TWI299991B - Cetp inhibitors - Google Patents
Cetp inhibitors Download PDFInfo
- Publication number
- TWI299991B TWI299991B TW094122197A TW94122197A TWI299991B TW I299991 B TWI299991 B TW I299991B TW 094122197 A TW094122197 A TW 094122197A TW 94122197 A TW94122197 A TW 94122197A TW I299991 B TWI299991 B TW I299991B
- Authority
- TW
- Taiwan
- Prior art keywords
- etoac
- trifluoromethyl
- doc
- isopropyl
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- Prior art date
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- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 142
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 133
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 113
- 125000000217 alkyl group Chemical group 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 42
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 238000011282 treatment Methods 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 201000001320 Atherosclerosis Diseases 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 565
- 235000019439 ethyl acetate Nutrition 0.000 description 282
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 273
- 238000006243 chemical reaction Methods 0.000 description 148
- 239000000243 solution Substances 0.000 description 141
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 136
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 description 108
- 239000000203 mixture Substances 0.000 description 106
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 100
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- 238000005481 NMR spectroscopy Methods 0.000 description 70
- -1 cholesteryl ester Chemical class 0.000 description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 60
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 54
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 52
- 238000000034 method Methods 0.000 description 51
- 238000003818 flash chromatography Methods 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- 239000000047 product Substances 0.000 description 45
- 101150041968 CDC13 gene Proteins 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 42
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 40
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 39
- 239000012267 brine Substances 0.000 description 38
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 34
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000011734 sodium Substances 0.000 description 24
- 239000010410 layer Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 21
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 21
- 239000000284 extract Substances 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 19
- 239000007789 gas Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 229910000104 sodium hydride Inorganic materials 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 239000000460 chlorine Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 14
- 238000004458 analytical method Methods 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 14
- 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 14
- 238000001819 mass spectrum Methods 0.000 description 14
- 239000012312 sodium hydride Substances 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 101000880514 Homo sapiens Cholesteryl ester transfer protein Proteins 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 102100037637 Cholesteryl ester transfer protein Human genes 0.000 description 12
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 12
- 239000002245 particle Substances 0.000 description 12
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- 238000012360 testing method Methods 0.000 description 12
- KEWSCDNULKOKTG-UHFFFAOYSA-N 4-cyano-4-ethylsulfanylcarbothioylsulfanylpentanoic acid Chemical compound CCSC(=S)SC(C)(C#N)CCC(O)=O KEWSCDNULKOKTG-UHFFFAOYSA-N 0.000 description 11
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 108010023302 HDL Cholesterol Proteins 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000004093 cyano group Chemical group *C#N 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 150000002923 oximes Chemical class 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
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- 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 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
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- 239000000543 intermediate Substances 0.000 description 7
- 229910052740 iodine Inorganic materials 0.000 description 7
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 7
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 7
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- 239000000126 substance Substances 0.000 description 7
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- MDKXYOBXGMDVNT-UHFFFAOYSA-N methyl 2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyacetate Chemical compound COC(=O)C(O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 MDKXYOBXGMDVNT-UHFFFAOYSA-N 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
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- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
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- FVAUCKIRQBBSSJ-LAIFMVDKSA-N sodium iodane Chemical compound [Na+].[131IH] FVAUCKIRQBBSSJ-LAIFMVDKSA-N 0.000 description 1
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- 239000011593 sulfur Substances 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
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- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N trimethylmethane Natural products CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- AYLKESQGYREYHF-UHFFFAOYSA-M trimethyloxidanium iodide Chemical compound [I-].C[O+](C)C AYLKESQGYREYHF-UHFFFAOYSA-M 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- WAXLMVCEFHKADZ-UHFFFAOYSA-N tris-decyl borate Chemical compound CCCCCCCCCCOB(OCCCCCCCCCC)OCCCCCCCCCC WAXLMVCEFHKADZ-UHFFFAOYSA-N 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229910000051 zinc hydride Inorganic materials 0.000 description 1
- ZULTYUIALNTCSA-UHFFFAOYSA-N zinc hydride Chemical compound [ZnH2] ZULTYUIALNTCSA-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- 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
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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1299991 九、發明說明: 【發明所屬之技術領域】 本發明係關於一類可抑制膽固醇酯轉運蛋白(CEPT)且因 此可具有治療與預防動脈粥樣硬化之用途的化學化合物。 【先前技術】 動脈粥樣硬化及其臨床後果(冠心病(CHD)、中風以及周 邊血管疾病)代表著工業化社會健康照護系統的一真正巨 大負擔。僅在美國就有約13,000,000患者已確診為患有 CHD,且每年有超過500,000例死亡係由CHD造成。此 外,預計此調查人數在接下來的25年中會隨著肥胖症與糖 尿病之流行性的繼續增長而增長。 吾人很早就意識到,哺乳動物中循環脂蛋白特性之變化 與動脈粥樣硬化及CHD風險有關。HMG-CoA還原酶抑制 劑(尤其為抑制素)在降低冠狀動脈事件中的臨床成功係基 於循環低密度脂蛋白膽固醇(LDL-C)(LDL-C水平與動脈粥 樣硬化之高風險直接相關)之降低。最近,流行病學研究 已闡明高密度脂蛋白膽固醇(HDL-C)水平與動脈粥樣硬化 之間存在一反比關係,由此得出結論:低血清HDL-C水平 與一 CHD之高風險有關。 脂蛋白水平之代謝控制係一涉及多種因素的複雜與動態 過程。人類中一重要代謝控制係膽固醇酯轉運蛋白 (CEPT)( —可催化膽固醇酯自HDL向含有月旨蛋白(尤其是 VLDL)之apoB運動的血漿糖蛋白)(參見,Hesler,C.B·,等人 (1987) Purification and characterization of human plasma 102763.doc 1299991 cholesteryl ester transfer protein. J. Biol. Chem. 262(5), 2275-2282))。在生理條件下,淨反應係一異質交換,其 中,CETP將甘油三酯自apoB脂蛋白運送至HDL上,並將 膽固醇酯自HDL轉運至apoB脂蛋白上。 在人類中,CETP在反向膽固醇轉運中發揮作用,藉由 此過程膽固醇由周邊組織返回至肝中。令人感興趣地是, 包括具有高HDL水平且已知抗冠心病之動物(諸如齧齒類 動物)在内的許多動物不具備CETP(參見Guyard-Dangremont, V.,^ A » (1998) Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility, Comp· Biochem. Physiol. B Biochem. Mol. BioL 120(3), 517-525)。已實施許多有關CETP活性之自然變異對於冠心病風 險之作用的流行病學研究,包括關於少數已知人類無效突 變之研究(參見 Hirano,Κ·_Ι·,Yamashita,S·與 Matsuzawa,Y·
