CN104557757A - Cetp抑制剂 - Google Patents
Cetp抑制剂 Download PDFInfo
- Publication number
- CN104557757A CN104557757A CN201410720701.2A CN201410720701A CN104557757A CN 104557757 A CN104557757 A CN 104557757A CN 201410720701 A CN201410720701 A CN 201410720701A CN 104557757 A CN104557757 A CN 104557757A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- phenyl
- etoac
- propyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 161
- 150000003839 salts Chemical class 0.000 claims abstract description 68
- 229910052799 carbon Inorganic materials 0.000 claims description 29
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 196
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 45
- 125000003118 aryl group Chemical group 0.000 abstract description 24
- 108010023302 HDL Cholesterol Proteins 0.000 abstract description 21
- 125000001424 substituent group Chemical group 0.000 abstract description 13
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 12
- 229910052740 iodine Inorganic materials 0.000 abstract description 12
- 108010028554 LDL Cholesterol Proteins 0.000 abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 7
- 229910052796 boron Inorganic materials 0.000 abstract description 2
- 238000008214 LDL Cholesterol Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 536
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 499
- 235000019439 ethyl acetate Nutrition 0.000 description 266
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 237
- 239000002585 base Substances 0.000 description 209
- 239000000243 solution Substances 0.000 description 207
- 238000006243 chemical reaction Methods 0.000 description 177
- 239000000203 mixture Substances 0.000 description 177
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 128
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 121
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 118
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 238000005160 1H NMR spectroscopy Methods 0.000 description 88
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 87
- 238000000034 method Methods 0.000 description 87
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 85
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 84
- 239000012044 organic layer Substances 0.000 description 78
- 238000005406 washing Methods 0.000 description 74
- 238000003756 stirring Methods 0.000 description 72
- 229910052757 nitrogen Inorganic materials 0.000 description 68
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 66
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 64
- 229910052938 sodium sulfate Inorganic materials 0.000 description 64
- 235000011152 sodium sulphate Nutrition 0.000 description 64
- 229910052736 halogen Inorganic materials 0.000 description 63
- 150000002367 halogens Chemical class 0.000 description 63
- -1 cholesteryl ester Chemical class 0.000 description 62
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- 238000003818 flash chromatography Methods 0.000 description 52
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 238000005481 NMR spectroscopy Methods 0.000 description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 45
- 239000002904 solvent Substances 0.000 description 44
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 42
- 239000007788 liquid Substances 0.000 description 42
- 239000012266 salt solution Substances 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 40
- 235000019441 ethanol Nutrition 0.000 description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 230000008569 process Effects 0.000 description 36
- 239000000284 extract Substances 0.000 description 35
- 238000000605 extraction Methods 0.000 description 35
- 229920006395 saturated elastomer Polymers 0.000 description 34
- 239000007787 solid Substances 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
- 239000000047 product Substances 0.000 description 31
- 238000010790 dilution Methods 0.000 description 30
- 239000012895 dilution Substances 0.000 description 30
- 239000003513 alkali Substances 0.000 description 29
- 125000000217 alkyl group Chemical group 0.000 description 29
- 239000007864 aqueous solution Substances 0.000 description 29
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 28
- 239000003112 inhibitor Substances 0.000 description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 239000011734 sodium Substances 0.000 description 27
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 26
- 239000010410 layer Substances 0.000 description 26
- 229910052760 oxygen Inorganic materials 0.000 description 25
- 239000000377 silicon dioxide Substances 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000004327 boric acid Substances 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 23
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 23
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 23
- 238000004587 chromatography analysis Methods 0.000 description 23
- 125000004093 cyano group Chemical group *C#N 0.000 description 23
- 229910052717 sulfur Inorganic materials 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 150000003851 azoles Chemical class 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 22
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
- 238000001035 drying Methods 0.000 description 21
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 19
- 239000012043 crude product Substances 0.000 description 19
- 238000001819 mass spectrum Methods 0.000 description 19
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 17
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 17
- 238000011282 treatment Methods 0.000 description 17
- 239000000556 agonist Substances 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000002002 slurry Substances 0.000 description 13
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 12
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- 229960001866 silicon dioxide Drugs 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 12
- 239000005557 antagonist Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 229910052739 hydrogen Inorganic materials 0.000 description 11
- 239000011630 iodine Substances 0.000 description 11
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-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
- 150000001414 amino alcohols Chemical class 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 10
- 235000008504 concentrate Nutrition 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 238000007363 ring formation reaction Methods 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 10
- 208000029078 coronary artery disease Diseases 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 9
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 238000003821 enantio-separation Methods 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 230000004060 metabolic process Effects 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 125000004076 pyridyl group Chemical group 0.000 description 8
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- ATLQGZVLWOURFU-UHFFFAOYSA-N 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(CBr)=CC(C(F)(F)F)=C1 ATLQGZVLWOURFU-UHFFFAOYSA-N 0.000 description 7
- 102000015779 HDL Lipoproteins Human genes 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 102400000064 Neuropeptide Y Human genes 0.000 description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- 230000032683 aging Effects 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 150000002460 imidazoles Chemical group 0.000 description 7
- 150000002576 ketones Chemical group 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 102000004895 Lipoproteins Human genes 0.000 description 6
- 108090001030 Lipoproteins Proteins 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 101710151321 Melanostatin Proteins 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 239000003937 drug carrier Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 6
- 235000010755 mineral Nutrition 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052700 potassium Inorganic materials 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- SOZGHDCEWOLLHV-UHFFFAOYSA-N 2-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=CC=C1C#N SOZGHDCEWOLLHV-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 239000007868 Raney catalyst Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- 238000006619 Stille reaction Methods 0.000 description 5
- 238000006069 Suzuki reaction reaction Methods 0.000 description 5
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 5
- QKNDAUTYSODFJV-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;sodium Chemical compound [Na].C[Si](C)(C)N[Si](C)(C)C QKNDAUTYSODFJV-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
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Classifications
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- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
具有结构式I的化合物,包括该化合物的可药用盐在内,是CETP抑制剂,并且可用于升高HDL-胆固醇、降低LDL-胆固醇,以及用于治疗或预防动脉粥样硬化。在式(I)化合物中,B或R2是苯基,其具有邻位芳基、杂环基、苯并杂环基或苯并环烷基取代基,并且在5原环上的一个其它位置具有与环直接相连或者经由-CH2-与环相连的芳基、杂环基、环烷基、苯并杂环基或苯并环烷基取代基。
Description
本申请是申请号为“201110245073.3”,发明名称为“CETP抑制剂”的发明专利申请的分案申请。
发明领域
本发明涉及抑制胆固醇酯转移蛋白(CETP)并因此可用于治疗和预防动脉粥样硬化的一类化合物。
发明背景
动脉粥样硬化及其临床结果、冠心病(CHD)、中风和周围血管疾病对发达国家的健康管理系统造成相当巨大的负担。仅在美国,约有一千三百万患者被诊断患有CHD,每年死于CHD的患者超过50万。另外,预计这项花费在未来的四分之一世纪随着肥胖症和糖尿病流行病的继续蔓延而增加。
很久以来,已经认识到,在哺乳动物中,循环脂蛋白分布的变化与动脉粥样硬化和CHD的危险有关。HMG-CoA还原酶抑制剂,特别是他汀类药物,在临床上成功减少冠状动脉事件是基于减少循环低密度脂蛋白胆固醇(LDL-C),LDL-C水平直接涉及增加的动脉粥样硬化危险。最近,流行病学研究显示,高密度脂蛋白胆固醇(HDL-C)水平和动脉粥样硬化逆相关,得出的结论是低血清HDL-C水平与增加的CHD危险有关。
脂蛋白水平的代谢控制是牵涉多种因素的复杂的和动态的过程。人类的一个重要的代谢控制是胆固醇酯转移蛋白(CETP),一种血浆糖蛋白,其催化胆固醇酯从HDL向含apoB的脂蛋白(特别是向VLDL)的转移(参见Hesler,C.B.等人,(1987)Purification and characterizationof human plasma cholesteryl ester transfer protein.,J.Biol.Chem.262(5),2275-2282))。在生理条件下,净反应是其中CETP从apoB脂蛋白携带甘油三酯到HDL和从HDL运输胆固醇酯到apoB脂蛋白的异源交换(heteroexchange)。
在人类中,CETP在反转胆固醇运输中起作用,通过该反转过程,胆固醇从外周组织返回肝脏。有趣的是,许多动物没有CETP,包括具有高HDL水平和已知对冠心病有抵抗力的那些,例如啮齿类动物(参见Guyard-Dangremont,V.等人,(1998)Phospholipid and cholesteryl estertransfer activities in plasma from 14vertebrate species.Relation toatherogenesis susceptibility,Comp.Biochem.Physiol.B Biochem.Mol.Biol.120(3),517-525)。已经进行了涉及CETP活性的自然变异对于冠心病危险的作用的许多流行病学研究,包括对少数已知的人无效突变的研究(参见Hirano,K.-I.,Yamashita,S.知Matsuzawa,Y.,(2000)Prosand cons of inhibiting cholesteryl ester transfer protein,Curr.Opin.Lipidol.11(6),589-596)。这些研究清楚地表明血浆HDL-C浓度和CETP活性之间的逆相关(参见Inazu,A.等人,(2000)Cholesteryl ester transferprotein and atherosclerosis,Curr.Opin.Lipidol.11(4),389-396),得到的假设是:通过增加HDL-C水平同时降低LDL水平对CETP脂质转移活性的药理学抑制对人类是有益的。
尽管由他汀类药物如辛伐他汀所代表的重大的治疗学进步,他汀类药物在动脉粥样硬化和随后发生的动脉粥样硬化疾病事件的治疗和预防中只实现了大约三分之一的危险降低。目前,只有很少的药理学治疗可用于有利地升高HDL-C的循环水平。某些他汀类药物和一些贝特类药物提供HDL-C的最适度增加。已在临床上有据可查的提供用于升高HDL-C最有效治疗的尼克酸受到患者顺应性问题的困扰,部分是由于副作用如潮红。安全地和有效地升高HDL胆固醇水平的药物可以适应重大的但至今仍未得到满足的医疗需要,其提供可以通过与现有治疗相互补充的机制显著改善循环脂质分布的药理学治疗手段。
有几个制药公司正在研究或者正在临床试验中试验抑制CETP的新类别的化合物。目前没有CETP抑制剂上市。需要新的化合物以便可以发现安全和有效的一种或多种药用化合物。本文描述的新化合物是非常有效的CETP抑制剂。具有类似结构的化合物可参见WO2003/032981。
发明概述
具有式I结构的化合物,包括该化合物的可药用盐,是具有如下所述用途的CETP抑制剂:
在式I的化合物中:
Y选自-C(=O)-和-(CRR1)-;
X选自-O-、-NH-、-N(C1-C5烷基)-和-(CRR6)-;
Z选自-C(=O)-、-S(O)2-和-C(=N-R9)-,其中R9选自H、-CN和-C1-C5烷基,所述烷基任选被1-11个卤素取代;
每个R独立地选自H、-C1-C5烷基和卤素,其中-C1-C5烷基任选被1-11个卤素取代;
B选自A1和A2,其中A1具有以下结构:
R1和R6分别独立地选自H、-C1-C5烷基、卤素和-(C(R)2)nA2,其中-C1-C5烷基任选被1-11个卤素取代;
R2选自H、-C1-C5烷基、卤素、A1和-(C(R)2)nA2,其中-C1-C5烷基任选被1-11个卤素取代;
其中B和R2当中有一个是A1;并且B、R1、R2和R6当中有一个是A2或-(C(R)2)nA2;这样式I化合物包含一个基团A1和一个基团A2;
A3选自:
(a)选自苯基和萘基的芳环;
(b)与任选包含1-2个双键的5-7元非芳族环烷基环稠合的苯基环;
(c)5-6元杂环,所述杂环具有1-4个独立地选自N、S、O和-N(O)-的杂原子,并且任选包含1-3个双键和羰基;其中A3与连接有A3的苯基环的连接点是碳原子;和
(d)包含与5-6元杂环稠合的苯基环的苯并杂环,所述杂环具有1-2个独立地选自O、N和S的杂原子,并任选具有1-2个双键(除了稠合苯基环的双键以外),其中A3与连接有A3的苯基环的连接点是碳原子;
A2选自:
(a)选自苯基和萘基的芳环;
(b)与任选包含1-2个双键的5-7元非芳族环烷基环稠合的苯基环;
(c)5-6元杂环,所述杂环具有1-4个独立地选自N、S、O和-N(O)-的杂原子,并且任选包含1-3个双键和羰基;
(d)包含与5-6元杂环稠合的苯基环的苯并杂环,所述杂环具有1-2个独立地选自O、N和S的杂原子,并任选具有1-2个双键(除了稠合苯基环的双键以外);和
(e)任选具有1-3个双键的-C3-C8环烷基环;
其中A3和A2分别任选被1-5个独立地选自Ra的取代基取代;
每个Ra独立地选自-C1-C6烷基、-C2-C6链烯基、-C2-C8炔基、任选具有1-3个双键的-C3-C8环烷基、-OC1-C6烷基、-OC2-C6链烯基、-OC2-C6炔基、任选具有1-3个双键的-OC3-C8环烷基、-C(=O)C1-C6烷基、-C(=O)C3-C8环烷基、-C(=O)H、-CO2H、-CO2C1-C6烷基、-C(=O)SC1-C6烷基、-OH、-NR3R4、-C(=O)NR3R4、-NR3C(=O)OC1-C6烷基、-NR3C(=O)NR3R4、-S(O)xC1-C6烷基、-S(O)yNR3R4、-NR3S(O)yNR3R4、卤素、-CN、-NO2和5-6元杂环,所述杂环具有1-4个独立地选自N、S和O的杂原子,所述杂环还任选包含羰基并且还任选包含1-3个双键,其中所述与连接有Ra的环的连接点是碳原子,其中所述杂环任选被1-5个独立地选自卤素、-C1-C3烷基和-OC1-C3烷基的取代基取代,其中-C1-C3烷基和-OC1-C3烷基任选被1-7个卤素取代;
其中对于其中Ra选自-C1-C6烷基、-C2-C6链烯基、-C2-C6炔基、任选具有1-3个双键的-C3-C8环烷基、-OC1-C6烷基、-OC2-C6链烯基、-OC2-C6炔基、任选具有1-3个双键的-OC3-C8环烷基、-C(=O)C1-C6烷基、-C(=O)C3-C8环烷基、-CO2C1-C6烷基、-C(=O)SC1-C6烷基、-NR3C(=O)OC1-C6烷基和-S(O)xC1-C6烷基的化合物,Ra任选被1-15个卤素取代,并且还任选被1-3个独立地选自下列的取代基取代:(a)-OH,(b)-CN,(c)-NR3R4,(d)任选具有1-3个双键并且任选被1-15个卤素取代的-C3-C8环烷基,(e)任选被1-9个卤素取代并且还任选被1-2个独立地选自-OC1-C2烷基和苯基的取代基取代的-OC1-C4烷基,(f)任选具有1-3个双键并且任选被1-15个卤素取代的-OC3-C8环烷基,(g)-CO2H,(h)-C(=O)CH3,(i)任选被1-9个卤素取代的-CO2C1-C4烷基,和(j)任选被1-3个独立地选自卤素、-CH3、-CF3、-OCH3和-OCF3的基团取代的苯基;
条件是:当B是A1,X和Y是-CH2-,Z是-C(=O)-,且R2是在4-位具有取代基Ra的苯基,其中Ra是任选如上所述被取代的-OC1-C6烷基时,则在R2上没有其它Ra取代基,其中Ra选自-OH、-OC1-C6烷基、-OC2-C6链烯基、-OC2-C6炔基和任选具有1-3个双键的-OC3-C8环烷基,所有这些基团任选如上所述被取代,
n是0或1;
p是0-4的整数;
x是0、1或2;
y是1或2;
R3和R4分别独立地选自H、-C1-C5烷基、-C(=O)C1-C5烷基和-S(O)yC1-C5烷基,其中在所有情况下,-C1-C5烷基任选被1-11个卤素取代;且R5选自H、-OH、-C1-C5烷基和卤素,其中-C1-C5烷基任选被1-11个卤素取代。
在式I化合物以及随后的化合物中,除非另有说明,烷基、链烯基和炔基可以是直链或支链的。
发明详述
很多本发明化合物具有以下式Ia,或其可药用盐:
很多本发明化合物具有以下式Ib,或其可药用盐:
很多其它本发明化合物具有以下式Ic,或其可药用盐:
其它本发明化合物具有以下式Id,或其可药用盐:
在一组式I化合物中,
每个Ra独立地选自-C1-C6烷基、-C2-C6链烯基、-C2-C6炔基、任选具有1-3个双键的-C3-C8环烷基、-OC1-C6烷基、-OC2-C6链烯基、-OC2-C6炔基、任选具有1-3个双键的-OC3-C8环烷基、-C(=O)C1-C6烷基、-C(=O)C3-C8环烷基、-C(=O)H、-CO2H、-CO2C1-C6烷基、-C(=O)SC1-C6烷基、-NR3R4、-C(=O)NR3R4、-NR3C(=O)OC1-C6烷基、-NR3C(=O)NR3R4、-S(O)xC1-C6烷基、-S(O)yNR3R4、-NR3S(O)yNR3R4、卤素、-CN、-NO2和5-6元杂环,所述杂环具有1-4个独立地选自N、S和O的杂原子,所述杂环还任选包含羰基并且还任选包含1-3个双键,其中所述杂环与连接的环的连接点是碳原子,其中所述杂环任选被1-5个独立地选自卤素、-C1-C3烷基和-OC1-C3烷基的取代基取代,其中-C1-C3烷基和-OC1-C3烷基任选被1-7个卤素取代;
其中对于其中Ra选自-C1-C6烷基、-C2-C6链烯基、-C2-C6炔基、任选具有1-3个双键的-C3-C8环烷基、-OC1-C6烷基、-OC2-C6链烯基、-OC2-C6炔基、任选具有1-3个双键的-OC3-C8环烷基、-C(=O)C1-C6烷基、-C(=O)C3-C8环烷基、-CO2C1-C6烷基、-C(=O)SC1-C6烷基、-NR3C(=O)OC1-C6烷基和-S(O)xC1-C6烷基的化合物,Ra任选被1-15个卤素取代,并且还任选被1-3个独立地选自下列的取代基取代:(a)-OH,(b)-CN,(c)-NR3R4,(d)任选具有1-3个双键并且任选被1-15个卤素取代的-C3-C8环烷基,(e)任选被1-9个卤素取代并且还任选被1-2个独立地选自-OC1-C2烷基的取代基取代的-OC1-C4烷基,(f)任选具有1-3个双键并且任选被1-15个卤素取代的-OC3-C8环烷基,(g)-CO2H,(h)-C(=O)CH3,和(i)任选被1-9个卤素取代的-CO2C1-C4烷基,
条件是:当B是A1,X和Y是-CH2-,Z是-C(=O)-,且R2是在4-位具有取代基Ra的苯基,其中Ra是任选被1-11个卤素取代的-OC1-C6烷基时,则在R2上没有其它Ra取代基,其中Ra选自-OH、-OC1-C6烷基、-OC2-C6链烯基、-OC2-C6炔基和任选具有1-3个双键的-OC3-C8环烷基,所有这些基团任选如上所述被取代。
在式I、Ia、Ib、Ic和Id化合物及其可药用盐中,
A3是苯基,所述苯基任选被1-4个取代基Ra取代,其中Ra独立地选自-C1-C5烷基、-OC1-C3烷基、-CO2C1-C3烷基、-CO2H、卤素、-NR3R4、-C(=O)C1-C3烷基、-C(=O)H、-C(=O)NR3R4、-SC1-C3烷基、-C2-C3链烯基、-CN、-NO2和1,2,4-二唑基,其中出现的所有-C1-C3烷基和-C1-C5烷基任选被1-6个独立地选自1-5个卤素和一个-OH基团的取代基取代;且-C2-C3链烯基任选被1-3个卤素取代。
在式I、Ia、Ib、Ic和Id化合物及其可药用盐中,
A2选自苯基、环己基和5-6元杂环,所述杂环具有1-2个独立地选自N、S、O和-N(O)-的杂原子,并且任选包含1-3个双键,其中A2任选被1-2个独立地选自下列的取代基取代:-C1-C4烷基、-OC1-C3烷基、-NO2、-CN、-S(O)xC1-C3烷基、-NHS(O)2C1-C3烷基、-NR3R4、-NR3C(=O)R4、-C2-C3链烯基、-C(=O)NR3R4、卤素和吡啶基,其中在所有情况下,C1-C3烷基、C1-C4烷基和C2-C3链烯基任选被1-3个卤素取代,条件是,对于式Ia化合物,当B是A1,X和Y是-CH2-,Z是-C(=O)-,且R2是苯基时,则在R2上的选自任选被取代的-OC1-C3烷基的Ra基团的数目是0或1。
在式I、Ia、Ib、Ic和Id化合物及其可药用盐中,R3和R4分别独立地选自H和-C1-C3烷基。
在式I、Ia、Ib、Ic和Id化合物及其可药用盐中,p是0-2。
在一亚组式I化合物,包括其可药用盐中,
A1是
其中R7和R8分别独立地选自H、卤素、-NR3R4、-C1-C3烷基、-OC1-C3烷基、-CN、-NO2和吡啶基,其中在所有情况下,C1-C3烷基任选被1-3个卤素取代。
在一亚组式I化合物中,A2选自苯基、吡啶基和环己基,其中A2任选被1-2个独立地选自-C1-C4烷基、-OC1-C4烷基、-NO2、-CN和卤素的取代基取代,其中在所有使用中的C1-C4烷基任选被1-3个卤素取代,条件是,对于式I化合物,当B是A1,X和Y是-CH2-,Z是-C(=O)-,且R2是苯基时,则在R2上的选自任选被1-3个卤素取代的-OC1-C4烷基的Ra基团的数目是0或1。
在其它亚组中,A2任选被1-2个独立地选自卤素、-C1-C4烷基和-CN的取代基取代,其中-C1-C4烷基任选被1-3个卤素取代。
在如上所述的很多本发明实施方案,包括其可药用盐中,
A1是
其中R7选自H、卤素、-NR3R4、-C1-C3烷基、-OC1-C3烷基、-CN、-NO2和吡啶基,其中在所有情况下,C1-C3烷基任选被1-3个卤素取代;且
R8选自H、卤素、-CH3、-CF3、-OCH3和-OCF3。
在本发明的很多优选实施方案中,A3是苯基,所述苯基被1-3个独立地选自下列的取代基取代:C1-C4烷基、OC1-C4烷基、-CN、Cl、F、-C(=O)CH3、-CH=CH2、-CO2H、-CO2CH3、-S-CH3、-S(O)CH3、-S(O)2CH3和-C(=O)NR3R4,其中C1-C4烷基和-OC1-C4烷基任选被1-5个F取代基取代,并且还任选被一个基团-OH取代。
在其它实施方案中,A3是苯基,所述苯基任选被1-3个独立地选自下列的取代基取代:Cl、F、-C1-C4烷基和-OC1-C4烷基,其中-C1-C4烷基和-OC1-C4烷基任选被1-5个F取代。
Y的优选值是-(CRR1)-。
在某些实施方案中,R和R6分别独立地选自H和-C1-C5烷基,其中-C1-C5烷基任选被1-11个卤素取代。在这些实施方案的组中,R1选自H、-C1-C5烷基和-(C(R)2)nA2,其中-C1-C5烷基任选被1-11个卤素取代。在这些方案中,B和R2当中有一个是A1;并且B、R1和R2当中有一个是A2或-(C(R)2)nA2;这样式I化合物包含一个基团A1和一个基团A2。
在化合物的亚组中,A3选自:
(a)选自苯基和萘基的芳环;
(b)5-6元杂环,所述杂环具有1-4个独立地选自N、S、O和-N(O)-的杂原子,并且任选包含1-3个双键和羰基,其中A3与连接有A3的苯基环的连接点是碳原子;和
(c)包含与5-6元杂环稠合的苯基环的苯并杂环,所述杂环具有1-2个独立地选自O、N和-S(O)x-的杂原子,并任选具有1-2个双键,其中A3与连接有A3的苯基环的连接点是碳原子。
在化合物的亚组中,A2选自:
(a)选自苯基和萘基的芳环;
(b)5-6元杂环,所述杂环具有1-4个独立地选自N、S、O和-N(O)-的杂原子,并且任选包含1-3个双键和羰基;
(c)包含与5-6元杂环稠合的苯基环的苯并杂环,所述杂环具有1-2个独立地选自O、N和S的杂原子,并任选具有1-2个双键;和
(d)任选具有1-3个双键的-C3-C8环烷基环。
在上面A3和A2的亚组中,A3和A2任选被1-4个独立地选自Ra的取代基取代。
Ra的亚组包括独立地选自下列的取代基:-C1-C6烷基、-C2-C6链烯基、任选具有1-3个双键的-C3-C8环烷基、-OC1-C6烷基、-C(=O)C1-C6烷基、-C(=O)H、-CO2H、-CO2C1-C6烷基、-OH、-NR3R4、-NRaC(=O)OC1-C6烷基、-S(O)xC1-C6烷基、卤素、-CN、-NO2和5-6元杂环,所述杂环具有1-4个独立地选自N、S和O的杂原子,所述杂环还任选包含羰基并且还任选包含1-3个双键,其中所述杂环与连接有Ra的环的连接点是碳原子,其中所述杂环任选被1-5个独立地选自卤素、-C1-C3烷基和-OC1-C3烷基的取代基取代,其中-C1-C3烷基和-OC1-C3烷基任选被1-7个卤素取代;
其中对于其中Ra独立地选自-C1-C6烷基、-C2-C6链烯基、任选具有1-3个双键的-C3-C8环烷基、-OC1-C6烷基、-C(=O)C1-C6烷基、-CO2C1-C6烷基、-NRaC(=O)OC1-C6烷基和-S(O)xC1-C6烷基的化合物,Ra任选被1-15个卤素取代,并且还任选被1个选自下列的取代基取代:(a)-OH,(b)-NR3R4,(c)任选被1-9个卤素取代并且还任选被1-2个独立地选自-OC1-C2烷基和苯基的取代基取代的-OC1-C4烷基,和(d)苯基,所述苯基任选被1-3个独立地选自卤素、-CH3、-CF3、-OCH3和-OCF3的基团取代;
条件是:当B是A1,X和Y是-CH2-,Z是-C(=O)-,且R2是在4-位具有取代基Ra的苯基,其中Ra是任选如上所述被取代的-OC1-C6烷基时,则在R2上没有其它Ra取代基,其中Ra选自-OH或任选如上所述被取代的-OC1-C6烷基。
在化合物的亚组中,n是0-2的整数。在其它亚组中,n是1或2。
在独立的亚组中,R3和R4分别独立地选自H和-C1-C5烷基,其中在所有情况下,-C1-C5烷基任选被1-11个卤素取代。在其它独立的亚组中,R3和R4分别独立地选自H和-C1-C3烷基,或者选自H和-C1-C2烷基。
在式I的亚组中,Z选自-C(=O)-、-S(O)2-和-C(=N-R9)-,其中R9选自H、-CN和CH3。Z的优选值是-C(=O)-。
在独立的亚组中,R5选自H、-OH和-C1-C5烷基,其中-C1-C5烷基任选被1-11个卤素取代。在其它亚组中,R5选自H和-C1-C3烷基,或者选自H和-C1-C2烷基。
在某些亚组中,每个R独立地选自H和C1-C3烷基。在其它组中,R选自H和C1-C2烷基。在其它组中R是H或CH3。
在某些亚组中,R6选自H和-C1-C3烷基,其中C1-C3烷基任选被1-5个卤素取代。在其它亚组中,R6选自H和C1-C2烷基。在其它组中,R6是H或CH3。
在某些亚组中,R1选自H、-C1-C3烷基和-(C(R)2)nA2,其中-C1-C3烷基任选被1-5个卤素取代;并且R2选自H、-C1-C3烷基、A1和-(C(R)2)nA2,其中-C1-C3烷基任选被1-5个卤素取代,且R6是H或烷基。在这些方案中,B和R2当中有一个是A1;并且B、R1和R2当中有一个是A2或-(C(R)2)nA2;这样式I化合物包含一个基团A1和一个基团A2。
在化合物的亚组中,A3选自:
(a)苯基;
(b)5-6元杂环,所述杂环具有1-2个独立地选自N、S、O和-N(O)-的杂原子,其中A3与连接有A3的苯基环的连接点是碳原子;和
(c)包含与5元芳族杂环稠合的苯基环的苯并杂环,所述杂环具有1-2个独立地选自O、N和-S(O)x-的杂原子,其中A3与连接有A3的苯基环的连接点是碳原子。
在亚组中,A2选自:
(a)苯基;
(b)5-6元杂环,所述杂环具有1-4个独立地选自N、S、O和-N(O)-的杂原子,并且还任选包含1-3个双键;
(c)包含与5元杂环稠合的苯基环的苯并杂环,所述杂环具有1-2个独立地选自O、N和S的杂原子;和
(d)-C5-C6环烷基环。
在很多化合物中,A3和A2分别任选被1-4个独立地选自Ra的取代基取代。在各个亚组中,A3任选被1-3个取代基Ra取代,或者被2-3个取代基Ra取代。在各个亚组中,A2任选被1-3个取代基Ra取代,或者被1-2个取代基Ra取代。R2经常被2个取代基Ra取代,或者被2-3个取代基Ra取代。
在很多化合物中,A3选自苯基、噻吩基、咪唑基、吡咯基、吡唑基、吡啶基、N-氧化-吡啶基、噻唑基、哒嗪基、嘧啶基、吡嗪基、苯并噻吩基、苯并噻吩基-S-氧化物和苯并噻吩基-S-二氧化物。
在很多化合物中,A2选自苯基、噻吩基、咪唑基、噻唑基、吡咯基、吡唑基、1,2,4-三唑基、四唑基、苯并二氧杂环戊烯基、吡啶基、N-氧化-吡啶基、哒嗪基、嘧啶基、吡嗪基、环戊基、环己基和四氢吡喃基。
在某些亚组中,Ra选自-C1-C4烷基、-C2-C4链烯基、环丙基、-OC1-C2烷基、-C(=O)C1-C2烷基、-C(=O)H,-CO2C1-C4烷基、-OH、-NR3R4、-NR3C(=O)OC1-C4烷基、-S(O)xC1-C2烷基、卤素、-CN、-NO2和5-6元杂环,所述杂环具有1-2个独立地选自N、S和O的杂原子,其中所述杂环与连接有Ra的环的连接点是碳原子,其中所述杂环任选被1-5个独立地选自卤素的取代基取代;
其中对于其中Ra选自-C1-C4烷基、-C2-C4链烯基、-OC1-C2烷基、-C(=O)C1-C2烷基、-CO2C1-C4烷基、-NR3C(=O)OC1-C4烷基和-S(O)xC1-C2烷基的化合物,Ra的烷基任选被1-5个卤素取代,并且任选被一个选自下列的取代基取代:(a)-OH,(b)-NR3R4,(C)任选被1-3个氟原子取代,并且还任选被一个苯基取代的-OCH3,和(d)苯基,所述苯基任选被1-3个独立地选自卤素、-CH3、-CF3、-OCH3和-OCF3的基团取代;
条件是:当B是A1,X和Y是-CH2-,Z是-C(=O)-,且R2是在4-位具有取代基Ra的苯基,其中Ra是任选如上所述被取代的-OC1-C2烷基时,则在R2上没有其它Ra取代基,其中Ra选自-OH或任选如上所述被取代的-OC1-C2烷基。
在优选的组中,X选自-O-、-NH-和-N(C1-C3烷基)-。X还可以选自-O-、-NH-和-N(CH3)。在高度优选的组中,X是O。
在很多组中,Z是-C(=O)-。
一个优选亚组的化合物具有式Ie,包括其可药用盐
在式Ie化合物中,X选自-O-、-NH-、-N(C1-C5烷基)-和-(CH2)-;
Z选自-C(=O)-、-S(O)2-和-C(=N-R9)-,其中R9选自H、-CN和任选被1-11个卤素取代的C1-C5烷基。
每个R独立地选自H和-CH3;
B选自A1和A2,其中A1具有以下结构:
R1选自H、-C1-C5烷基和-(C(R)2)nA2,其中-C1-C5烷基任选被1-11个卤素取代;
R2选自H、-C1-C5烷基、A1和-(C(R)2)nA2,其中-C1-C5烷基任选被1-11个卤素取代;
其中B和R2当中有一个是A1;并且B、R1和R2当中有一个是A2或-(C(R)2)nA2;这样式I化合物包含一个基团A1和一个基团A2;
A2选自苯基、环己基和吡啶基,其中A2任选被1-2个独立地选自卤素、-C1-C4烷基和-CN的取代基取代,其中-C1-C4烷基任选被1-3个卤素取代;
每个Ra独立地选自-C1-C3烷基和卤素,其中-C1-C3烷基任选被1-3个卤素取代;
每个Rb独立地选自Cl、F、-C1-C4烷基和-OC1-C4烷基,其中-C1-C4烷基和-OC1-C4烷基任选被1-5个F取代;
n是0或1;
p是0-2的整数;且
q是0-3的整数。
具有式Ie的化合物的组包括式If、Ig和Ih化合物及其可药用盐:
在式If、Ig和Ih化合物中,R1和R2分别独立地选自H和-C1-C5烷基,其中-C1-C5烷基任选被1-11个卤素取代。其它基团如上所定义。
在上述化合物的亚组中,A2可以选自苯基、环己基和吡啶基,其中A2任选被1-2个独立地选自卤素、-CH3、-CF3和-CN的取代基取代。
在上述化合物的亚组中,每个Ra独立地选自-CF3和Cl。
在上述化合物的亚组中,每个Rb独立地选自-C1-C3烷基、-OCH3和F。
在上述化合物的亚组中,R1和R2分别独立地选自H和-C1-C2烷基。
在上述化合物的亚组中,X选自-O-、NH-、-N(CH3)-和-CH2-。
在上述化合物的亚组中,Z选自-C(=O)-、-S(O)2-和-C(=N-CN)-。
在上述化合物的亚组中,p是1。
在上述化合物的亚组中,q是2或3。
上面定义的化合物的亚组包括具有式Ii的化合物及其可药用盐:
在式Ii中,R7选自Cl和-CF3;
Rc选自卤素、-CH3、-CF3和-CN;并且t是0-2的整数。其它基团如上所定义。
上面定义的化合物的亚组包括具有式Ij的化合物及其可药用盐:
在式Ij中,R7选自Cl和-CF3;
Rc选自卤素、-CH3、-CF3和-CN;并且
t是0-2的整数。其它基团如上所定义。
定义
“Ac”为乙酰基,即CH3C(=O)-。
除非另有定义,“烷基”是指可为直链或支链或其组合的饱和碳链。具有前缀“烷”的其它基团如烷氧基和烷酰基,也可为直链或支链或其组合的碳链,除非碳链另有定义。烷基的例子包括甲基、乙基、丙基、异丙基、丁基、仲丁基和叔丁基、戊基、己基、庚基、辛基、壬基等。
“亚烷基”是指具有双官能度而非单官能度的烷基。例如,甲基为烷基,而亚甲基(-CH2-)为相应的亚烷基。
“烯基”是指包含至少一个碳-碳双键的碳链,并且其可为直链或支链或其组合。烯基的例子包括乙烯基、烯丙基、异丙烯基、戊烯基、己烯基、庚烯基、1-丙烯基、2-丁烯基、2-甲基-2-丁烯基等。
“炔基”是指包含至少一个碳-碳三键的碳链,并且其可为直链或支链或其组合。炔基的例子包括乙炔基、炔丙基、3-甲基-1-戊炔基、2-庚炔基等。
除非另有说明,“环烷基”是指具有3到8个碳原子的饱和碳环。该术语还包括稠合于芳基的环烷基环。环烷基的例子包括环丙基、环戊基、环己基、环庚基等。“环烯基”是指具有一个或多个双键的非芳香碳环。
在用于描述结构中的取代基或基团时,“芳基”(和“亚芳基”)是指单环或双环的化合物,其中所述环为芳香环并且只包含成环碳原子。术语“芳基”还可指稠合于环烷基或杂环的芳基。优选的“芳基”为苯基和萘基。一般,苯基为最优选的芳基。
“EDC”是1-乙基-3-(3-二甲基氨基丙基)碳二亚胺。
除非另有说明,“杂环基”、“杂环”和“杂环的”是指在环中包含1-4个独立地选自N、S和O的杂原子的完全饱和或部分饱和的或芳香的5-6元环。
“苯并杂环”表示稠合于具有1-2个各自为O、N或S的杂原子的5-6元杂环的苯基环,其中杂环可为饱和的或不饱和的。其实例包括吲哚、苯并呋喃、2,3-二氢苯并呋喃和喹啉。
“DIPEA”是二异丙基乙胺。
“卤素”包括氟、氯、溴和碘。
“HOBT”是1-羟基苯并三唑。
“IPAC”是乙酸异丙酯。
“Me”表示甲基。
“Weinreb胺”是N,O-二甲基羟基胺。
药物组合物中出现的术语“组合物”意在包括含活性成分、构成载体的惰性成分的产物,以及从任何两种或多种成分的组合、络合或缔合直接或间接得到的任何产物,或从一种或多种成分的离解直接或间接得到的任何产物,或从一种或多种成分的其它反应类型或其它相互作用类型直接或间接得到的任何产物。因此,本发明的药物组合物包含通过将本发明的化合物和可药用载体混合制得的任何组合物。
取代基“四唑”是指2H-四唑-5-基取代基及其互变异构体。
光学异构体-非对映体-几何异构体-互变异构体
式I化合物可包含一个或多个不对称中心,因此可作为外消旋物、外消旋混合物、单独的对映体、非对映体的混合物和单独的非对映体存在。当显示具有立体化学构型的结构时,也单独和集合地包括其它立体化学结构,例如对映体、非对映体(当存在非对映体),以及对映体和/或非对映体的混合物,包括外消旋混合物。
本文中所述的一些化合物可以包含烯属双键,除非另外说明,其意在包括E和Z两种几何异构体。
本文中所述的一些化合物可以作为互变异构体存在。例子是酮及其烯醇形式,称为酮-烯醇互变异构体。单独的互变异构体及其混合物都被包括在式I化合物内。
具有一个或多个不对称中心的式I的化合物可通过本领域公知的方法分离为非对映异构体、对映体等。
或者,具有手性中心的对映体和其它化合物可通过立体有择合成使用具有已知构型的光学纯起始原料和/或试剂进行合成。
本文中的一些联苯和联芳化合物在NMR光谱中观察到为阻转异构体(旋转异构体)的混合物。单独的阻转异构体及其混合物都被包括在本发明的化合物的范围内。
盐
术语“可药用盐”是指从可药用的无毒的碱或酸制备的盐,包括从无机碱或有机碱和无机酸或有机酸制备的盐。得自无机碱的盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(II)、钾、钠、锌的盐等。特别优选铵、钙、镁、钾和钠的盐。固体形式的盐可以多于一种的晶体结构存在,并且也可为水合物的形式。得自可药用的无毒有机碱的盐包括伯胺、仲胺、叔胺、取代胺(包括天然存在的取代胺)、环胺和碱离子交换树脂,如精氨酸、甜菜碱、咖啡因、胆碱、N,N’-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡糖、组氨酸、哈胺、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺和氨基丁三醇等的盐等。
当本发明的化合物为碱性时,其盐可从可药用的无毒的酸如无机酸和有机酸制备。这种酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、双羟萘酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。特别优选柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸和酒石酸。
应该理解,如本文中使用的,式I的化合物还意在包括可药用盐。代谢物-前药
具有治疗活性的代谢物,其中代谢物本身落入本发明的范围内,也是本发明的化合物。在对患者给药时或对患者给药之后转化为本发明化合物的化合物,即前药也是本发明的化合物。
用途
本发明的化合物为CETP的强力抑制剂。因此它们可用于治疗由CETP抑制剂治疗的疾病和病症。
本发明的一个方面提供通过对需要治疗的患者给药治疗有效量的本发明的化合物治疗可通过CETP的抑制治疗或预防的疾病或病症或者降低发展为可通过CETP的抑制治疗或预防的疾病或病症的危险的方法。患者为人或哺乳动物,最经常为人。“治疗有效量”是在治疗特定疾病时有效获得所需临床结果的化合物的量。
可使用本发明的化合物治疗的疾病或病症和可通过使用本发明化合物进行治疗而降低发展为疾病的危险的疾病包括:动脉粥样硬化、周围血管疾病、异常脂血症、高β脂蛋白血症、高α脂蛋白血症、高胆固醇血症、高甘油三酯血症、家族性高胆固醇血症、心血管疾病、绞痛、局部缺血、心肌缺血、中风、心肌梗死、再灌注损伤、血管成形术后再狭窄、高血压、糖尿病性血管并发症、肥胖症、内毒素血症和代谢。
预计本发明的化合物在升高HDL-C和/或增加HDL-C与LDL-C的比例方面特别有效。HDL-C和LDL-C的这些变化对于治疗动脉粥样硬化、减少或反转动脉粥样硬化发展、降低发展为动脉粥样硬化的危险或预防动脉粥样硬化可是有利的。
给药和剂量范围
可采用任何适当的给药途径,用于对哺乳动物(特别是人)提供有效剂量的本发明的化合物。例如,可采用口服给药、直肠给药、局部给药、非肠道给药、经眼给药、经肺给药、经鼻给药等。剂型包括片剂、锭剂、分散体、悬浮液、溶液、胶囊、霜剂、膏剂、气雾剂等。优选地,式I化合物经口服给药。
采用的活性成分的有效剂量可根据使用的特定化合物、给药方式、治疗的状况和治疗状况的严重程度而定。这种剂量可由本领域技术人员容易地确定。
当治疗式I化合物适用的疾病时,通常在将本发明的化合物以每千克动物或人约0.01毫克到约100毫克的日剂量给药时得到令人满意的结果,优选作为单次日剂量或以每天分为约二到六次的剂量给药,或采用控释剂型。在70kg成人的情况中,总的日剂量通常为约0.5毫克到约500毫克。对于特别有效的化合物,成年人的剂量可低至0.1mg。剂量给药方案可在该范围之内、甚至在该范围之外进行调整,以提供最佳的治疗反应。
口服给药通常使用片剂进行。片剂中剂量的例子为0.5mg、1mg、2mg、5mg、10mg、25mg、50mg、100mg、250mg和500mg。其它口服剂型也可具有相同的剂量(如胶囊)。
药物组合物
本发明的另一个方面提供包括式I的化合物和可药用载体的药物组合物。本发明的药物组合物包括作为活性成分的式I的化合物或可药用盐,以及可药用载体和任选的其它治疗成分。术语“可药用盐”是指从可药用的无毒的碱或酸制备的盐,包括从无机碱或无机酸和有机碱或有机酸制备的盐。如果给药前药,则药物组合物也可包括前药,或包括其可药用盐。药物组合物也可基本上由式I的化合物和可药用载体组成。
组合物包括适合于口服给药、直肠给药、局部给药、非肠道给药(包括皮下、肌肉内和静脉内)、经眼给药(眼用)、经肺给药(经鼻或口颊吸入)或经鼻给药的组合物,但是在任何给定情况中最适当的途径将根据治疗状况的性质和严重程度和活性成分的性质而定。它们可方便地以单位剂型形式存在并且通过药学领域公知的任何方法制备。
在实际应用中,可将作为活性成分的式I化合物根据常规药学配制技术与药用载体均质混合而进行组合。载体可为多种形式,根据给药所需的制剂形式而定,如,口服或非肠道(包括静脉内)。在制备口服剂型的组合物时,可采用任何常用的药学介质,例如,在口服液体制剂如悬浮液、酏剂和溶液的情况中使用水、二醇、油类、醇、调味剂、防腐剂、着色剂等;或在口服固体制剂如粉末、硬胶囊和软胶囊及片剂的情况中使用载体如淀粉、糖、微晶纤维素、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等,固体口服制剂比液体制剂更优选。
因为片剂和胶囊易于给药,片剂和胶囊代表最有利的口服剂量单位形式,在这种情况中,显然使用固体药物载体。如果期望,片剂可通过标准的含水或非水技术进行包衣。这种组合物和制剂应包含至少0.1%的活性化合物。当然,这些组合物中的活性化合物的百分比可以变化并且可以方便地占剂量单位重量的约2%到约60%。这种治疗有用的组合物中活性化合物的量为获得有效剂量的量。活性化合物也可作为例如液体滴剂或喷雾剂经鼻给药。
片剂、丸剂、胶囊等还可以包含粘合剂,如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂例如磷酸二钙;崩解剂例如玉米淀粉、马铃薯淀粉、海藻酸;润滑剂例如硬脂酸镁;和甜味剂例如蔗糖、乳糖或糖精。当剂量单位形式为胶囊时,其除上述类型材料之外还可以包含液体载体,如脂肪油。
可存在多种其它材料作为包衣或用于改变剂量单位的物理外形。例如,片剂可用虫胶、糖或其两者进行包衣。糖浆剂或酏剂除活性成分之外还可以包含作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料和调味剂如樱桃调味剂或橙调味剂。
式I化合物也可经非肠道给药。可以与表面活性剂如羟丙基纤维素适当地混合在水中制备这些活性化合物的溶液或悬浮液。也可在油类中的甘油、液体聚乙二醇及其混合物中制备分散液。在普通的储存和使用条件下,这些制剂包含防腐剂,以防止微生物的生长。
适于注射应用的药物剂型包括无菌水溶液或分散液以及用于无菌注射溶液和分散液的临时配制的无菌粉末。在所有情况中,剂型必须是无菌的,并且必须具有达到可容易注射程度的流动性。其必须在生产和储存条件下是稳定的并且必须进行防腐以防微生物如细菌和真菌的污染。载体可为溶剂或分散介质,其包含例如水、乙醇、多元醇(如甘油、丙二醇和液体聚乙二醇)、其适当的混合物,以及植物油。
联合治疗
本发明的化合物(如式I和Ia-Ij)可与也可用于治疗或改善式I化合物适用的疾病或病症的其它药物组合使用。这些其它药物可通过其通常使用的途径和量与结构式I的化合物同时或顺序地给药。当式I的化合物与一种或多种其它药物同时使用时,优选单位剂型形式的药物组合物,其包含所述的其它药物和结构式I的化合物。然而,联合治疗还包括将式I的化合物和一种或多种其它药物按照不同的时间表给药的治疗。
当使用口服制剂时,可将药物组合为单一的组合片剂或其它口服剂型形式,或者将药物作为单独的片剂或其它口服剂型包装在一起。还考虑了在与一种或多种其它活性成分组合使用时,本发明的化合物和其它活性成分可比单独使用每一种时以更低的剂量使用。因此,本发明的药物组合物包括这样的组合物,即,其除了结构式I的化合物之外还包含一种或多种其它活性成分。
可以以与本发明的化合物(如式I)组合的形式给药、和分别地给药或以上述药物组合物的形式给药的其它活性成分的例子包括但不限于:改善患者脂质分布的其它化合物,例如(i)HMG-CoA还原酶抑制剂(其通常为他汀类药物,包括洛伐他汀、辛伐他汀、瑞舒伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、立伐他汀、伊伐他汀、匹伐他汀和其它他汀类药物),(ii)胆汁酸螯合剂(考来烯胺、考来替泊和交联右旋糖酐的二烷基氨基烷基衍生物、),(iii)尼克酸和相关化合物,例如烟醇、烟酰胺和烟酸或其盐,(iv)PPARα激动剂,例如吉非贝齐和非诺贝酸衍生物(贝特类),包括氯贝丁酯、非诺贝特、苯扎贝特、环丙贝特和依托贝特,(v)胆固醇吸收抑制剂,例如stanol酯、β-谷甾醇、甾醇糖苷例如替奎胺;和氮杂环丁烷酮类例如依泽替米贝,(vi)酰基CoA:胆固醇酰基转移酶(ACAT)抑制剂如阿伐麦布和亚油甲苄胺,并包括选择性ACAT-I和ACAT-2抑制剂和双重抑制剂;(vii)酚类抗氧化剂,例如普罗布考,(viii)微粒体甘油三酯转移蛋白(MTP)/ApoB分泌抑制剂,(ix)抗氧化剂维生素,例如维生素C和E以及β-胡萝卜素,(x)拟甲状腺药物,(xi)LDL(低密度脂蛋白)受体诱导剂,(xii)血小板聚集抑制剂,例如糖蛋白IIb/IIIa血纤蛋白原受体拮抗剂和阿司匹林,(xiii)维生素B12(还称为氰钴胺),(xiv)叶酸或其可药用盐或酯,例如钠盐和甲基葡糖胺盐,(xv)FXR和LXR配体,包括抑制剂和激动剂,(xvi)提高ABCA1基因表达的活性剂,和(xvii)回肠胆汁酸载体。
