羟基邻苯二甲酰亚胺酯(NHPI酯),其易于由天冬氨酸、谷氨酸等制备,从改变使用的芳香族碘化物可以制备各种芳香族氨基酸衍生物的观点出发,该方法可被认为是通用的方法。然而,在该文献中描述的方法中,需要使用过量的氨基酸的NHPI酯形式,这可能产生作为副产物的多种衍生自过量氨基酸的氨基酸衍生物。这样的副产物具有与预期的芳香族氨基酸衍生物相似的物理性质,从而可能导致难以获得高质量的芳香族氨基酸衍生物。此外,在芳香族卤化物中,只有芳香族碘化物适用于该方法,在底物通用性方面仍然存在问题。具体地,虽然反应以实验室规模进行,但非专利文献4中描述的制备苯丙氨酸衍生物和高苯丙氨酸衍生物的方法需要相对于芳香族碘化物过量的天冬氨酸的NHPI酯形式或谷氨酸的NHPI酯形式。此外,已经发现,在使用工业规模反应中使用的搅拌叶片的反应条件下,反应不会进行。
在非专利文献5记载的方法中,可能使用容易由谷氨酸制备的N-羟基邻苯二甲酰亚胺酯(NHPI酯)作为原料;然而,由于制备需要严格无水条件的芳香族锌化合物很麻烦,因此该方法作为工业制备方法可以说是有问题的。
在非专利文献6记载的方法中,能够通过弗里德尔-克拉夫茨反应引入的芳基仅限于富电子芳基基团。
如上所述,迄今为止,还没有已知的高效且通用的工业制备光学活性芳族氨基酸衍生物的方法,该方法涉及工业上所需的条件。
本发明的目的是提供使用工业设备从容易获得的光学活性氨基酸制备光学活性芳香族氨基酸衍生物的高效且通用的方法,以及可以通过该方法制备和可作为中等分子量化合物的原料的光学活性芳香族氨基酸衍生物。
解决问题的方案
作为对光学活性芳香族氨基酸衍生物的制备方法的专门研究的结果,本发明人已经找到了在催化剂存在下使特定酯化合物与芳香族卤化物和还原剂反应的反应条件。具体而言,本发明人发现了通过使用添加剂制备光学活性芳香族氨基酸衍生物的高效方法,该方法适用于使用工业上常用的搅拌叶片的反应条件。此外,本发明人发现了能够通过改变反应中使用的芳香族卤化物由常规酯化合物制备各种光学活性芳族氨基酸衍生物的高度通用的方法,从而完成了本发明。
在一个非限制性的具体实施方案中,本发明包括以下内容:
[1]式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物的制备方法:
式I:
其中
R1为氢或氨基的保护基团;
R2为氢或C1-C6烷基,R3为氢或羧基的保护基团,或R2和R3一起形成二价保护基团;
R6为任选取代的C6-C10芳基或任选取代的杂芳基;
R7为氢或C1-C4烷基;和
n是1或2,
所述方法包括将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物与还原剂、添加剂和R6-X(其中R6与式I表示的化合物的R6相同,且X为卤素、OTf或OMs)在溶剂和催化剂存在下混合的步骤,以得到式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物:
式II:
其中
R1、R2、R3、R7和n分别与式I表示的化合物的R1、R2、R3、R7和n相同;
R5选自由以下组成的组:
Rt、Ru、Rv和Rw独立地为氢、卤素或硝基;
Rx和Ry独立地为氢、C1-C4烷基或任选取代的苯基;
Rz为氢、C1-C4烷基或卤素;
Y为CH或N;和
*表示结合点。
[2]根据[1]所述的方法,其中R1为氨基的保护基团,所述氨基的保护基团选自由Fmoc、Boc、Alloc、Cbz、Teoc和三氟乙酰基组成的组。
[3]根据[1]或[2]所述的方法,其中R3为羧基的保护基团,所述羧基的保护基团选自由甲基、乙基、叔丁基、苄基、三苯甲基、枯基、甲氧基三苯甲基和2-(三甲基甲硅烷基)乙基组成的组。
[4]根据[1]或[2]所述的方法,其中
R2和R3一起形成二价保护基团,所述二价保护基团为-(CR8R9)-,式I用式IA表示:
其中
R1、R6、R7和n分别与式I表示的化合物的R1、R6、R7和n相同;和
R8和R9独立地为氢、C1-C4烷基、或C6-C10芳基,或R8和R9一起形成氧基(=O)。
[5]根据[1]至[4]中任一项所述的方法,其中所述添加剂为由式A表示的甲硅烷基化合物:
[其中
RAX和RAY独立地选自由C1-C4烷基、C1-C4烷氧基和苯基组成的组;和
L选自由-Cl、-Br、-I和-OTf组成的组]
或1,2-二溴乙烷。
[6]根据[5]所述的方法,其中所述甲硅烷基化合物选自由TMSCl、TMSBr、TMSI、TMSOTf、TBDMSCl、TESCl、TIPSCl、TBDPSCl和氯三乙氧基硅烷组成的组。
[7]根据[1]至[6]中任一项所述的方法,其中R5是:
[8]根据[1]至[7]中任一项所述的方法,其中X为碘或溴,R6为任选地取代的苯基或任选地取代的吡啶基。
[9-1]根据[8]所述的方法,其中任选地取代的苯基或任选地取代的吡啶基被0至3个独立地选自由C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C2-C6烯氧基、卤素、C3-C8环烷基、-NRpRq(其中Rp和Rq独立地为氢或C1-C4烷基)、-CONRrRs(其中Rr和Rs独立地选自由氢、羟基、受保护的羟基、C1-C4烷基和C1-C4烷基磺酰基)和环状硼基组成的组的取代基取代。
[9-2]根据[9-1]所述的方法,其中任选地取代的苯基或任选地取代的吡啶基被一个C1-C4烷基取代;一个-CONRrRs;一个C1-C4卤代烷基和一个或两个卤素;两个C1-C4烷氧基;一个C1-C4烷氧基和一个或两个卤素;或一个-CONRrRs和一个C1-C4烷氧基取代。
[9-3]根据[9-2]所述的方法,其中任选地取代的苯基或任选地取代的吡啶基被一个甲基;一个甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基;一个三氟甲基和一个或两个氟;一个三氟甲基和一个或两个氯;一个三氟甲基、一个氟和一个氯;两个甲氧基;一个甲氧基和一个或两个氟;一个甲基氨基羰基和一个甲氧基;或一个甲基磺酰基氨基羰基和一个甲氧基取代。
[10]根据[1]至[9-3]中任一项所述的方法,其中
催化剂是:
(a)金属;
(b)通过混合金属及其可能的配体化合物形成;
(c)金属及其配体的络合物;或者
(d)通过进一步混合金属及其配体的络合物,金属的可能的配体化合物而形成,和
其中所述金属是镍、铬、铁、铜、钯或这些金属的盐,或者是镍、铬、铁、铜、钯或这些金属的盐的溶剂化物。
[11]根据[10]所述的方法,其中所述金属选自由NiBr2、NiI2、NiCl2、NiF2、Ni(OAc)2、Ni(acac)2、Ni(OTf)2、NiCO3、Ni(NO3)2、NiSO4、(NH4)2Ni(SO4)2、烯丙基(环戊二烯基)镍(II)、双(环戊二烯基)镍和双(环辛二烯基)镍,或者是这些金属的溶剂化物。
[12]根据[10]或[11]所述的方法,其中可能的配体化合物选自:
由式B表示的化合物:
其中RBX和RBY独立地选自氢、C1-C4烷基、C1-C4烷氧基、杂环基和C6-C10芳基;
由式C表示的化合物:
其中RCX和RCY独立地选自氢、C1-C4烷基、C6-C10芳基和杂芳基;
由式D表示的化合物:
其中RDX和RDY独立地选自氢、C1-C4烷基、C1-C4卤代烷基和C6-C10芳基;
由式E表示的化合物:
其中REX和REY独立地选自氢、C1-C4烷基、C6-C10芳基C1-C6烷基和C6-C10芳基;
由式F表示的化合物:
其中RFX和RFY独立地选自氢、C1-C4烷基和C6-C10芳基;和
由式G表示的化合物:
其中RGX和RGY独立地选自氢、C1-C4烷基、C6-C10芳基C1-C6烷基和C6-C10芳基。
[13]根据[10]所述的方法,其中所述催化剂是金属及其配体的络合物,并且所述金属及其配体的络合物选自由四(三苯基膦)镍(0)、双(三苯基膦)二氯化镍(II)、双(三环己基膦)二氯化镍(II)、二溴双(三苯基膦)镍(II)、双[(2-二甲氨基)苯基]胺镍(II)氯化物、顺式-[2,2′-双(二苯基膦)-1,1′-联萘](2-甲基苯基)氯化镍(II)和[1,2-双(二苯基膦)乙烷]二氯镍(II)组成的组。
[14]根据[1]至[13]中任一项所述的方法,其中,所述还原剂选自由锌、锰、铁和镁组成的组。
[15]根据[1]至[14]中任一项所述的方法,其中
(a)在溶剂和催化剂的存在下将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、还原剂和R6-X混合,然后添加剂与之混合;
(b)在溶剂和催化剂的存在下将还原剂和添加剂混合,然后将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物和R6-X与之混合;或者
(c)将还原剂与溶剂和催化剂混合,然后将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、R6-X和添加剂与其混合。
[16]根据[1]至[15]中任一项所述的方法,其中相对于由式II表示的化合物、所述化合物的盐、或所述化合物或盐的溶剂合物,使用1至500mol%的所述添加剂。
[17]根据[1]至[16]中任一项所述的方法,其中,所述步骤在-10℃至70℃的反应温度下进行。
[18]式III表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物的制备方法:
其中R1、R6、R7和n分别与式I表示的化合物的R1、R6、R7和n相同,R2是氢或C1-C6烷基,
所述方法包括以下步骤:
按照[1]至[17]中任一项所述的方法制备由式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物;和
当R3为羧基的保护基团时,从式I表示的化合物、所述化合物的盐、或所述化合物或盐的溶剂化物中除去保护基团,得到式III表示的化合物、所述化合物的盐,或所述化合物或盐的溶剂化物。
[19]式IV表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物的制备方法:
其中R6、R7和n分别与式I表示的化合物的R6、R7和n相同,R2是氢或C1-C6烷基,
所述方法包括以下步骤:
按照[1]至[17]中任一项所述的方法制备由式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物;和
当R1为氨基的保护基团,R3为羧基的保护基团时,除去这些保护基团,得到式IV表示的化合物、所述化合物的盐、或所述化合物或盐的溶剂化物。
[20]式V表示的化合物、所述化合物的盐、或所述化合物或盐的溶剂化物的制备方法:
其中R2、R6、R7和n分别与式IV表示的化合物的R2、R6、R7和n相同;R1′是氨基的保护基团,
所述方法包括以下步骤:
根据[19]所述的方法制备由式IV表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物;和
将R1′引入式IV表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物中,得到式V表示的化合物、所述化合物的盐、或所述化合物或盐的溶剂化物。
[21]式VI表示的化合物、所述化合物的盐、或所述化合物或盐的溶剂化物的制备方法:
R1、R6、R7和n分别与式I表示的化合物的R1、R6、R7和n相同;
所述方法包括以下步骤:
根据[4]至[17]中任一项所述的方法制备由式IA表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物;和
打开式IA表示的化合物的噁唑烷酮环,得到式VI表示的化合物、所述化合物的盐、或所述化合物或盐的溶剂化物。
[22]通过根据[1]至[21]中任一项所述的方法制备的化合物、所述化合物的盐、或所述化合物或盐的溶剂化物。
[23]由式I表示的氨基酸衍生物、该氨基酸衍生物的盐、或该氨基酸衍生物或盐的溶剂化物:
其中
R1为氢或氨基的保护基团;
R2为氢或C1-C6烷基,R3为氢或羧基的保护基团,或R2和R3一起形成二价保护基团;
R6为任选取代的C6-C10芳基或任选取代的杂芳基;
R7为氢或C1-C4烷基;和
n是1或2。
[24]根据[23]所述的氨基酸衍生物、氨基酸衍生物的盐、或氨基酸衍生物或盐的溶剂化物,其中R1是氨基的保护基团,所述氨基的保护基团选自由Fmoc、Boc、Alloc、Cbz、Teoc和三氟乙酰基组成的组。
[25]根据[23]或[24]所述的氨基酸衍生物、该氨基酸衍生物的盐、或该氨基酸衍生物或盐的溶剂化物,其中R3是羧基的保护基团,所述羧基的保护基团选自由甲基、乙基、叔丁基、苄基、三苯甲基、枯基、甲氧基三苯甲基和2-(三甲基甲硅烷基)乙基组成的组。
[26]根据[23]或[24]所述的氨基酸衍生物、该氨基酸衍生物的盐、或该氨基酸衍生物或盐的溶剂化物,其中R2和R3一起形成二价保护基团,所述二价保护基团为-(CR8R9)-,式I由式IA表示:
其中
R1、R6、R7和n分别与式I表示的化合物的R1、R6、R7和n相同;和
R8和R9独立地为氢、C1-C4烷基、或C6-C10芳基,或R8和R9一起形成氧基(=O)。
[27]根据[23]至[26]中任一项所述的氨基酸衍生物、该氨基酸衍生物的盐、或该氨基酸衍生物或盐的溶剂化物,其中R6是任选取代的苯基或任选取代的吡啶基。
[28]根据[27]所述的氨基酸衍生物、该氨基酸衍生物的盐、或该氨基酸衍生物或盐的溶剂化物,其中任选取代的苯基或任选取代的吡啶基被0至3个独立地选自由C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C2-C6烯氧基、卤素、C3-C8环烷基、-NRpRq(其中Rp和Rq独立地为氢或C1-C4烷基)、-CONRrRs(其中Rr和Rs独立地选自由氢、羟基、受保护的羟基、C1-C4烷基和C1-C4烷基磺酰基组成的组)和环状硼基组成的组的取代基取代。
[29]根据[28]所述的氨基酸衍生物、该氨基酸衍生物的盐、或该氨基酸衍生物或盐的溶剂化物,其中任选取代的苯基或任选取代的吡啶基被一个C1-C4烷基取代;一个-CONRrRs;一个C1-C4卤代烷基和一个或两个卤素;两个C1-C4烷氧基;一个C1-C4烷氧基和一个或两个卤素;或一个-CONRrRs和一个C1-C4烷氧基取代。
[30]根据[29]所述的氨基酸衍生物、所述氨基酸衍生物的盐、或氨基酸衍生物或盐的溶剂化物,其中任选取代的苯基或任选取代的吡啶基被一个甲基;一个甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基;一个三氟甲基和一个或两个氟;一个三氟甲基和一个或两个氯;一个三氟甲基、一个氟和一个氯;两个甲氧基;一个甲氧基和一个或两个氟;一个甲基氨基羰基和一个甲氧基;或一个甲基磺酰基氨基羰基和一个甲氧基取代。
[31]选自以下组成的组的氨基酸衍生物、该氨基酸衍生物的盐、或该氨基酸衍生物或盐的溶剂化物:
(1-1)2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯,
(1-2)2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸叔丁酯,
(1-3)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯,
(1-4)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸叔丁酯,
(1-5)2-(((苄氧基)羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯,
(1-6)2-(((苄氧基)羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸叔丁酯,
(1-7)2-((叔丁氧基羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯,
(1-8)2-((叔丁氧基羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸叔丁酯,
(1-9)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯,
(1-10)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸叔丁酯,
(1-11)2-(((苄氧基)羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯,
(1-12)2-(((苄氧基)羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸叔丁酯,
(1-13)2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸,
(1-14)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸,
(1-15)2-(((苄氧基)羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸,
(1-16)2-((叔丁氧基羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸,
(1-17)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸,
(1-18)2-(((苄氧基)羰基)(甲基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸,
(1-19)2-氨基-4-(3-氯-4-(三氟甲基)苯基)丁酸,
(1-20)4-(3-氯-4-(三氟甲基)苯基)-2-(甲氨基)丁酸,
(1-21)2-((叔丁氧基羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸苄酯,
(1-22)2-((叔丁氧基羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸叔丁酯,
(1-23)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸苄酯,
(1-24)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸叔丁酯,
(1-25)2-(((苄氧基)羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸苄酯,
(1-26)2-(((苄氧基)羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸叔丁酯,
(1-27)2-((叔丁氧基羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸苄酯,
(1-28)2-((叔丁氧基羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸叔丁酯,
(1-29)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸苄酯,
(1-30)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸叔丁酯,
(1-31)2-(((苄氧基)羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸苄酯,
(1-32)2-(((苄氧基)羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸叔丁酯,
(1-33)2-((叔丁氧基羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸,
(1-34)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸,
(1-35)2-((((苄氧基)羰基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸,
(1-36)2-((叔丁氧基羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸,
(1-37)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸,
(1-38)2-((((苄氧基)羰基)(甲基)氨基)-3-(3-氯-4-(三氟甲基)苯基)丙酸,
(1-39)2-氨基-3-(3-氯-4-(三氟甲基)苯基)丙酸,
(1-40)3-(3-氯-4-(三氟甲基)苯基)-2-(甲氨基)丙酸,
(2-1)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-苯基丁酸叔丁酯,
(2-2)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(邻甲苯基)丁酸叔丁酯,
(2-3)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(间甲苯基)丁酸叔丁酯,
(2-4)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(对甲苯基)丁酸叔丁酯,
(2-5)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-乙基苯基)丁酸叔丁酯,
(2-6)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-氯苯基)丁酸叔丁酯,
(2-7)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氯苯基)丁酸叔丁酯,
(2-8)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-氯苯基)丁酸叔丁酯,
(2-9)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-氟苯基)丁酸叔丁酯,
(2-10)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氟苯基)丁酸叔丁酯,
(2-11)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-氟苯基)丁酸叔丁酯,
(2-12)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-环丙基苯基)丁酸叔丁酯,
(2-13)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-环丙基苯基)丁酸叔丁酯,
(2-14)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-环丙基苯基)丁酸叔丁酯,
(2-15)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-(三氟甲基)苯基)丁酸叔丁酯,
(2-16)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-(三氟甲基)苯基)丁酸叔丁酯,
(2-17)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-(三氟甲基)苯基)丁酸叔丁酯,
(2-18)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-异丙基苯基)丁酸叔丁酯,
(2-19)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-异丙基苯基)丁酸叔丁酯,
(2-20)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-异丙基苯基)丁酸叔丁酯,
(2-21)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-甲氧基苯基)丁酸叔丁酯,
(2-22)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-甲氧基苯基)丁酸叔丁酯,
(2-23)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸叔丁酯,
(2-24)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-(烯丙氧基)苯基)丁酸叔丁酯,
(2-25)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-(烯丙氧基)苯基)丁酸叔丁酯,
(2-26)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-(烯丙氧基)苯基)丁酸叔丁酯,
(2-27)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-异丙氧基苯基)丁酸叔丁酯,
(2-28)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(2-29)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(2-30)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,4-二甲氧基苯基)丁酸叔丁酯,
(2-31)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-氟-4-甲氧基苯基)丁酸叔丁酯,
(2-32)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氟-4-甲氧基苯基)丁酸叔丁酯,
(2-33)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-甲氧基苯基)丁酸叔丁酯,
(2-34)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(2-35)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丁酸叔丁酯,
(2-36)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丁酸叔丁酯,
(2-37)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丁酸叔丁酯,
(2-38)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸叔丁酯,
(2-39)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-甲氧基-4-((((四氢-2H-吡喃-2-基))氧基)氨基甲酰基)苯基)丁酸叔丁酯,
(2-40)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-2-基)丁酸叔丁酯,
(2-41)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-3-基)丁酸叔丁酯,
(2-42)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-4-基)丁酸叔丁酯,
(2-43)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(6-甲基吡啶-3-基)丁酸叔丁酯,
(2-44)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-甲基吡啶-3-基)丁酸叔丁酯,
(2-45)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲基吡啶-3-基)丁酸叔丁酯,
(2-46)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(6-甲氧基吡啶-3-基)丁酸叔丁酯,
(2-47)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-甲氧基吡啶-3-基)丁酸叔丁酯,
(2-48)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-氟吡啶-3-基)丁酸叔丁酯,
(2-49)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-氯吡啶-3-基)丁酸叔丁酯,
(2-50)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-溴吡啶-3-基)丁酸叔丁酯,
(2-51)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-碘吡啶-3-基)丁酸叔丁酯,
(2-52)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-(甲氨基)吡啶-4-基)丁酸叔丁酯,
(2-53)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-(二甲氨基)吡啶-4-基)丁酸叔丁酯,