(2000) Pros and cons of inhibiting cholesteryl ester transfer protein, Curr. Opin. Lipidol. 11(6),589-596)。此 等研究已清楚證實血漿HDL-C濃度與CETP活性之間的反 向關係(參見,Inazu,A·,等人(2000) Cholesteryl ester transfer protein and atherosclerosis,Curr· Opin· Lipidol· 11(4),3 89-3 96),由此假設:對CETP脂轉運活性之藥理抑 制會藉由增加HDL-C水平同時降低LDL水平而有利於人 類。 儘管諸如辛伐他汀(ZOCOR®)等抑制素取得了顯著治療 102763.doc 1299991
進展’但抑制素在動脈粥樣硬化及繼發性動脈粥樣硬化疾 病事件之治療與預防中僅使風險降低了約三分之一。當 月1J ’很少有可有助於提高HDL-C循環水平之藥理治療可 用。某些抑制素與一些貝特類(fibrate)藥物可提供中等 HDL-C增加。對於提高hdl_C而言可提供最有效治療的煙 酸(已在臨床上證實)部分由於諸如發熱等副作用而遭受患 者抱怨問題。一可安全且有效提高HDL膽固醇水平之藥劑 可精由提供一種藥理治療方法(其可通過一與現有治療互 補之機制來顯著改善循環脂質分佈特性)而滿足一重要但 尚未獲得滿足之醫學需求。 可抑制CETP之化學化合物的新種類正在^干醫藥公司 中進仃研九或處於臨床試驗階段。當前還沒有抑制 劑投放市場。需要新化合物從而可發現一或多種安全且有 2醫樂化合物。本文所述化合物係相當有效之CETP抑 【發明内容】 具有式I之化合物(包括該等仆 .rFTD4/ 寻化合物之醫藥上可接受之鹽 為CETP抑制劑’其具有下文所述用途:
B
I (R)2C、
X ?、R5 R2 在式I化合物中, 102763.doc 1299991 Y係選自-C( = 〇)-與-(CRRl)-; x係選自·〇_、-NH-、_N(Ci 至 C5 烷基)-以及-(CRR6)-; z係選自-C(=〇)·、_s(0)2-及一C(=N-R9)-,其中 R9係選自 、-CN以及視情況經1至11個鹵素取代的-C卜C5烷基組 成之群; 各R皆係獨立選自由Η、-c卜C5烷基以及鹵素組成之 群’其中-C卜C5烷基視情況可經1至η個鹵素取代; Β係選自由A1與α2組成之群,其中Α1具有如下結構··
-C1-C5烧基、_素以及 R1與R6各係獨立選自由η、 (c(R)2)nA2組成之群,其中{卜^^烷基視情況可經工至工工 個鹵素取代; R2係選 R2係選自由η、_匚卜(^ _(C(R)2)nA2組成之群,其中_( 個鹵素取代;
其中-C1-C5烷基視情況可經1至11 因而式I化合物包括一基團A1與一基團 其中B與R2之一係A1 ;且β 或-(C(R)2)nA2 ’因而式I化合 A2 ; 、Rl、R2以及R6之一係A2 A3係選自由下列組成之群: (a)—選自苯基及萘基之芳環
括1至2個雙鍵)之苯環; 102763.doc 1299991 ⑷5至6貝雜核,其具有1至4個雜原子(係獨立選自 N、S、0、以及卞(〇)〇且視情況亦包括⑴個雙鍵以及一 碳基,其巾A3至連接A3之苯環的連接點係-碳原子;及 ⑷本并雜裱,其包括一稠合至一 5至6員雜環(具有 ⑽獨立選自0、咖之雜原子)之苯環且視情況亦具 有1至2個雙鍵(除經稠合苯環的雙鍵以外),其中A3至連接 A3之笨環之連接點係一碳原子; A2係選自由下列組成之群:
(a)—選自苯基及萘基之芳環; ()稠a至5至7員非芳族環烧基環(其視情況可包 括1至2個雙鍵)之苯環; (0— 5至6員雜環,其具有丨至4個雜原子(係獨立選自 N、s、〇、以及—N(0>)且視情況亦包括1至3個雙鍵以及一 羰基; (d) —苯并雜環,其包括一稠合至一 5至6員雜環(具有 1至2個獨立選自〇、N&s之雜原子)之苯環且視情況亦具 有1至2個雙鍵(除經稠合苯環的雙鍵以外);及 (e) —視情況可具有1至3個雙鍵之-C3-C8環烷基環; 其中A3與a2各自視情況可由1至5個獨立選自Ra之取代 基取代; 各Ra皆係獨立選自由下列各基組成之群:^卜以烷 基、-C2-C6晞基、-C2-C6炔基、視情況具有1至3個雙鍵 之-C3-C8環烷基、-〇c卜C6烷基、-〇C2_C6烯基、-OC2-C6 炔基、視情況具有1至3個雙鍵之-OC3-C8環烷基、 102763.doc • 10· 1299991 -C(=0)Ci-C6 烧基、-C(=〇)C3-C8 環烧基、-C(=〇)H、 -C〇2H、-CO2C1-C6 烷基、-C(=0)SCi-C6 烷基、 -NR3R4、-C(=0)NR3R4、_NR3C(=0)0Ci_C6 烷基、 -NR3C(=0)NR3R4、_S(〇)xCi_C6烷基、_S(0)yNR3R4、 -NR3 S(0)yNR3R4、鹵素、-CN、-N〇2 以及 一 5 至 6 員雜環 (具有1至4個獨立選自N、S及Ο之雜原子),該雜環視情況 亦可包括一羰基且視情況亦可包括1至3個雙鍵,其中該雜 環至所連接環之連接點係一碳原子,其中該雜環視情況可 由1至5個獨立選自鹵素、-C卜C3烷基以及-OC卜C3烷基之 取代基取代’其中-C1-C3烧基以及-〇Ci-C3烧基視情況可 由1至7個_素取代; 其中對於其中Ra係選自由-C1-C6烷基、-C2-C6烯基、 -C2-C6炔基、視情況具有1至3個雙鍵之-C3-C8環烷基、 _OCl_C6烧基、-OC2-C6浠基、-OC2-C6快基、視情況具有 1至3個雙鍵之-OC3-C8環烷基、_C(=〇)C卜C6烷基' -C(=0)C3-C8 環烧基、-C〇2Cl-C6 烧基、-C(=0)SC 卜 C6 烧 基、-NR3c(=〇)〇Cl-C6烷基、以及-S(0)xC卜C6烷基組成 之群的化合物而言,Ra視情況可由1至15個鹵素取代且視 情況亦可由1至3個獨立選自下列的取代基取代:(a)-OH ; (b)-CN ; (c)-NR3R4 ; (d)視情況具有1至3個雙鍵且視情況 由1至15個鹵素取代之-C3-C8環烷基;(幻視情況由1至9個 鹵素取代且視情況亦可由1至2個獨立選自-OC1-C2烷基之 取代基取代的-OC卜C4烷基;(f)視情況具有1至3個雙鍵且 視情況可由1至15個鹵素取代之-OC3-C8環烷基;(g)- 102763.doc -11 - 1299991 C〇2H ; (h)-C(=〇)CH3 ;以及⑴視情況可由1至9個鹵素取 代之-C02C卜C4烷基; 條件是,當B為Al,X與γ為_CH2-,Z為-C(=0)-,R2為 A2’且a2為本基(其在4-位置處有一取代基Ra ’其中Ra為 一視情況可由1至11個鹵素取代之-0C卜C6烧基)時,則在 A2上不存在其他Ra取代基,其中Ra係選自_〇c卜C6烷 基、-OC2-C6烯基、-OC2-C6炔基以及視情況具有1至3個 雙鍵之-OC3_C8環烷基; η為0或1 ; Ρ為自0至4的一整數; X為0、1或2 ; y為1或2 ; R3與r4各係獨立選自η、-C卜C5烷基、-C(=〇)ChC5烷 基以及-S(0)yC卜C5烷基,其中-C卜C5烷基在所有實例中 皆可視情況由1至11個_素取代;及 R5係選自由下列各基組成之群:Η、-OH、-Ci_C5烷基 以及鹵素,其中_C卜C5烷基視情況可由1至11個鹵素取 代。 【實施方式】 許多本發明化合物具有下列式la之結構,或其一醫藥上 可接受之鹽: 102763.doc -12- 1299991
(9_η A2 la 許多本發明化合物具有式lb之結構,或其一醫藥上可接 受之鹽: f
許多其他化合物具有式Ic之結構,或其一醫藥上可接受 之鹽:
R (R)2C、N^Z、卜(c(R)2)nA2 Y—C-R5 R Ic 還有另一些本發明化合物具有式Id之結構,或其一醫藥 上可接受之鹽:
(R)2C、m/Z、y N A A2(C(R)2)n-C—C-R5 R R Id 在許多式I、la、lb、Ic及Id化合物及其醫藥上可接受之 102763.doc -13 - 1299991 鹽中, A3為視情況可由i至4個取代基Ra取代之苯基,其中Ra 係獨立選自-C卜C5烷基、-OC1-C3烷基、_C〇2C卜C3烷 基、-C〇2H、函素、-NR3R4、-C(=0)Ci-C3 烷基、 -C(=0)H、-C(=0)NR3R4、-SC1-C3 烷基、-C2-C3 烯基、 •CN、-N〇2、以及1,2,4-噁二唑基,其中-C卜C3烷基與-Cp C5烧基在所有情況中皆可視情況由1至6個獨立選自1至5個 鹵素及一-0H基團之取代基取代,且-C2-C3烯基視情況可 ,由1至3個鹵素取代。 在許多式I、la、lb、Ic及Id化合物及其醫藥上可接受之 鹽中, A2係選自由苯基、環己基以及一雜環5至6員環(包括}至 2個獨立選自〇、N、S以及-N(0)-之雜原子且視情況亦可包 括1至3個雙鍵)組成之群,其中A2視情況可由1至2個獨立 選自-C卜C4烧基、-OC1-C3烧基、-N〇2、-CN、-S(0)xCp C3烷基、_NH[S(〇)2Cl-C3烷基、-NR3R4、-NR3C(=〇)R4、 _ -C2-C3烯基、-c(=0)nr3r4、鹵素以及吡啶基之取代基取 代,其中C卜C3貌基、C1-C4烧基以及C2-C3烯基在所有實 例中皆可視情況由1至3個鹵素取代,但條件是對於式la化 合物而言,當X與丫為’ Z為_(C=0)_,n為〇,且a2為 苯基時,則A2上選自-〇Cl-C3烧基之Ra基團之數目為〇或 1 ° 在許多式I、Ia、Ib、1〇及Id化合物及其醫藥上可接受之 鹽中, 102763.doc • 14· 1299991 R3與r4各自獨立選自烷基。 在許多式I、la、lb、Ic及Id化合物及其醫藥上可接受之 鹽中,p為0至2。
在式I化合物亞群(包括其醫藥上可接受之鹽)中,…為 其中R7與R8各自獨立選自由η、鹵素、_nr3r4、-Cl-φ C3烧基、-OCiO烧基、-CN、·Ν〇2以及吼啶基組成之 群’其中C1-C3烷基在所有實例中皆視情況可由1至3個鹵 素取代。 在式I化合物亞群中,Α2係選自由苯基、0比啶基以及環 己基組成之群,其中Α2視情況可由1至2個獨立選自4 烷基、_OCl-C4烷基、-N〇2、-CN以及自素之取代基取 代’其中C1-C4烷基在所有應用中皆可視情況由1至3個鹵 素取代’但條件是對於式la化合物而言,當X與γ為CH〗, _ 2為-(C=0)-,且A2為苯基時,則A2上的Ra基團數目為〇或 1 ’其中Ra基團選自視情況可由1至3個鹵素取代之_Qc 1 _ C4烧基。 在其他亞群中’ A2視情況可由1至2個獨立選自_素、 -C卜C4烧基以及-CN之取代基取代,其中·〇卜以烷基視情 況可由1至3個鹵素取代。 在如上所述的許多本發明實施例(包括醫藥上可接受之 鹽)中, 102763.doc -15· 1299991
Al為 R8
其中R7係選自Η、鹵素、-NR3R4、-C1-C3烷基、-OCl-C3烷基、-CN、-NO2以及吡啶基,其中C1-C3烷基在所有 實例中皆可視情況由1至3個A素取代;及 R8 係選自由 Η、鹵素、-CH3、-CF3、-0CH3 以及-0CF3 組成之群。 在許多本發明較佳實施例中,A3為苯基,其由1至3個獨 立選自 Ci_C4 烷基、0C1-C4 烷基、-CN、Cl、F、 _C(=0)CH3、-CH=CH2、-C〇2H、-CO2CH3、-S-CH3、 -S(0)CH3、-S(0)2CH3、以及 _C(=0)NR3R4 之取代基取 代,其中C1-C4烷基與-〇Cl-C4烷基視情況可由1至5個F取 代基取代且視情況亦可由一 -0H基團取代。 在其他實施例中,A3為苯基,其視情況可由1至3個獨立 選自由CM、F、-C1-C4烷基以及-0C1-C4烷基組成之群之取 代基取代,其中-C1-C4烷基與-0C1-C4烷基視情況可由1至 5個F取代。 一較佳化合物亞群具有式Ie,包括其醫藥上可接受之鹽
B
(R)2C Z N a \丨 Η—C ——C 一 Η L ' R1 R2 le 在式Ie化合物中,X係選自由-Ο-、-NH-、-N(C卜C5烷 102763.doc -16- 1299991 基)-以及-(CH2)_組成之群; z係選自由-C(=0)·、_s(0)2_以及_C(=N_R9)_組成之群, 其中R9係選自由η、-CN以及視情況由_素取代之 C1-C5烧基組成之群; 各R皆係獨立選自由Η與·CH3組成之群; Β係選自由Α1與Α2組成之群,其中Αι具有如下結構
/(Rb)q (Ra)P- ’
R1係選自由H、-C卜C5烷基以&_(C(R)2)nA2組成之群, 其中-C 1-C5烧基視情況由1至11個鹵素取代; R2係選自由Η、_C^C5烷基、A1以及-(C(R)2)nA2組成 之群’其中-C卜C5烷基視情況由1至11個鹵素取代; 其中B與R2之一為A1 ;且B、R1以及R2之一為A2或 _(C(R)2)nA2 ;以使式Ie化合物包括一基團Al與一基團 A2 ; A2係選自由苯基、環己基以及。比咬基組成之群,其中 A2視情況由1至2個獨立選自鹵素、^卜以烷基以及-(:]^之 取代基取代,其中-Cl_C4烷基視情況由1至3個鹵素取代; 各Raf係獨立選自由-Cl-C3烷基以及鹵素組成之群,其 中-C卜C3烷基視情況由1至3個鹵素取代; 各Rb皆係獨立選自由Cl、F、-C卜C4烷基以及-〇Cl_C4 烷基組成之群,其中_Cl_C4烷基以及-〇Cl-C4烷基視情況 由1至5個F取代; 102763.doc -17· 1299991 2-甲基-2-丁烯基,等等。 可為線性或具支 、丙块基、3-曱 炔基」表示至少含—個碳_碳三鍵且 鏈或其組合之碳鏈。块基實例包括乙快基 基-1-戊炔基、2_庚炔基,等等。 除非另有說明(例如,環说其 ^、 衣沉基可疋義為含一或多個雙 鍵),否貝1j,「環说某 矣- ^ 衣烷基」表不一具有3至8個碳原子之飽和碳 … _合至一芳基上之環烷基環。環烷 基κ例包括環丙基、環戍美
「…· 衣戍基、J衣己基、環庚基,等等。 %稀基」表示—具有—或多個雙鍵之非芳族碳環。 「當:於闡述-結構中之取代基或基團時,「芳基」(及 •伸方基」)表不一其中碳環為芳族且僅含碳環原子之單 環或雙環化合物。術語「芳基」亦可指—稠合至__環烧基 或雜環上之芳基基團。較佳「芳基」為苯基與萘基。苯基 通常為最佳芳基基團。 C」為1-乙基-3-(3·二甲基胺丙基)碳化二亞胺。 除非另外說明,在:目丨丨,「故π甘 Γ ^ 月企則,「雜壞基」、「雜環」及「雜環 的」表示70全或部分飽和的或芳族之5至ό員環,其含1至4 個獨立選自N、S及〇的雜原子。 苯并雜表示一稠合至具1至2個雜原子(其各為〇、 Ν或S)之5至6員雜環上的苯環,其中雜環可以為飽和或不 飽和環5例包括吲哚、苯并呋喃、2,3-二氫苯并呋喃以 及喧琳。 DIPEA」為二異丙基乙基胺。 齒素」包括氟、氯、溴以及碘。 102763.doc • 21 - 1299991 HOBT」為1-經基苯并三唑。 IPAC」為乙酸異丙g旨。
Me」代表甲基。 「Weinreb醯胺」為队〇_二甲基羥胺。
術語「組合物」(如在醫藥組合物中)意欲涵蓋包括一或 多種活性成份與組成_的—或多種㈣成份之產品,以 及任-可直接或間接由該等成份中任兩種或多種之組合、 錯合或凝聚而產生、或由該等成份中—或多種之解離而產 生、或由該等成份中一或多種之其他類型反應或相互作用 而產生的產品。因此’本發明醫藥組合物涵蓋藉由混合一 本發明化合物與-醫藥上可接受之載劑而製成的任一組合 物0 取代基「四唑」表示一 2扒四唑_5_基取代基及其互變異 構體。 光學異構體-非對映異構體-幾何異構體_互變異構鱧 式I化合物可包含-或多個不對稱中心並因此可以外消 旋物、外消旋混合物、單-對映異構體、非對映異構體混 合物及個別非對映異構體形式存在。本發明擬包括式“匕 合物之所有此等異構體形式。當結構用一立體化學表示法 來顯示時’其他立體化學結構也包括在内,諸如對映異構 體、其他非對映異構體(在非對映異構體可能存在之情況 下)以及對映異構體及/或非對映異構體之混合物(包括外消 旋混合物)。 一些本文所述化合物可包含烯烴雙鍵,且除非另外特別 102763.doc -22- 1299991 說明,否則,其擬包括E與z幾何異構體二者。 一些本文所述化合物可作為互變異構體形式存在。一實 例為酮及其烯醇形式’稱為_ _烯醇互變異構體。各互變 異構體以及其混合物皆涵蓋於式j化合物中。 含-或多個不對稱中心之式j化合物可藉由業内熟知方 法分離為非對映異構體、對映異構體,等等。 或者蜚十映異構體及其他具有對掌中心之化合物可使用 旋光純起始材料及/或具有已知構型之試劑藉由立體選擇 性合成法來合成。 在NMR4中觀察到本文中一些聯笨基與聯芳基化合物為 π轉異構體(^疋轉異構體)之混合物。各滯轉異構體及其混 合物皆涵蓋於本發明化合物中。 鹽 么術語「醫藥上可接受之鹽」指由包括無機或有機鹼與無 機或有機酸在内的醫藥上可接受之無毒鹼或酸製得的鹽。 亍生自“、、械驗之鹽包括銘鹽、铵鹽、約鹽 '銅鹽、鐵鹽、 亞鐵鹽、鋰鹽、鎂鹽、錳鹽、二價錳鹽、鉀鹽、鈉鹽、辞 鹽,等等。尤佳者係銨鹽、鈣鹽、鎂鹽、鉀鹽以及鈉鹽。 固體形式之鹽可以一種以上之晶體結構形式存在,且亦可 it合物形式存在。衍生自醫藥上可接受之有機無毒驗的 鹽包括一級、二級以及三級胺、經取代胺(包括天然存在 之經取代胺)、環胺以及鹼性離子交換樹脂的鹽,諸如精 胺酸、甜菜鹼、咖啡因、膽鹼、N,N,_二苄基乙二胺、二 胺 2 —乙月女基乙醇、2 -二甲胺基乙醇、乙醇胺、乙一 102763.doc -23- 1299991 胺、N-乙基嗎啉、N_乙基哌啶、還原葡糖胺、葡萄糖胺、 組胺酸、哈胺(hydrabamine)、異丙胺、離胺酸、曱基還原 葡糖胺、嗎啉、哌嗪、哌啶、聚胺樹脂、普魯卡因、嘌 口令、可可驗、三乙胺、 审脸 一 T妝一丙胺、胺丁三醇等的 鹽° 當本發明化合物為鹼性時,鹽可由醫藥上可接受之無毒 酸(包括無機及有機酸)來製備。此等酸包括醋酸、苯碏 酸、笨曱酸、樟腦續酸、擰檬酸、乙確酸、富馬酸、葡萄 糖酸、麩胺酸、氫溴酸、鹽酸、羥乙磺酸、乳酸、馬來 酸、蘋果酸、苯乙醇酸、甲磺酸、黏酸、硝酸、巴莫酸、 泛酸、磷酸、琥珀酸、硫酸、酒石酸、對甲基苯磺酸,等 等。尤佳者係擰檬酸、氫溴酸、鹽酸、馬來酸、磷酸、砑 酸以及酒石酸。 應瞭解,如本文所用,當提及式ϊ化合物時擬同樣包括 醫藥上可接受之鹽。 代謝產物-前藥 治療活性代謝產物(其中代謝產物本身屬於本發明之範 圍)亦為本發明化合物。前藥係當其正施用給一患者時戋 在其已施用給一患者之後可轉化成本發明所主張化合物^ 化合物)亦為本發明化合物。 用途 本發明化合物為CETP之強效抑制劑。其因此可用於仏 療可藉由CEPT抑制劑治療之疾病與病症。 本發明一態樣提供一種用來治療或降低形成一疾病或病 102763.doc -24- 1299991 症(其可藉由α + & σ鸹要>σ療之患者施用一治療有效量本 明化合物央虹& 、。电來抑制CETP從而得到治療或預防)之風險的方 法i患者為人類或哺乳動物,且最常為人類。一「治療有 效里」4可於一具體疾病治療中有效獲得一期望臨床結 之化合物量。 " ^可用本發明化合物治療或使用本發明化合物治療後結果 /寻4者具有一較低病症形成風險的疾病或病症包括: 動脈粥樣硬化、周邊血管疾病、月旨質代謝障礙、高β脂蛋 白血症、低(X脂蛋白血症、高膽固醇血症、高甘油三酯血 症、家族性高膽固醇血症、心血管病症、絞痛症、局部缺 血、心臟局部缺血、中風、心肌梗塞、再灌注損傷、血管 成形術再狹窄症、高血壓、糖尿病血管性併發症、肥胖症 以及内毒素血症。 預計本發明化合物對於增高HDL-C及/或增加HDL_C與 LDL-C之比率尤其有效。LDL C之此等變化有益 於治療動脈粥樣硬化、降低或逆轉動脈粥樣硬化之形成、 降低形成動脈粥樣硬化之風險或預防動脈粥樣硬化。 施用與劑量範圍 可採用任何適宜施用之途徑來向一哺乳動物(尤其為人 類)提供一有效劑量之本發明化合物。例如,可採用口 服、經直腸、外敷、非經腸、經眼睛、經肺、經鼻等途 徑。劑型包括鍵劑、口含錠、分散液、懸浮液、溶液、膠 囊、乳霜、軟膏、氣溶膠,等等。較佳地,式;[化合物係 藉由口服施用。 102763.doc -25- 1299991