可与本发明化合物一起使用用于改善患者的脂质分布(即升高HDL-C和降低LDL-C)的治疗化合物的优选类别包括他汀类药物和胆固醇吸收抑制剂中的一种或两种。特别优选本发明化合物与辛伐他汀、依泽替米贝或与辛伐他汀和依泽替米贝二者的组合。还优选的是,本发明化合物与非辛伐他汀的他汀类药物,例如洛伐他汀、瑞舒伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、立伐他汀、伊伐他汀和ZD-4522的组合。
最后,本发明化合物可与用于治疗其它疾病如糖尿病、高血压和肥胖症的化合物以及其它抗动脉粥样硬化的化合物一起使用。这样的组合可用于治疗一种或多种疾病例如糖尿病、肥胖、动脉粥样硬化和异常脂血症,或者与代谢综合征有关的一种以上的疾病。这样的组合可以在治疗这些疾病中表现出协同作用,能够给予降低剂量的活性组分,例如剂量可以是对于单独使用时是治疗剂量以下的剂量。
可用于与本发明化合物联合给药的其它活性成分的实例包括但不限于主要抗糖尿病化合物,包括:
(a)PPARγ激动剂和部分激动剂,包括格列酮类和非格列酮类(如吡格列酮、恩格列酮、MCC-555、罗格列酮、balaglitazone、netoglitazone、T-131、LY-300512和LY-818);
(b)双胍类如二甲双胍和苯乙双胍;
(c)蛋白质酪氨酸磷酸酶-1B(PTP-1B)抑制剂;
(d)二肽基肽酶IV(DP-IV)抑制剂,包括vildagliptin、sitagliptin和saxagliptin;
(e)胰岛素或胰岛素模拟物,例如赖脯胰岛素、甘精胰岛素、胰岛素锌混悬液和吸入胰岛素制剂;
(f)磺酰脲类,例如甲苯磺丁脲、格列吡嗪、格列美脲、醋磺己脲、chlorpropamide、格列本脲或相关物质;
(g)α-葡糖苷酶抑制剂(例如阿卡波糖;adiposine;卡格列波糖;乙格列酯;米格列醇;伏格列波糖;普拉米星-Q;和salbostatin);
(h)PPARα/γ双重激动剂,例如muraglitazar、tesaglitazar、farglitazar和naveglitazar;
(i)PPARδ激动剂,例如GW501516和在WO97/28149中公开的那些;
(j)胰高血糖素受体拮抗剂;
(k)GLP-1;GLP-1衍生物;GLP-1类似物,例如exendins如exenatide(Byetta);和非肽基GLP-1受体激动剂;
(l)GIP-1;和
(m)非磺酰脲类胰岛素促分泌剂,例如氯茴苯酸类(例如那格列奈和rapeglinide)。
可以与本发明联合使用的其它活性组分还包括抗肥胖化合物,包括5-HT(血清素)抑制剂,神经肽Y5(NPY5)抑制剂,黑素皮质激素4受体(Mc4r)激动剂、大麻素受体1(CB-I)拮抗剂/反转激动剂,和β3肾上腺素能受体激动剂。后面在该节中更详细地描述它们。
这些其它活性组分还包括用于治疗炎性病症的活性组分,例如阿司匹林、非甾类抗炎药物、糖皮质激素、水杨酰偶氮磺胺吡啶和选择性环加氧酶-2(COX-2)抑制剂,包括艾托考昔、塞来考昔、罗非考昔和Bextra。
抗高血压化合物也可以与本发明化合物一起有利地用于联合治疗。可与本发明化合物联合使用的抗高血压化合物的实例包括(1)血管紧张素II激动剂,例如氯沙坦;(2)血管紧张素转化酶抑制剂(ACE抑制剂),例如依那普利和卡托普利;(3)钙通道阻断剂例如硝苯地平和地尔硫牙;和(4)内皮素拮抗剂。
可与本发明化合物联合给药的抗肥胖化合物包括:(1)生长激素促分泌剂和生长激素促分泌剂受体激动剂/拮抗剂,例如NN703、hexarelin和MK-0677;(2)蛋白酪氨酸磷酸酶-1B(PTP-IB)抑制剂;(3)大麻素受体配体,例如大麻素CB1受体拮抗剂或反转激动剂,例如利莫那班(Sanofi Synthelabo)、AMT-251和SR-14778以及SR 141716A(SanofiSynthelabo)、SLV-319(Solvay)、BAY 65-2520(Bayer);(4)抗肥胖血清素能剂(serotonergic agent),例如芬氟拉明、右芬氟拉明、芬特明和西布曲明;(5)β3-肾上腺受体激动剂,例如AD9677/TAK677(Dainippon/Takeda)、CL-316,243、SB 418790、BRL-37344、1-796568、BMS-196085、BRL-35135A、CGP12177A、BTA-243、曲卡君、ZenecaD7114和SR 59119A;(6)胰腺脂酶抑制剂,例如orlistatTriton WR1339、RHC80267、lipstatin、tetrahydrolipstatin、teasaponin和二乙基伞形基磷酸酯(diethylumbelliferyl phosphate);(7)神经肽Y1拮抗剂,例如BIBP3226、J-115814、BIBO 3304、LY-357897、CP-671906和GI-264879A;(8)神经肽Y5拮抗剂,例如GW-569180A、GW-594884A、GW-587081X、GW-548118X、FR226928、FR 240662、FR252384、1229U91、GI-264879A、CGP71683A、LY-377897、PD-160170、SR-120562A、SR-120819A和JCF-104;(9)黑素浓集激素(MCH)受体拮抗剂;10)黑素浓集激素1受体(MCH1R)拮抗剂,例如T-226296(Takeda);(11)黑素浓集激素2受体(MCH2R)激动剂/拮抗剂;(12)orexin-1受体拮抗剂,例如SB-334867-A;(13)黑素皮质激素激动剂,例如Melanotan II;(14)其它Mc4r(黑素皮质激素4受体)激动剂,例如CHIR86036(Chiron)、ME-10142和ME-10145(Melacure)、CHIR86036(Chiron);PT-141和PT-14(Palatin);(15)5HT-2激动剂;(16)5HT2C(血清素受体2C)激动剂,例如BVT933、DPCA37215、WAY161503和R-1065;(17)galanin拮抗剂;(18)CCK激动剂;(19)CCK-A(缩胆囊肽-A)激动剂,例如AR-R 15849、GI 181771、JMV-180、A-71378、A-71623和SR146131;(20)GLP-I激动剂;(21)促肾上腺皮质激素释放激素激动剂;(22)组胺受体-3(H3)调节剂;(23)组胺受体-3(H3)拮抗剂/反转激动剂,例如hioperamide、N-(4-戊基)氨基甲酸3-(1H-咪唑-4-基)丙基酯、clobenpropit、iodophenpropit、imoproxifan和GT2394(Gliatech);(24)β-羟基类固醇脱氢酶-1抑制剂(11β-HSD-1抑制剂),例如BVT 3498和BVT 2733,(25)PDE(磷酸二酯酶)抑制剂,例如茶碱、己酮可可碱、扎普司特、西地那非、氨力农、米力农、西洛酰胺、咯利普兰和cilomilast;(26)磷酸二酯酶-3B(PDE3B)抑制剂;(27)NE(去甲肾上腺素)转运抑制剂,例如GW 320659、despiramine、他舒普仑和诺米芬辛;(28)ghrelin受体拮抗剂;(29)瘦素,包括重组人瘦素(PEG-OB,Hoffman La Roche)和重组甲硫氨酰基人瘦素(Amgen;(30)瘦素衍生物;(31)BRS3(铃蟾肽受体亚型3)激动剂,例如[D-Phe6,β-Ala11,Phe13,Nle14]Bn(6-14)和[D-Phe6,Phe13]Bn(6-13)丙基酰胺;(32)CNTF(纤毛神经营养因子),例如GI-181771(Glaxo-SmithKline)、SR146131(Sanofi Synthelabo)、butabindide、PD170,292和PD 149164(Pfizer);(33)CNTF衍生物,例如axokine(Regeneron);(34)单胺再摄取抑制剂,例如西布曲明;(35)UCP-I(未偶联蛋白-1、2或3)激活剂,例如植烷酸、4-[(E)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)-1-丙烯基]苯甲酸(TTNPB)和视黄酸;(36)25 -->
甲状腺激素β激动剂,例如KB-2611(KaroBioBMS);(37)FAS(脂肪酸合成酶)抑制剂,例如Cerulenin和C75;(38)DGAT1(二酰基甘油酰基转移酶1)抑制剂;(39)DGAT2(二酰基甘油酰基转移酶2)抑制剂;(40)ACC2(乙酰基-CoA羧酶-2)抑制剂;(41)糖皮质激素拮抗剂;(42)酰基雌激素,例如油酰基雌酮;(43)二羧酸转运蛋白抑制剂;(44)肽YY、PYY 3-36、肽YY类似物、衍生物和片段,例如BIM-43073D、BIM-43004C,(45)神经肽Y2(NPY2)受体激动剂例如NPY3-36、N-乙酰基[Leu(28,31)]NPY 24-36、TASP-V和环-(28/32)-Ac-[Lys28-Gru32]-(25-36)-pNPY;(46)神经肽Y4(NPY4)激动剂例如胰肽(PP);(47)神经肽Y1(NPY1)拮抗剂例如BIBP3226、J-115814、BIBO 3304、LY-357897、CP-671906和GI-264879A;(48)阿片样物质拮抗剂,例如纳美芬3-甲氧基纳曲酮、纳洛酮和纳曲酮;(49)葡萄糖转运抑制剂;(50)磷酸酯转运抑制剂;(51)5-HT(血清素)抑制剂;(52)β-阻断剂;(53)神经激肽-1受体拮抗剂(NK-I拮抗剂);(54)氯苄雷司;(55)氯福雷司;(56)氯氨雷司;(57)氯特胺;(58)cyclexedrine;(59)右苯丙胺;(60)diphemethoxidine,(61)N-乙基苯丙胺;(62)芬布酯;(63)非尼雷司;(64)非普雷司;(65)氟多雷司;(66)氟氨雷司;(67)糠基甲基苯丙胺;(68)左苯丙胺;(69)左法哌酯;(70)美芬雷司;(71)甲胺苯丙酮;(72)去氧麻黄碱;(73)去甲伪麻黄碱;(74)喷托雷司;(75)苯双甲吗啉;(76)芬美曲嗪;(77)匹西雷司;(78)phytopharm 57;(79)唑尼沙胺;(80)阿米雷司;(81)安非氯醛;(82)苯丙胺;(83)苄非他明;和(84)对氯苯丁胺。
使用本发明化合物的上述组合治疗也可用于治疗代谢综合征。根据一个广泛使用的定义,患有代谢综合征的患者的特征在于具有选自以下五种症状的至少三种症状:(1)腹部肥胖;(2)高甘油三酯血症;(3)低的高密度脂蛋白胆固醇(HDL);(4)高血压;和(5)禁食葡萄糖升高,如果患者还患有糖尿病,则其可落在2型糖尿病的特征范围内。这些症状中的每一种都在最近发布的Third Report of the NationalCholesterol Education Program Expert Panel on Detection,Evaluation andTreatment of High Blood Cholesterol in Adults(Adult Treatment Panel III,或ATP III),National Institutes of Health,2001,NIH Publication No.01-3670中有临床上的定义。患有代谢综合征的患者具有增加的发展为上述大血管和微血管并发症,包括动脉粥样硬化和冠心病的危险。上述组合可同时改善代谢综合征的一种以上的症状(例如两种症状、三种症状、四种症状或所有五种症状)。
CETP试验
采用作为胆固醇酯脂质供体,根据由Epps等人描述的方法改进法进行用于测定IC50值以鉴别CETP抑制剂化合物的体外连续试验。参见Epps等人,(1995)Method for measuring the activitiesof chole steryl ester transfer protein(lipid transfer protein),Chem.Phys.Lipids.77,51-63。
用于试验的颗粒从以下来源产生:包含DOPC(二油酰基磷脂酰基胆碱)、(Molecular Probes C-3927)、三油精(甘油三酯)和apoHDL的合成供体HDL颗粒基本上通过Epps等人所述的探针超声处理产生,但是添加非散射淬灭分子,即dabcyl dicetylamide,以减少背景荧光。Dabcyl dicetylamide通过在二异丙胺催化剂的存在下将dabcyl n-琥珀酰亚胺与二(十六烷基)胺在DMF中在95℃加热过夜制备。将得自人血液的天然的脂蛋白用作受体颗粒。通过超速离心收集密度小于1.063g/ml的颗粒。这些颗粒包括VLDL、IDL和LDL。颗粒浓度以根据BCA试验(Pierce,USA)测定的蛋白质浓度表示。在使用之前将颗粒在4℃储存。
试验在Dynex Microfluor 2U型底黑色96孔板(Cat#-7205)中进行。制备包含CETP、1×CETP缓冲液(50mM Tris,pH 7.4、100mM NaCl、1mM EDTA)和受体颗粒最终浓度的一半的试验混合物,并向板的各个孔中加入100μL的试验混合物。加入3μL的含试验化合物的DMSO。将板在板振荡器上混合,然后在25℃培养1小时。制备包含供体颗粒、其余受体颗粒和1×CETP缓冲液的第二试验混合物。向反应孔中加入47μL的第二试验混合物以开始试验。试验在150μL的最终容积中在25℃下进行。材料的最终浓度为:5ng/μL的供体颗粒、30ng/μL的受体颗粒(各自通过蛋白质含量表示)、1X CETP缓冲液、0.8nM重组人CETP(在CHO细胞中表达并进行部分纯化)和在试验化合物时最多为2%的DMSO。试验在荧光读板器(Molecular Devices SpectramaxGeminiXS)中进行,该仪器设定为在25℃为45分钟的动力学运行,在Ex=480nm、Em=511nm下每45秒读取样品,使用495nm的截止滤光片,介质的光电倍增管设置,校准打开,和每孔6次读数。
数据通过获得初始速率进行评价,对于曲线的伪线性部分(通常是0-500或1000秒),以相对荧光单位/秒表示。将具有抑制剂与未受抑制(只有DMSO)的阳性对照样品的速率进行比较得到抑制百分比。将拟合到Sigmoidal 4参数方程的抑制百分比对抑制剂浓度的对数的图用于计算IC50。
实施例
提供以下实施例以更完全地理解和通晓本发明。原料是用已知方法制得的或者是如下所示制得的。
实施例不应看作是以任何方式限制本发明。本发明的范围由权利要求限定。本发明化合物具有小于或等于50μM的通过上述试验测量的IC50值。
反应方案1
本发明中使用的中间体1-2、1-3、1-4、1-5和1-6可购买到或如反应方案1所示制备。将其中Ra和p如权利要求书中所定义,且其中卤素优选为碘或溴的适当取代的2-卤代苯胺1-1在高温下在DMF中用CuCN处理,得到相应的2-氰基苯胺。或者,可以通过在钯(II)盐的存在下或在某些铜或镍络合物的存在下用KCN和CuI处理1-1来制备腈化合物(参见:Smith,M.B.和March,J.“March′s Advanced OrganicChemistry”,第5版,John Wiley和Sons,New York,pp.867(2001)及其中引用的参考文献)。碘化物1-3通过在二碘甲烷存在下用亚硝酸异戊酯、亚硝酸正戊酯或亚硝酸叔丁酯等处理1-2来制备(参见例如:Smith等人,J.Org.Chem.55,2543,(1990)和其中引用的参考文献),反应不采用溶剂或者在溶剂例如THF或乙腈中进行。或者,碘化物可以通过首先使用亚硝酸异戊酯、亚硝酸正戊酯、亚硝酸叔丁酯、亚硝酸钠或亚硝酸等形成重氮盐,随后在碘或碘化物盐如碘化铜、碘化钠、碘化钾、碘化四丁铵等存在下加热来制备。在二氯甲烷中用DIBAL将1-3还原,获得醛1-4。在甲醇或乙醇中使用硼氢化钠等将醛1-4还原,获得醇1-5。在溶剂例如二氯甲烷、二氯乙烷等中,使用四溴化碳和三苯基膦处理1-5,生成苄基溴1-6(参见:Smith,M.B.和March,J.“March′sAdvanced Organic Chemistry”,5th Ed.,John Wiley和Sons,New York,pp.518-519(2001)及其中引用的参考文献)。
反应方案2
其中Ra、p和A3如权利要求书中所定义的本发明中间体2-2和2-3可如反应方案2所示制得。2-氰基碘苯2-1可购买或者按照反应方案1所示方法制得。化合物2-2是通过Suzuki或Stille反应或其变型,采用碘化物2-1与适当取代的芳基或杂芳基硼酸、硼酸酯或三烷基锡化合物的钯催化的交联反应而制得的,该反应如Miyaua等人,Chem.Rev.95,2457(1995)和其中所引用的文献所述,并且如Smith,M.B.和March,J.“March′s Advanced Organic Chemistry”,5th Ed.,John Wiley和Sons,New York,pp.868-869(2001)及其中引用的参考文献中所述。在乙醚中使用氢化锂铝将腈2-2还原,获得了2-氨基甲基苯胺2-3。或者,可在甲醇、乙醇等中,在氢气氛下,使用披钯碳或阮内镍将腈还原。将腈还原成氨基甲基的其它方法可参见Smith,M.B.和March,J.“March′sAdvanced Organic Chemistry”,5th Ed.,John Wiley和Sons,New York,pp.1204(2001)及其中引用的参考文献。
反应方案3
其中R、Ra、p、A2、A3和n如权利要求书中所定义的本发明化合物3-4可根据反应方案3所示制得。苄基胺3-1可购买或者按照反应方案2所示方法制得。将3-1与在2-位携带离去基团的适当取代的乙酸烷基酯反应,获得仲胺3-2。乙酸烷基酯可购买或者使用已知方法制得。优选的离去基团可以是溴化物或碘化物,但是也可以是甲磺酸酯、甲苯磺酸酯等,并且溶剂可以是二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等。可采用或不采用碱例如三乙胺、二异丙基乙胺、N-甲基吗啉等来进行该反应。将3-2的酯官能团还原,获得氨基醇3-3。优选的还原剂是LiAlH4,在溶剂例如乙醚、四氢呋喃、二甲氧基乙烷、二氧杂环己烷等中。将酯还原的其它方法可参见“March′s AdvancedOrganic Chemistry”5th Ed.,John Wiley和Sons,New York,pp 1551。在溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等和碱例如三乙胺、二异丙基乙胺、N-甲基吗啉等中,使用光气(Y=Cl)或光气等同物例如三光气(Y=OCCl3)或羰基-二咪唑(Y=咪唑)等将氨基醇3-3环合成唑烷酮3-4。对映体纯产物可通过手性色谱法获得。
反应方案4
其中R、Ra、p、A2、A3和n如权利要求书中所定义的本发明化合物4-3可根据反应方案4所示制得。可将适当取代的苄基胺4-1与适当取代的环氧乙烷反应,获得了氨基醇4-2。环氧乙烷可购买或者油相应的醛和硫内盐制得,如March s Advanced Organic Chemistry”5th Ed.,John Wiley和Sons,New York,pp 1247中所述。或者,该环氧化物可以通过烯烃的环氧化、卤代醇或1,2-二醇的环合或“March′s AdvancedOrganic Chemistry”5th Ed.,John Wiley和Sons,New York,pp 1051中描述的其它方法来制得。对于该反应,优选的溶剂是异丙醇。此外,该环氧化物开环可在溶剂例如乙腈等中,借助于路易斯酸催化剂例如Yb(OTf)3等来进行。在溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等和碱例如三乙胺、二异丙基乙胺、N-甲基吗啉等中,使用光气(Y=Cl)或光气等同物例如三光气(Y=OCCl3)或羰基-二咪唑(Y=咪唑)等将氨基醇4-2环合成唑烷酮4-3。或者,通过在溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等中,在碱例如三乙胺,二异丙基乙胺等存在下,用试剂例如二碳酸二苄酯或氯甲酸苄酯处理,可将氨基醇4-2转化成合适的氨基甲酸酯。然后通过在溶剂例如四氢呋喃、二甲氧基乙烷等中用碱例如六甲基二硅氮烷锂、钠或钾处理,可将该氨基甲酸酯转化成唑烷二酮4-3。对映体纯产物可通过手性色谱法获得。
反应方案5
其中R、Ra、p、A2、A3和n如权利要求书中所定义的本发明化合物5-5可根据反应方案5所示制得。适当取代的氨基醇5-1可如反应方案4中所示制得,并且优选作为氨基甲酸酯例如氨基甲酸叔丁酯(BOC)或氨基甲酸苄酯(Cbz)保护起来。其它氨基甲酸酯和另外的氮保护基可参见“Protective Groups in Organic Synthesis”,3rd Ed.John Wiley和Sons,New York,pp 494。将氮用BOC或Cbz基团的保护可通过将5-1与二碳酸二叔丁酯或二碳酸二苄酯在合适的溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等中反应来进行。通过在合适的碱例如三乙胺、二异丙基乙胺、N-甲基吗啉等存在下,在二氯甲烷,二氯乙烷,四氢呋喃,二甲氧基乙烷等中与甲磺酰氯反应,可将醇5-2转化成叠氮化物5-3。此外,可将醇转化成另外的离去基团例如甲苯磺酸酯、碘化物、溴化物等。然后在合适的溶剂例如DMF、DMPU等中,用合适的叠氮化物源例如NaN3、LiN3、Bu4NN3等把甲磺酸酯置换。叠氮化物5-3还可以通过在THF中将醇5-2用二苯基磷酰叠氮、偶氮二甲酸二乙酯和三苯基膦处理来制得。可以在合适的溶剂例如EtOAc、THF、EtOH等中,采用金属催化剂例如PtO2或Pd/C等,通过氢化将叠氮化物5-3还原。还原和除去保护基后,获得二胺5-4。对于BOC保护基,TFA/CH2Cl2是优选的脱保护方法;对于CBZ保护基,在合适的溶剂例如EtOAc、THF、EtOH等中采用金属催化剂例如例如PtO2或Pd/C的氢化是优选的脱保护方法。在溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等和碱例如三乙胺、二异丙基乙胺、N-甲基吗啉等中,使用光气(Y=Cl)或光气等同物例如三光气(Y=OCCl3)或羰基-二咪唑(Y=咪唑)等将二胺5-4环合成咪唑烷酮5-5。对映体纯产物可通过手性色谱法获得。
反应方案6
其中R、Ra、p、A2、A3和n如权利要求书中所定义的本发明化合物6-4可根据反应方案6所示制得。在甲醇、乙醇、二氯乙烷、四氢呋喃等中,在还原剂例如硼氢化钠,氰基硼氢化钠,三乙酰氧基硼氢化钠等存在下,或者依据Smith,M.B.和March,J.“March′s AdvancedOrganic Chemistry”,5th Ed.,John Wiley和Sons,New York,pp.1187-1189(2001)及其中引用的参考文献中描述的方法,将6-1用可购买或者通过已知方法制得的适当取代的保护的氨基醛处理,获得6-2。对于该转化,优选的条件是在含有催化性乙酸的甲醇中使用氰基硼氢化钠。将6-2脱保护,获得6-3。对于BOC保护基,TFA/CH2Cl2是优选的脱保护方法。然后在溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等和碱例如三乙胺、二异丙基乙胺、N-甲基吗啉等中,使用光气(Y=Cl)或光气等同物例如三光气(Y=OCCl3)或羰基-二咪唑(Y=咪唑)等将二胺6-3环合成咪唑烷酮6-4。对映体纯产物可通过手性色谱法获得。
反应方案7
其中R、Ra、p、A2、A3和n如权利要求书中所定义的本发明化合物7-5可根据反应方案7所示制得。将如反应方案4所述制得的胺7-1用合适的二碳酸酯或氯甲酸酯处理,获得7-2。通过在二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等中,在合适的碱例如三乙胺、二异丙基乙胺、N-甲基吗啉等存在下与甲磺酰氯反应,可将7-2转化成叠氮化物7-3。或者,可将该醇转化成另外的离去基团例如甲苯磺酸酯、碘化物、溴化物等。然后在合适的溶剂例如DMF、DMPU等中,用合适的叠氮化物源例如NaN3、LiN3、Bu4NN3等把甲磺酸酯置换。叠氮化物7-3还可以通过在THF中将醇5-2用二苯基磷酰叠氮、偶氮二甲酸二乙酯和三苯基膦处理来制得。当R4是苄基时,可采用THF作为溶剂,使用PtO2通过H2将叠氮化物7-3还原成胺7-4。通过在合适的溶剂例如THF、二甲氧基乙烷、DMF、DMA等中,使用合适的碱例如二异丙基氨基锂或二(三甲基甲硅烷基)氨基锂、钠或钾等将7-4环合成咪唑烷酮7-5。对映体纯产物可通过手性色谱法获得。
反应方案8
通过在合适的溶剂例如THF、二甲氧基乙烷、DMF、DMA等中,在合适的碱例如二异丙基氨基锂或二(三甲基甲硅烷基)氨基锂、钠或钾等存在下,用合适的烷化剂例如烷基卤、甲苯磺酸烷基酯、甲磺酸烷基酯等(例如甲基碘)处理,可将其中R、Ra、A2、A3、p和n如权利要求书中所定义的化合物8-1(如反应方案5、6和7中所述制得的)转化成8-2。
反应方案9
其中Ra、p和A3如权利要求书中所定义的中间体9-3和9-4可如反应方案9中所述制得。可将如反应方案2所示制得的适当取代的苄基腈9-1与碱例如氢氧化钠或氢氧化钾等在合适的含水醇例如乙醇、丙醇等中加热,获得适当取代的苯甲酸9-2(参见:Smith,M.B.和March,J.“March′s Advanced Organic Chemistry”,5th Ed.,John Wiley和Sons,New York,pp.1179-1180(2001)及其中引用的参考文献)。可在溶剂例如四氢呋喃等中使用还原剂例如硼烷将苯甲酸9-2还原成苯甲醇9-3(参见:Smith,M.B.和March,J.“March′s Advanced Organic Chemistry”,5th Ed.,John Wiley和Sons,New York,pp.1549(2001)及其中引用的参考文献)。或者,可通过已知方法,包括用三甲基甲硅烷基重氮甲烷处理来将9-2酯化,并使用LiAIH4等将所得酯还原成醇9-3。可在溶剂例如二氯甲烷、二氯乙烷等中,使用试剂例如三苯基膦和四溴化碳将中间体9-3转化成苄基溴9-4(参见:Smith,M.B.和March,J.“March′sAdvanced Organic Chemistry”,5th Ed.,John Wiley和Sons,New York,pp.518-519(2001)及其中引用的参考文献)。
反应方案10
其中R、R1、A2、p和n如权利要求书中所定义的本发明中间体10-4可这样制得:如反应方案10所示,将适当取代的苯甲醛10-1与硝基烷缩合,获得取代的硝基醇10-2。该反应可在溶剂例如乙醇、甲醇等中通过碱水溶液例如氢氧化钠水溶液来催化。可在醇类溶剂例如甲醇、乙醇等中,在氢气和酸水溶液存在下,采用还原试剂例如阮内镍、披钯活性炭或氧化铂将硝基醇10-2还原成氨基醇10-3(参见:Langer,O.,等人,Bioorg.Med.Chem.,2001,9,677-694)。在溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等中,使用试剂例如光气(Y=Cl)、三光气(Y=OCCl3)或羰基二咪唑(Y=咪唑)和碱例如三乙胺、二异丙基乙胺等将氨基醇10-3环合成唑烷酮10-4。
反应方案11
其中R、R1、A2、p和n如权利要求书中所定义的本发明中间体11-4可如反应方案11所示制得。将可购买或通过已知方法制得的氨基酸11-1的N-氨基甲酰基-(N-甲氧基-N-甲基)酰胺用格式试剂或其它有机金属试剂例如有机锂处理,获得相应的酮11-2。将该酮在醇溶剂或THF中用硼氢化钠或硼氢化锌还原,或者在THF中使用其它还原剂例如苯基二甲基甲硅烷还原,获得醇11-3,通过在溶剂例如MeOH、EtOH等和THF、二氧杂环己烷、二甲氧基乙烷等中用碱例如KOH处理,可将11-3环合成唑烷酮11-4。
反应方案12
其中R、R1、Ra、A2、A3、p和n如权利要求书中所定义的本发明化合物12-3可如反应方案12所示制得。在溶剂例如四氢呋喃、二甲氧基乙烷、乙醚、二甲基甲酰胺、二甲基乙酰胺等中,采用碱例如六甲基二硅氮烷钠或氢化钠,用如反应方案9所示制得的苄基溴12-1将如反应方案10和11所示制得的唑烷酮12-2烷基化,获得产物12-3。
反应方案13
其中R、R1、Ra、A2、A3、p和n如权利要求书中所定义的本发明化合物13-4可如反应方案13所示制得。在溶剂例如四氢呋喃、二甲氧基乙烷、乙醚等中,采用碱例如六甲基二硅氮烷钠或氢化钠,用如反应方案1所示制得的苄基溴13-1将如反应方案10和11所示制得的唑烷酮13-2烷基化,获得产物13-3。化合物13-4是通过Suzuki或Stille反应或其变型,采用碘化物13-3与适当取代的芳基或杂芳基硼酸、硼酸酯或三烷基锡化合物的钯催化的交联反应而制得的,该反应如Miyaua等人,Chem.Rev.95,2457(1995)和其中所引用的文献所述,并且如Smith,M.B.和March,J.“March′s Advanced Organic Chemistry”,5th Ed.,John Wiley和Sons,New York,pp.868-869(2001)及其中引用的参考文献中所述。
反应方案14
其中R、Ra、A2、A3、p和n如权利要求书中所定义的本发明化合物14-5是如反应方案14所示制得的。苯甲醇14-1可购买或者根据反应方案9所述方法制得。将14-1与Dess-Martin periodinane反应,获得相应的苯甲醛14-2。还可以使用用于将伯羟基氧化成醛的其它方法,例如Swern氧化条件、过钌酸四丙基铵、吡啶氯铬酸盐、三氧化硫-吡啶等。2-氨基-1-苯基乙醇14-3可通过用三甲基甲硅烷基氰化物和催化性碘化锌处理,然后用氢化锂铝等还原剂还原,而经由相应的甲硅烷基化氰基醇由14-2制得。或者,2-氨基-1-苯基乙醇14-3可通过用氰化钾处理,然后还原,而经由相应的氰基醇由14-2制得。在溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等中,使用试剂例如光气(Y=Cl)、三光气(Y=OCCl3)或羰基二咪唑(Y=咪唑)和碱例如三乙胺、二异丙基乙胺等可将2-氨基-1-苯基乙醇14-3环合成唑烷酮14-4。可在溶剂例如四氢呋喃、二甲氧基乙烷、乙醚等中,采用碱例如六甲基二硅氮烷钠或氢化钠,用烷基、杂烷基、芳基或杂芳基溴化物将唑烷酮14-4烷基化,获得产物14-5。对映体纯产物可通过手性色谱法获得。
反应方案15
其中R、R1、Ra、A2、A3、p和n如权利要求书中所定义的本发明化合物15-6可如反应方案15所示制得。醛15-1可购买或者按照反应方案1中描述的方法制得。将15-1与硝基烷缩合,获得取代的硝基醇15-2。该反应可在溶剂例如乙醇、甲醇等中通过碱水溶液例如氢氧化钠水溶液来催化。可在醇类溶剂例如甲醇、乙醇等中,在氢气和酸水溶液存在下,采用还原试剂例如阮内镍、披钯活性炭或氧化铂将硝基醇15-2还原成氨基醇15-3(参见:Langer,O.,等人,Bioorg.Med.Chem.,2001,9,677-694)。可在溶剂例如二氯甲烷、二氯乙烷、四氢呋喃、二甲氧基乙烷等中,使用试剂例如光气(Y=Cl)、三光气(Y=OCCl3)或羰基二咪唑(Y=咪唑)和碱例如三乙胺、二异丙基乙胺等将氨基醇15-3环合成唑烷酮15-4。唑烷酮15-5是通过Suzuki或Stille反应或其变型,采用碘化物15-4与适当取代的芳基或杂芳基硼酸、硼酸酯或三烷基锡化合物的钯催化的交联反应而制得的,该反应如Miyaua等人,Chem.Rev.95,2457(1995)和其中所引用的文献所述,并且如Smith,M.B.和March,J.“March′s Advanced Organic Chemistry”,5th Ed.,JohnWiley和Sons,New York,pp.868-869(2001)及其中引用的参考文献中所述。可在溶剂例如四氢呋喃、二甲氧基乙烷、乙醚等中,采用碱例如六甲基二硅氮烷钠或氢化钠,用烷基、杂烷基、芳基或杂芳基溴化物将唑烷酮15-5烷基化,获得产物15-6。对映体纯产物可通过手性色谱法获得。
反应方案16
其中R、R1、Ra、A2、A3、p和n如权利要求书中所定义的本发明化合物16-5可如反应方案16所示制得。醛16-1可购买或者按照反应方案1中描述的方法制得。将16-1与手性N-酰基唑烷酮缩合,获得醇加成物16-2,如Evans,D.A.等人,J.Am.Chem.Soc,2002,124,392-3中所述。手性N-酰基唑烷酮可购买或者按照Ager,DJ.;Allen,D.A.;Schaad,D.R.Synthesis 1996,1283-5中描述的方法制得。可将化合物16-2水解成相应的羧酸,然后用叠氮磷酸二苯酯(diphenylphosphorazidate)和三烷基胺碱处理,以进行Curtius重排,获得手性唑烷酮16-3。唑烷酮16-4是通过Suzuki或Stille反应或其变型,采用碘化物16-3与适当取代的芳基或杂芳基硼酸、硼酸酯或三烷基锡化合物的钯催化的交联反应而制得的,该反应如Miyaua等人,Chem.Rev.95,2457(1995)和其中所引用的文献所述,并且如Smith,M.B.和March,J.“March′s Advanced Organic Chemistry”,5th Ed.,JohnWiley和Sons,New York,pp.868-869(2001)及其中引用的参考文献中所述。可在溶剂例如四氢呋喃、二甲氧基乙烷、乙醚等中,采用碱例如六甲基二硅氮烷钠或氢化钠,用烷基、杂烷基、芳基或杂芳基溴化物将唑烷酮16-4烷基化,获得产物16-5。或者,可用合适的溴化物将唑烷酮16-3烷基化,获得化合物16-6,采用芳基或杂芳基硼酸、硼酸酯或三烷基锡化合物,让化合物16-6进行过Suzuki或Stille反应或其变型,获得产物16-5。对映体纯产物可通过手性色谱法获得。
实施例1
2-氨基-5-(三氟甲基)苄腈
向2升烧瓶中加入100g(0.348mol)4-氨基-3-碘三氟甲苯、40gCuCN和750mL DMF。将该混合物加热至回流然后保持回流1小时。将该反应冷却并倒入含有300mL浓氢氧化铵的3L水内。向该混合物中加入1L CH2Cl2。然后将该混合物经由硅藻土过滤。分离各层,用CH2Cl2反萃取水层。将有机萃取液合并,把溶剂减压蒸发。把残余物溶解在1.5L乙醚中,将所得溶液用1N氢氧化铵、亚硫酸氢钠水溶液、1N盐酸和盐水洗涤。将该溶液用无水硫酸镁干燥,经由在顶部含有硫酸镁层的硅胶塞过滤。用0.5L乙醚洗涤该硅胶塞。把乙醚溶液合并,浓缩至750mL,在室温静置。2天后,收集所得固体,用己烷洗涤,并减压干燥,获得了2-氨基-5-(三氟甲基)苄腈。
1H NMR(CDCl3,500MHz)δ7.68(s,1H),7.58(d,J=8.5Hz,1H),6.81(d,J=8.5Hz,1H),4.80(br s,2H).
实施例2
2-碘-5-(三氟甲基)苄腈
在35℃,向2-氨基-5-(三氟甲基)苄腈(15.1g)和二碘甲烷(24mL)在乙腈(150mL)内的溶液中滴加亚硝酸叔丁酯(21mL)。在加入期间,把该反应保持在330-35℃。让该反应老化30分钟,然后在60℃加热30分钟。将该反应混合物冷却,用乙醚洗涤,依次用2×水、2×亚硫酸氢钠水溶液、水和盐水洗涤。将该溶液用无水硫酸镁干燥,经由硅胶塞过滤,然后浓缩,获得100g红色油状物。通过硅胶色谱纯化产物,依次用己烷、3∶1己烷/CH2Cl2和1∶1己烷/CH2Cl2洗脱,获得了2-碘-5-(三氟甲基)苄腈。
1H NMR(CDCl3,500MHz)δ8.10(d,J=8.5 Hz,1H),7.85(d,J=1.8Hz,1H),7.52(dd,J=8.5,1.8Hz,1H).
实施例3
5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲腈
向2-碘-5-(三氟甲基)苄腈(2.0g,6.7mmol)和(5-异丙基-2-甲氧基苯基)硼酸(1.6g,8.4mmol)在二甲基乙二醇(30.4mL)内的溶液中加入2MNa2CO3(6.8mL)、乙醇(9.6mL)和水(10mL)。将该溶液用氮气脱气2分钟。加入Pd(PPh3)4(774mg,0.67mmol),并将该溶液再次用氮气脱气2分钟。把该溶液等分到两个40mL微波管中。每个管用氮气脱气1分钟,密封,并置于微波反应器中。把瓦数设定为200W直至温度达到150℃,然后把温度在150℃保持10分钟。之后将微波管冷却至室温,合并,倒入H2O(50mL),并用EtOAc(100mL)萃取。将有机层用盐水(50mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化,使用15%CH2Cl2/己烷洗脱,获得了5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲腈,为浅黄色油状物。Rf=0.65(25%EtOAc/己烷)。
1H NMR(CDCl3,500MHz)δ7.97(s,1H),7.85(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),7.31(dd,J=8.5,2.0Hz,1H),7.12(d,J=2.0Hz,1H),6.97(d,J=8.5Hz,1H),3.82(s,3H),2.93(m,1H),1.27(d,J=7.0Hz,6H).
实施例4
1-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲胺
5将′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲腈(996.2mg,3.12mmol)溶解在乙醚(33mL)中,冷却至0℃。通过注射器滴加LAH(12.49mL 1M在乙醚中的溶液,12.49mmol)。在0℃搅拌10分钟后,将该反应温热至室温并在室温搅拌6小时。然后将该溶液缓慢地滴加1.5mLH2O(剧烈释放出气体)来中止反应,然后加入1.5mL 30%NaOH,然后加入3.0mL H2O。将所得胶状沉淀用5×20mL CH2Cl2洗涤;将有机洗涤液用硫酸钠干燥,过滤并浓缩。通过快速色谱法纯化残余物,使用含有0.1%Et3N的2%MeOH/CH2Cl2洗脱,获得了1-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲胺。Rf=0.30(10%MeOH/CH2Cl2)。
LCMS=324.3(M+1)+.1H NMR(CDCl3,500MHz)δ7.77(s,1H),7.55(d,J=6.8Hz,1H),7.32(d,J=7.8Hz,1H),7.25(dd,J=8.3,2.1Hz,1H),7.00(d,J=2.1Hz,1H),6.92(d,J=8.4Hz,1H),3.66-3.74(m,5H),2.91(m,1H),1.26(d,J=6.9Hz,6H).
实施例5
4-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
步骤A:[3,5-二(三氟甲基)苯基](羟基)乙酸甲酯
向[3,5-二(三氟甲基)苯基](羟基)乙酸(510mg,1.77mmol)在苯(10mL)内的溶液中加入MeOH(1.5mL),然后加入(三甲基甲硅烷基)重氮甲烷(1.06mL 2M在己烷中的溶液,2.12mmol)。10分钟后,通过加入几滴HOAc(加入直至黄色消失)来中止反应。将该反应浓缩,并通过快速色谱法纯化,用10-80%EtOAc/己烷洗脱,获得了[3,5-二(三氟甲基)苯基](羟基)乙酸甲酯。
1H NMR(CDCl3,500MHz)δ7.94(s,2H),7.85(s,1H),5.32(s,1H),3.83(s,3H),3.68(bs,1H).
步骤B:[3,5-二(三氟甲基)苯基](溴)乙酸甲酯
将[3,5-二(三氟甲基)苯基](羟基)乙酸甲酯(300mg,0.993mmol)溶解在CH2Cl2(10mL)中。将该溶液冷却至0℃,加入CBr4(659mg,1.986mmol),然后加入PPh3(521mg,1.986mmol)。1小时后,将该反应温热至室温并在室温搅拌1小时。将该反应经由短的硅胶塞过滤,用CH2Cl2洗涤。将该滤液浓缩并且将残余物通过快速色谱法纯化,用5%EtOAc/己烷洗脱,获得了[3,5-二(三氟甲基)苯基](溴)乙酸甲酯。Rf=0.24(5%EtOAc/己烷)。
1H NMR(CDCl3,500MHz)δ8.02(s,2H),7.87(s,1H),5.41(s,1H),3.83(s,3H).
步骤C:[3,5-二(三氟甲基)苯基]({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙酸甲酯
向含有[3,5-二(三氟甲基)苯基](溴)乙酸甲酯(237.7mg,0.651mmol)的烧瓶内加入在CH2Cl2(4mL)中的1-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲胺(102.1mg,0.316mmol)。将该反应在室温搅拌5小时,然后用EtOAc(50ml)稀释。将该有机溶液用水和盐水(分别是15mL)洗涤。将有机萃取液用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化(5-15%EtOAc/己烷),获得了[3,5-二(三氟甲基)苯基]({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙酸甲酯。Rf=0.33(15%EtOAc/己烷)。
LCMS=608.4(M+1)+.1H NMR(CDCl3,500MHz)δ7.76-7.79(m,3H),7.62(s,1H),7.56(d,J=7.8Hz,1H),7.31(d,J=7.8Hz,1H),7.23(dd,J=8.2,1.9Hz,1H),6.96(m,1H),6.89(d,J=8.5Hz,1H),4.30(m,1H),3.54-3.70(m,8H),2.87(m,1H),1.21-1.23(m,6H).
步骤D:2-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇
将[3,5-二(三氟甲基)苯基]({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙酸甲酯(13.2mg,0.0217mmol)溶解在Et2O(1.5mL)中,冷却至0℃。通过注射器滴加LAH(108.5μL 1M在LAH中的溶液,0.1085mmol)。将该反应温热至室温并在室温搅拌1小时。然后通过加入H2O(100μL)来中止反应,加入1N NaOH(100μL),然后加入H2O(300μL)。将该胶状沉淀用CH2Cl2洗涤几次。将有机洗涤液经由硅胶塞过滤,使用2%MeOH/CH2Cl2洗涤,并将该滤液浓缩。通过PTLC纯化残余物,使用25%EtOAc/己烷洗脱,获得了2-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇。Rf=0.27(25%EtOAc/己烷)。
LCMS=580.4(M+1)+.1H NMR(CD2Cl2,500MHz)δ7.79(s,1H),7.75(s,2H),7.63-7.68(m,1H),7.55(d,J=7.8Hz,1H),7.31(d,J=7.8Hz,1H),7.23(m,1H),6.94(m,1H),6.89(m,1H),3.43-3.76(m,9H),2.86(m,1H),1.90(bs,1H),1.20(d,J=6.8Hz,6H).
步骤E:4-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
向光气(21μL 20%在甲苯中的溶液,~0.0535mmol)在CH2Cl2(0.5mL)内的溶液中加入在CH2Cl2(0.5mL)中的2-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇(3.1mg,0.00535mmol),然后加入DIPEA(19μL,0.107mmol)。搅拌5分钟后,将该反应倒入水(1mL)内,将该混合物用EtOAc萃取(20mL)。将有机萃取液用H2O、饱和NaHCO3和盐水(分别是5mL)洗涤。然后将有机层用硫酸钠干燥,过滤,并浓缩。通过PTLC纯化残余物,获得了4-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮。Rf=0.27(25%EtOAc/己烷)。LCMS=606.3(M+1)+。1H NMR(CD2Cl2,500MHz)(观察到某些峰重叠;阻转异构体以1∶1比例存在)
δ7.84(s,1H),7.19-7.60(m,6H),6.80-6.87(m,2H),3.84-4.68(m,5H),3.68&3.64(2单峰,3H),2.82(m,1H),1.17-1.21(m,6H).
实施例6
5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
步骤A:2-[3,5-二(三氟甲基)苯基]环氧乙烷
向无水烧瓶中加入NaH(1.09g60%NaH,27.27mmol)。加入DMSO(90mL),然后加入三甲基碘化锍(7.0g,31.82mmol)。将该反应搅拌5分钟,然后加入3,5-二(三氟甲基)苯甲醛(1.5mL,9.09mmol)在DMSO(15mL)中的溶液。将该反应在室温搅拌1小时,然后倒入冰/水(300mL)内。将该混合物用戊烷(3×150mL)萃取。合并戊烷萃取液,并经由短的硅胶塞过滤,用10%Et2O/戊烷洗涤。将该滤液浓缩并且将残余物通过快速色谱法纯化,用10%Et2O/戊烷洗脱,获得了2-[3,5-二(三氟甲基)苯基]环氧乙烷。Rf=0.42(10%Et2O/戊烷)。
1H NMR(CDCl3,500MHz)7.82(s,1H),7.74(s,2H),3.99(dd,J=3.9,2.5Hz,1H),3.23(dd,J=5.2,4.1Hz,1H),2.79(dd,J=5.5,2.5Hz,1H).
步骤B:1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇
将1-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲胺(300mg,0.929mmol)和2-[3,5-二(三氟甲基)苯基]环氧乙烷(297mg,1.161mmol)在2-丙醇(9mL)中的溶液加热回流15小时,然后冷却至室温。将该溶液浓缩,并且通过快速色谱法纯化残余物,使用10-80%EtOAc/己烷洗脱,获得了1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇。Rf=0.24(25%EtOAc/己烷)。
LCMS=580.3(M+1)+.1H NMR(CDCl3,500MHz)δ7.75-7.76(m,3H),7.69(s,1H),7.58(d,J=7.8Hz,1H),7.34(d,J=7.7Hz,1H),7.25(m,1H),6.98(bs,1H),6.92(d,J=8.5Hz,1H),4.62(m,1H),3.65-3.82(m,5H),2.89(m,1H),2.79(dd,J=12.4,3.0Hz,1H),2.48(m,1H),1.23(d,J=6.8Hz,6H).
步骤C:5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
在0℃,向1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇(31.9mg,0.0551mmol)在CH2Cl2(5mL)内的溶液中加入DIPEA(67μL,0.386mmol),然后加入三光气(8.2mg,0.0276mmol)。将该反应在0℃搅拌30分钟。然后将该溶液倒入饱和NaHCO3(15mL)内,将该混合物用EtOAc(50mL)萃取。将有机层用盐水(15mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化(20%EtOAc/己烷),获得了5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮。Rf=0.32(25%EtOAc/己烷)。LCMS=606.3(M+1)+。1H NMR(CD2Cl2,500MHz)(阻转异构体以1∶1比例存在,某些峰重叠)
δ7.90(s,1H),7.77(s,2H),7.57-7.62(m,2H),7.37(d,J=8.0Hz,1H),7.27(m,1H),6.98(s,1H),6.93(dd,J=8.4,3.2Hz,1H),5.42-5.53(m,1H),4.15-4.59(m,2H),3.72&3.73(2单峰,3H),3.05-3.65(m,2H),2.88(m,1H),1.19-1.23(m,6H).
这两种对映体可通过手性HPLC,使用15%IP A/庚烷和AD手性柱来分离。
实施例7
3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-吡啶-2-基-1,3-唑烷-2-酮
步骤A:2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)-1-吡啶-2-基乙醇
将1-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲胺(300mg,0.929mmol)和2-环氧乙烷-2-基吡啶(640mg)[通过将2-吡啶甲醛与NaH和三甲基碘化锍在DMSO中反应制得的]在2-丙醇(9mL)中的溶液加热回流5小时,然后冷却至室温。将该溶液浓缩,并且将残余物通过快速色谱法纯化,用含有0.5%Et3N的50-100%EtOAc/己烷洗脱,获得了2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)-1-吡啶-2-基乙醇。通过LCMS分析表明所需产物含有几种少量杂质。该产物不用进一步纯化或分析直接用于下一反应。
步骤B:(2-羟基-2-吡啶-2-基乙基){[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯
在室温于氮气下,将(PhCH2OCO)2O(103mg,0.360mmol)在无水CH2Cl2(2mL)内的溶液中通过套管加到2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)-1-吡啶-2-基乙醇(160mg,0.360mmol)在无水CH2Cl2(10mL)内的搅拌着的溶液中。将该反应在室温搅拌2小时并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,25×160mm,0-50%EtOAc在己烷中的混合物梯度),获得了(2-羟基-2-吡啶-2-基乙基){[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯。Rf=0.63(50%EtOAc/己烷)。LCMS计算值=579.25;实测值=579.2(M+1)+。
步骤C:3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-吡啶-2-基-1,3-唑烷-2-酮
在室温于氮气下,将二(三甲基甲硅烷基)氨基锂(464μL 0.5M在甲苯中的溶液,0.232mmol)滴加到(2-羟基-2-吡啶-2-基乙基){[5′-异丙基-2′~甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯(134.3mg,0.232mmol)在无水THF(10mL)内的搅拌着的溶液中。在室温搅拌1小时后,用饱和NH4Cl(10mL)中止反应,用EtOAc(3×20mL)萃取。将合并的萃取液干燥(硫酸钠),并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,25×160mm,0-70%EtOAc在己烷中的混合物梯度),获得了3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-吡啶-2-基-1,3-唑烷-2-酮。Rf=0.58(50%EtOAc/己烷)。LCMS计算值=471.19;实测值=471.2(M+1)+。
实施例8
5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲酸
将5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲腈(727mg,2.28mmol)和KOH(767mg,13.7mmol)在H2O(7.70mL)和i-PrOH(11.55mL)中的溶液在密封管中进行微波照射(300W 130℃,4小时)。将该反应混合物真空浓缩以除去i-PrOH。将所得水浆液用水(50mL)稀释,用EtOAc萃取(50mL)。将有机萃取液干燥(Na2SO4)并真空浓缩,获得了5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲酰胺。用浓盐酸将水层酸化,并用EtOAc(3×50mL)萃取。将合并的有机萃取液干燥(Na2SO4)并真空浓缩,获得了5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲酸,为无色固体。
1H NMR(CDCl3,500MHz)δ8.01(s,1H),7.71(d,J=7.8Hz,1H),7.41(d,J=7.8Hz,1H),7.14(d,J=8.1Hz,1H),7.04(s,1H),6.77(d,J=8.1,1H),3.68(s,3H),2.84(七重峰,J=6.7Hz,1H),1.19(d,J=6.7Hz,6H).
实施例9
[5′-异丙基-2-甲氧基-4-(三氟甲基)联苯-2-基]甲醇
在室温于氮气下,将硼烷在THF中的溶液(1M,859μL,0.859mmol)滴加到5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲酸和5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲酰胺(3∶1,96.8mg,0.286mmol)在无水THF内的搅拌着的溶液中。将该反应在室温搅拌3小时,并且小心地用水(10mL)中止反应。将该混合物用EtOAc(3×20mL)萃取,并将合并的萃取液用盐水洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,125×160mm,0-30%EtOAc在己烷中的混合物梯度),获得了[5′-异丙基-2-甲氧基-4-(三氟甲基)联苯-2-基]甲醇,为无色油状物。Rf=0.27(10%EtOAc/己烷)。
1H NMR(CDCl3,500MHz)δ7.89(br s,1H),7.62(dd,J=8.0,1.3Hz,1H),7.36(d,J=8.0Hz,1H),7.29(dd,J=8.5,2.3Hz,1H),7.03(d,J=2.3Hz,1H),6.96(d,J=8.5,1H),4.51(m,2H),3.74(s,3H),2.93(七重峰,J=7.0Hz,1H),2.51(s,1H),1.29(d,J=7.0Hz,6H).
实施例10
2-(溴甲基)-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯
在0℃于氮气下,将CBr4(112mg,0.211mmol)和Ph3P(55mg,0.211mmol)依次加到[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲醇(57.1mg,0.176mmol)在无水CH2Cl2(1mL)内的搅拌着的溶液中。将该溶液在室温搅拌1小时,并且将该反应混合物真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-20%EtOAc在己烷中的混合物梯度),获得了2-(溴甲基)-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯,为无色油状物。Rf=0.95(20%EtOAc/己烷)。LCMS计算值=387.05;实测值=387.0(M+1)+。
1H NMR(CDCl3,500MHz)δ7.83(br s,1H),7.60(dd,J=8.0,1.3Hz,1H),7.37(d,J=8.0Hz,1H),7.29(dd,J=8.5,2.3Hz,1H),7.14(d,J=2.3Hz,1H),6.95(d,J=8.5,1H),4.45(d,J=10.6Hz,1H),4.33(d,J=10.6Hz,1H),3.76(s,3H),2.94(七重峰,J=6.9Hz,1H),1.29(d,J=6.9Hz,6H).
实施例11
1-(4-甲基苯基)-2-硝基乙醇
在0℃,将4-甲基苯甲醛(325mg,319μL,2.71mmol)和硝基甲烷(531μL,9.89mmol)在无水EtOH(20mL)内的搅拌着的溶液用10%NaOH水溶液(m/v)(1.14mL,2.84mmol)处理,搅拌1小时并用2%乙酸水溶液(m/v)(8.54mL,2.84mmol)处理。将该反应在室温搅拌1小时,然后在水(50mL)和EtOAc(50mL)之间分配。将水层用EtOAc(2×50mL)萃取,将合并的有机萃取液用饱和NaHCO3(50mL)和盐水(50mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了1-(4-甲基苯基)-2-硝基乙醇,为无色油状物。
1H NMR(CDCl3,500MHz)δ7.28(d,J=8.1Hz,2H),7.21(d,J=8.1Hz,2H),5.42(dt,J=9.6,3.3Hz,1H),4.60(dd,J=13.3,9.7Hz,1H),4.49(dd,J=13.3,3.1Hz,1H),2.79(d,J=3.7,1H),2.36(s,3H).
实施例12
2-氨基-1-(4-甲基苯基)乙醇
将10%Pd/C(24mg)在1-(4-甲基苯基)-2-硝基乙醇(50mg,0.276mmol)在无水EtOH(1mL)中的溶液内的悬浮液在室温于15psi H2下搅拌过夜。将该反应混合物经由硅藻土过滤并将该滤液真空浓缩,获得了2-氨基-1-(4-甲基苯基)乙醇,为油状物。LCMS计算值=152.10;实测值=152(M+1)+。
1H NMR(CDCl3,500MHz)δ7.20(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),4.57(dd,J=7.9,3.9Hz,1H),2.86(dd,J=12.7,3.9Hz,1H),2.76(dd,J=12.7,7.9Hz,1H),2.33(s,3H).
实施例13
5-(4-甲基苯基)-1,3-唑烷-2-酮
在0℃于氮气下,将二异丙基乙胺(181mg,244μL,1.40mmol)和三光气(138mg,0.466mmol)依次加到2-氨基-1-(4-甲基苯基)乙醇(35.2mg,0.233mmol)在无水CH2Cl2(22mL)内的搅拌着的溶液中。将该反应在0℃搅拌1小时,然后真空浓缩至约5mL的体积。将该混合物用水(50mL)稀释,并用EtOAc(3×50mL)萃取。将合并的有机萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-80%EtOAc在己烷中的混合物梯度),获得了5-(4-甲基苯基)-1,3-唑烷-2-酮。Rf=0.41(50%EtOAc/己烷)。LCMS计算值=178.08;实测值=178.1(M+1)+。
1H NMR(CDCl3,500MHz)δ7.25(d,J=7.4Hz,2H),7.19(d,J=7.4Hz,2H),6.69(br s,1H),5.55(t,J=7.8Hz,1H),3.93(t,J=8.6Hz,1H),3.52(t,J=8.1Hz,1H),2.35(s,3H).