(2-54)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(嘧啶-5-基)丁酸叔丁酯,
(3-1)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-苯基丁酸叔丁酯,
(3-2)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(邻甲苯基)丁酸叔丁酯,
(3-3)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(间甲苯基)丁酸叔丁酯,
(3-4)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(对甲苯基)丁酸叔丁酯,
(3-5)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-乙基苯基)丁酸叔丁酯,
(3-6)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-氯苯基)丁酸叔丁酯,
(3-7)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氯苯基)丁酸叔丁酯,
(3-8)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-氯苯基)丁酸叔丁酯,
(3-9)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-氟苯基)丁酸叔丁酯,
(3-10)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氟苯基)丁酸叔丁酯,
(3-11)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-氟苯基)丁酸叔丁酯,
(3-12)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-环丙基苯基)丁酸叔丁酯,
(3-13)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-环丙基苯基)丁酸叔丁酯,
(3-14)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-环丙基苯基)丁酸叔丁酯,
(3-15)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-(三氟甲基)苯基)丁酸叔丁酯,
(3-16)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-(三氟甲基)苯基)丁酸叔丁酯,
(3-17)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-(三氟甲基)苯基)丁酸叔丁酯,
(3-18)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-异丙基苯基)丁酸叔丁酯,
(3-19)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-异丙基苯基)丁酸叔丁酯,
(3-20)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-异丙基苯基)丁酸叔丁酯,
(3-21)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-甲氧基苯基)丁酸叔丁酯,
(3-22)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基苯基)丁酸叔丁酯,
(3-23)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-甲氧基苯基)丁酸叔丁酯,
(3-24)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-(烯丙氧基)苯基)丁酸叔丁酯,
(3-25)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-(烯丙氧基)苯基)丁酸叔丁酯,
(3-26)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-(烯丙氧基)苯基)丁酸叔丁酯,
(3-27)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-异丙氧基苯基)丁酸叔丁酯,
(3-28)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(3-29)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(3-30)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,4-二甲氧基苯基)丁酸叔丁酯,
(3-31)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-氟-4-甲氧基苯基)丁酸叔丁酯,
(3-32)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氟-4-甲氧基苯基)丁酸叔丁酯,
(3-33)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-甲氧基苯基)丁酸叔丁酯,
(3-34)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(3-35)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丁酸叔丁酯,
(3-36)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丁酸叔丁酯,
(3-37)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基-4-((甲基磺酰基)氨基甲酰基)苯基)丁酸叔丁酯,
(3-38)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸叔丁酯,
(3-39)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸叔丁酯,
(3-40)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-2-基)丁酸叔丁酯,
(3-41)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-3-基)丁酸叔丁酯,
(3-42)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-4-基)丁酸叔丁酯,
(3-43)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(6-甲基吡啶-3-基)丁酸叔丁酯,
(3-44)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-甲基吡啶-3-基)丁酸叔丁酯,
(3-45)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-甲基吡啶-3-基)丁酸叔丁酯,
(3-46)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(6-甲氧基吡啶-3-基)丁酸叔丁酯,
(3-47)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-甲氧基吡啶-3-基)丁酸叔丁酯,
(3-48)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-氟吡啶-3-基)丁酸叔丁酯,
(3-49)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-氯吡啶-3-基)丁酸叔丁酯,
(3-50)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-溴吡啶-3-基)丁酸叔丁酯,
(3-51)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-碘吡啶-3-基)丁酸叔丁酯,
(3-52)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-(甲氨基)吡啶-4-基)丁酸叔丁酯,
(3-53)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-(二甲氨基)吡啶-4-基)丁酸叔丁酯,
(3-54)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(嘧啶-5-基)丁酸叔丁酯,
(4-1)(((9H-芴-9-基)甲氧基)羰基)苯丙氨酸叔丁酯,
(4-2)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(邻甲苯基)丙酸叔丁酯,
(4-3)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(间甲苯基)丙酸叔丁酯,
(4-4)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(对甲苯基)丙酸叔丁酯,
(4-5)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-乙基苯基)丙酸叔丁酯,
(4-6)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-氯苯基)丙酸叔丁酯,
(4-7)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氯苯基)丙酸叔丁酯,
(4-8)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-氯苯基)丙酸叔丁酯,
(4-9)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-氟苯基)丙酸叔丁酯,
(4-10)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氟苯基)丙酸叔丁酯,
(4-11)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-氟苯基)丙酸叔丁酯,
(4-12)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-环丙基苯基)丙酸叔丁酯,
(4-13)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-环丙基苯基)丙酸叔丁酯,
(4-14)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-环丙基苯基)丙酸叔丁酯,
(4-15)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-(三氟甲基)苯基)丙酸叔丁酯,
(4-16)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-(三氟甲基)苯基)丙酸叔丁酯,
(4-17)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-(三氟甲基)苯基)丙酸叔丁酯,
(4-18)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-异丙基苯基)丙酸叔丁酯,
(4-19)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-异丙基苯基)丙酸叔丁酯,
(4-20)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-异丙基苯基)丙酸叔丁酯,
(4-21)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-甲氧基苯基)丙酸叔丁酯,
(4-22)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基苯基)丙酸叔丁酯,
(4-23)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-甲氧基苯基)丙酸叔丁酯,
(4-24)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-(烯丙氧基)苯基)丙酸叔丁酯,
(4-25)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-(烯丙氧基)苯基)丙酸叔丁酯,
(4-26)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-(烯丙氧基)苯基)丙酸叔丁酯,
(4-27)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-异丙氧基苯基)丙酸叔丁酯,
(4-28)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(4-29)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(4-30)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,4-二甲氧基苯基)丙酸叔丁酯,
(4-31)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-氟-4-甲氧基苯基)丙酸叔丁酯,
(4-32)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氟-4-甲氧基苯基)丙酸叔丁酯,
(4-33)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,5-二氟-4-甲氧基苯基)丙酸叔丁酯,
(4-34)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(4-35)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丙酸叔丁酯,
(4-36)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丙酸叔丁酯,
(4-37)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丙酸叔丁酯,
(4-38)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸叔丁酯,
(4-39)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸叔丁酯,
(4-40)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(吡啶-2-基)丙酸叔丁酯,
(4-41)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(吡啶-3-基)丙酸叔丁酯,
(4-42)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(吡啶-4-基)丙酸叔丁酯,
(4-43)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(6-甲基吡啶-3-基)丙酸叔丁酯,
(4-44)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-甲基吡啶-3-基)丙酸叔丁酯,
(4-45)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-甲基吡啶-3-基)丙酸叔丁酯,
(4-46)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(6-甲氧基吡啶-3-基)丙酸叔丁酯,
(4-47)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-甲氧基吡啶-3-基)丙酸叔丁酯,
(4-48)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-氟吡啶-3-基)丙酸叔丁酯,
(4-49)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-氯吡啶-3-基)丙酸叔丁酯,
(4-50)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-溴吡啶-3-基)丙酸叔丁酯,
(4-51)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-碘吡啶-3-基)丙酸叔丁酯,
(4-52)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-(甲氨基)吡啶-4-基)丙酸叔丁酯,
(4-53)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-(二甲氨基)吡啶-4-基)丙酸叔丁酯,
(4-54)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(嘧啶-5-基)丙酸叔丁酯,
(5-1)2-(((9H-芴-9-基)甲氧基)羰基)-N-甲基苯丙氨酸叔丁酯,
(5-2)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(邻甲苯基)丙酸叔丁酯,
(5-3)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(间甲苯基)丙酸叔丁酯,
(5-4)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(对甲苯基)丙酸叔丁酯,
(5-5)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-乙基苯基)丙酸叔丁酯,
(5-6)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氯苯基)丙酸叔丁酯,
(5-7)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氯苯基)丙酸叔丁酯,
(5-8)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-氯苯基)丙酸叔丁酯,
(5-9)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟苯基)丙酸叔丁酯,
(5-10)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟苯基)丙酸叔丁酯,
(5-11)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-氟苯基)丙酸叔丁酯,
(5-12)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-环丙基苯基)丙酸叔丁酯,
(5-13)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-环丙基苯基)丙酸叔丁酯,
(5-14)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-环丙基苯基)丙酸叔丁酯,
(5-15)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-(三氟甲基)苯基)丙酸叔丁酯,
(5-16)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-(三氟甲基)苯基)丙酸叔丁酯,
(5-17)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-(三氟甲基)苯基)丙酸叔丁酯,
(5-18)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-异丙基苯基)丙酸叔丁酯,
(5-19)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-异丙基苯基)丙酸叔丁酯,
(5-20)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-异丙基苯基)丙酸叔丁酯,
(5-21)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-甲氧基苯基)丙酸叔丁酯,
(5-22)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-甲氧基苯基)丙酸叔丁酯,
(5-23)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-甲氧基苯基)丙酸叔丁酯,
(5-24)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-(烯丙氧基)苯基)丙酸叔丁酯,
(5-25)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-(烯丙氧基)苯基)丙酸叔丁酯,
(5-26)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-(烯丙氧基)苯基)丙酸叔丁酯,
(5-27)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-异丙氧基苯基)丙酸叔丁酯,
(5-28)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(5-29)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(5-30)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,4-二甲氧基苯基)丙酸叔丁酯,
(5-31)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-甲氧基苯基)丙酸叔丁酯,
(5-32)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟-4-甲氧基苯基)丙酸叔丁酯,
(5-33)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-甲氧基苯基)丙酸叔丁酯,
(5-34)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(5-35)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丙酸叔丁酯,
(5-36)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丙酸叔丁酯,
(5-37)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丙酸叔丁酯,
(5-38)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸叔丁酯,
(5-39)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸叔丁酯,
(5-40)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(吡啶-2-基)丙酸叔丁酯,
(5-41)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(吡啶-3-基)丙酸叔丁酯,
(5-42)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(吡啶-4-基)丙酸叔丁酯,
(5-43)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(6-甲基吡啶-3-基)丙酸叔丁酯,
(5-44)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-甲基吡啶-3-基)丙酸叔丁酯,
(5-45)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-甲基吡啶-3-基)丙酸叔丁酯,
(5-46)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(6-甲氧基吡啶-3-基)丙酸叔丁酯,
(5-47)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-甲氧基吡啶-3-基)丙酸叔丁酯,
(5-48)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-氟吡啶-3-基)丙酸叔丁酯,
(5-49)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-氯吡啶-3-基)丙酸叔丁酯,
(5-50)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-溴吡啶-3-基)丙酸叔丁酯,
(5-51)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-碘吡啶-3-基)丙酸叔丁酯,
(5-52)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-(甲氨基)吡啶-4-基)丙酸叔丁酯,
(5-53)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-(二甲氨基)吡啶-4-基)丙酸叔丁酯,
(5-54)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(嘧啶-5-基)丙酸叔丁酯,
(6-1)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-苯基丁酸,
(6-2)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(邻甲苯基)丁酸,
(6-3)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(间甲苯基)丁酸,
(6-4)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(对甲苯基)丁酸,
(6-5)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-乙基苯基)丁酸,
(6-6)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-氯苯基)丁酸,
(6-7)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氯苯基)丁酸,
(6-8)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-氯苯基)丁酸,
(6-9)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-氟苯基)丁酸,
(6-10)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氟苯基)丁酸,
(6-11)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-氟苯基)丁酸,
(6-12)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-环丙基苯基)丁酸,
(6-13)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-环丙基苯基)丁酸,
(6-14)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-环丙基苯基)丁酸,
(6-15)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-(三氟甲基)苯基)丁酸,
(6-16)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-(三氟甲基)苯基)丁酸,