所採用活性成份之有效劑量可端視所用特定化合物、施 用方式、擬治療病症以及擬治療病症的嚴重程度而有所變 化。熟諳此項技術者可易於確定此劑量。 當治療需用式I化合物治療的疾病時,當本發明化合物 按每公斤動物或人1類體重自約0.01毫克到約100毫克之曰 ^里%用時通常可獲得滿意結果,較佳地,本發明化合物 按單一曰劑量或按每日2至6次之多劑量給藥,或按緩釋劑 型給藥。以一 70公斤成年人為例,總曰劑量通常係自約 〇·5毫克到約500毫克。倘為一特別有效的化合物,則其用 於一成年人之劑量可低達〇·丨毫克。劑量方案可在此範圍 内調整或甚至可超出此範圍以提供最優治療反應。 口服施用通常使用錠劑來實施。錠劑中之劑量實例為 0.5¾克、1毫克、2毫克、5毫克、10毫克、25毫克、50毫 克' 100¾克、25〇毫克、以及5〇〇毫克。其他口服形式亦 可具有相同劑量(例如膠囊)。 醫藥組合物
☆本發明另-態樣提供包括一式“匕合物與一醫藥上可接 又之載劑的醫藥組合物。本發明醫藥組合物包括一式他 合物或-醫藥上可接受之鹽作為_活性成份以及—醫藥上 可接受之載劑且視情況包括 其他治療成份。術語 醫藥上 可接受之鹽」指由醫藥上 無機鹼類或酸類與有機驗 前藥,則一醫藥組合物亦 接受之鹽。醫藥組合物亦 可接受之無毒鹼類與酸類(包括 類或酸類)製備的鹽。若施用一 可包括一前藥,或一其醫藥上可 可基本由一式I化合物以及一醫 102763.doc -26 - 1299991 藥上可接受之載劑構成而不含無其他治療成份。 該等組合物包括適於口服、經直腸、外敷、非經腸(包 括、:皮下肌内以及靜脈内)、經眼睛(經眼)、經肺(經鼻 腔或口腔吸入)或經鼻投藥之組合物,但是在任何給定情 形中最適且it徑將視擬治療疾病之性質與嚴重程度以及 活性成份之性質而^。該等組合物可便利地以單位劑型提 供且可由製藥領域中熟知之任何方法來製備。
在實際應用中,可依據習用醫藥混合技術將作為活性成 份之式I化合物與一醫藥載劑組合成均勻混合物。載劑可 採用多種形式,視期望施用(例如,口服或非經腸(包括靜 脈内))的製劑形式而定。在口服劑型組合物製備中可採用 任何币用醫藥介質,在諸如懸浮液、酏劑以及溶液等口服 液體製劑情形中可採用例如水、二醇類、油類、醇類、矯 味劑、防腐劑、著色劑等等;或者在諸如粉劑、硬膠囊與 軟膠囊以及旋劑等口服固體製劑情形中可採用諸如澱粉、 糖、微晶纖維素、稀釋劑、造粒劑、潤滑劑、黏結劑、崩 解劑等載劑,其中固體口服製劑較液體製劑更佳。 由於其易於施用,因此,旋劑與膠囊代表最有優勢之口 服劑量單元形式,在此情形中,顯然可採用固體醫藥載 劑。若需要,錠劑可藉由標準水性或非水性技術來塗佈。 此等組合物及製劑應包含至少0· 1 %之活性化合物。活性化 合物於此等組合物中之百分比當然會有所變化,且可方便 地佔單元重量的約2%至約60%之間。活性化合物於此等治 療有用組合物中的量應能獲得一有效劑量。活性化合物亦 102763.doc -27- 1299991 可經鼻内施用,如(例如)液滴或喷霧。 q錠劑、丸劑、膠囊等等亦可包含—諸如黃蓍膠、阿拉伯 膠、玉米殿粉或明膠等黏結劑;諸如鱗酸氣約等賦形劑; 諸如玉米氣粉、馬鈴薯澱粉、海藻酸等崩解劑;諸如硬脂 酸鎂,潤滑劑;以及諸如薦糖、乳糖或糖精等甜味劑。當 -劑ΐ単7L形式為膠囊時’其除上述類型物質之外還可包 合一諸如脂肪油之液體載劑。 多種其他物f可作為塗層存在或其存在可改進劑量單元 之物理形式。例如,錠劑可用蟲膠、糖或二者塗佈。一糖 漿或醜劑除活性成份之外還可包含薦糖作為甜味劑、對氧 苯甲酸甲醋以及對氧苯甲酸丙酉旨作為防腐劑、一染料及一 諸如櫻桃味或橙味矯味劑。
式I化合物亦可以非經腸方式施用。此等活性化合物之 溶液或懸浮液可在適當混合有諸如M 性劑的水_。分舰亦可在甘油、 於油中的混合物中製備。在一般儲存及使用條件下,此等 製劑包含一防腐劑以防止微生物生長。 適合於注較狀㈣形式包括無旨錢㈣或分 以及用於即時製備無菌注射溶液或分散液之無菌粉劑。在 所有情形中’該形式必須無菌且其流動程度必須使盆且 易注射性。其在製造與儲存條件下必須穩定,且必須以 其受到諸如細菌與真菌等微生物之污染作用。載劑 一溶劑或分散介質,包含(例如)水、 Λ w 油、丙二醇以及液體聚乙二醇w/:醇(例如甘 予)具迺且混合物,以及植 102763.doc -28- 1299991 物油。 組合治療 本發明化合物(例如式I及la至Ij)可與亦可用於治療或改 善式I化合物對其有用之疾病或病症的其他藥物組合使 用。此等其他藥物可藉由其常用途徑及用量與一式I化合 物同時或依序施用。 可與本發明化合物一起施用之治療化合物包括有助於改 善患者脂質分佈特性(即:增加HDL-C及降低LDL-C)之化 _ 合物。較佳化合物為抑制素,包括辛伐他、;丁 (simvastatin)、洛伐他 丁(lovastatin)、羅舒伐他、汀 (rosuvastatin)、普伐他汀(pravastatin)、氟伐他汀 (fluvastatin)、阿托伐他汀(atorvastatin)、瑞伐他汀 (rivastatin)、伊他伐他汀(itavastatin)以及 ZD-4522。 CETP分析 根據Epps等人所述方法之改進方案並採用BODIPY®-CE 作為膽固醇酯脂質供體實施一活體外連續分析以測定IC50 ® 從而鐾別化合物是否係CETP抑制劑。參見Epps等人(1995) Method for measuring the activities of cholesteryl ester transfer protein (lipid transfer protein) , Chem· Phys· Lipids, ΊΊ、。 用於該分析之顆粒係自下列來源產生:含DOPC(二油醯 基磷脂醯膽鹼)之合成供體HDL顆粒、BODIPY®-CE(分子 探針C-3 927)、三油酸甘油i旨(一種甘油三I旨)以及apoHDL 基本上係藉由如Epps等人所述之探針超聲波處理來產生, 102763.doc -29- 1299991 但需添加非可擴散之螢光淬滅劑分子(4-(4’_二甲胺基苯基 偶氮)苯甲酸二(十六烧基)酿胺(dabcyl dicetylamide))以降 低背景螢光。4-(4’-二甲胺基苯基偶氮)苯甲醯二(十六烷 基)醯胺係在二異丙胺觸媒存在下、於95 °C下、在DMF中 加熱4-(4*•二曱胺苯基偶氮)苯曱醯N-琥珀醯亞胺與二(十六 烷基)胺隔夜而產生。來自人類血液之天然脂蛋白可用作 受體顆粒。藉由超速離心收集具有小於1.063克/毫升密度 之顆粒。此等顆粒包括VLDL、IDL以及LDL。顆粒濃度以 藉由BCA分析(Pierce,USA)測定之蛋白濃度來表示。顆粒 使用前保存在4°C。 分析係在Dynex Microfluor 2 U-黑底96孔板(目錄號為 #7205)中實施。製備一含CETP、lxCETP緩衝液(50 mM THs,pH 7·4、100 mM NaC卜 1 mM EDTA)以及一半終濃 度之受體顆粒之分析混合劑,並將100微升該分析混合劑 添加至孔板各孔中。將溶於DMSO之測試化合物按3微升體 積添加。於一孔板振盪器上混合孔板,然後在25°C下培育 1小時。製備含供體顆粒、剩餘受體顆粒以及IX CETP緩 衝液之第二分析混合劑。將47微升第二分析混合劑添加至 反應孔中以開始分析。分析係於25 °C下在150微升終體積 中實施。當測試化合物時,各物質之終濃度為:5奈克/微 升之供體顆粒、30奈克/微升之受體顆粒(各自由蛋白含量 表示)、lxCETP緩衝液、0.8 nM之重組人類CETP(以CHO 細胞表示且為部分純化)、以及不超過2%之DMSO。隨後 於一設置為25 °C下45分鐘動力學循環之螢光平板讀數器 102763.doc -30- 1299991 (Molecular Devices SpectramaxGeminiXS)中實施該分析, 該螢光平板讀數器可每45秒在Ex=480奈米、Em = 5 11奈米 處讀取樣品一次,同時於495奈米處進行一截止過濾,光 電倍增管設置為中等,校準啟用,且每孔讀6次。 藉由獲得一初始速率來評估數據,該初始速率以每秒之 相對螢光單位表示,對於曲線偽線性部分,常為〇至500或 1000秒。比較含抑制劑樣品與一未經抑制(僅含DMSO)之陽 性對照的速率得到一抑制百分比。採用一抑制百分比對抑制 • 劑濃度之對數的曲線圖(擬合於Σ 4參數方程)來計算IC50。 實例 提供下列反應圖與實例用以更為全面地理解與瞭解本發 明。起始材料係使用已知或如下所示的程序來製造。 不應將該等實例理解為以任何方式限制本發明。本發明 範圍係由隨附申請專利範圍來界定。使用上述分析量測可 知本發明化合物具有一小於或等於50 μΜ的IC50值。 反應圖1
102763.doc -31 - 1299991 用於本發明之中間體Μ、1-3、1-4、1-5以及卜6可購得 或如反應圖1中所示來製備。-經適當取代之21代苯胺1· 1(其中Ra與ρ係如申請專利範圍中之定義且其中鹵素較佳 為碘或溴)在升溫下於DMF中用CuCN處理以生成相應的2· 氰基苯胺。或者,可在鈀(11)鹽存在下或在某些銅或鎳錯 合物存在下藉由用KCN與CuI處理w從而製備腈(參見:
Snuth,Μ· B·與 March,J· 「MarCh,S Advanced Organic ChemiStry」,第 5版,John Wiley與 Sons,New York,第 • 867頁(2001)以及其中參考文獻)。碘化物1-3可在純的或溶 於諸如THF或乙腈等溶劑中的二碘甲烷(參見例如:Smhh 等人,J· 0rg· Chm. 55,2543,(1990)及其中所引用參考 文獻)存在下藉由用亞硝酸異戊酯、亞硝酸正戊酯、亞硝 酸第二丁酯等處理1 -2來製備。或者,該碘化物可首先藉 由使用亞硝酸異戊酯、亞硝酸正戊酯、亞硝酸第三丁 g旨、 亞硝酸鈉、亞硝酸等形成重氮,之後藉由在碘或諸如埃化 銅、碘化鈉、碘化鉀、碘化四丁銨等碘鹽存在下加熱來製 籲 備。於二氯甲烷中用DIBAL還原1-3可獲得醛1-4。於甲醇 或乙醇等物質中用硼氫化鈉等物質還原醛丨_4可生成醇h 5。於诸如一氣甲烧、二氣乙烧等溶劑中用四演化碳與三 苯基膦處理1-5生成苄基溴1-6(參見·· Smith,Μ· Β·與
March,J. 「March’s Advanced Organic Chemistry」,第 5 版,John Wiley and Sons,New York,第 518頁至第 519頁 (2001)以及其中參考文獻)。 102763.doc -32- 1299991 反應圖2
本發明中間體2-2與2-3(其中Ra、p以及A3係如申請專利 範圍中之定義)可如反應圖2中所示製備。2-氰基碘代苯2-1 可購得或依據反應圖1中概述之程序製備。通過一採用碘 化物2-1與一經適當取代之芳基-或雜芳基-硼酸、-硼酸酯 或-三烧基錫之經把催化交叉偶聯的Suzuki或Stille反應或 其變體來製備化合物2-2,如Miyaua等人在CT^m. ieev. 95,2457 (1995)中及其中所引用參考文獻中所述以及如 Smith,Μ· B·與 March,J·在「March’s Advanced Organic Chemistry」,第 5版,John Wiley and Sons,New York,第 868頁至第869頁(2001)中及其中所引用參考文獻中所述。 腈2-2之還原係在乙醚中用氫化鋰鋁來達成以生成2-胺基甲 基苯胺2-3。或者,該腈可在氫氣氛圍下於甲醇、乙醇等 物質中使用碳上鈀或阮内(Raney)鎳來還原。用來將腈還 原成胺甲基基團之其他方法可參見Smith,Μ· B.與March, J.之「March’s Advanced Organic Chemistry」,第 5版, John Wiley and Sons,New York,第 1204 頁(2001)以及其 中之參考文獻。 102763.doc -33 - 1299991 反應圖3 ο
本發明化合物3-4(其中R、Ra、ρ、α2、A3與η係如申請 專利範圍中之疋義)可依據反應圖3中概述之程序製備。节 胺3-1可購得或可依據反應圖2中概述之程序製備。3-1與一 經適當取代之乙酸院基酯(在2-位有一離去基團)之反應可 生成一級胺3-2。乙酸烧基酯可購得或使用已知方法製 備。較佳離去基團為漠化物或蛾化物,但亦可為甲石黃酸 春基、甲苯磺酸基等,且溶劑可以為二氣甲烷、二氣乙烧、 四氣咬喃、一甲氧基乙烧專專。該反應可在有或無一諸如 二乙胺、二異丙基乙基胺、Ν-甲基嗎淋等驗的存在下進 "ί亍。還原3-2的S旨官能團可生成胺基醇3 -3。較佳還原試劑 為存於諸如醚、四氫呋喃、二曱氧基乙烷、二氧雜環己烧 等溶劑中之UAIH4。用於還原酯之其他方法可參見 「March’s Advanced Organic Chemistry」第 5 版,j〇hn
Wiley and Sons ’ New York,第 1551 頁。可使用光氣 102763.doc -34- 1299991 (Y=C1)或一諸如三光氣(Y=0CCl3)或羰基二咪唑(γ=咪唑) 等光氣等效物於一諸如二氯甲烷、二氯乙烷、四氫呋喃、 二甲氧基乙烷等溶劑中及諸如三乙胺、二異丙基乙基胺、 Ν-甲基嗎啉等鹼中將胺基醇3-3環化成噁唑烷酮3-4。對映 異構純產物可通過對掌層析法獲得。 反應圖4
4-3 (〇R2)nA2 本發明化合物4-3(其中R、Ra、p、A2、A3以及η係如申 請專利範圍中之定義)可如反應圖4中所示製備。一經適當 取代之节胺4-1可與一經適當取代之環氧乙烷反應生成胺 基醇4-2。該環氧乙烷可購得或自相應醛與一硫内鑌鹽 (sulfur ylide)來製備,如於「March’s Advanced Organic Chemistry」 第 5版,John Wiley and Sons,New York,第 1247頁中所述。或者,該環氧化物可由一烯烴之環氧化、 一鹵代醇或1,2-二醇之環化或闡述於「March’s Advanced Organic Chemistry」第 5 版,John Wiley and Sons,New York,第1051頁中之其他方法來製得。用於此反應之較佳 溶劑為異丙醇。或者,該環氧化物之開環可於一諸如乙腈 102763.doc •35- 1299991 等4劑:借助於一諸如Yb(〇Tf)3等路易士酸觸媒來完成。 可使用光氣(Y=Cl)或一諸如三光氣(Y=〇ccl3)或羰基二咪 坐(Y-咪唑)等光氣等效物於一諸如二氣甲烷、二氯乙烷、 四氫呋喃、二甲氧基乙烷等溶劑及諸如三乙胺、二異丙基 乙基胺、N-甲基嗎啉等鹼中將胺基醇4_2環化成噁唑烷酮 43。或者,可藉由在諸如三乙胺、二異丙基乙基胺等鹼 存在下、於一諸如二氣甲烷、二氣乙烷、四氫呋喃、二甲 氧基乙烷等溶劑中用諸如二碳酸二苄基酯或氣甲酸苄酯等 φ 忒劑加以處理將胺基醇4_2轉換成一適宜胺基甲酸酯。然 後,胺基甲酸酯可藉由在諸如四氫呋喃,二甲氧基乙烷等 溶劑中用如雙(三甲基矽烷)胺基化鋰、_鈉或-鉀等鹼來處 理而轉化成噁唑烷酮4-3。對映異構純產物可通過對掌層 析法獲得。 反應圖5
(Ra)r
HN、 5-1 (Ra), OH Λ (CR2)nA2 (Me3C0C0)?0
OH Me3CO (CR2)nA2 1. MsCI 2. NaN3
5-4 5-2
(Ra), NH2 一 1.H2/Pd HN0\ 一 2.TFA N^J/3 〇 ㈣A2 Me3CO-i〇 ^(cR2)nA2 5-3
0