实施例14
3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-(4-甲基苯基)-1,3-唑烷-2-酮
在室温于氮气下,将氢化钠(6.4mg 60%在矿物油中的分散液,0.161mmol)加到5-(4-甲基苯基)-1,3-唑烷-2-酮(37.7mg,0.0973mmol)在无水THF(1mL)内的搅拌着的溶液中。将该反应搅拌30分钟,通过套管加入2-(溴甲基)-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯(19.0mg,0.107mmol)在无水THF(2mL)内的溶液。将该反应在室温搅拌3天。用饱和NH4Cl(10mL)中止反应,用EtOAc(3×20mL)萃取。将合并的有机萃取液用盐水(10mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-80%EtOAc在己烷中的混合物梯度),获得了3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-(4-甲基苯基)-1,3-唑烷-2-酮,为无色油状物。Rf=0.37(20%EtOAc/己烷)。LCMS计算值=484.21;实测值=484.2(M+1)+。1H NMR(苯-d6,500MHz,阻转异构体的1∶1混合物)
δ7.76(s,0.5H),7.65(s,0.5H),7.31(d,J=7.7Hz,1H),7.08(dd,J=8.4,2.4Hz,1H),7.05(br d,J=7.8Hz,1H),6.95-6.86(m,5H),6.58(t,J=7.7Hz,1H),4.74(t,J=8.0Hz,0.5H),4.70(t,J=8.0Hz,0.5H),4.50(d,J=15.7Hz,0.5H),4.42(d,J=15.7Hz,0.5H),4.25(d,J=15.7Hz,0.5H),4.11(d,J=15.7Hz,0.5H),3.26(s,1.5H),3.21(s,1.5H),2.81(t,J=8.6Hz,0.5H),2.76(七重峰,J=7.0Hz,1H),2.68(t,J=8.6Hz,0.5H),2.55(t,J=8.6Hz,0.5H),2.53(t,J=8.6Hz,0.5H),2.04(s,3H),1.20(t,J=7.0Hz,3H),1.19(t,J=7.0Hz,3H).
实施例15
1-[3,5-二(三氟甲基)苯基]-2-硝基丙-1-醇
在0℃,将3,5-二(三氟甲基)苯甲醛(1.00g,4.13mmol)和硝基乙烷(1.13g,1.08mL,15.1mmol)在无水EtOH(20mL)内的搅拌着的溶液用10%NaOH水溶液(m/v)(1.73mL,4.34mmol)处理,搅拌1小时,用2%乙酸水溶液(m/v)(13.0mL,4.32mmol)处理。将该反应在室温搅拌1小时,然后在水(50mL)和EtOAc(50mL)之间分配。将水层用EtOAc(2×50mL)萃取,将合并的有机萃取液用饱和NaHCO3(50mL)和盐水(50mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了苏-和赤-1-[3,5-二(三氟甲基)苯基]-2-硝基丙-1-醇的1.5∶1混合物,为无色油状物。1H NMR(CDCl3,500MHz)苏-非对映体:
δ7.88(br s,1H),7.86(br s,2H),5.22(d,J=8.4Hz,1H),4.77(dq,J=8.4,6.9Hz,1H),3.03(br s 1H),1.42(d,J=6.9Hz,3H),
赤-非对映体:
δ7.90(br s,1H),7.86(br s,2H),5.59(d,J=3.2Hz,1H),4.72(dq,J=3.2,6.9Hz,1H),3.03(br s 1H),1.50(d,J=6.9Hz,3H).
实施例16
2-氨基-1-[3,5-二(三氟甲基)苯基]丙-1-醇
将阮内镍(50mg)在苏-和赤-1-[3,5-二(三氟甲基)苯基]-2-硝基丙-1-醇的1.5∶1混合物(50mg,0.158mmol)在30%(v/v)HCO2H水溶液(0.75mL)和MeOH(10mL)中的溶液内的悬浮液在室温于15psi H2下搅拌过夜。将该反应混合物经由硅藻土过滤,并将该滤液真空浓缩以除去MeOH。用28%NH4OH水溶液将该水浆液调节至pH 9-10,用水(20mL)稀释,并用EtOAc(3×20mL)萃取。将合并的萃取液用盐水(10mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了苏-和赤-2-氨基-1-[3,5-二(三氟甲基)苯基]丙-1-醇的混合物,为无色固体。LCMS计算值=288.08;实测值=288.1(M+1)+。1H NMR(CDCl3,500MHz)苏型-非对映体:
δ7.79(br s,3H),4.35(br s,1H),3.25(br s,1H),2.59(br s,3H),0.86(d,J=6.1Hz,3H),
赤型-非对映体:
δ7.79(br s,3H),4.71(br s,1H),3.00(br s,1H),2.59(br s,3H),1.06(d,J=5.0Hz,3H).
实施例17
5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
在0℃于氮气下,将二异丙基乙胺(106mg,142μL,0.817mmol)和三光气(20.2mg,0.068mmol)依次加到2-氨基-1-[3,5-二(三氟甲基)苯基]丙-1-醇(39.1mg,0.136mmol)在无水CH2Cl2(10mL)内的搅拌着的溶液中。将该反应在0℃搅拌1小时,然后真空浓缩至约5mL的体积。将该混合物用水(50mL)稀释,用EtOAc(3×50mL)萃取。将合并的有机萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-70%EtOAc在己烷中的混合物梯度),获得了苏-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(17.5mg)和赤-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(14.4mg),为无色固体,苏型-非对映体:Rf=0.63(50%EtOAc/己烷)。LCMS计算值=314.06;实测值=314.1(M+1)+。
1H NMR(CDCl3,600MHz)δ7.90(br s,1H),7.83(br s,2H),6.71(br s,1H),5.17(d,J=7.0Hz,1H),3.86(br pentet,J=6.2Hz,1H),1.48(d,J=6.2Hz,1H).
使用手性HPLC(AS柱,20×250mm,20%i-PrOH在庚烷中的混合物)将该化合物分离成其对映体(4R,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮和(4S,5S)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮,赤型-非对映体:Rf=0.38(50%EtOAc/己烷)。LCMS计算值=314.06;实测值=314.1(M+1)+。
1H NMR(CDCl3,600MHz)δ7.90(br s,1H),7.79(br s,2H),5.83(d,J=8.0Hz,1H),5.34(br s,1H),4.31(br pentet,J=7.0Hz,1H),0.84(d,J=6.6Hz,1H).
使用手性HPLC(AS柱,20×250mm,15%i-PrOH在庚烷中的混合物)将该化合物分离成其两种对映体(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮和(4R,5S)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮。
手性合成(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
该中间体可通过下面三步法由手性原料CBZ-1-丙氨酸直接制得。化合物(4R,5S)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮可通过类似方法由CBZ-D-丙氨酸制得。
步骤1
在氮气下,将CBZ-1-丙氨酸(6.5kg,28.5mol)、HOBT-水合物(4.8kg,34.8mol)、Weinreb胺-HCl盐(3.4kg,36.2mol)和THF(32L)加到干净的烧瓶中。将该混合物冷却至0-10℃,然后在低于25℃的温度下缓慢地加入DFEA(12.4L)。之后在15℃-25℃冷却下缓慢地加入EDC-HCl(7Kg,36.2mol)。将该浆液在20℃~25℃老化过夜。然后将该混合物冷却至0℃-10℃,缓慢地加入3N HCl(12L)。然后加入IPAC(32L),并分离各层。将有机层用HCl(13L)洗涤一次,用8%NaHCO3(13L)洗涤两次(注意:形成泡沫)。然后将有机层在50℃真空浓缩至约15L。将该澄清溶液缓慢地冷却至室温,让产物结晶。然后缓慢地加入庚烷(~70L)。把该浆液过滤,用庚烷(18L)洗涤,在滤器容器中于室温干燥。获得了具有>99.9%ee的产物,通过手性HPLC测定的。
步骤2
将得自步骤1的Weinreb酰胺(6kg,22.5mol)和3,5-二(三氟甲基)溴苯(4.85L,28.1mol)溶解在无水THF(24L)中。将该溶液用氮气吹扫以除去氧气。这是水含量应当<500ppm。如果需要的话,进行常压蒸馏以除去水。将该溶液冷却至-10℃,通过加液漏斗向该反应中缓慢地(2小时)加入异-PrMgCl在THF中的溶液(56.4mol),保持反应温度≤-5℃。让该溶液温热至20℃,在20℃老化过夜直至酰胺<0.5LCAP。然后将该溶液在氮气下冷却至-10℃,用2小时缓慢地加到保持在0-5℃的5N HCl(14L)中。加入MTBE(12L),将该双相混合物搅拌5分钟。温热至20℃-25℃后,将其放置30分钟,然后分离各层。将有机层用水(12L)洗涤两次。将有机层通过1微米在线PTEE容器转移到蒸馏烧瓶中,然后真空浓缩(内温<40℃)至~12L以保持搅拌体积。将该溶液用搅拌共沸干燥,再次浓缩至最小搅拌体积,该溶液直接用于下一步骤。
如果需要固体产物,将庚烷加到有机层中,然后浓缩至最小搅拌体积。继续在40℃-55℃进行真空蒸馏直至终体积为40L。将该溶液冷却至35℃-37℃,加入晶种(-0.5%,30克),然后老化30分钟以生长完全的晶种床。用2-3小时把该浆液冷却至10℃。然后将该浆液过滤,用5℃庚烷(18L)洗涤,使用真空/氮气吹扫过夜让其在滤器容器中完全干燥。获得的干燥的固体,其具有>99.9ee%。如果旋光纯度不足的话,可将该酰胺从纯庚烷中重结晶。
步骤3
在惰性气氛下,将TFA(9L)加到100L Buchi反应器中,并冷却至-5℃。加入固体形式的得自步骤2的酮产物(5.50kg,13.1mol),然后加入TFA洗涤液(2L)。将该溶液冷却至-5℃,并且搅拌直至所有固体溶解。用1小时(分两批)缓慢地加入甲硅烷(2.18kg,15.7mol),同时把温度保持在<0℃。让该反应在-2至-6℃老化15-20小时,这时LC表明剩余<2%的酮。通过将13.6kg KOH丸(87w%)缓慢地加到10L水中,同时保持该高放热溶解<30℃来制备50w/w%KOH溶液。将该溶液在冰箱中贮藏。
用~2L 50w/w%KOH溶液在剧烈搅拌和冷却下中止该反应,把温度保持在约20℃。加入THF(16.5L,上述在冰箱中贮藏的),然后缓慢地加入剩余KOH溶液(约13.7L),加入2L水洗涤液,同时保持温度<20℃。KOH的加入完成后,将该反应在室温老化。3小时后,将27.5L PAC和20L 20%w/v NaCl水溶液处理该反应。
分离出水层和有机层。将有机层依次用26L 20%w/v NaCl水溶液、36L水、31L 0.5N HCl和32L水洗涤。将有机层浓缩至约10L。加入庚烷(20L),形成了晶体。将有机层浓缩至约10L。再次加入庚烷(20L),并将有机层浓缩至约10L。加入庚烷(22L),把该浆液在室温老化。过滤出固体,用24L庚烷洗涤。获得了固体产物(98.8%纯度,>99.95%ee,通过LC测定)。将固体再溶解在12.5L MeOH中(放热)。在室温加入3L水,将该混合物老化以开始结晶。在室温用60分钟加入水(9.5L)。老化60分钟后,把该浆液过滤,将固体用5L MeOH/水(1/1.5)、5L MeOH/水(1/4)和4L水洗涤。将固体产物在50℃真空干燥(99.9%纯度,通过LC测定,>99.95%ee)。
还使用Al(O-i-Pr)3作为还原剂来进行步骤3中的反应。例如,将酮(6kg)与0.3当量Al(O-i-Pr)3(790g)在12L IPA和18L甲苯中于50℃加热15.5小时。将该溶液冷却至室温,在剧烈搅拌下加入固体KOH丸(1.35kg),同时将温度保持在<25℃。约2小时后,当HPLC表明>99.5%结晶时,加入33L 1N HCl溶液以中止反应,将其保持在<25℃。如果形成了碎片层固体,应当将其过滤以提高对映体过量。然后将有机层首先用36L 0.5N HCl洗涤。然后用6L IPA与45L水的混合物洗涤,最后用6L IPA与36L水的混合物洗涤。将有机层转移到在线滤器内。在约40℃把溶剂替换为庚烷(目标体积是~42L)直至剩余<2v%的甲苯。在室温老化2小时,获得了固体产物。
用于步骤3所用分析的HPLC方法:
Ace-C8柱250×4.6mm A:MeCN;B:0.1%H3PO4的H2O溶液;
梯度:在0分钟的5A∶95B至在9分钟的95A∶5B;保持95A∶5B直至13分钟;返回5A∶95B保持13-15分钟
条件:35℃,1.5mL/分钟,210nm
实施例18
赤型-5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
在室温于氮气下,将二(三甲基甲硅烷基)氨基锂(172μL 1M在THF中的溶液,0.172mmol)加到赤-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(50mg,0.129mmol)在无水THF(1mL)内的搅拌着的溶液中。将该反应搅拌15分钟,通过套管加入2-(溴甲基)-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯(27.0mg,0.0861mmol)在无水THF(2mL)内的溶液。将该反应在室温搅拌3天。用饱和NH4Cl(10mL)中止反应,用EtOAc(3×20mL)萃取。将合并的有机萃取液用盐水(10mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-40%EtOAc在己烷中的混合物梯度),获得了赤型-5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮,为无色油状物。Rf=0.64(20%EtOAc/己烷)。LCMS计算值=620.18;实测值=620.2(M+1)+。1H NMR(苯-d6,600MHz,阻转异构体的1∶1混合物)
δ7.94(s,0.5H),7.72(s,0.5H),7.64(s,0.5H),7.63(s,0.5H),7.39-7.34(m,3H),7.12-7.04(m,2H),6.95(d,J=2.1Hz,0.5H),6.86(d,J=1.7Hz,0.5H),6.64(d,J=8.5Hz,0.5H),6.56(d,J=8.5Hz,0.5H),4.99(d,J=15.9Hz,0.5H),4.93(d,J=15.9Hz,0.5H),4.73(d,J=7.9Hz,0.5H),4.61(d,J=7.9Hz,0.5H),3.88(d,J=15.9Hz,0.5H),3.82(d,J=15.9Hz,0.5H),3.35(s,1.5H),3.24(s,1.5H),3.05(七重峰,J=6.9Hz,0.5H),3.01(七重峰,J=6.9Hz,0.5H),2.75(m,1H),1.19(dd,J=6.9,2.7Hz,3H),1.17(dd,J=10.9,6.9Hz,3H),-0.18(d,J=6.4Hz,1.5H),-0.33(t,J=6.4Hz,1.5H).
使用手性HPLC(AD柱,20×250mm,3%i-PrOH在庚烷中的混合物)将该化合物分离成其两种对映体(4R,5S)-5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮和(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。
实施例19
4-[3,5-二(三氟甲基)苯基]-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}咪唑烷-2-酮
步骤A:{2-[3,5-二(三氟甲基)苯基]-2-羟基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯
向1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇(实施例6步骤B,325.0mg,0.561mmol)在CH2Cl2(15mL)内的溶液中加入BOC2O(122mg,0.561mmol)和DIPEA(98μL,0.561mmol)。将该反应在室温搅拌。5小时后,再加入BOC2O(50mg,0.229mmol)和DIPEA(50μL,0.287mmol)。将该反应在室温搅拌48小时。然后将该溶液浓缩至~2mL,用己烷(8mL)稀释,通过快速色谱法纯化,用10-20%EtOAc/己烷洗脱,获得了{2-[3,5-二(三氟甲基)苯基]-2-羟基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯。Rf=0.38(25%EtOAc/己烷)。
LCMS=580.3(M+1-BOC)+.1H NMR(CD2Cl2,500MHz)δ7.78(s,1H),7.54-7.67(m,4H),7.23-7.33(m,2H),6.90-6.95(m,2H),3.15-4.82(m,9H),2.87(m,1H),1.19-1.43(m,15H).
步骤B:甲磺酸1-[3,5-二(三氟甲基)苯基]-2-((叔丁氧基羰基){[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙基酯
向{2-[3,5-二(三氟甲基)苯基]-2-羟基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯(350.1mg,0.516mmol)在CH2Cl2(15mL)内的溶液中加入DIPEA(450μL,2.58mmol)。将该溶液冷却至0℃,加入MsCl(100μL,1.29mmol)。在0℃搅拌45分钟后,将该反应用EtOAc(100mL)稀释,用饱和NaHCO3(25mL)、盐水(25mL)、1N HCl(25mL)和盐水(2×25mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。让残余物通过短的硅胶塞,用25%EtOAc/己烷洗涤并浓缩。产物甲磺酸1-[3,5-二(三氟甲基)苯基]-2-((叔丁氧基羰基){[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙基酯不用进一步特征鉴定而立即用于下一反应。Rf=0.33(25%EtOAc/己烷)。步骤C:{2-叠氮基-2-[3,5-二(三氟甲基)苯基]乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯
将得自前一反应的甲磺酸1-[3,5-二(三氟甲基)苯基]-2-((叔丁氧基羰基){[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙基酯溶解在DMPU(15mL)和中,用NaN3(140mg,2.15mmol)处理。将该反应在室温搅拌15小时,然后用EtOAc(75ml)稀释。将该溶液用H2O(5×40mL)和盐水(40mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。用20%EtOAc/己烷纯化残余物,获得了{2-叠氮基-2-[3,5-二(三氟甲基)苯基]乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯。Rf=0.52(15%EtOAc/己烷)。
LCMS=605.3(M+1-BOC)+.1H NMR(C6D6,500MHz,70℃)δ7.80(s,1H),7.67(s,1H),7.48(s,2H),7.36(d,J=7.8Hz,1H),7.01-7.11(m,2H),6.89(m,1H),6.64(d,J=8.6Hz,1H),4.22-4.69(m,3H),3.28(s,3H),2.61-3.16(m,3H),1.34(s,9H),1.13-1.18(m,6H).
步骤D:{2-氨基-2-[3,5-二(三氟甲基)苯基]乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯和[1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙基]氨基甲酸叔丁酯的混合物
向{2-叠氮基-2-[3,5-二(三氟甲基)苯基]乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基)氨基甲酸叔丁酯(300mg,0.426mmol)在EtOAc(15mL)内的溶液中加入10%Pd/C(100mg)。将该反应置于H2下并在室温搅拌5小时。这时反应完全,获得了两种产物的混合物,{2-氨基-2-[3,5-二(三氟甲基)苯基]乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯和[1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙基]氨基甲酸叔丁酯。过滤出催化剂并将该滤液浓缩,获得了产物混合物。LCMS=679.3(M+1)+。产物不用进一步纯化或特征鉴定而用于下一反应。
步骤E:1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}乙烷-1,2-二胺
向283.5mg(0.418mmol){2-氨基-2-[3,5-二(三氟甲基)苯基]乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯和[1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙基]氨基甲酸叔丁酯的混合物在CH2Cl2(15mL)内的溶液中加入TFA(1.5mL)。将该反应在室温搅拌5小时,然后倒入1N NaOH(50mL)内。将该混合物用CH2Cl2(3×50mL)萃取,将有机萃取液合并,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用5-10%MeOH/CH2Cl2洗脱,获得了1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}乙烷-1,2-二胺。Rf=0.46(10%MeOH/CH2Cl2)。
LCMS=579.2(M+1)+.1H NMR(CD2Cl2,500MHz)δ7.83(s,2H),7.77(s,2H),7.55(d,J=7.8Hz,1H),7.31(d,J=8.1Hz,1H),7.24(dd,J=8.4,2.3Hz,1H),6.99(d,J=2.0Hz,1H),6.92(d,J=8.5Hz,1H),4.06(m,1H),3.59-3.76(m,2H),3.69(s,3H),2.88(m,1H),2.67(dd,J=11.9,4.3Hz,1H),2.51(m,1H),1.22(d,J=6.9Hz,6H).
步骤F:4-[3,5-二(三氟甲基)苯基]-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}咪唑烷-2-酮
将1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}乙烷-1,2-二胺(125.2mg,0.217mmol)在CH2Cl2(30mL)中的溶液冷却至0℃,加入DIPEA(227μL,1.30mmol)。然后加入三光气(32.2mg,0.109mmol)。将该反应在0℃搅拌45分钟,然后倒入饱和NaHCO3(20mL)内。将该混合物用EtOAc(100mL)萃取,将有机层用盐水(25mL)洗涤,用硫酸钠干燥,过滤并浓缩。将残余物通过快速色谱法纯化,用40%EtOAc/己烷洗脱,获得了4-[3,5-二(三氟甲基)苯基]-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}咪唑烷-2-酮。Rf=0.22(40%EtOAc/己烷)。LCMS=605.2(M+1)+。1H NMR(CDCl3,500MHz)(阻转异构体以1∶1比例存在;观察到某些峰重叠)
δ7.83(s,1H),7.78(s,2H),7.55-7.62(m,2H),7.32(d,J=7.8Hz,1H),7.22(m,1H),6.94(s,1H),6.88(d,J=8.3Hz,1H),5.33&5.24(2单峰,1H),4.80-4.88(m,1H),4.00-4.61(m,2H),3.72&3.70(2单峰,3H),3.55-3.59(m,1H),2.83-2.93(m,2H),1.17-1.23(m,6H).
可使用AD手性柱,使用5%IPA/庚烷洗脱,来分离出该化合物的两种对映体。
实施例20
(4R)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-苯基咪唑烷-2-酮
步骤A:[(1R)-2-羟基-1-苯基乙基]氨基甲酸叔丁酯
向(2R)-2-氨基-2-苯基乙醇(400mg,2.91mmol)在CH2Cl2(15mL)内的溶液中加入BOC2O(636mg,2.91mmol)和DIPEA(507μL,2.91mmol)。将该反应在室温搅拌18小时,用EtOAc(75mL)稀释,用H2O、盐水、1N HCl、盐水、饱和NaHCO3和盐水(分别是25mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用50%EtOAc/己烷洗脱,获得了[(1R)-2-羟基-1-苯基乙基]氨基甲酸叔丁酯。Rf=0.23(40%EtOAc/己烷)。
1H NMR(CDCl3,600MHz)δ7.27-7.37(m,5H),5.27(bs,1H),4.78(bs,1H),3.83(bs,2H),2.46(bs,1H),1.44(bs,9H).
步骤B:[(1R)-2-氧代-1-苯基乙基]氨基甲酸叔丁酯
在0℃,向[(1R)-2-羟基-1-苯基乙基]氨基甲酸叔丁酯(200mg,0.844mmol)在CH2Cl2(20mL)内的溶液中加入Dess-Martin periodinane(447mg,1.05mmol)。将该反应在0℃搅拌15分钟,然后在室温搅拌30分钟。然后将该溶液用EtOAc(75mL)稀释,用10%K2CO3(2×30mL)迅速洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。在短硅胶柱上纯化残余物,用50%EtOAc/己烷洗脱,获得了[(1R)-2-氧代-1-苯基乙基]氨基甲酸叔丁酯。1H NMR(CDCl3,600MHz)(观察到主要和次要构象异构体)给出主要构象异构体的数据)
δ9.53(s,1H),7.29-7.40(m,5H),5.80(bs,1H),5.31(m,1H),1.42(s,9H).
该产物立即用于以下反应。
步骤C:[(1R)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)-1-苯基乙基]氨基甲酸叔丁酯
向[(1R)-2-氧代-1-苯基乙基]氨基甲酸叔丁酯(113.8mg,0.484mmol)在MeOH(7mL)内的溶液中加入1-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲胺(98mg,0.303mmol),然后加入NaCNBH3(30mg,0.477mmol)和HOAc(2滴)。将该反应在室温搅拌过夜,用EtOAc稀释(75mL),用1N NaOH(25mL)和盐水(25mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用5-25%EtOAc/己烷洗脱,获得了[(1R)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)-1-苯基乙基]氨基甲酸叔丁酯。Rf=0.30(25%EtOAc/己烷)。LCMS=543.4(M+1)+。
步骤D:(1R)-N2-{[5-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1-苯基乙烷-1,2-二胺
向含有少量杂质的[(1R)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)-1-苯基乙基]氨基甲酸叔丁酯(150mg,0.277mmol)在CH2Cl2(10mL)内的溶液中加入TFA(1mL)。将该反应在室温搅拌2小时,然后倒入1N NaOH(25mL)。将该混合物用CH2Cl2(3×25mL)萃取。将合并的有机萃取液用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化所得残余物,用0-10%MeOH/CH2Cl2洗脱,获得了(1R)-N2-{[5-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1-苯基乙烷-1,2-二胺。Rf=0.27(10%MeOH/CH2Cl2)。LCMS=443.4(M+1)+。
步骤E:(4R)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-苯基咪唑烷-2-酮
将(1R)-N2-{[5-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1-苯基乙烷-1,2-二胺(96.0mg,0.22mmol)在CH2Cl2(15mL)中的溶液冷却至0℃,加入DIPEA(230μL,1.32mmol),然后加入三光气(32.6mg,0.11mmol)。45分钟后,将该反应倒入饱和NaHCO3(25mL)中。将该混合物用EtOAc(75mL)萃取。将有机层用盐水洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用10-60%EtOAc/己烷洗脱,获得了(4R)-1-{[5′-异丙基-2′~甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-苯基咪唑烷-2-酮。通过手性HPLC,使用AD手性柱和15%IPA/庚烷来除去次要对映体,获得了对映体纯的产物。Rf=0.16(40%EtOAc/己烷)。LCMS=469.3(M+1)+。1H NMR(CDCl3,500MHz)(阻转异构体以1∶1比例存在,观察到某些峰重叠)
δ7.65(m,1H),7.54(d,J=7.7Hz,1H),7.21-7.36(m,7H),6.87-6.94(m,2H),4.65-4.77(m,2H),4.10-4.49(m,2H),3.71&3.72(2单峰,3H),3.49-3.53(m,1H),2.94-2.97(m,1H),2.87(m,1H),1.19-1.24(m,6H).
实施例21
4-(4-氯苯基)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}咪唑烷-2-酮
步骤A:1-(4-氯苯基)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇
将1-[5′-异丙基-2′-甲氧基-5-(三氟甲基)联苯-2-基]甲胺(300mg,1.1mmol)和2-(4-氯苯基)环氧乙烷(143μL,1.2mmol)在异丙醇(10.5mL)中的溶液加热回流24小时。将该反应浓缩,并通过快速色谱法纯化,用5%-80%EtOAc/己烷洗脱,获得了1-(4-氯苯基)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇。Rf=0.37(50%EtOAc/己烷)。
LCMS=478.1(M+1)+.1H NMR(CDCl3,500MHz)δ7.70(s,1H),7.55(d,J=7.5Hz,1H),7.33-7.19(m,6H),6.97(s,1H),6.90(d,J=8.5Hz,1H),4.52(m,1H),3.77-3.62(m,5H),2.89(m,1H),2.71(m,1H),2.51(m,1H),1.24(d,J=7.0Hz,6H).
步骤B:[2-(4-氯苯基)-2-羟基乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯
向1-(4-氯苯基)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)乙醇(40mg,0.08mmol)在CH2Cl2(2mL)内的溶液中加入二碳酸二苄酯(24mg,0.08mmol)。将该反应在室温搅拌24小时,然后倒入H2O(15mL)内。将所得混合物用EtOAc(50mL)萃取,将有机层用盐水(15mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用5%-60%EtOAc/己烷洗脱,获得了[2-(4-氯苯基)-2-羟基乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯。Rf=0.20(25%EtOAc/己烷)。LCMS=612.2(M+1)+。1H NMR(C6D6,600MHz,峰变宽和/或重叠;存在旋转异构体和/或阻转异构体)
δ7.98-6.45(m,15H),5.00-3.46(m,6H),3.20-2.96(m,5H),2.72(m,1H),1.20-1.15(m,6H).
步骤C:[2-叠氮基-2-(4-氯苯基)乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯
将[2-(4-氯苯基)-2-羟基乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯(44mg,0.07mmol)在CH2Cl2(6mL)中的溶液冷却至0℃,加入N,N-二异丙基乙胺(63μL,0.36mmol),然后加入甲磺酰氯(14μL,0.18mmol)。将该反应在0℃搅拌30分钟,然后倒入饱和碳酸氢钠(15mL)内。将所得混合物用EtOAc(50mL)萃取,并将有机层用盐水(15mL)洗涤,用硫酸钠干燥,经由短的硅胶柱过滤,并浓缩。将残余物再溶解在DMPU(6mL)内,加入叠氮化钠(12mg,0.18mmol)。将该反应在室温搅拌24小时,然后倒入H2O(15mL)内。将所得混合物用EtOAc(50mL)萃取,将有机层用H2O(2×15mL)和盐水(15mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用25%EtOAc/己烷洗脱,获得了[2-叠氮基-2-(4-氯苯基)乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯。Rf=0.66(25%EtOAc/己烷)。LCMS=637.3(M+1)+。1H NMR(C6D6,600MHz,峰重叠;存在旋转异构体和/或阻转异构体)
δ8.03-6.52(m,15H),5.00-5.08(m,2H),4.76-4.12(m,3H),3.28-2.86(m,5H),2.77(m,1H),1.23-1.18(m,6H).
步骤D:[2-氨基-2-(4-氯苯基)乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯
向[2-叠氮基-2-(4-氯苯基)乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯(30mg,0.05mmol)在THF(1mL)内的溶液中加入PtO2(8mg),将该反应在室温于氢气下搅拌1小时。通过经由硅藻土塞过滤来除去催化剂,用100%EtOAc洗涤,并将该滤液浓缩,获得了[2-氨基-2-(4-氯苯基)乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯粗产物。Rf=0.66(25%EtOAc/己烷)。LCMS=611.3(M+1)+。
步骤E:4-(4-氯苯基)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}咪唑烷-2-酮
向[2-氨基-2-(4-氯苯基)乙基]{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸苄酯(30mg,0.05mmol)在THF(2mL)内的溶液中加入二(三甲基甲硅烷基)氨基锂(295μL 0.5M在甲苯中的溶液,0.147mmol),将该反应在室温搅拌30分钟,然后用饱和NH4Cl(15mL)中止反应。将所得混合物用EtOAc(25mL)萃取,将有机层用H2O(15mL)和盐水(15mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用5%-60%EtOAc/己烷洗脱,获得了4-(4-氯苯基)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}咪唑烷-2-酮。Rf=0.46(5%MeOH/CH2Cl2)。LCMS=503.1(M+1)+。1H NMR(C6D6,600MHz,观察到阻转异构体;峰重叠)
δ7.90-7.03(m,6H),6.89-6.20(m,4H),4.69-3.88(m,3H),3.16(s,3H),2.88-2.30(m,3H),1.18-1.13(m,6H).
实施例22
(4R)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-3-甲基-4-苯基咪唑烷-2-酮
向(4R)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-苯基咪唑烷-2-酮(12.6mg,0.0269mmol)在THF(1.5mL)内的溶液中加入MeI(10μL,0.162mmol),然后加入KHMDS(162μL 0.5M在甲苯中的溶液,0.081mmol)。将该反应在室温搅拌10分钟,然后倒入水(10mL)内。将该混合物用EtOAc(30mL)萃取,将有机层用盐水(10mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用50%EtOAc/己烷洗脱,获得了(4R)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-3-甲基-4-苯基咪唑烷-2-酮。Rf=0.26(40%EtOAc/己烷)。LCMS=483.2(M+1)+。1H NMR(CDCl3,500MHz,观察到阻转异构体;峰重叠)
δ7.68-7.53(m,2H),7.21-7.36(m,7H),6.87-6.94(m,2H),4.08-4.56(m,3H),3.72&3.71(2单峰,3H),3.34-3.38(m,1H),2.77-2.89(m,2H),2.67&2.63(2单峰,3H),1.18-1.26(m,6H).
按照实施例1-22中描绘的方法制得了在表1中列出的化合物:
表1
实施例50
4-[3,5-二(三氟甲基)苯基]-2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,2,5-噻二唑烷1,1-二氧化物
将1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}乙烷-1,2-二胺(8.0mg,0.014mmol)和磺酰胺(2.0mg,0.021mmol)在吡啶(300μL)中的溶液在密封管中加热至120℃。3小时后,将该反应冷却至室温,用25mL EtOAc稀释。将该有机溶液用1NHCl(2×5mL)和盐水(1×5mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过PTLC纯化残余物,使用25%EtOAc/己烷洗脱,获得了4-[3,5-二(三氟甲基)苯基]-2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,2,5-噻二唑烷1,1-二氧化物。Rf=0.29(25%EtOAc/己烷)。LCMS=641.1(M+1)+。1H NMR(CDCl3,500MHz;存在阻转异构体)
δ7.58-7.85(m,5H),7.35-6.86(m,4H),4.82-4.94(m,2H),3.54-4.42(m,6H),2.71-2.91(m,2H),1.11-1.26(m,6H).
实施例51
5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮
步骤A:[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲醇
向1.08g 5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲腈(实施例3)在25mL n-PrOH内的溶液中加入0.97g KOH。将该混合物加热至回流,并在该温度下搅拌36小时,然后冷却并浓缩至澄清油状物。将该油状物在15mL水与10mL Et2O之间分配。将水相用10mL Et2O萃取。将合并的有机层用盐水(15mL)洗涤,用硫酸钠干燥,并浓缩。将残余物在Biotage Horizon 4OS柱上通过快速色谱法纯化,使用1CV 95%己烷-5%5%甲酸在丙酮中的混合物洗脱,然后使用5-100%丙酮在己烷中的混合物用10CV进行线性梯度洗脱。将所得白色固体溶解在10mL9∶1苯-MeOH中,加入过量TMSCH2N2。将该混合物在室温搅拌10分钟,然后用三氟乙酸中止反应并浓缩。把残余物溶解在15mL乙醚中并冷却至0℃。经由加液漏斗滴加1-M LiAlH4在乙醚中的溶液(5.4mL)。一旦加入完全,移去冷却浴,将该混合物在室温搅拌2小时,然后再冷却至0℃,通过滴加0.2mL水、0.2mL 15%NaOH水溶液和0.5mL水来中止反应。一旦加入完全,移去冷却浴,并将该混合物在室温搅拌30分钟,过滤(用Et2O洗涤固体)并浓缩。在Biotage Horizon,4OS柱上进行快速色谱法纯化,使用1CV 4%EtOAc在己烷中的混合物洗脱,然后使用4-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)307.2(M-17)。
1HNMR(500MHz,CDCl3):δ7.85(s,1H),7.60(d,J=8Hz,1H),7.33(d,J=8Hz,1H),7.25(dd,J=2Hz,9Hz,1H),6.99(d,J=2.5Hz,1H),6.93(d,J=8.5Hz,1H),4.49(m,2H),3.74(s,3H),2.90(七重峰,J=7Hz,1H),1.25(d,J=7Hz,6H).
步骤B:5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲醛
向0.725g[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲醇在10mL CH2Cl2内的溶液中加入1.14g Dess-Martin periodinane。将该混合物在室温搅拌30分钟,然后过滤并浓缩。将残余物在Biotage Horizon,4OS柱上通过快速色谱法纯化,用1CV 1%EtOAc在己烷中的混合物洗脱,然后使用1-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)323.2(M+1)。
1H NMR(500MHz,CDCl3):δ9.81(s,1H),8.28(s,1H),7.88(dd,J=1.5Hz,8Hz,1H),7.54(d,J=8Hz,1H),7.33(dd,J=2Hz,8Hz,1H),7.16(d,J=2.5Hz,1H),6.95(d,J=8.5Hz,1H),3.74(s,3H),2.95(七重峰,J=7Hz,1H),1.29(d,J=7Hz,6H).
步骤C:2-氨基-1-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]乙醇
向0.679g 5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲醛在1.5mLCH2Cl2内的溶液中加入约5mg ZnI2,然后加入0.23g三甲基甲硅烷基氰化物。将该混合物在室温搅拌3小时,然后在15mL水与10mL Et2O之间分配。将水相用2×10mL Et2O萃取。将合并的有机相用硫酸钠干燥并浓缩。把残余物溶解在15mL乙醚中,冷却至0℃。经由加液漏斗滴加1-M L1AIH4在乙醚中的溶液(4.2mL)。一旦加入完全,移去冷却浴,将该混合物在室温搅拌过夜,然后在冷却至0℃,滴加0.15mL水、0.15mL 15%NaOH水溶液和0.4mL水来中止反应。一旦加入完全,移去冷却浴,将该混合物在室温搅拌30分钟,过滤(用Et2O洗涤固体)并浓缩,获得了本标题化合物,其不用进一步纯化直接使用。质谱(ESI)354.2(M+1)。某些1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.88(s,1H),7.55(app t,J=7.5Hz,1H),7.22-7.28(m,2H),6.99,6.95(d,J=2.5Hz,1H),6.92,6.90(sm 1H),4.52(m,1H),3.70(s,3H),2.90(七重峰,J=7Hz,1H),2.81(m,1H),2.60-2.70(m,2H),1.23-1.28(m,6H).
步骤D:5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮
向0.44g 2-氨基-1-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]乙醇在15mL CH2Cl2内的0℃溶液中加入0.241g二异丙基乙胺,然后加入0.185g三光气。将该混合物在0℃搅拌30分钟,然后用30mL EtOAc和20mL饱和NaHCO3稀释。分离各相,将有机相用20mL盐水洗涤,干燥(Na2SO4)并浓缩。将残余物在Biotage Horizon,4OS柱上通过快速色谱法纯化,用1CV 5%EtOAc在己烷中的混合物洗脱,然后使用5-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)380.2(M+1)。1H NMR信号由于旋转对映异构现象而重叠
1H NMR(500MHz,CDCl3):δ7.90,7.86(s,1H),7.66(d,J=8Hz,1H),7.35(d,J=8Hz,1H),7.27(dd,J=2.5Hz,8.5Hz 1H),7.03(d,J=2.5Hz,0.5H),6.87-6.93(m,1.5H),5.65,5.50(t,J=8Hz,1H),5.23,5.09(s,1H),3.75(s,1.5H),3.69(s,1.5H),3.68,3.51(t,J=9Hz,1H),3.31,3.19(t,J=8.5Hz,0.5H),2.90(七重峰,J=7Hz,1H),1.25,1.24(d,J=7Hz,6H).
在Chiralpak AD 2×25cm上通过HPLC进一步纯化,使用10%异丙醇在庚烷中的混合物以9mL/分钟洗脱,获得了两种对映体:对映体A,tR=15.1分钟;对映体B,tR=17.4分钟。
实施例52
3-苄基-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮
向44mg 5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮在1mL DMF内的0℃溶液中加入10mg氢化钠。将该混合物在室温搅拌10分钟,然后加入24mg苄基溴。将该混合物在室温搅拌过夜,然后用15mL EtOAc和5mL水稀释。分离各相,将有机相用各5mL水和盐水洗涤,用硫酸钠干燥并浓缩。将残余物在BiotageHorizon,25S柱上通过快速色谱法纯化,用1CV己烷洗脱,然后使用0-50%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)470.1(M+1)。
1H NMR(500MHz,CDCl3):δ7.86,7.76(s,1H),7.62(d,J=8Hz,1H),7.14-7.40(m,7H),7.01,6.77(d,J=2.5Hz,1H),6.87,6.83(d,J=8.5Hz,1H),5.45,5.53(m,1H),4.30-4.53(m,2H),3.73,3.55(s,3H),3.48,3.30(m,1H),3.10,2.96(t,J~8.5Hz,1H),2.89,2.82(七重峰,J=7Hz,1H),1.24,1.16(m,6H).
实施例53
3-[3,5-二(三氟甲基)苄基]-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮(外消旋)
按照实施例50中描述的方法,使用43mg 5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮和43mg 3,5-二(三氟甲基)苄基溴,获得了本标题化合物。质谱(ESI)606.1(M+1)。1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.58-7.88(m,5H),7.34(d,J=8Hz,1H),7.23(m,1H),7.02,6.79(d,J=2Hz,1H),6.88,6.85(d,J=8.5Hz,1H),5.45,5.42(m,1H),4.52-4.64(m,1.5H),4.36(d,J=15.5Hz,0.5H),3.74,3.57(s,3H),3.49,3.34(m,1H),3.09,2.99(t,J~8.5Hz,1H),2.89,2.81(七重峰,J=7Hz,1H),1.24,1.12(m,6H).
实施例54
3-[3,5-二(三氟甲基)苄基]-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮(对映体A)
按照实施例50中描述的方法,使用43mg 5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮,对映体A和43mg 3,5-二(三氟甲基)苄基溴,获得了本标题化合物。在Chiralpak AS 4.6×250mm上进行分析HPLC,用5%异丙醇在庚烷中的混合物以0.5mL/分钟洗脱:tR=9.9分钟
实施例55
3-[3,5-二(三氟甲基)苄基]-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮(对映体B)
按照实施例50中描述的方法,使用44mg 5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮,对映体B和43mg 3,5-二(三氟甲基)苄基溴,获得了本标题化合物。在Chiralpak AS 4.6×250mm上进行分析HPLC,用5%异丙醇在庚烷中的混合物以0.5mL/分钟洗脱:tR=11.0分钟
实施例56
1-(4-氟苯基)-1-羟基丙酮
在氮气氛下,将LaCl3(26mg,0.104mmol)在无水THF(7.8mL)中的悬浮液冷却至-78℃并搅拌1分钟。加入n-BuLi溶液(1.6M在己烷中的溶液,195μL,0.312mmol)加入并继续搅拌15分钟。将该反应温热至0℃并搅拌30分钟。加入三甲基甲硅烷基氰化物(31mg,42μL,0.312mmol),将该反应在0℃搅拌30分钟,并用30分钟温热至室温。通过套管加入乙酰基三甲基甲硅烷(Cunico,R.F.,Kuan,C.-P.,J.Org.Chem.,1985,50,5410-5413)(121mg,1.04mmol)和4-氟苯甲醛(142mg,1.14mmol)在无水THF(19mL)中的溶液中,并将该反应在室温搅拌2小时。然后加入1N HCl(24mL),将该反应搅拌1小时。加入Et2O(25mL),分离出有机层并用水(2×25mL)洗涤。将合并的水层用乙醚(3×50mL)萃取。将合并的有机萃取液干燥(MgSO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,25×160mm,0-50%EtOAc在己烷中的混合物梯度),获得了1-(4-氟苯基)-1-羟基丙酮,为无色固体。Rf=0.31(20%EtOAc/己烷)。
1H NMR(CDCl3,500MHz)δ7.29(m,2H),7.08-7.04(H,2H),5.06(d,J=3.6Hz,1H),4.35(t,J=6.5Hz,1H),2.05(s,3H).
实施例57
赤型-和苏型-1-(4-氟苯基)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)丙-1-醇
在室温,将NaCNBH3(19mg,0.306mmol)加到{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}胺(67mg,0.204mmol)和1-(3,5-二氯苯基)-1-羟基丙酮(45mg,0.204mmol)在MeOH内的溶液中,然后加入乙酸(2滴)。将该反应在室温搅拌5小时。将该反应混合物用EtOAc(20mL)、H2O(20mL)和盐水(5mL)稀释。将水层用EtOAc(2×20mL)萃取。将合并的有机萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-50%EtOAc在己烷中的混合物梯度),获得了两种可能的非对映体,赤型-1-(4-氟苯基)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)丙-1-醇(68.4mg)和苏型-1-(4-氟苯基)-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)丙-1-醇(48.9mg),为无色油状物。赤型-非对映体:Rf=0.40(20%EtOAc/己烷)。LCMS计算值=476.22;实测值=476.2(M+1)+。
1H NMR(500MHz,CDCl3)δ7.72(s,1H),7.60(d,J=7.8Hz,1H),7.36(m,1H),7.27(dd,J=8.5,2.3Hz,1H),7.19(m,2H),7.04-6.92(m,4H),4.63-4.56(m,1H),3.85-3.65(m,7H),2.92(m,1H),2.72(m,1H),1.26(t,J=8.0Hz,6H),0.64(t,J=5.4Hz,3H).
苏型-非对映体:Rf=0.20(20%EtOAc/己烷)。LCMS计算值=476.22;实测值=476.2(M+1)+。
1H NMR(500MHz,CDCl3)δ7.73(d,J=9.0Hz,1H),7.58(d,J=7.9Hz,1H),7.32(m,1H),7.24(m,3H),7.07-6.97(m,3H),6.92(d,J=8.5Hz,1H),4.05(d,J=7.9Hz,1H),3.82-3.70(m,5H),3.59(d,J=13Hz,1H),3.51(d,J=13Hz,1H),2.90(m,1H),2.51(m,1H),1.25(m,6H),0.73(d,J=6.4Hz,3H).
实施例58
赤型-5-(4-氟苯基)-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
按照实施例7步骤3中的方法进行制备。Rf=0.38(20%EtOAc/己烷)。LCMS计算值=502.20;实测值=502.2(M+1)+。1H NMR(500MHz,苯-d6,阻转异构体的1∶1混合物)
δ7.96(s,0.5H),7.75(s,0.5H),7.35(d,J=7.7Hz,1H),7.10-7.06(m,2H),6.94(d,J=2.1Hz,0.5H),6.88(d,J=2.1Hz,0.5H),6.69-6.62(m,4.5H),6.55(d,J=8.4Hz,0.5H),4.95(d,J=15.9Hz,0.5H),4.86(d,J=15.8Hz,0.5H),4.80(d,J=7.9Hz,0.5H),4.70(d,J=7.8Hz,0.5H),4.04(d,J=15.8Hz,0.5H),3.93(d,J=15.9Hz,0.5H),3.36(s,1.5H),3.22(s,1.5H),3.14(m,0.5H),3.05(m,0.5H),2.79-2.71(m,1H),1.18(m,6H),0.02(d,J=6.5Hz,1.5H),-0.04(d,J=6.5Hz,1.5H).
使用手性HPLC(AD柱,20×250mm,3%EtOH在庚烷中的混合物)将该化合物分离成其两种对映体(4R,5S)-5-(4-氟苯基)-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮和(4S,5R)-5-(4-氟苯基)-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。
按照实施例58中描述的方法制得了在表2中列出的化合物:
表2
实施例64
1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-苯基吡咯烷-2-酮
在室温于氮气下将二(三甲基甲硅烷基)氨基钠(114μL 1M在THF中的溶液,0.114mmol)加到4-苯基吡咯烷-2-酮(Winans,C.F.,Adkins,H.,J.Am.Chem.Soc,1933,55,4167-4176)(17mg,0.103mmol)在无水THF(1mL)内的搅拌着的溶液中。将该反应搅拌5分钟,通过套管加入2-(溴甲基)-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯(20mg,0.0516mmol)在无水THF(2mL)内的溶液。将该反应在室温搅拌3天。将该反应用饱和NH4Cl(10mL)处理,用EtOAc(3×20mL)萃取。将合并的有机萃取液用盐水(10mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-90%EtOAc在己烷中的混合物梯度),获得了1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-苯基吡咯烷-2-酮,为无色油状物。Rf=0.11(20%EtOAc/己烷)。LCMS计算值=468.22;实测值=468.2(M+1)+。1H NMR(600MHz,苯-d6,阻转异构体的1∶1混合物)
δ7.79(s,0.5H),7.73(s,0.5H),7.33(d,J=7.7Hz,1H),7.08-7.04(m,4H),6.99(m,1H),6.92(s,0.5H),6.88(s,0.5H),6.76(dd,J=16.0,7.4Hz,2H),6.60(dd,J=8.5,3.1Hz,1H),4.58(d,J=15.4Hz,1H),4.38(t,J=13.9Hz,1H),3.29(s,1.5H),3.26(s,1.5H),2.85-2.73(m,3H),2.63-2.57(m,1H),2.38-2.28(m,1H),2.21-2.11(m,1H),1.20-1.16(m,6H).
实施例65
4-(3,4-二氟苯基)-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}吡咯烷-2-酮
按照类似于实施例64中描述的方法,使用4-(3,4-二氟苯基)吡咯烷-2-酮(通过类似于Marivet,M.C,Bourguignon,J.-J.;Lugnier,C,Mann,A.,Stoclet,J.-C,Wermuth,C.-G.J.Med.Chem.,1989,32,1450-1457中描述的方法制得)制得。LCMS计算值=504.20;实测值=504.2(M+1)+。
实施例66
5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-1,3-唑烷-2-酮
在0℃于氮气氛下,将氢化钠(60%在油中的分散液,167mg,4.18mmol)在THF(5mL)中的搅拌着的悬浮液用溶解在THF(1mL)中的5-[3,5-二(三氟甲基)苯基]-1,3-唑烷-2-酮(500mg,1.67mmol)处理。将该反应搅拌20分钟,滴加2-(溴甲基)-1-碘-4-(三氟甲基)苯(610mg,1.67mmol)在THF(1mL)内的溶液。将该反应在室温搅拌18小时。将该反应用H2O(1mL)处理,在EtOAc(80mL)和H2O(25mL)之间分配。将水相再用EtOAc(2×20mL)萃取,将合并的有机萃取液用盐水(30mL)洗涤,干燥(MgSO4)并真空浓缩,获得了粗产物。通过快速硅胶色谱纯化(0-30%EtOAc在己烷中的混合物梯度),获得了5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-1,3-唑烷-2-酮。Rf=0.55(515%EtOAc/己烷)。
LCMS 584(M+1)+.1H NMR(CDCl3,500MHz)δ8.05(d,J=8.2Hz,1H),7.95(br s,1H),7.85(br s,2H),7.51(brs,1H),7.32(m,1H),5.72(t,J=8.0Hz,1H),4.74(d,J=15.5Hz,1H),4.64(d,J=15.3Hz),4.14(t,J=7.1Hz,1H),3.47(dd,J=7.1,1.6Hz).
实施例67
(4S)-4-苄基-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
步骤A:(4S)-4-苄基-3-[2-碘-5-(三氟甲基)苄基]1,3-唑烷-2-酮
在0℃于氮气氛下,将氢化钠(60%在油中的分散液,27mg,0.68mmol)在THF(3mL)中的搅拌着的悬浮液用溶解在THF(1mL)中的(S)-4-苄基-2-唑烷酮(49mg,0.27mmol)处理。将该反应搅拌20分钟,滴加2-(溴甲基)-1-碘-4-(三氟甲基)苯(100mg,0.27mmol)在THF(1mL)内的溶液。将该反应在室温搅拌18小时。将该反应用H2O(1mL)处理,在EtOAc(80mL)与H2O(25mL)之间分配。将水相再用EtOAc(2×20mL)萃取,将合并的有机萃取液用盐水(30mL)洗涤,干燥(MgSO4)并真空浓缩,获得了粗产物。通过快速硅胶色谱纯化(0-30%EtOAc在己烷中的混合物梯度),获得了(4S)-4-苄基-3-[2-碘-5-(三氟甲基)苄基]1,3-唑烷-2-酮。Rf=0.45(15%EtOAc/己烷)。
LCMS 462(M+1)+.1H NMR(CDCl3,500MHz)δ8.04(d,J=8.2Hz,1H),7.54(br s,1H),7.33-7.27(m,5H),7.11-7.10(m,2H),7.32(m,1H),4.80(d,J=16.0Hz,1H),4.49(d,J=16.1Hz),4.28(t,J=8.7Hz,1H),4.25(t,J=9.1,4.8Hz,1H),3.94(m,1H),3.16(dd,J=13.5,4.8Hz,1H),2.73(dd,J=9.1,4.4Hz,1H).
步骤B:(4S)-4-苄基-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
将(45)-4-苄基-3-[2-碘-5-(三氟甲基)苄基]1,3-唑烷-2-酮(63mg,0.137mmol)、2-甲氧基-5-异丙基苯基硼酸(52mg,0.274mmol),K2CO3(47mg,0.34mmol)和Pd(OAc)2(9.2mg,0.0137mmol)在丙酮∶H2O(5∶1)(6mL)中的搅拌着的悬浮液加热回流1小时。将该反应混合物真空浓缩,用H2O(15mL)稀释,用EtOAc(3×30mL)萃取。将合并的有机萃取液用盐水(30mL)洗涤,干燥(MgSO4),过滤并浓缩。粗产物通过快速硅胶色谱纯化(0-20%EtOAc在己烷中的混合物梯度),获得了(4S)-4-苄基-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮。Rf=0.35(15%EtOAc/己烷)。LCMS 484(M+1)+。1H NMR(CDCl3,500MHz)(存在阻转异构体;在1H NMR中观察到某些峰重叠)
δ7.72(br s1H),7.65(br s,1H),7.42(m,1H),7.32-7.22(m,3H),7.08(d,J=2.3Hz,1H),6.90-6.84(m,3H),4.80(d,J=15.8Hz,1H),4.35(d,J=15.8Hz),4.28(t,J=8.7Hz,1H),3.96-3.92(m,3H),3.78(s,3H),3.62-3.52(m,1H),2.94-2.86(m,1H),2.82(dd,J=9.4,3.9Hz,1H),2.42(dd,J=9.6,3.9Hz),1.26(s,3H),1.10(s,3H).