(6-17)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-(三氟甲基)苯基)丁酸,
(6-18)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-异丙基苯基)丁酸,
(6-19)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-异丙基苯基)丁酸,
(6-20)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-异丙基苯基)丁酸,
(6-21)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-甲氧基苯基)丁酸,
(6-22)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-甲氧基苯基)丁酸,
(6-23)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸,
(6-24)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-(烯丙氧基)苯基)丁酸,
(6-25)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-(烯丙氧基)苯基)丁酸,
(6-26)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-(烯丙氧基)苯基)丁酸,
(6-27)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-异丙氧基苯基)丁酸,
(6-28)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氟-4-(三氟甲基)苯基)丁酸,
(6-29)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-氟-4-(三氟甲基)苯基)丁酸,
(6-30)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,4-二甲氧基苯基)丁酸,
(6-31)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-氟-4-甲氧基苯基)丁酸,
(6-32)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氟-4-甲氧基苯基)丁酸,
(6-33)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-甲氧基苯基)丁酸,
(6-34)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(6-35)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丁酸,
(6-36)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丁酸,
(6-37)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丁酸,
(6-38)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸,
(6-39)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基))氨基甲酰基)苯基)丁酸,
(6-40)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-2-基)丁酸,
(6-41)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-3-基)丁酸,
(6-42)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-4-基)丁酸,
(6-43)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(6-甲基吡啶-3-基)丁酸,
(6-44)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-甲基吡啶-3-基)丁酸,
(6-45)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲基吡啶-3-基)丁酸,
(6-46)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(6-甲氧基吡啶-3-基)丁酸,
(6-47)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-甲氧基吡啶-3-基)丁酸,
(6-48)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-氟吡啶-3-基)丁酸,
(6-49)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-氯吡啶-3-基)丁酸,
(6-50)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-溴吡啶-3-基)丁酸,
(6-51)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(5-碘吡啶-3-基)丁酸,
(6-52)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-(甲氨基)吡啶-4-基)丁酸,
(6-53)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(2-(二甲氨基)吡啶-4-基)丁酸,
(6-54)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(嘧啶-5-基)丁酸,
(7-1)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-苯基丁酸,
(7-2)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(邻甲苯基)丁酸,
(7-3)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(间甲苯基)丁酸,
(7-4)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(对甲苯基)丁酸,
(7-5)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-乙基苯基)丁酸,
(7-6)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-氯苯基)丁酸,
(7-7)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氯苯基)丁酸,
(7-8)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-氯苯基)丁酸,
(7-9)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-氟苯基)丁酸,
(7-10)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氟苯基)丁酸,
(7-11)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-氟苯基)丁酸,
(7-12)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-环丙基苯基)丁酸,
(7-13)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-环丙基苯基)丁酸,
(7-14)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-环丙基苯基)丁酸,
(7-15)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-(三氟甲基)苯基)丁酸,
(7-16)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-(三氟甲基)苯基)丁酸,
(7-17)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-(三氟甲基)苯基)丁酸,
(7-18)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-异丙基苯基)丁酸,
(7-19)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-异丙基苯基)丁酸,
(7-20)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-异丙基苯基)丁酸,
(7-21)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-甲氧基苯基)丁酸,
(7-22)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基苯基)丁酸,
(7-23)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-甲氧基苯基)丁酸,
(7-24)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-(烯丙氧基)苯基)丁酸,
(7-25)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-(烯丙氧基)苯基)丁酸,
(7-26)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-(烯丙氧基)苯基)丁酸,
(7-27)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-异丙氧基苯基)丁酸,
(7-28)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氟-4-(三氟甲基)苯基)丁酸,
(7-29)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-氟-4-(三氟甲基)苯基)丁酸,
(7-30)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,4-二甲氧基苯基)丁酸,
(7-31)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-氟-4-甲氧基苯基)丁酸,
(7-32)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-氟-4-甲氧基苯基)丁酸,
(7-33)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-甲氧基苯基)丁酸,
(7-34)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(7-35)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丁酸,
(7-36)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丁酸,
(7-37)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基-4-((甲基磺酰基)氨基甲酰基)苯基)丁酸,
(7-38)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸,
(7-39)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸,
(7-40)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-2-基)丁酸,
(7-41)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-3-基)丁酸,
(7-42)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-4-基)丁酸,
(7-43)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(6-甲基吡啶-3-基)丁酸,
(7-44)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-甲基吡啶-3-基)丁酸,
(7-45)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(4-甲基吡啶-3-基)丁酸,
(7-46)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(6-甲氧基吡啶-3-基)丁酸,
(7-47)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-甲氧基吡啶-3-基)丁酸,
(7-48)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-氟吡啶-3-基)丁酸,
(7-49)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-氯吡啶-3-基)丁酸,
(7-50)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-溴吡啶-3-基)丁酸,
(7-51)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(5-碘吡啶-3-基)丁酸,
(7-52)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-(甲氨基)吡啶-4-基)丁酸,
(7-53)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(2-(二甲氨基)吡啶-4-基)丁酸,
(7-54)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(嘧啶-5-基)丁酸,
(8-1)(((9H-芴-9-基)甲氧基)羰基)苯丙氨酸,
(8-2)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(邻甲苯基)丙酸,
(8-3)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(间甲苯基)丙酸,
(8-4)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(对甲苯基)丙酸,
(8-5)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-乙基苯基)丙酸,
(8-6)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-氯苯基)丙酸,
(8-7)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氯苯基)丙酸,
(8-8)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-氯苯基)丙酸,
(8-9)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-氟苯基)丙酸,
(8-10)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氟苯基)丙酸,
(8-11)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-氟苯基)丙酸,
(8-12)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-环丙基苯基)丙酸,
(8-13)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-环丙基苯基)丙酸,
(8-14)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-环丙基苯基)丙酸,
(8-15)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-(三氟甲基)苯基)丙酸,
(8-16)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-(三氟甲基)苯基)丙酸,
(8-17)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-(三氟甲基)苯基)丙酸,
(8-18)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-异丙基苯基)丙酸,
(8-19)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-异丙基苯基)丙酸,
(8-20)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-异丙基苯基)丙酸,
(8-21)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-甲氧基苯基)丙酸,
(8-22)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基苯基)丙酸,
(8-23)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-甲氧基苯基)丙酸,
(8-24)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-(烯丙氧基)苯基)丙酸,
(8-25)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-(烯丙氧基)苯基)丙酸,
(8-26)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-(烯丙氧基)苯基)丙酸,
(8-27)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-异丙氧基苯基)丙酸,
(8-28)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氟-4-(三氟甲基)苯基)丙酸,
(8-29)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-氟-4-(三氟甲基)苯基)丙酸,
(8-30)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,4-二甲氧基苯基)丙酸,
(8-31)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-氟-4-甲氧基苯基)丙酸,
(8-32)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-氟-4-甲氧基苯基)丙酸,
(8-33)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,5-二氟-4-甲氧基苯基)丙酸,
(8-34)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(8-35)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丙酸,
(8-36)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丙酸,
(8-37)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丙酸,
(8-38)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸,
(8-39)2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基))氨基甲酰基)苯基)丙酸,
(8-40)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(吡啶-2-基)丙酸,
(8-41)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(吡啶-3-基)丙酸,
(8-42)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(吡啶-4-基)丙酸,
(8-43)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(6-甲基吡啶-3-基)丙酸,
(8-44)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-甲基吡啶-3-基)丙酸,
(8-45)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(4-甲基吡啶-3-基)丙酸,
(8-46)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(6-甲氧基吡啶-3-基)丙酸,
(8-47)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-甲氧基吡啶-3-基)丙酸,
(8-48)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-氟吡啶-3-基)丙酸,
(8-49)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-氯吡啶-3-基)丙酸,
(8-50)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-溴吡啶-3-基)丙酸,
(8-51)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(5-碘吡啶-3-基)丙酸,
(8-52)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-(甲氨基)吡啶-4-基)丙酸,
(8-53)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(2-(二甲氨基)吡啶-4-基)丙酸,
(8-54)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(嘧啶-5-基)丙酸,
(9-1)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基苯丙氨酸,
(9-2)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(邻甲苯基)丙酸,
(9-3)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(间甲苯基)丙酸,
(9-4)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(对甲苯基)丙酸,
(9-5)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-乙基苯基)丙酸,
(9-6)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氯苯基)丙酸,
(9-7)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氯苯基)丙酸,
(9-8)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-氯苯基)丙酸,
(9-9)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟苯基)丙酸,
(9-10)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟苯基)丙酸,
(9-11)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-氟苯基)丙酸,
(9-12)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-环丙基苯基)丙酸,
(9-13)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-环丙基苯基)丙酸,
(9-14)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-环丙基苯基)丙酸,
(9-15)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-(三氟甲基)苯基)丙酸,
(9-16)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-(三氟甲基)苯基)丙酸,
(9-17)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-(三氟甲基)苯基)丙酸,
(9-18)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-异丙基苯基)丙酸,
(9-19)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-异丙基苯基)丙酸,
(9-20)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-异丙基苯基)丙酸,
(9-21)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-甲氧基苯基)丙酸,
(9-22)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-甲氧基苯基)丙酸,
(9-23)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-甲氧基苯基)丙酸,
(9-24)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-(烯丙氧基)苯基)丙酸,
(9-25)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-(烯丙氧基)苯基)丙酸,
(9-26)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-(烯丙氧基)苯基)丙酸,
(9-27)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-异丙氧基苯基)丙酸,
(9-28)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟-4-(三氟甲基)苯基)丙酸,
(9-29)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-(三氟甲基)苯基)丙酸,
(9-30)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,4-二甲氧基苯基)丙酸,
(9-31)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-甲氧基苯基)丙酸,
(9-32)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟-4-甲氧基苯基)丙酸,
(9-33)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-甲氧基苯基)丙酸,
(9-34)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(9-35)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丙酸,
(9-36)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丙酸,
(9-37)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丙酸,