5-5 (CR2)nA2 102763.doc -36 - 1299991 本發明化合物5-5(其中R、Ra、p、A2、A3以及n係如申 請專利範圍中之定義)可如反應圖5中所示製備。經適當取 代之胺基醇5·1可如反應圖4中所示製備且作為一胺基甲酸 酯(諸如第三丁基胺基甲酸酯(BOC)或苄基胺基甲酸酯 (Cbz))優先受到保護。其他胺基甲酸酯及其他可供選擇之 氮保護基團可參見「Protective Groups in Organic Synthesis」,第 3版,John Wiley and Sons,New York,第 494頁。使用一BOC或Cbz基團對氮加以保護可藉由使5-1 與二碳酸二-第三丁酯或二碳酸二苄基酯於一諸如二氯曱 烷、二氣乙烷、四氫呋喃、二甲氧基乙烷等適宜溶劑中反 應來實施。醇5-2可藉由在一諸如三乙胺、二異丙基乙基 胺、N-甲基嗎啉等適宜鹼存在下與曱烷磺醯氣於二氯甲 烷、二氣乙烷、四氫呋喃、二甲氧基乙烷等物質中反應而 轉化成疊氮化物5-3。或者,該醇可轉化成一可供選擇之 離去基團,諸如甲苯磺酸根、碘化物、溴化物等。然後, 甲磺酸根在一諸如DMF、DMPU等適宜溶劑中由一疊氮化 物源(諸如NaN3、LiN3、BU4NN3等)置換。疊氮化物5-3亦 可藉由在THF中用二苯基磷醯基疊氮化物、偶氮二甲酸二 乙酯以及三苯基膦處理醇5-2來製備。疊氮化物5-3可藉由 在一諸如Pt〇2或Pd/C等金屬觸媒上於一諸如EtOAc、 THF、EtOH等適宜溶劑中進行氫化作用來還原。在還原及 保護基團去除之後,得到二胺5-4。對於BOC保護基團, TFA/CH2C12為較佳去除方法;對於CBZ保護基團,於諸如 Pt〇2或Pd/C等金屬觸媒上在一諸如EtOAc、THF、EtOH等 102763.doc -37- 1299991 適宜溶劑中進行氫化作用為較佳去除方法。可使用光氣 ( )或諸如二光氣(Y=〇CCl3)或幾基二喃嗤(γ=味嗤) 等光氣等效物於一諸如二氣甲烷、二氣乙烷、四氫呋喃、 一甲氧基乙烷等溶劑及一諸如三乙胺、二異丙基乙基胺、 Ν-甲基嗎啉等鹼中將二胺5_4環化成咪唑啶酮5_5。對映異 構純產物可通過對掌層析法獲得。
反應圖6
TFA
本發明化合物6-4(其中R、Ra、ρ、Α2、A3以及η係如申 請專利範圍中之定義)可如反應圖6中所示製備。於一諸如 侧氫化鈉、氰基硼氫化鈉、三乙醯氧基硼氫化鈉等還原劑 存在下且在甲醇、乙醇、二氯乙烷、四氫呋喃等物質中用 一經適當取代且受到保護之胺基醛處理6-1或依據Smith, Μ. Β·與 March,J.在「March’s Advanced Organic 102763.doc -38- 1299991
Chemistry」,第 5版,John Wiley與 Sons,New York,第 1187頁至第1189頁(2001)中及其中所引用參考文獻中所述 方法處理6-1可生成6-2,該胺基駿可購得或可藉由已知方 法來製備。用於此轉化之較佳條件係氰基硼氫化鈉存於甲 醇與具有催化作用之醋酸中。將6-2去保護可生成6-3。對 於BOC保護基團,丁 FA/CH2C12為較佳去保護方法。然 後,可使用光氣(Y=C1)或一諸如三光氣(Y=〇cci3)或羰基 二咪唾(Y=咪唑)等光氣等效物於一諸如二氣甲烷、二氯乙 烧、四氫呋喃、二甲氧基乙烷等溶劑中及一諸如三乙胺、 二異丙基乙基胺、Ν-甲基嗎啉等鹼中將二胺6-3環化成咪 唾啶酮6-4。對映異構純產物可使用對掌層析法獲得。 反應圖7
7.5 (CR2)nA2 本發明化合物7-5(其中R、Ra、p、a2、A3以及η係如申 102763.doc -39- 1299991
δ月專利靶圍中之定義)可如反應圖7中所示製備。用一適宜 一奴酸酯或氯甲酸酯處理胺7-1(如反應圖4中所述製備)可 生成7-2。7-2可藉由在二氯甲烷、二氯乙烷、四氫呋喃、 二甲氧基乙燒等物質中且在-諸如三乙胺、二異丙基乙基 胺、N_甲基嗎琳等適宜驗存在下與甲糾醯氯反應而轉化 成疊氮化物7-3。或者,該醇可轉換成一可供選擇之離去 基團,諸如甲苯磺酸基、碘化物、溴化物等。然後,該甲 磺酸基在一諸如DMF、DMpu等適宜溶劑中由諸如NaN〕、 L1N3、B114NN3等疊氮化物源置換。疊氮化物7_3亦可藉由 在THF中用—苯基碟醯基疊氮化物、偶氮二甲酸二乙醋以 及三苯基膦處理醇5-2來製備。當以為苄基時,疊氮化物 7 3可用H2於Pt〇2上(以THF作為一溶劑)還原成胺7-4。藉 由使用一諸如二異丙基醯胺鋰或雙(三甲基甲矽烷基)醯胺 鐘、-鈉、或-卸等適宜驗在一諸如THF、二甲氧基乙嫁、 DMF、DMA等適宜溶劑中可使7-4環化成咪唑啶_7巧。對 映異構純產物可通過對掌層析法獲得。 反應圖8
化合物8-1(如反應圖5、6以及7中所述製備,其中r
Ra、A2、a3、 在一諸如THF P以及係如申請專利範圍中之定義)可藉由 一甲氧基乙烷、DMF、DMA等適宜溶劑 102763.doc -40- 1299991 中、在一諸如二異丙基醯胺鋰或雙(三甲基甲矽烷基)醯胺 鋰、-鈉、或-鉀等適宜鹼存在下用一諸如鹵代烷、烷基甲 苯磺酸酯、烷基甲磺酸酯等適宜烷基化試劑(例如碘代甲 烷)處理而轉化成8-2。 反應圖9
本發明中採用之中間體9-3與9_4(其中Ra、?與人3係如申 請專利範圍中之定義)可如反應圖9中所示製備。一經適當 取代之苯甲腈9-1(如反應圖2中所示製備)可於一諸如乙 醇、丙醇等適宜水溶性醇中與一諸如氫氧化鈉或氫氧化鉀 等驗一起加熱以生成經適當取代之苯甲酸9_2(參見:
Smith,Μ· B·與 March,J·之「March、Advanced Organic Chemistry」,第 5版,John Wiley and Sons,New York,第 Π79頁-第1180頁(2001)以及其中之參考文獻)。於諸如四 氫呋喃等溶劑中使用諸如硼烷等還原劑可將苯甲酸9-2還 原成苯甲醇 9-3(參見·· Smith,Μ· B·與 March, J·之「March’s Advanced 〇rganic chemistry」,第 5版,J〇hn Wiley and Sons,New Y〇rk,第1549頁(2001)以及其中之參考文獻)。 或者,可藉由已知方法(包括用三曱·基曱矽烷基重氮甲烷 102763.doc -41 - 1299991 處理)S日化9_2 ’亚用LlAlH4等將所得酯還原成醇9_3。可使 用諸如三苯基膦及㈣化碳等試劑於諸如二氣甲燒、二氯 乙院等溶劑中將中間體9_3轉化成f基漠(參見:Smith,M. B.與March,j.「March,s or—。ch—心」, 第 5版 ’ John Wiley and Sons,〜Y〇rk,第 5i8 頁第 5i9 頁(2001)以及其中之參考文獻)。
o2n 〇 X H (〇R2)nA2 10-1 反應圖1 〇 R^CH2N〇2
OH R1 (CR2)nA2 10-2 Λ
R1 (CR2)nA2 10-3
O
X HN 〇 R1 (〇R2)nA2 10-4
本發明中間體10-4(其中R、R1、A2' p以及n係如申請專 利範圍中之定義)可如反應圖10中所示藉由與一硝基烷縮 合自一經適當取代之苯甲醛10·;!生戒經取代之硝基醇1〇_2 來製備。此反應可藉由諸如氫氧化鈉等水溶性鹼於諸如乙 醇、甲醇等溶劑中催化。可用諸如阮内鎳、活性碳上鈀或 氧化翻等還原劑在氫氣與水溶性酸存在下於諸如甲醇、乙 醇等醇溶劑中將硝基醇10-2還原成胺基醇10_3(參見:
Langer,〇·等人之Med· C/zem·,2001,p,677 694)。使用諸如光氣(Y=Ci)、三光氣(Y==〇ccl3)或幾基二 味哇(Y=咪唑)等試劑與諸如三乙胺、二異丙基乙基胺等鹼 一起於諸如二氯甲烷、二氣乙烷、四氫呋喃、二甲氧基乙 102763.doc -42- 1299991 烧等溶劑中將胺基醇10-3環化成噁唑烷酮1 〇_4。
反應圖11 A2(CR2)nMgX R1、 〇
(CR2)nA2
N
MeO^NH I
MeO^NH T 11-2
PhMe2SiH TFA Ο
11-4
KOH/MeOH/THF R1 (CR2)nA2
MeO OHRly\cR2)nA2
Y NH 11-3
本發明中間體11-4(其中R、R1、A2、p以及n係如申請專 利範圍中之定義)可如反應圖丨丨中所示製備。使用一格氏 (Grignard)試劑或其他有機金屬試劑(諸如一有機鋰)處理一 胺基酸11-1之N-胺基甲醯_(N-甲氧基甲基)醯胺(其可購 知或藉由已知方法製得)可生成對應的_丨1_2。可用蝴氫化 納或獨氫化鋅於醇溶劑或THF等溶劑中,或可使用諸如苯 基二甲基矽烷等其他還原劑在THF中將該酮還原以生成醇 11-3,該醇可藉由使用諸如KOH等鹼於諸如Me0Ii、EtOH 102763.doc 等與THF、二氧雜環己烷、二甲氧基乙烷等溶劑中環化成 噁唑烷酮11-4。
本發明化合物12_3(其中R、Rl、Ra、a2、A3、p以及 -43- 1299991 係如申請專利範圍中之定義)可如反應圖12中所示製備。 使用諸如雙(三甲基矽烷)胺基化鈉或氫化鈉等鹼於諸如四 氫呋喃、二甲氧基乙烷、乙醚、二甲基曱醯胺、二甲基乙 醯胺等溶劑中,可用苄基溴12-1(其可如反應圖9中所示製 備)將噁唑烷酮12_2(其可如反應圖10與11中所示製備)烷基 化以生成產物12-3。
反應圖13 (RV
本發明化合物13-4(其中R、Rl、Ra、A2、a3、p以及η 係如申請專利範圍中之定義)可如反應圖13中所示製備。 使用諸如雙(三甲基矽烷)胺基化鈉或氫化鈉等鹼於諸如四 氫°夫喃、二甲氧基乙烧、乙醚等溶劑中,用苄基溴13 -1 (其 可如反應圖1中所示製備)將噁唑烷酮13-2(其可如反應圖10 以及11中所示製備)烷基化以生成產物13-3。然後,通過一 採用蛾化物13_3與一經適當取代之芳基-或雜芳基_硼酸、 -獨酸醋或·三烷基錫的經鈀催化交叉偶聯之Suzuki或Stille 102763.doc -44- 1299991 反應或其變體來製備化合物13-4,如Miyaua等人在〔/^济· 95,2457 (1995)及其中所引用之參考文獻中所述以及 Smith,Μ· B.與 March,J·在「March’s Advanced Organic Chemistry」,第 5版,John Wiley and Sons,New York,第 868頁至第869頁(2001)中及其中所引用之參考文獻中所 述 反應圖14
(Ra)P
A3 CHO 14-2
(Ra)P
14-1 A3 戴斯-馬 丁過碘烷 ❿
CHoOH
Λ 1. Znl2l TMSCN, CH2CI2 2. LiA旧4, Et20
14-3 1. NaH, DMF 2. Br—(CR2)nA2
本發明化合物14-5(其中R、Ra、A2、A3、p以及n於申 請專利範圍中定義)可如反應圖14中所示製備。苯曱醇14-1 可購得或可依據反應圖9中概述之程序製備。14-1與戴斯-馬丁(Dess-Martin)過碘烷反應可生成對應之苯曱醛14-2。 亦可採用用來將第一羥基氧化成醛之其他方法,例如 Swern氧化反應條件、過釕酸四丙基銨、氯鉻酸°比σ定鑌、 102763.doc -45 - 1299991 三氧化硫-吡啶等。2-胺基-1-苯基乙醇14·3可自14-2通過對 應之經石夕烷化氰醇藉由用三甲基甲矽烷基氰化物與具催化 作用之碘化鋅處理並隨後用氫化鋰鋁等還原劑還原來製 備。或者,2-胺基-1-苯基乙醇14-3可自14-2通過對應之氰 醇藉由氰化鉀處理並隨後加以還原來製備。可使用諸如光 氣(Y C1)、二光氣(Y=〇cci3)或幾基二11米唾(Υ=味σ坐)等試 與堵如二乙胺、一異丙基乙基胺等驗一起於諸如二氯甲 烧、一氯乙烧、四氫吱喃、二甲氧基乙烧等溶劑中將2_胺 基-1-本基乙醇14-3環化成α惡嗤烧酮14-4。嚼嗤燒_ μ-4可 用烷基、雜烷基、芳基或雜芳基溴化物、使用諸如雙(三 曱基矽烷)胺基化鈉或氫化鈉等鹼於諸如四氫呋喃、二甲 氧基乙烧、乙醚等溶劑中烷基化以生成產物14_5。對映異 構純產物可通過對掌層析法獲得。 反應圖15 R1n〇2,
H2, RaNi, aq. HC〇2H
(HO)2B〆 3 Pd(OAc)2> K2C03, H20-丙酮 3
102763.doc -46- 1299991 本發明化合物15-6(其中r、ri、Ra ' A2、A3、p以及n 係如申睛專利範圍中之定義)可如反應圖丨5中所示來製 備。醛15-1可購得或依據反應圖1中概述之方法製備。 與一硝基烷縮合可生成經取代之硝基醇丨5_2。此反應可由 諸如氫氧化鈉等水溶性鹼於諸如乙醇、甲醇等溶劑中催 化。可用諸如阮内鎳、活性碳上鈀或氧化鉑等還原劑在氫 氣與水溶性酸存在下於諸如甲醇、乙醇等醇溶劑中將硝基 醇15-2還原成胺基醇15_3(參見:〇·,等人, &罐g· Md. CTz㈣.,2001,p,677_694)。可使用諸如光 氣(Y C1)、二光氣(y=qCCi3)或緣基二咪嗤(γ=咪嗤)等試 劑與諸如三乙胺、二異丙基乙基胺等鹼一起於諸如二氯甲 烷、二氯乙烷、四氫呋喃、=甲氧基乙烷等溶劑中將胺基 醇15-3環化成噁唑烷酮15_4。通過一採用碘化物15_4與一 經適當取代之芳基-或雜芳基-硼酸、_硼酸酯或·三烷基錫 化合物之經鈀催化交叉偶聯的Suzuki或Stiiie反應或其變體 來製備化合物喔嗤烧酮i 5·5,如Miyaua等人在㈤队及以 95, 2457 (1995)中及其中所引用之參考文獻中所述,以及 如Smith,Μ· B.與March,厂在「M⑽h,s杨⑽⑻叫― Chemistry」,第 5版,John Wiley and s〇ns,,第 868頁至第869頁(腦)及其中所引用之參考文獻中所述。 °惡德同15_5可用烧基、雜燒基、芳基或雜芳基演化物、 使用諸如雙(三甲基石夕烧)胺基化納或氫化納等驗於諸如四 氫口夫H氧基乙烧、乙鱗等溶劑中燒基化以生成產物 15-6。對映異構純產物可通過對掌層析法獲得。 102763.doc -47- 1299991
16-1 反應圖16
本發明化合物16-5(其中R、Rl、Ra、A2、A3、p以及η 係如申請專利範圍中之定義)可如反應圖16中所示製備。
駿16_1可購得或依據反應圖1中概述之方法製備。丨…丨與對 掌醯基噁唑烷酮縮合可生成醛醇加合物丨6_2,如於
Evans,D.A·等人·之 J. C/zem. 6W.,2002,7以,392_3 中所述。對掌iV-醯基ϋ惡嗤烧酮可購得或如在Ager,d.J·;
Allen,D.A· ; Schaad,D.R· 以 1996,1283-5 中所述 製備。化合物16-2可水解成對應的酸,然後用二苯基磷參 氮鹽(diphenylphosphorazidate)與三烧基胺驗處理以實施〆 克爾蒂斯(Curtins)重排反應,生成對掌噁唑烷|同16-3。通 過一採用碘化物16_3與一經適當取代之芳基或雜芳基-湖 102763.doc -48- 1299991 酸、-硼酸酯或-三燒基錫化合物之經妃催化交叉偶聯的 Suzuki或Stille反應或其變體來製備噁唑烷酮16-4,如 Miy aura 等人在 C/^m. 95,2457 (1995)中及其中所引 用參考文獻中所述,以及如Smith,Μ· Β·與March,J·在 「March’s Advanced Organic Chemistry」,第 5版,John Wiley and Sons,New York,第 868 頁至第 869 頁(2001)中及 其中所引用參考文獻中所述。噁唑烷酮16-4可用烷基、雜 烷基、芳基或雜芳基溴化物、使用諸如雙(三甲基矽烷)胺 基化鈉或氫化鈉等鹼於諸如四氫呋喃、二甲氧基乙烷、乙 醚等溶劑中烷基化以生成產物16-5。或者,噁唑烷酮16-3 可使用適宜溴化物來烷基化以生成化合物16-6,其與經適 當取代之芳基或雜芳基-硼酸、-硼酸酯或-三烷基錫化合物 的Suzuki或Stille反應或其變體以生成產物16-5。 實例1
Φ 2-胺基-5-(三氟甲基)笨甲腈
將100克(0.348莫耳)4_胺基-3-蛾代三氟甲苯、40克CuCN 與750毫升DMF裝至一 2_公升燒瓶中。將該混合物加熱至 回流並隨後維持在回流狀態1小時。冷卻反應物並倒入3公 升έ 3 0 0宅升/辰氫氧化銨之水中。向此混合物中添加1公升 CHaCh °然後通過矽藻土過濾該混合物。分層後用ch2C12 反萃取水性層。合併有機萃取物,並在低壓下去除溶劑。 將殘留物溶解於i.5公升醚中,並用1 N氫氧化銨、亞硫酸 102763.doc -49· 1299991 氣納水溶液、1 N HC1溶液以及鹽水洗滌所得溶液。經由 無水MgS〇4乾燥該溶液,並通過其頂部含一層MgS04之矽 膝检基加以過濾。用·5公升醚洗滌該栓塞。合併醚溶液, 並濃縮成750毫升,且使之在室溫下靜置。2天後,收集得 到之固體,用己烷洗滌並在低壓下乾燥以生成2_胺基乃_ (三氟甲基)苯甲腈。1H NMR (CDC13, 500 ΜΗζ) δ 7.68 (s, 1Η), 7.58 (d3 8.5 Hz, 1H), 6.81 (d, 8.5 Hz, 1H)5 4.80 (br s,2H) 〇 • 實例2
2-蛾_5_(三氟甲基)苯甲腈 在35t下向2-胺基-5-(三氟甲基)苯甲腈(151克)與二碘 甲烷(24毫升)溶於乙腈(150毫升)的溶液中逐滴滴加亞硝酸 弟二丁自曰(21宅升)。在添加期間,將反應維持在%至3 5 °C。該反應持續30分鐘,然後加熱至60°c,維持3〇分鐘。 • 冷卻反應混合物,用醚稀釋並用水洗滌2次,用亞硫酸氫 納水溶液、水並隨後用鹽水各洗滌2次。使該溶液經由無 水MgS〇4乾燥,通過一矽膠栓塞過濾並隨後濃縮以得到 100克紅色油。藉由矽膠層析法依序用己烷、3:1己烧 /CHzCh以及1:1己烷/CHzCl2洗提來純化該產物以生成2_碘· 5-(三氟甲基)苯甲腈。1H NMR(CDCl3,500 ΜΗζ) δ 8.10 (d,J - 8.5 Ηζ,1Η),7.85 (d,J = 1·8 Ηζ,1Η),7_52 (dd,J = 8·5, 1.8 Hz,1H)。 102763.doc •50- 1299991 實例3
5’-異丙基_2’_甲氧基_4_(三氟甲基)聯苯基_2_甲腈 向2务5·(三I甲基)笨甲腈(2.G克,6.7毫莫耳)與(5-異 丙基-2-甲氧苯基)爛酸(1.6克,8·4毫莫耳)溶於二甲基乙二 醇(30.4耄升)的溶液中添加2]^1^2(:〇3(6.8毫升)、乙醇 (9.6毫升)以及水(1〇毫升)。該溶液用氮氣除氣2分鐘。添 _ 加Pd(PPh3)4(774毫克,〇·67毫莫耳),且該溶液再用氮氣 除氣2分鐘。將該溶液等分至2個4〇毫升微波管中。每管用 氮氣除氣1分鐘、密封並置於一微波反應器中。瓦數設置 為200瓦一直到溫度達到1 5〇它,且然後將溫度於丨5〇。〇維 持1 〇分鐘。然後將該等管冷卻至室溫,合併後倒入H2〇(5〇 毫升)中,並用EtOAc( 100毫升)萃取。有機層用鹽水(5〇毫 升)洗滌,經由Na2S〇4乾燥,過濾並濃縮。使用15% CH2C12/己烷藉由快速層析法實施純化可生成淺黃色油狀 _ 5’-異丙基-2’-甲氧基_4_(三氟甲基)聯苯基-2-甲腈。R/ = 0.65 (25% EtOAc/己烷)。4 NMR (CDC13,500 ΜΗζ) δ 7.97 (s5 1H)5 7.85 (d, 8.0 Hz, 1H)5 7.63 (d5 J= 8.0 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz5 1H), 7.12 (d, J = 2.0 Hz3 1H), 6.97 (d3 J = 8.5 Hz, 1H)5 3.82 (s, 3H), 2.93 (m, 1H), 1·27 (d,7·0 Hz,6H)。 實例4 102763.doc -51 - 1299991