实施例68
2-碘-5-(三氟甲基)苯甲酸
将氢氧化钾(3.78g;0.0673mol)加到2-碘-5-(三氟甲基)苄腈(实施例2;4g;0.0135mol)在1∶1异丙醇∶H2O溶液(60mL)内的搅拌着的溶液中。将该反应加热回流14小时,然后在H2O(50mL)和EtOAc(50mL)之间分配。将水层用EtOAc(5OmL)萃取,并用6N HCl酸化至pH 5。将水层进一步用EtOAc(4×50mL)萃取,将合并的萃取液用盐水(50mL)洗涤,用硫酸镁干燥,过滤,并真空浓缩,获得了2-碘-5-(三氟甲基)苯甲酸,为黄色固体。
LCMS=317.0(M+1)+.1H NMR(CDCl3,500MHz):δ8.27(d,J=1.6Hz,1H),8.25(d,J=8.2Hz,1H),7.47(dd,J=8.2,1.8Hz,1H).
实施例69
[2-碘-5-(三氟甲基)苯基]甲醇
在0℃于氮气氛下,将硼烷-THF(1.0M在THF中的溶液;94mL;94mmol)加到2-碘-5-(三氟甲基)苯甲酸(2.97g;9.4mmol)在THF(300mL)内的搅拌着的溶液中。将该反应加热回流90分钟,然后小心地用6N HCl处理直至没有气体释放出来。将该反应用水(250mL)稀释,用EtOAc(3×250mL)萃取。将合并的萃取液用盐水(300mL)洗涤,用硫酸镁干燥,过滤,并真空浓缩。通过快速色谱法纯化粗产物(0-25%EtOAc/己烷梯度),获得了[2-碘-5-(三氟甲基)苯基]甲醇,为白色固体。
LCMS=285.0(M-17)+.1H NMR(CDCl3,500MHz):δ7.97(d,J=8.3Hz,1H),7.79(s,1H),7.28(d,J=8.4Hz,1H),4.75(s,2H).
另一种方法如下所述:在0℃向2-碘-5-(三氟甲基)苯甲醛(实施例80,步骤A,9g)在THF(100mL)和水(10mL)内的溶液中加入NaBH4(0.5g)。将该反应搅拌30分钟。向该反应混合物中加入稀盐酸(小心地)。将该混合物用乙醚萃取,将乙醚层依次用水和盐水洗涤。然后将乙醚层用无水硫酸镁干燥,过滤并浓缩。通过二氧化硅色谱纯化粗产物,依次使用1∶3CH2Cl2/己烷、1∶1CH2Cl2/己烷和100%CH2Cl2进行梯度洗脱,获得了[2-碘-5-(三氟甲基)苯基]甲醇,为白色固体。
实施例70
2-(溴乙基)-1-碘-4-(三氟甲基)苯
在0℃于氮气氛下,将四溴化碳(1.86g;5.6mmol)和三苯基膦(1.47g;5.6mmol)依次加到[2-碘-5-(三氟甲基)苯基]甲醇(1.13g;3.74mmol)在CH2Cl2(25mL)内的搅拌着的溶液中。将该反应在室温搅拌48小时。再加入一部分四溴化碳(1.2g;3.74mmol)和三苯基膦(0.98g;3.74mmol),将该反应再搅拌14小时。真空除去溶剂并将残余物通过快速色谱法纯化(0-25%EtOAc/己烷梯度),获得了2-(溴乙基)-1-碘-4-(三氟甲基)苯,为澄清油状物。
1H NMR(CDCl3,500MHz):δ8.02(d,J=8.2Hz,1H),7.73(d,J=1.8Hz,1H),7.26(dd,J=8.3,1.8Hz,1H),4.64(s,2H).
实施例71
5-[3,5-二(三氟甲基)苯基]-1,3-唑烷-2-酮
按照实施例13中描述的方法,使用5.46g 2-氨基-1-[3,5-二(三氟甲基)苯基]乙醇,获得了5-[3,5-二(三氟甲基)苯基]-1,3-唑烷-2-酮,为灰白色固体。
LCMS=300.1(M+1)+.1H NMR(CDCl3,500MHz):δ7.94(s,1H),7.89(s,2H),5.81-5.77(m,1H),5.29(s,1H),4.17-4.12(m,1H),3.59-3.55(m,1H).
实施例72
5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
将5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-1,3-唑烷-2-酮(60mg;0.103mmol)、(4-氟-5-异丙基-2-甲氧基苯基)硼酸(27mg;0.129mmol)、乙酸钯(7mg;0.0103mmol)和碳酸钾(36mg;0.257mmol)在5∶1丙酮/水(6mL)中的混合物加热回流1小时。真空除去丙酮,把残余物用水(10mL)稀释,用CH2Cl2(3×10mL)萃取。将合并的萃取液用盐水(10mL)洗涤,用硫酸钠干燥,过滤,并真空浓缩。将残余物通过快速色谱法纯化(0-25%EtOAc/己烷梯度),获得了5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮,为澄清玻璃状物。LCMS=624.2(M+1)+。1H NMR(苯-d6,500MHz,阻转异构体的1∶1混合物):
δ7.60(s,1.5H),7.45(s,0.5H),7.31-7.25(m,3H),6.98-6.94(m,1H),6.87-6.82(m,1H),6.43-6.37(m,1H),4.54(d,J=15.6Hz,0.5H),4.40-4.36(m,1H),4.47(d,J=15.6Hz,0.5H),3.96(d,J=15.5Hz,0.5H),3.80(d,J=15.8Hz,0.5H),3.24-3.15(m,1H),3.02(s,3H),2.62-2.58(m,0.5H),2.53-2.48(m,0.5H),2.12-2.07(m,0.5H),2.04-2.00(m,0.5H)1.22-1.11(m,6H).
使用15%IP A/庚烷和OD柱,通过手性HPLC将外消旋产物分离成其两种对映体。
(5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮:LCMS=624.2(M+1)+。1H NMR(苯-d6,500MHz,阻转异构体的1∶1混合物):
δ7.62(s,1.5H),7.47(s,0.5H),7.34-7.27(m,3H),6.99-6.95(m,1H),6.88-6.83(m,1H),6.44-6.39(m,1H),4.54(d,J=15.5Hz,0.5H),4.47-4.41(m,1H),4.33(d,J=15.6Hz,0.5H),3.98(d,J=15.7Hz,0.5H),3.82(d,J=15.8Hz,0.5H),3.24-3.15(m,1H),3.05(s,3H),2.67-2.62(m,0.5H),2.57-2.52(m,0.5H),2.16-2.11(m,0.5H),2.09-2.04(m,0.5H)1.22-1.11(m,6H).
(5S)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮:LCMS=624.2(M+1)+。1H NMR(苯-d6,500MHz,阻转异构体的1∶1混合物):
δ7.63(s,1.5H),7.48(s,0.5H),7.35-7.27(m,3H),7.00-6.95(n,1H),6.88-6.83(m,1H),6.44-6.38(m,1H),4.54(d,J=15.8Hz,0.5H),4.48-4.42(m,1H),4.34(d,J=15.8Hz,0.5H),3.99(d,J=15.8Hz,0.5H),3.83(d,J=15.8Hz,0.5H),3.25-3.15(m,1H),3.05(s,3H),2.68-2.63(m,0.5H),2.58-2.53(m,0.5H),2.18-2.12(m,0.5H),2.10-2.05(m,0.5H)1.23-1.11(m,6H).
实施例73
步骤1:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
在0℃于氮气氛下,向氢化钠(60%在矿物油中的分散液;1.3g;0.0325mol)在THF(60mL)内的搅拌着的悬浮液中滴加(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(实施例17)(4.077g;0.013mol)在THF(50mL)中的溶液。观察到气体释放出来。将所得混合物在0℃搅拌30分钟,然后加入2-(溴甲基)-1-碘-4-(三氟甲基)苯(4.754g;0.013mol)在THF(20mL)中的溶液。将该反应温热至室温并搅拌14小时。将该反应小心地用水(15mL)处理,在EtOAc(250mL)和H2O(75mL)之间分配。将水层用EtOAc(3×100mL)萃取。将合并的有机层用盐水(100mL)洗涤,干燥(MgSO4),过滤并真空浓缩。将残余物通过快速色谱法纯化(0-20%EtOAc/己烷梯度),获得了6.4g(82.5%)(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮,为白色固体。
LCMS=598.1(M+1)+.1H NMR(CDCl3,500MHz):δ8.03(d,J=8.2Hz,1H),7.90(s,1H),7.79(s,2H),7.58(s,1H),7.30(dd,J=8.2Hz,J=2.0Hz,1H),5.76(d,J=8Hz,1H),4.88(d,J=15.8Hz,1H),4.37(d,J=15.8Hz,1H),4.09-4.02(m,1H),0.8(d,J=6.6Hz,3H).
步骤2:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(4.29g;7.19mmol)、(4-氟-5-异丙基-2-甲氧基苯基)硼酸(实施例78)(4.57g;21.57mmol)、四(三苯基膦)钯(0)(1.0g;0.86mmol)和碳酸钠(6.35g)在C6H6/EtOH/H2O(120mL/17mL/51mL)中的搅拌着的混合物于氮气氛下加热回流(100℃)14小时。将该反应在EtOAc(200mL)和H2O(100mL)之间分配。将水相用EtOAc(3×200mL)萃取。将合并的有机相用盐水(100mL)洗涤,干燥(MgSO4),过滤并真空浓缩。将残余物通过快速硅胶色谱纯化(0-25%EtOAc/己烷梯度),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮,为黄色固体。为了除去黄色杂质,将2.7g溶解在165mL EtOH中,加入275mg脱色用炭(活性炭,Darco,G-60,100目粉末,Aldrich)。将该混合物在室温搅拌40分钟,过滤,并真空浓缩。用约25mL己烷研制,获得了2.46g本标题化合物,为白色固体。1H NMR表明通过快速硅胶色谱除去的微量杂质(0-15%EtOAc/己烷梯度)。通过从乙腈中冷冻干燥来除去残余溶剂。LCMS=638.3(M+1)+。1H NMR(苯-d6,500MHz,阻转异构体的1∶1混合物):
δ7.82(s,0.5H),7.60(s,0.5H),7.57(s,1H),7.33(d,J=8Hz,1H),7.27(d,J=9.9Hz,2H),7.02-6.98(m,1H),6.89(d,J=8.5Hz,0.5H),6.82(d,J=8.5Hz,0.5H),6.45(d,J=12.1Hz,0.5H),6.35(d,J=11.9Hz,0.5H),4.94(d,J=16.0Hz,0.5H),4.87(d,J=15.8Hz,0.5H),4.54(d,J=8.0Hz,0.5H),4.50(d,J=7.8Hz,0.5H),3.74-3.66(m,1H),3.23-3.15(m,1H),3.12(s,1.5H),2.99(s,1.5H),2.97-2.92(m,0.5H),2.89-2.84(m,0.5H),1.21-1.09(m,6H),-0.27(d,J=6.7Hz,1.5H),-0.40(d,J=6.7Hz,1.5H).
制备(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮的另一种方法:
将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(50mg;0.084mmol)、(4-氟-5-异丙基-2-甲氧基苯基)硼酸(实施例78,22mg;0.105mmol)、乙酸钯(6mg;0.0103mmol)和碳酸钾(29mg;0.257mmol)在5∶1丙酮/水(6mL)中的混合物加热回流1小时。真空除去丙酮,将残余物用(10mL)水稀释,用CH2Cl2(3×10mL)萃取。将合并的萃取液用(10mL)盐水洗涤,用硫酸钠干燥,过滤,并真空浓缩。将残余物通过快速色谱法纯化(0-25%EtOAc/己烷梯度),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮为澄清玻璃状物。该产物还可以通过实施例372中描述的方法制得。
实施例74
(4R,5S)-4-[3,5-二(三氟甲基)苯基]-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基咪唑烷-2-酮
步骤A:(4S,5S)-5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
将((4S,5S)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮)(46.2mg,0.148mmol)置于无水烧瓶中,加入DMA(3mL)。加入NaHMDS(296μL 1M在THF中的溶液,0.296mmol),将该反应搅拌分钟。通过套管加入在DMA(2mL)中的2′-(溴甲基)-5-异丙基-4′-(三氟甲基)联苯-2-基甲基醚(80.0mg,0.207mmol)。30分钟后,将该反应用饱和NH4Cl(2mL)处理。将该混合物用EtOAc(40mL)稀释。将有机层用水(15mL)和盐水(15mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用25%EtOAc/己烷洗脱,获得了(4S,5S)-5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.27(25%EtOAc/己烷)。LCMS=620.2(M+1)+。1H NMR(CDCl3,500MHz;存在阻转异构体)
δ6.90-7.88(m,9H),4.04-5.05(m,3H),3.25-3.74(m,4H),2.88(m,1H),1.19-1.24(m,6H),0.99-1.07(m,3H).
步骤B:(1S,2S)-1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)丙-1-醇
向(4S,5S)-5-[3,5-二(三氟甲基)苯基]-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(147.7mg,0.239mmol)在EtOH(7.5mL)内的溶液中加入H2O(1.5mL)和KOH(150mg,2.67mmol)。将该溶液于75℃加热30小时,然后冷却至室温。加入EtOAc(75mL)内的溶液中,将有机层用H2O(15mL)和盐水(2×15mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。将残余物通过快速色谱法纯化,获得了(1S,2S)-1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)丙-1-醇。Rf=0.44(40%EtOAc/己烷)。
LCMS=594.2(M+1)+.1H NMR(CDCl3,500MHz)δ6.93-7.78(m,9H),3.51-4.20(m,6H),2.91(m,1H),2.49(m,1H),1.22-1.26(m,6H),0.79-0.81(m,3H).
步骤C:{(1S,2S)-2-[3,5-二(三氟甲基)苯基]-2-羟基-1-甲基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯
向(1S,2S)-1-[3,5-二(三氟甲基)苯基]-2-({[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基)丙-1-醇(135.5mg,0.228mmol)在CH2Cl2(5mL)内的溶液中加入BOC2O(49.7mg,0.228mmol)。将该反应在室温搅拌2天;期间再加入两批BOC2O(25mg each)。2天后,将该反应浓缩,并将残余物通过快速色谱法纯化,用20%EtOAc/己烷洗脱,获得了{(1S,2S)-2-[3,5-二(三氟甲基)苯基]-2-羟基-1-甲基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯。Rf=0.41(40%EtOAc/己烷)。LCMS=594.2(M+1-BOC)+。
步骤D:{(1S,2R)-2-叠氮基-2-[3,5-二(三氟甲基)苯基]-1-甲基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯
向干燥烧瓶中加入THF(1mL)、偶氮二甲酸二乙酯(DEAD)(11μL,0.0698mmol)和二苯基磷酰叠氮(DPPA)(15μL,0.0698mmol)。通过套管加入在THF(1mL)中的{(1S,2S)-2-[3,5-二(三氟甲基)苯基]-2-羟基-1-甲基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯(20.7mg,0.0698mmol)。然后加入Ph3P(18.3mg,0.0698mmol)。将该反应在室温搅拌30分钟,然后再加入DEAD(11μL,0.0698mmol)、DPPA(15μL,0.0698mmol)和Ph3P(18.3mg,0.0698mmol)。30分钟后,将该反应用EtOAc(40mL)稀释,用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用15%EtOAc/己烷洗脱,获得了{(1S,2R)-2-叠氮基-2-[3,5-二(三氟甲基)苯基]-1-甲基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯。Rf=0.60(25%EtOAc/己烷)。LCMS=619.3(M+1-BOC)+。
步骤E:(1R,2S)-1-叠氮基-1-[3,5-二(三氟甲基)苯基]-N-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}丙-2-胺
向{(1S,2R)-2-叠氮基-2-[3,5-二(三氟甲基)苯基]-1-甲基乙基}{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}氨基甲酸叔丁酯(21.7mg,0.030mmol)在CH2Cl2(2mL)内的溶液中加入TFA(200μL)。将该反应在室温搅拌1小时,然后用CH2Cl2(25mL)稀释。将该CH2Cl2溶液用1N NaOH(15mL)洗涤,将水相再用CH2Cl2(25mL)萃取。将有机萃取液合并,用盐水(20mL)洗涤,用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用15%EtOAc/己烷洗脱,获得了(1R,2S)-1-叠氮基-1-[3,5-二(三氟甲基)苯基]-N-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}丙-2-胺。Rf=0.45(15%EtOAc/己烷)。LCMS=619.2(M+1)+。
步骤F:(1R,2S)-1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}丙-1,2-二胺
向(1R,2S)-1-叠氮基-1-[3,5-二(三氟甲基)苯基]-N-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}丙-2-胺(17.8mg,0.0288mmol)在THF(3mL)内的溶液中加入PtO2(12mg,0.053mmol)。将该反应置于氢气囊气氛下,并在室温搅拌3小时。通过过滤除去催化剂并将该滤液浓缩。让残余物通过短的硅胶塞,用0-10%MeOH/CH2Cl2洗涤,获得了(1R,2S)-1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}丙-1,2-二胺。LCMS=619.2(M+1)+。
步骤G:(4R,5S)-4-[3,5-二(三氟甲基)苯基]-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基咪唑烷-2-酮
将(1R,2S)-1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}丙-1,2-二胺(8.0mg,0.0135mmol)在CH2Cl2(2mL)中的溶液冷却至0℃,加入DIPEA(14μL,0.081mmol),然后加入三光气(2mg,0.00657mmol)。将该反应在0℃搅拌30分钟,然后用EtOAc(30mL)稀释。将该反应用饱和碳酸氢钠(10mL)和盐水(10mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用40%EtOAc/己烷洗脱,获得了(4R,5S)-4-[3,5-二(三氟甲基)苯基]-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基咪唑烷-2-酮。Rf=0.24(40%EtOAc/己烷)。LCMS=619.2(M+1)+。1H NMR(CD2Cl2,600MHz;存在阻转异构体)
δ6.91-7.84(m,9H),3.84-4.94(m,4H),3.64-3.80(m,4H),2.88(m,1H),1.18-1.26(m,6H),0.27-0.42(m,3H).
实施例75
(3S,4R)-4-[3,5-二(三氟甲基)苯基]-2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-3-甲基-1,2,5-噻二唑烷1,1-二氧化物
向玻璃反应管中加入(1R,2S)-1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}丙-1,2-二胺(15.9mg,0.0269mmol)、磺酰胺(4mg,0.0403mmol)和吡啶(600μL)。将反应管用氮气吹扫,密封,在120℃加热2小时。然后将该溶液冷却至室温,用EtOAc(40mL)稀释,用H2O、1N HCl和盐水(分别是10mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化残余物,使用25%EtOAc/己烷洗脱,获得了(3S,4R)-4-[3,5-二(三氟甲基)苯基]-2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-3-甲基-1,2,5-噻二唑烷1,1-二氧化物。Rf=0.27(25%EtOAc/己烷)。LCMS=655.2(M+1)+。1H NMR(C6D6,500MHz;存在阻转异构体)
δ6.51-8.19(m,9H),3.64-4.53(m,4H),3.00-3.18(m,4H),2.73(m,1H),1.13-1.20(m,6H),-0.03-0.09(m,3H).
实施例76
2-氟-1-异丙烯基-4-甲氧基苯
步骤A:2-(2-氟-4-甲氧基苯基)丙-2-醇
在0℃,向2′-氟-4′-甲氧基苯乙酮(4.45g,26.5mmol)在THF(50ml)内的溶液中加入2.4M MeMgBr溶液(11.6mmol,27.8mmol)。将该混合物在0℃搅拌,然后在室温搅拌4小时。将该反应用饱和氯化铵溶液处理。将有机相用乙酸乙酯(3×50ml)萃取。将合并达到乙酸乙酯层用盐水洗涤并用硫酸钠干燥。通过快速柱纯化,使用EtOAc∶己烷=2∶8作为洗脱剂,获得了所得醇,为油状物。
步骤B:2-氟-1-异丙烯基-4-甲氧基苯
在0℃向得自步骤A的2-(2-氟-4-甲氧基苯基)丙-2-醇(3.89g,21.14mmol)在二氯甲烷(50ml)内的溶液中加入MsCl(1.95ml,25.4mmol)和三乙胺(6.52ml,46.5mmol)。将该溶液在0℃搅拌,然后在室温搅拌2小时。将该溶液用二氯甲烷(100ml)稀释,用水洗涤,并用硫酸钠干燥。通过快速柱纯化,使用EtOAc∶己烷=1∶9作为洗脱剂,获得了本标题化合物,为油状物。
1H NMR(CDCl3,500MHz)δ7.25(t,J=9.0Hz,1H),6.68(dd,J=8.5,2.5Hz,1H),6.63(dd,J=13,2.5Hz,1H),5.20(d,J=17.0Hz,2H),3.82(s,3H),2.18(s,3H).
制备2-氟-1-异丙烯基-4-甲氧基苯的另一种方法:
将二(三甲基甲硅烷基)氨基钠,1.0M在四氢呋喃中的溶液(714ml,0.714m)加到溴化甲基三苯基(255g,0.714m)在THF(2.50L)内的用冰浴冷却的溶悬浮液中。将所得黄色悬浮液在冰浴温度搅拌30分钟,然后冷却至-78℃。滴加在THF(200mL)内的所有2-氟-4-甲氧基苯乙酮(100g,0.595m),在-78℃搅拌1.5小时。将该反应混合物温热至室温并保持小时,用乙酸(~80ml)处理,观察到颜色从黄色变为灰白色,并搅拌30分钟(pH~7)(注意到轻度放热)。将该混合物浓缩至浆液,用7∶2己烷∶乙酸乙酯稀释,让其静置过夜。通过过滤除去固体并将该滤液浓缩至黄色油状物。通过快速柱纯化,使用9∶1己烷∶乙酸乙酯作为洗脱剂,获得了本标题化合物。
实施例77
1-氟-4-碘-2-异丙基-5-甲氧基苯
将2-氟-1-异丙烯基-4-甲氧基苯(实施例76,1.96g,11.81mmol)在MeOH(30ml)中的溶液施加1atm氢气和催化量的Pd/C。将该混合物在室温搅拌1小时。将该混合物经由硅藻土过滤。然后把滤液加到硫酸银(3.68g,11.81mmol)和碘(3.00g,11.81mmol)在MeOH(10ml)内的混合物中。将该混合物在室温搅拌3小时直至溶液颜色变为浅黄色。将该混合物过滤并将该滤液浓缩。通过快速柱纯化,使用EtOAe己烷5∶95作为洗脱剂,获得了本标题化合物。
1H NMR(CDCl3,500MHz)δ7.61(d,J=8.0Hz,1H),6.56(d,J=12.5Hz,1H),3.90(s,3H),3.18(m,1H),1.28(m,6H).
实施例78
(4-氟-5-异丙基-2-甲氧基苯基)硼酸
在-78℃,向1-氟-4-碘-2-异丙基-5-甲氧基苯(实施例77,2.61g,8.88mmol)在THF内的溶液中滴加n-BuLi(4.26ml,10.65mmol,2.5M)。将该溶液在-78℃搅拌30分钟。加入硼酸三甲酯(2.98ml,26.6mmol)。然后将该溶液在-78℃搅拌3小时。将该反应在-78℃用饱和氯化铵处理,将该混合物温热至室温。将有机相用乙酸乙酯(3×50ml)萃取。将合并的乙酸乙酯层用盐水洗涤并用硫酸钠干燥。获得了本标题化合物,为纯度足以用于下一步骤的固体。通过硅胶进一步纯化,因为产物分解。
1H NMR(CDCl3,500MHz)δ7.74(d,J=10.0Hz,1H),6.62(d,J=12.5Hz,1H),5.65(br s,2H),3.92(s,3H),3.20(m,1H),1.22(m,6H).
该硼酸中间体还可以通过下面的四步法制得:
将1转化成2:
在室温将THF(24L)加到100L圆柱形反应器中。向其中加入2.75kg CeCl3。把所得浆液在室温老化1.5小时。然后在显微镜下监测样本,以证实已经发生了所需形式。把浆液冷却至9℃,加入MeMgCl。调节加入速度以保持内温低于19℃。将该混合物冷却至-11℃,滴加苯乙酮1(4.0kg用THF稀释至10L)。保持内温低于0℃。然后将该反应混合物在0℃以下的温度老化1小时。向该反应中滴加5.7L 3N HCl,保持内温低于15℃。然后将处理的该反应混合物在5-10℃老化1.5小时,经由Solka Floe塞过滤。
将2氢化成3:
将2的THF溶液中的溶剂替换为乙醇(~18L体积),加入1.9L HCl,然后加入190g 10%Pd/C(50%水)。将该混合物在15psi氢气下于40℃放置直至HPLC分析表明反应完全。将该混合物冷却至室温。通过过滤除去催化剂,使用Solka-Flok作为滤器辅助剂。然后将乙醇中的茴香醚产物的溶剂转换为乙腈以用于下一步骤。
将3溴化成4:
将茴香醚3在乙腈中稀释(1.72L,4mL MeCN/mMol 3)。将该混合物温热至35℃,一次性加入固体NBS(1.1eq,84g)。反应在2-4小时内完全。将该溶液浓缩至400mL总体积,用1L甲苯稀释。然后将该溶液用硫代硫酸钠和水洗涤以除去琥珀酰亚胺副产物。然后将有机层浓缩,并且把溶剂换为甲苯。
将芳基溴化物4转化成硼酸5:
向75L玻璃反应容器中加入1.87kg芳基溴4(7.6MoI),其是作为6.4kg29.1wt%4在甲苯中的溶液加入的。将该溶液用5.6L THF稀释。用氮气吹扫容器,加入硼酸三异丙酯(1.35eq,2.35L,10.3Mol)。将该混合物冷却至<-70℃。然后用4小时缓慢地加入5.9L 1.6M n-BuLi在己烷中的溶液(9.5Mol),保持温度<-55℃。n-BuLi加入完成后30分钟,通过LC分析表明反应完全。将该反应温热至-35℃,用3.0M H2SO4溶液(5.6L)处理。处理后的水相应当呈酸性(pH~2)。将MTBE(7.5L)加到该混合物中以稀释有机层。将该混合物搅拌(15分钟),将水层除去。将有机层用5.6L 3.0M H2SO4溶液(15min)洗涤。再次分离各层后,将MTBE/甲苯层用1M KOH(首先15.1L,然后7.6L)萃取两次。将两份KOH萃取液合并,用2-丙醇(6.4L)稀释,冷却至15℃。然后使用3.0M硫酸(~7.6L)将该溶液缓慢地酸化至pH~2,同时把温度保持在15-20℃。将所得浆液搅拌1小时,然后过滤。把滤饼用水(2×6L)洗涤,在空气流下干燥1天。将过滤的固体置于50℃真空烘箱中2-3天,以分解二芳基杂质和干燥固体。分离出灰白色固体结晶,获得了1.59kg硼酸5。
实施例79
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-氯-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
步骤A:1-溴-2-(溴甲基)-4-氯苯
将2-溴-5-氯-甲苯(2.00g,9.75mmol)、NBS(2.08g,11.7mmol)和催化量的AIBN在四氯化碳(50ml)中的混合物在回流条件下搅拌4小时。TLC(EtOAc∶己烷=5∶95)表明没有原料。将该混合物过滤并将该滤液浓缩。通过快速柱纯化,使用EtOAc∶己烷=5∶95作为洗脱剂,获得了本标题化合物,为白色固体。
1H NMR(CDCl3,500MHz)δ7.53(d,J=9.0Hz,1H),7.47(d,J=2.5Hz,1H),7.18(dd,J=8.5,2.5Hz,1H),4.60(s,2H).
步骤B.(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-溴-5-氯苄基)-4-甲基-1,3-唑烷-2-酮
在0℃,向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(0.050g,0.16mmol)在THF(1ml)内的溶液中加入NaH(7.6mg,0.19mmol,60%)。将该混合物在0℃搅拌30分钟。加入得自步骤A的本标题化合物(0.059g,0.21mmol)。将整个混合物在0℃搅拌1小时,温热至室温保持4小时。将该反应用饱和氯化铵处理。将有机相用乙酸乙酯(3×15ml)萃取。将合并达到乙酸乙酯层用盐水洗涤并用硫酸钠干燥。制备TLC纯化,使用EtOAc∶己烷=2∶8作为洗脱剂,获得了本标题化合物。
1H NMR(CDCl3,500MHz)δ7.92(s,1H),7.82(s,2H),7.55(d,J=8.5Hz,1H),7.43(d,J=2.5Hz,1H),7.23(dd,J=8.5,2.5Hz,1H),5.77(d,J=8.0Hz,1H),4.86(d,J=16.0Hz,1H),436(d,J=16.0Hz,1H),4.11(m,1H),0.82(d,J=6.5Hz,3H).
步骤C.(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-氯-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-溴-5-氯苄基)-4-甲基-1,3-唑烷-2-酮(44mg,0.085mmol)、(4-氟-5-异丙基-2-甲氧基苯基)硼酸(实施例78,23mg,0.11mmol)、碳酸钾(25mg,0.18mmol)和催化量的PdOA在丙酮/水4∶1混合物中的混合物加热回流1小时。除去丙酮,并加入水。将有机层用二氯甲烷(3×15ml)萃取。将合并的二氯甲烷层用盐水洗涤并用硫酸钠干燥。通过制备反相HPLC纯化,获得了本标题化合物,为固体。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.90(s,1H),7.73(s,2H),7.49(m,1H),7.40(m,1H),7.20(m,1H),7.00(m,1H),6.68(dd,J=12.0,3.0Hz,1H),5.63(d,J=8.0Hz,1/2H),5.44(d,J=8.0Hz,1/2H),4.85(d,J=10.0Hz,1/2H),4.82(d,J=10.0Hz,1/2H),4.03(d,J=16.0Hz,1/2H),3.84(m,11/2H),3.80(s,3H),3.20(m,1H),1.20(m,6H),0.56(d,J=6.5Hz,3/2H),0.38(d,J=6.5H,3/2H).LC-MS(M+1):604.3,4.61min.
实施例80
5-[2-碘-5-(三氟甲基)苯基]-1,3-唑烷-2-酮
步骤A:2-碘-5-(三氟甲基)苯甲醛
在-78℃,向2-碘-5-(三氟甲基)苄腈(实施例2,42g)在CH2Cl2(300mL)内的溶液中用30分钟加入DIBAL在CH2Cl2中的溶液(175mL,1M)。形成了沉淀。将该反应温热至0℃。用30分钟滴加25mL DIBAL溶液。将该反应倒入200mL 2N盐酸中,用乙醚稀释,搅拌1小时。TLC分析表明仍然存在亚胺,加入100mL 2N水溶液,将该反应搅拌过夜。TLC分析表明仍然存在亚胺,加入200mL 2N盐酸,将该混合物搅拌2小时。分离各层,用乙醚反萃取水层。合并乙醚萃取液,用盐水洗涤,用无水硫酸镁干燥,过滤并浓缩。通过硅胶色谱纯化产物,使用95∶5己烷/EtOAc洗脱,获得了2-碘-5-(三氟甲基)苯甲醛,为白色固体。
1H NMR(500MHz,CDCl3):δ10.00(s,1H),8.12(s,1H),8.11(d,J=8Hz,1H),7.53(dd,J=2Hz,8Hz,1H).
步骤B:5-[2-碘-5-(三氟甲基)苯基]-1,3-唑烷-2-酮
向0.2g2-碘-5-(三氟甲基)苯甲醛在3mL EtOH内的0℃溶液中加入0.13mL硝基甲烷,然后加入0.28mL 2.5N NaOH溶液。将该混合物在0℃搅拌3小时,然后通过加入2.1mL 0.33N AcOH水溶液来中和。将该混合物在10mL水和10mL EtOAc之间分配。将水相用2×5mLEtOAc萃取。将合并的有机层用10mL盐水洗涤,用硫酸钠干燥,并浓缩。把残余物溶解在4mL MeOH中,加入0.5mL88%甲酸水溶液。加入约200mg阮内镍浆液,将该混合物用氢气吹扫,在氢气囊下搅拌4小时。将该混合物经由硅藻土过滤,用MeOH洗涤,并将该滤液浓缩。将残余物在10mL 10%NH4OH水溶液和20mL EtOAc之间分配。将水相用2×10mL EtOAc萃取。将合并的有机层用10mL盐水洗涤,用硫酸钠干燥,并浓缩。把残余物溶解在2mL CH2Cl2中。向该溶液中加入加入0.114mL二异丙基乙胺,然后加入0.065g三光气。将该混合物在0℃搅拌30分钟,然后用10mL EtOAc和10mL饱和NaHCO3稀释。将水相用2×10mL EtOAc萃取。将合并的有机层用10mL盐水洗涤,用硫酸钠干燥,并浓缩。将残余物在Biotage Horizon,25S柱上通过快速色谱法纯化,使用1CV 4%EtOAc在己烷中的混合物洗脱,然后使用4-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)350.0(M+1)。
1H NMR(500MHz,CDCl3):δ8.00(d,J=8Hz,1H),7.74(br s,1H),7.33(br d,J=8Hz,1H),5.80(dd,J=7Hz,9Hz1H),5.05-5.50(br,1H),4.28(t,J=9Hz,1.5H),3.36(dd,J=7Hz,9Hz,1H).
实施例81
5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮
向65mg 5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1,3-唑烷-2-酮、45mg(5-异丙基-2-甲氧基苯基)硼酸和66mg碳酸钾在6mL丙酮和1.5mL水内的溶液中加入约5mg乙酸钯。将该混合物加热至回流,在该温度下搅拌1.5小时。通过旋转蒸发除去丙酮和将残余物,用10mL EtOAc和10mL水稀释。将水相用10mL EtOAc萃取。将合并的有机层用10mL盐水洗涤,用硫酸钠干燥,并浓缩。将残余物在Biotage Horizon,25S柱上通过快速色谱法纯化,使用1CV 10%EtOAc在己烷中的混合物洗脱,然后使用10-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。光谱数据在实施例49中提供。
按照实施例52中描述的方法制得了在表3中列出的化合物。
表3
实施例90
5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
按照实施例80中描述的方法,使用硝基乙烷、0.2g2-碘-5-(三氟甲基)苯甲醛,获得了0.102g所需产物,通过以下方法将其分离成顺式和反式非对映体:在Biotage Horizon,25S柱上进行快速色谱法,使用1CV 10%EtOAc在己烷中的混合物洗脱,然后使用10-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱。
反式-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮:质谱(ESI)372.1(M+1)。
1H NMR(500MHz,CDCl3):δ8.02(d,J=8Hz,1H),7.61(d,J=1.5Hz,1H),7.32(dd,J=2Hz,8Hz,1H),6.16(s,1H),5.39(d,J=4Hz,1H),3.76(dq,J=6Hz,4.5Hz,1H),1.62(d,J=6Hz,3H).
顺式-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮:质谱(ESI)372.1(M+1)。
1H NMR(500MHz.,CDCl3):δ7.98(d,J=8Hz,1H),7.60(br s,1H),7.33(dd,J=1.5Hz,8Hz,1H),6.25(s,1H),5.85(d,J=8Hz,1H),3.76(dq,J=8Hz,7Hz,1H),0.81(d,J=7Hz,3H).
实施例91
反式-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮(外消旋)
向0.036g反式-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮、0.024g(5-异丙基-2-甲氧基苯基)硼酸和0.04g碳酸钾在2mL丙酮和0.5mL水内的溶液中加入2mg乙酸钯。将该混合物加热至回流,在该温度下搅拌1.5小时。通过旋转蒸发除去丙酮和将残余物,用10mLEtOAc和10mL水稀释。将水相用10mL EtOAc萃取。将合并的有机层用10mL盐水洗涤,用硫酸钠干燥,并浓缩。将残余物在BiotageHorizon,25S柱上通过快速色谱法纯化,使用1CV 10%EtOAc在己烷中的混合物洗脱,然后使用10-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)394.2(M+1)。1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.80,7.78(s,1H),7.64,7.63(d,J~8Hz,1H),7.35(d,J=7.5Hz,1H),7.27,7.26(d,J~8Hz 1H),7.00,6.95(d,J=2.5Hz,1H),6.93,6.92(d,J~8Hz,1H),5.87,5.81(s,1H),5.16,5.10(d,J~5Hz,1H),3.70-3.78(m,3.5H),3.49(m,0.5H),2.89(m,1H),1.24(m,6H),0.90,0.70(d,J=6.5Hz,3H).
实施例92
顺式-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮(外消旋)
按照实施例91中描述的方法,使用0.046g顺式-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮,获得了所需产物。质谱(ESI)394.2(M+1)。1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.89,7.88(s,1H),7.65,7.64(d,J~7.5Hz,1H),7.34,7.32(d,J~8Hz,1H),7.26(d,J=8.5Hz,1H),6.98,6.86(d,J=2.5Hz,1H),6.91,6.89(d,J~8Hz,1H),5.83,5.75(s,1H),5.69,5.61(d,J~8Hz,1H),3.75(s,1.8H),3.58-3.70(m,2H),3.32(m,0.6H),2.88(m,1H),1.23(m,6H),0.89,0.71(d,J=6.5Hz,3H).
实施例93
反式-3-[3,5-二(三氟甲基)苄基]-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮(外消旋)
向30mg反式-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮在1mL DMF内的0℃溶液中加入8mg氢化钠。将该混合物在室温搅拌10分钟,然后加入32mg 3,5-二(三氟甲基)苄基溴。将该混合物在室温搅拌过夜,然后用10mL EtOAc和10mL水稀释。分离各层并且将水相用5mL EtOAC萃取。将合并的有机层用5mL盐水洗涤,干燥(Na2SO4)并浓缩。将残余物在Biotage Horizon,25S柱上通过快速色谱法纯化,使用1CV 4%EtOAc在己烷中的混合物洗脱,然后使用4-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)620.2(M+1)。1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.53-7.80(m,5H),7.33(d,J=8Hz,1H),7.21-7.29(m,1H),7.00,6.76(d,J=2.5Hz,1H),6.91,6.86(d,J=8.5Hz,0.4H),5.15,5.10(d,J=4.5Hz,1H),4.80,4.74(d,J=16Hz,1H),4.25,4.21(d,16Hz,1H),3.76(s,2H),3.49(s,1H),3.43(m,0.4H),3.18(m,0.5H),2.77-2.98(m,1H),1.24(m,3H),1.16(m,3H),0.78,0.61(d,J=6.5Hz,3H).
实施例94
顺式-3-[3,5-二(三氟甲基)苄基]-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮(外消旋)
按照实施例93中描述的方法,使用40mg顺式-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮和42mg 3,5-二(三氟甲基)苄基溴,获得了本标题化合物。质谱(ESI)620.2(M+1)。1HNMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.82-7.94(m,2H),7.62-7.74(m,3H),7.39,7.37(d,J~8Hz,1H),7.25,7.17(br d,J=8.5Hz,1H),7.00,6.78(s,1H),6.87,6.84(d,J=8.5Hz,1H),5.59,5.56(d,J=4.5Hz,1H),4.96(d,J=16Hz,1H),4.22,4.11(d,J=16Hz,1H),3.76(s,2H),3.58(s,1H),3.40(m,0.4H),2.85-3.00(m,1H),2.78(m,0.5H),1.23(d,J=7Hz,3H),1.06(m,3H),0.88,0.69(d,J=6.5Hz,3H).
实施例95
(4R,5R)-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
步骤A:(4S)-4-苄基-3-{(2R,3S)-3-羟基-3-[2-碘-5-(三氟甲基)苯基]-2-甲基丙酰基}-1,3-唑烷-2-酮
将1.8g5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲醛(实施例80,步骤A)、1.16g(4S)-4-苄基-3-丙酰基-1,3-唑烷-2-酮、0.048g氯化镁、1.40mL三乙胺和0.91mL氯三甲基甲硅烷在10mL EtOAc中的混合物于室温搅拌24小时,然后过滤经由10×10cm硅胶塞过滤,用400mLEt2O洗脱。将该滤液浓缩,加入10mL MeOH和2滴三氟乙酸。将该溶液在室温搅拌30分钟,浓缩至浅黄色油状物。将残余物在BiotageHorizon,65i柱上通过快速色谱法纯化,使用15CV10%丙酮在己烷中的混合物洗脱,获得了本标题化合物。质谱(ESI)516.2(M-OH)。
1H NMR(500MHz,,CDCl3):δ8.00(d,J=8.5 Hz,1H),7.76(d,J=2Hz,1H),7.22-7.32(m.4H),7.07(br d,J=6.5Hz,2H),5.18(dd,J=6.5Hz,7.5Hz,1H),4.67(m,1H),4.46(dq,J=6.5Hz,7.5Hz,1H),4.17(t,J=9Hz,1H),4.11(dd,J=3Hz,9Hz,1H),3.97(d,J=8Hz,1H),3.19(dd,J=7Hz,13.5Hz,1H),2.57(dd,J=9.5Hz,13.5Hz,1H),1.34(d,J=7.5Hz,3H).
步骤B:(4R,5R)-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
向0.65g(4S)-4-苄基-3-{(2R,3S)-3-羟基-3-[2-碘-5-(三氟甲基)苯基]-2-甲基丙酰基}-1,3-唑烷-2-酮在6mL3∶1四氢呋喃-水内的0℃溶液中加入0.102g氢氧化锂在1.5mL水中的溶液,然后加入0.554mL30%过氧化氢水溶液。将该溶液在0℃搅拌1小时,这时LC/MS分析表明没有任何原料。向该冷溶液中加入1.5M亚硫酸钠溶液(3.7mL),然后倒入分液漏斗中,用2×10mL二氯甲烷萃取。将合并的CH2Cl2萃取液用20mL3∶1水-饱和碳酸氢钠水溶液反萃取。用6N HCl将合并的水层酸化(pH<1),用4×10mL EtOAc萃取。将合并的EtOAc萃取液用10mL盐水洗涤,用硫酸钠干燥,并浓缩。将残余物溶解在10mL甲苯中。加入二苯基磷酰叠氮(0.315mL)和0.24mL三乙胺,将该混合物在100℃搅拌过夜,然后冷却并浓缩。将残余物在Biotage Horizon,4OS柱上通过快速色谱法纯化,使用1CV 5%EtOAc在己烷中的混合物洗脱,然后使用5-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)372.1(M+1)。
1H NMR(500MHz,CDCl3):δ8.02(d,J=8Hz,1H),7.61(d,J=1.5Hz,1H),7.32(dd,J=2Hz,8Hz,1H),6.16(s,1H),5.39(d,J=4Hz,1H),3.76(dq,J=6Hz,4.5Hz,1H),1.62(d,J=6Hz,3H).
在Chiralpak AD 4.6×250mm上进行分析HPLC,用4%乙醇在庚烷中的混合物以0.75mL/分钟洗脱(tR=21.56分钟,对于R,R;tR=18.00分钟,对于S,S),表明98%e.e。
实施例96
(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
向95mg(4R,5R)-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮在1mL DMF内的0℃溶液中加入20mg氢化钠。将该混合物在0℃搅拌10分钟;然后加入94mg 3,5-二(三氟甲基)苄基溴。将该混合物在0℃搅拌10分钟,然后用10mL EtOAc和10mL水稀释。分离各层并且将水相用10mL EtOAc萃取。将合并的有机相用10mL盐水洗涤,用硫酸钠干燥,并浓缩。将残余物在Biotage Horizon,25M柱上通过快速色谱法纯化,使用1CV2%EtOAc在己烷中的混合物洗脱,然后使用2-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)598.1(M+1)。
1H NMR(500MHz,CDCl3):δ8.00(d,J=8.5Hz,1H),7.77(s,1H),7.58(br s,3H),7.34(dd,J=1.5Hz,8Hz,1H),5.36(d,J=4Hz,1H),4.89(d,J=16Hz,1H),4.31(d,J=16Hz,1H),4.48(dq,J=6Hz,4Hz,1H),1.55(d,J=6.5Hz,3H).
实施例97
(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮
按照实施例81中描述的方法,使用41mg(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮和17mg(5-异丙基-2-甲氧基苯基)硼酸,获得了本标题化合物。质谱(ESI)620.4(M+1)。1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.53-7.80(m,5H),7.33(d,J=8Hz,1H),7.21-7.29(m,1H),7.00,6.76(d,J=2.5Hz,1H),6.91,6.86(d,J=8.5Hz,0.4H),5.15,5.10(d,J=4.5Hz,1H),4.80,4.74(d,J=16Hz,1H),4.25,4.21(d,16Hz,1H),3.76(s,2H),3.49(s,1H),3.43(m,0.4H),3.18(m,0.5H),2.77-2.98(m,1H),1.24(m,3H),1.16(m,3H),0.78,0.61(d,J=6.5Hz,3Hz).
实施例98
(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮
按照实施例81中描述的方法,使用38.5mg(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮和18mg(4-氟-5-异丙基-2-甲氧基苯基)硼酸(实施例78),获得了本标题化合物。质谱(ESI)638.3(M+1)。1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.55-7.80(m,5H),7.29(d,J=8Hz,1H),7.00,6.77(d,J=8.5Hz,1H),6.68,6.63(d,J~12Hz,1H),5.08,5.04(d,J~5Hz,1H),4.81,4.75(d,J=16Hz,1H),4.26,4.23(d,15.5Hz,1H),3.75(s,2H),3.50(s,1H),3.43(m,0.5H),3.12-3.24(m,1.5H),1.24,1.22(d,J~5Hz,3H),1.17,1.06(d,J=7Hz,3H),0.84,0.70(d,J=6Hz,3H).
实施例99
(4S,5S)-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
步骤A:(4R)-4-苄基-3-{(25,3R)-3-羟基-3-[2-碘-5-(三氟甲基)苯基]-2-甲基丙酰基}-1,3-唑烷-2-酮
按照实施例95步骤A中描述的方法,使用0.72g 5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲醛(实施例80,步骤A)、0.466g(4R)-4-苄基-3-丙酰基-1,3-唑烷-2-酮、0.02g氯化镁、0.56mL三乙胺和0.38mL氯三甲基甲硅烷,获得了本标题化合物。质谱(ESI)516.2(M-OH)。
1H NMR(500MHz,CDCl3):δ8.00(d,J=8.5Hz,1H),7.76(d,J=2Hz,1H),7.22-7.32(m.4H),7.07(br d,J=6.5Hz,2H),5.18(dd,J=6.5Hz,7.5Hz,1H),4.67(m,1H),4.46(dq,J=6.5Hz,7.5Hz,1H),4.17(t,J=9Hz,1H),4.11(dd,J=3Hz,9Hz,1H),3.97(d,J=8Hz,1H),3.19(dd,J=7Hz,13.5Hz,1H),2.57(dd,J=9.5Hz,13.5Hz,1H),1.34(d,J=7.5Hz,3H).
步骤B:(4S,5S)-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
按照实施例95步骤B中描述的方法,使用0.214g(4R)-4-苄基-3-{(25,3R)-3-羟基-3-[2-碘-5-(三氟甲基)苯基]-2-甲基丙酰基}-1,3-唑烷-2-酮、0.034g氢氧化锂、0.16mL 30%过氧化氢水溶液、0.1mL二苯基磷酰叠氮和0.072mL三乙胺,获得了本标题化合物。质谱(ESI)372.1(M+1)。
1H NMR(500MHz,CDCl3):δ8.02(d,J=8Hz,1H),7.61(d,J=1.5Hz,1H),7.32(dd,J=2Hz,8Hz,1H),6.16(s,1H),5.39(d,J=4Hz,1H),3.76(dq,J=6Hz,4.5Hz,1H),1.62(d,J=6Hz,3H).
在Chiralpak AD 4.6×250mm上进行分析HPLC,用4%乙醇在庚烷中的混合物以0.75mL/分钟洗脱(tR=21.56分钟,对于R,R;tR=18.00分钟,对于S,S),表明99%e.e。
实施例100
(4S,5S)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
按照实施例96中描述的方法,使用0.108g(4S,5S)-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮、23mg氢化钠和107mg 3,5-二(三氟甲基)苄基溴,获得了本标题化合物。质谱(ESI)598.1(M+1)。
1HNMR(500MHz,CDCl3):δ8.00(d,J=8.5Hz,1H),7.77(s,1H),7.58(br s,3H),7.34(dd,J=1.5Hz,8Hz,1H),5.36(d,J=4Hz,1H),4.89(d,J=16Hz,1H),4.31(d,J=16Hz,1H),4.48(dq,J=6Hz,4Hz,1H),1.55(d,J=6.5Hz,3H).
实施例101
(4S,5S)-3-[3,5-二(三氟甲基)苄基]-5-[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮
按照实施例81中描述的方法,使用40mg(4S,5S)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮和17mg(5-异丙基-2-甲氧基苯基)硼酸,获得了本标题化合物。质谱(ESI)620.4(M+1)。1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.53-7.80(m,5H),7.33(d,J=8Hz,1H),7.21-7.29(m,1H),7.00,6.76(d,J=2.5Hz,1H),6.91,6.86(d,J=8.5Hz,0.4H),5.15,5.10(d,J=4.5Hz,1H),4.80,4.74(d,J=16Hz,1H),4.25,4.21(d,16Hz,1H),3.76(s,2H),3.49(s,1H),3.43(m,0.4H),3.18(m,0.5H),2.77-2.98(m,1H),1.24(m,3H),1.16(m,3H),0.78,0.61(d,J=6.5Hz,3Hz).
实施例102
(4R,5R)-5-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮
按照实施例81中描述的方法,使用240mg(4R,5R)-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮和171mg(4-氟-5-异丙基-2-甲氧基苯基)硼酸(实施例78),获得了本标题化合物。质谱(ESI)412.3(M+1)。1H NMR信号由于旋转对映异构现象而重叠。
1H NMR(500MHz,CDCl3):δ7.79.7.77(s,1H),7.64,7.62(dd,J~2.5Hz,8Hz,1H),7.32,7.31(d,J~8Hz,1H),7.00,6.95(d,J=8.5Hz,1H),6.70,6.67(d,J=12Hz,1H),6.47,6,43(s,1H),5.08,5.04(d,J=5Hz,0.1H),3.68-3.80(m,3.5H),3.53(m,0.5H),3.21(m,1H),1.19-1.30(m,6H),0.95,0.77(d,J=6Hz,3H).
按照实施例96中描述的方法,由(4R,5R)-5-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮制得了在表4中列出的化合物:
表4
实施例111
((4R,5S)-4-[3,5-二(三氟甲基)苯基]-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基咪唑烷-2-亚基)氨基氰
向(1R,2S)-1-[3,5-二(三氟甲基)苯基]-N2-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}丙-1,2-二胺(25.1mg,0.0424mmol)在二氯乙烷(1.5mL)内的溶液中加入三乙胺(15μL,0.105mmol)和氰基甲亚胺酸二苯酯(13mg,0.053mmol)。将该反应在60℃加热过夜,冷却至室温,过滤,直接负载到硅胶柱以通过快速色谱法纯化,使用10-40%EtOAc/己烷洗脱,获得了((4R,5S)-4-[3,5-二(三氟甲基)苯基]-1-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基咪唑烷-2-亚基)氨基氰。Rf=0.20(25%EtOAc/己烷)。LCMS=643.3(M+1)+。1H NMR(C6D6,500MHz;存在阻转异构体,某些峰重叠)
δ6.53-8.83(m,10H),3.61-4.91(m,3H),3.28-2.70(m,5H),1.14-1.25(m,6H),-0.39--0.26(m,3H).