(9-38)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸,
(9-39)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-甲氧基-4-((((四氢-2H-吡喃-2-基))氧基)氨基甲酰基)苯基)丙酸,
(9-40)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(吡啶-2-基)丙酸,
(9-41)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(吡啶-3-基)丙酸,
(9-42)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(吡啶-4-基)丙酸,
(9-43)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(6-甲基吡啶-3-基)丙酸,
(9-44)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-甲基吡啶-3-基)丙酸,
(9-45)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(4-甲基吡啶-3-基)丙酸,
(9-46)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(6-甲氧基吡啶-3-基)丙酸,
(9-47)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-甲氧基吡啶-3-基)丙酸,
(9-48)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-氟吡啶-3-基)丙酸,
(9-49)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-氯吡啶-3-基)丙酸,
(9-50)2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-溴吡啶-3-基)丙酸,
(9-51)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(5-碘吡啶-3-基)丙酸,
(9-52)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-(甲氨基)吡啶-4-基)丙酸,
(9-53)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-(二甲氨基)吡啶-4-基)丙酸,
(9-54)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(嘧啶-5-基)丙酸,
(10-1)2-氨基-4-苯基丁酸,
(10-2)2-氨基-4-(邻甲苯基)丁酸,
(10-3)2-氨基-4-(间甲苯基)丁酸,
(10-4)2-氨基-4-(对甲苯基)丁酸,
(10-5)2-氨基-4-(4-乙基苯基)丁酸,
(10-6)2-氨基-4-(2-氯苯基)丁酸,
(10-7)2-氨基-4-(3-氯苯基)丁酸,
(10-8)2-氨基-4-(4-氯苯基)丁酸,
(10-9)2-氨基-4-(2-氟苯基)丁酸,
(10-10)2-氨基-4-(3-氟苯基)丁酸,
(10-11)2-氨基-4-(4-氟苯基)丁酸,
(10-12)2-氨基-4-(2-环丙基苯基)丁酸,
(10-13)2-氨基-4-(3-环丙基苯基)丁酸,
(10-14)2-氨基-4-(4-环丙基苯基)丁酸,
(10-15)2-氨基-4-(2-(三氟甲基)苯基)丁酸,
(10-16)2-氨基-4-(3-(三氟甲基)苯基)丁酸,
(10-17)2-氨基-4-(4-(三氟甲基)苯基)丁酸,
(10-18)2-氨基-4-(2-异丙基苯基)丁酸,
(10-19)2-氨基-4-(3-异丙基苯基)丁酸,
(10-20)2-氨基-4-(4-异丙基苯基)丁酸,
(10-21)2-氨基-4-(2-甲氧基苯基)丁酸,
(10-22)2-氨基-4-(3-甲氧基苯基)丁酸,
(10-23)2-氨基-4-(4-甲氧基苯基)丁酸,
(10-24)2-氨基-4-(2-(烯丙氧基)苯基)丁酸,
(10-25)2-氨基-4-(3-(烯丙氧基)苯基)丁酸,
(10-26)2-氨基-4-(4-(烯丙氧基)苯基)丁酸,
(10-27)2-氨基-4-(4-异丙氧基苯基)丁酸,
(10-28)2-氨基-4-(3-氟-4-(三氟甲基)苯基)丁酸,
(10-29)2-氨基-4-(2-氟-4-(三氟甲基)苯基)丁酸,
(10-30)2-氨基-4-(3,4-二甲氧基苯基)丁酸,
(10-31)2-氨基-4-(2-氟-4-甲氧基苯基)丁酸,
(10-32)2-氨基-4-(3-氟-4-甲氧基苯基)丁酸,
(10-33)2-氨基-4-(3,5-二氟-4-甲氧基苯基)丁酸,
(10-34)2-氨基-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(10-35)2-氨基-4-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丁酸,
(10-36)2-氨基-4-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丁酸,
(10-37)2-氨基-4-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丁酸,
(10-38)2-氨基-4-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸,
(10-39)2-氨基-4-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸,
(10-40)2-氨基-4-(吡啶-2-基)丁酸,
(10-41)2-氨基-4-(吡啶-3-基)丁酸,
(10-42)2-氨基-4-(吡啶-4-基)丁酸,
(10-43)2-氨基-4-(6-甲基吡啶-3-基)丁酸,
(10-44)2-氨基-4-(5-甲基吡啶-3-基)丁酸,
(10-45)2-氨基-4-(4-甲基吡啶-3-基)丁酸,
(10-46)2-氨基-4-(6-甲氧基吡啶-3-基)丁酸,
(10-47)2-氨基-4-(5-甲氧基吡啶-3-基)丁酸,
(10-48)2-氨基-4-(5-氟吡啶-3-基)丁酸,
(10-49)2-氨基-4-(5-氯吡啶-3-基)丁酸,
(10-50)2-氨基-4-(5-溴吡啶-3-基)丁酸,
(10-51)2-氨基-4-(5-碘吡啶-3-基)丁酸,
(10-52)2-氨基-4-(2-(甲氨基)吡啶-4-基)丁酸,
(10-53)2-氨基-4-(2-(二甲氨基)吡啶-4-基)丁酸,
(10-54)2-氨基-4-(嘧啶-5-基)丁酸,
(11-1)2-(甲氨基)-4-苯基丁酸,
(11-2)2-(甲氨基)-4-(邻甲苯基)丁酸,
(11-3)2-(甲氨基)-4-(间甲苯基)丁酸,
(11-4)2-(甲氨基)-4-(对甲苯基)丁酸,
(11-5)2-(甲氨基)-4-(4-乙基苯基)丁酸,
(11-6)2-(甲氨基)-4-(2-氯苯基)丁酸,
(11-7)2-(甲氨基)-4-(3-氯苯基)丁酸,
(11-8)2-(甲氨基)-4-(4-氯苯基)丁酸,
(11-9)2-(甲氨基)-4-(2-氟苯基)丁酸,
(11-10)2-(甲氨基)-4-(3-氟苯基)丁酸,
(11-11)2-(甲氨基)-4-(4-氟苯基)丁酸,
(11-12)2-(甲氨基)-4-(2-环丙基苯基)丁酸,
(11-13)2-(甲氨基)-4-(3-环丙基苯基)丁酸,
(11-14)2-(甲氨基)-4-(4-环丙基苯基)丁酸,
(11-15)2-(甲氨基)-4-(2-(三氟甲基)苯基)丁酸,
(11-16)2-(甲氨基)-4-(3-(三氟甲基)苯基)丁酸,
(11-17)2-(甲氨基)-4-(4-(三氟甲基)苯基)丁酸,
(11-18)2-(甲氨基)-4-(2-异丙基苯基)丁酸,
(11-19)2-(甲氨基)-4-(3-异丙基苯基)丁酸,
(11-20)2-(甲氨基)-4-(4-异丙基苯基)丁酸,
(11-21)2-(甲氨基)-4-(2-甲氧基苯基)丁酸,
(11-22)2-(甲氨基)-4-(3-甲氧基苯基)丁酸,
(11-23)2-(甲氨基)-4-(4-甲氧基苯基)丁酸,
(11-24)2-(甲氨基)-4-(2-(烯丙氧基)苯基)丁酸,
(11-25)2-(甲氨基)-4-(3-(烯丙氧基)苯基)丁酸,
(11-26)2-(甲氨基)-4-(4-(烯丙氧基)苯基)丁酸,
(11-27)2-(甲氨基)-4-(4-异丙氧基苯基)丁酸,
(11-28)2-(甲氨基)-4-(3-氟-4-(三氟甲基)苯基)丁酸,
(11-29)2-(甲氨基)-4-(2-氟-4-(三氟甲基)苯基)丁酸,
(11-30)2-(甲氨基)-4-(3,4-二甲氧基苯基)丁酸,
(11-31)2-(甲氨基)-4-(2-氟-4-甲氧基苯基)丁酸,
(11-32)2-(甲氨基)-4-(3-氟-4-甲氧基苯基)丁酸,
(11-33)2-(甲氨基)-4-(3,5-二氟-4-甲氧基苯基)丁酸,
(11-34)2-(甲氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(11-35)2-(甲氨基)-4-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丁酸,
(11-36)2-(甲氨基)-4-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丁酸,
(11-37)2-(甲氨基)-4-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丁酸,
(11-38)2-(甲氨基)-4-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸,
(11-39)2-(甲氨基)-4-(3-甲氧基-4-((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丁酸,
(11-40)2-(甲氨基)-4-(吡啶-2-基)丁酸,
(11-41)2-(甲氨基)-4-(吡啶-3-基)丁酸,
(11-42)2-(甲氨基)-4-(吡啶-4-基)丁酸,
(11-43)2-(甲氨基)-4-(6-甲基吡啶-3-基)丁酸,
(11-44)2-(甲氨基)-4-(5-甲基吡啶-3-基)丁酸,
(11-45)2-(甲氨基)-4-(4-甲基吡啶-3-基)丁酸,
(11-46)2-(甲氨基)-4-(6-甲氧基吡啶-3-基)丁酸,
(11-47)2-(甲氨基)-4-(5-甲氧基吡啶-3-基)丁酸,
(11-48)2-(甲氨基)-4-(5-氟吡啶-3-基)丁酸,
(11-49)2-(甲氨基)-4-(5-氯吡啶-3-基)丁酸,
(11-50)2-(甲氨基)-4-(5-溴吡啶-3-基)丁酸,
(11-51)2-(甲氨基)-4-(5-碘吡啶-3-基)丁酸,
(11-52)2-(甲氨基)-4-(2-(甲氨基)吡啶-4-基)丁酸,
(11-53)2-(甲氨基)-4-(2-(二甲氨基)吡啶-4-基)丁酸,
(11-54)2-(甲氨基)-4-(嘧啶-5-基)丁酸,
(12-1)苯丙氨酸,
(12-2)2-氨基-3-(邻甲苯基)丙酸,
(12-3)2-氨基-3-(间甲苯基)丙酸,
(12-4)2-氨基-3-(对甲苯基)丙酸,
(12-5)2-氨基-3-(4-乙基苯基)丙酸,
(12-6)2-氨基-3-(2-氯苯基)丙酸,
(12-7)2-氨基-3-(3-氯苯基)丙酸,
(12-8)2-氨基-3-(4-氯苯基)丙酸,
(12-9)2-氨基-3-(2-氟苯基)丙酸,
(12-10)2-氨基-3-(3-氟苯基)丙酸,
(12-11)2-氨基-3-(4-氟苯基)丙酸,
(12-12)2-氨基-3-(2-环丙基苯基)丙酸,
(12-13)2-氨基-3-(3-环丙基苯基)丙酸,
(12-14)2-氨基-3-(4-环丙基苯基)丙酸,
(12-15)2-氨基-3-(2-(三氟甲基)苯基)丙酸,
(12-16)2-氨基-3-(3-(三氟甲基)苯基)丙酸,
(12-17)2-氨基-3-(4-(三氟甲基)苯基)丙酸,
(12-18)2-氨基-3-(2-异丙基苯基)丙酸,
(12-19)2-氨基-3-(3-异丙基苯基)丙酸,
(12-20)2-氨基-3-(4-异丙基苯基)丙酸,
(12-21)2-氨基-3-(2-甲氧基苯基)丙酸,
(12-22)2-氨基-3-(3-甲氧基苯基)丙酸,
(12-23)2-氨基-3-(4-甲氧基苯基)丙酸,
(12-24)2-氨基-3-(2-(烯丙氧基)苯基)丙酸,
(12-25)2-氨基-3-(3-(烯丙氧基)苯基)丙酸,
(12-26)2-氨基-3-(4-(烯丙氧基)苯基)丙酸,
(12-27)2-氨基-3-(4-异丙氧基苯基)丙酸,
(12-28)2-氨基-3-(3-氟-4-(三氟甲基)苯基)丙酸,
(12-29)2-氨基-3-(2-氟-4-(三氟甲基)苯基)丙酸,
(12-30)2-氨基-3-(3,4-二甲氧基苯基)丙酸,
(12-31)2-氨基-3-(2-氟-4-甲氧基苯基)丙酸,
(12-32)2-氨基-3-(3-氟-4-甲氧基苯基)丙酸,
(12-33)2-氨基-3-(3,5-二氟-4-甲氧基苯基)丙酸,
(12-34)2-氨基-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(12-35)2-氨基-3-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丙酸,
(12-36)2-氨基-3-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丙酸,
(12-37)2-氨基-3-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丙酸,
(12-38)2-氨基-3-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸,
(12-39)2-氨基-3-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸,
(12-40)2-氨基-3-(吡啶-2-基)丙酸,
(12-41)2-氨基-3-(吡啶-3-基)丙酸,
(12-42)2-氨基-3-(吡啶-4-基)丙酸,
(12-43)2-氨基-3-(6-甲基吡啶-3-基)丙酸,
(12-44)2-氨基-3-(5-甲基吡啶-3-基)丙酸,
(12-45)2-氨基-3-(4-甲基吡啶-3-基)丙酸,
(12-46)2-氨基-3-(6-甲氧基吡啶-3-基)丙酸,
(12-47)2-氨基-3-(5-甲氧基吡啶-3-基)丙酸,
(12-48)2-氨基-3-(5-氟吡啶-3-基)丙酸,
(12-49)2-氨基-3-(5-氯吡啶-3-基)丙酸,
(12-50)2-氨基-3-(5-溴吡啶-3-基)丙酸,
(12-51)2-氨基-3-(5-碘吡啶-3-基)丙酸,
(12-52)2-氨基-3-(2-(甲氨基)吡啶-4-基)丙酸,
(12-53)2-氨基-3-(2-(二甲氨基)吡啶-4-基)丙酸,
(12-54)2-氨基-3-(嘧啶-5-基)丙酸,
(13-1)甲基苯丙氨酸,
(13-2)2-(甲氨基)-3-(邻甲苯基)丙酸,
(13-3)2-(甲氨基)-3-(间甲苯基)丙酸,
(13-4)2-(甲氨基)-3-(对甲苯基)丙酸,
(13-5)2-(甲氨基)-3-(4-乙基苯基)丙酸,
(13-6)2-(甲氨基)-3-(2-氯苯基)丙酸,
(13-7)2-(甲氨基)-3-(3-氯苯基)丙酸,
(13-8)2-(甲氨基)-3-(4-氯苯基)丙酸,
(13-9)2-(甲氨基)-3-(2-氟苯基)丙酸,
(13-10)2-(甲氨基)-3-(3-氟苯基)丙酸,
(13-11)2-(甲氨基)-3-(4-氟苯基)丙酸,
(13-12)2-(甲氨基)-3-(2-环丙基苯基)丙酸,
(13-13)2-(甲氨基)-3-(3-环丙基苯基)丙酸,
(13-14)2-(甲氨基)-3-(4-环丙基苯基)丙酸,
(13-15)2-(甲氨基)-3-(2-(三氟甲基)苯基)丙酸,
(13-16)2-(甲氨基)-3-(3-(三氟甲基)苯基)丙酸,
(13-17)2-(甲氨基)-3-(4-(三氟甲基)苯基)丙酸,
(13-18)2-(甲氨基)-3-(2-异丙基苯基)丙酸,
(13-19)2-(甲氨基)-3-(3-异丙基苯基)丙酸,
(13-20)2-(甲氨基)-3-(4-异丙基苯基)丙酸,
(13-21)2-(甲氨基)-3-(2-甲氧基苯基)丙酸,
(13-22)2-(甲氨基)-3-(3-甲氧基苯基)丙酸,
(13-23)2-(甲氨基)-3-(4-甲氧基苯基)丙酸,
(13-24)2-(甲氨基)-3-(2-(烯丙氧基)苯基)丙酸,
(13-25)2-(甲氨基)-3-(3-(烯丙氧基)苯基)丙酸,
(13-26)2-(甲氨基)-3-(4-(烯丙氧基)苯基)丙酸,
(13-27)2-(甲氨基)-3-(4-异丙氧基苯基)丙酸,
(13-28)2-(甲氨基)-3-(3-氟-4-(三氟甲基)苯基)丙酸,
(13-29)2-(甲氨基)-3-(2-氟-4-(三氟甲基)苯基)丙酸,
(13-30)2-(甲氨基)-3-(3,4-二甲氧基苯基)丙酸,
(13-31)2-(甲氨基)-3-(2-氟-4-甲氧基苯基)丙酸,
(13-32)2-(甲氨基)-3-(3-氟-4-甲氧基苯基)丙酸,
(13-33)2-(甲氨基)-3-(3,5-二氟-4-甲氧基苯基)丙酸,
(13-34)2-(甲氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(13-35)2-(甲氨基)-3-(3-甲氧基-4-(甲基氨基甲酰基)苯基)丙酸,
(13-36)2-(甲氨基)-3-(4-甲氧基-3-(甲基氨基甲酰基)苯基)丙酸,
(13-37)2-(甲氨基)-3-(3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基)丙酸,
(13-38)2-(甲氨基)-3-(4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸,
(13-39)2-(甲氨基)-3-(3-甲氧基-4-((((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基)丙酸,
(13-40)2-(甲氨基)-3-(吡啶-2-基)丙酸,
(13-41)2-(甲氨基)-3-(吡啶-3-基)丙酸,
(13-42)2-(甲氨基)-3-(吡啶-4-基)丙酸,
(13-43)2-(甲氨基)-3-(6-甲基吡啶-3-基)丙酸,
(13-44)2-(甲氨基)-3-(5-甲基吡啶-3-基)丙酸,
(13-45)2-(甲氨基)-3-(4-甲基吡啶-3-基)丙酸,
(13-46)2-(甲氨基)-3-(6-甲氧基吡啶-3-基)丙酸,
(13-47)2-(甲氨基)-3-(5-甲氧基吡啶-3-基)丙酸,
(13-48)2-(甲氨基)-3-(5-氟吡啶-3-基)丙酸,
(13-49)2-(甲氨基)-3-(5-氯吡啶-3-基)丙酸,
(13-50)2-(甲氨基)-3-(5-溴吡啶-3-基)丙酸,
(13-51)2-(甲氨基)-3-(5-碘吡啶-3-基)丙酸,
(13-52)2-(甲氨基)-3-(2-(甲氨基)吡啶-4-基)丙酸,
(13-53)2-(甲氨基)-3-(2-(二甲氨基)吡啶-4-基)丙酸,
(13-54)2-(甲氨基)-3-(嘧啶-5-基)丙酸,
(14-1)2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸叔丁酯,
(14-2)2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸苄酯,
(14-3)2-((叔丁氧基羰基)(乙基)氨基)-3-(对甲苯基)丙酸叔丁酯,
(14-4)2-((叔丁氧基羰基)(乙基)氨基)-3-(对甲苯基)丙酸苄酯,
(14-5)2-(((苄氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸叔丁酯,
(14-6)2-(((苄氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸苄酯,
(14-7)2-(((烯丙氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸叔丁酯,
(14-8)2-(((烯丙氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸苄酯,
(14-9)2-(乙基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)-3-(对甲苯基)丙酸叔丁酯,
(14-10)2-(乙基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)-3-(对甲苯基)丙酸苄酯,
(14-11)2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸,
(14-12)2-((叔丁氧基羰基)(乙基)氨基)-3-(对甲苯基)丙酸,
(14-13)2-(((苄氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸,
(14-14)2-(((烯丙氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸,
(14-15)2-(乙基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)-3-(对甲苯基)丙酸,和
(14-16)2-(乙氨基)-3-(对甲苯基)丙酸。
[发明的有益效果]
根据本发明,可以高效地制备可用于寻找肽药物和/或提供药物活性成分的光学活性芳香族氨基酸衍生物。此外,由于还可能制备各种光学活性芳香族氨基酸衍生物,因此本发明可以提供结构变化的光学活性芳香族氨基酸衍生物。
具体实施方式
(缩写)
本发明中使用的缩写如下所述。
AA或AcONH4:乙酸铵
AcOEt:乙酸乙酯
Alloc基团:烯丙氧基羰基基团
BF3·OEt2:三氟化硼-二乙醚络合物
Bn基团:苄基基团
Boc基团:叔丁氧基羰基基团
Cbz基团:苄氧羰基基团
DCM:二氯甲烷
DIC:N,N′-二异丙基碳二亚胺
DMA:N,N-二甲基乙酰胺
DMF:N,N-二甲基甲酰胺
DMI:1,3-二甲基-2-咪唑烷酮
DMPU:N,N′-二甲基丙烯脲
DMSO:二甲亚砜
dtbbpy:4,4′-二叔丁基-2,2′-联吡啶
EDTA·2Na:乙二胺四乙酸二钠
FA:甲酸
Fmoc-Cl:9-芴基甲基氯甲酸酯
Fmoc-OSu:N-[(9H-芴-9-基甲氧基)羰基氧基]琥珀酰亚胺
Fmoc基团:9-芴基甲氧羰基基团
HPLC:高效液相色谱
LC/MS:液相色谱/质谱
MeCN:乙腈
Ms基团:甲磺酰基团
MTBE:甲基叔丁基醚
NHPI:N-羟基邻苯二甲酰亚胺
NMP:N-甲基吡咯烷酮
NMR:核磁共振谱
PhSiH3:苯基硅烷
Ph基团:苯基基团
TBDMSCl:叔丁基二甲基氯硅烷
TBDMS基团:叔丁基二甲基甲硅烷基基团
TBDPSCl:叔丁基二苯基氯硅烷
TBDPS基团:叔丁基二苯基甲硅烷基基团
tBu或t-Bu基团:叔丁基基团
Teoc基团:2-(三甲基甲硅烷基)乙氧基羰基基团
TESCl:三乙基氯硅烷
TES基团:三乙基甲硅烷基基团
TFA:三氟乙酸
TfOH:三氟甲磺酸
Tf基团:三氟甲磺酰基基团
THF:四氢呋喃
TIPSCl:三异丙基氯硅烷
TIPS基团:三异丙基甲硅烷基基团
TMSBr:三甲基溴化甲硅烷
TMSCl:三甲基氯硅烷
TMSI:三甲基碘硅烷
TMSOTf:三甲基硅烷基三氟甲磺酸酯
TMS基团:三甲基甲硅烷基基团
Tr基团:三苯甲基基团
Ts基团:甲苯磺酰基基团
Gly:甘氨酸
Ala:丙氨酸
Ser:丝氨酸
Thr:苏氨酸
Val:缬氨酸
Leu:亮氨酸
Ile:异亮氨酸
Phe:苯丙氨酸
Tyr:酪氨酸
Trp:色氨酸
His:组氨酸
Glu:谷氨酸
Asp:天冬氨酸
Gln:谷氨酰胺
Asn:天冬酰胺
Cys:半胱氨酸
Met:甲硫氨酸
Lys:赖氨酸
Arg:精氨酸
Pro:脯氨酸
(官能团等的定义)
本文中“卤素原子”的例子包括F、Cl、Br或I。
如本文所用,术语“烷基”是指通过从脂族烃中除去任何一个氢原子而衍生的一价基团,并且涵盖包含氢和碳原子但不包含杂原子(其指除碳和氢原子以外的原子)或骨架中的不饱和碳-碳键的烃基或烃基团的亚集。烷基包括直链或支链基团。烷基是具有1至20个碳原子的烷基(C1-C20;下文中,“Cp-Cq”是指它具有p至q个碳原子),其优选实例包括C1-C6烷基。具体实例包括甲基、乙基、丙基、丁基、戊基、己基、异丙基、叔丁基和仲丁基。
如本文所用,术语“烷氧基”是指与上述定义的“烷基”键合的含氧基团。优选的实例包括C1-C4烷氧基和C1-C3烷氧基。烷氧基的具体实例包括甲氧基、乙氧基、1-丙氧基、2-丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。
在本文中,术语“烯基”是指具有至少一个双键(两个相邻的sp2碳原子)的一价基团。根据双键和取代基(如果存在)的排列,双键可以采取entgegen(E)或zusammen(Z)和顺式或反式几何形式。烯基的实例包括直链或支链,包括含有内烯烃的直链。其优选实例包括C2-C10烯基,更优选C2-C6烯基和C2-C4烯基。烯基的具体实例包括乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基(包括顺式和反式)、3-丁烯基、戊烯基和己烯基。
本文使用的术语“烯氧基”是指与上述定义的“烯基”键合的含氧基团,优选的实例包括C2-C6烯氧基和C2-C4烯氧基。
在本文中,术语“炔基”是指具有至少一个三键(两个相邻的sp碳原子)的一价基团。其实例包括直链或支链炔基,包括内亚烷基。其优选实例包括C2-C10炔基,更优选C2-C6炔基和C2-C4炔基。炔基的具体实例包括乙炔基、1-丙炔基、炔丙基、3-丁炔基、戊炔基、己炔基、3-苯基-2-丙炔基、3-(2′-氟苯基)-2-丙炔基、2-羟基-2-丙炔基、3-(3-氟苯基)-2-丙炔基和3-甲基-(5-苯基)-4-戊炔基。
如本文所用,术语“炔氧基”是指与上述定义的“炔基”键合的含氧基团,优选实例包括C2-C6炔氧基和C2-C4炔氧基。
本文所用的术语“卤代烷基”是指上述“烷基”的一个或多个氢原子被卤素原子取代得到的基团,优选的实例包括C1-C6卤代烷基、C1-C4卤代烷基、C1-C3卤代烷基和C1-C2卤代烷基。
本文使用的术语“卤代烷氧基”是指与上述“卤代烷基”键合的含氧基团,优选的实例包括C1-C4卤代烷氧基、C1-C3卤代烷氧基和C1-C2卤代烷氧基。
本文所用术语“氟烷基”是指通过用氟原子取代“烷基”的一个或多个氢原子而获得的基团,优选实例包括C1-C6氟烷基、C1-C4氟烷基、C1-C3氟烷基和C1-C2氟烷基。氟烷基的具体实例包括二氟甲基、三氟甲基、2,2,2-三氟乙基、五氟乙基、2,2,3,3-四氟丙基和七氟丙基。
本文使用的术语“氟烷氧基”是指与上述“氟烷基”键合的含氧基团,优选的实例包括C1-C4氟烷氧基、C1-C3氟烷氧基和C1-C2氟烷氧基。氟烷氧基的具体实例包括三氟甲氧基、二氟甲氧基、2,2,2-三氟乙氧基、五氟乙氧基、2,2,3,3-四氟丙氧基和七氟丙氧基。
如本文所用,术语“烷基磺酰基”是指与上述“烷基”键合的磺酰基基团(即,烷基-SO2-)。烷基磺酰基的优选实例包括C1-C6烷基磺酰基和C1-C4烷基磺酰基,具体实例包括甲基磺酰基、乙基磺酰基、正丙基磺酰基和异丙基磺酰基。
如本文所用,术语“烷基磺酰基氨基”是指通过用上述“烷基磺酰基”取代氨基(-NH2)的一个氢原子而获得的基团。烷基磺酰氨基的优选实例包括C1-C6烷基磺酰氨基和C1-C4烷基磺酰氨基,具体实例包括甲基磺酰氨基、乙基磺酰氨基、正丙基磺酰氨基和异丙基磺酰氨基。
如本文所用,术语“环烷基”是指饱和或部分饱和的环状一价脂族烃基,包括单环、双环和螺环。环烷基的优选实例包括C3-C10环烷基。环烷基可以是部分不饱和的。环烷基的具体实例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和双环[2.2.1]庚基。
如本文所用,术语“氨基羰基”是指其中任选取代的氮与羰基键合的基团(即,-C=O-NHR),并且也称为甲酰胺基团。由R表示的取代基没有特别指定,实例包括羟基基团、烷基基团和烷基磺酰基基团。取代基的具体实例包括甲基、乙基、丙基、丁基、甲磺酰基和乙磺酰基。
如本文所用,术语“芳基”是指一价芳烃环,其优选实例包括C6-C10芳基。芳基的具体实例包括苯基、1-萘基和2-萘基。芳基可以被任何取代基取代,优选地,它可以被烷基、烷氧基、氟烷基、氟烷氧基、氧代、氨基羰基或卤素原子取代。
如本文所用,术语“杂芳基”是指在构成环的原子中优选在环中具有1至5个杂原子的芳族一价杂环基团。杂原子优选为N、O或S,杂原子数优选为1或2。杂芳基可以是部分饱和的,并且可以是单环或稠环(例如苯环或单环杂芳环稠合的双环杂芳基)。构成环的原子数优选为5至10(5至10元杂芳基)。杂芳基可以被任何取代基取代,并且可以优选被烷基、烷氧基、氟烷基、氟烷氧基、氧代、氨基羰基或卤素原子取代。杂芳基的具体实例包括呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、三唑基、四唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、三嗪基、苯并呋喃基、苯并噻吩基、苯并噻二唑基、苯并噻唑基、苯并噁唑基、苯并噁二唑基、苯并咪唑基、吲哚基、异吲哚基、氮杂吲哚基、吲唑基、喹啉基、异喹啉基、肉桂基、喹唑啉基、喹喔啉基、苯并二噁唑基、吲哚嗪基和咪唑并吡啶基。