MeO. nh2 l-[5’-異丙基I甲氧基三氟甲基)聯苯基j基】甲胺 將5 —異丙基~2’-甲氧基-4-(三氟甲基)聯苯基_2_甲腈 (996.2¾克’ 312毫莫耳)溶解於叱〇㈤毫升)中並冷卻至〇 C。藉由注射器逐滴滴加LAH(12.49毫升溶於Et2〇中之! M 溶液,I2·49毫莫耳)。於〇°C攪拌1〇分鐘之後,將反應物加 _ 熱至室溫並於室溫攪拌6小時。然後,藉由緩慢逐滴滴加 1,5宅升H2〇(氣體劇烈釋放)、接著滴加1.5毫升30% NaOH、再接著添加3〇毫升h2〇來淬滅反應。用5χ2()毫升 CH2C12洗滌得到之凝膠狀沉澱;有機洗滌物經由Na2S〇4 乾燥、經過濾並濃縮。使用含〇·1% Et3N之2% MeQH/CH2C12藉由快速層析法純化殘留物可生成1-[5’-異 丙基-21-甲氧基-4-(三氟甲基)聯苯基-2-基]甲胺。R/= 〇·30 (10% MeOH/CH2Cl2)。LCMS = 324·3 (M+l)+ 〇 4 NMR • (CDC13, 500 MHz) δ 7.77 (s,1H),7.55 (d,= 6.8 Ηζ,1Η), 7.32 (d, J = 7.8 Hz, 1H), 7.25 (dd, J = 8.35 2.1 Hz5 1H)? 7.00 (d, 2.1 Hz, 1H), 6.92 (d? J= 8.4 Hz, 1H), 3.66-3.74 (m,5H),2.91 (m,1H),1.26 (d,·/= 6·9 Hz,6H)。 實例5 102763.doc -52- 1299991
4-[3,5-雙(三氟甲基)苯基】-3-{[5f-異丙基-2,-甲氧基_4-(三 氟甲基)聯苯基-2-基】甲基卜1,3-噁唑烷-2_酮 步驟A:甲基[3,5-雙(三氟甲基)苯基](羥基)乙酸酯 | 向[3,5-雙(三氟甲基)苯基](羥基)乙酸(510毫克,1.77毫 莫耳)溶於苯(10毫升)的溶液中添加MeOH(1.5毫升),之後 添加(三甲基甲石夕烧基)重氮甲烧(1·〇6毫升溶於己烧之2 Μ 溶液,2·12毫莫耳)。10分鐘後,用數滴h〇Ac淬滅反應(一 直添加直到黃色消失為止)。濃縮該反應物並使用丨〇至80〇/〇 之EtO Ac/己烧藉由快速層析法加以純化,生成甲基[3, %雙 (三氟曱基)苯基](羥基)乙酸酯。lH NMR (CDC13,500 MHz) δ 7·94 (s,2H),7·85 (s,1H),5.32(s,1H),3·83 (s,3H), φ 3.68 (bs, 1Η) 〇 步驟Β:甲基[3,5-雙(三氟甲基)苯基】(溴)乙酸酯 將甲基[3,5-雙(三氟甲基)苯基](羥基)乙酸酯(3〇〇毫克, 0.993毫莫耳)溶解在CH2Cl2(1〇毫升)中。將該溶液冷卻至〇 C,並添加CBr4(659毫克,1986毫莫耳),之後添加pph3 (521毫克,1986¾莫耳)。;[小時後,將反應物加熱至室溫 並於室溫下擾拌1小時。m過一含CH2Cl2的短石夕膠检塞過 濾此反應物。濃縮所得濾液並使用5% Et〇Ac/己烷藉由快 102763.doc -53 - 1299991
速層析法來純化殘留物,生成甲基[3,5_雙(三氟甲基)苯 基](溴)乙酸酯。R/ = 0·24 (5〇/〇 Et〇Ac/己烷)。lH NMR (CDCI3,500 MHz) δ 8.02 (s,2H),7.87 (s,1H),5·41 (s, 1Η),3·83 (s5 3Η)。 步驟C :甲基[3,5·雙(三氟甲基)苯基】({[5,_異丙基-2,_甲氧 基-4-(三氟甲基)聯苯基基】甲基}胺基)乙酸酯 向έ甲基[3,5-雙(二氟甲基)苯基](漠)乙酸酉旨(2 37.7毫 克,0.651毫莫耳)之燒瓶中添加溶於CH2Cl2(4毫升)中之卜 • [5匕異丙基甲氧基_4_(三氟甲基)聯苯基-2-基]六亞甲基 四胺(102.1¾克,0.316毫莫耳)。將此反應物於室溫下擾 拌5小時並隨後用EtOAe(5〇毫升)稀釋。用水與鹽水(各15 毫升)洗條該有機溶液。有機萃取物經由Na2S〇4乾燥,經 過遽並濃縮。殘留物藉由快速層析法(5至15〇/〇 Et〇Ac/己 烧)純化可生成曱基[3,5-雙(三氟甲基)苯基κ{[5,-異丙基-2*-甲氧基-4-(三氟曱基)聯苯基_2_基]甲基}胺基)乙酸酯。 R,= 0.33 (15% EtOAc/ 己烧)。LCMS = 608·4 (M+l)+ 〇 4 —NMR (CDC13, 500 MHz) δ 7·76-7·79 (m,3H),7.62 (s,1H), 7.56 (d,7·8 Ηζ,1Η),7.31 (d,·/= 7.8 Ηζ,1Η),7.23 (dd, 8.2,1.9 Hz,1H),6.96 (m,1H),6.89 (d,8·5 Hz,1H), 4.30 (m,1H),3.54-3.70 (m,8H),2·87 (m,1H),1.21-1.23 (m,6H)。 步驟D : 2-[3,5_雙(三氟甲基)苯基卜2-g[5,_異丙基甲氧 基-4-(三氟甲基)聯苯基-2-基]曱基}胺基)乙醇 將甲基[3,5-雙(二氟曱基)苯基](《[5’_異丙基_>2,-曱氧基_4- 102763.doc -54- 1299991 (三氟甲基)聯苯基-2-基]甲基}胺基)乙酸酯(13_2毫克, 0.0217毫莫耳)溶液溶解在Et2〇(1.5毫升)中並冷卻至〇°C。 藉由注射器逐滴滴加LAH(108.5微升之1 Μ於Et2〇溶液, 0.1085毫莫耳)。將反應物加熱至室溫並於室溫下攪拌1小 時。然後藉由添加H20(100微升)、接著添加1 N NaOH(100 微升)、再接著添加H20(300微升)來淬滅反應。所得凝膠 狀沉澱用CH2C12洗滌數次。通過一含2% MeOH/CH2Cl2之 矽膠栓塞過濾所得有機洗滌物,並將濾液濃縮。使用25% EtOAc/己烷藉由PTLC純化殘留物生成2-[3,5-雙(三氟甲基) 苯基]-2-({[5·-異丙基-2’-甲氧基-4-(三氟曱基)聯苯基-2-基] 甲基}胺基)乙醇。R,= 〇·27 (25% EtOAc/己烷)。LCMS = 580.4 (M+l)+。lH NMR (CD2CI2, 50Q ΜΗζ) δ 7.79 (s,1H), 7.75 (s5 2H)5 7.63-7.68 (m3 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.31 (d,/= 7.8 Hz,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,6.8 Hz,6H) 〇 步驟E : 4·[3,5_雙(三氟曱基)苯基卜3-{[5,異丙基-2匕甲氧 基-4-(二氟甲基)聯苯基-2-基】甲基卜ι,3·«惡嗤烧 向光氣(21微升溶於甲苯之2〇%溶液,約〇〇535毫莫耳) 溶於CH2Cl2(〇.5毫升)的溶液中添加溶mCH2C12(〇5毫升) 之2-[3,5-雙(二氟甲基)笨基]-2_(([5,·異丙基-2,_甲氧基_心 (三氟曱基)聯苯基-2-基]甲基}胺基)乙醇(31毫克,〇〇〇535 宅莫耳),之後添加DIPEA(19微升,0.107毫莫耳)。攪拌5 分鐘後,將反應物倒入水(1毫升)中,並用Et〇Ac(2〇毫升) 102763.doc -55- 1299991 萃取該混合物。有機萃取物用水、飽和NaHC〇3以及鹽水 (各5¾升)洗滌。然後,有機層經由Na2S〇4乾燥,過濾並 濃縮。殘留物藉由PTLC純化,生成4-[3,5_雙(三氟曱基)苯 基]_3-{[5’_異丙基-2’-甲氧基-4-(三氟甲基)聯苯基_2_基]甲 基}-1,3-口惡唾烧-2-酮。R/ = 〇·27 (25% EtOAc/己烷)。LCMS =606.3 (M+l)+。4 NMR (CD2C12, 500 MHz)(觀察到一些 峰加倍,滯轉異構體出現於1: i比率中)3 7.84 (s,1H), 7.19-7.60 (m, 6H), 6.80-6.87 (m, 2H), 3.84-4.68 (m5 5H), _ 3·68 與 3·64 (2個單峰,3H),2·82 (m,1H),1·17-1·21 (m, 6H) 〇 實例6
φ 5_[3,5·雙(三氟甲基)苯基]_3·{[5,_異丙基-2,_甲氧基_4-(三 氣曱基)聯本基-2-基】甲基卜1,3 -1*惡嗤烧嗣 步驟A: 2-[3,5-雙(三氟曱基)苯基]環氧乙烷 將NaH(1.09克之60% NaH,27.27毫莫耳)置於一乾燥燒 瓶中。添加DMSO(90毫升)之後添加碘化三曱基氧錶(7.0 克,31· 82毫莫耳)。攪拌反應物5分鐘,然後以溶於DMSO (15毫升)溶液之形式添加3,5-雙(三氟甲基)苯甲醛(1.5毫 升,9.09毫莫耳)。於室溫下攪拌反應物1小時,然後倒入 冰/水(300毫升)中。用戊烷(3x150毫升)萃取該混合物。合 102763.doc -56- 1299991 併戊烷萃取物並通過一含10% Et2〇/戊烷之短矽膠栓塞加 以過濾。濃縮濾液,並使用10% EhO/戊烷藉由快速層析 法來純化殘留物,生成2-[3,5-雙(三氟甲基)苯基]環氧乙 烷。R/==0.42 (10% Et2〇/戊烷)。1H NMR (CDC13, 500 MHz) 7.82 (s5 1H)5 7.74 (s5 2H), 3.99 (dd5 3.9, 2.5 Hz3 1H),3.23 (dd,5.2, 4.1 Hz,1H),2·79 (dd,5.5, 2.5
Hz,1H)。 步驟B : 1_[3,5-雙(三氟甲基)苯基】_2_({[5,_異丙基-2,-甲氧 修 基-4-(二敗甲基)聯苯基-2-基]甲基}胺基)乙醇 將卜[5^異丙基-2’-甲氧基-4-(三氟甲基)聯苯基-2-基]六 亞甲基四胺(300毫克,0·929毫莫耳)與2-[3,5-雙(三氟甲基) 苯基]環氧乙烷(297毫克,1·161毫莫耳)溶於2-丙醇(9毫 升)的溶液加熱至回流並維持15分鐘,然後冷卻至室溫。 將該溶液濃縮,並使用10%至80%的EtOAc/己烷藉由快速 層析法純化殘留物,生成1-[3,5-雙(三氟甲基)苯基]-2-({[51-異丙基-2*-甲氧基-4-(三氟甲基)聯苯基-2-基]曱基}胺 •基)乙醇。R/=〇.24 (25% EtOAc/己烷)。LCMS = 580.3 (M+l)+。NMR (CDC13, 500 ΜΗζ) δ 7.75-7.76 (m,3H), 7·69 (s,1H),7·58 (d,/ = 7·8 Hz,1H),7·34 (d,J = 7·7 Hz, iH),7·25 (m,1H),6·98 (bs,1H),6.92 (d,8.5 Hz,1H), 4.62 (m? 1H), 3.65-3.82 (m, 5H), 2.89 (m, 1H)? 2.79 (dd, J =12.4,3.0 Hz,1H),2·48 (m,1H),1.23 (d,J = 6.8 Hz, 6H) 0 步驟C : 5_[3,5-雙(三氟甲基)苯基]-3-{[5,-異丙基-2,-甲氧 102763.doc -57- 1299991 基-4-(二氟甲基)聯苯基-2-基】甲基}-1,3·噁唑烧_2-酮 向1 [3,5雙(二氟甲基)苯基]_2_({[5’·異丙基氧基· 4-(二氟甲基)聯苯基-2-基]甲基}胺基)乙醇(31.9毫克, 0.0551宅莫耳)溶於CH2C丨2(5毫升)的〇 t溶液中添加 DIPEA(67微升,0.386毫莫耳),之後添加三光氣(82毫 克,0.0276毫莫耳)。將所得反應物於攪拌3〇分鐘。然 後將反應物倒入飽和NaHC03(15毫升)中,並用EtOAc(50 t升)萃取該混合物。用鹽水(15毫升)洗滌有機層,經由 _ Na2S〇4乾爍’過濾並濃縮。藉由快速層析法(20% EtOAc/ 己烷)純化殘留物可生成5-[3,5-雙(三氟甲基)苯基>3_{[5,_ 異丙基-2’-甲氧基-4·(三氟甲基)聯苯基_2-基]甲基卜丨,弘噁 唑烷-2-酮。1^=0.32 (25% EtOAc/己烷)。LCMS = 606·3 (M+l)+。1Η NMR (CD2C12, 500 MHz)(滞轉異構體出現於 1:1比率中,一些峰加倍)5 7.90(8,111),7.77(8,211),7.57- 7.62 (m,2H),7.37 (d,J = 8·0 Hz,1H),7.27 (m,1H),6.98 (s,1H),6.93 (dd,/= 8.4, 3.2 Hz,1H),5.42-5.53 (m,1H), 4· 1 5-4.59 (m,2H),3.72與 3.73 (2個單峰,3H),3·〇5_3.65 (m, 2Η),2·88 (m,1Η),1.19-1.23 (m,6Η)。 使用15%的IPA/庚烧與一 AD對掌管柱藉由對掌性Hplc 能夠分離2種對映異構體。 實例7 102763.doc -58- 1299991
3-{[5’-異丙基_2,_曱氧基_4_(三氟甲基)聯苯基_2_基】甲基卜 5-吨啶-2-基-i,3_噁唑烷-2-酮 步驟A : 2-(U5,-異丙基-2,-甲氧基-4-(三氟甲基)聯笨基_2_ _ 基】曱基}胺基)-l-n比啶_2_基乙醇 將1·[5’-異丙基_2,_甲氧基_4_(三氟甲基)聯苯基_2_基]六 亞甲基四胺(300毫克,0.929毫莫耳)與2-環氧乙烷_2•基〇比 啶(640毫克)[藉由2_吡啶甲醛與NaH及碘化三甲基氧鋅於 DMSO中之反應來製備]溶於孓丙醇(9毫升)的溶液加熱至回 流,維持5小時,並隨後冷卻至室溫。將該溶液濃縮,並 使用含0.5% Et3N之50%至1〇〇〇/0 Et0Ac/己烷藉由快速層析 法來純化殘留物,生成2_({[5,-異丙基-2,-甲氧基_4_(三氟 _ 甲基)聯苯基基]甲基}胺基)_;[_吡啶_2_基乙醇。藉由 LCMS分析表明,期望產物受到若干種少量雜質污染。此 物質未經進一步純化或分析即用於下步反應。 步驟B :苄基(2-羥基-2-吡啶_2_基乙基){[5,-異丙基_2,_甲氧 基_4-(三氟甲基)聯苯基基】甲基}胺基甲酸酯 於室溫及N2下,藉由套管將(phcH2〇CO)2〇(103毫克, 0·360毫莫耳)溶於無水CH2Cl2(2毫升)的溶液添加至一經攪 拌之2-({ [5’-異丙基-2’-甲氧基-4-(三氟甲基)聯苯基-2-基]甲 102763.doc -59- 1299991 基}胺基)-1-吡啶-2_基乙醇(16〇毫克,〇.36〇毫莫耳)溶於無 水CH2C12(10毫升)的溶液中。將所得反應物於室溫下攪拌 2小時’並在真空中濃縮以生成粗產物。此產物藉由快速 層析法(Si ’ 25XI60毫米,溶於己烷中之Et〇Ac的梯度為〇 至50%)純化以生成苄基(2•羥基_2_吡啶基乙基,·異丙 基甲氧基-4_(三氟甲基)聯苯基-2-基]甲基}胺基甲酸 _。R/ = 0·63 (50% EtOAc/ 己烷)。LCMS 計算值= 579.25 ;試驗值=:579.2 (M+l)+。 • 步驟C : 3气丨5,_異丙基-2,-甲氧基_4-(三氟甲基)聯苯基-2-基】甲基}_5_吡啶_2_基-:1,3-噁唑烷酮 於室溫及N2下,將雙(三甲基甲矽烷基)醯胺鉀(464微升 溶於甲苯之〇·5 Μ溶液,0.232毫莫耳)溶液逐滴滴加至一經 攪拌之苄基(2-羥基-2-吡啶-2-基乙基){[5,-異丙基-2,-甲氧 基-4-(三氟甲基)聯苯基-2_基]甲基}胺基甲酸酯(134.3毫 克’ 0·232毫莫耳)溶於無水THF(10毫升)的溶液中。於室溫 下攪拌1小時後,用飽和NH4C1(10毫升)淬滅該反應並用 ® EtOAc (3x20毫升)萃取。經合併之萃取物經乾燥(Na2S〇4) 並在真空中濃縮以生成粗產物。此產物藉由快速層析法 (Si,25XI60毫米,溶於己烷中之EtOAc的梯度為0至70%) 以生成3-{[5,_異丙基-2,-甲氧基-4-(三氟甲基)聯苯基_2_基] 甲基}-5_ 吡啶-2-基 _1,3_ 噁唑烷·2_ 酮。R/=〇.58 (50% EtOAc/ 己烷)。LCMS計算值=471.19 ;試驗值=471.2 (M+1)+。 實例8 102763.doc -60- 1299991
MeO, f3c"An^^co2h 5’-異丙基甲氧基-4-(三氟甲基)聯苯基-2-羧酸
使5’_異丙基_2,_甲氧基·4_(三氟甲基)聯苯基_2_甲腈(727 毫克,2.28毫莫耳)與ΚΟΗ(767毫克,13.7毫莫耳)溶於水 (7.70毫升)與異-Pr〇H(iL55毫升)的溶液在一密封管中經受 微波輻照(300瓦130°C,4小時)。將該反應混合物在真空中 濃縮以去除異-PrOH。用水(50毫升)稀釋得到的水性漿液 並用EtOAc(50毫升)萃取。有機萃取物經乾燥(Na2s〇4)& 在真空中濃縮生成5,-異丙基-2,-甲氧基-4-(三氟甲基)聯笨 基-2-曱醯胺。水性層用濃HC1酸化並用EtOAc(3x5〇毫升) 萃取。經合併之有機萃取物經乾燥(Na2S〇4)並在真空中濃 縮以生成一無色固體狀5·_異丙基-2,-甲氧基_4-(三氟甲 聯苯基-2-羧酸。4 NMR (CDC13, 500 MHz) δ 8.01 (s,1Ή)
7·71 (d,7·8 Ηζ,1Η),7·41 (d,《/= 7.8 Ηζ,1Η),7·14 (d /= 8.1 Ηζ,1Η),7·04 (s,1Η),6.77 (d,/= 8·1,1Η),3·68 (s 3Η),2·84 (七重峰= 6·7 Ηζ,1Η),1·19 (d,= 6·7 Ηζ ’ 6Η)。 實例9