按照上述一般方法制得了在表5中的化合物:
表5
中间体1
(4S,5S)-5-(3,5-二氟苯基)-4-甲基-1,3-唑烷-2-酮
步骤A:[(1S)-2-(3,5-二氟苯基)-1-甲基-2-氧代乙基]氨基甲酸苄酯
向{(1S)-2-[甲氧基(甲基)氨基]-1-甲基-2-氧代乙基}氨基甲酸苄酯(1.96g,7.36mmol)在THF(9.4mL)内的-15℃溶液中加入异丙基氯化镁(3.6mL 2M在乙醚中的溶液,7.2mmol)。将该反应在-15℃搅拌15分钟,然后3,5-二氟苯基溴化镁(29.44mL 0.5M在THF中的溶液,14.72mmol)。将该反应温热至室温并搅拌24小时。然后将该溶液倒入饱和NH4Cl(100mL)内,用EtOAc萃取(3×100mL)。将有机萃取液用水和盐水洗涤(分别是100mL),用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(15%EtOAc/己烷),获得了[(1S)-2-(3,5-二氟苯基)-1-甲基-2-氧代乙基]氨基甲酸苄酯。Rf=0.34(15%EtOAc/己烷)。LCMS=342.3(M+Na)+。
步骤B:[(1S,2S)-2-(3,5-二氟苯基)-2-羟基-1-甲基乙基]氨基甲酸苄酯
向[(1S)-2-(3,5-二氟苯基)-1-甲基-2-氧代乙基]氨基甲酸苄酯(1.35g,4.23mmol)在THF(75mL)内的-78℃溶液中加入1-Selectride(6.35mL 1M在THF中的溶液,6.35mmol)。在-78℃搅拌1小时后,将该反应倒入IN HCl(50mL)内。将该混合物用EtOAc(2×100mL)萃取。将有机萃取液用水和盐水洗涤(分别是50mL),用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(5-40%EtOAc/己烷),获得了[(1S,2S)-2-(3,5-二氟苯基)-2-羟基-1-甲基乙基]氨基甲酸苄酯(主产物)。LCMS=322.3(M+1)+。
步骤C:(4S,5S)-5-(3,5-二氟苯基)-4-甲基-1,3-唑烷-2-酮
[(1S,2S)-2-(3,5-二氟苯基)-2-羟基-1-甲基乙基]氨基甲酸苄酯(900mg,2.80mmol)在THF(28.6mL)内的溶液中加入MeOH(14.3mL)和7.5N KOH(7.2mL)。将该反应在室温搅拌4小时,然后用EtOAc(2×75mL)萃取。将有机萃取液用水和盐水洗涤(分别是50mL),用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(10-75%EtOAc/己烷),获得了(4S,5S)-5-(3,5-二氟苯基)-4-甲基-1,3-唑烷-2-酮。Rf=0.07(25%EtOAc/己烷)。
LCMS=214.3(M+1)+.1H NMR(CDCl3,500MHz)δ6.89-6.93(m,2H),6.82(m,1H),6.24(bs,1H),5.01(d,J=6.8Hz,1H),3.79(m,1H),1.42(d,J=6.2Hz,3H).
中间体2
6-氯-5-氟-2-碘吡啶-3-醇
向6-氯-5-氟吡啶-3-醇(307.8mg,2.08mmol)在水(11mL)内的溶液中加入Na2CO3(441mg,4.16mmol)和I2(549mg,2.08mmol)。2小时后,将该反应混合物用1N HCl酸化至pH 3,用EtOAc(100mL)稀释,用NaHSO3水溶液和盐水(分别是50mL)洗涤。将有机层用硫酸钠干燥,过滤并浓缩,获得了6-氯-5-氟-2-碘吡啶-3-醇。
LCMS=273.9(M+1)+.1H NMR(CDCl3,500MHz)δ7.11(d,J=8.5Hz,1H),5.47(d,J=1.4Hz,1H).
中间体3
2-溴-6-异丙烯基-3-甲氧基吡啶
向管中加入2-溴-6-碘-3-甲氧基吡啶(700mg,2.236mmol)、异丙烯基硼酸(212mg,2.460mmol)、DME(7.5mL)、EtOH(2.8mL)和1MNa2CO3水溶液(5.6mL)。将该混合物用氮气脱气。加入Pd(PPh3)4(206mg,0.179mmol),再次将该混合物用氮气脱气。将管密封,在80℃加热16小时。然后将该溶液冷却至室温,用EtOAc(100mL)稀释,用饱和NaHCO3和盐水(分别是50mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(0-15%EtOAc/己烷),获得了2-溴-6-异丙烯基-3-甲氧基吡啶。Rf=0.38(25%EtOAc/己烷)。
LCMS=230.0(M+1)+.1H NMR(CDCl3,500MHz)δ7.36(d,J=8.5Hz,1H),7.07(d,J=9.4Hz,1H),5.81(s,1H),5.21(s,1H),3.92(s,3H),2.16(s,3H).
中间体4
2-碘-3-甲氧基吡啶
向2-碘吡啶-3-醇(45.3mg,0.205mmol)在DMF(3mL)内的溶液中加入Cs2CO3(334mg,1.030mmol)和MeI(25μL,0.410mmol)。1小时后,将该反应倒入水(10mL)中,用EtOAc(20mL)稀释,用水(3×10mL)和盐水(10mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。获得了2-碘-3-甲氧基吡啶。
LCMS=236.1(M+1)+.1H NMR(CDCl3,500MHz)δ8.00(dd,J=1.4,4.6Hz,1H),7.20(dd,J=4.6,8.0Hz,1H),7.00(dd,1.4,8.3Hz,1H),3.90(s,3H).
中间体5
2-溴-6-碘吡啶-3-醇
向2-溴吡啶-3-醇(1.00g,5.80mmol)在水(30mL)内的溶液中加入Na2CO3(1.23g,11.60mmol)和I2(1.53g,5.80mmol)。1小时后,将该反应用N HCl(20mL)处理,用EtOAc(2×100mL萃取),用NaHSO3水溶液和盐水(分别是50mL)洗涤。将有机层用硫酸钠干燥,过滤并浓缩。通过快速硅胶色谱法纯化(20-40%EtOAc/己烷),获得了2-溴-6-碘吡啶-3-醇。Rf=0.44(25%EtOAc/己烷)。
LCMS=301.9(M+1)+.1H NMR(CDCl3,500MHz)δ7.56(d,J=8.3Hz,1H),6.99(d,J=8.3Hz,1H),5.65(s,1H).
中间体6
1-(2-溴-1,3-噻唑-5-基)乙醇
向2-溴-5-甲酰基噻唑(100.6mg,0.524mmol)在THF(5mL)内的0℃溶液中加入MeMgBr(175μL 3M在乙醚中的溶液,0.524mmol)。30分钟后,加热MeMgBr(50μL 3M在乙醚中的溶液,0.150mmol)。30分钟后,将该反应倒入饱和NH4Cl(20mL)内。将该混合物用EtOAc(50mL)萃取,将有机层用水和盐水洗涤(分别是25mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化(0-80%EtOAc/己烷),获得了1-(2-溴-1,3-噻唑-5-基)乙醇。Rf=0.13(25%EtOAc/己烷)。
LCMS=210.0(M+1)+.1H NMR(CDCl3,500MHz)δ7.40(s,1H),5.12(q,J=6.4Hz,1H),1.59(d,J=6.4Hz,3H).
中间体7
4-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-2-碘-1,3-噻唑
步骤A:4-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-1,3-噻唑
向1,3-噻唑-4-基甲醇(311.4mg,2.7mmol)在CH2Cl2(15mL)内的溶液中加入Et3N(1.9mL,13.6mmol)。将该溶液冷却至-78℃,加入TBSOTf(776μL,3.38mmol)。将该反应温热至室温并搅拌1小时。然后将该反应用EtOAc(75mL)稀释,用饱和NaHCO3、盐水、1N HCl和盐水(分别是20mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。将残余物通过快速硅胶色谱法纯化(0-15%EtOAc/己烷),获得了4-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-1,3-噻唑。Rf=0.28(15%EtOAc/己烷)。
LCMS=230.1(M+1)+.1H NMR(CDCl3,600MHz)δ8.77(d,J=2.0Hz,1H),7.25(m,1H),4.93(d,J=1.1Hz,2H),0.95(s,9H),0.12(s,6H).
步骤B:4-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-2-碘-1,3-噻唑
向4-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-1,3-噻唑(106.4mg,0.465mmol)在THF(5mL)内的-78℃溶液中滴加n-BuLi(465μL 1.6M在己烷中的溶液,0.744mmol)。将该反应在-78℃搅拌30分钟,然后通过套管碘(295mg,1.16mmol)在THF(5mL)中的溶液。将该反应温热至室温保持15分钟,然后倒入NaHSO3水溶液(20mL)内。将该混合物用EtOAc(60mL)萃取。将有机层用盐水、饱和NaHCO3和盐水(分别是20mL)洗涤,将有机层用硫酸钠干燥,过滤,并浓缩。通过快速色谱法纯化(15%EtOAc/己烷),获得了4-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-2-碘-1,3-噻唑。Rf=0.55(15%EtOAc/己烷)。
LCMS=356.0(M+1)+.1H NMR(CDCl3,600MHz)δ7.16(s,1H),4.86(s,2H),0.93(s,9H),0.10(s,6H).
中间体8
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(975mg,1.633mmol)在DMSO(16mL)内的溶液中加入二(频哪醇)二硼(1.24g,4.899mmol)、[1,1′-二(二苯基膦基)-二茂铁]二氯化钯(II)与二氯甲烷的络合物(1∶1)(133mg,0.1633mmol)和KOAc(320mg,3.266mmol)。将该混合物用氮气脱气,然后在80℃加热16小时。然后将该溶液冷却至室温,用EtOAc稀释(200mL)和,用饱和NaHCO3和盐水(分别是80mL)洗涤。将有机层用硫酸钠干燥,经由二氧化硅塞过滤,并浓缩。将残余物通过反相色谱法纯化(C-18,10-95%MeCN/水,含有0.1%TFAA),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮。
LCMS=598.1(M+1)+.1H NMR(CDCl3,500MHz)δ7.98(d,J=7.8Hz,1H),7.88(s,1H),7.78(s,2H),7.67(s,1H),7.57(d,J=7.8Hz,1H),5.68(d,J=7.5Hz,1H),5.01(d,J=15.6Hz,1H),4.76(d,J=15.5Hz,1H),3.98-3.93(m,1H),1.35(d,J=6.9Hz,12H),0.77(d,J=6.7Hz,3H).
实施例118
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[3′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向管中加入(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(52.5mg,0.0879mmol)、3-异丙基苯硼酸(17.3mg,0.106mmol)、DME(370[mu]h)、EtOH(120μL)和1M Na2CO3水溶液(264μL,0.264mmol)。将该混合物用氮气脱气然后加入Pd(PPh3)4(10.2mg,8.8×10-3mmol),将该混合物再次用氮气脱气。将管密封,在100℃加热2小时。然后将该溶液冷却至室温,用EtOAc(50mL)稀释,用水和盐水(分别是15mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(0-15%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[3′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.29(15%EtOAc/己烷)。
LCMS=590.1(M+1)+.1HNMR(CDCl3,500MHz)δ7.85(s,1H),7.72(s,1H),7.68(s,2H),7.64(d,J=8.0Hz,1H),7.44(d,J=8.0Hz,1H),7.39(t,J=7.6Hz,1H),7.29(d,J=7.8Hz,1H),7.15(bs,1H),7.11(bd,J=7.5Hz,1H),5.46(d,J=8.0Hz,1H),4.91(d,J=15.7Hz,1H),4.21(d,J=15.8Hz,1H),3.69(m,1H),2.96(m,1H),1.26-1.28(m,6H),0.38(d,J=6.4Hz,3H).
实施例119
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-异丙烯基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向管中加入(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[3′-氯-4′-氟-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例146)(30.2mg,0.0504mmol)、异丙烯基硼酸(27mg,0.31mmol)、1,1-二(二叔丁基膦基)二茂铁二氯化钯(5.5mg,8.4×10-3mmol)、THF(350μL)和1M K2CO3水溶液(350μL)。将管用氮气脱气,密封,在100℃加热5小时。然后将该溶液冷却至室温,用EtOAc(50mL)稀释,用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(0-15%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-异丙烯基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.29(15%EtOAc/己烷)。
LCMS=606.2(M+1)+.1H NMR(CDCl3,500MHz)δ7.86(s,1H),7.70(s,3H),7.64(d,J=8.0Hz,1H),7.42(d,J=8.0Hz,1H),7.23(dd,J=7.8,2.0Hz,1H),7.12-7.17(m,2H),5.54(d,J=8.0Hz,1H),5.28(s,1H),5.26(s,1H),4.90(d,J=15.8Hz,1H),4.18(d,J=15.8Hz,1H),3.78(m,1H),2.16(s,3H),0.47(d,J=6.7Hz,3H).
实施例120
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(1H-吡咯-3-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-{5-(三氟甲基)-2-[1-(三异丙基甲硅烷基)-1H-吡咯-3-基]苄基}-1,3-唑烷-2-酮(实施例149)(22.6mg,0.0326mmol)在THF(2mL)内的0℃溶液中加入TBAF(65μL 1M在THF中的溶液,0.065mmol)。30分钟后,将该反应用饱和NH4Cl(5mL)处理。将该混合物用EtOAc(35mL)萃取,将有机层用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(25-60%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(1H-吡咯-3-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮。Rf=0.11(25%EtOAc/己烷)。
LCMS=537.1(M+1)+.1H NMR(CDCl3,600MHz)δ8.49(s,1H),7.85(s,1H),7.71(s,2H),7.64(s,1H),7.58(d,J=8.1Hz,1H),7.51(d,J=8.0Hz,1H),6.88-6.91(m,2H),6.33(d,J=1.6Hz,1H),5.53(d,J=8.0Hz,1H),5.02(d,J=15.7Hz,1H),4.46(d,J=15.6Hz,1H),3.80(m,1H),0.49(d,J=6.6Hz,3H).
实施例121
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(1-异丙基-1H-吡咯-3-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(1H-吡咯-3-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮(6.8mg,0.0127mmol)(实施例120)在DMSO(300μL)的溶液中加入粉末KOH(3.6mg,0.0643mmol)。搅拌15分钟后,加入2-碘丙烷(3.2μL,0.032mmol)。在室温搅拌1.5小时后,加入水(5mL),将该混合物首先用CH2Cl2(2×15mL)萃取,然后用EtOAc(2×15mL)萃取。将合并的有机相用硫酸钠干燥,过滤,并浓缩。通过PTLC纯化残余物(25%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(1-异丙基-1H-吡咯-3-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.33(25%EtOAc/己烷)。
LCMS=579.2(M+1)+.1HNMR(CDCl3,500MHz)δ7.85(s,1H),7.71(s,2H),7.61(s,1H),7.56(d,J=8.0Hz,1H),7.50(d,J=8.0Hz,1H),6.83(t,J=2.1H[z,1H),6.79(t,J=2.5Hz,1H),6.24(t,J=2.3Hz,1H),5.49(d,J=8.0Hz,1H),5.04(d,J=15.5Hz,1H),4.48(d,J=15.6Hz,1H),4.27(m,1H),3.76(m,1H),1.48(d,J=6.6Hz,6H),0.49(d,J=6.6Hz,3H).
实施例122
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-硝基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例143)(159.4mg,0.276mmol)在HOAc(5mL)内的溶液中加入HNO3(1.5mL)。45分钟后,再加入HNO3(1.5mL)。45分钟后,将该反应倒入冰水(30mL)内。将该混合物用EtOAc(75mL)萃取,用1N NaOH、饱和NaHCO3和盐水(分别是25mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(8-40%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-硝基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.11(25%EtOAc/己烷)。
LCMS=623.1(M+1)+.1HNMR(CDCl3,500MHz,rotamers present)δ8.34(m,1H),8.10(m,1H),7.85(d,J=6.9Hz,1H),7.61-7.71(m,4H),7.40(m,1H),7.11(m,1H),5.66(d,J=8.0Hz),5.28(d,J=8.2Hz),4.89-4.94(m,1H),3.74-4.09(m,5H),0.61(d,J=6.6Hz),0.47(d,J=6.5Hz).
实施例123
(4S,5R)-3-{[5′-氨基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-硝基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例122)(48.2mg,0.077mmol)在EtOAc(4mL)内的溶液中加入PtO2(12mg),将该反应置于氢气氛下(气囊),剧烈搅拌。45分钟后,通过经由硅胶塞过滤除去催化剂,用100%EtOAc洗涤。将该滤液浓缩,获得了(4S,5R)-3-{[5′-氨基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮。Rf=0.20(40%EtOAc/己烷)。LCMS=593.2(M+1)+。1H NMR(CDCl3,500MHz,存在旋转异构体)
δ7.85(s,1H),7.60-7.70(m,4H),7.36(d,J=7.8Hz,1H),6.74-6.84(m,2H),6.56(s,1H),5.45-5.54(m,1H),4.82-4.87(m,1H),3.64-4.17(m,2H),3.70(s,3H),0.43-0.53(m,3H).
实施例124
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-(甲硫基)-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-3-{[5′-氨基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(实施例123)(40mg,0.0676mmol)在CHCl3(1mL)内的已经用氮气脱气的溶液中加入二甲二硫(10μL,0.101mmol)和亚硝酸叔丁酯(16μL,0.135mmol)。将该反应在室温搅拌30分钟,然后加热回流2小时。将该溶液冷却至室温,用己烷(3mL)稀释。将该溶液直接负载到硅胶柱上,用25%EtOAc/己烷洗脱。将含有所需产物的级份合并,通过硅胶色谱再纯化,用5-25%EtOAc/己烷洗脱,获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-(甲硫基)-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.52(40%EtOAc/己烷)。LCMS=624.1(M+1)+。1H NMR(CDCl3,600MHz,存在旋转异构体)
δ6.94-7.85(m,9H),5.58(d,J=8.1Hz)5.25(d,J=7.8Hz),4.94(d,J=15.8Hz),4.85(d,J=15.7Hz),3.65-4.12(m,5H),2.47(s),2.44(s),0.54(d,J=6.6Hz),0.40(d,J=6.6Hz).
实施例125
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-(甲基亚磺酰基)-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-(甲硫基)-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例124)(32.5mg,0.0522mmol)在CH2Cl2(5mL)内的-60℃溶液中加入m-CPBA(14.6mg,77%纯度,0.0652mmol)。将该反应缓慢地温热至-20℃,然后用EtOAc(35mL)稀释,用NaHSO3水溶液、盐水、饱和NaHCO3和盐水(分别是15mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱纯化(20-100%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-(甲基亚磺酰基)-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.10(75%EtOAc/己烷。
LCMS=640.1(M+1)+.1H NMR(CDCl3,600MHz)δ7.10-7.86(m,9H),4.87-5.59(m,2H),3.56-4.14(m,5H),2.79(s),2.75(s),2.73(s),0.61(d,J=6.5Hz),0.57(d,J=6.4Hz),0.46(d,J=6.4Hz),0.43(d,J=6.5Hz).
实施例126
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-(甲基磺酰基)-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-(甲硫基)-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例124)(7.8mg,0.013mmol)在CH2Cl2(1mL)内的0℃溶液中加入m-CPBA(14mg,77%纯度,0.063mmol)。将该反应在室温搅拌30分钟,然后用EtOAc(35mL)稀释,用NaHSO3水溶液、盐水、饱和NaHCO3和盐水(分别是15mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过PTLC纯化残余物(50%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-5′-(甲基磺酰基)-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.11(40%EtOAc/己烷)。LCMS=656.2(M+1)+。1H NMR(CDCl3,600MHz,存在旋转异构体)
δ7.99-8.02(m,1H),7.84-7.86(m,1H),7.75-7.78(m,1H),7.58-7.72(m,4H),7.38-7.42(m,1H),7.15-7.18(m,1H),5.55(d,J=8.0Hz),5.26(d,J=8.1Hz),4.91-4.97(m,1H),3.63-4.03(m,5H),3.12(s),3.10(s),0.62(d,J=6.6Hz),0.48(d,J=6.6Hz).
实施例127
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(6-异丙烯基吡啶-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
步骤A:2-溴-6-异丙烯基吡啶
向管中加入2,6-二溴吡啶(100mg,0.422mmol)、异丙烯基硼酸(40mg,0.464mmol)、DME(1.5mL)、EtOH(500μL)和1M碳酸钠水溶液(1mL,1.0mmol)。将该混合物用氮气脱气。然后加入Pd(PPh3)4(37mg,0.032mmol),将该混合物再次用氮气脱气。将管密封和在100℃加热1小时。然后将该溶液冷却至室温,用EtOAc(50mL)稀释,用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(5%EtOAc/己烷),获得了2-溴-6-异丙烯基吡啶。Rf=0.45(15%EtOAc/己烷)。
LCMS=200.0(M+1)+.1H NMR(CDCl3,500MHz)δ7.49(t,J=7.8Hz,1H),7.39(d,J=7.8Hz,1H),7.34(d,J=8.0Hz,1H),5.93(s,1H),5.32(m,1H),2.17(s,3H).
步骤B:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(6-异丙烯基吡啶-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向管中加入2-溴-6-异丙烯基吡啶(17.5mg,0.0878mmol)、(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮(26.2mg,0.0439mmol)、DME(190μL)、EtOH(62μL)和1M碳酸钠水溶液(100μL,0.1mmol)。将该混合物用氮气脱气。然后加入Pd(PPh3)4(9mg,7.8×10-3mmol),将该混合物再次用氮气脱气。将管密封,在100℃加热2小时。然后将该溶液冷却至室温,用EtOAc(50mL)稀释,用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(5-25%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(6-异丙烯基吡啶-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.15(15%EtOAc/己烷)。
LCMS=589.1(M+1)+.1HNMR(CDCl3,500MHz)δ7.81-7.85(m,2H),7.74(s,1H),7.69-7.69(m,3H),7.58(d,J=8.0Hz,1H),7.53(d,J=7.7Hz,1H),7.34(d,J=7.6Hz,1H),5.94(s,1H),5.48(d,J=7.7Hz,1H),5.36(s,1H),5.06(d,J=16.0Hz,1H),4.47(d,J=16.1Hz,1H),3.91(m,1H),2.23(s,3H),0.50(d,J=6.6Hz,3H).
实施例128
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(3-甲氧基-6-甲基-1-氧代吡啶-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(3-甲氧基-6-甲基吡啶-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(实施例174)(7.6mg,0.0128mmol)在CH2Cl2(1.3mL)内的0℃溶液中加入m-CPBA(5.8mg,77%纯度,0.0256mmol)。将该反应在室温搅拌1小时,然后用CH2Cl2(10mL)稀释,用NaHSO3水溶液、饱和K2CO3和盐水(分别5mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过PTLC纯化残余物(50%Et2O/CH2Cl2),获得了本标题化合物。
Rf=0.23(50%Et2O/CH2Cl2).LCMS=609.2(M+1)+.1H NMR(CDCl3,500MHz)δ7.85(s,1H),7.78(d,J=7.7Hz,1H),7.70(s,2H),7.62(s,1H),7.53(d,J=7.8Hz,1H),732(d,J=8.9Hz,1H),7.04(d,J=9.2Hz,1H),5.74(d,J=8.3Hz,1H),4.88(d,J=14.8Hz,1H),4.11-3.96(m,1H),3.88(d,J=14.9Hz,1H),3.86(s,3H),2.49(s,3H),0.65(d,J=6.6Hz,3H).
实施例129
(4S,5R)-3-[2-(3-氨基-6-异丙基吡啶-2-基)-5-(三氟甲基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(6-异丙烯基-3-硝基吡啶-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(实施例177)(19.3mg,0.0305mmol)在EtOH(300μL)内的溶液中加入10%Pd/C(5mg)。将该反应将该反应置于氢气氛下(气囊),剧烈搅拌。90分钟后,将该混合物负载到PTLC板上,并纯化(30%EtOAc/己烷,展开两次),获得了(4S,5R)-3-[2-(3-氨基-6-异丙基吡啶-2-基)-5-(三氟甲基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮。Rf=0.63(30%EtOAc/己烷,展开两次)。
LCMS=606.2(M+1)+.1H NMR(CDCl3,500MHz)δ7.84(s,1H),7.78(s,1H),7.72(d,J=8.0Hz,1H),7.69(s,2H),7.55(d,J=8.0Hz,1H),7.09-7.05(m,2H),5.53-5.52(m,1H),4.92(d,J=5.5Hz,1H),4.15-4.10(m,1H),3.89-3.78(m,1H),3.48(s,2H),3.00-2.95(m,1H),1.26-1.23(m,6H),0.44(d,J=5.1Hz,3H).
实施例130
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(3-氯-6-异丙基吡啶-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向CuCl2(9.3mg)和亚硝酸叔丁酯(6.6μL,0.0559mmol)在MeCN(300μL)内的溶液中经由套管加入在MeCN(300μL)中的(4S,5R)-3-[2-(3-氨基-6-异丙基吡啶-2-基)-5-(三氟甲基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(实施例129)(16.9mg,0.0279mmol)。将该反应在60℃加热1小时,然后冷却至室温,用EtOAc(20mL)稀释,用水和盐水洗涤(分别8mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过PTLC纯化残余物(30%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(3-氯-6-异丙基吡啶-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.56(30%EtOAc/己烷)。
LCMS=625.1(M+1)+.1H NMR(CDCl3,500MHz)δ7.85(s,1H),7.78(d,J=8.3Hz,1H),7.73-7.71(m,2H),7.68(s,2H),7.53(d,J=7.8Hz,1H),7.24(d,J=8.2Hz,1H),5.55(d,J=7.7Hz,1H),5.05(d,J=15.4Hz,1H),3.97(d,J=15.4Hz,1H),3.88-3.82(m,1H),3.17-3.08(m,1H),1.30-1.32(m,6H),0.53(d,J=6.7Hz,3H).
实施例131
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(2-异丙烯基-1,3-噻唑-4-基)-5-(三氟甲基)苄基1-4-甲基-1,3-唑烷-2-酮
步骤A:4-溴-2-异丙烯基-1,3-噻唑
向管中加入2,4-二溴噻唑(100mg,0.411mmol)、异丙烯基硼酸(39mg,0.452mmol)、DME(1.625mL)、EtOH(563μL)和IM碳酸钠水溶液(1.03mL,1.03mmol)。将该混合物用氮气脱气。然后加入Pd(PPh3)4(24mg,0.0206mmol),将该混合物再次用氮气脱气。将管密封和在100℃加热2小时。然后将该溶液冷却至室温,用EtOAc(50mL)稀释并用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(0-15%EtOAc/己烷),获得了4-溴-2-异丙烯基-1,3-噻唑;NMR表明存在没有被除去的杂质。Rf=0.53(15%EtOAc/己烷)。
LCMS=206.0(M+1)+.1H NMR(CDCl3,500MHz)δ7.13(s,1H),5.87(s,1H),5.33(d,J=1.3Hz,1H),2.21(s,3H).
步骤B:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(2-异丙烯基-1,3-噻唑-4-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向管中加入4-溴-2-异丙烯基-1,3-噻唑(20mg,0.097mmol)、(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮(29.4mg,0.0492mmol)、THF(340μL)、1M K2CO3水溶液(340μL)和1,1-二(二叔丁基膦基)二茂铁二氯化钯(3.2mg,4.9×10-3mmol)。将该混合物用氮气脱气。将管密封,在100℃加热1.5小时。然后将该溶液冷却至室温,用EtOAc稀释(50mL)并用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(5-25%EtOAc/己烷),然后通过PTLC纯化(90%CH2Cl2/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(2-异丙烯基-1,3-噻唑-4-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.16(15%EtOAc/己烷)。
LCMS=595.1(M+1)+.1HNMR(CD2Cl2,500MHz)δ7.90(s,1H),7.64-7.76(m,5H),7.38(s,1H),5.89(s,1H),5.60(d,J=8.1Hz,1H),5.37(d,J=1.2Hz,1H),4.99(d,J=16.0Hz,1H),4.66(d,J=16.0Hz,1H),3.94(m,1H),2.25(s,3H),0.59(d,J=6.4Hz,3H).
实施例132
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(羟基甲基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(实施例178)(54.0mg,0.0774mmol)在THF(10mL)内的0℃溶液中加入TBAF(194μL 1M在THF中的溶液,0.194mmol)。将该反应在0℃搅拌30分钟,然后倒入饱和NH4Cl(15mL)内。将该混合物用EtOAc(60mL)萃取,将有机层用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(60%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(羟基甲基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.11(40%EtOAc/己烷)。
LCMS=585.1(M+1)+.1H NMR(CDCl3,500MHz)δ7.85(s,1H),7.81(d,J=8.0Hz,1H),7.70-7.73(m,4H),7.36(s,1H),5.52(d,J=8.0Hz,1H),5.39(d,J=15.3Hz,1H),4.81(s,2H),4.55(d,J=15.3Hz,1H),3.87(m,1H),0.69(d,J=6.7Hz,3H).
实施例133
2-[2-({(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-2-氧代-1,3-唑烷-3-基}甲基)-4-(三氟甲基)苯基]-1,3-噻唑-4-甲醛
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(羟基甲基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(实施例132)(40.9mg,0.070mmol)在CH2Cl2(5mL)内的0℃溶液中加入DMP(59.4mg,0.140mmol)。将该反应温热至室温并搅拌45分钟。Next将该反应用EtOAc稀释(40mL),并用1N NaOH(2×15mL)和盐水(2×15mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(50%EtOAc/己烷),获得了2-[2-({(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-2-氧代-1,3-唑烷-3-基}甲基)-4-(三氟甲基)苯基]-1,3-噻唑-4-甲醛。Rf=0.24(40%EtOAc/己烷)。
LCMS=583.1(M+1)+.1H NMR(CDCl3,500MHz)δ10.09(s,1H),8.33(s,1H),7.87(s,2H),7.82(d,J=8.2Hz,1H),7.79(s,2H),7.72,(d,J=8.1Hz,1H),5.70(d,J=8.0Hz,1H),5.13(d,J=16.0Hz,1H),4.83(d,J=16.0Hz,1H),4.23(m,1H),0.75(d,J=6.6Hz,3H).
实施例134
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(1-羟基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向2-[2-({(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-2-氧代-1,3-唑烷-3-基}甲基)-4-(三氟甲基)苯基]-1,3-噻唑-4-甲醛(实施例133)(43.9mg,0.075mmol)在Et2O(7.5mL)内的-40℃溶液中加入MeMgBr(30μL3M在乙醚中的溶液,0.10mmol)。将该反应通过TLC紧密监测,再滴加MeMgBr直至几乎所有原料醛消耗完。然后将该反应倒入饱和NH4Cl(15mL)内。将该混合物用EtOAc(50mL)萃取,将有机层用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(5-50%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(1-羟基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.17(40%EtOAc/己烷)。
LCMS=599.1(M+1)+.1H NMR(CDCl3,500MHz)δ7.70-7.86(m,6H),7.31-7.32(m,1H),5.53-5.55(m,1H),5.35-5.41(m,1H),5.06(m,1H),4.57-4.62(m,1H),3.88(m,1H),1.61-1.63(m,3H),0.69(d,J=6.7Hz,3H).
实施例135
(4S,5R)-3-[2-(4-乙酰基-1,3-噻唑-2-基)-5-(三氟甲基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(1-羟基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(实施例134)(31.0mg,0.052mmol)在CH2Cl2(6mL)内的0℃溶液中加入DMP(55mg,0.130mmol)。将该反应温热至室温并搅拌45分钟。然后将该反应用EtOAc(40mL)稀释,用1N NaOH(2×15mL)和盐水(2×15mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(40%EtOAc/己烷),获得了(4S,5R)-3-[2-(4-乙酰基-1,3-噻唑-2-基)-5-(三氟甲基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮。Rf=0.26(40%EtOAc/己烷)。
LCMS=597.1(M+1)+.1H NMR(CDCl3,600MHz)δ8.27(s,1H),7.89(s,1H),7.77-7.82(m,4H),7.71(d,J=7.9Hz,1H),5.68(d,J=7.9Hz,1H),5.22(d,J=16.3Hz,1H),4.85(d,J=16.4Hz,1H),4.08(m,1H),2.70(s,3H),0.71(d,J=6.6Hz,3H).
实施例136
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(1-羟基-1-甲基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-3-[2-(4-乙酰基-1,3-噻唑-2-基)-5-(三氟甲基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(实施例135)(38.1mg,0.064mmol)在THF/庚烷(1∶1,8mL)内的-40℃溶液中加入MeMgBr(21μL 3M在乙醚中的溶液,0.07mmol)。将温度保持在-40℃至-20℃并,将该反应通过TLC紧密监测,再滴加MeMgBr直至几乎所有原料酮消耗完。然后将该反应倒入饱和NH4Cl(15mL)内。将该混合物用EtOAc(50mL)萃取,将有机层用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(10-60%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(1-羟基-1-甲基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.20(40%EtOAc/己烷)。
LCMS=613(M+1)+.1H NMR(CD2Cl2,500MHz)δ7.90(s,1H),7.85(d,J=8.0Hz,1H),7.77(s,3H),7.71(d,J=8.3Hz,1H),7.32(s,1H),5.59(d,J=8.0Hz,1H),5.28(d,J=15.8Hz,1H),4.74(d,J=15.8Hz,1H),3.89(m,1H),3.01(bs,1H),1.63(s,3H),1.62(s,3H),0.64(d,J=6.5Hz,3H).
实施例137
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(4-异丙烯基-1,3-噻唑-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[4-(1-羟基-1-甲基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(实施例136)(9.5mg,0.015mmol)在甲苯(4mL)内的溶液中加入对甲苯磺酸一水合物(20mg,0.105mmol)。将该反应在80℃加热30分钟,然后冷却至室温,用EtOAc(35mL)稀释,用饱和NaHCO3和盐水(分别是15mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(25%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(4-异丙烯基-1,3-噻唑-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.55(40%EtOAc/己烷)。
LCMS=595.1(M+1)+.1HNMR(CD2Cl2,500MHz)δ7.91(s,1H),7.78-7.83(m,4H),7.68(d,J=8.5Hz,1H),7.33(s,1H),5.95(d,J=0.9Hz,1H),5.66(d,J=8.0Hz,1H),5.24(m,1H),5.07(d,J=16.4Hz,1H),5.00(d,J=16.3Hz,1H),4.03(m,1H),2.17(s,3H),0.63(d,J=6.4Hz,3H).
实施例138
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-异丙烯基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例119)(18.8mg,0.031mmol)在EtOH(4.5mL)内的溶液中加入10%Pd/C(15mg)。将该反应置于氢气氛下(气囊),剧烈搅拌。45分钟后,通过过滤除去催化剂。将该滤液浓缩,并将残余物通过快速硅胶色谱法纯化,用15%EtOAc/己烷洗脱。通过PTLC进一步纯化,使用75%CH2Cl2/己烷洗脱,获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.35(15%EtOAc/己烷)。
LCMS=608.2(M+1)+.1H NMR(CDCl3,500MHz)δ7.86(s,1H),7.71(s,1H),7.70(s,2H),7.64(d,J=8.0Hz,1H),7.41(d,J=8.0Hz,1H),7.15(m,1H),7.08-7.12(m,2H),5.52(d,J=8.0Hz,1H),4.89(d,J=15.7Hz,1H),4.18(d,J=15.8Hz,1H),3.76(m,1H),3.28(m,1H),1.25-1.29(m,6H),0.42(d,J=6.4Hz,3H).
实施例139
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[5-(1-甲氧基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[5-(1-羟基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(实施例154)(13.2mg,0.0221mmol)在THF(1mL)内的0℃溶液中加入NaHMDS(26.5μL1M在THF中的溶液,0.0265mmol),然后加入MeI(1滴)。1.5小时后,再向该反应中加入NaHMDS(15μL 1M在THF中的溶液,0.015mmol)和MeI(1滴)。将该反应温热至室温保持20分钟,然后倒入饱和NH4Cl(10mL)内。将该混合物用EtOAc(35mL)萃取,将有机层用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(15-75%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-[5-(1-甲氧基乙基)-1,3-噻唑-2-基]-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.37(40%EtOAc/己烷)。
LCMS=613.0(M+1)+.1H NMR(CDCl3,500MHz)δ7.87(s,1H),7.74-7.82(m,5H),7.67(d,J=8.0Hz,1H),6.63-5.66(m,1H),5.08-5.14(m,1H),4.83-4.88(m,1H),4.64-4.68(m,1H),4.01-4.08(m,1H),3.34(m,3H),1.60(d,J=6.4Hz,3H),0.69(d,J=6.7Hz,3H).
实施例140和141
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(1,1-二氧化-1-苯并噻吩-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮和2.2mg(15%)(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(1-氧化-1-苯并噻吩-2-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮
向(4S,5R)-3-[2-(1-苯并噻吩-2-基)-5-(三氟甲基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(实施例150)(14.5mg,0.024mmol)在CH2Cl2(2mL)内的溶液中加入m-CPBA(16mg,77%纯度,0.071mmol)。将该反应在室温搅拌3小时,然后用EtOAc(40mL)稀释,用NaHSO3水溶液(15mL)、饱和NaHCO3(15mL)和盐水(15mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过PTLC纯化残余物(25%EtOAc/己烷,2个洗脱液),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(1,1-二氧化-1-苯并噻吩-2-基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮和2.2mg(15%)(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-(1-氧化-1-苯并噻吩-2-基)-5-(三氟甲基)苄基]-1,3-唑烷-2-酮。141的数据:Rf=0.09(25%EtOAc/己烷)。
LCMS=636.2(M+1)+.1H NMR(CDCl3,500MHz)δ7.96(d,J=8.0Hz,1H),7.83(s,1H),7.68-7.77(m,5H),7.63(m,1H),7.57(m,1H),7.50(d,J=7.6Hz,1H),7.28(s,1H),5.75(d,J=8.0Hz,1H),5.21(d,J=15.8Hz,1H),4.21(d,J=15.8Hz,1H),4.01(m,1H),0.70(d,J=6.7Hz,3H).
140的数据:Rf=0.06(25%EtOAc/己烷)。
LCMS=620.2(M+1)+.1H NMR(CDCl3,500MHz)δ7.15-7.95(m,11H),5.72-5.75(m,1H),5.36(d,J=15.6Hz),5.07(d,J=15.8Hz),4.41(d,J=16.0Hz),4.22(d,J=15.8Hz),3.88-4.08(m,1H),0.68(d,J=6.6Hz),0.61(d,J=6.6Hz).
实施例142
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲氧基)联苯-2-基]甲基)-4-甲基-1,3-唑烷-2-酮
步骤A:2-(溴甲基)-1-硝基-4-(三氟甲氧基)苯
将发烟硝酸(5mL)冷却至0℃,加入3-(三氟甲氧基)苄基溴(1mL,6.l6mmol)。15分钟后,将该反应倒入冰水(100mL)内,用EtOAc(200mL)萃取。将有机层用水、饱和NaHCO3和盐水(分别75)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱纯化残余物(0-15%EtOAc/己烷),获得了2-(溴甲基)-1-硝基-4-(三氟甲氧基)苯。Rf=0.54(15%EtOAc/己烷)。
1H NMR(CDCl3,500MHz)δ8.14(d,J=8.9Hz,1H),7.43(m,1H),7.31(m,1H),4.82(s,2H).
步骤B:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-硝基-5-(三氟甲氧基)苄基]-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(840mg,2.68mmol)在DMA(25mL)内的溶液中加入NaHMDS(2.68mL 1M在THF中的溶液,2.68mmol)。将该反应在室温搅拌5分钟,然后通过套管加入在DMA(5mL)中的2-(溴甲基)-1-硝基-4-(三氟甲氧基)苯(967mg,3.22mmol)。15分钟后,将该反应倒入饱和NH4Cl(50mL)内。将该混合物用EtOAc(150mL)萃取,将有机层用水和盐水洗涤(分别是40mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(5-25%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-硝基-5-(三氟甲氧基)苄基]-1,3-唑烷-2-酮。Rf=0.10(15%EtOAc/己烷)。
LCMS=533.2(M+1)+.1H NMR(CDCl3,500MHz)δ8.16(d,J=8.9Hz,1H),7.92(s,1H),7.80(s,2H),7.44(s,1H),7.33(d,J=8.9Hz,1H),5.78(d,J=7.8Hz,1H),4.94(d,J=17.0Hz,1H),4.79(d,J=16.9Hz,1H),4.25(m,1H),0.81(d,J=6.7Hz,3H).
步骤C:(4S,5R)-3-[2-氨基-5-(三氟甲氧基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-3-[2-硝基-5-(三氟甲氧基)苄基]-1,3-唑烷-2-酮(1.07g,2.01mmol)在EtOAc(30mL)内的溶液中加入PtO2(100mg,0.44mmol)。将该反应置于氢气氛下(气囊),剧烈搅拌。1小、时后,通过过滤除去催化剂,并将该滤液浓缩。通过快速色谱法纯化(5-40%EtOAc/己烷),获得了(4S,5R)-3-[2-氨基-5-(三氟甲氧基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮。Rf=0.45(40%EtOAc/己烷)。
LCMS=503.2(M+1)+.1HNMR(CDCl3,600MHz)δ7.89(s,1H),7.75(s,2H),7.03(dd,J=8.7,2.0Hz,1H),6.90(d,J=2.1Hz,1H),6.67(d,J=8.7Hz,1H),5.67(d,J=8.5Hz,1H),4.73(d,J=15.4Hz,1H),4.35(bs,2H),4.09(d,J=15.4Hz,1H),4.04(m,1H),0.78(d,J=6.6Hz,3H).
步骤D:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲氧基)苄基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-3-[2-氨基-5-(三氟甲氧基)苄基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(582mg,1.16mmol)在CHCl3(35mL)内的溶液中加入亚硝酸叔丁酯(275μL,2.32mmol)。10分钟后,加入I2(736mg,2.9mmol)。将该反应在室温搅拌30分钟,然后在65℃加热2小时。然后将该溶液冷却至室温,用EtOAc(150mL)稀释,用NaHSO3水溶液、水、盐水、饱和NaHCO3和盐水(分别是50mL)洗涤。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱纯化残余物(2-15%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲氧基)苄基]-4-甲基-1,3-唑烷-2-酮。Rf=0.30(15%EtOAc/己烷)。
LCMS=614.1(M+1)+.1H NMR(CDCl3,500MHz)δ7.89-7.91(m,2H),7.79(s,2H),7.23(m,1H),6.95(m,1H),5.75(d,J=8.0Hz,1H),4.81(d,J=15.8Hz,1H),4.32(d,J=15.8Hz,1H),4.07(m,1H),0.78(d,J=6.6Hz,3H).
步骤E:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲氧基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向微波管中加入(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲氧基)苄基]-4-甲基-1,3-唑烷-2-酮(41.6mg,0.0679mmol)、(4-氟-5-异丙基-2-甲氧基苯基)硼酸(18mg,0.085mmol)、DME(305μL)、EtOH(100μL)和1M碳酸钠水溶液(140μL,0.140mmol)。将该混合物用氮气脱气。然后加入Pd(PPh3)4(4mg,3.4×10-3mmol),将该混合物再次用氮气脱气。将管密封,在微波下于150℃和200W照射10分钟。然后将该溶液冷却至室温,用EtOAc(40mL)稀释,用水和盐水洗涤(分别是15mL)。将有机层用硫酸钠干燥,过滤,并浓缩。通过快速硅胶色谱法纯化(2-15%EtOAc/己烷),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲氧基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.24(15%EtOAc/己烷)。LCMS=654.3(M+1)+。1H NMR(CDCl3,500MHz,存在旋转异构体)
δ7.85(s,1H),7.69(s,2H),7.21-7.30(m,4H),6.95-7.00(m,1H),6.65-6.68(m,1H),5.59(d,J=8.0Hz),5.41(d,J=8.0Hz),4.74-4.81(m,1H),3.75-4.09(m,5H),3.19(m,1H),1.16-1.27(m,6H),0.51(d,J=6.7Hz),0.36(d,J=6.6Hz).
通过上述一般方法制得了表6中的化合物:
表6
通过上述一般方法制得了表7中的化合物:
表7
中间体9
4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲醇
将[2-碘-5-(三氟甲基)苯基]甲醇(实施例69)(3.09g,10.2mmol)、(4-氟-5-异丙基-2-甲氧基苯基)硼酸(4.34g,20.5mmol)、(Ph3P)4Pd(1.42g,1.23mmol)和Na2CO3(9.11g,85.9mmol)在苯/EtOH/H2O(7∶1∶3,250mL)中的混合物于氮气下加热回流24小时。冷却至室温后,将水相分离出来,用CH2Cl2(3×50mL)萃取。将合并的有机层干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,65×200mm,0-20%EtOAc在己烷中的混合物梯度),获得了4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲醇。Rf=0.50(20%EtOAc在己烷中的混合物)。
1H NMR(500MHz,CDCl3)δ7.86(s,1H),7.59(d,J=6.7Hz,1H),7.30(d,J=7.9Hz,1H),6.99(d,J=8.6Hz,1H),6.68(d,J=12.0Hz,1H),4.52(br s,1H),4.46(br s,1H),3.73(s,3H),3.25-3.17(m,1H),1.82(br s,1H),1.24(d,J=6.8Hz,6H).
中间体10
2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯
在0℃于氮气氛下,通过套管将三苯基膦(3.11g,11.8mmol)在无水CH2Cl2(7mL)内的溶液加到四溴化碳(3.93g,11.8mmol)和4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲醇(3.38g,9.87mmol)在无水CH2Cl2(56mL)内的搅拌着的溶液中。将该反应温热至室温。2小时后,将该反应混合物真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,65×200mm,0-20%EtOAc在己烷中的混合物梯度),获得了2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯。
1H NMR(500MHz,CDCl3)δ7.83(s,1H),7.61(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),7.15(d,J=8.6Hz,1H),6.72(d,J=12.0Hz,1H),4.43(brd,J=10.0Hz,1H),4.30(br d,J=10.2Hz,1H),3.76(s,3H),3.30-3.22(m,1H),1.29(d,J=6.9Hz,6H).
中间体11
5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4,4-二甲基-1,3-唑烷-2-酮
步骤A:{2-[甲氧基(甲基)氨基]-1,1-二甲基-2-氧代乙基}氨基甲酸苄酯
在0℃于氮气氛下,将N-甲基吗啉(682mg,741μL,6.74mmol)和氯甲酸异丁酯(460mg,441μL,3.37mmol)依次加到N-苄氧羰基-2-甲基丙氨酸(0.64g,2.69mmol)在无水CH2Cl2内的搅拌着的溶液中。将所得浑浊混合物在0℃搅拌90分钟。分批加入N,O-二甲基羟基胺盐酸盐(316mg,3.24mmol),将该混合物温热至室温并搅拌3小时。将该混合物倒入1N HCl(30mL),用CH2Cl2(3×40mL)萃取。将合并的萃取液用1N HCl(30mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,40×160mm,0-80%EtOAc在己烷中的混合物梯度),获得了{2-[甲氧基(甲基)氨基]-1,1-二甲基-2-氧代乙基}氨基甲酸苄酯。Rf=0.47(50%EtOAc在己烷中的混合物)。LCMS计算值=303.1;实测值=303.2(M+Na)+。
1H NMR(500MHz,CDCl3)δ7.37-7.29(m,5H),5.82(s,1H),5.09(s,2H),3.60(s,3H),3.18(s,3H),1.60(s,6H).
步骤B:(1,1-二甲基-2-氧代乙基)氨基甲酸苄酯
在-78℃于氮气下,将氢化二异丁基铝(1.77mL,1M在甲苯中的溶液,0.708mmol)加入{2-[甲氧基(甲基)氨基]-1,1-二甲基-2-氧代乙基}氨基甲酸苄酯(198.5mg,0.708mmol)在无水THF(7.1mL)内的搅拌着的溶液中。将该反应在-78℃搅拌4小时。加入MeOH(100μL)和1N HCl(250μL),并将该反应温热至室温。将该混合物用Et2O(50mL)稀释,用1N HCl(2×50mL)、50%饱和NaHCO3(50mL)和水(50mL)洗涤,然后干燥(MgSO4)并真空浓缩,获得了(1,1-二甲基-2-氧代乙基)氨基甲酸苄酯。Rf=0.40(20%EtOAc在己烷中的混合物)。LCMS计算值=244.1;实测值=244.1(M+Na)+。
1H NMR(500MHz,CDCl3)δ9.43(s,1H),7.38-7.30(m,5H),5.34(s,1H),5.09(s,2H),1.37(s,6H).
步骤C:{2-[3,5-二(三氟甲基)苯基]-2-羟基-1,1-二甲基乙基}氨基甲酸苄酯
在室温于氮气下,将溴化乙基镁(1.63mL,1M在THF中的溶液,1.63mmol)滴加到1-碘-3,5-二(三氟甲基)苯(608mg,317μL,1.79mmol)在无水THF(1mL)内的搅拌着的溶液中。并将该反应搅拌30分钟。在-20℃,将所得溶液加到(1,1-二甲基-2-氧代乙基)氨基甲酸苄酯(163.5mg,0.739mmol)在无水THF(1mL)内的搅拌着的溶液中。并将该反应用3小时温热至室温。加入饱和NH4Cl(10mL)和水(10mL),并将该混合物用EtOAc萃取(3×20mL)。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,25×160mm,0-40%EtOAc在己烷中的混合物梯度),获得了{2-[3,5-二(三氟甲基)苯基]-2-羟基-1,1-二甲基乙基}氨基甲酸苄酯。Rf=0.40(20%EtOAc在己烷中的混合物)。LCMS计算值=436.1;实测值=436.0(M+1)+。
1H NMR(600MHz,CDCl3)δ7.80(s,1H),7.77(s,2H),7.39-7.33(m,5H),5.12-5.08(m,2H),1.36(s,1H),4.90(d,J=4.4Hz,1H),4.81(s,1H),1.36(s,3H),1.23(s,3H).
中间体12
[(1S)-2-(4-氯吡啶-2-基)-1-甲基-2-氧代乙基]氨基甲酸苄酯
将2-(二甲基氨基)乙醇(471mg,531mL,5.28mmol)在无水己烷(3.3mL)中的溶液冷却至-5℃,在氮气下滴加正丁基锂(1.6M在己烷中的溶液,6.60mL,10.6mmol)。在0℃保持30分钟后,将该溶液冷却至-78℃,通过套管滴加4-氯吡啶(通过将相应的HCl盐(264mg,1.76mmol)在CH2Cl2(20mL)中的溶液用饱和K2CO3(10mL)洗涤,然后用CH2Cl2(2×20mL)反萃取,合并有机层,干燥(Na2SO4)并真空浓缩而获得的)在己烷(3.3mL)内的溶液在-78℃1小时后,该溶液变为深红色。通过套管加入亲电子试剂的溶液(通过在-15℃于氮气下将异丙基氯化镁(2M在THF中的溶液,1.29mL,2.59mmol)加到{(1S)-2-[甲氧基(甲基)氨基]-1-甲基-2-氧代乙基}氨基甲酸苄酯(702mg,2.64mmol)在无水THF(3.5mL)中的溶液中并搅拌15分钟而制备的)。让该反应缓慢地温热至室温并保持过夜。加入水(25mL)和饱和NH4Cl(50mL),并将该混合物用EtOAc(3×50mL)萃取。将合并的萃取液干燥(MgSO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,40×160mm,0-30%EtOAc在己烷中的混合物梯度),获得了[(1S)-2-(4-氯吡啶-2-基)-1-甲基-2-氧代乙基]氨基甲酸苄酯。Rf=0.46(20%EtOAc在己烷中的混合物)。LCMS计算值=319.1;实测值=319.3(M+1)+。
1H NMR(500MHz,CDCl3)δ8.58(d,J=5.0Hz,1H),8.04(s,1H),7.47(dd,J=5.2,2.0Hz,1H),7.35-7.30(m,5H),5.78(s,1H),5.72(m,1H),5.11(m,2H),1.47(d,J=7.0Hz,3H).
中间体13
[(1S)-1-甲基-2-氧代-2-(1,3-噻唑-2-基)乙基]氨基甲酸苄酯
在-78℃于氮气下,将正丁基锂(1.6M在己烷中的溶液,1.76mL,2.83mmol)滴加到2-溴噻唑(462mg,251μL,2.82mmol)在无水THF(13mL)内的搅拌着的溶液中,搅拌45分钟。单独地,在-15℃于氮气下,将异丙基氯化镁(2M在THF中的溶液,0.94mL,1.99mmol)加到{(1S)-2-[甲氧基(甲基)氨基]-1-甲基-2-氧代乙基}氨基甲酸苄酯(500mg,1.88mmol)在无水THF(4mL)内的搅拌着的溶液中。将该溶液在-15℃搅拌15分钟,在-78℃滴加到上述2-锂化噻唑溶液中。将该反应温热至室温过夜,加入饱和NH4Cl(20mL)和水(10mL),并将该混合物用EtOAc(3×30mL)萃取。将合并的萃取液用盐水洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,25×160mm,0-50%EtOAc在己烷中的混合物梯度),获得了[(1S)-1-甲基-2-氧代-2-(1,3-噻唑-2-基)乙基]氨基甲酸苄酯。Rf=0.28(20%EtOAc在己烷中的混合物)。LCMS计算值=291.1;实测值=291.3(M+1)+。
1H NMR(600MHz,CDCl3)δ8.03(s,1H),7.70(d,J=3.1Hz,1H),7.34-7.29(m,5H),5.79(d,J=6.6Hz,1H),5.53-5.49(m,1H),5.14-5.08(m,2H),1.55(d,J=6.4Hz,3H).