在本文中,术语“在环中具有杂原子”是指构成环的原子包括杂原子。杂原子优选为N、O或S,杂原子数优选为1或2,优选为4至6元环。这种环的实例包括芳香杂环如吡啶,和非芳香杂环如哌啶、吗啉、吡咯烷和氮杂环丁烷。当杂原子为氧原子时,表示为“环中具有氧原子”等,此类环的实例包括芳族杂环如呋喃和非芳族杂环如四氢呋喃和1,4-二噁烷。当杂原子为硫原子时,表示为“在环中具有硫原子”等,此类环的例子包括芳香族杂环例如噻吩、非芳香族杂环例如四氢噻吩。当杂原子为氮原子和氧原子时,表示为“环中具有氮原子和氧原子”等,此类环的例子包括芳族杂环如噁唑和非芳族杂环如噁唑啉、噁唑烷和噁唑烷酮。此外,当杂原子是氮原子和硫原子时,表示为“在环中具有氮原子和硫原子”等,此类环的例子包括芳族杂环如噻唑和非芳族杂环,例如噻唑啉、噻唑烷和噻唑烷酮。
在本文中,术语“杂环基团”或“杂环基”是指环中具有至少一个杂原子(例如N、O或S)的基团,并且该环可以是芳香族或非芳香族的,即可以是饱和的,或可以完全或部分不饱和。环中包含的杂原子数优选为1或2,并且环优选为3至7元。杂环基基团可以被任何取代基取代,并且可以优选被烷基、烷氧基、氟烷基、氟烷氧基、氧代、氨基羰基、卤素原子或芳基取代。杂环基的具体实例包括吡啶基、哌啶基、吗啉基、吡咯烷基、噁二唑基(oxadiazolonyl)、噁唑烷-2-基、噁唑啉-2-基、氮丙啶基、二氢噁唑基和氮杂啶基。
如本文所用,术语“芳基烷基(芳烷基)”是同时包含上述芳基和上述烷基的基团,并且指例如通过用芳基取代烷基的至少一个氢原子而获得的基团。芳基烷基的优选实例包括“C6-C10芳基C1-C6烷基”,具体实例包括苄基和苯乙基。芳基烷基的芳基可以被任何取代基取代,并且可以优选被烷基、烷氧基、氟烷基、氟烷氧基、氧代、氨基羰基或卤素原子取代。
在本文中使用的术语“杂芳基烷基(杂芳烷基)”是指同时包含杂芳基和烷基的基团,并且指例如通过用杂芳基取代烷基的至少一个氢原子而获得的基团。杂芳基烷基的优选实例包括“5-至10-元杂芳基C1-C6烷基”,具体实例包括吡啶基甲基和吡啶基乙基。杂芳基烷基的杂芳基可以被任何取代基取代,并且可以优选被烷基、烷氧基、氟烷基、氟烷氧基、氧代、氨基羰基或卤素原子取代。
如本文所用,术语“亚烷基”是指通过从“烷基”除去任何一个氢原子而衍生的二价基团。亚烷基的优选实例包括C1-C2亚烷基、C1-C3亚烷基、C1-C4亚烷基、C1-C5亚烷基和C1-C6亚烷基。亚烷基的具体实例包括-CH2-、-(CH2)2-、-(CH2)3-、CH(CH3)CH2-、-C(CH3)2-、-(CH2)4-、CH(CH3)CH2CH2-、-C(CH3)2CH2-、-CH2CH(CH3)CH2-、-CH2C(CH3)2-、-CH2CH2CH(CH3)-、-(CH2)5-和-(CH2)6-。
如本文所用,术语“亚芳基”是指通过进一步从芳基除去任何一个氢原子而衍生的二价基团。亚芳基可以是单环或稠环。成环原子的数目没有特别限制,但优选为6至10个(C6-C10亚芳基)。亚芳基的具体实例包括亚苯基。亚芳基可以被任何取代基取代,并且可以优选被烷基、烷氧基、氟烷基、氟烷氧基、氧代、氨基羰基或卤素原子取代。
如本文所用,术语“杂亚芳基”是指通过进一步从杂芳基除去任何一个氢原子而衍生的二价基团。杂亚芳基可以是单环或稠环。成环原子的数量没有特别限制,但优选为5至10个(5至10元杂亚芳基)。杂亚芳基的具体实例包括咪唑二基、吡啶二基、噁二唑二基、噻唑二基和噻二唑二基。杂亚芳基可以被任何取代基取代,并且可以优选被烷基、烷氧基、氟烷基、氟烷氧基、氧代、氨基羰基或卤素原子取代。
如本文所用,术语“稠合(缩合)环结构”是指其中在具有两个或更多个环的环状化合物中多个环共享两个或更多个原子的环状结构。“由两个或更多个芳环构成的稠环结构”是指在具有两个或更多个芳环的环状化合物中,多个芳环共享两个或更多个原子的环状结构。稠环结构的实例包括但不限于吲哚骨架、苯并呋喃骨架、苯并咪唑骨架、喹啉骨架和双环[4.4.0]癸烷骨架。
在本文中,“氨基保护基团”包括氨基甲酸酯类保护基团、酰胺类保护基团、芳基磺酰胺类保护基团、烷基胺类保护基团、酰亚胺类保护基团等。氨基保护基团的具体实例包括Fmoc基团、Boc基团、Alloc基团、Cbz基团、Teoc基团、三氟乙酰基基团、苯磺酰基基团、甲苯磺酰基基团、nosyl基团、dinitronosyl基团、叔丁基基团、三苯甲基基团、枯基基团、苯亚甲基基团、4-甲氧基苯亚甲基基团和二苯基亚甲基基团。
在本文中,“羧基保护基团”包括烷基酯类保护基团、苄酯类保护基团、取代的烷基酯类保护基团等。羧基保护基团的具体实例包括甲基基团、乙基基团、叔丁基基团、苄基基团、三苯甲基基团、枯基基团、甲氧基三苯甲基团基、2-(三甲基甲硅烷基)乙基基团、2,2,2-三氯乙基基团和烯丙基基团。
在本文中,“羟基保护基团”包括烷基醚类保护基团、芳烷基醚类保护基团、甲硅烷基醚类保护基团、碳酸酯类保护基团等。羟基保护基团的具体实例包括甲氧基甲基基团、苄氧基甲基基团、四氢吡喃基基团、叔丁基基团、烯丙基基团、2,2,2-三氯乙基基团、苄基基团、4-甲氧基苄基基团、三甲基甲硅烷基基团、三乙基甲硅烷基基团、三异丙基甲硅烷基基团、叔丁基二甲基甲硅烷基基团、叔丁基二苯基甲硅烷基基团、甲氧基羰基基团、9-芴基甲氧基羰基基团和2,2,2-三氯乙氧基羰基基团。
在本文中,“被保护的羟基”是指被羟基的保护基团保护的羟基。
在本文所述的化合物的制备中,当所定义的基团在所进行的方法的条件下发生不期望的化学转化时,可以通过例如官能团的保护和脱保护来制备所述化合物。在本文中,选择和连接/脱开保护基团的操作可以包括例如“Greene′s,“Protective Groups inOrganic Synthesis”(第5版,John Wiley&Sons 2014)”中描述的方法,并且这些根据反应条件适当地使用。此外,可以根据需要改变诸如引入取代基的反应步骤的顺序。
在本文中,当添加修饰词“任选取代的”时,取代基的实例包括烷基基团、烷氧基基团、氟烷基基团、氟烷氧基基团、氧代、氨基羰基基团、烷基磺酰基基团、烷基磺酰基氨基基团、环烷基基团、芳基基团、杂芳基基团、杂环基基团、芳烷基基团、杂芳烷基基团、卤素原子、硝基基团、氨基基团、单烷基氨基基团、二烷基氨基基团、氰基基团、羧基基团、烷氧基羰基基团和甲酰基基团。
此外,额外的取代基可以连接到这些取代基上。此类额外的取代基不受限制,并且一个或两个或更多个可以自由地独立地选自任何取代基,包括例如卤素原子、氧原子、硫原子、氮原子、硼原子、硅原子、和磷原子。实例包括任选取代的烷基、烯基、炔基、芳基、杂芳基、芳烷基和环烷基。
本发明各式表示的化合物可以是化合物的盐或化合物或盐的溶剂化物。由各式表示的化合物的盐的实例包括盐酸盐;氢溴酸盐;氢碘化物;磷酸盐;膦酸盐;硫酸盐;磺酸盐例如甲磺酸盐、对甲苯磺酸盐;羧酸盐,例如乙酸盐、柠檬酸盐、苹果酸盐、酒石酸盐、琥珀酸盐和水杨酸盐;或碱金属盐,如钠盐和钾盐;碱土金属盐例如镁盐和钙盐;铵盐,如铵盐、烷基铵盐、二烷基铵盐、三烷基铵盐和四烷基铵盐。这些盐例如通过使化合物与酸或碱接触而制备。各式所代表的化合物的溶剂化物是指溶质分子强烈吸引溶液中的溶剂分子形成一个分子基团的现象,当溶剂为水时,溶剂化物是指水合物。本发明的各式表示的化合物除了能够与选自有机溶剂如醇(例如甲醇、乙醇、1-丙醇2-丙醇)、二甲基甲酰胺或二甘醇二甲醚和水的单个溶剂形成溶剂化物之外,还能够与选自上述的多种溶剂形成溶剂化物。
如本文所用,术语“氨基酸”包括天然和非天然氨基酸(也可称为氨基酸衍生物)。如本文所用,术语“天然氨基酸”是指Gly、Ala、Ser、Thr、Val、Leu、Ile、Phe、Tyr、Trp、His、Glu、Asp、Gln、Asn、Cys、Met、Lys、Arg、或Pro。非天然氨基酸(氨基酸衍生物)的实例包括但不特别限于,β-氨基酸、D-氨基酸、N-取代的氨基酸、α,α-二取代的氨基酸、具有不同于天然氨基酸的侧链的氨基酸和羟基羧酸。本文中的氨基酸可具有任何构象。对氨基酸侧链的选择没有特别限制,但除氢原子外,可自由地选自例如烷基基团、烯基基团、炔基基团、芳基基团、杂芳基基团、芳烷基基团、杂芳烷基基团、环烷基基团和螺键合环烷基基团。每个基团可以有取代基,对取代基没有限制。例如,一个或两个或更多个取代基可自由且独立地选自任何取代基,包括卤素原子、O原子、S原子、N原子、B原子、Si原子或P原子。实例包括任选取代的烷基基团、烷氧基基团、烯基基团、炔基基团、芳基基团、杂芳基基团、芳烷基基团和环烷基基团、或氧代、氨基羰基和卤素原子。在非限制性实施方案中,本文中的氨基酸可以是在同一分子中具有羧基基团和氨基基团的化合物(即使在这种情况下,氨基酸中也包括亚氨基酸如脯氨酸和羟脯氨酸)。
源自卤素的取代基包括氟(-F)、氯(-Cl)、溴(-Br)和碘(-I)。
源自O原子的取代基包括羟基(-OH)、氧基(-OR)、羰基(-C=OR)、羧基(-CO2H)、氧羰基(-C=O-OR)、羰基氧基(-O-C=O-R)、硫代羰基(-C=O-SR)、羰基硫基(-S-C=O-R)、氨基羰基(-C=O-NHR)、羰基氨基(-NH-C=O-R)、氧羰基氨基(-NH-C=O-OR)、磺酰氨基(-NH-SO2-R)、氨基磺酰基(-SO2-NHR)、氨磺酰氨基(-NH-SO2-NHR)、硫代羧基(-C(=O)-SH)和羧基羰基(-C(=O)-CO2H)。
氧基(-OR)的实例包括烷氧基、环烷氧基、烯氧基、炔氧基、芳氧基、杂芳氧基和芳烷氧基。
羰基(-C=O-R)的实例包括甲酰基(-C=O-H)、烷基羰基、环烷基羰基、烯基羰基、炔基羰基、芳基羰基、杂芳基羰基和芳烷基羰基。
氧羰基(-C=O-OR)的实例包括烷氧羰基、环烷氧羰基、烯氧羰基、炔氧羰基、芳氧羰基、杂芳氧羰基和芳烷氧羰基。
羰基氧基(-O-C=O-R)的实例包括烷基羰基氧基、环烷基羰基氧基、烯基羰基氧基、炔基羰基氧基、芳基羰基氧基、杂芳基羰基氧基和芳烷基羰基氧基。
硫代羰基(-C=O-SR)的实例包括烷基硫代羰基、环烷基硫代羰基、烯基硫代羰基、炔基硫代羰基、芳基硫代羰基、杂芳基硫代羰基和芳烷基硫代羰基。
羰基硫基(-S-C=O-R)的实例包括烷基羰基硫基、环烷基羰基硫基、烯基羰基硫基、炔基羰基硫基、芳基羰基硫基、杂芳基羰基硫基和芳烷基羰基硫基。
氨基羰基(-C=O-NHR)的实例包括烷基氨基羰基、环烷基氨基羰基、烯基氨基羰基、炔基氨基羰基、芳基氨基羰基、杂芳基氨基羰基和芳烷基氨基羰基。其他实例包括其中与-C=O-NHR中的N原子键合的H原子进一步被烷基、环烷基、烯基、炔基、芳基、杂芳基或芳烷基取代的化合物。
羰基氨基(-NH-C=O-R)的实例包括烷基羰基氨基、环烷基羰基氨基、烯基羰基氨基、炔基羰基氨基、芳基羰基氨基、杂芳基羰基氨基和芳烷基羰基氨基。其他实例包括其中与-NH-C=O-R中的N原子键合的H原子进一步被烷基、环烷基、烯基、炔基、芳基、杂芳基或芳烷基取代的化合物。
氧羰基氨基(-NH-C=O-OR)的实例包括烷氧羰基氨基、环烷氧羰基氨基、烯氧羰基氨基、炔氧羰基氨基、芳氧羰基氨基、杂芳氧羰基氨基和芳烷氧羰基氨基。其他实例包括其中与-NH-C=O-OR中的N原子键合的H原子进一步被烷基、环烷基、烯基、炔基、芳基、杂芳基或芳烷基取代的化合物。
磺酰氨基(-NH-SO2-R)的实例包括烷基磺酰氨基、环烷基磺酰氨基、烯基磺酰氨基、炔基磺酰氨基、芳基磺酰氨基、杂芳基磺酰氨基和芳烷基磺酰氨基。其他实例包括其中与-NH-SO2-R中的N原子连接的H原子进一步被烷基、环烷基、烯基、炔基、芳基、杂芳基或芳烷基取代的化合物。
氨基磺酰基(-SO2-NHR)的实例包括烷基氨基磺酰基、环烷基氨基磺酰基、烯基氨基磺酰基、炔基氨基磺酰基、芳基氨基磺酰基、杂芳基氨基磺酰基和芳烷基氨基磺酰基。其他实例包括其中与-SO2-NHR中的N原子连接的H原子进一步被烷基、环烷基、烯基、炔基、芳基、杂芳基或芳烷基取代的化合物。
氨磺酰氨基(-NH-SO2-NHR)的实例包括烷基氨磺酰氨基、环烷基氨磺酰氨基、烯基氨磺酰氨基、炔基氨磺酰氨基、芳基氨磺酰氨基、杂芳基氨磺酰氨基和芳烷基氨磺酰氨基。与-NH-SO2-NHR中N原子键合的两个H原子可以进一步被取代基取代,所述取代基独立地选自由烷基、环烷基、烯基、炔基、芳基、杂芳基和芳烷基组成的组,并且这两个取代基可以形成环。
衍生自S原子的取代基包括硫醇(-SH)、硫代(-S-R)、亚磺酰基(-S=O-R)、磺酰基(-S(O)2-R)、磺基(-SO3H)和五氟磺酰基(-SF5)。
硫代(-S-R)的实例选自烷硫基、环烷硫基、烯硫基、炔硫基、芳硫基、杂芳硫基、芳烷硫基等。
亚磺酰基(-S=O-R)的实例包括烷基亚磺酰基、环烷基亚磺酰基、烯基亚磺酰基、炔基亚磺酰基、芳基亚磺酰基、杂芳基亚磺酰基和芳烷基亚磺酰基。
磺酰基(-S(O)2-R)的实例包括烷基磺酰基、环烷基磺酰基、烯基磺酰基、炔基磺酰基、芳基磺酰基、杂芳基磺酰基和芳烷基磺酰基。
源自N原子的取代基包括叠氮基(-N3,也称为“叠氮基团”)、氰基(-CN)、伯氨基(-NH2)、仲氨基(-NH-R)、叔氨基(-NR(R′))、脒基(-C(=NH)-NH2)、取代的脒基(-C(=NR)-NR′R″),胍基(-NH-C(=NH)-NH2)、取代的胍基(-NR)-C(=NR″′)-NR′R″)和氨基羰基氨基(-NR-CO-NR′R″)。
仲氨基(-NH-R)的实例包括烷基氨基、环烷基氨基、烯基氨基、炔基氨基、芳基氨基、杂芳基氨基和芳烷基氨基。
叔氨基(-NR(R′))的实例包括具有任意两个取代基的氨基基团,每个取代基各自独立地选自烷基、环烷基、烯基、炔基、芳基、杂芳基、芳烷基等,例如烷基(芳烷基)氨基,其中任意两个此类取代基可形成环。
取代脒基(-C(=NR)-NR′R″)的实例包括其中N原子上的三个取代基R、R′和R″各自独立地选自烷基、环烷基、烯基、炔基、芳基、杂芳基和芳烷基的基团,例如烷基(芳烷基)(芳基)脒基。
取代的胍基(-NR-C(=NR″′)-NR′R″)的实例包括其中R、R′、R″和R″′各自独立地选自烷基、环烷基、烯基、炔基、芳基、杂芳基和芳烷基的基团,或这些取代基形成环的基团。
氨基羰基氨基(-NR-CO-NR′R″)的实例包括其中R、R′和R″各自独立地选自氢原子、烷基、环烷基、烯基、炔基、芳基、杂芳基和芳烷基的基团,或这些取代基形成环的基团。
B原子衍生的取代基的实例包括硼基(-BR(R′))和二氧硼基(-B(OR)(OR′))。这两个取代基R和R′各自独立地选自烷基、环烷基、烯基、炔基、芳基、杂芳基和芳烷基;或者它们可以形成环。具体实例包括环状硼基基团,更具体的实例包括频哪醇硼基基团、新戊二醇硼基基团和儿茶酚硼基基团。
本文中N-取代氨基酸的氮原子上的取代基的具体实例包括烷基、C1-C6烷基、C1-C4烷基和甲基。
在本文中,“芳香族氨基酸衍生物”的实例包括,在上述氨基酸衍生物中,在氨基酸侧链中含有芳香族取代基的那些。芳香族取代基的具体实例包括任选取代的芳基和任选取代的杂芳基。
氨基酸的主链氨基基团可以是未取代的(-NH2)或取代的(即-NHR:其中R表示任选取代的烷基、烯基、炔基、芳基、杂芳基、芳烷基或环烷基,与N原子键合的碳链和α位的碳原子可形成环,如脯氨酸)。主链氨基被取代的这种氨基酸在本文中可以称为“N-取代的氨基酸”。在本文中“N-取代的氨基酸”的优选实例包括但不限于N-烷基氨基酸、N-C1-C6烷基氨基酸、N-C1-C4烷基氨基酸和N-甲基氨基酸。
如本文所用,“氨基酸”包括相应的所有同位素。在“氨基酸”的同位素中,至少一个原子被具有相同原子序数(质子数)和不同质量数(质子和中子总数)的原子取代。本文“氨基酸”中所含同位素的实例包括氢原子、碳原子、氮原子、氧原子、磷原子、硫原子、氟原子和氯原子,分别包括2H、3H、13C、14C、15N、17O、18O、32P、35S、18F和36Cl。
(式I表示的化合物的制备方法)
在实施方案中,本发明涉及由式I表示的化合物、所述化合物的盐、或所述化合物或盐的溶剂化物的制备方法:
式I:
其中
R1为氢或氨基的保护基团;
R2为氢或C1-C6烷基,R3为氢或羧基的保护基团,或R2和R3一起形成二价保护基团;
R6为任选取代的C6-C10芳基或任选取代的杂芳基;
R7为氢或C1-C4烷基;和
n是1或2,
所述方法包括将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物与还原剂、添加剂和R6-X(其中R6与式I表示的化合物的R6相同,且X为卤素、OTf或OMs)在溶剂和催化剂存在下混合的步骤,以得到式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物:
式II:
其中
R1、R2、R3、R7和n分别与式I表示的化合物的R1、R2、R3、R7和n相同;
R5选自由以下组成的组:
Rt、Ru、Rv和Rw独立地为氢、卤素或硝基;
Rx和Ry独立地为氢、C1-C4烷基或任选取代的苯基;
Rz为氢、C1-C4烷基或卤素;
Y为CH或N;和
*表示结合点。
在式I中,R1为氢或氨基的保护基团。当R1是氨基的保护基团时,保护基团的具体实例包括Fmoc、Boc、Alloc、Cbz、Teoc、三氟乙酰基、苯磺酰基基团、甲苯磺酰基基团、nosyl基团、dinitronosyl基团、叔丁基基团、三苯甲基基团、枯基基团、苯亚甲基基团、4-甲氧基苯亚甲基基团和二苯基亚甲基基团,其中优选Fmoc、Boc、Alloc、Cbz、Teoc或三氟乙酰基。
在式I中,R2为氢或C1-C6烷基,R3为氢或羧基的保护基团,或R2和R3一起形成二价保护基团。
当式I中的R2为C1-C6烷基时,C1-C6烷基优选为甲基、乙基、丙基、丁基等时,特别优选甲基或乙基。
当式I中的R3为羧基的保护基团时,保护基团的具体实例包括甲基、乙基、叔丁基、苄基、三苯甲基、枯基、甲氧基三苯甲基、2-(三甲基甲硅烷基)乙基、2,2,2-三氯乙基和烯丙基,其中优选甲基、乙基、叔丁基、苄基、三苯甲基、枯基、甲氧基三苯甲基或2-(三甲基甲硅烷基)乙基。
当R2和R3一起形成二价保护基团时,二价保护基团可以是任选被一个或两个取代基取代的亚甲基,优选为-(CR8R9)-。当R2和R3一起形成-(CR8R9)-时,式I可以用式IA表示:
在一个实施方案中,R8和R9可以独立地为氢、C1-C4烷基或C6-C10芳基。更具体地说,R8和R9都可以是氢、C1-C4烷基或C6-C10芳基;一个可以是氢,另一个可以是C1-C4烷基或C6-C10芳基;或者一个可以是C1-C4烷基,另一个可以是C6-C10芳基。当R8和R9之一或两者为C1-C4烷基时,C1-C4烷基优选为甲基。当R8和R9之一或两者为C6-C10芳基时,C6-C10芳基优选为苯基。当R8和R9之一或两者为C1-C4烷基或C6-C10芳基时,C1-C4烷基或C6-C10芳基可具有取代基,优选C1-C4烷基为甲基,C6-C10芳基是苯基。在另一个实施方案中,R8和R9一起形成氧代(=O)。
由式IA表示的化合物的具体实例包括具有以下结构的那些:
其中式中的R1、R6和n如本文所定义。
在式I中,R6是任选取代的C6-C10芳基或任选取代的杂芳基。当R6为任选取代的C6-C10芳基时,C6-C10芳基优选为苯基。此外,当R6是任选取代的杂芳基时,杂芳基优选是吡啶基。任选取代的C6-C10芳基的取代基或任选取代的杂芳基的取代基的实例包括C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C6烯氧基、卤素、C3-C8环烷基、-NRpRq(其中Rp和Rq独立地是氢或C1-C4烷基)、-CONRrRs(其中Rr和Rs独立地选自由氢、羟基、受保护的羟基、C1-C4烷基和C1-C4烷基磺酰基组成的组)和环状硼基。这些取代基的更具体实例包括甲基、甲氧基、氯、氟、异丙基、环丙基、三氟甲基、甲基氨基羰基、甲基磺酰氨基、羟基氨基甲酰基(包括其中羟基被保护基团保护的那些,例如(四氢-2H-吡喃-2-基)氧基氨基甲酰基和甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)、频哪醇硼基、新戊二醇硼基、儿茶酚硼基和烯丙氧基。任选取代的C6-C10芳基或任选取代的杂芳基的取代基数没有特别限制,例如优选具有0至3个取代基。当取代基的数目为两个或更多时,优选的取代基组合的实例包括一个C1-C4卤代烷基和一个或两个卤素;两个C1-C4烷氧基基团,一个C1-C4烷氧基和一个或两个卤素;和一个-CONRrRs和一个C1-C4烷氧基。这些取代基组合的更具体的实例包括组合例如三氟甲基和一个或两个氟;三氟甲基和一个或两个氯;一个三氟甲基和一个氟和一个氯;两个甲氧基;甲氧基和一个或两个氟;一个甲氨基羰基和一个甲氧基;和一个甲磺酰氨基和一个甲氧基。
R6的具体实例包括以下基团。这里,式中的“*”表示结合点。
在式I中,R7为氢或C1-C4烷基,优选为氢或甲基。
式I中的n为1或2。
式II中的R1、R2、R3、R7和n分别与式I中的R1、R2、R3、R7和n相同。
式II中的R5可以是:
其中“*”表示结合点,并且Rt、Ru、Rv和Rw独立地为氢、卤素或硝基。在这种情况下,R5的具体实例包括具有以下结构的基团:
式II中的R5可以是:
其中“*”表示结合点,且Rx和Ry独立地为氢、C1-C4烷基或任选取代的苯基。在这种情况下,R5的具体实例包括具有以下结构的基团:
式II中的R5可以是:
其中“*”表示结合点,Rz是氢、C1-C4烷基或卤素。在这种情况下,R5的具体实例包括具有以下结构的基团:
式II中的R5可以是:
其中“*”表示结合点,Y是CH或N。在这种情况下,R5的具体实例包括具有以下结构的基团:
对于本步骤中使用的“R6-X”,R6为任选取代的C6-C10芳基或任选取代的杂芳基,X为卤素、OTf或OMs。至于R6,可以使用与式I中的R6相同的基团R6。X优选为碘、溴或OTf。
R6-X的更具体实例包括溴苯、1-溴-2-甲基苯、1-溴-3-甲基苯、1-溴-4-甲基苯、1-溴-4-乙基苯、1-溴-2-氯苯、1-溴-3-氯苯、1-溴-4-氯苯、1-溴-2-氟苯、1-溴-3-氟苯、1-溴-4-氟苯、1-溴-2-环丙苯、1-溴-3-环丙苯、1-溴-4-环丙苯、1-溴-2-(三氟甲基)苯、1-溴-3-(三氟甲基)苯、1-溴-4-(三氟甲基)苯、1-溴-2-异丙苯、1-溴-3-异丙苯、1-溴-4-异丙苯、1-溴-2-甲氧基苯、1-溴-3-甲氧基苯、1-溴-4-甲氧基苯、1-(烯丙氧基)-2-溴苯、1-(烯丙氧基)-3-溴苯、1-(烯丙氧基)-4-溴苯、1-溴-4-异丙氧基苯、4-溴-2-氯-1-(三氟甲基)苯、4-溴-2-氟-1-(三氟甲基)苯、1-溴-2-氟-4-(三氟甲基)苯、4-溴-1,2-二甲氧基苯、1-溴-2-氟-4-甲氧基苯、4-溴-2-氟-1-甲氧基苯、5-溴-1,3-二氟-2-甲氧基苯、5-溴-1,3-二氟-2-(三氟甲基)苯、4-溴-2-甲氧基-N-甲基苯甲酰胺、5-溴-2-甲氧基-N-甲基苯甲酰胺、5-溴-1,3-二氯-2-(三氟甲基)苯、5-溴-1-氯-3-氟-2-(三氟甲基)苯、4-溴-2-甲氧基-N-(甲基磺酰基)苯甲酰胺,4-溴-N-甲基-N-((四氢-2H-吡喃-2-基)氧基)苯甲酰胺、4-溴-2-甲氧基-N-((四氢-2H-吡喃-2-基)氧基)苯甲酰胺、2-溴吡啶、3-溴吡啶、4-溴吡啶、5-溴-2-甲基吡啶、3-溴-5-甲基吡啶、3-溴-4-甲基吡啶、5-溴-2-甲氧基吡啶、3-溴-5-甲氧基吡啶、3-溴-5-氟吡啶、3-溴-5-氯吡啶、3,5-二溴吡啶、4-溴-N-甲基吡啶-2-胺、4-溴-N,N-二甲基吡啶-2-胺、5-溴嘧啶、碘苯、1-碘-2-甲基苯、1-碘-3-甲基苯、1-碘-4-甲基苯、1-乙基-4-碘苯、1-氯-2-碘苯、1-氯-3-碘苯、1-氯-4-碘苯、1-氟-2-碘苯、1-氟-3-碘苯、1-氟-4-碘苯、1-环丙基-2-碘苯、1-环丙基-3-碘苯、1-环丙基-4-碘苯、1-碘-2-(三氟甲基)苯、1-碘-3-(三氟甲基)苯、1-碘-4-(三氟甲基)苯、1-碘-2-异丙苯、1-碘-3-异丙苯、1-碘-4-异丙苯、1-碘-2-甲氧基苯、1-碘-3-甲氧基苯、1-碘-4-甲氧基苯、1-(烯丙氧基)-2-碘-苯、1-(烯丙氧基)-3-碘-苯、1-(烯丙氧基)-4-碘-苯、1-碘-4-异丙氧基苯、2-氯-4-碘-1-(三氟甲基)苯、2-氟-4-碘-1-(三氟甲基)苯、2-氟-1-碘-4-(三氟甲基)苯,4-碘-1,2-二甲氧基苯、2-氟-1-碘-4-甲氧基苯、2-氟-4-碘-1-甲氧基苯、1,3-二氟-5-碘-2-甲氧基苯、1,3-二氟-5-碘-2-(三氟甲基)苯、4-碘-2-甲氧基-N-甲基苯甲酰胺、5-碘-2-甲氧基-N-甲基苯甲酰胺、1,3-二氯-5-碘-2-(三氟甲基)苯、1-氯-3-氟-5-碘-2-(三氟甲基)苯、4-碘-2-甲氧基-N-(甲基磺酰基)苯甲酰胺、4-碘-N-甲基-N-((四氢-2H-吡喃-2-基)氧基)苯甲酰胺、4-碘-2-甲氧基-N-((四氢-2H-吡喃-2-基)氧基)苯甲酰胺、2-碘吡啶、3-碘吡啶、4-碘吡啶、5-碘-2-甲基吡啶、3-碘-5-甲基吡啶、3-碘-4-甲基吡啶、5-碘-2-甲氧基吡啶、3-碘-5-甲氧基吡啶、3-氟-5-碘吡啶、3-氯-5-碘吡啶、3-溴-5-碘吡啶、3,5-二碘吡啶、4-碘-N-甲基吡啶-2-胺,4-碘-N,N-二甲基吡啶-2-胺,5-碘嘧啶、苯基三氟甲磺酸酯,邻甲苯基三氟甲磺酸酯,间甲苯基三氟甲磺酸酯,对甲苯基三氟甲磺酸酯,4-乙基苯基三氟甲磺酸酯、2-氯苯基三氟甲磺酸酯、3-氯苯基三氟甲磺酸酯、4-氯苯基三氟甲磺酸酯、2-氟苯基三氟甲磺酸酯、3-氟苯基三氟甲磺酸酯、4-氟苯基三氟甲磺酸酯、2-环丙基苯基三氟甲磺酸酯、3-环丙基苯基三氟甲磺酸酯、4-环丙基苯基三氟甲磺酸酯、2-(三氟甲基)苯基三氟甲磺酸甲酯、3-(三氟甲基)苯基三氟甲磺酸甲酯、4-(三氟甲基)苯基三氟甲磺酸甲酯、2-异丙基苯基三氟甲磺酸盐、3-异丙基苯基三氟甲磺酸酯、4-异丙基苯基三氟甲磺酸酯、2-甲氧基苯基三氟甲磺酸酯、3-甲氧基苯基三氟甲磺酸酯、4-甲氧基苯基三氟甲磺酸酯、2-(烯丙氧基)苯基三氟甲磺酸酯、3-(烯丙氧基)苯基三氟甲磺酸酯、4-(烯丙氧基)苯基三氟甲磺酸酯、4-异丙氧基苯基三氟甲磺酸酯、3-氯-4-(三氟甲基)苯基三氟甲磺酸酯,3-氟-4-(三氟甲基)苯基三氟甲磺酸酯、2-氟-4-(三氟甲基)苯基三氟甲磺酸酯、3,4-二甲氧基苯基三氟甲磺酸酯、2-氟-4-甲氧基苯基三氟甲磺酸酯、3-氟-4-甲氧基苯基三氟甲磺酸酯、3,5-二氟-4-甲氧基苯基三氟甲磺酸酯、3,5-二氟-4-(三氟甲基)苯基三氟甲磺酸酯、3-甲氧基-4-(甲基氨基甲酰基)苯基三氟甲磺酸酯、4-甲氧基-3-(甲基氨基甲酰基)苯基三氟甲磺酸酯、3,5-二氯-4-(三氟甲基)苯基三氟甲磺酸酯、3-氯-5-氟-4-(三氟甲基))苯基三氟甲磺酸酯、3-甲氧基-4-((甲磺酰基)氨基甲酰基)苯基三氟甲磺酸酯、4-(甲基(((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基三氟甲磺酸酯、3-甲氧基-4-(((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基三氟甲磺酸酯、吡啶-2-基三氟甲磺酸酯、吡啶-3-基三氟甲磺酸酯、吡啶-4-基三氟甲磺酸酯、6-甲基吡啶-3-基三氟甲磺酸酯、5-甲基吡啶-3-基三氟甲磺酸酯、4-甲基吡啶-3-基三氟甲磺酸酯、6-甲氧基吡啶-3-基三氟甲磺酸酯、5-甲氧基吡啶-3-基三氟甲磺酸酯、5-氟吡啶基-3-基三氟甲磺酸酯、5-氯吡啶-3-基三氟甲磺酸酯、5-溴吡啶-3-基三氟甲磺酸酯、2-(甲氨基)吡啶-4-基三氟甲磺酸酯、2-(二甲氨基)吡啶-4-基三氟甲磺酸酯和嘧啶-5-基三氟甲磺酸酯。
本步骤中,R6-X可以相对于式II表示的化合物等量或过量使用。具体地,例如,相对于由式II表示的化合物,可以使用1当量至10当量并且优选地1当量至5当量的R6-X。
本步骤所用催化剂为:
(a)金属;
(b)通过混合金属及其可能的配体化合物形成;
(c)金属及其配体的络合物;或者
(d)通过进一步混合金属及其配体的络合物、金属的可能的配体化合物而形成。
在上述(a)至(d)的每一种情况下,所使用的金属包括镍、铬、铁、铜、钯或这些金属的盐,或者是镍、铬、铁、铜、钯或这些金属的盐的溶剂化物。这种金属的具体实例包括镍、双(1,5-环辛二烯)镍(0)、NiBr2、NiI2、NiCl2、NiF2、Ni(OAc)2、Ni(acac)2、Ni(OTf)2、NiCO2、Ni(NO3)2、NiSO4、(NH4)2Ni(SO4)2、烯丙基(环戊二烯基)镍(II)、双(环戊二烯基)镍、双(环辛二烯基)镍,或与水、甲氧基乙醚、二甘醇二甲醚,或乙二醇二甲醚形成的溶剂化物。
当催化剂通过混合金属和可能的配体化合物形成时,可能的配体化合物例如由下式B至G表示。
式B:
式C:
式D:
式E:
式F:
式G:
在式B中:
RBX和RBY独立地选自氢、C1-C4烷基、C1-C4烷氧基、杂环基和C6-C10芳基。由式B表示的化合物的具体实例包括2,2′-联吡啶、6-甲基-2,2′-联吡啶、4,4′-二甲基-2,2′-联吡啶、5,5′-二甲基-2,2′-联吡啶、4,4′-二叔丁基-2,2′-联吡啶、4,4′-二甲氧基-2,2′-联吡啶、4,4′-二苯基-2,2′-联吡啶,6,6′-双(4,5-二氢噁唑-2-基)-2,2′-联吡啶,6,6′-双(4-苯基-4,5-二氢噁唑-2-基)-2,2′-联吡啶、6,6′-双(4-异丙基-4,5-二氢噁唑-2-基)-2,2′-联吡啶和6,6′-双(4-(叔丁基))-4,5-二氢噁唑-2-基)-2,2′-联吡啶。