[5f-異丙基- 2^ -甲氣基- 4- (二氣甲基)聯苯基_2_基】甲醇 於室溫及Ν2下,將硼烷溶於THF之溶液(1 μ,859微 102763.doc -61 - 1299991 升,0.859¾莫耳)逐滴滴加至一經攪拌之5,_異丙基_2,-甲氧 基-4-(二氟甲基)聯苯基_2-魏酸與5’_異丙基_2,_甲氧基 (三氟甲基)聯苯基-2·甲醯胺(3:1,96.8毫克,〇·286毫莫耳) 溶於無水THF的溶液中。該反應物於室溫下檀拌3小時並 用水(10毫升)小心淬滅。用EtOAc(3x20毫升)萃取該混合 物’且合併之萃取物用鹽水洗滌,年乾燥(Na2§〇4)並在真 空中丨辰縮以生成粗產物。該產物藉由快速層析法(y, 125x160毫米,溶於己烷中之EtOAc的梯度為〇至30%)以生 • 成一無色油狀[5’_異丙基-2’-甲氧基-4-(三氟甲基)聯苯基_2_ 基]甲醇。R/= 0.27 (10% EtOAc/己烷)。4 NMR (CDC13, 500 ΜΗζ) δ 7.89 (br s,1H),7.62 (dd,/= 8.0,1·3 Hz,1H), 7.36 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 8.5, 2.3 Hz, 1H), 7.03 (d,/ = 2.3 Hz,1H),6.96 (d,J = 8.5,1H),4·51 (m5 2H),3.74 (s,3H),2.93 (七重峰,/ = 7.0 Hz,1H),2.51 (s, 1H),1.29 (d,J = 7.0 Hz, 6H) 〇 實例10
2-(溴甲基)-5,-異丙基·2’_甲氧基-4-(三氟甲基)聯苯基 於〇°C及N2下,將CBr4(112毫克,0.211毫莫耳)與 Ph3P(55毫克,0.211毫莫耳)相繼添加至一經攪拌之[5,-異 丙基-2·-甲氧基-4-(三氟甲基)聯苯基-2-基]甲醇(57.1毫克, 0.176毫莫耳)溶於無水CH2Cl2(l毫升)的溶液中。該溶液於 102763.doc -62- 1299991 室溫下攪拌1小時,並在真空下將該反應物濃縮以生成粗 產物。該產物藉由快速層析法(si,12xl60毫米,溶於己 烷中之EtOAc的梯度為〇至2〇%)純化以生成一無色油狀2_ (>臭甲基)-5’-異丙基-2’·甲氧基_4-(三氟甲基)聯苯基。R/ = 0.95 (20% EtOAc/己烷)。LCMS計算值=387 〇5 ;試驗值 =387.0 (M+l)+ 〇 1H NMR (CDC13j 500 MHz) δ 7.83 (br s, 1H), 7.60 (dd, J = 8.0, 1.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.29 (dd? J = 8.5, 2.3 Hz, 1H), 7.14 (d, J = 2.3 Hz, 馨 1H), 6.95 (d, J = 8.5, 1H), 4.45 (d, J = 10.6 Hz, 1H), 4.33 (d,J = 10.6 Hz,1H),3.76 (s,3H),2.94 (七重峰,6_9 Hz,1H),1.29 (d,/= 6·9 Hz,6H) 〇
實例11 OH
1-(4-甲基苯基)-2-硝基乙醇 用10%的NaOH水溶液(m/v)(1.14毫升,2·84毫莫耳)處理 一經攪拌之4-甲基苯甲醛(325毫克,319微升,2 71毫莫 耳)與硝基甲烧(531微升,9.89毫莫耳)溶於無水Et〇H(20毫 升)的0C溶液,攪拌1小時並用2。/0乙酸水溶液(m/v)(854毫 升’ 2.84毫莫耳)處理。該反應物於室溫下攪拌1小時,然 後分為水層(50毫升)與EtOAc層(50毫升)。水性層用 EtOAc(2x50毫升)萃取,且經合併之有機萃取物用飽和 NaHC〇3(50毫升)與鹽水(5〇毫升)洗務,經乾燥(Na2S〇4)並 在真空中濃縮以生成一無色油狀1_(4_甲基苯基)_2_硝基乙 102763.doc -63- 1299991 醇。lH NMR (CDC13, 500 MHz) δ 7·28 (d,J = 8·1 Hz,2H), 7·21 (d5 J = 8.1 Hz, 2H), 5.42 (dt, J = 9.6, 3.3 Hz, 1H)? 4.60 (dd,《/= 13.3, 9·7 Hz,1H),4.49 (dd,《/= 13.3, 3.1 Hz, 出),2.79 (d,3·7, 1H),2.36 (s,3H)。
實例12 OH
2-胺基-1-(4-甲基苯基)乙醇 於室溫及15 psi H2下,將存於一 1-(4-甲基苯基)-2-硝基 乙醇(50毫克,0.276毫莫耳)溶於無水EtOH(l毫升)之溶液 中的10% Pd/C(24毫克)懸浮液攪拌過夜。該反應混合物通 過一矽藻土墊層過濾,且在真空下濃縮所得濾液以生成一 油狀2-胺基-1-(4•曱基苯基)乙醇。LCMS計算值=152.10 ; 試驗值=152 (M+l)+。lH NMR (CDC13,500 ΜΗζ) δ 7.20 (d5 J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 4.57 (dd? J = 7.9, 3.9 Hz,1H),2·86 (dd5 12.7, 3·9 Hz,1H),2.76 (dd, ^ 12·7, 7·9 Hz,1H),2.33 (s,3H)。 實例13
5-(4-甲基苯基)-i,3-噁唑烷-2-酮 於〇°C及N2下,將二異丙基乙基胺(181毫克,244微升, 1.40¾莫耳)與三光氣(138毫克,〇·466毫莫耳)相繼添加至 102763.doc -64- 1299991 一經攪拌之2-胺基_l-(4-甲基苯基)乙醇(35·2毫克,〇·233毫 莫耳)溶於無水CH2Cl2(22毫升)之溶液中。將該反應物於〇 °C下攪拌1小時,然後在真空下濃縮成約5毫升體積。用水 (50毫升)稀釋該混合物並用EtOAc(3x50毫升)萃取。經合併 之有機萃取物經乾燥(Na2S〇4)並在真空下濃縮以生成粗產 物。此產物藉由快速層析法(Si,12X 160毫米,溶於己烧 中之EtOAc的梯度為0-80%)純化以生成5-(4-甲基苯基)-1,3-噁唑烷-2-酮。1^=0.41 (50% EtOAc/己烷)。LCMS計算值= 178.08;試驗值=178.1 (M+l)+。lH NMR (CDC13,500 MHz) δ 7.25 (d3 J = 7.4 Hz, 2H), 7.19 (d? J = 7.4 Hz, 2H), 6.69 (br s,1H),5·55 (t,J = 7.8 Hz, 1H),3_93 (t,J = 8·6 Hz,1H),3.52 (t,8·1 Hz,1H),2·35 (s,3H)。 實例14
3-{[5,-異丙基_2,_甲氧基_4-(三氟甲基)聯苯基_2_基]甲基}_ 5-(4-甲基苯基)-l,3-噁唑烷_2_酮 於室溫及N2下,將氫化納(6.4毫克存於礦物油中之60〇/〇 分散液,〇·161毫莫耳)添加至一經攪拌之5_(‘甲基苯基)_ 1,3-噁唑烷-2-酮(37.7毫克,0.0973毫莫耳)溶於無水THF(1 毫升)的溶液中。攪拌該反應物30分鐘,並藉由套管添加 102763.doc -65- 1299991 一 2-(溴曱基)-5·-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基 (19·0毫克,0.107毫莫耳)溶於無水THF(2毫升)的溶液。該 反應物於室溫下攪拌3天。用飽和NH4C1(10毫升)猝滅該反 應,並用EtOAc(3x20毫升)萃取之。經合併之有機萃取物 用鹽水(10毫升)洗滌,經乾燥(Na2S〇4)並在真空中濃縮以 生成粗產物。此產物藉由純化快速層析法(Si , 12xl6〇毫 米,溶於己烷中之EtOAc的梯度為〇至80%)以生成一無色 油狀3-{[5’-異丙基-2’-甲氧基-4-(三氟甲基)聯苯基基]甲 基}-5_(4_ 甲基苯基)-1,3_ 噁唑烷-2-酮。R, =0.37 (20%
EtOAc/ 己烧)。LCMS 計异值=484.21 ;試驗值=484.2 (M+l)+。4 NMR (苯-^/6,500 MHz,1:1滞轉異構體混合物) δ 7·76 (s,0.5H),7.65 (s,0.5H),7.31 (d,J = 7·7 Hz,1H), 7.08 (dd, /= 8.4,2·4 Hz,1H),7.05 (br d,《/= 7·8 Hz,1H), 6.95-6.86 (m, 5H), 6.58 (t, J = 7.7 Hz, 1H), 4.74 (t, J = 8.0
Hz,0.5H),4.70 (t,/= 8.0 Hz,0.5H),4.50 (d,/= 15.7 Hz, 0.5H), 4.42 (d, J = 15.7 Hz, 0.5H), 4.25 (d, J = 15.7 Hz5 0.5H),4.11 (d,15.7 Hz,0.5H),3.26 (s,1.5H),3.21 (s, 1.5H),2.81 (t,/ = 8·6 Hz,0.5H),2.76 (七重峰,/ = 7·〇 Hz, 1H)5 2.68 (t, J = 8.6 Hz, 0.5H), 2.55 (t? J = 8.6 Hz, 0.5H), 2·53 (t,《/= 8·6 Hz,0·5Η),2·04 (s,3H),1.20 (t,7.0 Hz, 3H),1.19 (t,J = 7.0 Hz,3H) 〇 實例15 102763.doc -66- 1299991
l-[3,5-雙(三氟甲基)笨基】_2_硝基丙q•醇 用10% NaOH水溶液(m/v)(1.73毫升.,4·34毫莫耳)處理— 經攪拌之3,5-雙(三氟甲基)苯甲盤(1〇〇克,413毫莫耳)與 硝基乙烧(1·13克,丨·08毫升,15·1毫莫耳)溶於無; EtOH(20毫升)的(TC溶液,攪拌丨小時並用2%醋酸水溶液 • (m/V)(13·0毫升,4·32毫莫耳)處理。將該反應物於室溫下 攪拌1小時,然後分為水層(5〇毫升)與Et〇Ac層毫升)。 水性層用EtOAc(2x50毫升)萃取,且經合併之有機萃取物 用飽和NaHCO3(50毫升)與鹽水(5〇毫升)洗滌,經乾燥 (Na2S〇4)並在真空下濃縮以生成一無色油狀蘇型與赤型^ [3,5-雙(二氟甲基)苯基]-2-硝基丙-i_醇之15:1混合物。lH NMR(CDCl3,500 MHz)蘇型非對映異構體·· δ 7.88 (bi> s, 1H),7·86 (br s,2H),5.22 (d,J = 8·4 Ήζ,1H),4.77 (dq,J = • 8.4, 6.9 Hz, 1H), 3.03 (br s 1H)5 1.42 (d5 6.9 Hz, 3H)5
赤型非對映異構體·· δ 7.90 (br s,1H),7_86 (;br % 2HL (d,3.2 Hz,1H),4.72 (dq,3·2, 6·9 Hz,1H),3·03 (br s 1H),1.50 (d,*/= 6·9 Hz,3H) 〇 實例16
OH
NH2 2-胺基- l-[3,5-雙(三象甲基)苯基]丙-1_醇 102763.doc -67- 1299991 於室溫及15 psi H2下,將一存於蘇型與赤型l-[3,5-雙 (三氟曱基)苯基]-2-硝基丙-1-醇(50毫克,0.158毫莫耳)溶 於3 0%(v/v)HC〇2H水溶液(0.75毫升)與MeOH(10毫升)的 1.5:1混合物之溶液中之阮内鎳(50毫克)懸浮液攪拌過夜。 通過一矽藻土墊層過濾該反應混合物,並將所得濾液在真 空下濃縮以去除MeOH。該水性漿液用28% NH4OH水溶液 調整至pH 9至10,用水(20毫升)稀釋,並用EtOAc(3x20毫 升)萃取。經合併之萃取物用鹽水(10毫升)洗滌,經乾燥 (Na2S〇4)並在真空下濃縮以生成一無色固體狀蘇型與赤型 2-胺基-l-[3,5-雙(三氟甲基)苯基]丙-1-醇之混合物。LCMS 計算值=288.08 ;試驗值=288.1 (M+l)+。lH NMR (CDC13, 500 MHz)蘇型-非對映異構體·· δ 7·79 (br s,3H),4·35 (br s,1Η),3.25 (bi* s,1Η),2·59 (br s,3Η),0·86 (d,6·1 Ηζ, 3H),赤型非對映異構體·· δ 7·79 (br s,3H),4,71 (br s, 1H),3.00 (br s,1H),2.59 (br s,3H),1·06 (d,J = 5.0 Hz, 3H)。 實例17
5_[3,5_雙(三氟甲基)苯基卜4-甲基“一-噁唑烷^-酮 於〇°C及N2下,將二異丙基乙基胺(106毫克,142微升, 〇·817毫莫耳)與三光氣(20.2毫克,〇·〇68毫莫耳)相繼添加 至一經攪拌之2·胺基-1-[3,5-雙(三氟甲基)苯基]丙-1-醇 102763.doc • 68 - 1299991 (39·1毫克,0.136毫莫耳)溶於無水CH2Cl2(l〇毫升)的溶液 中。該反應物於0°C下攪拌1小時,然後在真空下濃縮至約 5毫升體積。該混合物用水(50毫升)稀釋,並用 EtOAc(3x50毫升)萃取。經合併之有機萃取物經乾燥 (Na2S〇4)並在真空下濃縮以生成粗產物。此產物藉由快速 層析法(Si,12x160毫米,溶於己烷中之EtOAc的梯度為〇 至70%)純化以生成無色固體狀蘇型-5·[3,5-雙(三氟甲基)苯 基]-4-甲基-1,3_噁唑烷-2-酮(17·5毫克)與赤型5_[3,5_雙(三 φ 氟甲基)苯基]-4-甲基-1,3-噁唑烷-2-酮(14·4毫克)。蘇型-非 對映異構體:R/= 0.63 (5 0% EtOAc/己烷)。LCMS計算值= 314.06 ;試驗值=314·1 (M+l)+。lH NMR (CDC13,600 MHz) δ 7.90 (br s,1H),7·83 (br s,2H),6·71 (br s,1H), 5·17 (d,J = 7.0 Hz,1H),3.86 (br 五重峰,J = 6·2 Hz,1H), 1·48 (d,/ = 6·2 Hz,1H)。使用對掌性HPLC(AS管柱, 20x250毫米,20%異-Pr〇H溶於庚烷中之溶液)可將此化合 物分成其對映異構體(4R,5R)_5-[3,5-雙(三氣甲基)苯基]_4_ W 曱基-1,3·噁唑烷-2-酮與(4S,5S)-5-[3,5-雙(三氟甲基)苯基]一 4-甲基-1,3-β惡峻烧-2-酮。赤型-非對映異構體:0.38 (50% EtOAc/己烷)。LCMS計算值=314.06 ;試驗值= (M+l)+。NMR (CDC13, 600 MHz) δ 7·90 (br s,1H),7.79 (br s,2Η),5·83 (d5 J = 8·0 Ηζ,1Η),5·34 (br s,1Η),4.31 (br 五重峰,7·〇 Hz,1H),〇·84 (d,6·6 Hz,1H)。使 用對掌性HPLC(AS管柱,20x250毫米,15%異-Pr〇H溶於庚 烧中之溶液)可將此化合物分成其兩種對映異構體(4S,5R)_ 102763.doc -69- 1299991 5-[3,5 -雙(三氟甲基)苯基]-4-甲基-1,3 -嚼嗤烧-2-酮與 (4匕58)-5-[3,5-雙(三氟甲基)苯基]-4-甲基-1,3_噁唑烷-2- 酉同0 (4S,5R)-5-[3,5_雙(三氟甲基)苯基】-4-甲基-i,3-n惡嗤烧·2·明 之對掌合成 可藉由下面所示3_步驟途徑直接自對掌性起始材料CBZ-1-丙胺酸來產生此中間體。化合物(411,58)-5-[3,5-雙(三氣 曱基)苯基]_4_甲基-1,3-β惡。坐烧-2-_可藉由一始於cbZ-D-φ 丙胺酸之類似途徑來產生。 步驟1
1. H0BT-H20, EDC-HC1 DIPEA, Me(MeO)NH2Cl NHCBZ ___
2. HC1/IPAC 3. 庚烷結晶作用 將CBZ-L-丙胺酸(6.5公斤,28.5莫耳)、HOBT-水合物 (4·8公斤,34.8莫耳)、Weinreb S盘胺基-HC1鹽(3.4公斤, 36.2莫耳)與THF(32公升)於氮氣下裝至一潔淨燒瓶中。將 該混合物冷卻至〇至1(TC,然後在低於2(rc之溫度下缓慢 _ 添加DJPEAU]/公升)。然後稍微冷卻至i5°C至25°C,緩 k添加EDC-HC1(7公斤,36.2莫耳)。將該漿液在2〇。(:至25 C下保持過夜。然後將該混合物冷卻至〇 t至丨〇它,並緩 k添加3 N HC1(13公升)。然後添mIPAC(45.5升)並分層。 有機層用HC1(13公升)洗滌1次並用8% NaHC03(13公升)洗 務2次。然後在5〇 t及真空下將有機層濃縮至少於2〇公 升。將該澄清溶液緩慢冷卻至室溫,使產物結晶。然後缓 k添加庚燒(約70公升)。漿液經過濾,用庚烷(18公升)洗 102763.doc -70- 1299991 滌,並於室溫下在濾罐上乾燥。得到藉由對掌性HPLc量 測為具有大於9 9 · 9 % e e之產物。 步驟2
將來自步驟1之Weinreb醯胺(6公斤,22.5莫耳)與3,5-雙 (二氟甲基)溴苯(4.85公升,28·1莫耳)溶解於無水THF(24公 φ 升)中。該溶液用氮氣吹掃以去除沸騰氧。將該溶液冷卻 至-10 C,並通過加料漏斗將溶於thf(56.4莫耳)之異_ PrMgCl緩慢(2小時)添加至該反應物中,並將反應溫度維 持在-5°C。將該溶液加溫至2(TC並於20°c下保持過夜。然 後於氮氣下將該反應冷卻至_ 1 〇 ,並於2小時内緩慢淬滅 至維持在0至5°C之5 N HC1(14公升)中。添加MTBE(6〇公 升)並將雙相混合物攪動5分鐘。加溫至2〇°c至25°C後,使 其靜置3 0分鐘’然後分層。有機層用水(丨2公升)洗滌2次。 • 通過一 1 -微米在線PTFE過濾器將有機層真空轉移至一蒸 館燒瓶中’且隨後於真空下(内部溫度<4(rc)濃縮成約12 公升。添加庚烷,且於真空及4〇它至55它下繼續蒸餾直到 終體積達40公升。將該溶液冷卻至^它至^,放入晶種 (約0.5%,30 gms),然後放置3〇分鐘以使一完整晶種床得 以生長。在2至3小時内將該漿液冷卻至丨。然後過濾該 漿液,用5 C庚烷(1 8公升)洗滌,並於濾罐上、使用一真空 /氮氣吹掃過夜使其完全乾燥。得到具有>999ee%之乾燥 102763.doc -71 - 1299991 固體。若光學純度不夠,則可使該醯胺自直鏈庚烷重結 晶。 步驟3