中间体14
[(1S)-1-甲基-2-(1-甲基-1H-咪唑-4-基)-2-氧代乙基]氨基甲酸苄酯
将{(1S)-2-[甲氧基(甲基)氨基]-1-甲基-2-氧代乙基}氨基甲酸苄酯(64mg,0.24mmol)在CH2Cl2(1mL)中的溶液于氮气下冷却至-20℃,滴加异丙基氯化镁(120μL 2.0M在THF中的溶液)。将该混合物在-20℃搅拌20分钟。在一个单独的烧瓶中,于室温将乙基溴化镁(480μL 2.0M在乙醚中的溶液)加到4-碘-1-甲基-1-H-咪唑(109mg,0.48mmol)在无水CH2Cl2(1.5mL)内的溶液中。将所得混合物搅拌20分钟,然后通过套管缓慢地加入上述溶液。所得溶液搅拌过夜。将饱和NH4Cl加入该反应溶液中,将该混合物用水稀释,将水相用CH2Cl2(2×25mL)萃取。将合并的有机萃取液干燥(Na2SO4)并真空浓缩。通过快速色谱法纯化残余物,获得了[(1S)-1-甲基-2-(1-甲基-1H-咪唑-4-基)-2-氧代乙基]氨基甲酸苄酯。LCMS计算值=288.14;实测值=288.3(M+1)+。
1H NMR(500MHz,CDCl3)δ7.65(s,1H);7.47(s,1H);7.35-7.28(m,5H);5.93(d,J=6.9Hz,1H);5.29-5.25(m,1H);5.13(s,2H);3.73(s,3H);1.26(d,J=7.1Hz,3H).
中间体15
((1S)-2-{1-[(苄氧基)甲基]-1H-咪唑-2-基}-1-甲基-2-氧代乙基)氨基甲酸苄酯
步骤A:1-[(苄氧基)甲基]-1H-咪唑
将氯甲基醚(4.3mL,29mmol)和咪唑(6g,58mmol)在乙腈(200mL)中的混合物加热回流3.5小时。真空除去溶剂。把所得油状残余物在CH2Cl2(300mL)和水(150mL)之间分配。然后将有机萃取液用水(2×150mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了1-[(苄氧基)甲基]-1H-咪唑,不用进一步纯化而直接使用。LCMS计算值=189.10;实测值=189.1(M+1)+。
1H NMR(500MHz,CDCl3)δ7.63(s,1H);7.40-7.30(m,5H);7.16(t,J=6.5Hz,1H);7.09(t,J=10.6Hz,1H);5.34(s,2H);4.45(s,2H).
步骤B:((1S)-2-{1-[(苄氧基)甲基]-1H-咪唑-2-基}-1-甲基-2-氧代乙基)氨基甲酸苄酯
在-78℃于氮气下,向1-[(苄氧基)甲基]-1H-咪唑(706mg,3.75mmol)在THF(4mL)内的溶液中加入正丁基锂(2.3mL 1.6M在己烷中的溶液)。将该混合物在-78℃搅拌30分钟。在-15℃于氮气下,向{(1S)-2-[甲氧基(甲基)氨基]-1-甲基-2-氧代乙基}氨基甲酸苄酯(200mg,0.75mmol)在THF(2mL)内的溶液中加入异丙基氯化镁(375μL 2.0M在THF中的溶液)。将所得混合物在-15℃搅拌15分钟。在-78℃,通过套管将该混合物加到上述溶液中。将该混合物在-78℃搅拌约3小时,然后逐渐温热至室温,搅拌过夜。将该混合物用饱和NH4Cl处理。将水层用CH2Cl2(3×25mL)萃取。将有机层合并,干燥(Na2SO4)并真空浓缩。将残余物通过快速色谱法纯化,获得了((1S)-2-{1-[(苄氧基)甲基]-1H-咪唑-2-基}-1-甲基-2-氧代乙基)氨基甲酸苄酯,含有约30%未反应的原料{(1S)-2-[甲氧基(甲基)氨基]-1-甲基-2-氧代乙基}氨基甲酸苄酯。将该混合物不用进一步纯化直接用于下一步骤。LCMS计算值=394.18;实测值=394.2(M+1)+。
中间体16
2-溴-4,5-二氯-1-甲基-1H-咪唑
将2-溴-4,5-二氯咪唑(1g,4.6mmol)、甲基碘(346μL,5.56mmol)、碳酸钾(1.27g,9.2mmol)和溴化四丁基铵(148mg,0.46mmol)在乙腈(2mL)中的混合物在70-80℃剧烈搅拌1.0小时。冷却至室温后,过滤出无机盐,用乙腈洗涤。将滤液蒸发并将残余物通过快速色谱法纯化(Si),获得了2-溴-4,5-二氯-1-甲基-1H-咪唑,为白色固体。LCMS计算值=230.89;实测值=230.9(M+1)+。
1H NMR(500MHz,CDCl3)δ3.61(s,3H).
中间体17
4-碘-1-甲基-1H-吡唑
在氮气下向18-冠-6(132mg,0.5mmol)在Et2O(8mL)内的溶液中加入叔丁醇钾(616mg,5.5mmol)。将该混合物搅拌,在室温一次性加入4-碘吡唑(1g,5mmol)。将该反应冷却至0℃,在0℃滴加碘甲烷(342μL,5.5mmol)在Et2O(2mL)内的溶液。将所得混合物温热至室温,搅拌过夜。然后将该溶液用水稀释,用Et2O(2×50mL)萃取。将合并的有机层用盐水(45mL)洗涤,用无水硫酸钠干燥并真空浓缩。通过快速色谱法纯化,获得了4-碘-1-甲基-1H-吡唑。LCMS计算值=208.96;实测值=209.0(M+1)+。
1H NMR(500MHz,CDCl3)δ7.52(s,1H);7.43(s,1H);3.95(s,3H).
中间体18
3-碘-1-甲基-1H-吡唑
将1-甲基-1-H-吡唑-3-胺(250mg,2.57mmol)与亚硝酸叔丁酯(336μL,2.83mmol)在二碘甲烷(5mL)中加热回流3小时。真空除去溶剂和挥发性物质,通过快速色谱法纯化所得残余物(Si),获得了3-碘-1-甲基-1H-吡唑。LCMS计算值=208.96;实测值=209.0(M+1)+。
1H NMR(500MHz,CDCl3)δ7.21(d,J=2.1Hz,1H);6.42(d,J=2.2Hz,1H);3.94(s,3H).
中间体19,20
(4S,5S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(1-甲基-1H-四唑-5-基)-1,3-唑烷-2-酮和(4S,5S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(2-甲基-2H-四唑-5-基)-1,3-唑烷-2-酮
步骤A:[(1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(1H-四唑-5-基)乙基]氨基甲酸苄酯和[{1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(2H-四唑-5-基)乙基]氨基甲酸苄酯
将((1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-2-氰基-1-甲基乙基)氨基甲酸苄酯(106.6mg,0.306mmol)、三乙胺盐酸盐(211mg,1.53mmol)和叠氮化钠(99.4mg,1.56mmol)在无水甲苯(6mL)中的混合物在氮气下加热回流20小时,在室温保持2天。将该反应用1N HCl(20mL)稀释,用EtOAc(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。其不用进一步纯化直接使用。LCMS计算值=392.2;实测值=392.1(M+1)+。
步骤B:[(1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(1-甲基-1H-四唑-5-基)乙基]氨基甲酸苄酯和[(1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(2-甲基-2H-四唑-5-基)乙基]氨基甲酸苄酯
在室温于氮气下,将(三甲基甲硅烷基)重氮甲烷(2M在己烷中的溶液,459μL,0.918mmol)滴加到[(1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(1H-四唑-5-基)乙基]氨基甲酸苄酯和[{1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(2H-四唑-5-基)乙基]氨基甲酸苄酯粗产物在二氯甲烷/甲醇(3∶2,5mL)内的溶液中。15分钟后,气体释放停止,将该反应混合物真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-70%EtOAc在己烷中的混合物梯度),获得了[(1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(1-甲基-1H-四唑-5-基)乙基]氨基甲酸苄酯和[(1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(2-甲基-2H-四唑-5-基)乙基]氨基甲酸苄酯,为区域异构体的2∶1混合物。LCMS计算值=406.2;实测值=406.2(M+1)+。步骤C:[(1S,2S)-2-羟基-1-甲基-2-(2-甲基-2H-四唑-5-基)乙基]氨基甲酸苄酯和[(1S,2S)-2-羟基-1-甲基-2-(1-甲基-1H-四唑-5-基)乙基]氨基甲酸苄酯.
在0℃,将氟化四丁基铵(1M,在THF中的溶液,177μL,0.177mmol)滴加到[(1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(1-甲基-1H-四唑-5-基)乙基]氨基甲酸苄酯和[(1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-2-(2-甲基-2H-四唑-5-基)乙基]氨基甲酸苄酯(区域异构体的2∶1混合物,65.2mg,0.161mmol)在THF(2mL)内的搅拌着的溶液中。将该反应在0℃搅拌2小时,用饱和NH4Cl(10mL)稀释,用EtOAc(3×30mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-80%EtOAc在己烷中的混合物梯度),获得了[(1S,2S)-2-羟基-1-甲基-2-(2-甲基-2H-四唑-5-基)乙基]氨基甲酸苄酯和[(1S,2S)-2-羟基-1-甲基-2-(1-甲基-1H-四唑-5-基)乙基]氨基甲酸苄酯。2-甲基异构体(中间体20):LCMS计算值=292.1;实测值=292.1(M+1)+。
1H NMR(500MHz,CDCl3)δ7.33-7.29(m,5H),5.59(d,J=8.5Hz,1H),5.09-5.00(m,5H),4.49(m,1H),4.26(s,3H),1.07(d,J=6.9Hz,3H).
1-甲基异构体(中间体19):LCMS计算值=292.1;实测值=292.1(M+1)+。
1H NMR(500MHz,CDCl3)δ7.33-7.29(m,5H),5.72(s,1H),5.07(m,3H),4.99(m,2H),4.18(m,1H),4.10(s,3H),1.24(d,J=6.7Hz,3H).
实施例196
(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-吡啶-4-基-1,3-唑烷-2-酮
步骤A:[(1S)-1-甲基-2-氧代-2-吡啶-4-基乙基]氨基甲酸苄酯
在-15℃于氮气下,将异丙基氯化镁(1.6mL,1M在THF中的溶液,3.23mmol)滴加到{(1S)-2-[甲氧基(甲基)氨基]-1-甲基-2-氧代乙基}氨基甲酸苄酯(实施例17,步骤1)(879mg,3.30mmol)在无水THF(4.2mL)内的搅拌着的溶液中。将该反应在-15℃搅拌30分钟,然后通过通过滴加4-吡啶基溴化镁在无水THF中的溶液(通过在室温于氮气下将乙基溴化镁(6mL,2M在THF中的溶液,6.00mmol)加到4-碘吡啶(1.35g,6.60mmol)在无水THF(45mL)内的搅拌着的溶液中并搅拌30分钟而制得的)。将该反应温热至室温并搅拌5小时。加入1N HCl(15mL)以中止反应,用饱和NaHCO3将该混合物调节至碱性pH。将该混合物用EtOAc(2×50mL)和CH2Cl2(3×50mL)萃取。将EtOAc和CH2Cl2萃取液分别用盐水洗涤,干燥(Na2SO4),合并,真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,40×160mm,0-100%EtOAc在己烷中的混合物梯度),获得了[(2R)-1-甲基-2-氧代-2-吡啶-4-基乙基]氨基甲酸苄酯,为无色固体。Rf=0.33(50%EtOAc/己烷)。LCMS计算值=285.1;实测值=285.3(M+1)+。
1H NMR(500MHz,CDCl3)δ8.85(d,J=3.3Hz,2H),7.76(d,J=5.5Hz,2H),7.36-7.32(m,5H),5.70(d,J=6.8Hz,1H),5.31-5.25(m,1H),5.13(s,2H),1.43(s,3H).
步骤B:[(1S,2R)-2-羟基-1-甲基-2-吡啶-4-基乙基]氨基甲酸苄酯
在-78℃于氮气下,将三叔丁氧基氢化锂铝(964mg,3.79mmol)加到[(2R)-1-甲基-2-氧代-2-吡啶-4-基乙基]氨基甲酸苄酯(539.1mg,1.90mmol)在无水EtOH(40mL)内的溶液中。将该反应在-78℃搅拌2小时。加入2%乙酸水溶液以中止反应,用饱和NaHCO3(约50mL)将该混合物调节至碱性pH。将该混合物用EtOAc(3×100mL)萃取,将合并的萃取液用盐水(50mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,40×160mm,0-100%EtOAc在己烷中的混合物梯度),获得了[(1S,2R)-2-羟基-1-甲基-2-吡啶-4-基乙基]氨基甲酸苄酯,为无色固体。Rf=0.49(EtOAc)。LCMS计算值=287.1;实测值=287.3(M+1)+。
1H NMR(500MHz,CDCl3)δ8.41(d,J=5.7Hz,2H),7.36-7.32(m,7H),5.27(d,J=7.4Hz,1H),5.10(s,2H),4.89(s,1H),4.02(br s,1H),0.96(d,J=6.7Hz,3H).
步骤C:(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-吡啶-4-基-1,3-唑烷-2-酮
在室温于氮气下,将氢化钠(52.4mg,60%在矿物油中的分散液,1.31mmol)加到[(1S,2R)-2-羟基-1-甲基-2-吡啶-4-基乙基]氨基甲酸苄酯(150mg,0.524mmol)在无水THF(6mL)内的溶液中。在室温搅拌30分钟后,通过套管加入2-(溴甲基)-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯(255mg,0.629mmol)在无水THF(3mL)内的溶液。将该反应混合物在室温搅拌过夜。加入饱和NH4Cl(10mL),将该混合物用EtOAc(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,25×160mm,0-70%EtOAc在己烷中的混合物梯度),获得了(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-吡啶-4-基-1,3-唑烷-2-酮,为无色油状物。Rf=0.49(EtOAc)。LCMS计算值=503.2;实测值=503.3(M+1)+。1HNMR(600MHz,CDCl3,阻转异构体的1∶1混合物)
δ8.61(d,J=4.1Hz,2H),7.68(s,0.5H),7.61(s,1H),7.60(s,0.5H),7.33(dd,J=7.4,3.8,Hz 1H),7.16(br s,2H),6.97(dd,J=17.8,8.4Hz,1H),6.67(dd,J=12.0,3.4Hz,1H),5.44(d,J=8.2Hz,0.5H),5.28(d,J=8.0Hz,0.5H),4.79(d,J=15.8Hz,0.5H),4.76(d,J=15.8Hz,0.5H),4.15-4.09(m,1H),3.88(d,J=15.8Hz,0.5H),3.79-3.70(m,0.5H),3.74(s,3H),3.23-3.17(m,1H),1.26-1.16(m,6H),0.52(d,J=6.5Hz,1.5H),0.38(d,J=6.5Hz,1.5H).
实施例197
(4S,5S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(4-甲基-1,3-噻唑-2-基)-1,3-唑烷-2-酮
步骤A:[(1S)-1-甲基-2-氧代乙基]氨基甲酸苄酯
在-78℃于氮气下,将二甲基亚砜(1.01g,918μL,12.9mmol)滴加到草酰氯(790mg,543μL,6.23mmol)在无水CH2Cl2(12.6mL)内的搅拌着的溶液中,将该反应搅拌15分钟。通过套管滴加[(1S)-2-羟基-1-甲基乙基]氨基甲酸酯(965mg,4.61mmol)在无水CH2Cl2(12.6mL)内的溶液,将该混合物在-78℃搅拌30分钟。加入三乙胺(1.34g,1.85mL,13.2mmol),将该反应温热至室温并搅拌2小时。加入水(15mL),分离出水相,用CH2Cl2(3×15mL)萃取。将合并的有机萃取液用饱和NaHCO3和盐水洗涤,然后干燥(MgSO4)并真空浓缩,获得了[(1S)-1-甲基-2-氧代乙基]氨基甲酸苄酯,为无色油状物。Rf=0.75(50%EtOAc在己烷中的混合物)。
1H NMR(500MHz,CDCl3)δ9.58(s,1H),7.39-7.35(m,5H),5.39(br s,1H),5.15(s,2H),4.33(m,1H),1.40(d,J=7.1Hz,3H).
步骤B:[(1,S)-2-氰基-2-羟基-1-甲基乙基]氨基甲酸苄酯
在-78℃于氮气下,将二乙基氰化铝(4.53mL,1M在甲苯中的溶液,4.53mmol)滴加到[(1S)-1-甲基-2-氧代乙基]氨基甲酸苄酯(0.853g,4.12mmol)在无水甲苯(33mL)内的搅拌着的溶液中。将该混合物在-78℃搅拌6小时,然后温热至室温过夜。加入饱和NH4Cl(20mL)和水(10mL),然后将该混合物用EtOAc(3×50mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,40×160mm,0-40%EtOAc在己烷中的混合物梯度),获得了[(1,S)-2-氰基-2-羟基-1-甲基乙基]氨基甲酸苄酯,为非对映体的3∶1混合物。Rf=0.63(50%EtOAc在己烷中的混合物)。LCMS计算值=257.1;实测值=257.1(M+1)+。1H NMR(500MHz,CDCl3)主要非对映体:
δ7.39-7.31(m,5H),5.11(m,2H),4.60br(s,1H),3.96(m,1H),1.34(d,J=6.7Hz,3H),
次要非对映体:
δ7.39-7.31(m,5H),5.14(m,2H),4.50br(s,1H),4.10(m,1H),1.30(d,J=7.0Hz,3H).
步骤C:((1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-2-氰基-1-甲基乙基)氨基甲酸苄酯
在室温于氮气下,叔丁基二甲基甲硅烷基氯(471mg,3.12mmol)和咪唑(483mg,7.10mmol)依次加到[(1S)-2-氰基-2-羟基-1-甲基乙基]氨基甲酸苄酯(665mg,2.84mmol)在无水CH2Cl2(13mL)内的搅拌着的溶液中。将该混合物搅拌过夜。加入水(30mL),将该混合物用Et2O(3×30mL)萃取。将合并的萃取液干燥(MgSO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,40×160mm,0-15%EtOAc在己烷中的混合物梯度),获得了((1S,2R)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-2-氰基-1-甲基乙基)氨基甲酸苄酯和((1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-2-氰基-1-甲基乙基)氨基甲酸苄酯。(1S,2R)-非对映体:Rf=0.29(10%EtOAc在己烷中的混合物)。LCMS计算值=349.2;实测值=349.1(M+1)+。
1H NMR(500MHz,CDCl3)δ7.39-7.33(m,5H),5.16(d,J=12.1Hz,1H),5.07(d,J=12.1Hz,1H),4.89(br d,J=6.6Hz,1H),4.68(br,d,3.6Hz,1H),3.92(m,1H),1.31(d,J=6.7Hz,3H),0.91(s,9H),0.21(s,3H),0.17(s,3H).
(1S,2S)-非对映体:Rf=0.24(10%EtOAc在己烷中的混合物)。LCMS计算值=349.2;实测值=349.1(M+1)+。
1H NMR(500MHz,CDCl3)δ7.38-7.32(m,5H),5.10(s,2H),4.76(br d,J=6.9Hz,1H),4.63(br s,1H),4.00(m,1H),1.31(d,J=6.8Hz,3H),0.90(d,J=2.9Hz,9H),0.17(s,3H),0.08(s,3H).
步骤D:((1S,2S)-3-氨基-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-3-硫代丙基)氨基甲酸苄酯
将((1S,2S)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-2-氰基-1-甲基乙基)氨基甲酸苄酯(115.6mg,0.287mmol)、二硫代磷酸二乙酯(1mL)和水(3滴)的混合物在室温搅拌过夜。将该反应混合物在饱和NaHCO3(40mL)和EtOAc(40mL)之间分配。分离出水层,用EtOAc(2×40mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-40%EtOAc在己烷中的混合物梯度),获得了((1S,2S)-3-氨基-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-3-硫代丙基)氨基甲酸苄酯,为无色油状物。Rf=0.30(20%EtOAc在己烷中的混合物)。LCMS计算值=383.2;实测值=383.1(M+1)+。
1H NMR(500MHz,CDCl3)δ8.36(s,1H),7.87(s,1H),7.37-7.29(m,5H),5.13(m,2H),4.85(d,J=8.2Hz,1H),4.72(s,1H),4.47(m,1H),1.05(d,J=6.7Hz,3H),0.96(s,9H),0.08(s,3H),0.07(s,3H).
步骤E:[(1S,2S)-2-羟基-1-甲基-2-(4-甲基-1,3-噻唑-2-基)乙基]氨基甲酸苄酯
将((1S,2S)-3-氨基-2-{[叔丁基(二甲基)甲硅烷基]氧基}-1-甲基-3-硫代丙基)氨基甲酸苄酯(96.8mg,0.253mmol)和氯丙酮(117mg,101μL,1.27mmol)在无水EtOH(5mL)中的溶液于氮气下加热回流20小时,然后在室温搅拌2天。将该反应混合物真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-100%EtOAc在己烷中的混合物梯度),获得了[(1S,2S)-2-羟基-1-甲基-2-(4-甲基-1,3-噻唑-2-基)乙基]氨基甲酸苄酯。Rf=0.44(50%EtOAc在己烷中的混合物)。LCMS计算值=307.1;实测值=307.1(M+1)+。
1H NMR(500MHz,CDCl3)δ7.31(m,5H),6.80(s,1H),5.49(br s,1H),5.06(m,3H),4.26-4.18(m,1H),2.38(s,3H),1.09(d,J=6.5Hz,3H).
步骤F:(4S,5S)-4-甲基-5-(4-甲基-1,3-噻唑-2-基)-1,3-唑烷-2-酮
将[(1S,2S)-2-羟基-1-甲基-2-(4-甲基-1,3-噻唑-2-基)乙基]氨基甲酸苄酯(53.4mg,0.174mmol)在7.5N KOH水溶液(1mL)、MeOH(2mL)和THF(4mL)中的溶液在室温搅拌过夜。将该反应混合物用3N HCl酸化,用EtOAc(3×20mL)萃取。将合并的萃取液用盐水洗涤,干燥(Na2SO4)并真空浓缩,获得了产物。LCMS计算值=199.1;实测值=199.1(M+1)+。
1H NMR(500MHz,CDCl3)δ6.92(s,1H),6.82(s,1H),5.91(d,J=8.2Hz,1H),4.39-4.35(m,1H),2.44(s,3H),0.95(d,J=6.4Hz,3H).
步骤G:(4S,5S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(4-甲基-1,3-噻唑-2-基)-1,3-唑烷-2-酮
在室温于氮气下,将氢化钠(60%在矿物油中的分散液,8.1mg,0.202mmol)加到(4S,5S)-4-甲基-5-(4-甲基-1,3-噻唑-2-基)-1,3-唑烷-2-酮(33.4mg,0.168mmol)在无水THF(1mL)内的搅拌着的溶液中。将该反应搅拌15分钟,然后通过套管加入2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯(81.0mg,0.202mmol)在无水THF(2mL)内的溶液中。将该反应在室温搅拌过夜。加入饱和NH4Cl(10mL),将该混合物用EtOAc(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法(Si,25×160mm,0-70%EtOAc在己烷中的混合物梯度)和手性HPLC(IA柱,20×250mm,5%i-PrOH在庚烷中的混合物)纯化,获得了(4S,5S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(4-甲基-1,3-噻唑-2-基)-1,3-唑烷-2-酮。Rf=0.18(20%EtOAc在己烷中的混合物)。LCMS计算值=523.2;实测值=523.1(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.68(s,0.5H),7.63(s,0.5H),7.59(d,J=8.0Hz,1H),7.32(d,J=7.9Hz,1H),6.99(d,J=8.5Hz,0.5H),6.95(d,J=8.5Hz,0.5H),6.88(s,1H),6.68(d,J=5.0Hz,0.5H),6.66(d,J=4.9Hz,0.5H),5.70(d,J=8.3Hz,0.5H),5.55(d,J=8.2Hz,0.5H),4.72(d,J=15.9Hz,0.5H),4.64(d,J=15.9Hz,0.5H),4.20(d,J=15.9Hz,0.5H),3.95(d,J=15.9Hz,0.5H),3.91-3.83(m,1H),3.75(s,1.5H),3.74(s,1.5H),3.23-3.15(m,1H),2.40(s,3H),1.26-1.18(m,6H),0.65(d,J=6.5Hz,1.5H),0.55(d,J=6.5Hz,1.5H).
按照上述一般方法,制得了表8中的化合物。制备实施例198是用作参照化合物。
表8
实施例253,254
(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-[3-(甲基亚磺酰基)苯基]-1,3-唑烷-2-酮(实施例253)
(45,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-[3-(甲基磺酰基)苯基]-1,3-唑烷-2-酮(实施例254)
在氮气下于0℃,向(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-[3-(甲硫基)苯基]-1,3-唑烷-2-酮(实施例208)(25mg,0.0457mmol)在无水二氯甲烷(1.5mL)内的溶液中滴加3-氯过苯甲酸(77%,26mg,0.114mmol)在CH2Cl2(0.5mL)中的溶液。加入后,将该混合物温热至室温并搅拌2小时。将该反应混合物用饱和Na2SO3(15mL)处理。将水层用Et2O(3×20mL)萃取。将合并的有机萃取液用饱和NaHCO3洗涤,干燥(Na2SO4)并真空浓缩。通过快速色谱法纯化粗产物(Si,12×160mm,0-60%EtOAc在己烷中的混合物梯度),获得了(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-[3-(甲基亚磺酰基)苯基]-1,3-唑烷-2-酮和(45,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-[3-(甲基磺酰基)苯基]-1,3-唑烷-2-酮。实施例253:LCMS计算值=564.19;实测值=564.3(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.73(s,0.5H);7.66-7.52(m,4.5H);7.42(s,0.5H);7.40(s,0.5H);7.37(d,J=3.4Hz,0.5H);7.36(d,J=3.5Hz,0.5H);7.02(d,J=8.4Hz,0.5H);6.99(d,J=8.4Hz,0.5H);6.71(d,J=3.1Hz,0.5H);6.69(d,J=2.9Hz,0.5H);5.59(d,J=5.9Hz,0.5H);5.57(d,J=5.9Hz,0.5H);5.42(t,J=8.4Hz,1H);4.85(d,J=3.4Hz,0.5H);4.82(d,J=3.4Hz,0.5H);4.80(d,J=7.8Hz,0.5H);4.77(d,J=7.7Hz,0.5H);4.16(d,J=15.8Hz,0.5H);3.92(d,J=15.8Hz,0.5H);3.76(s,3H);3.85-3.72(m,1H);3.26-3.19(m,1H);2.73(d,J=4.7Hz,3H);1.30-1.26(m,4.5H);1.20(d,J=6.9Hz,1.5H);0.55(d,J=6.7Hz,0.75H);0.52(d,J=6.7Hz,0.75H);0.41(d,J=4.0Hz,0.75H);0.39(d,J=4.1Hz,0.75H).
实施例254:LCMS计算值=580.17;实测值=580.3(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.95(s,0.5H);7.94(s,0.5H);7.81(s,0.5H);7.80(s,0.5H);7.73(s,0.5H);7.65-7.58(m,3H);7.57(s,0.5H);7.38(d,J=3.5Hz,0.5H);7.36(d,J=3.8Hz,0.5H);7.02(d,J=8.4Hz,0.5H);6.99(d,J=8.4Hz,0.5H);6.72(s,0.5H);6.69(s,0.5H);5.58(d,J=8.1Hz,0.5H);5.42(d,J=8.0Hz,0.5H);4.86(d,J=15.9Hz,0.5H);4.81(d,J=15.9Hz,0.5H);4.17(d,J=15.8Hz,0.5H);3.91(d,J=15.8Hz,0.5H);3.81-3.75(m,1H);3.78(s,3H);3.27-3.19(m,1H);3.07(s,3H);1.30-1.26(m,4.5H);1.21(t,J=8.7Hz,1.5H);0.53(d,J=6.5Hz,1.5H);0.39(d,J=6.5Hz,1.5H).
实施例255
3-((4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)苯甲醛
将(4S,5R)-5-[3-(1,3-二氧杂环己烷-2-基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例210)(380mg,0.647mmol)在THF和1N HCl(3∶1)(4mL)中的溶液在室温搅拌2小时。将该反应混合物用EtOAc稀释,用碳酸氢钠和盐水洗涤。将有机层干燥并真空浓缩。通过快速色谱法纯化粗产物(Si),获得了3-((4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)苯甲醛。LCMS计算值=530.19;实测值=530.4(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ10.03(s,1H);7.88(s,0.5H);7.87(s,0.5H);7.77-7.52(m,5H);7.37(d,J=3.5Hz,0.5H);7.36(d,J=3.4Hz,0.5H);7.02(d,J=8.4Hz,0.5H);6.99(d,J=8.4Hz,0.5H);6.71(d,J=3.5Hz,0.5H);6.69(d,J=3.4Hz,0.5H);4.17(d,J=15.8Hz,0.5H);6.98(d,J=15.8Hz,0.5H);3.78(s,3H);3.85-3.71(m,1H);3.26-3.19(m,1H);1.30-1.26(m,4.5H);1.19(d,J=6.9Hz,1.5H);0.53(d,J=6.6Hz,1.5H);0.40(d,J=6.6Hz,1.5H).
实施例256
(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3-(羟基)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3-(羟基
在0℃于氮气氛下,向3-((4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)苯甲醛(12mg,0.023mmol)在无水EtOH(1mL)内的溶液中加入NaBH4粉末(4.5mg,0.119mmol)。将该溶液温热至室温并搅拌1小时。将该混合物用2%HOAc处理,用水稀释。将水层用EtOAc萃取(3×10mL)。将合并的有机萃取液用饱和NaHCO3(12mL)和盐水(12mL)洗涤,干燥(Na2SO4)并真空浓缩。通过快速色谱法纯化粗产物,获得了(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3-(羟基)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3-(羟基。LCMS计算值=532.0;实测值=532.4(M+1)+。1HNMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.73(s,0.5H);7.67(s,0.5H);7.64(s,0.5H);7.62(s,0.5H);7.42-7.32(m,3H);7.24(s,1H);7.15(s,0.5H);7.14(s,0.5H);7.01(d,J=8.4Hz,0.5H);6.98(d,J=8.5Hz,0.5H);6.71(s,0.5H);6.68(s,0.5H);5.51(d,J=8.1Hz,0.5H);5.37(d,J=8.0Hz,0.5H);4.81(d,J=15.9Hz,0.5H);4.74(d,J=16Hz,0.5H);4.73(s,2H);4.15(d,J=15.9Hz,1H);3.92(d,J=15.9Hz,1H);3.77(s,3.0H);3.79-3.74(m,0.5H);3.74-3.68(m,0.5H);3.25-3.18(m,1H);1.29-1.25(m,4.5H);1.19(d,J=6.9Hz,1.5H);0.53(d,J=6.4Hz,1.5H);0.40(d,J=6.4Hz,1.5H).
实施例257
(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3-(1-羟基乙基)苯基]-4-甲基-1,3-唑烷-2-酮
在-78℃于氮气下,向3-((4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)苯甲醛(11mg,0.021mmol)在THF(1mL)内的溶液中加入甲基溴化镁(30μL3.0M在乙醚中的溶液)。将该混合物在-78℃搅拌2小时。将该混合物用饱和NH4Cl(10mL)处理。将水层用EtOAc(3×10mL)萃取。将合并的有机层用盐水(15mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si),获得了(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3-(1-羟基乙基)苯基]-4-甲基-1,3-唑烷-2-酮。LCMS计算值=546.22;实测值=546.4(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.74(s,0.5H);7.67(s,0.5H);7.64(s,0.5H);7.63(s,0.5H);7.36(m,3H);7.24(s,1H);7.15(s,0.5H);7.14(s,0.5H);7.01(d,J=8.5Hz,0.5H);6.99(d,J=8.5Hz,0.5H);6.71(s,0.5H);6.68(s,0.5H);5.52(d,J=8.0Hz,0.5H);5.36(d,J=7.9Hz,0.5H);4.92(q,J=6.4Hz,1H);4.83(d,J=15.7,0.5H);4.77(d,J=16.0,0.5H);4.16(d,J=15.5Hz,0.5H);3.92(d,J=15.5Hz,0.5H);3.77(d,J=7.1Hz,3H);3.81-3.68(m,1H);3.25-3.18(m,1H);1.64(br,s,1H);1.49(d,J=6.4Hz,3H);1.30-1.26(m,4.5H);1.19(d,J=6.9Hz,1.5H);0.53(d,J=6.5Hz,1.5H);0.40(d,J=6.5Hz,1.5H).
按照上述一般方法,制得表9中的化合物:
表9
实施例 | R | LCMS(M+1)+ |
258 | Et | 560.4 |
259 | n-Pr | 574.4 |
实施例260
(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-{3-[(甲基氨基)甲基]苯基}-1,3-唑烷-2-酮
向3-((4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)苯甲醛(15mg,0.028mmol)在1,2-二氯乙烷(1mL)内的溶液中加入甲基胺(1mL 2.0M在THF中的溶液)。将所得混合物用三乙酰氧基硼氢化钠(34.8mg,0.16mmol)和AcOH(0.05mL)处理。将该混合物在氮气下于室温搅拌5天。将该反应混合物用1N NaOH处理,并将水层用乙醚(3×15mL)萃取。将乙醚萃取液用盐水洗涤,干燥(Na2SO4)并真空浓缩。将残余物通过快速色谱法纯化(Si),获得了(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-{3-[(甲基氨基)甲基]苯基}-1,3-唑烷-2-酮。LCMS计算值=545.23;实测值=545.4(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.74(s,0.5H);7.67(s,0.5H);7.64(s,0.5H);7.62(s,0.5H);7.33(m,3H);7.20(s,1H);7.13(s,0.5H);7.12(s,0.5H);7.01(d,J=8.4Hz,0.5H);6.98(d,J=8.5Hz,0.5H);6.71(d,J=2.9Hz,0.5H);6.68(d,J=2.8Hz,0.5H);5.51(d,J=8.1Hz,0.5H);5.37(d,J=8.0Hz,0.5H);4.82(d,J=15.9Hz,0.5H);4.75(d,J=15.9Hz,0.5H);4.16(d,J=15.9Hz,0.5H);3.92(d,J=15.9Hz,0.5H);3.77(m,5.5H);3.70(t,J=6.6Hz,0.5H);3.25-3.18(m,1H);2.45(s,3H);1.93(br,s,1H);1.27(m,4.5H);1.19(d,J=6.9Hz,1.5H);0.53(d,J=6.5Hz,1.5H);0.40(d,J=6.5Hz,1.5H).
实施例261
(4S,5R)-5-{3-[(二甲基氨基)甲基]苯基}-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向3-((4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)苯甲醛(15mg,0.028mmol)在EtOH(1mL)内的溶液中加入二甲基胺(140μL 2.0M在MeOH中的溶液)和异丙醇钛(79μL,0.28mmol)。将所得白色悬浮液搅拌过夜。加入硼氢化钠(7.1mg,0.188mmol),将该混合物搅拌过夜。通过将该混合物倒入2N氨水(2mL)内来中止反应。过滤出所得无机沉淀,用二氯甲烷洗涤。将合并的滤液用二氯甲烷(2×15mL)萃取。将萃取液干燥(Na2SO4)并真空浓缩。将残余物通过快速色谱法纯化(Si),获得了(4S,5R)-5-{3-[(二甲基氨基)甲基]苯基}-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。LCMS计算值=559.25;实测值=559.4(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.74(s,0.5H);7.67(s,0.5H);7.64(s,0.5H);7.62(s,0.5H);7.37-7.29(m,3H);7.18(s,1H);7.16(s,0.5H);7.13(s,0.5H);7.01(d,J=8.4Hz,0.5H);6.99(d,J=8.5Hz,0.5H);6.71(d,J=3.0Hz,0.5H);6.68(d,J=2.9Hz,0.5H);5.52(d,J=8.1Hz,0.5H);5.37(d,J=8.0Hz,0.5H);4.82(d,J=15.9Hz,0.5H);4.77(d,J=16.0Hz,0.5H);4.15(d,J=16.0Hz,0.5H);3.91(d,J=15.9Hz,0.5H);3.76(s,3H);3.80-3.73(m,0.5H);3.72-3.68(m,0.5H);3.43(s,2H);3.25-3.18(m,1H);2.23(s,6H);1.27(m,4.5H);1.19(d,J=6.9Hz,1.5H);0.53(d,J=6.5Hz,1.5H);0.39(d,J=6.6Hz,1.5H).
实施例262
(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-(1H-咪唑-2-基)-4-甲基-1,3-唑烷-2-酮
将(4S,5S)-5-{1-[(苄氧基)甲基]-1H-咪唑-2-基}-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例244)(16.9mg,0.028mmol)、20%氢氧化钯/碳(8.3mg)和1N HCl(28uL)在MeOH(1mL)中的混合物在氢气(气囊)下搅拌过夜,然后将该混合物经由硅藻土过滤,并真空浓缩。通过快速色谱法纯化粗产物,获得了(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-(1H-咪唑-2-基)-4-甲基-1,3-唑烷-2-酮。LCMS计算值=492.18;实测值=492.2(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.71(s,0.5H);7.67(s,0.5H);7.65(s,0.5H);7.64(s,0.5H);7.37(d,J=3.2Hz,0.5H);7.35(d,J=3.3Hz,0.5H);7.09(d,2H);7.02(d,J=8.4Hz,0.5H);6.99(d,J=8.5Hz,0.5H);6.72(d,J=4.3Hz,0.5H);6.69(d,J=4.2Hz,0.5H);5.76(d,J=8.3Hz,0.5H);5.64(d,J=8.7Hz,0.5H);4.72(d,J=15.8Hz,0.5H);4.68(d,J=15.8Hz,0.5H);4.20(d,J=15.7Hz,0.5H);4.01(d,J=15.7Hz,0.5H);3.90(br,s,1H);3.79-3.72(m,4H);3.25-3.18(m,1H);1.28-1.22(m,6H);0.67(d,J=6.5Hz,1.5H);0.59(d,J=6.5Hz,1.5H).
实施例263
(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(1-氧化吡啶-4-基)-1,3-唑烷-2-酮
在0℃将间氯苯甲酸(77%,47.9mg,0.214mmol)加到(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-吡啶-4-基-1,3-唑烷-2-酮(53.7,0.107mmol)在无水CH2Cl2(10.8mL)内的溶液中。在0℃保持15分钟后,将该反应在室温搅拌3小时。将该反应用CH2Cl2(40mL)稀释,用饱和Na2SO3(20mL)和饱和K2CO3(2×20mL)洗涤。将有机层干燥(Na2SO4)并真空浓缩,获得了(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(1-氧化吡啶-4-基)-1,3-唑烷-2-酮,为油状物。LCMS计算值=519.2;实测值=519.3(M+1)+。
实施例264
4-((4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)吡啶-2-甲腈
在室温于氮气下,将三甲基甲硅烷基氰化物(39.9mg,54μL,0.402mmol)加到(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(1-氧化吡啶-4-基)-1,3-唑烷-2-酮(37.9mg,0.0732mmol)在无水CH2Cl2(2mL)内的搅拌着的溶液中。将该反应搅拌5分钟,加入苯甲酰氯(20.5mg,17μL,0.146mmol)。将该反应在室温搅拌过夜。加入50%饱和K2CO3(10mL),将该混合物用CH2Cl2(20mL)稀释。分离出水层并用CH2Cl2(2×10mL)萃取。将合并的有机萃取液干燥(K2CO3)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-70%EtOAc在己烷中的混合物梯度),获得了产物(11.6mg,30%),为无色油状物。通过手性HPLC(AD柱,20×250mm,10%i-PrOH在庚烷中的混合物)将产物拆分成其对映体,获得了4-((4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)吡啶-2-甲腈和4-((4R,5S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-2-氧代-1,3-唑烷-5-基)吡啶-2-甲腈。Rf=0.72(50%EtOAc在己烷中的混合物)。LCMS计算值=528.2;实测值=528.3(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ8.73(s,1H),7.67-7.59(m,2H),7.55(d,J=3.3Hz,1H),7.40(d,J=4.2Hz,1H),7.35(dd,J=7.8,3.3Hz,1H),6.99(d,J=8.4Hz,1H),6.95(d,J=8.4Hz,1H),6.69(d,J=3.1Hz,1H),6.67(d,J=3.1Hz,1H),5.47(d,J=8.1Hz,0.5H),5.30(d,J=8.1Hz,0.5H),4.81(t,J=15.1Hz,1H),4.11(d,J=15.8Hz,0.5H),3.89(d,J=15.8Hz,0.5H),3.83-3.73(m,1H),3.76(s,3H),3.24-3.16(m,1H),1.27-1.17(m,6H),0.54(d,J=6.5Hz,1.5H),0.39(d,J=6.5Hz,1.5H).
实施例265
(4S,5R)-5-(2-氯吡啶-4-基)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
将(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(1-氧化吡啶-4-基)-1,3-唑烷-2-酮(53.7mg,0.104mmol)在三氯氧化磷(4mL)中的溶液于氮气下加热回流2小时。将该反应混合物冷却至室温,真空浓缩,用EtOAc(20mL)和水(5mL)稀释,然后用饱和NaHCO3(10mL)洗涤。将水层用EtOAc(2×20mL)萃取。将合并的有机层干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-70%EtOAc在己烷中的混合物梯度),获得了产物,为无色油状物。将产物拆分成其对映体手性HPLC(AD柱,20×250mm,5%i-PrOH在庚烷中的混合物),获得了(4S,5R)-5-(2-氯吡啶-4-基)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.17(20%EtOAc在己烷中的混合物)。LCMS计算值=537.2;实测值=537.3(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ8.40(br s,1H),7.70(s,0.5H),7.63(s,1.5H),7.37(m,1H),7.24(brs,1H),7.10(br s,1H),7.01(d,J=8.2Hz,0.5H),6.98(d,J=8.2Hz,0.5H),6.72-6.68(m,1H),5.44(d,J=8.1Hz,0.5H),5.29(d,J=8.1Hz,0.5H),4.81(t,J=16.9Hz,1H),4.14(d,J=15.9Hz,0.5H),3.91(d,J=15.9Hz,0.5H),3.81-3.71(m,1H),3.76(s,3H),3.27-3.19(m,1H),1.29-1.19(m,6H),0.58(d,J=6.5Hz,1.5H),0.44(d,J=6.5Hz,1.5H).
实施例266
(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(2-甲基吡啶-4-基)-1,3-唑烷-2-酮
将(4S,5R)-5-(2-氯吡啶-4-基)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(20.9mg,0.0389mmol)、三甲基环硼氧烷(14.7mg,16μL,0.116mmol)、Cs2CO3(38.0mg,0.117mmol)和(Ph3P)4Pd(9.0mg,0.00778mmol)在无水1,4-二氧杂环己烷(1mL)中的溶液加热回流过夜。将该反应混合物经由硅藻土塞过滤,用EtOAc洗涤。将该滤液真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-70%EtOAc在己烷中的混合物梯度),获得了产物,为无色油状物。通过手性BDPLC(AD柱,20×250mm,10%i-PrOH在庚烷中的混合物)将产物拆分成其对映体,获得了(4S,5R)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(2-甲基吡啶-4-基)-1,3-唑烷-2-酮和(4R,5S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-5-(2-甲基吡啶-4-基)-1,3-唑烷-2-酮。Rf=0.22(50%EtOAc在己烷中的混合物)。LCMS计算值=517.2;实测值=517.1(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ8.48(d,J=4.9Hz,1H),7.69(s,0.5H),7.61(s,1H),7.60(s,0.5H),7.33(m,1H),7.05(s,1H),6.99-6.93(m,2H),6.69(d,J=3.2Hz,1H),6.66(d,J=3.2Hz,1H),5.40(d,J=8.1Hz,0.5H),5.24(d,J=8.1Hz,0.5H),4.79(d,J=15.9Hz,0.5H),4.74(d,J=15.9Hz,0.5H),4.13(d,J=15.9Hz,0.5H),3.89(d,J=15.9Hz,0.5H),3.78-3.66(m,1H),3.75(s,3H),3.23-3.17(m,1H),2.56(s,3H),1.25-1.17(m,6H),0.53(d,J=6.5Hz,1.5H),0.39(d,J=6.5Hz,1.5H).
按照上述一般方法制得了在表10中的化合物:
表10
按照上述一般方法制得了在表11中的化合物:
表11
按照上述一般方法制得了在表12中的化合物:
表12
实施例281
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′-羟基-5′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
步骤A:4-氟-2′-(碘甲基)-5-异丙基-4′-(三氟甲基)联苯-2-醇
在密封管中,将[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲醇(71.5mg,0.209mmol)和碘(610mg,2.40mmol)在苯基三甲基甲硅烷(877μL)中的溶液于110℃加热过夜。将该反应冷却至室温,用1NHCl(10mL)稀释,用EtOAc(3×20mL)萃取。将合并的萃取液用10%Na2S2O3(20mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-20%EtOAc在己烷中的混合物梯度),获得了4-氟-2′-(碘甲基)-5-异丙基-4′-(三氟甲基)联苯-2-醇。Rf=0.65(20%EtOAc在己烷中的混合物)。
1H NMR(500MHz,CDCl3)δ7.81(s,1H),7.60(d,J=7.9Hz,1H),7.34(d,J=7.9Hz,1H),7.10(d,J=8.3Hz,1H),6.69(d,J=11.1Hz,1H),4.82(s,1H),4.41(d,J=9.4Hz,1H),4.23(d,J=9.3Hz,1H),3.27-3.19(m,1H),1.27(br s,6H).
步骤B:2-{[4-氟-2′-(碘甲基)-5-异丙基-4′-(三氟甲基)联苯-2-基]氧基}四氢-2H-吡喃
在室温于氮气下,将对甲苯磺酸(2.8mg,0.0145mmol)加到4-氟-2′-(碘甲基)-5-异丙基-4′-(三氟甲基)联苯-2-醇(63.4mg,0.145mmol)和3,4-二氢-2H-吡喃(60.8mg,66μL,0.723mmol)在无水CH2Cl2(7.2mL)内的溶液中,将该反应搅拌3天。将该反应混合物用饱和NaHCO3(20mL)稀释,并用CH2Cl2(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-20%EtOAc在己烷中的混合物梯度),获得了2-{[4-氟-2′-(碘甲基)-5-异丙基-4′-(三氟甲基)联苯-2-基]氧基}四氢-2H-吡喃。Rf=0.74(10%EtOAc在己烷中的混合物)。
1H NMR(500MHz,CDCl3)δ7.75(s,1H),7.62(d,J=8.3Hz,0.5H),7.59(d,J=8.3Hz,0.5H),7.53(t,J=7.3Hz,0.5H),7.41(s,0.5H),7.32(d,J=7.9Hz,0.5H),7.25(d,J=7.9Hz,0.5H),7.15(t,J=9.4Hz,0.5H),6.99(d,J=12.2Hz,0.5H),6.94(d,J=12.2Hz,0.5H),6.69(d,J=11.0Hz,0.5H),5.37(s,0.5H),5.23(s,0.5H),5.13(s,1H),4.45(d,J=9.6Hz,0.5H),4.40(d,J=9.6Hz,0.5H),4.31(d,J=9.6Hz,0.5H),4.23(d,J=9.6Hz,0.5H)3.76(m,0.5H),3.66-3.54(m,1.5H),3.29-3.21(m,1H),1.68-1.44(m,4H)1.32-1.26(m,6H).
步骤C:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′-羟基-5′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
将氢化钠(60%在矿物油中的分散液,1.9mg,0.0485mmol)加到(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮在无水DMF(1mL)内的搅拌着的溶液中。将该反应搅拌30分钟,通过套管加入2-{[4-氟-2′-(碘甲基)-5-异丙基-4′-(三氟甲基)联苯-2-基]氧基}四氢-2H-吡喃(16.9mg,0.324mmol)在无水DMF(1mL)内的溶液,并将该反应在室温搅拌过夜。将该反应用饱和NH4Cl(10mL)和水(5mL)稀释,用EtOAc(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将粗产物和对甲苯磺酸(0.6mg,0.00324mmol)在MeOH(5mL)中的溶液在室温搅拌过夜。将该反应混合物真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-35%EtOAc在己烷中的混合物梯度),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′-羟基-5′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.33(20%EtOAc在己烷中的混合物)。LCMS计算值=624.2;实测值=624.3(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.86(s,1H),7.67(m,4H),7.42(d,J=7.1Hz,0.5H),7.41(d,J=7.1Hz,0.5H),6.95(d,J=7.3Hz,0.5H),6.94(d,J=7.3Hz,0.5H),6.70(d,J=5.6Hz,0.5H),6.68(d,J=5.6Hz,0.5H),5.66(d,J=8.0Hz,0.5H),5.36(d,J=8.1Hz,0.5H),4.93(d,J=15.8Hz,0.5H),4.88(d,J=15.8Hz,0.5H),4.18(d,J=15.8Hz,0.5H),4.00(d,J=15.8Hz,0.5H),3.87-3.83(m,0.5H),3.77-3.71(m,0.5H),3.22-3.14(m,1H),1.77(br s,1H),1.27-1.17(m,6H),0.57(d,J=6.5Hz,1.5H),0.45(d,J=6.5Hz,1.5H).
按照上述一般方法制得了在表13中的化合物:
表13
实施例283
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-羟基-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
步骤A:叔丁基{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲氧基}二甲基甲硅烷
在室温于氮气下,将叔丁基二甲基甲硅烷基氯(0.48g,3.21mmol)和咪唑(0.50g,7.30mmol)依次加到[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲醇(1.00g,2.93mmol)在无水CH2Cl2(13.4mL)内的搅拌着的溶液中,并将该反应搅拌过夜。加入水(50mL),并将该混合物用EtOAc(3×50mL)萃取。将合并的萃取液干燥(MgSO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,25×160mm,1%EtOAc在己烷中的混合物),获得了叔丁基{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲氧基}二甲基甲硅烷,为无色油状物。Rf=0.16(1%EtOAc在己烷中的混合物)。LCMS计算值=457.2;实测值=457.2(M+1)+。
1H NMR(500MHz,CDCl3)δ7.94(s,1H),7.57(d,J=7.8Hz,1H),7.29(d,J=7.6Hz,1H),7.00(d,J=8.6Hz,1H),6.69(d,J=12.1Hz,1H),4.63(br s,1H),4.50(br s,1H),3.75(s,3H),3.29-3.21(m,1H),1.28(d,J=6.9Hz,6H),0.93(s,9H),0.03(s,6H).
步骤B:2′-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇
在-78℃于氮气下,将正丁基锂(1.6M在己烷中的溶液,261μL,0.417mmol)经由注射器泵用30-45分钟滴加到叔丁基{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲氧基}二甲基甲硅烷(200mg,0.438mmol)在无水THF(0.5mL)内的搅拌着的溶液中。加入完成后,将该反应在-78℃搅拌2小时,获得了紫色溶液。滴加硼酸三甲酯(43.4mg,47μL,0.417mmol),并将该反应在-78℃搅拌3小时。将该反应混合物温热至0℃,迅速加入乙酸(25.1mg,24μL,0.626mmol),然后滴加30%过氧化氢水溶液(52μL,0.459mmol)。将该反应在室温搅拌过夜,用水稀释(10mL)并用Et2O(3×20mL)萃取。将合并的萃取液用50%饱和FeSO4(20mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-100%EtOAc在己烷中的混合物梯度),获得了2′-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇。Rf=0.32(10%EtOAc在己烷中的混合物)。LCMS计算值=473.1;实测值=473.2(M+1)+。
1H NMR(600MHz,CDCl3)δ7.95(s,1H),7.56(d,J=7.8Hz,1H),7.35(d,J=7.9Hz,1H),6.53(d,J=7.8Hz,1H),5.65(s,1H),4.68(br s,1H),4.54(br s,1H),3.42(s,3H),3.26-3.20(m,1H),1.25(d,J=6.9Hz,6H),0.90(s,9H),0.02(s,6H).
步骤C:4-氟-2′-(羟基甲基)-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇
在0℃,将氟化叔丁基铵(1M在THF中的溶液,179μL,0.179mmol)滴加到2′-({[叔丁基(二甲基)甲硅烷基]氧基}甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇(76.8mg,0.163mmol)在THF(2mL)内的搅拌着的溶液中,并将该反应温热至室温过夜。加入饱和NH4Cl(10mL),将该混合物用EtOAc(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-40%EtOAc在己烷中的混合物梯度),获得了4-氟-2′-(羟基甲基)-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇。Rf=0.26(20%EtOAc在己烷中的混合物)。
1HNMR(600MHz,CDCl3)δ7.85(s,1H),7.63(d,J=7.9Hz,1H),7.41(d,J=8.0Hz,1H),6.53(d,J=7.7Hz,1H),4.50(br s,1H),4.47(s,1H),3.42(s,3H),3.25-3.19(m,1H),1.24(br s,6H).