在式C中:
RCX和RCY独立地选自氢、C1-C4烷基、C6-C10芳基和杂芳基。由式C表示的化合物的具体实例包括1,10-邻二氮杂菲、5-甲基-1,10-邻二氮杂菲、2,9-二甲基-1,10-邻二氮杂菲、5,6-二甲基-1,10-邻二氮杂菲和4,7-二甲氧基-1,10-邻二氮杂菲。
在式D中:
RDX和RDY独立地选自氢、C1-C4烷基、C1-C4卤代烷基和C6-C10芳基。由式D表示的化合物的具体实例包括2-(吡啶-2-基)-4,5-二氢噁唑、4-异丙基-2-(吡啶-2-基)-4,5-二氢噁唑、4-(叔丁基)-2-(吡啶-2-基)-4,5-二氢噁唑、4-异丙基-2-(6-甲基吡啶-2-基)-4,5-二氢噁唑、4-(叔丁基)-2-(6-甲基吡啶-2-基)-4,5-二氢噁唑、4-(叔丁基)-2-(5-(三氟甲基)吡啶-2-基)-4,5-二氢噁唑、4-(叔丁基)-2-(5-(三氟甲基)吡啶-2-基)-4,5-二氢噁唑和4-苯基-2-(吡啶-2-基)-4,5-二氢噁唑。
在式E中:
REX和RFY独立地选自氢、C1-C4烷基、C6-C10芳基C1-C6烷基和C6-C10芳基。由式E表示的化合物的具体实例包括4,4′,5,5′-四氢-2,2′-二噁唑、4,4′-二甲基-4,4′,5,5′-四氢-2,2′-二噁唑、4,4′-二异丙基-4,4′,5,5′-四氢-2,2′-二噁唑、4,4′-二叔丁基-4,4′,5,5′-四氢-2,2′-二噁唑、4,4′-二苯基-4,4′,5,5′-四氢-2,2′-二噁唑和4,4′-二苯基-4,4′,5,5′-四氢-2,2′-二噁唑。
在式F中:
RFX和RFY独立地选自氢、C1-C4烷基和C6-C10芳基。由式F表示的化合物的具体实例包括2,6-双(4,5-二氢噁唑-2-基)吡啶、2,6-双(4-异丙基-4,5-二氢噁唑-2-基)吡啶、2,6-双(4-(叔丁基)-4,5-二氢噁唑-2-基)吡啶和2,6-双(4-苯基-2-噁唑啉-2-基)吡啶。
在式G中:
RGX和RGY独立地选自氢、C1-C4烷基、C6-C10芳基C1-C6烷基和C6-C10芳基。由式G表示的化合物的具体实例包括2,2′-(丙-2,2-二基)双(4,5-二氢噁唑)、2,2′-(丙-2,2-二基)双(4-异丙基-4,5-二氢噁唑)、2,2′-(丙-2,2-二基)双(4-(叔丁基)-4,5-二氢噁唑)、2,2′-(丙-2,2-二基)双(4-苄基-4,5-二氢噁唑)和2,2′-(丙-2,2-二基)双(4-苯基-4,5-二氢噁唑)。
当催化剂为金属及其配体的络合物时,金属及其配体的络合物的具体实例包括四(三苯基膦)镍(0)、双(三苯基膦)二氯化镍(II)、双(三环己基膦)二氯化镍(II)、二溴双(三苯基膦)镍(II),双[(2-二甲氨基)苯基]氨基镍(II)氯化物,顺-[2,2′-双(二苯基膦)-1,1′-联萘](2-甲基苯基)氯化镍(II)和[1,2-双(二苯基膦基)乙烷]二氯化镍(II)。
当通过进一步混合金属及其配体的络合物、金属的可能的配体化合物而形成催化剂时,金属及其配体的络合物的具体实例包括四(三苯基膦)镍(0)、双(三苯基膦)二氯化镍(II)、顺式-[2,2′-双(二苯基膦基)-1,1′-联萘基](2-甲基苯基)氯化镍(II)和[1,2-双(二苯基膦基))乙烷]二氯化镍(II)。可能的配体化合物的具体实例包括2,2′-联吡啶、6-甲基-2,2′-联吡啶、4,4′-二甲基-2,2′-联吡啶、5,5′-二甲基-2,2′-联吡啶、4,4′-二叔丁基-2,2′-联吡啶、4,4′-二甲氧基-2,2′-联吡啶、4,4′-二苯基-2,2′-联吡啶、6,6′-双(4,5-二氢噁唑-2-基)-2,2′-联吡啶、6,6′-双(4-苯基-4,5-二氢噁唑-2-基)-2,2′-联吡啶、6,6′-双(4-异丙基-4,5-二氢噁唑-2-基)-2,2′-联吡啶和6,6′-双(4-(叔丁基)-4,5-二氢噁唑-2-基)-2,2′-联吡啶。
该步骤中使用的还原剂可以是用于减少该步骤中使用的催化剂的正电荷的材料。这种还原剂的实例包括具有比催化剂中包含的金属更大的电离倾向的金属。这些金属的具体实例包括锌、锰、铁和镁,其中优选锌和锰,特别优选锌。
在实施方案中,当使用含镍催化剂时,比镍具有更大电离倾向的金属,例如锌、铁和镁,可以用作还原剂。
相对于由式II表示的化合物,还原剂的用量可以为1摩尔至10摩尔当量,优选1摩尔至5摩尔当量,更优选1摩尔至3摩尔当量。
本步骤中使用的添加剂可以是能够高效地将作为本步骤起始材料的式II表示的化合物转化为作为目标材料的式I表示的化合物的材料,例如与不使用添加剂的情况相比,能够缩短起始材料转化为目标材料所需的时间。这种添加剂的具体实例包括甲硅烷基化合物和1,2-二溴乙烷。甲硅烷基化合物的具体实例包括由式A表示的化合物:
式中的RAX和RAY独立地选自C1-C4烷基、C1-C4烷氧基和苯基。RAX和RAY的更具体实例包括甲基、乙基、异丙基、叔丁基、甲氧基、乙氧基、异丙氧基和苯基。
L选自由-Cl、-Br、-I和-OTf组成的组。
由式A表示的化合物的更具体实例包括TMSCl、TMSBr、TMSI、TMSOTf、TBDMSCl、TESCl、TIPSCl、TBDPSCl和氯三乙氧基硅烷,其中优选TMSCl、TMSBr、TESCl和TIPSCl。
相对于由式II表示的化合物,添加剂的用量可以为1mol%至500mol%,优选10mol%至500mol%,更优选25mol%至500mol%。
通过在本步骤中加入添加剂,与不使用添加剂的情况相比,可以大大提高式II表示的化合物向式I表示的化合物的转化率。例如,与使用搅拌方式例如搅拌叶片的搅拌或使用搅拌棒的搅拌无关,可以使反应以高转化率高效地进行。
该步骤中使用的溶剂可以是例如非质子溶剂如酰胺溶剂或脲溶剂。这种溶剂的具体实例包括DMF、DMA、NMP、DMI和DMPU。
该步骤的反应可以在-20℃至约溶剂沸点的温度下进行。反应可以在优选-10℃~110℃、-10℃~90℃、更优选-10℃~70℃的反应温度下进行。
该步骤的反应可以进行10分钟至1周的反应时间。反应可以进行优选10分钟至6小时,更优选0.5小时至4小时的反应时间。
本步骤中,式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、还原剂、添加剂和R6-X的混合顺序没有特别限制;然而,混合例如通过以下方式进行:(a)在溶剂和催化剂的存在下将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、还原剂和R6-X混合,然后添加剂与之混合;(b)在溶剂和催化剂存在下将还原剂和添加剂混合,然后将式II表示的化合物、化合物的盐、或化合物或盐的溶剂合物和R6-X与之混合;或(c)将还原剂与溶剂和催化剂混合,然后将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、R6-X和添加剂与之混合。
上述(a)的更具体的实施方案包括,例如,将通过将催化剂溶解在溶剂中获得的溶液滴加到通过将由式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、还原剂和R6-X溶解在溶剂中获得的溶液中,然后向其中加入添加剂;或将通过将催化剂溶解在溶剂中而获得的溶液滴加到通过将式II表示的化合物、化合物的盐、或化合物或盐的溶剂合物和R6-X溶解在溶剂中而获得的溶液中,然后加入还原剂后,再加入添加剂。
上述(b)的更具体的实施方案包括,例如,将还原剂和添加剂加入通过将催化剂溶解在溶剂中而获得的溶液中,然后向其中加入通过将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物和R6-X溶解在溶剂中获得的溶液中。
上述(c)的更具体的实施方案包括,例如,将还原剂加入通过将催化剂溶解在溶剂中而获得的溶液中,然后向其中加入通过将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、R6-X和添加剂溶解在溶剂中获得的溶液中。
当在该步骤中使用式II表示的光学活性化合物时,保持其空间构型,可以获得式I表示的光学活性化合物。
(式II表示的化合物的制备方法)
作为上述步骤的起始材料的式II表示的化合物可以使用本领域已知的各种方法合成。
在实施方案中,当R2为氢时,本发明的式II表示的化合物可以例如根据以下方案合成。该方案中,R1、R3、R5、R7和n分别与式II的R1、R3、R5、R7和n相同。
该步骤可以按照Albert等人的方法(Synthesis,1987,7,635-637)等通过将醇(R5-OH)和羧酸与脱水缩合剂例如碳二亚胺化合物混合以缩合醇和羧酸来进行。
在另一实施方案中,当R2为氢时,本发明的式II表示的化合物可以例如根据以下方案合成。该方案中,R1、R3、R5、R7和n分别与式II的R1、R3、R5、R7和n相同,R10和R11独立地为氢、C1-C4烷基或C6-C10芳基,或R10和R11一起形成氧代(=O)。
连接/脱开保护基团的步骤可以按照Greene′s,″Protective Groups in OrganicSynthesis″(第5版,John Wiley&Sons 2014)中描述的方法进行。
在另一个实施方案中,本发明的式II表示的其中R2为C1-C6烷基的化合物可以例如根据以下方案合成。该方案中,R1、R3、R5、R7和n分别与式II的R1、R3、R5、R7和n相同,R4为羧基的保护基团,“Alk”为C1-C6烷基。
其中,连接/脱开保护基团的步骤可以按照“Greene′s,″Protective Groups inOrganic Synthesis″(第5版,John Wiley&Sons 2014)”中描述的方法进行。对于N-烷基化步骤,可以通过使烷基化剂在碱性条件下反应来制备在氮原子上引入烷基基团的化合物。引入R5的步骤可以按照Albert等人的方法(Synthesis,1987,7,635-637)等通过将醇(R5-OH)和羧酸与脱水缩合剂例如碳二亚胺化合物混合以缩合醇和羧酸来进行。
在另一个实施方案中,本发明的式II表示的其中R2为C1-C6烷基的化合物可以例如根据以下方案合成。该方案中,R1、R3、R5、R7和n分别与上述式II的R1、R3、R5、R7和n相同,R4为羧基的保护基团,“Alk”为C1-C6烷基,R12为氢或C1-C5烷基。
在这些步骤中,连接/脱开保护基团的步骤可以按照“Greene′s,“ProtectiveGroups in Organic Synthesis”(第5版,John Wiley&Sons 2014)中描述的方法进行。涉及脱保护的N-烷基化步骤也可以按照Freidinger等人的方法(J.Org.Chem.,1983,48,77-81)或Buba等人的方法(Eur.J.Org.Chem.,2013,4509-4513)进行。引入R5的步骤可以按照Albert等人的方法(Synthesis,1987,7,635-637)等通过将醇(R5-OH)和羧酸与脱水缩合剂例如碳二亚胺化合物混合以缩合醇和羧酸来进行。
在另一实施方案中,当R2和R3一起形成-(CR8R9)-时,本发明的式IIA表示的化合物可以根据以下方案合成。该方案中,R1、R5、R7、R8、R9和n分别与上述式IIA的R1、R5、R7、R8、R9和n相同,R4为羧基的保护基团。
在这些反应中,引入保护基团的步骤可以按照Freidinger等人的方法(J.Org.Chem.,1983,48,77-81)等,或“Greene′s,″Protective Groups inOrganicSynthesis″(第5版,John Wiley&Sons 2014)”中描述的方法,在酸催化剂的存在下,通过醛化合物脱水缩合的方法进行。脱保护步骤可以按照“Greene′s,”Protective Groups inOrganic Synthesis″(第5版,John Wiley&Sons 2014)”中描述的方法进行。引入侧链的步骤可以按照Long等人的方法等(J.Med.Chem.,2008,51,6371-6380)进行。引入R5的步骤可以按照Albert等人的方法(Synthesis,1987,7,635-637)等通过将醇(R5-OH)和羧酸与脱水缩合剂例如碳二亚胺化合物混合以缩合醇和羧酸来进行。
在另一实施方案中,当R2和R3一起形成-(CR8R9)-时,本发明的式IIA表示的化合物可以根据以下方案合成。在以下方案中,R1、R5、R7、R8、R9和n分别与上述式IIA的R1、R5、R7、R8、R9和n相同,R4为羧基的保护基团。
在这些反应中,引入保护基团的步骤可以按照Freidinger等人的方法(J.Org.Chem.,1983,48,77-81)等,或“Greene′s,″Protective Groups in OrganicSynthesis″(第5版,John Wiley&Sons2014)”中描述的方法,在酸催化剂的存在下,通过醛化合物脱水缩合的方法进行。脱保护步骤可以按照“Greene′s,″Protective Groups inOrganic Synthesis″(第5版,John Wiley&Sons2014)”中描述的以下方法进行。引入R5的步骤可以按照Albert等人的方法(Synthesis,1987,7,635-637)等通过缩合醇和羧酸来进行。
(式I表示的化合物的修饰)
从根据上述方法制备的式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物开始,本发明能够制备进一步的各种氨基酸类似物、类似物的盐、或类似物或盐的溶剂化物。
在实施方案中,当式I表示的化合物的R3是羧基的保护基团时,式III表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物可以通过使用式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物为起始材料,除去保护基团而制备。
脱保护步骤可以按照“Greene′s,″Protective Groups in Organic Synthesis″(第5版,John Wiley&Sons2014)”中描述的以下方法进行。
在实施方案中,当式I表示的化合物、化合物的盐、或化合物或盐的溶剂合物的R1为氨基的保护基团,R3为羧基的保护基团时,式V表示的化合物可以通过同时除去这些保护基团来制备式IV表示的化合物,并进一步在氨基基团上引入保护基团R1′来制备,如以下方案所示。
连接/脱开这些保护基团的步骤可以按照“Greene′s,″Protective Groups inOrganic Synthesis″(第5版,John Wiley&Sons 2014)”中描述的方法进行。
在实施方案中,当式I表示的化合物的R2和R3一起形成-(CR8R9)-并且因此式I表示的化合物由式IA表示时,式VI表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物可以通过以式IA表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物为起始材料,通过脱保护反应打开噁唑烷酮环来制备。
上述脱保护步骤可以按照“Greene′s,″Protective Groups in OrganicSynthesis″(第5版,John Wiley&Sons 2014)”中描述的以下方法进行。
在实施方案中,本发明能够使用式IA表示的化合物作为起始材料制备N-烷基氨基酸,如以下方案所示。
其中,连接/脱开保护基团的步骤可以按照“Greene′s,“Protective Groups inOrganic Synthesis”(第5版,John Wiley&Sons 2014)中描述的方法进行。按照Seebach等人的方法(Helv.Chim.Acta,1987,70,237-261)等,通过使烷基化剂在碱性条件下作用,可以制备在氮原子上引入烷基基团的化合物。
本发明还涉及式I表示的氨基酸衍生物,以及通过修饰氨基酸衍生物获得的上述各个式的氨基酸衍生物。
在实施方案中,此类氨基酸衍生物优选包括在式(I)化合物中具有以下基团组合的那些:
(a)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为氢或甲基,R3为氢、甲基、叔丁基或苄基,R6为3-氯-4-(三氟甲基)苯基,R7为氢,n为1或2;
(b)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为乙基,R3为氢、甲基、叔丁基或苄基,R6为4-甲基苯基,R7为氢,n为1;
(c)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为氢或甲基,R3为氢、甲基或叔丁基,R6为3,5-二氟-4-(三氟甲基)苯基,R7为氢,n为1或2;
(d)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为氢或甲基,R3为氢、甲基或叔丁基,R6为3-甲氧基-4-(甲基氨基甲酰基)苯基,R7为氢,n为1或2;
(e)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为氢或甲基,R3为氢、甲基或叔丁基,R6为4-甲氧基-3-(甲基氨基甲酰基)苯基,R7为氢,n为1或2;
(f)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为氢或甲基,R3为氢、甲基或叔丁基,R6为3-甲氧基-4-((甲基磺酰基)氨基甲酰基)苯基,R7为氢,n为1或2;
(g)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为氢或甲基,R3为氢、甲基或叔丁基,R6为4-(甲基((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基,R7为氢,n为1或2;
(h)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为氢或甲基,R3为氢、甲基或叔丁基,R6为3-甲氧基-4-(((四氢-2H-吡喃-2-基)氧基)氨基甲酰基)苯基,R7为氢,n为1或2;或者
(i)R1为氢、Boc、Fmoc、Cbz、Alloc或Teoc,R2为氢或甲基,R3为氢、甲基或叔丁基,R6为6-甲氧基吡啶-3-基,R7为氢,n为1或2。
本发明的氨基酸衍生物更优选地包括由式(1)表示的氨基酸衍生物:
其中
R1是氢或氨基的保护基团,所述氨基的保护基团选自由Boc、Fmoc、Cbz、Alloc和Teoc组成的组;
R2是氢或甲基;
R3是氢或羧基的保护基团,所述羧基的保护基团选自由甲基、叔丁基和苄基组成的组;
R7是氢;
n是1或2;和
X1、X2和X3独立地为氢或卤素;
前提是
当X1为卤素时,X2和X3为氢;和
当X1为氢时,X2和X3均为卤素,或X2和X3之一为卤素。
在式(1)中,当X1为卤素时,卤素优选为F或Cl。
在式(1)中,当X2和X3均为卤素时,卤素的类型可以相同或不同。X2和X3优选为X2=F和X3=F;X2=F和X3=Cl;或X2=Cl和X3=Cl。
在式(1)中,当X2和X3之一为卤素时,卤素优选为F或Cl。
式(1)的氨基酸衍生物的具体实例包括以下化合物、化合物的盐、以及化合物或盐的溶剂化物:
(C-001)2-(((苄氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(C-002)2-(((苄氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸甲酯,
(C-003)2-(((苄氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(C-004)2-(((苄氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸苄酯,
(C-005)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(C-006)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸甲酯,
(C-007)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(C-008)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸苄酯,
(C-009)2-((叔丁氧基羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(C-010)2-((叔丁氧基羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸甲酯,
(C-011)2-((叔丁氧基羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(C-012)2-((叔丁氧基羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸苄酯,
(C-013)2-(((烯丙氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(C-014)2-(((烯丙氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸甲酯,
(C-015)2-(((烯丙氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(C-016)2-(((烯丙氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸苄酯,
(C-017)4-(3,5-二氟-4-(三氟甲基)苯基)-2-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丁酸,
(C-018)4-(3,5-二氟-4-(三氟甲基)苯基)-2-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丁酸甲酯,
(C-019)4-(3,5-二氟-4-(三氟甲基)苯基)-2-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丁酸叔丁酯,
(C-020)4-(3,5-二氟-4-(三氟甲基)苯基)-2-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丁酸苄酯,
(C-021)2-((((苄氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(C-022)2-(((苄氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸甲酯,
(C-023)2-(((苄氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(C-024)2-(((苄氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸苄酯,
(C-025)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(C-026)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸甲酯,
(C-027)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(C-028)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸苄酯,
(C-029)2-((叔丁氧基羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(C-030)2-((叔丁氧基羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸甲酯,
(C-031)2-((叔丁氧基羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(C-032)2-((叔丁氧基羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸苄酯,
(C-033)2-(((烯丙氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸,
(C-034)2-(((烯丙氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸甲酯,
(C-035)2-(((烯丙氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯,
(C-036)2-(((烯丙氧基)羰基)(甲基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸苄酯,
(C-037)4-(3,5-二氟-4-(三氟甲基)苯基)-2-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丁酸,
(C-038)4-(3,5-二氟-4-(三氟甲基)苯基)-2-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丁酸甲酯,
(C-039)4-(3,5-二氟-4-(三氟甲基)苯基)-2-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丁酸叔丁酯,
(C-040)4-(3,5-二氟-4-(三氟甲基)苯基)-2-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丁酸苄酯,
(C-041)2-(((苄氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(C-042)2-(((苄氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸甲酯,
(C-043)2-(((苄氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(C-044)2-(((苄氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸苄酯,
(C-045)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(C-046)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸甲酯,
(C-047)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(C-048)2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸苄酯,
(C-049)2-((叔丁氧基羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(C-050)2-((叔丁氧基羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸甲酯,
(C-051)2-((叔丁氧基羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(C-052)2-((叔丁氧基羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸苄酯,
(C-053)2-(((烯丙氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(C-054)2-(((烯丙氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸甲酯,
(C-055)2-(((烯丙氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(C-056)2-(((烯丙氧基)羰基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸苄酯,
(C-057)3-(3,5-二氟-4-(三氟甲基)苯基)-2-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丙酸,
(C-058)3-(3,5-二氟-4-(三氟甲基)苯基)-2-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丙酸甲酯,
(C-059)3-(3,5-二氟-4-(三氟甲基)苯基)-2-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丙酸叔丁酯,
(C-060)3-(3,5-二氟-4-(三氟甲基)苯基)-2-(((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丙酸苄酯,