在一惰性氣氛下,將TFA(9公升)添加至一 1〇〇公升Buchi 反應器中,且冷卻至-5°C。添加來自步驟2之固體狀酮產 物(5·50公斤,13·;1莫耳),之後用TFA(2公升)沖洗。將該 溶液冷卻至-5°C,並攪拌直到所有固體溶解。經約1小時 缓慢添加矽烷(2.18公斤,15·7莫耳)(分兩份添加),同時將 溫度維持在<〇°C。將該反應物保持在_2至_6°C持續15至20 小時,此時,LC顯示酮剩餘物<2%。藉由向1〇公升水中緩 慢添加13.6公斤KOH顆粒(87 w%)來製備50 w/w% KOH溶 液,同時於<30°C温度下保持高放熱溶解性。將該溶液保 存在一冰箱中。 用約2公升5 0 w/w% KOH溶液猝滅該反應,同時劇烈授 拌並冷卻,溫度維持在約2〇。(:。添加冷THF(16.5公升,預 先冷凍保存),之後緩慢添加剩餘K〇H溶液(約13.7公升), 再之後用2公升水沖洗,同時溫度維持在<2(rc。完成koh 添加後,將該反應物維持在室溫。3小時後,該反應用 27.5公升IPAC與20公升20% w/v NaCl水溶液猝滅。
分離水性層與有機層。有機層用26公升2〇% w/v NaCl水 溶液洗務’然後用36公升水洗滌,再然後用3丨公升〇·5 N 102763.doc -72- 1299991 HC1洗滌,且最後用32公升水洗滌。將有機層濃縮至約j 〇 公升。添加庚烷(20公升),以生成晶體。將有機層濃縮至 約10公升。再添加庚烷(2〇公升),且將有機層濃縮至約i 〇 公升。添加庚烷(22公升)並將漿液維持於室溫。過滤出固
98.8%純度,>99.95%ee)。然後將該固體重新溶於125公 升MeOH中(吸熱反應)。於室溫下,添加3公升水,並將該 混合物維持一段時間以開始結晶。於室溫下經約6〇分鐘添 # 加水(9·5公升)。維持60分鐘後,將該漿液過濾,並用5公 升MeOH/水(1/1.5)、5公升MeOH/水(1/4)並隨後用4公升水 洗滌該固體。於真空及5(TC下乾燥該固體產物(藉由顯 示 99.9%純度,>99.95%ee)。 用於步驟3所用分析之HPLC方法:
Ace-C8管柱25〇χ4·6毫米 A : MeCN ; B :溶於水之 〇·ΐ% η3ρο4 ; 梯度· 0分鐘時5Α:95Β至9分鐘時95Α·5Β
條件:35°C,1·5毫升/分鐘,21〇奈米
維持95AJB 實例18
102763.doc -73- 1299991 赤型-5-[3,5-雙(三氟甲基)苯基】-3-{[5,_異丙基-2,·甲氧基 4- (三氟甲基)聯苯基-2-基】甲基卜4-甲基-1,3-噁唑烷-2-酮 於室溫及N2下,將雙(三甲基甲矽烷基)醯胺鈉(172微升 溶於THF之1 Μ溶液,0.172毫莫耳)添加至一經攪拌之赤型 5- [3,5_雙(三氟曱基)苯基]_4·甲基-1,3-噁唑烷-2-酮(50毫 克,0.129毫莫耳)溶於無水THF(1毫升)的溶液中。攪拌該 反應15分鐘,並藉由套管添加2-(溴甲基)-5,-異丙基-2,-甲 氧基-4-(三氟甲基)聯苯基(27.0毫克,0.0861毫莫耳)溶於 無水THF(2毫升)的溶液。將該反應物於室溫下攪拌3天。 用飽和NH4C1(10毫升)猝滅該反應,並用EtOAc(3x20毫升) 萃取。經合併之有機萃取物用鹽水(1〇毫升)洗滌,經乾燥 (Na2S〇4)並在真空下濃縮以生成粗產物。此產物藉由快速 層析法(Si,12x160毫米,溶於己烷中之EtOAc的梯度為0 至40%)純化以生成一無色油狀赤型_5_[3,5-雙(三氟曱基)苯 基]-3-{[5*-異丙基-2,·曱氧基-4-(三氟甲基)聯苯基-2-基]曱 基}-4-甲基-l,3-噁唑烷-2-酮。R/ = 0.64 (20% EtOAc/ 己 烷)。LCMS計算值=620.18 ;試驗值=620.2 (M+l)+。4 NMR (苯d6, 600 MHz,滞轉異構體之1:1混合物)δ 7.94 (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,2·1 Ηζ,0·5Η), 6.86 (d,/= 1.7 Hz,0·5Η),6.64 (d,J = 8·5 Hz,0·5Η),6·56 (d, J- 8.5 Hz, 0.5H), 4.99 (d, J= 15.9 Hz, 0.5H), 4.93 (d, /= 15.9 Hz, 0.5H), 4.73 (d? J= 7.9 Hz, 0.5H)5 4.61 (d, J = 7.9 Hz5 0.5H), 3.88 (d? 15.9 Hz, 0.5H)? 3.82 (d, J= 15.9 102763.doc -74- 1299991 Ηζ,0·5Η),3·3 5 (s,1.5H),3.24 (s,1·5Η),3.05 (七重峰,/ = 6·9 Hz,0.5H),3.01 (七重峰,6.9 Ηζ,〇·5Η),2·75 (m, 出),1·19 (dd,*/= 6·9, 2·7 Ηζ5 3Η),l·17 (dd,1〇·9, 6·9 Ηζ,3Η),-〇·ΐ8 (d,二 6.4 Ηζ,1·5Η),-〇·33 (t,/ = 6·4 Ηζ, 15Η)。使用對掌性HPLC(AD管柱,20x250毫米,存於庚 烷中之3%異-Pr〇H)可將該化合物分成其兩種對映異構體 (4i?,5S)-5-[3,5-雙(三氟甲基)苯基]-3-{[5匕異丙基-2’-甲氧 基-4-(三氟曱基)聯苯基-2-基]甲基甲基-1,3-噁唑烷-2-酮與(4&57?)-5-[3,5·雙(三氟甲基)苯基]-3-{[5’_異丙基-2*-甲 氧基-4-(三氟甲基)聯苯基-2-基]甲基甲基-1,3-噁唑烷-2-酮。 實例19
4-[3,5-雙(三氟甲基)苯基】_1_{[5,_異丙基-2,-甲氧基三 氟甲基)聯苯基-2-基]甲基}咪唑啶-2-酮 步驟A:第三丁基{2-[3,5-雙(三氟甲基)苯基】_2_經乙 基}{[5’-異丙基-2’-曱氧基-4-(三襄甲基)聯苯基_2_基]甲基} 胺基曱酸酯 向一 雙(二氟甲基)苯基]_2-({[5’-異丙基_2,_甲氧 基-4-(二鼠甲基)聯苯基-2-基]曱基}胺基)乙醇(實例6步驟 102763.doc -75- 1299991 B,325.0毫克,0.561毫莫耳)溶於CH2Cl2(15毫升)之溶液 中添加BOC2〇(122毫克,0.561毫莫耳)與DIPEA (98微升, 0.561毫莫耳)。於室溫下攪拌該反應物。5小時後,添加額 外之BOC2〇(50毫克,0.229毫莫耳)與DIPEA(50微升, 0.287毫莫耳)。於室溫下攪拌該反應物48小時。然後,將 該反應物濃縮至約2毫升,用己烷(8毫升)稀釋並用1〇〇/0至 20% EtOAc/己烷藉由快速層析法純化以生成第三丁基(2-[3,5-雙(三氟曱基)苯基]-2-羥乙基}{[5,-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基-2-基]甲基}胺基甲酸酯。= 0.38 (25% EtOAc/己烧)。LCMS = 580.3 (M+l-BOC)+。4 NMR (CD2C12, 500 ΜΗζ)δ 7.78 (s, 1H), 7.54-7.67 (m5 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,15 H) 〇 步驟B : l-[3,5_雙(三氟甲基)苯基卜2-((第三丁氧基羰 基){[5’-異丙基-2’-曱氧基-4-(三氟甲基)聯苯基基]甲基} 胺基)乙基甲烷磺酸酯 向一第三丁基{2_[3,5-雙(三氟甲基)苯基]-2-羥乙基}{[5,-異丙基-2 ^甲氧基-4-(三氟甲基)聯笨基·2-基]甲基}胺基甲 酸酯(350.1毫克,0.516毫莫耳)溶於CH2Cl2(15毫升)的溶 液中添加DIPEA(450微升,2.58毫莫耳)。將該溶液冷卻至 0°C並添加MsCl(100微升,1·29毫莫耳)。於〇°c下擾拌45分 鐘後,該反應物用EtOAc( 100毫升)稀釋並用飽和 NaHC〇3(25毫升)、鹽水(25毫升)、1 N HC1(25毫升)以及鹽 水(2x25毫升)洗滌。有機層經由Na2S〇4乾燥,經過濾並濃 102763.doc -76- 1299991 縮。使殘留物通過一含25% EtOAc/己烷之短矽膠栓塞並濃 縮之。所得產物1-[3,5-雙(三氟甲基)苯基]-2-((第三丁氧基 罗炭基){[5*-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基-2-基]甲 基}胺基)乙基甲烧石黃酸醋未經進一步定性而立即用於下步 反應。R/= 0.33 (25% EtOAc/己烷)。 步驟C:第三丁基{2-疊氮基_2-[3,5-雙(三氟甲基)苯基]乙 基}{[5,-異丙基-2,-甲氧基_4-(三氟甲基)聯苯基-2-基】甲基} 胺基甲酸酯 將來自先前反應之1-[3,5-雙(三氟甲基)苯基]-2-((第三丁 氧基羰基){[5、異丙基-2,-甲氧基-4-(三氟甲基)聯苯基_2_ 基]甲基}胺基)乙基甲烷磺酸酯溶解於DMPU( 1 5毫升)中, 並用^1^3(14〇耄克,2.15毫莫耳)處理。將該反應物於室溫 下攪拌15小時,且然後用EtOAc(75毫升)稀釋。用 Η2〇(5χ40毫升)與鹽水(4〇毫升)洗滌該溶液。有機層經由 Na2S〇4乾燥’經過濾並濃縮。殘留物用20% EtOAc/己烧 純化以生成第二丁基{2 -疊氮基-2-[3,5-雙(三氟甲基)苯基] 乙基}{[5’-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基·2_基]甲 基}胺基甲酸酯。R/ = 0.52 (15% EtOAc/己烷)。LCMS = 605.3 (M+1-B0C)+。1H NMR (C6D6,500 MHz,70°C) δ 7·80 (s,1Η),7·67 (s,1Η),7.48 (s,2Η),7·36 (d,J= 7·8 Ηζ, 1H),7·01-7·11 (m,2H)5 6.89 (m,1H), 6·64 (d,8.6 Hz, 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)。 步驟D ··第三丁基{2_胺基_2-[3,5-雙(三氟曱基)苯基】乙 102763.doc -77- 1299991 基}{[5’-異丙基-2’·甲氧基-4-(三氟甲基)聯苯基·2-基】甲基} 胺基甲酸酯與第三丁雙(三氟甲基)苯基卜 異丙基-2’-甲氧基_4_(三氟甲基)聯苯基基】甲基}胺基)乙 基]胺基甲酸酯之混合物 向一第三丁基{2-疊氮基-2-[3,5-雙(三氟甲基)苯基]乙 基} {[5’-異丙基-2,-甲氧基_4_(三氟甲基)聯苯基-2-基]甲基} 胺基甲酸酯(300毫克,0.426毫莫耳)溶於EtOAc(15毫升)之 /谷液中添加10%的碳上Pd (100毫克)。將該反應物置kH2 下並於室溫下攪拌5小時。此時該反應完成並生成兩種產 物即第二丁基{2-胺基-2-[3,5-雙(三氟甲基)苯基]乙基}{[5,-異丙基-2’-甲氧基-4_(三氟甲基)聯苯基-2-基]甲基}胺基甲 酸醋與第三丁基[^3,%雙(三氟甲基)苯基]_2_({[5,·異丙 基-2’-甲氧基(三氟曱基)聯苯基基]甲基}胺基)乙基] 胺基甲酸醋之混合物。過濾掉觸媒並將濾液濃縮以生成產 物混合物。LCMS=679_3 (M+l)+。該等產物未經進一步純 化或定性而用於下步反應。 步驟E : 1-[3,5_雙(三氟甲基)苯基卜#2_{[5匕異丙基曱氧 基三氟甲基)聯苯基-2-基]甲基}乙烷_1,2-二胺 向一 283.5毫克(0.418毫莫耳)的第三丁基{2_胺基-2· [3,5-雙(二氟甲基)笨基]乙基}{[5,-異丙基-2,-甲氧基-4-(三氟甲 基)聯苯基-2-基]甲基}胺基甲酸酯與第三丁基[1_[3,5_雙(三 敗甲基)苯基]-2-({[5f-異丙基-2,-甲氧基-4-(三氟曱基)聯苯 基2基]甲基}胺基)乙基]胺基甲酸g旨之混合物溶於 CH2C12(15毫升)之溶液中添加TFA(15毫升)。將該反應物 102763.doc -78- 1299991 於室溫下攪拌5小時,然後倒入i N Na〇H (5〇毫升)中。用 CH2C12(3x50毫升)萃取該混合物,且合併該等有機萃取物 後,經由Na2S〇4乾燥,經過濾並濃縮。用5%至1〇% MeOH/CH2Cl2藉由快速層析法純化殘留物以生成卜[3,5_雙 (三氟甲基)苯基]·# 2-{[5,_異丙基-2,_甲氧基_4_(三氟甲基) 聯苯基-2-基]甲基}乙烷」,2_二胺。〇 46 (ι〇%
MeOH/CH2Cl2)。LCMS = 579.2 (M+l)+。iH NMR
(CD2Cl2, 500 MHz) δ 7.83 (s, 2Η), 7.77 (s, 2H)3 7.55 (d, J =7·8 Hz,1H),7.31 (d,8」Hz,1H),7.24 (dd,8.4, 2.3 Hz,1H),6·99 (d,2.0 Hz,1H),6.92 (d,/= 8.5 Hz, 1H),4.06 (m,1H),3.59-3.76 (m,2H),3·69 (s,3H),2.88 (m,1H),2.67 (dd,/= Π·9, 4·3 Hz,1H),2.51 (m,1H),1·22 (d,/ = 6·9 Hz,6H)。 步驟F : 4_[3,5-雙(三氟甲基)苯基卜lus,·異丙基-2,·甲氧 '基-4-(二氟甲基)聯苯基-2 _基】甲基}味唾咬-2-酮 將一 1-[3,5_雙(三氟甲基)苯基,·異丙基甲氧 基-4-(三氟甲基)聯苯基基]甲基}乙烷_U2•二胺(125.2毫 克,0.217毫莫耳)溶於CH2Cl2(3〇毫升)之溶液冷卻至並 添加DIPEA(227微升,ΐ·3〇毫莫耳)。接下來,添加三光氣 (32.2¾克,〇·ι〇9毫莫耳)。將該反應物於下攪拌45分 鐘,且然後倒入飽和NaHCO3(20毫升)中。該混合物用 EtOAc(l〇〇毫升)萃取,且有機層用鹽水(25毫升)洗滌,經 由Na2S〇4乾燥,經過濾並濃縮。殘留物用4〇% Et〇Ac/己 烷藉由快速層析法純化以生成4_[3,5-雙(三氟甲基)苯基卜卜 102763.doc -79- 1299991 {[51-異丙基曱氧基-4-(三氟甲基)聯苯基-2-基]甲基}咪 唆啶-2-酮。R,= 〇·22 (40% EtOAc/己烷)。LCMS = 605.2 (M+l)+。lH NMR (CDC13,500 MHz)(滯轉異構體出現於 1:1比率中;觀察到一些峰加倍)δ 7.83 (s,1H),7·78 (S, 2Η),7.55-7.62 (m,2Η),7.32 (d,《/= 7.8 Ηζ,1Η),7·22 (m, 1Η),6.94 (s,1Η),6·88 (d,8·3 Ηζ,1Η),5·33 與 5·24 (2 個 單峰,1Η),4.80-4.88 (m,1Η),4.00-4.61 (m,2Η),3·72與 3.70 (2個單峰,3H),3.55-3.59 (m,1H),2.83-2.93 (m,2H), 1·17-1·23 (m,6H)。 使用一 AD對掌性管柱用5% IPA/庚烷能夠將此化合物之 兩種對映異構體分離。 實例20
(4i〇_l-{[5’_異丙基-2、甲氧基_4-(三氟甲基)聯苯基_2_基]甲 基}-4-苯基味嗤咬-2-酮 步驟A :第三丁基羥基-1-苯基乙基】胺基甲酸酯 向一(27?)-2•胺基·2-苯基乙醇(400毫克,2.91毫莫耳)溶 於CH2Cl2(15毫升)的溶液中添加BOC2〇(636毫克,2·91毫 莫耳)與DIPEA(507微升,2.91毫莫耳)。將該反應物於室 溫下攪拌18小時,用EtOAc(75毫升)稀釋並用H2〇、鹽 水,1 N HC1、鹽水、飽和NaHC〇3以及鹽水(各25毫升)洗 I02763.doc -80- 1299991 滌。有機層經由Na2S〇4乾燥,經過濾並濃縮。用5〇% EtOAc/己烷藉由快速層析法純化殘留物生成第三丁基 [(li?)-2-羥基-1-苯基乙基]胺基甲酸酯。R/ = 〇·23 (4〇%