步骤D:2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇
在0℃于氮气下,将三苯基膦(102.8mg,0.392mmol)在无水CH2Cl2(2mL)中的溶液中通过套管加到四溴化碳(130mg,0.392mmol)和4-氟-2′-(羟基甲基)-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇(58.5mg,0.163mmol)在无水CH2Cl2(2mL)内的搅拌着的溶液中,并将该反应在室温搅拌过夜。将该反应混合物真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-40%EtOAc在己烷中的混合物梯度),获得了2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇。Rf=0.55(20%EtOAc在己烷中的混合物)。
1H NMR(600MHz,CDCl3)δ7.84(s,1H),7.61(d,J=7.9Hz,1H),7.42(d,J=8.0Hz,1H),6.69(d,J=7.8Hz,1H),5.59(s,1H),4.50(d,J=9.6Hz,1H),4.39(d,J=9.7Hz,1H),3.47(s,3H),3.29-3.23(m,1H),1.27(d,J=6.9Hz,6H).
步骤E:2-{[2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-基]氧基}四氢-2H-吡喃
在室温于氮气下,将3,4-二氢-2H-吡喃(51.9mg,56μL,0.617mmol)加到对甲苯磺酸(2.3mg,0.0123mmol)和2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇(52.0mg,0.123mmol)在无水CH2Cl2(6.1mL)内的搅拌着的溶液中,并将该反应搅拌过夜。将该反应混合物用CH2Cl2(45mL)稀释,用饱和NaHCO3(5mL)和30%饱和Na2SO3(5mL)洗涤,干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-40%EtOAc在己烷中的混合物梯度),获得了2-{[2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-基]氧基}四氢-2H-吡喃。Rf=0.59(20%EtOAc在己烷中的混合物)。
1H NMR(600MHz,CDCl3)δ7.82(s,1H),7.60(d,J=7.0Hz,1H),7.41(d,J=8.0Hz,1H),6.67(d,J=7.8Hz,1H),5.77(s,1H),4.97(dd,J=4.9,2.9Hz,1H),4.49(d,J=9.8Hz,1H),4.37(d,J=9.8Hz,1H),3.89-3.87(m,1H),3.61-3.49(m,1H),3.46(s,3H),3.27-3.21(m,1H),1.89-1.83(m,1H),1.78-1.70(m,1H)1.64-1.48(m,3H),1.26(d,J=6.8Hz,6H).
步骤F:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-羟基-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
在室温将氢化钠(60%在矿物油中的分散液,14.7mg,0.368mmol)加到(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(57.7mg,0.184mmol)在无水THF(2mL)内的搅拌着的溶液中。30分钟后,通过套管加入2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯-3-醇(62.0mg,0.123mmol)在无水THF(2mL)中的溶液,并将该反应混合物搅拌过夜。加入饱和NH4Cl(10mL),将该混合物用EtOAc(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过快速色谱法纯化(Si,12×160mm,0-40%EtOAc在己烷中的混合物梯度),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-羟基-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.25(20%EtOAc在己烷中的混合物)。LCMS计算值=654.2;实测值=654.2(M+1)+。1H NMR(500MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.86(m,1H),7.73-7.63(m,4H)7.44(m,1H),6.55(d,J=7.6Hz,0.5H),6.52(d,J=7.7Hz,0.5H),5.71(br s,1H),5.60(d,J=8.0Hz,0.5H),5.54(d,J=8.0Hz,0.5H),4.87(d,J=16.0Hz,0.5H),4.72(d,J=16.1Hz,0.5H),4.23(d,J=16.1Hz,0.5H),3.98(d,J=15.9Hz,0.5H),3.93-3.85(m,0.5H),3.77-3.71(m,0.5H),3.51(s,1.5H),3.47(s,1.5H),3.25-3.17(m,1H),1.26-1.18(m,6H),0.58(d,J=6.5Hz,1.5H),0.38(d,J=6.6Hz,1.5H).
实施例284
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′,3′-二羟基-5′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
在-78℃于氮气下,将三溴化硼(17.4mg,6.6μL,0.0692mmol)加到(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-3′-羟基-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(22.6mg,0.0346mmol)在无水CH2Cl2(1mL)内的搅拌着的溶液中,并将该反应搅拌8小时。将该反应用水(5mL)稀释并用EtOAc(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了粗产物。将其通过手性HPLC纯化(IA柱,20×250mm,15%i-PrOH在庚烷中的混合物),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′,3′-二羟基-5′-异丙基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮。Rf=0.24(20%EtOAc在己烷中的混合物)。LCMS计算值=640.2;实测值=640.2(M+1)+。1H NMR(600MHz,CDCl3,阻转异构体的1∶1混合物)
δ7.85(s,1H),7.70-7.62(m,4H),7.41(m,1H),6.52(s,0.5H),6.51(s,0.5H),6.20(br s,2H),5.65(d,J=7.9Hz,0.5H),5.38(d,J=8.0Hz,0.5H),5.00(d,J=15.5Hz,0.5H),4.92(d,J=15.6Hz,0.5H),4.15(d,J=15.5Hz,0.5H),4.02(d,J=15.6Hz,0.5H),3.88(t,J=6.7Hz,0.5H),3.77(t,J=6.7Hz,0.5H),3.19-3.13(m,1H),1.26-1.17(m,6H),0.59(d,J=6.1Hz,1.5H),0.48(d,J=6.2Hz,1.5H).
中间体20
步骤A:2-(2-氟-3,4-二甲氧基苯基)丙-2-醇
在-20℃于氮气下,将甲基氯化镁(3M在THF中的溶液,1.74mL,5.22mmol)滴加到1-(2-氟-3,4-二甲氧基苯基)乙酮(J.Chem.Soc.PerkinTrans.21994,547-555)(646mg,3.26mmol)在庚烷(3.1mL)和THF(1.4mL)内的搅拌着的溶液中。将该反应温热至室温,搅拌4小时。加入50%饱和NH4Cl(20mL),将该混合物用EtOAc(3×20mL)萃取。将合并的萃取液干燥(Na2SO4)并真空浓缩,获得了2-(2-氟-3,4-二甲氧基苯基)丙-2-醇,为无色油状物。LCMS计算值=197.1;实测值=197.1(M-OH)+。
1H NMR(600MHz,CDCl3)δ7.14(t,J=8.8Hz,1H),6.61(dd,J=8.8,1.4Hz,1H),3.86(s,3H),3.83(s,3H),2.56-2.25(br s,1H),1.58(s,6H).
步骤B:2-氟-1-异丙基-3,4-二甲氧基苯
将10%披钯碳(69.8mg)在2-(2-氟-3,4-二甲氧基苯基)丙-2-醇(698mg,3.26mmol)在5N HCl(0.7mL)和EtOH(5.6mL)中的溶液中的悬浮液在室温于H2(15psi)下搅拌过夜。将该混合物经由硅藻土塞过滤并用EtOAc(~75mL)洗涤。将滤液用50%饱和盐水(10mL)洗涤,干燥(MgSO4)并真空浓缩,获得了2-氟-1-异丙基-3,4-二甲氧基苯。
1H NMR(500MHz,CDCl3)δ6.86(t,J=8.3Hz,1H),6.63(dd,J=8.7,1.5Hz,1H),3.89(s,3H),3.84(s,3H),3.19-3.11(m,1H),1.22(d,J=6.8Hz,6H).
步骤C:1-溴-3-氟-2-异丙基-4,5-二甲氧基苯
在室温将溴(80.6mg,26μL,0.504mmol)加到2-氟-1-异丙基-3,4-二甲氧基苯(50.0mg,0.252mmol)和乙酸钾(49.5mg,0.504mmol)在乙酸(1mL)内的溶液中,并将该反应搅拌过夜。将该反应用水(10mL)和饱和Na2SO3(10mL)稀释,任何用EtOAc(3×20mL)萃取。将合并的萃取液用饱和NaHCO3(2×10mL)洗涤,干燥(MgSO4)并真空浓缩,获得了1-溴-3-氟-2-异丙基-4,5-二甲氧基苯。
1HNMR(600MHz,CDCl3)δ6.86(d,J=2.0Hz,1H),3.87(s,3H),3.81(s,3H),3.43-3.34(m,1H),1.31-1.29(dd,J=7.1,1.4Hz,6H).
按照上述一般方法制得了在表14中的化合物:
表14
实施例289
5-[3,5-二(三氟甲基)苯基]-3-{[5′-(二氟甲基)-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
步骤A:2′-({5-[3,5-二(三氟甲基)苯基]-2-氧代-1,3-唑烷-3-基}甲基)-6-甲氧基-4′-(三氟甲基)联苯-3-甲醛
将5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-1,3-唑烷-2-酮(实施例66,50mg;0.0858mmol)、5-甲酰基-2-甲氧基苯基硼酸(46mg;0.257mmol)、四(三苯基膦)钯(0)(12mg;0.0103mmol)和碳酸钠(74mg)在苯/乙醇/水(2.8/0.4/1.2mL)中的混合物加热回流60小时。将该反应用EtOAc(30mL)稀释,依次用H2O(10mL)和盐水(10mL)洗涤,用硫酸镁干燥,过滤,并真空浓缩。粗产物通过快速硅胶色谱纯化(0-50%EtOAc/己烷梯度),获得了2′-({5-[3,5-二(三氟甲基)苯基]-2-氧代-1,3-唑烷-3-基}甲基)-6-甲氧基-4′-(三氟甲基)联苯-3-甲醛,为黄色油状物。LCMS=592.1(M+1)+。1H NMR(CDCl3,500MHz,阻转异构体混合物):
δ9.98(s,1H),7.99-7.96(m,1H),7.90(s,1H),7.75(s,2H),7.69-7.64(m,2Hz),7.53(s,1H),7.41-7.38(m,1H),7.17-7.14(m,1H),5.37(t,J=8.2Hz,1H),4.59(d,J=15.3Hz,1H),4.37(d,J=15.6Hz,1H),3.92(s,3H),3.67-3.64(m,1Hz),3.19-3.16(m,1H).
步骤B:5-[3,5-二(三氟甲基)苯基]-3-{[5′-(二氟甲基)-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
在0℃,将三氟化二乙基氨基硫(22μL,0.1675mmol)滴加到2′-({5-[3,5-二(三氟甲基)苯基]-2-氧代-1,3-唑烷-3-基}甲基)-6-甲氧基-4′-(三氟甲基)联苯-3-甲醛(步骤A,50mg,0.0838mmol)在CH2Cl2(1mL)内的搅拌着的溶液中。将该反应在室温搅拌14小时。在0℃将该反应用水处理,用CH2Cl2(10mL)稀释,用H2O(10mL)和盐水(10mL)洗涤,用硫酸钠干燥,过滤,并真空浓缩。粗产物通过快速硅胶色谱纯化(0-25%EtOAc/己烷梯度),获得了5-[3,5-二(三氟甲基)苯基]-3-{[5′-(二氟甲基)-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮,为澄清玻璃状物。LCMS=594.2(M-19)+。1H NMR(苯-d6,500MHz,阻转异构体混合物):
δ7.64(s,1H),7.38-7.36(m,2H),7.30-7.26(m,2H),7.14-7.11(m,2H),6.85(d,J=8Hz,1H),6.45(d,J=8.5Hz,1H),6.37-6.13(m,1H),4.46-4.38(m,2H),3.79-3.76(m,1H),3.21(s,3H),2.36(t,J=8.7Hz,1H),2.05(t,J=S.4Hz,1H).
使用手性HPLC(15%IPA/庚烷,AS柱)将该化合物分离成其对映体(5S)-5-[3,5-二(三氟甲基)苯基]-3-{[5′-(二氟甲基)-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮和(5R)-5-[3,5-二(三氟甲基)苯基]-3-{[5′-(二氟甲基)-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮。
实施例290
5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-4,5′-二(三氟甲基)-联苯-2-基]甲基}-1,3-唑烷-2-酮
步骤A:2-碘-1-甲氧基-4-(三氟甲基)苯
向2-甲氧基-5-(三氟甲基)苯胺(500mg,2.62mmol)在CH2Cl2(10mL)内的搅拌着溶液中加入亚硝酸叔丁酯(467μL,3.93mmol)。将该反应搅拌5分钟,然后加入碘(1.3g,5.24mmol),在70℃加热2小时。将该反应冷却,用CH2Cl2(10mL)稀释、用饱和Na2S2O3(10mL)和盐水(10mL)洗涤,用硫酸钠干燥,过滤并真空浓缩。粗产物通过快速硅胶色谱纯化(己烷),获得了2-碘-1-甲氧基-4-(三氟甲基)苯,为浅黄色固体。
1H NMR(CDCl3,500MHz):δ8.05(d,J=2Hz,1H),7.61(dd,J=8.7,1.8Hz,1H),6.89(d,J=8.7Hz,1H),3.97(s,3H).
步骤B:[2-甲氧基-5-(三氟甲基)苯基]硼酸
在-78℃于氮气下将正丁基锂(1.6M在己烷中的溶液,456μL,0.729mmol)滴加到2-碘-1-甲氧基-4-(三氟甲基)苯(步骤A,200mg,0.662mmol)在THF(1,5mL)内的搅拌着的溶液中。将该反应在-78℃搅拌30分钟,然后加入硼酸三异丙酯(458μL,1.986mmol)。将该反应在-78℃再搅拌2小时,用饱和NH4Cl中止反应。将该混合物用CH2Cl2萃取,将有机相用NaHCO3(15mL)和盐水(15mL)洗涤,干燥(Na2SO4),过滤,真空浓缩,获得了[2-甲氧基-5-(三氟甲基)苯基]硼酸其不用纯化直接使用。
步骤C:5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-4,5′-二(三氟甲基)-联苯-2-基]甲基}-1,3-唑烷-2-酮
将5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-1,3-唑烷-2-酮(实施例66,100mg;0.171mmol)用[2-甲氧基-5-(三氟甲基)苯基]硼酸(步骤B,113mg;0.514mmol)、四(三苯基膦)钯(0)(24mg;0.0206mmol)和碳酸钠(148mg)如实施例291所述进行处理,获得了5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-4,5′-二(三氟甲基)-联苯-2-基]甲基}-1,3-唑烷-2-酮,为澄清玻璃状物。LCMS=612.1(M-19)+。1H NMR(苯-d6,500MHz,阻转异构体混合物):
δ7.61(s,1H),7.40-7.36(m,1H),7.31(s,1H),7.27-7.23(m,4H),6.74-6.72(m,1H),6.35(d,J=8.7Hz,1H),4.42-4.32(m,2H),3.70(d,J=15.8Hz,1H),3.14(s,3H),2.28(t,J=8.7Hz,1H),1.98(t,J=8.2Hz,1H).
使用手性HPLC(5%EtOH/庚烷,AS柱)将该化合物分离成其对映体(5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-4,5′-二(三氟甲基)-联苯-2-基]甲基}-1,3-唑烷-2-酮和(55)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-甲氧基-4,5′-二(三氟甲基)-联苯-2-基]甲基}-1,3-唑烷-2-酮。
中间体21
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(400mg,1.28mmol)用NaH(60%在油中的分散液,128mg,3.2mmol)和2-(溴甲基)-1-碘-4-(三氟甲基)苯(实施例70,466mg,1,28mmol)如实施例66所述进行处理,获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮,为白色固体。
LCMS=598.0(M+1)+.1H NMR(CDCl3,500MHz):δ8.06(d,J=82Hz,1H),7.93(s,1H),7.82(s,2H),7.61(s,1H),7.33(dd,J=8.2,1.4Hz,1H),5.79(d,J=7.8hz,1H),4.91(d,J=16Hz,1H),4.40(d,J=16Hz,1H),4.16-4.06(m,1H),0.83(d,J=6.4Hz,3H).
实施例291
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(2-甲氧基-5-甲基-3-噻吩基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
步骤A:3,5-二溴-2-甲氧基噻吩
在0℃,向2-甲氧基噻吩(1g,8.76mmol)在CH2Cl2(18mL)内的搅拌着的溶液中缓慢地加入N-溴琥珀酰亚胺(3.12g,17.52mmol)。将该反应温热至室温并搅拌14小时。将该反应在冰浴中冷却并过滤。将滤液用饱和NaHCO3(2×25mL)洗涤。将水层用1N HCl中和并用CHCl3(3×25mL)萃取。将合并的有机层用盐水(25mL)洗涤,干燥(Na2SO4),过滤并真空浓缩。粗产物通过快速硅胶色谱纯化(己烷),获得了3,5-二溴-2-甲氧基噻吩,为浅粉红色油状物。LCMS=272.9(M+)+。
步骤B:3-溴-2-甲氧基-5-甲基噻吩
在-78℃于氮气下将正丁基锂(2.0M在戊烷中的溶液,0.97mL,1.93mmol)加到3,5-二溴-2-甲氧基噻吩(步骤A,500mg,1.84mmol)在THF(5mL)内的搅拌着的溶液中。将该反应在-78℃搅拌1小时,然后加入甲基碘(114μL,1.84mmol)。将该反应温热至室温并搅拌20小时。减压除去溶剂,将残余物在EtOAc(15mL)和H2O(15mL)之间分配。将水层再用(2×15mL)萃取,将合并的有机层用H2O(15mL)和盐水(15mL)洗涤,干燥(MgSO4),过滤并真空浓缩。粗产物通过快速硅胶色谱纯化(己烷),获得了3-溴-2-甲氧基-5-甲基噻吩,为黄色油状物。
1HNMR(CDCl3,500MHz):δ6.44(s,1H),3.95(s,3H),2.41(s,3H).
步骤C:(2-甲氧基-5-甲基-3-噻吩基)硼酸
在氮气下,将3-溴-2-甲氧基-5-甲基噻吩(步骤B,296mg,1.43mmol)和硼酸三异丙酯(396μL,2.15mmol)在甲苯/THF(2.3/0.6mL)中的搅拌着的混合物冷却至-70℃。通过注射器泵用1小时滴加正丁基锂(2.0M在戊烷中的溶液,1.07mL,2.15mmol)。将该反应搅拌在-70℃再搅拌40分钟,用2N HC。(2mL)于-20℃处理。将该反应在EtOAc(15mL)和H2O(15mL)之间分配。将水层用EtOAc(10mL)萃取;将合并的有机层用盐水(15mL)洗涤,干燥(Na2SO4)、过滤,并真空浓缩,获得了(2-甲氧基-5-甲基-3-噻吩基)硼酸,为黄色油状物。产物不用进一步纯化直接使用。
步骤D:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(2-甲氧基-5-甲基-3-噻吩基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(中间体21,13mg;0.0219mmol)用(2-甲氧基-5-甲基-3-噻吩基)硼酸(步骤C,10.4mg;0.0657mmol)、四(三苯基膦)钯(0)(3mg;0.0026mmol)和碳酸钠(20mg)如实施例291所述进行处理,获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-(2-甲氧基-5-甲基-3-噻吩基)-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮,为黄色玻璃状物。
LCMS=598.2(M+1)+.1H NMR(benzene-d6,500MHz):δ7.75(s,1H),7.57(s,1H),7.31-29(m,1H),7.24(s,2H),7.12-7.10(m,1H),6.14(s,1H),4.96(d,J=16Hz,1H),4.57(d,J=8Hz,1H),3.99(d,J=15.8Hz,1H),3.30(s,3H),2.95-2.92(m,1H),2.05(s,3H),-0.28(d,J=6.7Hz,3H).
按照上述一般方法制得了在表15中的化合物:
表15
实施例298
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′-甲氧基-5′-(2-甲基-1,3-二氧杂环戊烷-2-基)-4-(三氟甲基)联苯-2-基]甲基}-4-1,3-唑烷-2-酮
将(4S,5S)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮(中间体21,7.34g,12.29mol)、[4-氟-2-甲氧基-5-(2-甲基-1,3-二氧杂环戊烷-2-基)苯基]硼酸(5.5g,21.48mol)、四(三苯基膦)钯(0)(1.7g;1.47mol)和碳酸钠(10g)在苯/EtOH/H2O(203/29/86mL)中的混合物加热回流14小时。将该反应用H2O处理,在EtOAc(250mL)和H2O(75mL)之间分配。将水层再用EtOAc(3×200mL)萃取。将合并的萃取液用盐水(100mL)洗涤,干燥(MgSO4),过滤,并真空浓缩。粗产物通过快速硅胶色谱纯化(0-25%EtOAc/己烷梯度),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′-甲氧基-5′-(2-甲基-1,3-二氧杂环戊烷-2-基)-4-(三氟甲基)联苯-2-基]甲基}-4-1,3-唑烷-2-酮,为无定形固体。LCMS=682.2(M+1)+。1H NMR(CDCl3,500MHz,阻转异构体混合物):
δ7.86(s,1H),7.71(S,3H),7.65-7.61(m,1H),7.37-7.34(m,1H),7.32-7.28(m,1H),6.75(dd,J=12.4,3.6Hz,1H),5.58(d,J=8.1Hz,1H),4.89(d,J=15.8Hz,1H),4.08-4.04(m,2H),3.91-3.76(m,7H),1.73(d,J=10.5Hz,3H),0.4(d,J=6.5Hz,3H).
实施例299
(4S,5R)-3-{[5′-乙酰基-4′-氟-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′-甲氧基-5′-(2-甲基-1,3-二氧杂环戊烷-2-基)-4-(三氟甲基)联苯-2-基]甲基}-4-1,3-唑烷-2-酮(8g,0.0118mol)在丙酮(400mL)内的溶液中加入对甲苯磺酸一水合物(670mg,0.0035mol)。将该反应在室温搅拌14小时。将该反应在EtOAc(250mL)和饱和NaHCO3(250mL)之间分配。将水层再用EtOAc萃取(3×250mL),将合并的有机层用盐水(200mL)洗涤,干燥(MgSO4),过滤,并真空浓缩。粗产物通过快速硅胶色谱纯化(0-25%EtOAc/己烷梯度),获得了(4S,5R)-3-{[5′-乙酰基-4′-氟-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮,为黄色固体。LCMS=638.2(M+1)+。1H NMR(CDCl3,500MHz,阻转异构体混合物):
δ7.87(s,1H),7.81-7.79(m,1H),7.74(s,1H),7.70(s,2H),7.59(s,1H),7.39(d,J=8Hz,1H),6.80(d,J=12.8Hz,1H),5.27(d,J=8.2Hz,1H),4.97(d,J=15.3Hz,1H),4.04(d,J=15.5Hz,1H),3.94(s,3H),3.72-3.66(m,1H),2.67-2.64(m,3H),0.62(d,J=6.4Hz,3H).
实施例300
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{{4′-氟-5′-异丙烯基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
在室温将甲基碘化镁(29μL,0.085mmol)滴加到(4S,5R)-3-{[5′-乙酰基-4′-氟-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(30mg,0.047mmol)在乙醚(2mL)内的溶液中。将该反应小心地加热回流4小时。在加入甲基碘化镁(63μL,0.19mmol)和乙醚(1mL),将该反应回流3小时。将该反应用饱和NH4Cl处理并用EtOAc(3×25mL)萃取。将合并的萃取液用盐水(25mL)洗涤、干燥(Na2SO4)、过滤,并真空浓缩。粗产物通过快速硅胶色谱纯化(0-25%EtOAc/己烷梯度),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙烯基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮,为澄清玻璃状物。LCMS=636.3(M+1)+。1H NMR(苯-d6,500MHz,阻转异构体混合物):
δ7.59(s,1H),7.55(s,1H),7.35(d,J=8Hz,1H),7.30-7.27(m,2H),6.99-6.96(m,2H),6.45(d,J=12.9Hz,1H),5.32(d,J=16.9Hz,1H),5.16-5.15(m,1H),4.90(d,J=16.3Hz,1H),4.48(d,J=7.7Hz,1H),3.70(d,J=6.4Hz,1H),3.16(s,3H),2.85-2.79(m,1H),2.12(s,3H),-0.025(d,J=6.5Hz,3H).
实施例301
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′-羟基-5′-异丙烯基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙烯基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例300,50mg,0.078mmol)在DMF(450μL)内的搅拌着的溶液中加入氯化锂(13.4mg,0.315mmol)。将瓶密封,并将该反应在160℃加热14小时。加入10%NaOH(10mL),将所得溶液用乙醚(3×10mL)萃取。将水层用3N HCl酸化至pH~3,用乙醚(3×25mL)再萃取。将合并的有机萃取液用盐水(25mL)洗涤、干燥(MgSO4)、过滤,并真空浓缩。粗产物通过快速硅胶色谱纯化(0-25%EtOAc/己烷梯度),获得了(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-2′-羟基-5′-异丙烯基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮,为澄清玻璃状物。LCMS=622.1(M+1)+。1H NMR(CDCl3,500MHz,阻转异构体混合物):
δ7.90(s,1H),7.76-7.70(m,4H),7.48-7.45(m,1H),7.11-7.07(m,1H),6.75(d,J=11.7Hz,1H),5.71(d,J=7.8Hz,1H),5.59-5.56(m,1H),5.25-5.21(m,2H),4.81(d,J=15.4Hz,1H),4.04(d,J=15.6Hz,1H),3.97-3.92(m,1H),2.13(s,3H),0.58(d,J=6.6Hz,3H).
实施例302
(4S)-4-苄基-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
在0℃于氮气下,将氢化钠(60%在油中的分散液,37mg,0.926mmol)在THF(1mL)中的搅拌着的悬浮液用溶解在THF(1mL)中的(S)-4-苄基-2-唑烷酮(33mg,0.185mmol)处理。将该反应搅拌20分钟,滴加2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯(中间体10,50mg,0.124mmol)在THF(1mL)内的溶液。将该反应在室温搅拌60小时。将该反应用H2O(1mL)处理,在EtOAc(25mL)和H2O(10mL)之间分配。将水相再用EtOAc(3×15mL)萃取,将合并的有机萃取液用盐水(25mL)洗涤、干燥(MgSO4)并真空浓缩,获得了粗产物。通过快速硅胶色谱纯化(0-25%EtOAc/己烷梯度),获得了(4S)-4-苄基-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮,为澄清玻璃状物。LCMS=502.3(M+1)+。1H NMR(CDCl3,500MHz,阻转异构体混合物)
δ7.69-7.64(m,1H),7.58(s,1H),7.39-7.36(m,1H),7.29-7.24(m,3H),7.06(d,J=8.5Hz,1H),6.97-6.91(m,2H),6.73(d,J=11.7,1H),4.79(d,J=15.8Hz,1H),4.30(d,J=15.8Hz,1H),4.08-4.05(m,1H),3.99-3.97(m,1H),3.76(s,3H),3.65-3.58(m,1H),3.27-3.17(m,1H),2.81(dd,J=13.5,4.1Hz,1H),2.45-2.40(m,1H),1.30-1.4(m,6H).
实施例303
(4S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-(4-甲基苄基)-1,3-唑烷-2-酮
步骤A:(2S)-2-氨基-3-(4-甲基苯基)丙-1-醇
将氢化锂铝(254mg,6.696mmol)在THF(20mL)中的混合物加热回流1小时,然后在冰浴中冷却。分批加入(S)-4-甲基苯基丙氨酸(500mg,2.79mmol),将使得混合物加热回流14小时。将过量氢化锂铝通过依次加入H2O(1mL)、10%NaOH水溶液(10mL)和H2O(2.5mL)来分解。将该混合物过滤,用THF洗涤固体。将该滤液真空浓缩和把残余物溶解在CHCl3(50mL)中,用5%NaOH水溶液(25mL)、H2O(25mL)和盐水(25mL)洗涤,干燥(MgSO4),过滤,并真空浓缩,获得了(25)-2-氨基-3-(4-甲基苯基)丙-1-醇,为灰白色固体。
1H NMR(CD3OD,500MHz)δ7.13-7.09(m,4H),3.52(dd,J=10.7,4.6Hz,1H),3.36(dd,J=10.7,6.9Hz,1H),3.04-2.99(m,1H),2.73(dd,J=13.5,6.2Hz,1H),2.53(dd,J=13.5,7.7Hz,1H),2.30(s,3H).
步骤B:(4S)-4-(4-甲基苄基)-1,3-唑烷-2-酮
在0℃于氮气下,将(2S)-2-氨基-3-(4-甲基苯基)丙-1-醇(步骤A,460mg,2.79mmol)在CH2Cl2(20mL)中的搅拌着的溶液用二异丙基乙胺(2.92mL,16.74mmol)和三光气(414mg,1.39mmol)处理。将该反应在0℃搅拌3小时。将该反应用饱和NaHCO3(10mL)处理并用EtOAc(4×20mL)萃取。将合并的有机层用盐水(25mL)洗涤、干燥(MgSO4)、过滤并真空浓缩。粗产物通过快速硅胶色谱纯化(0-70%EtOAc/己烷梯度),获得了(4S)-4-(4-甲基苄基)-1,3-唑烷-2-酮,为白色固体。
LCMS=192.2(M+1)+.1H NMR(CDCl3,500MHz)δ7.17(d,J=8Hz,2H),7.09(d,J=7.7Hz,2H),5.39(br s,1H),4.48(t,J=8.4Hz,1H),4.37(dd,J=8.6,5.6Hz,1H),4.11-4.06(m,1H),2.86(d,J=7.1Hz,2H),2.36(s,3H).
步骤C:(4S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-(4-甲基苄基)-1,3-唑烷-2-酮
将(4S)-4-(4-甲基苄基)-1,3-唑烷-2-酮(步骤B,14mg,0.074mmol)用氢化钠(60%在油中的分散液,6.2mg,0.154mmol)和2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯(中间体10,25mg,0.062mmol)如实施例305中所述进行处理,获得了(4S)-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-(4-甲基苄基)-1,3-唑烷-2-酮,为澄清树胶状物。LCMS=516.4(M+1)+。1H NMR(CDCl3,500MHz,阻转异构体混合物)
δ7.65-7.60(m,1H),7.53(s,1H),7.35-7.32(m,1H),7.06-7.20(m,2H),6.82-6.75(m,2H),6.69(d,J=11.7Hz,1H),4.67(d,J=15.8Hz,1H),4.06(d,J=15.8Hz,1H),4.04-4.00(m,1H),3.96-3.93(m,1H),3.73(s,3H),3.55-3.48(m,1H),3.23-3.15(m,1H),2.63(dd,J=13.5,3.6Hz,1H),2.35(d,J=13.5Hz,1H),2.29(s,3H),1.25-1.13(m,6H).
按照上述一般方法制得了在表16中的化合物:
表16
实施例317
(4S,5S)-4-苄基-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-1,3-唑烷-2-酮
步骤A:[1(S)-1-苄基-2-氧代丙基]氨基甲酸叔丁酯
在-15℃于氮气下,将N-(叔丁氧基羰基)-N-甲氧基-N-甲基-1-苯基丙氨酰胺(500mg,1.62mmol)在THF(3mL)中的搅拌着的溶液用甲基溴化镁(540μL,1.62mmol)处理。将该反应在-15℃搅拌15分钟,然后滴加甲基溴化镁(1.08mL,3.24mmol)。将该反应搅拌在室温搅拌14小时,用1N HCl(5mL)处理。将该混合物在H2O(15mL)和EtOAc(20mL)之间分配,将水层再用EtOAc(2×20mL)萃取。将合并的有机层用H2O(20mL)和盐水(20mL)洗涤,干燥(Na2SO4)、过滤并真空浓缩。粗产物通过快速硅胶色谱法纯化,获得了[1(S)-1-苄基-2-氧代丙基]氨基甲酸叔丁酯,为白色固体。
LCMS=164.2(M-BOC)+.1H NMR(CDCl3,500MHz)δ7.34-7.26(m,3H),7.18(d,J=7.1Hz,2H),5.15(br s,1H),4.59-4.56(m,1H),3.14-2.99(m,2H),2.16(s,3H),1.44(s,9H).
步骤B:[(1S)-1-苄基-2-羟基丙基]氨基甲酸叔丁酯
在-20C,将[1(S)-1-苄基-2-氧代丙基]氨基甲酸叔丁酯(步骤A,150mg,0.57mmol)在无水MeOH(5mL)中的搅拌着的溶液用硼氢化钠(44.2mg,1.169mmol)处理。将该反应搅拌在-20℃搅拌1小时,用H2O(1mL)处理并真空浓缩。把残余物溶解在EtOAc(25mL)中,依次用H2O(15mL)和盐水(15mL)洗涤,干燥(Na2SO4),过滤并真空浓缩。粗产物通过制备薄层色谱法纯化,用15%丙酮/己烷洗脱,获得了[(1S,2R)-1-苄基-2-羟基丙基]氨基甲酸叔丁酯(45mg)和[(1S,2S)-1-苄基-2-羟基丙基]氨基甲酸叔丁酯,为白色固体。[(1S,2R)-1-苄基-2-羟基丙基]氨基甲酸叔丁酯:
LCMS=166.2(M-BOC)+.1H NMR(CDCl3,500MHz)δ7.34-7.31(m,2H),7.26-7.23(m,3H),4.81(br s,1H),3.83(dq,J=6.4,2.7Hz,1H),3.71-3.69(m,1H),2.90(d,J=7.3Hz,2H),1.43(s,9H),1.22(d,J=6.5Hz,3H).
[(1S,2S)-1-苄基-2-羟基丙基]氨基甲酸叔丁酯
LCMS=166.2(M-BOC)+.1H NMR(CDCl3,500MHz)δ7.34-7.31(m,2H),7.26-7.23(m,3H),4.58(br s,1H),3.3.93-3.85(m,2H),2.90(dd,J=14.2,5Hz,1H),2.82-2.73(m,1H),1.40(s,9H),1.25(d,J=6.4Hz,3H).
步骤C:(4S,5S)-4-苄基-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-1,3-唑烷-2-酮
将[(1S,2S)-1-苄基-2-羟基丙基]氨基甲酸叔丁酯(步骤B,39mg,0.148mmol)用氢化钠(60%在油中的分散液,12mg,0.309mmol)和2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯(中间体10,50mg,0.123mmol)如实施例305所述进行处理,获得了(4S,5S)-4-苄基-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-1,3-唑烷-2-酮,为澄清玻璃状物。LCMS=516.4(M+1)+。1H NMR(CDCl3,500MHz,阻转异构体混合物)
δ7.68(d,J=11.5Hz,1H),7.66-7.63(m,1H),7.39-7.36(m,1H),7.28-7.23(m,3H),7.07(d,J=8.5Hz,1H),6.94(d,J=6.9Hz,2H),6.73(d,J=4.8Hz,1H),4.81(d,J=16Hz,1H)4.38(d,J=16.1Hz,1H),4.28-4.23(m,1H),3.78(s,3H),3.29-3.17(m,2H),2.81(dd,J=13.3,3.9Hz,1H),2.38-2.28(m,1H),1.29-1.13(m,6H),0.98(d,J=6.2Hz,3H).
实施例318
(4S,5R)-4-苄基-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-1,3-唑烷-2-酮
将[(15,25)-1-苄基-2-羟基丙基]氨基甲酸叔丁酯(实施例317,步骤B,39mg,0.148mmol)用氢化钠(60%在油中的分散液,12mg,0.309mmol)和2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯(中间体10,50mg,0.123mmol)如实施例305所述进行处理,获得了(4S,5R)-4-苄基-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-1,3-唑烷-2-酮,为澄清玻璃状物,LCMS=516.4(M+1)+。1H NMR(CDCl3,500MHz,阻转异构体混合物)
δ7.64-759(m,2H),7.33-7.30(m,1H),7.28-7.21(m,2H),7.16(s,1H),7.00-6.91(m,3H),6.67(d,J=3Hz,1H),4.70(d,J=2.7Hz,1H),4.52-4.47(m,1H),3.95(d,J=15.8Hz,1H),3.70(s,3H),3.68-3.62(m,1H),3.24-3.18(m,1H),2.72-2.53(m,2H),1.28-1.21(m,6H),1.19(d,J=6.8Hz,3H).
实施例319
(4R)-4-苄基-3-{[5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-1,3-唑烷-2-酮
本标题化合物是根据实施例67中描述的方法由(R)-4-苄基-2-唑烷酮(49mg,0.27mmol)和2-(溴甲基)-1-碘-4-(三氟甲基)苯(100mg,0.27mmol)制得的,获得了本标题化合物,为无色油状物。Rf=0.35(15%EtOAc/己烷)。LCMS 484(M+1)+。1H NMR(CDCl3,500MHz)(存在阻转异构体)
δ7.72(br s 1H),7.65(br s,1H),7.42(m,1H),7.32-7.22(m,3H),7.08(m,1H),6.90-6.84(m,3H),4.81(d,J=15.8Hz,1H),4.35(d,J=15.8Hz),4.28(t,J=8.7Hz,1H),3.96-3.92(m,3H),3.78(s,3H),3.62-3.52(m,1H),2.94-2.86(m,1H),2.82(dd,J=9.4,3.9Hz,1H),2.42(dd,J=9.6,3.9Hz),1.26(s,3H),1.10(s,3H).
实施例320
实施例322是根据实施例14中描述的方法由(S)-4-苄基-5,5-二甲基-2-唑烷酮(10mg,0.05mmol)和2-(溴甲基)-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯(20mg,0.05mmol)制得的,获得了本标题化合物,为无色油状物。LCMS 512(M+1)+。1H NMR(CDCl3,500MHz)(存在阻转异构体)
δ7.72(br s 1H),7.31(br s,1H),7.12-7.02(m,2H),6.85-6.82(m,3H),6.45-6.35(m,4H),4.61(d,J=15.8Hz,1H),4.21(d,J=15.8Hz),3.21(s,2H),3.16(s,3H),2.62-2.52(m,1H),2.42-218(m,1H),1.98(m,2H),1.22(d,J=7.1Hz),1.05(d,J=7.1Hz),0.98(s,3H),0.88(s,3H).
实施例321
(4R,5S)-4-[3,5-二(三氟甲基)苯基]-1-{[4′-氟-5′-异丙基]-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-吡咯烷-2-酮
步骤A:3-[3,5-二(三氟甲基)苯基]丙烯酸乙酯
在0℃于氮气下向NaH(60%在油中的悬浮液,168mg,4.96mmol)在THF(3mL)内的溶液中加入膦酰乙酸三乙酯(0.5mL,2.52mmol)。将该反应在0℃搅拌30分钟,加入3,5-二(三氟甲基)苯甲醛(609mg,2.52mmol)。将该反应温热至室温,再搅拌2小时,然后真空浓缩。将残余物用EtOAc(20mL)稀释,用H2O、盐水洗涤,用硫酸镁干燥,浓缩,并通过快速色谱法纯化,用10%EtOAc/己烷洗脱,获得了本标题化合物,为白色固体。LCMS 313(M+1)+。
步骤B.3-[3,5-二(三氟甲基)苯基]-4-硝基戊酸甲酯
将3-[3,5-二(三氟甲基)苯基]丙烯酸乙酯(170mg,0.54mmol)和硝基甲烷(736uL,10.29mmol)用四丁基氢氧化铵溶液(1.0M在MeOH中的溶液,1.5mL)处理,将该混合物加热回流3小时,用10%氯化铵水溶液(10mL)稀释并用EtOAc(4×30mL)萃取。将合并的有机萃取液用10%氯化铵(20mL)洗涤,用硫酸镁干燥,真空浓缩,获得了粗产物。将其通过快速色谱法纯化,使用10%EtOAC/己烷洗脱,获得了3-[3,5-二(三氟甲基)苯基]-4-硝基戊酸甲酯,为无色油状物。
1HNMR(CDCl3,500MHz)δ7.82(br s 1H),7.64(br s,2H),4.91(m,1H),3.91(m,1H),3.61(s,3H),2.82(m,2H),1.42(d,J=6.7Hz,3H).
步骤C:4-[3,5-二(三氟甲基)苯基]-5-甲基吡咯烷-2-酮
将阮内镍的悬浮液(50%w/v在水中的浆液,200mg)加入3-[3,5-二(三氟甲基)苯基]-4-硝基戊酸甲酯在无水EtOH(5mL)内的溶液中,将所得混合物在室温于氢气囊下搅拌过夜。将该反应混合物经由硅藻土过滤并将该滤液真空浓缩以除去EtOH。将残余物通过快速色谱法纯化,使用75%EtOAC/己烷洗脱,获得了苏-4-[3,5-二(三氟甲基)苯基]-5-甲基吡咯烷-2-酮和赤-4-[3,5-二(三氟甲基)苯基]-5-甲基吡咯烷-2-酮,为白色固体。苏型-非对映体:
LCMS 353(M+1)+.1H NMR(CDCl3,500MHz)δ7.82(br s 1H),7.64(br s,2H),5.72(br s,1H),3.85(m,1H),3.31(dd,J=8.9,8.2Hz,1H),2.61(dd,J=8.9,8.2Hz,1H),1.34(d,J=6.1Hz,3H).
赤型-非对映体:
LCMS 353(M+1)+.1H NMR(CDCl3,500MHz)δ7.82(br s 1H),7.64(br s,2H),5.76(br s,1H),4.20(m,1H),3.90(m,1H),2.81(dd,J=8.5,8.2Hz,1H),2.73(dd,J=8.5,8.2Hz,1H),0.88(d,J=6.7Hz,3H).
步骤D:(4R,5S)-4-[3,5-二(三氟甲基)苯基]-1-{[4′-氟-5′-异丙基]-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-吡咯烷-2-酮
在0℃于氮气下,向NaH(60%在油中的分散液,4.4mg,0.11mmol)在THF(3mL)内的搅拌着的悬浮液中加入赤-4-[3,5-二(三氟甲基)苯基]-5-甲基吡咯烷-2-酮(16mg,0.051mmol)在THF(1mL)中的溶液。将所得混合物在0℃搅拌30分钟,然后加入2′-(溴甲基)-4-氟-5-异丙基-2-甲氧基-4′-(三氟甲基)联苯(16mg,0.051mmol)。3小时后,将该反应用15mL EtOAc和5mL H2O稀释。分离各层并且将有机相用H2O、盐水洗涤,干燥(MgSO4)并浓缩。将残余物通过快速色谱法纯化,使用10%EtOAC/己烷洗脱,获得了本标题化合物,为无色油状物。LCMS 636(M+1)+。1H NMR(CDCl3,500MHz)(存在阻转异构体)
1H NMR δ7.82(br s1H),7.80(br s,1H),7.45-7.36(m,3H),7.32-7.22(m,3H),7.08(d,J=10.1Hz,1H),6.60(m,1H),5.05(m,1H),4.01(d,J=15.5Hz),3.78(s,3H),3.71-3.52(m,2H),3.24(m,1H),1.32-1.20(m,6H),0.56(d,J=6.4Hz,3H).
使用手性HPLC(IA柱,20×250mm,3%i-PrOH在庚烷中的混合物)将该化合物分离成其两种对映体(4R,5S)-4-[3,5-二(三氟甲基)苯基]-1-{[4′-氟-5′-异丙基]-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-吡咯烷-2-酮和(4S,5R)-4-[3,5-二(三氟甲基)苯基]-1-{[4′-氟-5′-异丙基]-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-5-甲基-吡咯烷-2-酮。
按照上述一般方法制得了在表17中的化合物:
表17
实施例327
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-6-甲基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
步骤A:[2,6-二甲基-4-(三氟甲基)苯基]胺
将2,6-二溴-4-三氟甲基苯胺(1.00g,3.14mmol)、三甲基环硼氧烷(1.16ml,1.04g,8.33mmol)、碳酸钾(1.15g,8.33mmol)和催化量(10%)Pd(PPh3)4在DMF(5ml)中的混合物在90℃加热14小时。加入水(10ml)。将该混合物用乙酸乙酯(3×20ml)萃取。将合并的EtOAc层用盐水洗涤并用硫酸钠干燥。通过快速柱纯化,使用EtOAc∶己烷(1∶9)作为洗脱剂,获得本标题化合物,为无色油状物。
1H NMR(CDCl3,500MHz):δ7.28(s,1H),7.22(s,1H),3.88(br s,2H),2.21(s,6H).
步骤B:2-碘-1,3-二甲基-5-(三氟甲基)苯
将得自步骤A的标题化合物(0.27g,1.43mmol)、亚硝酸正戊酯(0.50g,2.86mmol)和I2(0.72g,2.86mmol)在氯仿(10ml)中的混合物回流1小时。将该混合物用二氯甲烷(20ml)稀释并用饱和硫代硫酸钠溶液和盐水洗涤。将有机层用硫酸钠干燥。通过快速柱纯化,使用己烷洗脱,获得本标题化合物,为浅黄色液体。
1H NMR(CDCl3,500MHz)δ7.31(s,2H),2.58(s,6H).
步骤C:1-(溴甲基)-2-碘-3-甲基-5-(三氟甲基)苯
将得自步骤B的标题化合物(0.26g,0.87mmol)、NBS(0.154g,0.87mmol)和催化量的AEBN中CCl4中的混合物回流6小时。TLC(己烷)表明存在原料混合物和新的点。再加入AIBN后,将该反应再回流2小时。没有观察到变化。将该反应混合物冷却至室温,除去溶剂。通过制备TLC纯化,使用己烷作为洗脱剂,获得本标题化合物,为白色固体,以及原料。
1H NMR(CDCl3,500MHz):δ7.54(s,1H),7.42(s,1H),4.67(s,2H),2.60(s,3H).
步骤D.(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-3-甲基-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
在0℃,向得自实施例xx步骤xx的唑烷酮(0.058g,0.186mmol)在THF(5ml)内的溶液中加入NaH。将该混合物在0℃搅拌30分钟。通过注射器加入得自步骤C的苄基溴(0.064g,0.169mmol)在THF(5mL)内的溶液。然后将该混合物在室温搅拌12小时。将该反应用饱和氯化铵溶液处理。将该混合物用乙酸乙酯(3×15ml)萃取。将合并的EtOAc层用盐水洗涤并用硫酸钠干燥。通过制备TLC板纯化,使用EtOAc∶己烷=1∶9作为洗脱剂,获得本标题化合物。
1HNMR(CDCl3,500MHz):δ7.92(s,1H),7.82(s,2H),7.49(s,1H),7.38(s,1H),5.77(d,J=8Hz,1H),4.93(d,J=16Hz,1H),4.45(d,J=16Hz,1H),4.05(m,1H),2.60(s,3H),0.81(d,J=6.5Hz,3H).
步骤E:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-6-甲基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
将得自步骤D的标题化合物(0.07g,0.11mmol)、2-甲氧基-4-氟-5-异丙基苯基硼酸(0.036g,0.17mmol)、碳酸钠(0.024g,0.23mmol)和催化量的Pd(PPh3)4在2∶1∶4EtOH/H2O/甲苯混合物中的混合物加热回流3小时。除去溶剂,将水层用二氯甲烷(3×20ml)萃取。将合并的二氯甲烷层用盐水洗涤,并用硫酸钠干燥。通过制备TLC板纯化,使用EtOAc∶己烷=1∶9作为洗脱剂,获得本标题化合物。通过手性OD柱,使用EtOH/n-庚烷作为洗脱剂来分离本标题化合物的两种非对映阻转异构体。异构体A(较快洗脱下来):
1H NMR(CDCl3,500MHz):δ7.89(s,1H),7.75(s,2H),7.52(s,2H),6.85(d,J=8.5Hz,1H),6.71(d,J=12Hz,1H),5.63(d,J=8Hz,1H),4.71(d,J=16Hz,1H),3.93(m,1H),3.87(d,J=16Hz,1H),3.72(s,3H),3.22(m,1H),2.09(s,3H),1.26(m,6H),0.53(d,J=6.5Hz,3H);LC-MS(M+1):652.3.
异构体B(较慢洗脱下来):
1H NMR(CDCl3,500MHz):δ7.89(s,1H),7.73(s,2H),7.53(s,2H),6.90(d,J=8.5Hz,1H),6.73(d,J=12Hz,1H),5.60(d,J=8Hz,1H),4.69(d,J=15.5Hz,1H),3.88(m,1H),3.86(d,J=15.5Hz,1H),3.76(s,3H),3.22(m,1H),2.11(s,3H),1.23(m,6H),0.48(d,J=6.5Hz,3H);LC-MS(M+1):652.3.
实施例328
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[6-氯-4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
步骤A.[2-氯-6-甲基-4-(三氟甲基)苯基]胺
将2-溴-6-氯-4-三氟甲基苯胺(1.00g,3.64mmol)、三甲基环硼氧(0.66ml,0.59g,4.47mmol)、碳酸钾(1.00g,7.30mmol)和催化量(10%)的Pd(PPh3)4在DMF(5ml)中的混合物在90℃加热14小时。加入水(20ml)。将该混合物用乙酸乙酯(3×50ml)萃取。将合并的EtOAc层用盐水洗涤并用硫酸钠干燥。通过快速柱纯化,使用EtOAc∶己烷(1∶9)作为洗脱剂,获得本标题化合物,为无色油状物。
1H NMR(CDCl3,500MHz):δ7.43(s,1H),7.24(s,1H),4.38(br s,2H),2.22(s,3H).
步骤B[2-氯-6-(碘甲基)4-(三氟甲基)苯基]胺
将得自步骤A的标题化合物(0.67g,3.20mmol)、亚硝酸正戊酯(0.75g,6.41mmol)和I2(1.05g,4.17mmol)在氯仿(10ml)中的混合物回流1小时。将该混合物用二氯甲烷(20ml)稀释并用饱和硫代硫酸钠溶液和盐水洗涤。将有机层用硫酸钠干燥。通过快速柱纯化,使用己烷作为洗脱剂,获得2-碘-3-氯-4-三氟甲基苄基碘。
1H NMR(CDCl3,500MHz):δ7.60(s,2H),4.65(s,2H).
步骤C.(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[3-氯-2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-唑烷-2-酮
在0℃,向得自实施例xx步骤xx的唑烷酮(0.058g,0.186mmol)在THF(5ml)内的溶液中进入NaH。将该混合物在0℃搅拌30分钟。通过注射器加入得自步骤B的2-碘-3-氯-4-三氟甲基苄基碘(0.226g,0.51mmol)在THF(5mL)内的溶液。将该混合物在室温搅拌3小时。将该反应用饱和氯化铵溶液处理,将该混合物用乙酸乙酯(3×20ml)萃取。将合并的EtOAc层用盐水洗涤并用硫酸钠干燥。通过快速柱纯化,使用EtOAc∶己烷=1∶9作为洗脱剂,获得本标题化合物。LC-MS(M+1):432.0。
步骤D:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[6-氯-4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
将得自步骤C的标题化合物(0.10g,0.16mmol)、2-甲氧基-4-fruoro-5-异丙基苯基硼酸(0.067g,0.32mmol)、碳酸钠(0.034g,0.32mmol)和催化量的Pd(PPh3)4在2∶1∶4EtOH/H2O/甲苯混合物中的混合物加热回流4小时。除去溶剂,将水层用氯甲烷(3×15ml)萃取。将合并的二氯甲烷层用盐水洗涤,并用硫酸钠干燥。通过制备TLC板纯化,使用EtOAc∶己烷=1∶9作为洗脱剂,获得本标题化合物。通过手性AD柱,使用i-PrOH/n-庚烷来分离本标题化合物的两种非对映阻转异构体。异构体A(较快洗脱下来):
1H NMR(CDCl3,500MHz):δ7.91(s,1H),7.75(s,3H),7.61(s,1H),6.92(d,J=8.5Hz,1H),6.73(d,J=12Hz,1H),5.64(d,J=8Hz,1H),4.72(d,J=16Hz,1H),3.95(d,J=16Hz,1H),3.93(m,1H),3.78(s,3H),3.22(m,1H),1.23(m,6H),0.55(d,J=7Hz,3H);LC-MS(M+1):672.1.
异构体B(较慢洗脱下来):
1H NMR(CDCl3,500MHz):δ7.89(s,1H),7.75(s,1H),7.73(s,2H),7.62(s,1H),6.98(d,J=8.5Hz,1H),6.74(d,J=12Hz,1H),5.61(d,J=8.5Hz,1H),4.72(d,J=16Hz,1H),3.91(d,J=16Hz,1H),3.87(m,1H),3.79(s,3H),3.22(m,1H),1.22(m,6H),0.48(d,J=6.5Hz,3H);LC-MS(M+1):672.1.