(C-061)2-(((苄氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(C-062)2-(((苄氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸甲酯,
(C-063)2-(((苄氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(C-064)2-(((苄氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸苄酯,
(C-065)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(C-066)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸甲酯,
(C-067)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(C-068)2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸苄酯,
(C-069)2-((叔丁氧基羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(C-070)2-((叔丁氧基羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸甲酯,
(C-071)2-((叔丁氧基羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(C-072)2-((叔丁氧基羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸苄酯,
(C-073)2-((((烯丙氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸,
(C-074)2-(((烯丙氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸甲酯,
(C-075)2-(((烯丙氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸叔丁酯,
(C-076)2-(((烯丙氧基)羰基)(甲基)氨基)-3-(3,5-二氟-4-(三氟甲基)苯基)丙酸苄酯,
(C-077)3-(3,5-二氟-4-(三氟甲基)苯基)-2-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丙酸,
(C-078)3-(3,5-二氟-4-(三氟甲基)苯基)-2-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丙酸甲酯,
(C-079)3-(3,5-二氟-4-(三氟甲基)苯基)-2-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丙酸叔丁酯,和
(C-080)3-(3,5-二氟-4-(三氟甲基)苯基)-2-(甲基((2-(三甲基甲硅烷基)乙氧基)羰基)氨基)丙酸苄酯。
在另一实施方案中,本发明的氨基酸衍生物的具体实例包括下表中提供的化合物、化合物的盐、以及化合物或盐的溶剂化物。
表中的R1、R2、R3、R6、R7和n分别表示下式中的R1、R2、R3、R6、R7和n。此外,*表示结合点。
[表1]
[表2]
[表3]
[表4]
[表5]
[表6]
[表7]
[表8]
[表9]
[表10]
[表11]
[表12]
[表13]
[表14]
通过上述反应步骤获得的目标化合物的分离/纯化可以通过应用常规的化学操作例如提取、浓缩、蒸馏、结晶、过滤、重结晶和各种类型的色谱法来进行。
本发明的化合物、该化合物的盐、或该化合物或盐的溶剂化物包括通过上述反应步骤得到的目标化合物的所有立体异构体(如对映异构体和非对映异构体(包括顺式和反式几何异构体)、异构体的外消旋体和其他混合物。例如,本发明的化合物可以具有一个或多个不对称中心,并且本发明包括这种化合物的外消旋混合物、非对映异构体混合物和对映异构体。
当本发明的化合物以游离形式获得时,该化合物可以根据常规方法转化为化合物的盐、或化合物或化合物可能形成的盐的水合物或溶剂化物的状态。
当根据本发明的化合物以化合物的盐、水合物或溶剂化物的形式获得时,可以根据常规方法将化合物转化为其游离形式。
本说明书中引用的所有现有技术文献均通过引用并入本文。
实施例
本发明通过以下实施例进一步说明,但不限于此。
对于在本发明的工作中使用的溶剂,例如DMF、DMA、NMP、DMI和DMPU,使用市售产品而无需纯化。在不添加水作为溶剂的反应中,使用市售的脱水溶剂、超脱水溶剂、无水溶剂等而无需纯化。
对于本发明工作中使用的试剂,例如以甲硅烷基化合物或1,2-二溴乙烷为例的添加剂、金属、可能的配体化合物、金属-配体络合物、还原剂、在引入保护基团的步骤中使用的试剂和脱保护步骤中使用的试剂,除非另有特别说明,否则使用市售产品而无需纯化。
对于在本发明的工作中使用的芳香族氨基酸衍生物的起始材料,以苯丙氨酸衍生物和高苯丙氨酸衍生物为代表,除非另有说明,否则使用市售产品而无需纯化。此外,这些起始材料根据需要通过公知的方法制备并使用。
使用AVANCE III HD 400 BBFO-SMART探针(由Bruker制造)测量1H-NMR光谱,用作内标材料的Me4Si的化学位移设置为0ppm,来自样品溶剂的氘锁信号为参照。分析物化合物信号的化学位移表示为ppm。信号分裂的缩写为s=单峰,brs=宽单峰,d=双峰,t=三重峰,q=四重峰,dd=双双峰,m=多重峰,信号分裂的宽度表示为J值(Hz)。基于各个信号的信号面积强度之间的比率计算信号的积分值(integrated value)。
[高效液相色谱条件1]
仪器:岛津公司制造
柱子:Ascentis Express RP-酰胺(3.0毫米内径×50毫米)
流动相:含0.05%三氟乙酸的水(A)和含0.05%三氟乙酸的乙腈(B)
洗脱方法:从5%B到95%B(5.0分钟)的逐步溶剂梯度洗脱,保持在95%B(2.0分钟)
流速:0.7mL/min
柱温:30℃
[高效液相色谱条件2]
仪器:Waters Acquity UPLC/SQD
柱子:Ascentis Express C18(2.1毫米内径×50毫米)
流动相:含0.1%甲酸的水(A)和含0.1%甲酸的乙腈(B)
洗脱方法:从5%B到100%B(5.0分钟)的逐步溶剂梯度洗脱,保持在100%B(2.0分钟)
流速:1.0mL/min
[高效液相色谱条件3]
仪器:Waters Acquity UPLC/SQD
柱子:Ascentis Express C18(2.1毫米内径×50毫米)
流动相:10mM乙酸铵水溶液(A)和10mM乙酸铵乙腈溶液(B)
洗脱方法:从5%B到100%B(1.0分钟)的逐步溶剂梯度洗脱,保持在100%B(0.4分钟)
流速:1.0mL/min
[高效液相色谱条件4]
仪器:Waters Acquity UPLC/SQD
柱子:Ascentis Express C18(2.1毫米内径×50毫米)
流动相:含0.1%甲酸的水(A)和含0.1%甲酸的乙腈(B)
洗脱方法:从5%B到100%B(1.0分钟)的逐步溶剂梯度洗脱,保持在100%B(0.4分钟)
流速:1.0mL/min
[高效液相色谱条件5]
仪器:岛津公司制造
柱子:Ascentis Express C18(3.0毫米内径×50毫米)
流动相:含0.05%三氟乙酸的水(A)和含0.05%三氟乙酸的乙腈(B)
洗脱方法:从5%B到95%B(2.0分钟)的逐步溶剂梯度洗脱,保持在95%B(0.7分钟)
流速:1.0mL/min
[高效液相色谱条件6]
仪器:岛津公司制造
柱子:Ascentis Express C18(3.0毫米内径×50毫米)
流动相:含0.05%三氟乙酸的水(A)和含0.05%三氟乙酸的乙腈(B)
洗脱方法:从5%B到95%B(1.1分钟)的逐步溶剂梯度洗脱,保持在95%B(0.5分钟)
流速:1.0mL/min
[参考例1]不使用TMSCl作为添加剂,用搅拌叶片进行搅拌的情况
(S)-2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯的制备
将溴化镍三水合物(0.12g,0.44mmol)和4,4′-二叔丁基-2,2′-联吡啶(0.12g,0.44mmol)溶解在DMA(15mL)中,并将混合物用氮气吹扫,然后搅拌10分钟以制备催化剂溶液。将锌粉(2.0g,31mmol)、1-苄基5-(1,3-二氧异吲哚啉-2-基)(叔丁氧基羰基)-L-谷氨酸(3.0g,6.2mmol)和DMA(15mL)加入装有搅拌叶片的烧瓶中,加入4-溴-2-氯-1-(三氟甲基)苯(4.8g,19mmol),然后用氮气吹扫混合物。在氮气气氛下将制备的催化剂溶液滴加到反应溶液中,溶液在25℃下搅拌2小时,反应混合物通过HPLC分析。原料与目标化合物的紫外强度比为92.5∶7.5(检测波长:210nm),因此确认90%或更多的原料残留。
(S)-2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯:
保留时间:原料2.7分钟,目标化合物3.4分钟(高效液相色谱条件2)
ESI(LC/MS正离子模式m/z 472(M+H)+)
[实施例1]使用5mol%TMSCl作为添加剂,用搅拌叶片进行搅拌的情况
(S)-2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯的制备
将溴化镍三水合物(0.20g,0.73mmol)和4,4′-二叔丁基-2,2′-联吡啶(0.20g,0.73mmol)溶解在DMA(25mL)中,并将混合物用氮气吹扫,然后搅拌10分钟以制备催化剂溶液。将锌粉(3.4g,52mmol)、1-苄基5-(1,3-二氧异吲哚啉-2-基)(叔丁氧基羰基)-L-谷氨酸(5.0g,10mmol)和DMA(25mL)加入装有搅拌叶片的烧瓶中,加入4-溴-2-氯-1-(三氟甲基)苯(8.1g,31mmol),然后用氮气吹扫混合物。在氮气氛下将制备的催化剂溶液滴加到反应溶液中后,加入TMSCl(56mg,0.52mmol)。将溶液在25℃搅拌2小时,然后通过HPLC分析反应混合物。原料与目标化合物的紫外强度比为67∶33(检测波长:210nm),由此确认,与不使用TMSCl的情况(参考例1)相比,虽然原料残留,但目标化合物的产量显著增加。
(S)-2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯:
保留时间:原料4.3分钟,目标化合物5.0分钟(高效液相色谱条件1)
ESI(LC/MS正离子模式m/z 472(M+H)+)
[实施例2]使用50mol%TMSCl作为添加剂,用搅拌叶片进行搅拌的情况
(S)-2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯的制备
将溴化镍三水合物(39mg,0.15mmol)和4,4′-二叔丁基-2,2′-联吡啶(40mg,0.15mmol)溶解在DMA(5.0mL)中,并将混合物用氮气吹扫,然后搅拌10分钟以制备催化剂溶液。将锌粉(0.68g,10mmol)、1-苄基5-(1,3-二氧异吲哚啉-2-基)(叔丁氧基羰基)-L-谷氨酸(1.0g,2.1mmol)和DMA(5.0mL)加入装有搅拌叶片的烧瓶中,加入4-溴-2-氯-1-(三氟甲基)苯(1.6g,6.2mmol),然后用氮气吹扫混合物。在氮气氛下将制备的催化剂溶液滴加到反应溶液中后,加入TMSCl(0.11g,1.0mmol)。将溶液在25℃搅拌2小时,然后通过HPLC分析反应混合物。原料与目标化合物的紫外强度比为0∶100(检测波长:210nm),确认原料完全消失,目标化合物为主要产物。通过色谱法纯化反应溶液以提供(S)-2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸酯(0.79g,产率80%)。
(S)-2-((叔丁氧基羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸苄酯:
保留时间:原料4.0分钟,目标化合物4.7分钟(高效液相色谱条件1)
1H-NMR(DMSO-D6)δ:7.76(1H,d,J=8.1Hz),7.55(1H,s),7.44(0.8H,d,J=7.8Hz),7.36-7.34(6H,m),7.10(0.2H,m),5.15(1H,d,J=12.5Hz),5.08(1H,d,J=12.5Hz),3.98-3.96(0.8H,m),3.87(0.2H,br s),2.71(2H,t,J=7.9Hz),2.01-1.87(2H,m),1.39(8H,s),1.27(1H,s)
[实施例3]使用52mol%TMSCl作为添加剂,用搅拌叶片进行搅拌的情况
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸的制备
将溴化镍三水合物(0.20g,0.73mmol)和4,4′-二叔丁基-2,2′-联吡啶(0.20g,0.73mmol)溶解在DMA(25mL)中,并将混合物用氮气吹扫,然后搅拌10分钟以制备催化剂溶液。将锌粉(3.4g,52mmol)、1-苄基5-(1,3-二氧异吲哚啉-2-基)(叔丁氧基羰基)-L-谷氨酸(5.0g,10mmol)和DMA(25mL)加入装有搅拌叶片的烧瓶中,加入4-溴-2-氯-1-(三氟甲基)苯(8.1g,31mmol),然后用氮气吹扫混合物。在氮气气氛下,将制备的催化剂溶液滴加到反应液中后,加入TMSCl(0.56g,5.2mmol),25℃搅拌3h。当反应混合物通过HPLC分析时,证实原料已经完全消失,目标化合物为主要产物。向反应溶液中加入乙酸乙酯(50mL)和10%EDTA·2Na水溶液(50mL),有机层用10%NaCl水溶液(50mL)洗涤。减压浓缩所得有机层,加入甲苯(25mL)以制备溶液,并将溶液分成两部分。将溶液冷却至0℃,滴加TfOH(2.3g),升温至25℃,然后加入水(2.5mL)。混合物搅拌45分钟后,加入10mL水进行分离。将40%K3PO4水溶液(2.0mL)和乙腈(13mL)加入水层。加入FmocOSu(1.8g),并加入40%K3PO4水溶液(3.5mL)。排出下层后,加入5N HCl(2.2mL),过滤析出的固体,将所得固体干燥,得到(S)-2-((((9H-芴-9-基)甲氧基))羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸(1.8g,产率68%),为白色固体。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3-氯-4-(三氟甲基)苯基)丁酸:
目标化合物保留时间:3.1分钟(高效液相色谱条件2)
1H-NMR(DMSO-D6)δ:12.65(1H,s),7.90(2H,d,J=7.5Hz),7.77-7.58(5H,m),7.44-7.32(5H,m),4.37-4.18(3H,m),3.91-3.88(1H,m),2.79-2.66(2H,m),2.07-1.86(2H,m).
[实施例4](S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-氟苯基)丁酸叔丁酯的制备
将溴化镍三水合物(4.0mg,0.015mmol)和4,4′-二-叔丁基-2,2′-联吡啶(3.9mg,0.015mmol)溶解在DMA(0.50mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。加入1-(叔丁基)5-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-谷氨酸(0.12g,0.21mmol)和1-氟-4-碘苯(0.14g,0.62mmol)并溶解在DMA(0.5mL)中。在氮气氛下滴加制备的催化剂溶液,加入锌粉(68mg,1.0mmol),然后加入TMSCl(11mg,0.1mmol),反应容器在25℃下振荡2h。当反应混合物通过HPLC分析时,证实原料已经完全消失,目标化合物为主要产物。反应溶液经色谱纯化得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-氟苯基)丁酸叔丁酯(70mg,产率71%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-氟苯基)丁酸叔丁酯:
目标化合物保留时间:1.1分钟(高效液相色谱条件3)
ESI(LC/MS正离子模式m/z 498(M+Na)+)
[实施例5](S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-3-基)丁酸叔丁酯的制备
将溴化镍三水合物(0.14g,0.53mmol)和4,4′-二-叔丁基-2,2′-联吡啶(0.14g,0.53mmol)溶解在DMA(8.0mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将锌粉(0.57g,8.8mmol)、5-(1,3-二氧异吲哚啉-2-基)1-叔丁基N-(((9H-芴-9-基)甲氧基)羰基)-L-谷氨酸(1.0g,1.8mmol)和DMA(8.0mL)加入烧瓶中,加入3-碘吡啶(1.1g,5.3mmol),然后用氮气吹扫混合物。在氮气气氛下将制备的催化剂溶液滴加到反应溶液中后,加入TMSCl(95mg,0,88mmol)和1,2-二溴乙烷(0.33g,1.8mmol),混合物在25℃下搅拌3h。当通过HPLC分析反应混合物时,确认原料完全消失,产生了目标化合物。反应溶液用EDTA·2Na水溶液猝灭,用MTBE萃取的有机层用盐水洗涤,有机层用硫酸钠干燥,滤去干燥剂,滤液减压浓缩。所得粗产物通过色谱法纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-3-基)丁酸叔丁酯(0.21g,产率26%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(吡啶-3-基)丁酸叔丁酯:
目标化合物保留时间:1.0分钟(高效液相色谱条件3)
ESI(LC/MS正离子模式m/z 459(M+H)+)
[实施例6](S)-2-(((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯的制备
将溴化镍三水合物(2.9g,11mmol)和4,4′-二叔丁基-2,2′-联吡啶(2.8g,11mmol)溶解在DMA(175mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将锌粉(11g,175mmol)、5-(1,3-二氧异吲哚啉-2-基)1-叔丁基N-(((9H-芴-9-基)甲氧基)羰基)-L-谷氨酸(20g,35mmol)和DMA(175mL)加入烧瓶中,加入5-溴-1,3-二氟-2-(三氟甲基)苯(27g,105mmol),然后用氮气吹扫该混合物。在氮气气氛下,将制备的催化剂溶液滴加到反应溶液中,然后加入TMSCl(1.9g,18mmol),混合物在25℃下搅拌1h。当反应混合物通过HPLC分析时,证实原料已经完全消失,目标化合物为主要产物。用EDTA·2Na水溶液淬灭反应溶液,然后用MTBE萃取混合物。有机层用碳酸氢钠水溶液和氯化铵水溶液洗涤后,浓缩有机层,所得粗产物通过重结晶纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯(15g,产率76%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(3,5-二氟-4-(三氟甲基)苯基)丁酸叔丁酯:
目标化合物保留时间:1.3分钟(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 562(M+H)+)
[实施例7]5-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸的制备
将(S)-2-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-5-(烯丙氧基)-5-氧代戊酸(19g,46mmol)溶于二氯甲烷(40mL)中,并逐滴加入2,2,2-三氯乙酰胺酸叔丁酯(22g,100mmol)的环己烷(80mL)溶液。向溶液中加入BF3·OEt2(0.87mL,6.8mmol),并将混合物在25℃下搅拌20分钟。加入碳酸氢钠,搅拌混合物,然后过滤除去不溶物。滤液用MTBE稀释并用Na2CO3水溶液和盐水洗涤。浓缩有机层以提供N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L5-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸(20g,产率91%)。
5-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸:
目标化合物保留时间:1.1分钟(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 502(M+Na)+)
[实施例8](S)-4-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-5-(叔丁氧基)-5-氧代戊酸的制备
5-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸(22g,46mmol)和四(三苯基膦)钯(0.53g,0.46mmol)溶解在二氯甲烷(91mL)中,并加入苯基硅烷(3.4g,32mmol)。搅拌混合物2小时后,加入四(三苯基膦)钯(0.53g,0.46mmol),反应溶液在25℃搅拌2.5小时。将MTBE(500mL)和碳酸钠水溶液加入到反应溶液中以将溶液分成两层。加入H3PO4(30mL)酸化水层,目标化合物用MTBE(500mL)萃取。将用盐水洗涤后的有机层浓缩得到(S)-4-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-5-(叔丁氧基)-5-氧代戊酸(19g,产率97%)。
(S)-4-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-5-(叔丁氧基)-5-氧代戊酸:
目标化合物保留时间:0.88分钟(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 440(M+H)+)
[实施例9]1-(叔丁基)5-(1,3-二氧异吲哚啉-2-基)N-((((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸的制备
将(S)-4-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-5-(叔丁氧基)-5-氧代戊酸(7.7g,47mmol)和N-羟基邻苯二甲酰亚胺(19g,43mmol)溶解在THF(130mL)中,滴加N,N′-二异丙基碳二亚胺(8.1g,4mmol)的THF(10mL)溶液。反应溶液在25℃下搅拌1小时后,加入甲苯(40mL),过滤除去固体。浓缩滤液,加入MTBE(150mL)形成悬浮液,过滤除去沉淀。浓缩滤液以提供1-(叔丁基)5-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸(26g,产率100%)。
1-(叔丁基)5-(1,3-二氧异吲哚啉-2-基)N-((((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸:
目标化合物保留时间:1.1分钟(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 585(M+H)+)
[实施例10](S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-3-基)丁酸叔丁酯的制备
将溴化镍三水合物(4.0mg,0.015mmol)和4,4′-二-叔丁基-2,2′-联吡啶(3.9mg,0.015mmol)溶解在DMA(0.50mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将1-(叔丁基)5-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸(0.12g,0.21mmol)和3-碘吡啶(0.13g,0.62mmol)加入并溶解在DMA(0.5mL)中。在氮气氛下滴加制备的催化剂溶液,加入锌粉(68mg,1.0mmol),然后加入TMSCl(56mg,0.52mmol),反应容器在25℃下振荡20h。当通过HPLC分析反应混合物时,确认原料完全消失,产生了目标化合物。反应溶液通过色谱纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-3-基)丁酸叔丁酯(20mg,产率20%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(吡啶-3-基)丁酸叔丁酯:
目标化合物保留时间:1.1分钟(高效液相色谱条件3)
ESI(LC/MS正离子模式m/z 473(M+H)+)
[实施例11]1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-天冬氨酸的制备
将(S)-3-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(叔丁氧基)-4-氧代丁酸(2.0g,4.9mmol)和N-羟基邻苯二甲酰亚胺(0.87g,5.4mmol)溶解在THF(19mL)中,并滴加N,N′-二异丙基碳二亚胺(0.92g,7.3mmol)。将反应溶液在25℃搅拌30分钟,浓缩溶液,加入甲苯(20mL),过滤除去固体。浓缩滤液,并通过色谱法纯化,得到1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-天冬氨酸(2.7g,产率100%)。
1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-天冬氨酸:
目标化合物保留时间:1.0分钟(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 479(M+Na)+)
[实施例12](S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基苯基)丙酸叔丁酯的制备
将溴化镍三水合物(4.0mg,0.015mmol)和4,4′-二叔丁基-2,2′-联吡啶(3.9mg,0.015mmol)溶解在DMA(0.50mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-天冬氨酸(0.12g,0.21mmol)和1-碘-3-甲氧基苯(0.15g,0.62mmol)加入并溶解在DMA(0.5mL)中。在氮气氛下滴加制备的催化剂溶液,加入锌粉(68mg,1.0mmol),然后加入TMSCl(11mg,0.10mmol),反应容器在25℃下振荡2h。当反应混合物通过HPLC分析时,确认原料已经完全消失,目标化合物为主要产物。反应溶液经色谱纯化得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基苯基)丙酸叔丁酯(70mg,产率71%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-3-(3-甲氧基苯基)丙酸叔丁酯:
目标化合物保留时间:1.1分钟(高效液相色谱条件3)
ESI(LC/MS正离子模式m/z 496(M+Na)+)
[实施例13]4-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸的制备
将(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(烯丙氧基)-4-氧代丁酸(16g,39mmol)溶于二氯甲烷(36mL)中,并逐滴加入2,2,2-三氯乙酰胺酸叔丁酯(14g,77mmol)的环己烷(72mL)溶液。向溶液中加入BF3·OEt2(0.73mL,5.8mmol),并将混合物在25℃下搅拌10分钟。加入NaHCO3,搅拌混合物,然后过滤除去不溶物。滤液用MTBE稀释并用Na2CO3水溶液洗涤。浓缩有机层,并通过色谱法纯化,得到4-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(20g,产率95%)。
4-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸:
目标化合物保留时间:1.1分钟(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 488(M+Na)+)
[实施例14](S)-3-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(叔丁氧基)-4-氧代丁酸的制备