中间体22
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-溴-5-氟苄基)-4-甲基-1,3-唑烷-2-酮
在0℃,向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(2.0g,6.39mmol)在THF(40mL)内的溶液中一次性加入NaH(285mg,60w/w%在矿物油中的悬浮液,7.13mmol,1.1eq.)。将所得泡沫混合物在冰浴中搅拌。将THF(50mL)加到该反应中。将该混合物在0℃搅拌30分钟。加入2-溴-5-氟苄基溴(1.712g,6.39mmol)在THF(20mL)中的溶液。将所得混合物搅拌冷却30分钟,然后温热至室温。将该反应在3小时完全。通过LC-MS监测。将该反应用饱和氯化铵水溶液处理(80mL)。真空除去挥发性组分。将粗混合物用EtOAc萃取,并用硫酸钠干燥。把所得澄清凝胶状物通过二氧化硅纯化(Biotage 40+Mcartridge,EtOAc/己烷,梯度)。获得本标题化合物,为澄清油状物。
LC-MS:500.09(M+1)+.1H NMR(CDCl3,500MHz)δ7.88(s,1H),7.79(s,2H),7.55(dd,J=8.8,5.2Hz,1H),7.17(dd,J=8.7,4.5Hz,1H),6.95(m,1H),5.74(d,J=8.0Hz,1H),4.83(d,J=15.8,1H),4.54(d,J=16.0Hz,1H),4.11(m,1H),0.80(d,J=6.6Hz,3H).
实施例329
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4,4′-二氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-溴-5-氟苄基)-4-甲基-1,3-唑烷-2-酮(1.0g,2.0mmol)在1,4-二氧杂环己烷(6mL)内的溶液中加入(4-氟-5-异丙基-2-甲氧基苯基)硼酸(509mg,2.4mmol)、[1,1′-二(二苯基膦基)-二茂铁]二氯化钯(II)(82mg,5mol%)和氢氧化钾水溶液(1.3mL,3M,2eq.)。将该反应混合物用氮气吹扫,然后在微波容器中密封。将该反应容器在150℃进行微波照射40分钟。将粗混合物用水后处理。用将挥发性物质蒸发。将所得混合物用EtOAc萃取。将合并的萃取液用硫酸钠干燥。所得紫色残余物通过二氧化硅纯化(Biotage40+M筒,用EtOAc/己烷洗脱,梯度;5%-25%)。获得本标题化合物,为澄清固体。LC-MS:588.23(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的6∶4混合物
δ7.85(s,1H),7.69(s,2H),7.16-7.21(m,1.5H),7.04-7.13(m,1.5H),6.96(dd,J=14.3,8.80Hz,1H),6.65(d,J=10.0Hz,1H),5.59(d,J=8.0Hz,0.6H),5.43(d,J=8.0Hz,0.4H),4.85(d,J=15.8Hz,0.6H),4.82(d,J=15.8Hz,0.4H),4.02(d,J=15.8Hz,0.6H),3.85(m,0.6H),3.76-3.81(m,0.8H),3.75(s,1.8H),3.73(s,1.2H),3.19(m,1H),1.14-1.26(m,6H),0.56(d,J=6.6Hz,1.2H),0.38(d,J=6.6Hz,1.8H).
中间体23
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-氯-4-氟苄基)-4-甲基-1,3-唑烷-2-酮
在0℃,向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(1.0g,3.19mmol)/THF(40mL)溶液中一次性加入NaH(153mg,60w/w%在矿物油中的悬浮液,3.83mmol,1.2eq.)。将所得泡沫混合物在冰浴中搅拌30分钟,然后加2-氯-4-氟苄基氯(572mg,3.19mmol)。将所得混合物在0℃搅30分钟,温热至室温过夜。将该反应在室温不能进行,将其在60℃油浴中温热20小时。等份试样表明将该反应完全。将其用NH4Cl水溶液(50mL)处理。将挥发性物质蒸发。将所得混合物用EtOA萃取。将合并的萃取液用硫酸钠干燥,过滤并真空浓缩至黄色油状物。油状物通过二氧化硅纯化(Biotage 40+M筒,用EtOAc/己烷洗脱,梯度;5%-40%)。获得本标题化合物,为无色玻璃状物。
LC-MS:456.12(M+1)+.1H NMR(CDCl3,500MHz)δ7.89(s,1H),7.77(s,2H),7.46(dd,J=8.7,6.0Hz,1H),7.17(dd,J=8.4,2.5Hz,1H),7.03(m,1H),5.68(d,J=8.2Hz,1H),4.83(d,J=15.6,1H),4.36(d,J=15.3Hz,1H),4.06(m,1H),0.79(d,J=6.4Hz,3H).
实施例330
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4′,5-二氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-氯-4-氟苄基)-4-甲基-1,3-唑烷-2-酮(100mg,0.22mmol)在1,4-二氧杂环己烷(1mL)内的溶液中加入(4-氟-5-异丙基-2-甲氧基苯基)硼酸(55.8mg,0.26mmol)、乙酸钯(II)(10mg,20mol%)、氢氧化钾水溶液(147μL,3M,2eq.)和三-叔丁基膦(13.4mg,0.066mmol,30mol%,10%w/w己烷溶液)。将该反应混合物用氮气吹扫,在微波容器中密封。将该反应容器在140℃进行微波照射40分钟。LC-MS表明形成了所需产物。将其用水(50mL)处理。将挥发性物质蒸发。将所得混合物用EtOAc萃取。将合并的萃取液用硫酸钠干燥,过滤并真空浓缩至油状物。通过采用硅胶进行和一个反相prep-HPLC进行两次纯化后,获得本标题化合物LC-MS:588.25(M+1)+。
中间体24
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-氯-6-氟苄基)-4-甲基-1,3-唑烷-2-酮
在0℃,向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(1.0g,3.19mmol)在THF(40mL)内的溶液中一次性加入NaH(153mg,60w/w%在矿物油中的悬浮液,3.83mmol,1.2eq.)。将所得泡沫混合物在冰浴中搅拌30分钟,然后加入苄基氯(572mg,3.19mmol)。将所得混合物在0℃搅拌30分钟,然后温热至60℃保持30小时。等份试样表明剩余约10%起始(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮。将该反应冷却,用饱和NH4Cl(50mL)处理。将挥发性物质蒸发。将所得混合物用EtOAc萃取。将合并的萃取液用硫酸钠干燥,过滤并真空浓缩至黄色油状物。通过SiO2纯化(Biotage 40+M,用EtOAc/己烷洗脱,梯度;5%-40%)后,获得本标题化合物,为无色玻璃状物。
LC-MS:456.11(M+1)+.1H NMR(CDCl3,500MHz)δ7.87(s,1H),7.77(s,2H),7.22-7.34(m,2H),7.01-7.09(m,1H),5.62(d,J=8.2Hz,1H),5.01(dd,J=14.8,2.0Hz,1H),4.45(d,J=14.6Hz,1H),3.91(m,1H),0.81(d,J=6.4Hz,3H).
实施例331
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(3,4′-二氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-氯-6-氟苄基)-4-甲基-1,3-唑烷-2-酮(327mg,0.72mmol)在1,4-二氧杂环己烷(4mL)内的溶液中加入(4-氟-5-异丙基-2-甲氧基苯基)硼酸(228mg,1.08mmol)、乙酸钯(II)(33mg,20mol%)、氢氧化钾(588μL,3M,2.5eq.)和三-叔丁基膦(44mg,0.22mmol,30mol%,10%w/w己烷溶液)。将所得反应混合物用氮气吹扫,在微波容器中密封。将该反应容器在135℃进行微波照射50分钟。LC-MS表明原料/产物比例为约55∶45。给反应混合物再次施加反应条件(在135℃μw 50分钟)。LC-MS微量测定表明从第二次照射反应没有产生进展。再向反应混合物中加入乙酸钯(II)(33mg,20mol%)、氢氧化钾(588μL,3M,2.5eq.)和三-叔丁基膦(44mg,0.22mmol,30mol%,10%w/w己烷溶液)。再给反应混合物再次施加反应条件(在135℃μw 1小时)LC-MS表明反应没有显著进展。将反应混合物用水处理。将挥发性物质蒸发。将所得混合物用EtOAc萃取。将合并的萃取液用硫酸钠干燥,过滤并真空浓缩至黄色油状物。把油状物溶解在DMSO中,通过反相prep-HPLC纯化两次(柱:Kromasil,100-5C18,100×21.1mm),用10%-90%H2O(0.1%TFA,v/v)/MeCN(0.1%TFA,v/v)洗脱。所得玻璃状物在prep-TLC板上纯化,用100%二氯甲烷洗脱,获得了本标题化合物。LC-MS:588.21(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.83(s,1H),7.67(s,1H)7.65(s,1H),7.32-7.41(m,1H),7.09-7.16(m,1H),6.96-7.06(m,1H),6.64-6.70(m,1H),5.47(d,J=8.0Hz,0.5H),5.19(d,J=7.8Hz,0.5H),4.96(d,J=14.9Hz,0.5H),4.80(d,J=15.1Hz,0.5H),4.31(d,J=15.1Hz,0.5H),3.91(d,J=15.1Hz,0.5H),3.78(s,1.5H),3.75(s,1.5H),3.62-3.69(m,1H),3.15-3.26(m,1H),1.14-1.25(m,6H),0.54(d,J=6.6Hz,1.5H),0.33(d,J=6.4Hz,1.5H).
实施例332
步骤A:2-溴-5-硝基苯基)甲醇
将2-溴-5-硝基苯甲酸甲酯(10g,38.46mmol)溶解在THF(100mL)中,冷却至内温=-15~-10℃。向该混合物中缓慢地加入二异丁基氢化铝溶液(1.0M在甲苯中的溶液,57mL,57mmol),保持内温<0℃。将所得混合物在室温搅拌1小时,然后用NH4Cl水溶液(150mL)处理。将粗混合物用EtOAc(100mL)稀释,然后过滤。减压除去挥发性物质,然后用EtOA(200mL×2)萃取。将合并的萃取液用硫酸钠干燥,过滤并蒸发至油状物。将所得油状物通过二氧化硅纯化(Biotage 65i,EtOAc/己烷,梯度;10%-15%)。获得本标题化合物,为黄色固体结晶。
1H NMR(CDCl3,500MHz)δ8.44(d,J=2.74Hz 1H),8.02(dd,J=8.7,2.8Hz.1H),7.72(d,J=8.7,1H),4.83(s,3H).
步骤B:1-溴-2-(溴甲基)-4-硝基苯
在0℃向2-溴-5-硝基苯基)甲醇(4.746g,20.45mmol)在无水二氯甲烷(150mL)内的溶液中加入三苯基膦(6.43g,24.5mmol)和四溴化碳(8.15g,24.5mmol)。将该混合物在0℃搅拌30分钟,然后在20℃搅拌1小时。TLC表明原料完全消耗。减压除去挥发性物质。将所得油状物通过二氧化硅纯化(Biotage 4OM,用EtOAc/己烷洗脱,梯度),获得了本标题化合物,为无色固体。
1H NMR(CDCl3,500MHz)δ8.33(d,J=2.74Hz 1H),8.03(dd,J=8.7,2.5Hz.1H),7.78(d,J=8.7,1H),4.63(s,3H).
步骤C:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-溴-5-硝基苄基)-4-甲基-1,3-唑烷-2-酮
在0℃,向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(5.3g,16.95mmol)在THF(100mL)内的溶液中一次性加入NaH(746mg,60w/w%在矿物油中的悬浮液,18.65mmol,1.1eq.)。将所得泡沫混合物在冰浴中搅拌。把THF(100mL)加入该反应。将该混合物在0℃搅拌30分钟。加入1-溴-2-(溴甲基)-4-硝基苯(5.0g,16.95mmol)在THF(25mL)中的溶液。将所得混合物搅拌冷却30分钟,然后温热至室温。该反应在1.5小时完全。将该反应用饱和NH4Cl水溶液(100mL)处理。将粗混合物用EtOAc萃取,并用硫酸钠干燥。所得澄清凝胶状物通过二氧化硅纯化(Biotage 4OM筒,EtOAc/己烷,梯度,25%-45%)。获得本标题化合物,为固体结晶。
LC-MS:529.11(M+1)+.1HNMR(CDCl3,500MHz)δ8.24(d,J=2.5Hz,1H),8.07(dd,J=8.7,2.8Hz,1H),7.91(s,1H),7.79-7.83(m,3H),5.82(d,J=7.8Hz,1H),4.82(d,J=16.2Hz,1H),4.44(d,J=16.3,1H),4.11-4.20(m,1H),0.84(d,J=6.6Hz,3H).
步骤D:(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4′-氟-5′-异丙基-2′-甲氧基-4-硝基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-溴-5-硝基苄基)-4-甲基-1,3-唑烷-2-酮(3.877g,7.35mmol)在甲苯(24mL)∶乙醇(12mL)∶水(6mL)混合物内的溶液中加入加入(4-氟-5-异丙基-2-甲氧基苯基)硼酸(2.337g,11.03mmol)、四(三苯基膦)钯(0)(425mg,5mol%)和碳酸钠(1.56g,14.72mmol)。将所得混合物中通入氮气,然后在90℃油浴中加热10小时。等份试样表明原料完全消耗。将该反应用盐水处理。将所得混合物用EtOAc萃取并用硫酸钠干燥。所得玻璃状混合物通过二氧化硅纯化(Biotage 4OS筒,EtOAc/己烷,梯度)。获得本标题化合物,为固体结晶。LC-MS:615.26(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ8.31(s,1H),8.20-8.26(m,1H),7.86(s,1H),7.70(s,2H),7.39-7.43(m,1H),6.96-7.01(m,1H),6.67-6.72(m,1H),5.64(d,J=8.0Hz,0.5H),5.48(d,J=8.0Hz,0.5H),4.90(d,J=16.3Hz,0.5H),4.86(d,J=16.3Hz,0.5H),4.10-4.16(m,0.5H),3.84-3.94(m,1.5H),3.77(s,1.5H),3.75(s,1.5H),3.15-3.26(m,1H),1.15-1.29(m,6H),0.57(d,J=6.6Hz,1.5H),0.40(d,J=6.6Hz,1.5H).
实施例333
(4S,5R)-3-[(4-氨基-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4′-氟-5′-异丙基-2′-甲氧基-4-硝基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮(1.94g,3.16mmol)在甲醇(20mL)中的溶液施加H2(40psi.,帕尔摇动器)于20℃1.5小时。LCMS表明存在微量原料。将粗混合物经由硅藻土床过滤(521)。将滤液真空蒸发,获得了玻璃状产物。LC-MS:585.32(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.83(s,1H),7.67(s,2H),6.93-7.06(m,2H),6.87(s,0.5H),6.72-6.82(m,1.5H),5.57(d,J=8.0Hz,0.5H),5.36(d,J=8.0Hz,0.5H),4.77(d,J=5.5Hz,0.5H),4.74(d,J=6.5Hz,0.5H),3.95(d,J=15.5Hz,0.5H),3.75-3.86(m,1.5H),3.73(s,3H),3.12-3.24(m,1H),1.11-1.29(m,6H),0.47(d,J=6.5Hz,1.5H),0.29(d,J=6Hz,1.5H).
实施例334
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-溴-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-3-[(4-氨基-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(526mg,0.90mmol)在溴仿(2.5mL)内的溶液中加入亚硝酸叔丁酯(186mg,1.80mmol)。将所得混合物在80℃搅拌20分钟。等份试样表明反应完全。通过硅胶色谱纯化反应粗产物,获得了本标题化合物,为黄色玻璃状物。LC-MS:650.09(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.85(s,1H),7.69(s,2H),7.60(s,0.5H),7.48-7.53(m,1.5H),7.07-7.11(m,1H),6.93-6.99(m,1H),6.62-6.67(m,1H),5.59(d,J=8.0Hz,0.5H),5.39(d,J=7.0Hz,0.5H),4.82(d,J=6.5Hz,0.5H),4.75(d,J=6.5Hz,0.5H),3.98(d,J=16.0Hz,0.5H),3.76-3.85(m,1.5H),3.75(s,1.5H),3.74(s,1.5H),3.13-3.23(m,1H),1.13-1.29(m,6H),0.52(d,J=6.5Hz,1.5H),0.34(d,J=7.0Hz,1.5H).
实施例335
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-环丙基-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-溴-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮(100mg,0.15mmol)在1,4-二氧杂环己烷(0.5mL)内的溶液中加入环丙基硼酸(10mg,0.19mmol)、[1,1′-二(二苯基膦基)二茂铁]二氯化钯(II)(82mg,8mol%)、二(三叔丁基膦)钯(0)(10mg,13mol%)和氢氧化钾水溶液(78μL,3M,1.5eq.)。将该反应混合物用氮气吹扫,然后密封在微波容器中。给该反应在150℃施加微波照射30分钟。等份试样表明原料完全消耗。将该反应粗产物用水后处理。将所得混合物用EtOAc萃取,用硫酸钠干燥。使用两个制备TLC板纯化,分别使用20%EtOAc在己烷中的混合物和5%EtOAc在二氯甲烷中的混合物作为洗脱剂,获得了本标题化合物,为玻璃状物。LC-MS:610.26(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.84(s,1H),7.65-7.70(m,2H),7.21(s,0.5H),7.08-7.14(m,1.5H),6.95-7.04(m,2H),6.61-6.67(m,1H),5.52(d,J=8.5Hz,0.5H),5.27(d,J=8.0Hz,0.5H),4.85(d,J=15.5Hz,0.5H),4.81(d,J=15.5Hz,0.5H),4.00(d,J=15.5Hz,0.5H),3.69-3.81(m,4.5H),3.13-3.24(m,1H),1.90-1.99(m,1H),1.12-1.30(m,6H),0.98-1.15(m,2H),0.71-0.77(m,2H),0.48(d,J=6.5Hz,1.5H),0.29(d,J=6.5Hz,1.5H).
实施例336
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(甲硫基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-3-[(4-氨基-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(200mg,0.34mmol)在二甲二硫(2mL)内的溶液中加入亚硝酸叔丁酯(70mg,0.68mmol)。将所得混合物在80℃搅拌30分钟。等份试样表明反应完全。使用两个制备TLC板纯化,分别使用20%EtOAc在己烷中的混合物和10%EtOAc在二氯甲烷中的混合物作为洗脱剂,获得了本标题化合物,为玻璃状物。LC-MS:616.21(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.84(s,1H),7.67(s,2H),7.35(s,0.5H),7.22-7.28(m,1.5H),7.12-7.19(m,1H),6.94-7.02(m,1H),6.61-6.68(m,1H),5.55(d,J=8.0Hz,0.5H),5.31(d,J=9.5Hz,0.5H),4.85(d,J=16.0Hz,0.5H),4.83(d,J=15.5Hz,0.5H),3.99(d,J=15.5Hz,0.5H),3.69-3.81(m,4.5H),3.12-3.24(m,1H),2.54,(s,1.5H),2.53(s,1.5H),1.11-1.27(m,6H),0.50(d,J=6.5Hz,1.5H),0.31(d,J=7.0Hz,1.5H).
实施例337
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(甲基磺酰基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(甲硫基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(156mg,0.25mmol)在二氯甲烷(3mL)内的溶液中加入3-氯过苯甲酸(175mg,1.01mmol)。将所得混合物在20℃搅拌1小时。等份试样表明反应完全。将该反应粗产物在水与二氯甲烷之间分配。分离出有机层,并用硫酸钠干燥。使用三个制备TLC板纯化,分别使用50%EtOAc在己烷中的混合物、20%EtOAc在二氯甲烷中的混合物和二氯甲烷作为洗脱剂,获得了本标题化合物,为玻璃状物。LC-MS:648.29(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.99(s,0.5H),7.92-7.96(m,1.5H),7.86(s,1H),7.70(s,2H),7.42-7.46(m,1H),6.96-7.00(m,1H),6.69(d,J=12Hz,1H),5.64(d,J=8.0Hz,0.5H),5.45(d,J=8.0Hz,0.5H),4.93(d,J=6.0Hz,0.5H),4.90(d,J=6.5Hz,0.5H),4.09(d,J=16Hz,0.5H),3.88(d,J=16Hz,0.5H),3.80-3.88(m,1H),3.78(s,1.5H),3.75(s,1.5H),3.16-3.25(m,1H),3.14(s,1.5H),3.13(s,1.5H),1.22-1.28(m,6H),0.57(d,J=6.5Hz,1.5H),0.38(d,J=6.5Hz,1.5H).
实施例338
2-({(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-2-氧代-1,3-唑烷-3-基}甲基)-4′-氟-5′-异丙基-2′-甲氧基联苯-4-甲腈
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-溴-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮(100mg,0.15mmol)在N,N-二甲基甲酰胺(1.5mL)内的溶液中加入氰化铜(I)(17mg,0.19mmol)。将所得反应混合物与氮气吹扫,密封在微波容器中。给该容器在150℃施加微波照射30分钟。LC-MS表明仅存在溴化物原料。向该反应混合物中加入四(三苯基膦)钯(0)(10mg,6mol%),再次在150℃施加微波照射30分钟。等份试样表明形成了所需产物,并且所有原料溴化物都已经消耗。将该反应粗产物在水与己烷之间分配。将水相用乙醚反萃取。将合并的萃取液用硫酸钠干燥。使用两个制备TLC板纯化,分别使用20%EtOAc在己烷中的混合物和4%EtOAc在二氯甲烷中的混合物展开,获得了本标题化合物,为玻璃状物。LC-MS:595.03(MH+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.86(s,1H),7.61(S,0.5H),7.67-7.71(m,2.5H),7.64-7.68(m,1H),7.32-7.36(m,1H),6.98(d,J=8.5Hz,0.5H),6.95(d,J=8.5Hz,0.5H),6.68(d,J=12Hz,1H),5.62(d,J=8.0Hz,0.5H),5.46(d,J=8.0Hz,0.5H),4.85(d,J=16.0Hz,0.5H),4.80(d,J=16.0Hz,0.5H),4.06(d,J=16Hz,0.5H),3.79-3.86(m,1H),3.70-3.78(m,3.5H),3.16-3.24(m,1H),3.75(s,1.5H),3.16-3.25(m,1H),3.14(s,1.5H),3.13(s,1.5H),1.15-1.27(m,6H),0.54(d,J=7.0Hz,1.5H),0.37(d,J=6.5Hz,1.5H).
实施例339
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4′-氟-5′-异丙基-2′-甲氧基-4-甲基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-溴-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮(82.5mg,0.13mmol)在1,4-二氧杂环己烷(1mL)内的溶液中加入三甲基环硼氧烷(39mg,0.31mmol)、Pd(PPh3)4(15mg,10mol%)和碳酸钾(35mg,0.25mmol)。将所得反应混合物用氮气吹扫,密封在微波容器中。给该容器在130℃施加微波照射15分钟。将该粗混合物用盐水稀释,用EtOAc萃取。将合并的有机萃取液用硫酸钠干燥。使用两个制备TLC板纯化,分别使用20%EtOAc在己烷中的混合物和二氯甲烷展开,获得了本标题化合物,为玻璃状物。LC-MS:584.08(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.84(s,1H),7.65-7.70(m,2H),7.29(s,0.5),7.18-7.22(m,1.5H),7.10-7.15(m,1H),7.01(d,J=8.0Hz,0.5H),6.98(d,J=8.5Hz,0.5H),6.66(d,J=5.0Hz,0.5H),6.64(d,J=5.5Hz,0.5H),5.54(d,J=8.5Hz,0.5H),5.31(d,J=8.0Hz,0.5H),4.82(d,J=15.5Hz,1H),4.02(d,J=15Hz,0.5H),3.71-3.82(m,5H),3.15-3.24(m,1H),2.42(s,1.5H),2.41(s,1.5H),1.13-1.27(m,6H),0.48(d,J=6.5Hz,1.5H),0.31(d,J=6.5Hz,1.5H).
实施例340
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4′-氟-4-异丙烯基-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-溴-4′-氟-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮(38mg,0.059mmol)在1,4-二氧杂环己烷(0.5mL)内的溶液中加入(2-氯-5-异丙基苯基)硼酸(10mg,0.12mmol)、[1,1′-二(二苯基膦基)二茂铁]二氯化钯(II)(2.4mg,5mol%)和氢氧化钾水溶液(40μL,3M,2eq.)。将该反应混合物用氮气吹扫,然后密封在微波容器中。给该反应在140℃施加微波照射20分钟。将粗混合物用水和EtOAc后处理。将合并的有机萃取液用硫酸钠干燥并真空浓缩,获得了粗产物。将其通过制备TLC板纯化,用20%EtOAc在己烷中的混合物洗脱,获得了本标题化合物。LC-MS:610.04(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.84(s,1H),7.64-7.70(m,2H),7.56(s,0.5),7.45-7.50(m,1.5H),7.18-7.23(m,1H),7.02(d,J=9.0Hz,0.5H),6.99(d,J=8.5Hz,0.5H),6.67(d,J=7.0Hz,0.5H),6.64(d,J=5.5Hz,0.5H),5.52(d,J=8.0Hz,0.5H),5.43(d,J=8.5Hz,1H),5.26(d,J=8.0Hz,0.5H),5.13-5.17(m,1H),4.91(d,J=15.0Hz,0.5H),4.86(d,J=15.5Hz,0.5H),4.04(d,J=15.5Hz,0.5H),3.83(d,J=15.5,0.5H),3.70-3.78(m,3H),3.14-3.25(m,1H),2.18-2.22(m,3H),1.14-1.29(m,6H),0.50(d,J=6.5Hz,1.5H),0.31(d,J=6.5Hz,1.5H).
实施例341
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4′-氟-4,5′-二异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
给(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4′-氟-4-异丙烯基-5′-异丙基-2′-甲氧基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮(15mg,0.025mmol)在甲醇(1mL)中的溶液施加H2(气囊气氛)于20℃过夜。将粗混合物经由注射滤器过滤。将滤液真空蒸发,通过制备TLC板纯化,用20%EtOAc在己烷中的混合物展开,获得了本标题化合物。LC-MS:612(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.84(s,1H),7.64-7.68(m,2H),7.30(s,0.5),7.20-7.27(m,1.5H),7.13-7.17(m,1H),7.02(d,J=8.5Hz,0.5H),6.99(d,J=8.0Hz,0.5H),6.65(d,J=6.0Hz,0.5H),6.63(d,J=6.0Hz,0.5H),5.52(d,J=8.0Hz,0.5H),5.25(d,J=8.0Hz,1H),4.87(d,J=15.5Hz,0.5H),4.82(d,J=15.5Hz,0.5H),4.03(d,J=15.0Hz,0.5H),3.81(d,J=15.0Hz,0.5H),3.69-3.77(m,4H),3.14-3.24(m,1H),2.92-3.02(m,1H),1.14-1.33(m,12H),0.48(d,J=6.5Hz,1.5H),0.30(d,J=7.0Hz,1.5H).
中间体25
(4S,5R)-3-(5-氨基-2-溴苄基)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-溴-5-硝基苄基)-4-甲基-1,3-唑烷-2-酮(614mg,1.17mmol)、氯化锡(II)脱水物(1.314g,5.823mmol)和乙醇(3mL)的混合物在20℃搅拌36小时。将该反应粗产物用水后处理。将所得混合物用EtOAc萃取,并用硫酸钠干燥。SiO2纯化(Biotage 40+M,梯度,0%-35%EtOAc在己烷中的混合物)后,获得了本标题化合物,为玻璃状物。
LC-MS:499.05(M+1)+.1H NMR(CDCl3,500MHz)δ7.88(s,1H),7.77(s,2H),7.31(d,J=8.5,1H),6.77(d,J=2.7,1H),6.54(dd,J=8.5,2.7Hz,1H),5.69(d,J=8.0Hz,1H),4.77(d,J=15.3,1H),4.29(d,J=15.3Hz,1H),4.05-4.12(m,1H),0.79(d,J=6.4Hz,3H).
中间体26
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-溴-5-(甲硫基)苄基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-3-(5-氨基-2-溴苄基)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(457mg,0.92mmol)在二甲二硫(4mL)内的溶液中加入亚硝酸叔丁酯(182μL,d=0.867,1.38mmol)。将所得混合物在80℃搅拌1小时。等份试样表明反应完全。通过制备TLC板纯化,用25%EtOAc在己烷中的混合物,获得了本标题化合物,为玻璃状物。LC-MS:529.71(M+1)+。
实施例342
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[2′-氯-4′-氟-5′-异丙基-4-(甲硫基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-溴-5-(甲硫基)苄基]-4-甲基-1,3-唑烷-2-酮(60mg,0.114mmol)在1,4-二氧杂环己烷(1mL)内的溶液中加入(2-氯-4-氟-5-异丙基苯基)硼酸(10mg,0.12mmol)、[1,1′-二(二苯基膦基)二茂铁]二氯化钯(II)(28mg,30mol%)和氢氧化钾水溶液(95μL,3M,2eq.)。将该反应混合物用氮气吹扫,然后密封在微波容器中。给该反应在150℃施加微波照射30分钟。将粗混合物用水和EtOAc后处理。将合并的有机萃取液用硫酸钠干燥并真空浓缩,获得了粗产物。将其通过制备TLC板纯化,获得了本标题化合物。LC-MS:619.95(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ7.83-7.88(m,1H),7.72(s,1H)7.68(s,1H),7.30-7.35(m,1H),7.24-7.29(m,1H),7.11-7.19(m,2.5H),7.04-7.07(m,0.5H),5.62(d,J=8.2Hz,0.5H),5.24(d,J=8.0Hz,0.5H),4.87(d,J=15.3Hz,0.5H),4.70(d,J=15.8Hz,0.5H),3.79-3.98(m,2H),3.18(m,1H),2.55(s,1.5H),2.54(s,1.5H),1.20-1.29(m,6H),0.53(d,J=6.4Hz,1.5H),0.47(d,J=6.6Hz,1.5H).
实施例343
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(2′-氯-5′-异丙基-4-硝基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-(2-溴-5-硝基苄基)-4-甲基-1,3-唑烷-2-酮(950mg,1.80mmol)在甲苯(5.2mL)∶乙醇(2.6mL)∶水(1.3mL)混合物内的溶液中加入(2-氯-5-异丙基苯基)硼酸(325mg,1.64mmol)、四(三苯基膦)钯(0)(188mg,10mol%)和碳酸钠(346mg,3.26mmol)。将所得混合物在80℃油浴中加热12小时。将该反应粗产物蒸发至干。将所得残余物通过水与EtOAc的混合物进行后处理。将合并的有机萃取液用硫酸钠干燥并真空浓缩,获得了粗产物,将其通过SiO2纯化(Biotage 40+S筒,EtOAc/己烷,梯度),获得了本标题化合物。LC-MS:601.19(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的1∶1混合物
δ8.31-8.30(m,1H),8.24-8.28(m,1H),7.85-7.89(m,1H),7.68-7.76(m,2H),7.42-7.48(m,2H),7.26-7.30(m,1H),7.04-7.11(m,1H),5.74(d,J=7.8Hz,0.5H),5.58(d,J=8.0Hz,0.5H),4.92(d,J=15.8Hz,0.5H),4.76(d,J=16.2Hz,0.5H),3.97-4.04(m,1.5H),3.82(dt,J=8.0,6.6Hz,0.5H),2.89-2.99(m,1H)1.22-1.29(m,6H),0.60(d,J=6.4Hz,1.5H),0.52(d,J=6.6Hz,1.5H).
实施例344
(4S,5R)-3-[(4-氨基-2′-氯-5′-异丙基联苯-2-基)甲基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(2′-氯-5′-异丙基-4-硝基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮(425mg,0.71mmol)在甲醇(10mL)中的溶液于20℃施加H2(40psi.,帕尔摇动器)6小时。将粗混合物经由硅藻土床过滤(521)。将滤液真空蒸发,获得了玻璃状物。通过制备TLC板纯化,用20%EtOAc在己烷中的混合物展开,获得了本标题化合物。LC-MS:571.22(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的6∶4混合物
δ7.82-7.86(m,1H),7.65-7.71(m,2H),7.34-7.38(m,1H),7.11-7.17(m,2H),7.02-7.06(m,1H),6.76-6.82(m,1H),6.68-6.74(m,1H),5.58(d,J=8.0Hz,0.4H),5.51(d,J=8.2Hz,0.6H),4.82(d,J=15.3Hz,0.6H),4.70(d,J=15.6Hz,0.4H),3.69-4.00(m,4H),2.84-2.94(m,1H),1.19-1.28(m,6H),0.45(d,J=6.6Hz,1.2H),0.40(d,J=6.6Hz,1.8H).
实施例345
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-溴-2′-氯-5′-异丙基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-3-[(4-氨基-2′-氯-5′-异丙基联苯-2-基)甲基]-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(100mg,0.175mmol)在溴仿(0.5mL)和二氯甲烷(1mL)内的溶液中加入亚硝酸叔丁酯(23μL,d=0.867,90%纯,0.193mmol)。将所得混合物在50℃搅拌1小时。等份试样表明反应完全。将该反应粗产物沉积在2个制备TLC板上,用二氯甲烷洗脱,获得了本标题化合物。LC-MS:635.80(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的6∶4混合物
δ7.84-7.88(m,1H),7.67-7.74(m,2H),7.60-7.63(m,1H),7.51-7.57(m,1H),7.38-7.42(m,1H),7.19-7.23(m,1H),7.11-7.16(m,1H),7.09(d,J=2.3Hz,0.6H),7.03(d,J=2.3Hz,0.4H),5.66(d,J=8.0Hz,0.4H),5.55(d,J=8.0Hz,0.6H),4.86(d,J=15.6Hz,0.6H),4.70(d,J=15.6Hz,0.4H),3.77-4.00(m,2H),2.87-2.95(m,1H),1.20-1.28(m,6H),0.53(d,J=6.6Hz,1.2H),0.45(d,J=6.4Hz,1.8H).
实施例346
(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(2′-氯-4-环丙基-5′-异丙基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮
向(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[(4-溴-2′-氯-5′-异丙基联苯-2-基)甲基]-4-甲基-1,3-唑烷-2-酮(27mg,0.043mmol)在1,4-二氧杂环己烷(1mL)内的溶液中加入环丙基硼酸(9mg,0.10mmol)、[1,1′-二(二苯基膦基)二茂铁]二氯化钯(II)(10.4mg,30mol%)和氢氧化钾水溶液(42μL,3M,3eq.)。将该反应混合物用氮气吹扫,然后密封在微波容器中。给该反应在120℃施加微波照射20分钟。将粗混合物用水和EtOAc后处理。将合并的有机萃取液用硫酸钠干燥并真空浓缩,获得了粗产物。将其通过制备TLC板纯化,用20%EtOAc在己烷中的混合物洗脱,获得了本标题化合物。LC-MS:595.99(M+1)+。1H NMR(CDCl3,500MHz)旋转异构体的6∶4混合物
δ7.82-7.86(m,1H),7.66-7.72(m,2H),7.36-7.40(m,1H),7.21-7.23(m,0.5H),7.11-7.19(m,3H),7.01-7.08(m,1.5H),5.58(d,J=8.0Hz,0.4H),5.50(d,J=8.0Hz,0.6H),4.88(d,J=15.1Hz,0.6H),4.71(d,J=15.6Hz,0.4H),3.76-3.95(m,2H),2.84-2.95(m,1H),1.92-2.00(m,1H),1.18-1.29(m,6H),1.00-1.07(m,2H),0.71-0.82(m,2H),0.47(d,J=6.6Hz,1.2H),0.42(d,J=6.6Hz,1.8H).
按照实施例96中描述的方法,由(4R,5R)-5-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)-联苯-2-基]-4-甲基-1,3-唑烷-2-酮制得了在表18中描述的化合物。
表18
实施例360
(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[5′-异丙基-2′-(三氟甲氧基)-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮
向80mg(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮在2mL苯、1mL水和0.5mL乙醇内的溶液中加入100mg 5-异丙基-2-(三氟甲氧基)苯基硼酸、0.15mL 2M碳酸钠水溶液和21mg Pd(PPh3)4。附加上回流冷凝器,将该混合物加热至100℃。将该混合物在100℃搅拌24小时,然后用10mL EtOAc和10mL水稀释。分离各相,并且将水相用10mL EtOAc萃取。将合并的有机相用10mL盐水洗涤,用硫酸钠干燥,并浓缩。将残余物在BiotageHorizon,25M柱上通过快速色谱法纯化,用1CV 2%EtOAc在己烷中的混合物洗脱,然后使用2-100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱。使用相同条件再纯化产物,获得了本标题化合物。质谱(ESI)674.4(M+1)。
按照上述一般方法,制得了在表19中列出的化合物。
表19
中间体27
(4R,5R)-4-乙基-5-[2-碘-5-(三氟甲基)苯基]-1,3-唑烷-2-酮
步骤A:(4S)-4-苄基-3-丁酰基-1,3-唑烷-2-酮
用约1分钟向S-苄基-唑烷酮在15mL THF内的-78℃溶液中加入n-BuLi,然后加入丁酰氯。将该混合物在-78℃搅拌30分钟,然后用约30分钟温热至室温。通过加入3mL饱和NH4Cl水溶液来处理过量酰氯,然后通过旋转蒸发除去大部分溶剂。将残余物用17mL饱和NH4Cl水溶液和30mL CH2Cl2稀释。分离各相并且将水相用20mLCH2Cl2萃取。将合并的有机萃取液用20mL 1N NaOH溶液和20mL盐水洗涤,干燥(Na2SO4)并浓缩。将残余物在Biotage Horizon,40M柱上通过快速色谱法纯化,用1CV 2%EtOAc在己烷中的混合物洗脱,然后使用2→100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱。将残余物在冷冻室中贮存过夜,期间残余物结晶。将所得固体用己烷研制,过滤,并在高度真空下干燥。质谱(ESI)178.2(M-C3H7CO)。步骤B:(4S)-4-苄基-3-((2R)-2-{(S)-羟基[2-碘-5-三氟甲基)苯基]甲基}丁酰基)-1,3-唑烷-2-酮
按照实施例95步骤A中描述的方法,由5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲醛(实施例80,步骤A)和(4S)-4-苄基-3-丁酰基-1,3-唑烷-2-酮制得了本标题化合物。质谱(ESI)530.1(M-OH)。
步骤C:(4R,5R)-4-乙基-5-[2-碘-5-(三氟甲基)苯基]-1,3-唑烷-2-酮
按照实施例95步骤B中描述的方法,由(4S)-4-苄基-3-((2R)-2-{(S)-羟基[2-碘-5-(三氟甲基)苯基]甲基}丁酰基)-1,3-唑烷-2-酮制得了本标题化合物。质谱(ESI)386.2(M+1)。
中间体28
(4R,5R)-4-苄基-5-[2-碘-5-(三氟甲基)苯基]-1,3-唑烷-2-酮
步骤A:(4S)-4-苄基-3-(3-苯基丙酰基)-1,3-唑烷-2-酮
按照中间体27步骤A中描述的方法,由S-苄基-唑烷酮和氢化肉桂酰氯制得了本标题化合物。质谱(ESI)178.2(M-PhC2H4CO)。
步骤B:(4S)-4-苄基-3-{(2R,3S)-2-苄基-3-羟基-3-[2-碘-5-(三氟甲基)苯基]丙酰基}-1,3-唑烷-2-酮
按照实施例95步骤A中描述的方法,由5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲醛(实施例80,步骤A)和(4S)-4-苄基-3-(3-苯基丙酰基)-1,3-唑烷-2-酮制得了本标题化合物。质谱(ESI)592.3(M-OH)。
步骤C:(4R,5R)-4-苄基-5-[2-碘-5-(三氟甲基)苯基]-1,3-唑烷-2-酮
按照实施例95步骤B中描述的方法,由(4S)-4-苄基-3-{(2R,3S)-2-苄基-3-羟基-3-[2-碘-5-(三氟甲基)苯基]丙酰基}-1,3-唑烷-2-酮制得了本标题化合物。质谱(ESI)448.2(M+1)。
按照上述一般方法,制得了在表20中列出的化合物。
表20
实施例372
制备(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-{[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]甲基}-4-甲基-1,3-唑烷-2-酮(实施例73)的另一种方法
实施例73的化合物可通过如下所示的方法制得:
步骤1:硼酸1与芳基氯2的Suzuki偶联反应
通过将4.71kg固体K2CO3加到10.3L水中来制得3M K2CO3溶液。施加冷却以把该溶液保持在20-25℃。将THF(12L)、芳基氯2(2.69kg)和在实施例78中制得的硼酸1(2.74kg)加到该K2CO3中,然后加入1LTHF洗涤液。使用HPLC分析来证实1/2的1.00/1.00比例。通过用氮气吹扫70分钟来将该溶液脱气。加入固体催化剂1,1-二(二-叔丁基膦基)二茂铁二氯化钯(42g),然后加入脱气的THF洗涤液(1.5L)。有机层立即变为深棕色。将该双相混合物在剧烈搅拌下于36℃-40℃冷却。HPLC表明转化完全(15-18小时),将该混合物冷却至室温,除去水层。向有机层中加入庚烷(25.6L)和水(25.6L),分离各层。将有机层用水洗涤(19L)。将有机层用680g Darco KB-B在室温处理60分钟,经由solka-floc过滤,用10%THF/庚烷(~15L)洗涤。将溶剂在约45-50℃换成庚烷(~35L)直至剩余<0.5v%THF。再加入庚烷以使得总体积为约45-50L。如果没有形成晶床的话,向该溶液中加入得自以前制备操作的晶种。把该浆液缓慢地冷却至室温,然后冷却至-15℃。在-15℃老化1-2小时后,上清液的LC表明上清液中损失了~2g/l产物,把该浆液过滤,用冷庚烷(~25L)洗涤,获得了化合物3。
步骤2:将3氯化成4:
向保持在10℃的联芳化物3(3.4kg)在DMF(17L)内的溶液中加入亚硫酰氯(940ml),然后将该混合物温热至室温。将该混合物老化直至通过HPLC测定>99.8%的转化氯。然后加入水(3.4L)。加入晶种(1wt%),将该混合物老化30分钟,然后用1小时缓慢地加入5.1L水。将该固体过滤,首先用20L 1∶1 DMF∶水洗涤,然后用3×20L水洗涤。将固体产物4在20℃干燥直至剩余<0.1wt%水。
步骤3:将实施例17的产物用化合物4烷基化以生成实施例73的产物:
将在实施例17中制备的手性中间体(4S,5R)-5-[3,5-二(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮溶解在DMF(2.8kg溶解在32.7L中),冷却至-15℃。然后用1.5小时加入2.0M NaHMDS(3.92L,1.05eq),之后加入在DMF中的联芳基氯4(2.8kg)。将该混合物温热至+12℃,老化直至完全转化。然后加入5N HCl(3.4L),之后加入16L 10%IPAC/庚烷和34L水,把温度保持在10℃-20℃。分离各层,并将有机层用14L 1∶1DMF∶水洗涤两次,然后用14L水洗涤2次。分析有机层的产率,然后经由2.4kg硅胶过滤以除去过量唑烷酮至<0.5%。用5%IPAC/庚烷洗涤硅胶。将合并的有机溶液蒸馏以除去IPAC至<1%。之后把温热的庚烷溶液缓慢地转移到含有含有10wt%晶种的20℃庚烷溶液中。把浆液冷却至-20℃并过滤。把滤饼用冷庚烷洗涤,然后干燥,获得最初是在实施例73中制得的化合物。
中间体29
(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-3-硝基-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮
在0℃将(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮分批加到2mL发烟硝酸中。将该反应混合物在室温搅拌过夜,然后在75℃加热4小时。将该反应混合物冷却,然后滴加到10mL水和10mL EtOAc的快速搅拌着的混合物中。分离各相并且将有机相用分别10mL饱和NaHCO3和盐水洗涤,干燥(Na2SO4)并浓缩。将残余物在Biotage Horizon,25S柱上通过快速色谱法纯化,使用1CV 5%EtOAc在己烷中的混合物洗脱,然后使用5→100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)643(M+1)。
实施例373
(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[4′-氟-5′-异丙基-2′-甲氧基-6-硝基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮
按照实施例81中描述的方法,使用48mg(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-3-硝基-5-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮和48mg(4-氟-5-异丙基-2-甲氧基苯基)硼酸(实施例78),获得了两种阻转异构体,可在Biotage Horizon,25S柱上通过快速色谱法分离,用1CV 5%EtOAc在己烷中的混合物洗脱,然后使用5→100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了位阻异构体A[质谱(ESI)683.4(M+1)]和位阻异构体B[质谱(ESI)683.3(M+1)]。
实施例374
(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[4′-氟-5′-异丙基-2′-甲氧基-6-碘-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮(位阻异构体A)
向17mg(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[4′-氟-5′-异丙基-2′-甲氧基-6-硝基-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮,位阻异构体A(实施例373)在1mL EtOAc内的溶液中加入5mg PtO2(Adam′s催化剂)。将该反应混合物用氢气吹扫,然后在氢气囊下搅拌2小时,此时LC/MS分析表明大部分是亚硝基产物。将该反应混合物经由硅藻土过滤,用EtOAc洗涤,将该滤液浓缩,在于反应条件下放置过夜。将该反应混合物经由硅藻土过滤,用EtOAc洗涤,并将该滤液浓缩。把残余物溶解在0.5mL CH2I2中,加入6μL亚硝酸叔丁酯。将该反应混合物在80℃搅拌1.5小时。将该反应混合物在1000μM平板上通过制备薄层色谱纯化,用20%EtOAc在己烷中的混合物洗脱,获得了本标题化合物。质谱(ESI)764.3(M+1)。
实施例375
(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[4′-氟-5′-异丙基-2′-甲氧基-6-碘-4-(三氟甲基)联苯-2-基]-4-甲基-1,3-唑烷-2-酮(位阻异构体B)
向70mg(4R,5R)-3-[3,5-二(三氟甲基)苄基]-5-[2-碘-3-硝基-4-(三氟甲基)苯基]-4-甲基-1,3-唑烷-2-酮(中间体30)在1mL EtOH内的溶液中加入124mg SnCl2。将该反应混合物在室温搅拌过夜;然后再加入60mg SnCl2,将该混合物加热至80℃并搅拌过夜。将该反应混合物浓缩,将残余物在10mL CH2Cl2与10mL 1N NaOH之间分配。将水相用2×10mL CH2Cl2萃取,将合并的有机相干燥(Na2SO4)并浓缩。按照实施例81中描述的方法,使用得自该还原的残余物和70mg(4-氟-5-异丙基-2-甲氧基苯基)硼酸(实施例78),获得了相应的联苯化合物,为位阻异构体的混合物。将该混合物溶解在0.5mL CH2I2中,加入14μL亚硝酸叔丁酯。将该反应混合物在80℃搅拌1.5小时,然后冷却,直接加到两个1000-μM薄层色谱平板上,用20%EtOAc在己烷中的混合物洗脱,获得了大约等量的本标题化合物的位阻异构体A和B。质谱(ESI)764.2(M+1)。
中间体31
4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲醛
按照实施例81中描述的方法,使用200mg 2-碘-5-(三氟甲基)苯甲醛(实施例80,步骤A)和170mg(4-氟-5-异丙基-2-甲氧基苯基)硼酸(实施例78),获得了本标题化合物。质谱(ESI)341.3(M+1)。
中间体32
5-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1-(4-甲氧基苄基)咪唑烷-2-酮
步骤A:[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基][(4-甲氧基苄基)氨基]乙腈
向203mg 4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-甲醛(中间体31)在2mL CH2Cl2内的溶液中加入100μL TMSCN,然后加入1mgZnI2。将该混合物在室温搅拌30分钟。加入在2mL MeOH中的对甲氧基苄基胺(157μL),将该混合物加热回流1.5小时。将该反应混合物冷却并浓缩。将残余物在Biotage Horizon,25M柱上通过快速色谱法纯化,用1CV 2%EtOAc在己烷中的混合物洗脱,然后使用2→100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)487.2(M+1)。
步骤B:5-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1-(4-甲氧基苄基)咪唑烷-2-酮
向100mg[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基][(4-甲氧基苄基)氨基]乙腈在4mL THF内的0℃溶液中加入620μL 1MLiAlH4在Et2O内的溶液中。移去冷却浴,将该混合物在室温搅拌45分钟。将该混合物再冷却至0℃,通过小心地滴加24μL水、24μL 15%NaOH水溶液和60μL水来处理。将固体过滤,用Et2O洗涤,并将该滤液浓缩。把残余物溶解在2mL CH2Cl2中,冷却至0℃。加入三乙胺(55μL),然后加入三光气(32mg)。将该混合物在0℃搅拌45分钟。将该反应混合物在10mL EtOAc与10mL水之间分配。将水相用10mLEtOAc萃取,把合并的有机层用10mL盐水洗涤,干燥(Na2SO4)并浓缩。将残余物在Biotage Horizon,25S柱上通过快速色谱法纯化,用1CV15%EtOAc在己烷中的混合物洗脱,然后使用15→100%EtOAc在己烷中的混合物用10CV进行线性梯度洗脱,获得了本标题化合物。质谱(ESI)517.3(M+1)。
实施例376
1-[3,5-二(三氟甲基)苄基]-4-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]咪唑烷-2-酮
步骤A:1-[3,5-二(三氟甲基)苄基]-4-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-3-(4-甲氧基苄基)咪唑烷-2-酮
向19mg 5-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1-(4-甲氧基苄基)咪唑烷-2-酮(中间体32)在1mL DMF内的0℃溶液中加入3mg NaH(60%在油中的分散液)。将该溶液在0℃搅拌10分钟,然后加入8μL 3,5-二-三氟甲基苄基溴,将该混合物在0℃搅拌3小时。将该反应混合物用一滴水处理,然后过滤,通过反相HPLC纯化[Waters XTerra C8 19×50mm柱,以20mL/分钟的流速用90%水(0.1%TFA)-100%乙腈(0.1%TFA)洗脱5.15分钟,保持1.45分钟,然后再用90%水洗脱0.5分钟],获得了本标题化合物。质谱(ESI)743.2(M+1)。
步骤B:1-[3,5-二(三氟甲基)苄基]-4-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]咪唑烷-2-酮
将15mg 1-[3,5-二(三氟甲基)苄基]-4-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-3-(4-甲氧基苄基)咪唑烷-2-酮在0.5mL TFA中的溶液于室温搅拌过夜。将该反应混合物浓缩,然后通过反相HPLC纯化[Waters XTerra C8 19×50mm柱,以20mL/分钟的流速用90%水(0.1%TFA)-100%乙腈(0.1%TFA)洗脱5.15分钟,保持1.45分钟,然后再用90%水洗脱0.5分钟],获得了本标题化合物。质谱(ESI)623.4(M+1)。
实施例377
1-苄基-4-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]咪唑烷-2-酮
步骤A:1-苄基-4-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-3-(4-甲氧基苄基)咪唑烷-2-酮
按照实施例379步骤A中描述的方法,使用31mg 5-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-1-(4-甲氧基苄基)咪唑烷-2-酮(中间体32)和9μL苄基溴,获得了本标题化合物。质谱(ESI)607.5(M+1)。
步骤B:1-苄基-4-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]咪唑烷-2-酮
按照实施例379步骤B中描述的方法,使用5mg 1-苄基-4-[4′-氟-5′-异丙基-2′-甲氧基-4-(三氟甲基)联苯-2-基]-3-(4-甲氧基苄基)咪唑烷-2-酮,获得了本标题化合物。质谱(ESI)487.4(M+1)。273 -->
Claims (1)
1.具有式Ii的化合物或其可药用盐:
其中
R7选自Cl和-CF3;
每个Rb独立地选自-C1-C3烷基、-OCH3和F;
R1选自H和-C1-C2烷基;
每个Rc独立地选自卤素、-CH3、-CF3和-CN;
q是2或3;且
t是0-2的整数。
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2009
- 2009-11-25 US US12/625,783 patent/US8735435B2/en active Active
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2010
- 2010-02-16 JP JP2010031195A patent/JP4491062B1/ja not_active Expired - Fee Related
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2011
- 2011-01-27 JP JP2011015653A patent/JP5543932B2/ja not_active Expired - Fee Related
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2012
- 2012-01-12 IL IL217530A patent/IL217530A0/en unknown
- 2012-07-30 AR ARP120102770A patent/AR087382A2/es unknown
- 2012-12-03 HR HRP20120993TT patent/HRP20120993T1/hr unknown
- 2012-12-21 CY CY20121101259T patent/CY1117930T1/el unknown
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2014
- 2014-04-14 US US14/252,256 patent/US20140221383A1/en not_active Abandoned
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2015
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CN106032362A (zh) * | 2015-03-10 | 2016-10-19 | 湖南千金湘江药业股份有限公司 | 安塞曲匹的制备方法 |
CN106032362B (zh) * | 2015-03-10 | 2018-06-19 | 湖南千金湘江药业股份有限公司 | 安塞曲匹的制备方法 |
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