将4-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(14g,31mmol)和四(三苯基膦)钯(0.36g,0.31mmol)溶解在二氯甲烷(61mL)中,并加入苯基硅烷(2.3g,22mmol)。将反应溶液在25℃搅拌40分钟后,将MTBE(500mL)和碳酸钠水溶液加入到反应溶液中,将溶液分成两层。加入H3PO4(80mL)酸化水层,目标化合物用MTBE(700mL)萃取。将用盐水洗涤后的有机层浓缩以提供(S)-3-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(叔丁氧基)-4-氧代丁酸(14g,产率100%)。
(S)-3-(((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(叔丁氧基)-4-氧代丁酸:
目标化合物保留时间:0.90分钟(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 448(M+Na)+)
[实施例15]1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸的制备
将(S)-3-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(叔丁氧基)-4-氧代丁酸(0.27g,0.6mmol)和N-羟基邻苯二甲酰亚胺(0.12g,0.71mmol)溶解在THF(2.6mL)中,并滴加N,N′-二异丙基碳二亚胺(0.12g,1.0mmol)。将反应溶液在25℃搅拌90分钟后,浓缩溶液,加入甲苯(2mL),过滤除去固体。浓缩滤液,并通过色谱法纯化,得到1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(0.22g,产率59%)。
1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸:
目标化合物保留时间:1.1分钟(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 593(M+Na)+)
[实施例16](S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(嘧啶-5-基)丙酸叔丁酯的制备
将溴化镍三水合物(4.0mg,0.015mmol)和4,4′-二叔丁基-2,2′-联吡啶(3.9mg,0.015mmol)溶解在DMA(0.50mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(0.12g,0.21mmol)和5-溴嘧啶(99mg,0.62mmol)加入并溶解在DMA(0.5mL)中。在氮气氛下向反应溶液滴加制备的催化剂溶液,加入锌粉(68mg,1.0mmol),然后加入TMSCl(34mg,0.31mmol),反应容器在25℃下振荡2h。当通过HPLC分析反应混合物时,确认原料完全消失,产生了目标化合物。反应溶液通过色谱纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(嘧啶-5-基)丙酸叔丁酯(32mg,产率34%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(嘧啶-5-基)丙酸叔丁酯:
目标化合物保留时间:1.0分钟(高效液相色谱条件3)
ESI(LC/MS正离子模式m/z 460(M+H)+)
[实施例17](S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-(三氟甲基)苯基)丙酸叔丁酯的制备
将溴化镍三水合物(0.21g,0.77mmol)和4,4′-二叔丁基-2,2′-联吡啶(0.25g,0.95mmol)溶解在DMA(15mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将锌粉(1.0g,16mmol)、1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(1.8g,3.2mmol)和DMA(8.0mL)加入烧瓶中,加入1-溴-2-氟-4-(三氟甲基)苯(2.3g,9.5mmol),然后用氮气吹扫混合物。在氮气气氛下,将制备的催化剂溶液滴加到反应溶液中后,加入TMSCl(0.17g,1.6mmol),25℃搅拌混合物30min。当反应混合物通过HPLC分析时,证实原料已经完全消失,目标化合物为主要产物。用EDTA·2Na水溶液淬灭反应溶液,然后用MTBE萃取混合物。有机层用盐水洗涤后,有机层浓缩,所得粗产物经色谱纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-(三氟甲基)苯基)丙酸叔丁酯(0.93g,产率55%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-(三氟甲基)苯基)丙酸叔丁酯:
目标化合物保留时间:1.2min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 566(M+Na)+)
[实施例18](S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟-4-(三氟甲基)苯基)丙酸叔丁酯的制备
将溴化镍三水合物(0.21g,0.77mmol)和4,4′-二叔丁基-2,2′-联吡啶(0.25g,0.95mmol)溶解在DMA(15mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将锌粉(1.0g,16mmol)、1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(1.8g,3.2mmol)和DMA(8.0mL)加入烧瓶中,加入4-溴-2-氟-1-(三氟甲基)苯(2.3g,9.5mmol),然后用氮气吹扫混合物。在氮气气氛下,将制备好的催化剂溶液滴加到反应溶液中后,加入TMSCl(0.17g,1.6mmol),25℃搅拌混合物30min。当反应混合物通过HPLC分析时,确认原料已经完全消失,目标化合物为主要产物。用EDTA·2Na水溶液淬灭反应溶液,然后用MTBE萃取混合物。有机层用盐水洗涤后,浓缩有机层,所得粗产物经色谱法纯化,提供(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟-4-(三氟甲基)苯基)丙酸叔丁酯(1.2g,产率68%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(3-氟-4-(三氟甲基)苯基)丙酸叔丁酯:
目标化合物保留时间:1.1min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 566(M+Na)+)
[实施例19](S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-甲氧基苯基)丙酸叔丁酯的制备
将溴化镍三水合物(0.37g,1.4mmol)和4,4′-二叔丁基-2,2′-联吡啶(0.45g,1.7mmol)溶解在DMA(25mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将锌粉(1.8g,28mmol)、1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(3.2g,5.6mmol)和DMA(25mL)加入烧瓶中,加入1-溴-2-氟-4-甲氧基苯(3.5g,17mmol),然后用氮气吹扫混合物。在氮气气氛下,滴加制备的催化剂溶液后,加入TMSCl(0.31g,2.8mmol),25℃搅拌混合物30min。当反应混合物通过HPLC分析时,证实原料已经完全消失,产生目标化合物。用EDTA·2Na水溶液淬灭反应溶液,然后用MTBE萃取混合物。有机层用盐水洗涤后,浓缩有机层,所得粗产物经色谱纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-甲氧基苯基)丙酸叔丁酯(0.48g,产率17%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(2-氟-4-(甲氧基苯基)丙酸叔丁酯:
目标化合物保留时间:1.1min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 506(M+H)+)
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸的制备
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸根据以下合成方案制备。
[实施例20](9H-芴-9-基)甲基(4S)-4-(2-(烯丙氧基)-2-氧乙基)-2-甲基-5-氧噁唑烷-3-羧酸盐的制备
在室温下将三氟乙酸(29g,0.38mol)加入到(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基(-4-(烯丙氧基)-4-氧代丁酸(50g,0.13mol)、硫酸镁(55g,0.38mol)和三聚乙醛(25g,0.19mol)的甲苯(0.50L)悬浮液中。将混合物在90℃下搅拌16小时,然后冷却至室温,用乙酸乙酯稀释,并用碳酸氢钠水溶液洗涤。有机层用硫酸钠干燥并在减压下浓缩,提供(9H-芴-9-基)甲基(4S)-4-(2-(烯丙氧基)-2-氧乙基)-2-甲基-5-氧噁唑烷-3-羧酸盐(45g,产率82%)。
(9H-芴-9-基)甲基(4S)-4-(2-(烯丙氧基)-2-氧乙基)-2-甲基-5-氧噁唑烷-3-羧酸盐:
目标化合物保留时间:1.4min(高效液相色谱条件6)
ESI(LC/MS正离子模式m/z 422(M+H)+)
[实施例21](S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-4-(烯丙氧基)-4-氧代丁酸的制备
将(9H-芴-9-基)甲基(4S)-4-(2-(烯丙氧基)-2-氧乙基)-2-甲基-5-氧噁唑烷-3-羧酸盐(46g,0.11mol)和三乙基硅烷(38g,0.32mol)溶解在二氯甲烷(0.45L)中,并在25℃下加入三氟乙酸(0.45L)。将溶液在25℃下搅拌48小时,然后减压浓缩。将MTBE加入浓缩残渣中,用碳酸氢钠水溶液萃取到水层中,水层用己烷洗涤3次。水层用盐酸调节至pH 2,并用MTBE萃取两次。有机层用硫酸钠干燥,然后减压浓缩,提供(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-4-(烯丙氧基)-4-氧代丁酸(33g,产率71%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-4-(烯丙氧基)-4-氧代丁酸:
目标化合物保留时间:1.9min(高效液相色谱条件5)
ESI(LC/MS正离子模式m/z 424(M+H)+)
[实施例22]4-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-乙基-L-天冬氨酸的制备
将(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-4-(烯丙氧基)-4-氧代丁酸(5.0g,12mmol)溶于二氯甲烷(10mL)中,并逐滴加入2,2,2-三氯乙酰胺酸叔丁酯(5.1g,24mmol)的环己烷(20mL)溶液。将BF3·OEt2(17mg,0.12mmol)添加到溶液中,并将混合物在25℃下搅拌16小时。过滤除去不溶物,浓缩滤液,然后用MTBE稀释,用碳酸氢钠水溶液洗涤。有机层用硫酸钠干燥并浓缩,提供4-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(4.9g,产率85%)。
4-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸:
目标化合物保留时间:1.6min(高效液相色谱条件6)
ESI(LC/MS正离子模式m/z 480(M+H)+)
[实施例23](S)-3-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-4-(叔丁氧基)-4-氧代丁酸的制备
将4-烯丙基1-(叔丁基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(4.9g,10mmol)和四(三苯基膦)钯(0.12g,0.10mmol)溶解在二氯甲烷(25mL)中,并加入苯基硅烷(0.77g,7.2mmol)。将反应溶液在25℃下搅拌16小时,然后浓缩,加入MTBE溶解浓缩液。目标化合物用碳酸钠水溶液萃取到水层中。向水层中加入磷酸酸化水层,目标化合物用MTBE萃取3次。有机层用盐水洗涤,然后用硫酸钠干燥,浓缩液通过色谱纯化,提供(S)-3-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-4-(叔丁氧基)-4-氧代丁酸(2g,产率46%)。
(S)-3-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-4-(叔丁氧基)-4-氧代丁酸:
目标化合物保留时间:1.7min(高效液相色谱条件5)
ESI(LC/MS正离子模式m/z 440(M+H)+)
[实施例24]1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-乙基-L-天冬氨酸的制备
将(S)-3-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-4-(叔丁氧基)-4-氧代丁酸(0.65g,1.5mmol)和N-羟基邻苯二甲酰亚胺(0.27g,1.6mmol)悬浮在乙酸乙酯(6.5mL)中,并滴加N,N′-二异丙基碳二亚胺(0.28g,2.2mmol)。反应溶液在25℃下搅拌60min后,过滤除去固体。浓缩滤液,并通过色谱法纯化,得到1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-乙基-L-天冬氨酸(0.78g,产率90%)。
1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-乙基-L-天冬氨酸:
目标化合物保留时间:1.1min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 607(M+Na)+)
[实施例25](S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸叔丁酯的制备
将溴化镍三水合物(4.0mg,0.015mmol)和4,4′-二叔丁基-2,2′-联吡啶(3.9mg,0.015mmol)溶解在DMA(0.50mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-乙基-L-天冬氨酸(0.12g,0.21mmol)和1-碘-4-甲基苯(0.14g,0.62mmol)加入并溶解在DMA(0.5mL)中。在氮气氛下向反应溶液滴加制备的催化剂溶液,加入锌粉(68mg,1.0mmol),然后加入TMSCl(11mg,0.10mmol),反应容器在25℃下振荡2h。当通过HPLC分析反应混合物时,确认原料完全消失,产生了目标化合物。反应溶液经色谱纯化得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸叔丁酯(66mg,产率65%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸叔丁酯:
目标化合物保留时间:1.2min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 508(M+Na)+)
[实施例26](S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸的制备
将(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸叔丁酯(50mg,0.10mmol)溶解在三氟乙醇中(0.50mL),在室温下加入TMSCl(17mg,0.15mmol),并将混合物搅拌2h。减压浓缩反应溶液,浓缩液经色谱纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸(38mg,产率86%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(乙基)氨基)-3-(对甲苯基)丙酸:
目标化合物保留时间:0.95min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 430(M+H)+)
[实施例27](S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(对甲苯基)丙酸叔丁酯的制备
将溴化镍三水合物(3.8mg,0.014mmol)和4,4′-二叔丁基-2,2′-联吡啶(3.8mg,0.014mmol)溶解在DMA(0.50mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。将锌粉(65mg,1.0mmol)和TMSCl(11mg,0.10mmol)添加到溶液中,并将混合物振荡10分钟。将1-(叔丁基)4-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-天冬氨酸(0.11g,0.20mmol)和1-碘-4-甲基苯(0.13g,0.60mmol)的DMA(0.50mL)溶液在氮气氛下滴加到催化剂溶液中,反应容器在25℃下振荡2h。通过HPLC分析反应混合物,确认原料完全消失,产生了目标化合物。反应溶液经色谱纯化得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(对甲苯基)丙酸叔丁酯(56mg,产率59%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-3-(对甲苯基)丙酸叔丁酯:
目标化合物保留时间:1.2min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 494(M+Na)+)
[实施例28](S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基苯基)丁酸叔丁酯的制备
将溴化镍三水合物(3.8mg,0.014mmol)和4,4′-二叔丁基-2,2′-联吡啶(3.8mg,0.014mmol)溶解在DMA(0.50mL)中,并将混合物用氮气吹扫,然后搅拌,进一步向溶液中加入锌粉(65mg,1.0mmol)以制备催化剂溶液。将1-(叔丁基)5-(1,3-二氧异吲哚啉-2-基)N-(((9H-芴-9-基)甲氧基)羰基)-N-甲基-L-谷氨酸(0.12g,0.20mmol)和1-碘-3-甲氧基苯(0.14g,0.60mmol)溶解在DMA(0.50mL)中,然后加入TMSCl(11mg,0.10mmol)。在氮气气氛下将溶液滴加到催化剂溶液中,将反应容器在25℃下振荡2小时。通过HPLC分析反应混合物,确认原料完全消失,产生了目标化合物。反应溶液通过色谱纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基苯基)丁酸叔丁酯(67mg,产率67%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)(甲基)氨基)-4-(3-甲氧基苯基)丁酸叔丁酯:
目标化合物保留时间:1.1min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 524(M+Na)+)
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸的制备
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸可以根据以下合成方案制备,包括使用与上述实施例相同的条件和方法使N-羟基邻苯二甲酰亚胺酯与芳香族溴化物反应的步骤,得到芳香族氨基酸衍生物。
[实施例29]1-甲基5-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-谷氨酸的制备
将(S)-4-((((9H-芴-9-基)甲氧基)羰基)氨基)-5-(甲氧基)-5-氧代戊酸(1.0g,2.6mmol)和N-羟基邻苯二甲酰亚胺(0.47g,2.9mmol)悬浮在乙酸乙酯(10mL)中,并滴加N,N′-二异丙基碳二亚胺(0.61mL,3.9mmol)。反应溶液在25℃下搅拌60min后,过滤除去固体。浓缩滤液,并通过色谱法纯化,得到1-甲基5-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-谷氨酸(1.0g,产率73%)。
1-甲基5-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-谷氨酸:
目标化合物保留时间:1.0min(高效液相色谱条件3)
ESI(LC/MS正离子模式m/z 529(M+H)+)
[实施例30](S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸甲酯的制备
将溴化镍三水合物(4.0mg,0.015mmol)和4,4′-二叔丁基-2,2′-联吡啶(4.0mg,0.015mmol)溶解在DMA(0.50mL)中,混合物用氮气吹扫,然后搅拌以制备催化剂溶液。在另一容器中,将锌粉(69mg,1.1mmol)、1-甲基5-(1,3-二氧异吲哚啉-2-基)(((9H-芴-9-基)甲氧基)羰基)-L-谷氨酸(0.11g,0.21mmol)和1-碘-4-甲氧基苯(0.15g,0.63mmol)加入并溶解在DMA(0.50mL)中。在氮气氛下向反应溶液滴加制备的催化剂溶液,加入TMSCl(11mg,0.11mmol),反应容器在25℃下振荡1h。当通过HPLC分析反应混合物时,确认原料完全消失,产生了目标化合物。反应溶液经色谱纯化得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸甲酯(64mg,产率68%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸甲酯:
目标化合物保留时间:0.9min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 446(M+H)+)
[实施例31](S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸的制备
将水(0.49mL)和2-丙醇(2.0mL)加入氯化钙(0.19g,1.7mmol)和氢氧化锂水合物(19mg,0.45mmol)中,并将混合物在室温下搅拌15分钟。在室温下向其中逐滴加入(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸甲酯(50mg,0.11mmol)的THF(0.49mL)中的溶液,并将混合物搅拌20小时。过滤除去不溶物,用THF洗涤固体。将滤液浓缩,然后通过色谱法纯化,得到(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸(35mg,72%)。
(S)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-4-(4-甲氧基苯基)丁酸:
目标化合物保留时间:0.8min(高效液相色谱条件4)
ESI(LC/MS正离子模式m/z 432(M+H)+)
[工业适用性]
本发明提供可用作药物产品原料的光学活性芳香族氨基酸衍生物的新的制备方法。使用本发明的制备方法,能够高效地制备和供给光学活性芳香族氨基酸衍生物。
Claims (15)
1.式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物的制备方法:
式I:
其中
R1为氢或氨基的保护基团;
R2为氢或C1-C6烷基,R3为氢或羧基的保护基团,或R2和R3一起形成二价保护基团;
R6为任选取代的C6-C10芳基或任选取代的杂芳基;
R7为氢或C1-C4烷基;和
N为1或2,
所述方法包括将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物与还原剂、添加剂和R6-X(其中R6与式I表示的化合物的R6相同,且X为卤素、OTf或OMs)在溶剂和催化剂存在下混合,以得到式I表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物的步骤:
式II:
其中
R1、R2、R3、R7和n分别与式I表示的化合物的R1、R2、R3、R7和n相同;
R5选自由以下组成的组:
Rt、Ru、Rv和Rw独立地为氢、卤素或硝基;
Rx和Ry独立地为氢、C1-C4烷基或任选取代的苯基;
Rz为氢、C1-C4烷基或卤素;
Y为CH或N;和
*表示结合点。
2.根据权利要求1所述的方法,其中R1为氨基的保护基团,所述氨基的保护基团选自由Fmoc、Boc、Alloc、Cbz、Teoc和三氟乙酰基组成的组。
3.根据权利要求1或2所述的方法,其中R3是羧基的保护基团,所述羧基的保护基团选自由甲基、乙基、叔丁基、苄基、三苯甲基、枯基、甲氧基三苯甲基和2-(三甲基甲硅烷基)乙基组成的组。
6.根据权利要求5所述的方法,其中所述甲硅烷基化合物选自由TMSCl、TMSBr、TMSI、TMSOTf、TBDMSCl、TESCl、TIPSCl、TBDPSCl和氯三乙氧基硅烷组成的组。
8.根据权利要求1至7中任一项所述的方法,其中X为碘或溴,R6为任选地取代的苯基或任选地取代的吡啶基。
9.根据权利要求8所述的方法,其中所述任选地取代的苯基或任选地取代的吡啶基被0至3个独立地选自由C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C6烯氧基、卤素、C3-C8环烷基、-NRpRq(其中Rp和Rq独立地为氢或C1-C4烷基)、-CONRrRs(其中Rr和Rs独立地选自由氢、羟基、受保护的羟基、C1-C4烷基和C1-C4烷基磺酰基)和环状硼基组成的组的取代基取代。
10.根据权利要求1至9中任一项所述的方法,其中
催化剂是:
(a)金属;
(b)通过混合金属及其可能的配体化合物形成;
(c)金属及其配体的络合物;或者
(d)通过将金属及其配体的络合物进一步与该金属可能的配体化合物混合而形成,和
其中所述金属是镍、铬、铁、铜、钯或这些金属的盐,或者是镍、铬、铁、铜、钯或这些金属的盐的溶剂化物。
11.根据权利要求10所述的方法,其中所述金属选自由NiBr2、NiI2、NiCl2、NiF2、Ni(OAc)2、Ni(acac)2、Ni(OTf)2、NiCO3、Ni(NO3)2、NiSO4、(NH4)2Ni(SO4)2、烯丙基(环戊二烯基)镍(II)、双(环戊二烯基)镍和双(环辛二烯基)镍,或者是这些金属的溶剂化物。
12.根据权利要求10或11所述的方法,其中可能的配体化合物选自:
由式B表示的化合物:
其中RBX和RBY独立地选自氢、C1-C4烷基、C1-C4烷氧基、杂环基和C6-C10芳基;
由式C表示的化合物:
其中RCX和RCY独立地选自氢、C1-C4烷基、C6-C10芳基和杂芳基;
由式D表示的化合物:
其中RDX和RDY独立地选自氢、C1-C4烷基、C1-C4卤代烷基和C6-C10芳基;
由式E表示的化合物:
其中REX和REY独立地选自氢、C1-C4烷基、C6-C10芳基C1-C6烷基和C6-C10芳基;
由式F表示的化合物:
其中RFX和RFY独立地选自氢、C1-C4烷基和C6-C10芳基;和
由式G表示的化合物:
其中RGX和RGY独立地选自氢、C1-C4烷基、C6-C10芳基C1-C6烷基和C6-C10芳基。
13.根据权利要求10所述的方法,其中所述催化剂是金属及其配体的络合物,并且所述金属及其配体的络合物选自由四(三苯基膦)镍(0)、双(三苯基膦)二氯化镍(II)、双(三环己基膦)二氯化镍(II)、二溴双(三苯基膦)镍(II)、双[(2-二甲氨基)苯基]胺镍(II)氯化物,顺式-[2,2′-双(二苯基膦)-1,1′-联萘](2-甲基苯基)氯化镍(II)和[1,2-双(二苯基膦)乙烷]二氯化镍(II)组成的组。
14.根据权利要求1至13中任一项所述的方法,其中,所述还原剂选自由锌、锰、铁和镁组成的组。
15.根据权利要求1至14中任一项所述的方法,其中
(a)在溶剂和催化剂的存在下将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、还原剂和R6-X混合,然后与添加剂混合;
(b)在溶剂和催化剂的存在下将还原剂和添加剂混合,然后将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物和R6-X与其混合;或者
(c)将还原剂与溶剂和催化剂混合,然后将式II表示的化合物、该化合物的盐、或该化合物或盐的溶剂化物、R6-X和添加剂与其混合。
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