EtOAc/己烷)。lH NMR (CDC13, 600 ΜΗζ) δ 7.27-7.37 (m 5Η),5·27 (bs,1Η),4.78 (bs,1Η),3·83 (bs,2Η),2.46 (bs 1H),1.44 (bs,9H)。 步驟B ··第三丁基[(1Λ)-2-氧代-l-苯基乙基】胺基甲酸酯 向一第三丁基[(1/?)-2-羥基-1-苯基乙基]胺基甲酸酯(2〇〇 φ 毫克,〇·844毫莫耳)溶於CH2Cl2(2〇毫升)的0°C溶液中添加 戴斯-馬丁(Dess-Martin)過碘烷(447毫克,1.05毫莫耳)。將 該反應物於0 °C下攪拌15分鐘,然後於室溫下攪拌3 〇分 鐘。然後用EtOAc(75毫升)稀釋該反應物並用1〇% K2C〇3(2x30毫升)快速洗滌。有機層經由Na2S〇4乾燥,經 過濾並濃縮。於一矽膠短管柱上使用50% EtOAc/己烷純化 殘召物’生成弟二丁基[(li?)-2 -氧代-1-苯基乙基]胺基甲酸 酯。lH NMR (CDC13,600 MHz)(觀察到一主要與一次要 ❿構像,給出主要構像之數據)。δ 9.53 (s,1H),7.29-7.40 (m,5Η),5.80 (bs,1Η),5.31 (m,1Η),1·42 (s,9Η)。該物質 立即用於下面反應中。 步驟C :第三丁基[(11?)_2_({[5,-異丙基_2,_甲氧基(三氟 甲基)聯苯基-2-基]甲基}胺基)-1-苯基乙基]胺基甲酸酯 向一第三丁基[(li〇-2-氧代-1-苯基乙基]胺基甲酸酯 (113.8毫克,0.484毫莫耳)溶於MeOH(7毫升)之溶液中添 加1-[5’-異丙基-2’-甲氧基-4-(三氟甲基)聯苯基_2_基]六亞 102763.doc -81 · 1299991 甲基四胺(98毫克,0.303毫莫耳),之後添加NaCNBH3(3Ο 宅克’ 0.477¾莫耳)與H0Ac(2滴)。該反應物於室溫下攪 拌過夜,用EtOAc(75毫升)稀釋,並用1 N NaOH(25毫升) 與鹽水(25毫升)洗滌。有機層經由Na2S〇4乾燥,經過據並 濃縮。用5至25% EtOAc/己烷藉由快速層析法純化殘留物 生成第三丁基[(li?)-2-({[5,_異丙基-2,-曱氧基-4-(三氟甲基) 聯本基-2-基]曱基}胺基)-1-苯基乙基]胺基甲酸酯。= 0.30(25% EtOAc/己烷)。LCMS = 543·4(Μ+1)+。 # 步驟D : 異丙基-2,_甲氧基-4·(三氟曱基)聯苯 基-2-基】甲基}-1-苯基乙烧-1,2-二胺 向一含少量雜質的第三丁基[(li?)-2-({[5’_異丙基_2’_甲氧 基·4-(三氟甲基)聯苯基-2-基]甲基}胺基)-1-苯基乙基]胺基 甲酸酯(150毫克,0.277毫莫耳)溶於CH2Cl2(l〇毫升)的溶 液中添加TFA( 1毫升)。將該反應物於室溫下攪拌2小時, 且然後倒入1 N NaOH(25毫升)中。所得混合物用 CH2Cl2(3x25毫升)萃取。經合併之有機萃取物經由 ® Na2S〇4乾燥,經過濾並濃縮。用〇至10% MeOH/CH2Cl2藉 由快速層析法純化所得殘留物生成(li〇-iV2-{[5L異丙基-2’-曱氧基·4-(三氟甲基)聯苯基-2-基]甲基卜1-苯基乙烷-1,2-二胺。R/ = 0.27(10% MeOH/CH2Cl2)。LCMS = 443.4 (M+l)+。 步驟E : (4i?)-l-{[5,-異丙基-2*_甲氧基_4_(三氟曱基)聯苯 基-2-基]甲基}-4-苯基味吐咬嗣 將一(1及)異丙基-2’-曱氧基-4-(三氟甲基)聯苯 102763.doc -82 - 1299991 基-2-基]甲基}-l-苯基乙烷-1,2-二胺(96.〇毫克,0.22毫莫 耳)溶於CH2Cl2(15毫升)之溶液冷卻至〇它,並添加 DIPEA(230微升,1.32毫莫耳),之後添加三光氣(32·6毫 克,0· 11毫莫耳)。45分鐘後,將該反應物倒入飽和 NaHC〇3(25毫升)中。該混合物用EtOAc(75毫升)萃取。有 機層用鹽水洗滌,經由Na2S〇4乾燥,經過濾並濃縮。用 10至60% EtOAc/己烷藉由快速層析法純化殘留物生成 (4i〇-l-{[5’·異丙基-2’-甲氧基-4-(三氟甲基)聯苯基-2-基]甲 基卜4-苯基咪唑啶-2-酮。可藉由對掌性HPLC使用一 AD對 掌管柱與15% IPA/庚烷去除次要對映異構體以生成對映異 構純產物。R,= 0.16(40% EtOAc/ 己烷)。LCMS = 469·3(Μ+1)+。1H NMR(CDCl3, 500 MHz)(滯轉異構體出現 於1:1比率中,觀察到一些峰加倍)δ 7·65 (m,1H),7.54 (d, J = 7·7 Hz,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 與 3·72 (2個單峰, 3Η),3.49-3.53 (m,1Η),2.94-2.97 (m,1Η),2·87 (m,1Η), (m,6H) 〇 實例21
4-(4-氣苯基異丙基甲氧基-4兴三氟甲基)聯苯 102763.doc * 83 - 1299991 基-2-基】甲基}咪唑啶-2-酮 步驟A ·· 1·(4-氣苯基)-2_({[5,_異丙基-2,-甲氧基-4-(三氟甲 基)聯苯基-2-基]甲基}胺基)乙醇 將一 1-[5^異丙基_2’·甲氧基_5-(三氟甲基)聯苯基-2-基] 甲胺(300毫克,1.1毫莫耳)與2-(4-氣苯基)環氧乙烷(143微 升,1.2毫莫耳)溶於異丙醇(ι〇·5毫升)的溶液加熱至回流, 維持24小時。該反應物經濃縮後使用5%至80% EtOAc/己 烷藉由快速層析法純化以生成1-(4-氣苯基)-2-({[5,-異丙 基-2^甲氧基-4-(三氟甲基)聯苯基-2-基]甲基}胺基)乙醇。
0.37(50% EtOAc/己烷)。LCMS = 478.1 (M+l)+。1H NMR (CDC13, 500 MHz) δ 7.70 (s5 1H), 7.55 (d, J = 7.5
Hz,1H),7.33-7.19 (m,6H),6.97 (s,1H),6.90 (d,《/= 8.5 Hz,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,/= 7·0 Hz,6H)。 步驟B ··苄基[2-(4-氣苯基)-2-羥乙基】{[5’-異丙基-2,-甲氧 基-4-(三氟甲基)聯苯基-2-基】甲基}胺基甲酸酯 向一 1-(4-氯苯基)-2-({[5、異丙基_2,_曱氧基-4-(三氟甲 基)聯苯基-2-基]甲基}胺基)乙醇(40毫克,0.08毫莫耳)溶 於CH2Cl2(2毫升)的溶液中添加二礙酸二苄基酯(24毫克, 〇·〇8毫莫耳)。將該反應物於室溫下攪拌24小時且隨後倒入 出0(15毫升)中。得到之混合物用EtOAc(50毫升)萃取,且 有機層用鹽水洗滌(15毫升),經由Na2S〇4乾燥,經過濾並 濃縮。使用5%至60% EtOAc/己烷藉由快速層析法純化殘 留物生成苄基[2-(4-氯苯基)-2-羥乙基]{[5,-異丙基_2,-甲氧 102763.doc -84- 1299991 基-4-(三氟甲基)聯苯基_2_基]甲基}胺基曱酸酯。~ = 0.20(25% EtOAc/ 己烷)。LCMS = 612 2(M+1)+。旧 NMR(C6D6,600 MHz,峰變寬及/或加倍;存在旋轉異構 體及 / 或滯轉異構體)7.98-6.45 (m,ι5Η),5.〇〇_3.46 (m, 6H)? 3.20-2.96 (m, 5H), 2.72 (m, 1H), 1.20-1.15 (m, 6H) 〇 步驟C ··苄基[2-疊氮基-2-(4-氯苯基)乙基】{[5,_異丙基_2,_ 甲氧基_4_(二氟甲基)聯苯基基]曱基}胺基甲酸酯 將一苄基氯苯基)_2_羥乙基]{[5,_異丙基-2匕甲氧 籲基-4-(二氟曱基)聯苯基-2-基]甲基}胺基甲酸酯(44毫克, 0.07毫莫耳)溶於CH2Cl2(6毫升)的溶液冷卻至,且添加 二異丙基乙基胺(63微升,〇·36毫莫耳),之後添加甲烷 磺醯氣(14微升,0.18毫莫耳)。將該反應物於〇〇Ct 攪拌30 分鐘,然後倒入飽和NaHC03(15毫升)中。所得混合物用 £丈0八〇(50耄升)萃取,且有機層用鹽水(15毫升)洗滌,經由 Na2S〇4乾燥’通過一短矽膠栓塞過濾並濃縮之。將殘留 物重溶於DMPU(6毫升)中,並添加疊氮化鈉(12毫克,〇18 參毫莫耳)。將該反應物於室溫下攪拌24小時,然後倒入 H2〇(15毫升)中。得到之混合物用Et〇Ac(5〇毫升)萃取,且 有機層用H2〇(2xl5毫升)與鹽水(15毫升)洗滌,經由 Na2S〇4乾燥’經過濾並濃縮。使用25% EtOAc/己烷藉由 快速層析法純化殘留物,生成苄基[2_疊氮基4-(4-氯苯基) 乙基]{[5’·異丙基-2,-甲氧基-4-(三氟甲基)聯苯基-2-基]甲 基}胺基甲酸酯。R/ = 〇·66 (25% EtOAc/ 己烷)。LCMS = 637.3 (M+l)+。lH NMR (C6D6,600 MHz,峰加倍;存在 102763.doc -85 - 1299991 旋轉異構體及/或滯轉異構體)8.03-6.52 (m,15 Η),5·00_ 5·08 (m,2Η),4.76-4.12 (m,3Η),3.28-2.86 (m,5Η),2.77 (m,1H),1.23-1.18 (m,6H)。 步驟D :苄基胺基-2_(4-氣苯基)乙基】([5,異丙基_2,甲 氧基-4-(三氟曱基)聯苯基基】甲基}胺基甲酸酯 向一苄基[2-疊氮基-2-(4-氯苯基)乙基]{[5,-異丙基-2,-甲 氧基-4-(二氟甲基)聯苯基_2_基]甲基丨胺基甲酸酯(3〇毫 克’ 0.05宅莫耳)溶於THF(1毫升)的溶液中添加pt〇2(8毫 # 克且該反應物在氫氣與室溫下攪拌1小時。藉由通過一 含100% EtOAc之梦藻土栓塞過濾來去除觸媒,並濃縮濾 液以生成粗苄基[2_胺基-2·(4-氣苯基)乙基]{[5,-異丙基-2,-曱氧基-4-(三氟曱基)聯苯基基]曱基}胺基甲酸酯。R/ = 0.66(25% EtOAc/己烷)。LCMS = 611·3(Μ+1)+。 步驟Ε : 4·(4_氣苯基)_1-{[5匕異丙基-2,_甲氧基-4兴三氟曱 基)聯苯基-2 _基】甲基}啼峻咬酮 向一苄基[2-胺基-2-(4-氯苯基)乙基]{[5,-異丙基-2,-曱氧 ® 基-4-(二氟甲基)聯苯基-2-基]曱基}胺基甲酸酯(3〇毫克, 0.05毫莫耳)溶於THF(2毫升)的溶液中添加雙(三甲基甲矽 烧基)Si胺鉀(295微升溶於甲苯之0.5 Μ溶液,0.147毫莫 耳)。將該反應於室溫下攪拌30分鐘,且然後用飽和 NH4C1(15毫升)猝滅。得到之混合物用Et〇Ac(25毫升)萃 ^ 取’且有機層用H2〇(15毫升)與鹽水(15毫升)洗滌,經由 . Na2S〇4乾燥,經過濾並濃縮。用5%至60% EtOAc/己烷藉 由快速層析法純化殘留物生成4-(4-氣苯基)-1-{[5,-異丙基- 102763.doc -86- 1299991 2’-甲氧基-4-(三氟曱基)聯苯基-2-基]曱基}咪唑啶-2-酮。 11/= 0.46 (5% MeOH/CH2Cl2)。LCMS = 503.1 (M+l)+。 NMR (C^Dg,600 MHz,觀察到滯轉異構體;峰加倍。) 7.90-7.03 (m, 6H), 6.89-6.20 (m5 4H), 4.69-3.88 (m, 3H), 3·16 (s,3H),2.88-2.30 (m,3H),1·18-1·13 (m,6H)。 實例22
(4i?)-l-{[5’_異丙基-2,-甲氧基_4-(三氟甲基)聯苯基-2-基]甲 基}-3_曱基-4-苯基味嗤唆-2-酮 向一(4幻-1_{[5’_異丙基-2,_甲氧基-4-(三氟曱基)聯苯基-2-基]甲基}-4-苯基咪唑啶-2-酮(12.6毫克,0.0269毫莫耳) 溶於THF(1.5毫升)的溶液中添加MeI(l〇微升,0.162毫莫 φ 耳),之後添加KHMDS(162微升溶於甲苯之〇·5 Μ溶液, 0.081毫莫耳)。將該反應物於室溫下攪拌10分鐘,然後倒 入水(10毫升)中。該混合物用EtOAc(30毫升)萃取,且有機 層用鹽水(10毫升)洗滌,經由Na2S〇4乾燥,經過濾並濃 縮。用50% EtOAc/己烷藉由快速層析法純化殘留物以生成 (4i?)-l-{[5·-異丙基-2’-甲氧基-4-(三氟甲基)聯苯基-2-基]甲 基}-3-甲基-4-苯基咪唑啶-2-酮。R/= 〇·26 (40% EtOAc/己 烷)。LCMS = 483.2 (M+l)+。4 NMR (CDC13, 500 MHz, 102763.doc -87- 1299991 觀察到滯轉異構體;峰加倍)7.68 - 7.53 (m,2H),7.21-7.36 (m,7H),6.87-6.94 (m,2H),4.08-4.56 (m,3H),3.72與 3·71 (2個單峰,3H),3.34-3.38 (m,1H),2.77-2.89 (m,2H), 2.67與 2.63 (2個單峰,3H),1.18-1.26 (m,6H)。 遵循於實例1至22中概述之方法來製備列於表1中之化合 物: 表1
102763.doc -88- 1299991
29 ^―\ 471.2 30 ^―\ 。乂 538.2 31 ^Ν-Λ Cl 0 乂 504.2 32 〇 476.2 33 471.2 34 〇 乂^) 484.2 35 〇!>"〇 484.2 36 〇i^CF3 CF, 620.2 37 β / PFs CF, 620.2 38 。乂? 470.2 39 0¾Ο Η 469.2 102763.doc -89- 1299991
102763.doc -90- 1299991 實例50
4-[3,5-雙(三氟甲基)苯基卜2·{[5’_異丙基-2,-甲氧基-4-(三 B 氟甲基)聯苯基-2-基】甲基}_1,2,5_嗟二嗤唆1,1-二氧化物 將一 1-[3,5_雙(三氟曱基)苯基]異丙基·2,_甲氧 基_4-(三氟甲基)聯苯基-2_基]甲基}乙烷-12-二胺(8β0毫 克,0.014毫莫耳)與磺醯胺(2.0毫克,〇·〇21毫莫耳)溶於吡 啶(300微升)之溶液於一封閉管中加熱至120°C。3小時後, 將該反應物冷卻至室溫並用25毫升EtOAc稀釋。有機溶液 用1 N HC1(2><5毫升)與鹽水(lx5毫升)洗滌,經由Na2S〇4 φ 乾燥,經過濾並濃縮。用25% EtOAc/己烷藉由PTLC純化 殘留物以生成4-[3,5-雙(三氟甲基)苯基卜2-{[5,-異丙基-2,-曱氧基-4-(三氟甲基)聯苯基-2_基]曱基卜^弘噻二唑啶 1,1-二氧化物。R,= 〇·29 (25% EtOAc/ 己烷)。LCMS = 641.1 (M+l)+。lH NMR (CDC13, 500 MHz ;存在滯轉異構 體)δ 7.58-7.85 (m,5H),7.35-6.86 (m,4H),4.82-4.94 (m, 2Η),3.54-4.42 (m,6Η),2.71-2.91 (m,2Η),1.11-1.26 (m, 6H)。 102763.doc -91 - 1299991 實例5 1
異丙基·2,_甲氧基-4-(三氟甲基)聯苯基基卜^^噁 唑烷_2_酮 步驟A : [S,-異丙基-2,·甲氧基_4_(三氣甲基)聯苯基_2•基】 甲醇 • 向一 ^08克5’_異丙基―2,-曱氧基-4-(三氟甲基)聯笨基_2_ 曱腈(實例3)溶於25毫升正-Pr0H之溶液中添加〇97克 KOH。將該混合物加熱至回流並於此溫度下攪拌%小時, 然後冷卻並濃縮成一澄清油。該油分配在15毫升水與1〇毫 升Et2〇之間。水相用1〇毫升Et2〇萃取。合併之有機物用鹽 水(15毫升)洗滌,經由Na2S〇4乾燥,並濃縮。於一 Biotage Horizon 40S管柱上藉由快速層析法、用i cv 95% 己烷加上5%溶於丙酮之5%甲酸之混合物來洗提、之後用 _ 超過CV之溶於己烷之丙酮混合物自5。/()至100%的線性梯 度來洗提來純化殘留物。將得到之白色固體溶解於1 Q毫升 9:1苯-MeOH中,並添加過量TMSCH2N2。將混合物於室
溫下攪拌1 〇分鐘,然後用三氟乙酸猝滅並濃縮。使殘留物 溶解於15毫升Et2〇中並冷卻至〇°C。通過加料漏斗逐滴滴 加一溶於Et2〇(5.4毫升)之1 M UA1H4溶液。一旦添加完成 就去除冷卻浴,且混合物於室溫下攪拌2小時,然後重新 冷卻至0°C並藉由逐滴滴加〇·2毫升水、〇·2毫升15% NaOH 102763.doc -92- 1299991 水溶液以及0.5毫升水來猝滅。一旦添加完成就去除冷卻 浴,且混合物於室溫下攪拌3〇分鐘,過濾(用Et2〇充分洗 滌孩專固體)並漢縮。於一 Bi〇tage Horizon 40S管柱上藉由 快速層析法、用1 CV溶於己烷之4% EtOAc洗提、之後用 一超過10 CV之溶於己烷之EtOAc自4%至100%的線性梯度 洗提可提供標題化合物。質譜(ESI)307.2 (Μ·17)。4 NMR (500 MHz, CDCI3) : (5 7.85 (s, 1H), 7.60 (d, J=8 Hz5 1H)5 7.33 (d, J==8 Hz, 1H), 7.25 (dd, J==2 Hz, 9 Hz, 1H), • 6.99 (d5 J=2.5 Hz, 1H), 6.93 (d, J=8.5 Hz5 1H)5 4.49 (m5 2H),3.74 (s,3H),2.90 (七重峰,J=7 Hz, 1H),1.25 (d,J=7
Hz,6H) 〇 步驟B : 5’-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基-2-甲醛 向一 0.725克[5,-異丙基-2,-曱氧基-4_(三氟甲基)聯苯基_ 2-基]甲醇溶於10毫升CH2C12的溶液中添加1.14克戴斯-馬 丁(Dess-Martin)過碘烷。將該混合物於室溫下攪拌3〇分 鐘’然後過遽並濃縮。在一Biotage Horizon 40S管柱上藉 w 由快速層析法、用1 CV溶於己烷之1% EtOAc洗提、之後 用超過10 CV之溶於己烧之EtOAc自1至100%的線性梯度洗 提來純化殘留物以提供標題化合物。質譜 (ESI)323.2(M+1)。lH NMR (500 MHz,CDC13): 5 9.81 (s,1H),8.28 (s,1H),7·88 (dd,J=1.5 Hz,8 Hz,1H),7·54 (d,J=8 Hz,1H),7.33 (dd,J=2 Hz,8 Hz,1H),7·16 (d,J=2.5 Hz,1H),6.95 (d,J=8.5 Hz,1H),3.74 (s,3H),2.95 (七重峰, J=7 Hz,1H),1.29 (d,J=7 Hz,6H)。 102763.doc •93- 1299991 甲氧基_4_(三氟甲基)聯苯 步驟C : 2-胺基-l-[5,_異丙基 基基]乙醇 向-0·679克5’·異丙m氧基冰(三氟甲基)聯苯基| 甲終溶於!.5毫升CH2Cl2的溶液中添加約5毫克⑽,然後
添力卿三甲基甲石夕_化物。將該混合物於室溫下 ㈣3小時’然後其分配在15毫升水與1〇毫升阳〇之間。 U目用2x10毫升Et2〇萃取。合併之有機物經由乾 燥並濃縮。使殘留物溶解於15毫升Et2〇中並冷卻至〇艺。 通過加料漏斗逐滴滴加一溶於Et2〇溶液(4·2毫升)之丨m UA1H4。一旦添加完成就去除冷卻浴,並將混合物於室溫 下攪拌過夜,然後重新冷卻至ot:並藉由逐滴滴加015毫 升水、0.15毫升15% NaOH水溶液以及〇·4毫升水來猝滅。 一旦添加完成就去除冷卻浴,並將混合物於室溫下攪拌3 〇 分鐘’過濾(用EhO充分洗滌該等固體),並濃縮以提供標 喊化合物’其未經進一步純化就得到使用。質譜 (ESI)354.2(M+1)。一些1H NMR信號由於滯轉對映異構現 象(atropoisomerism)而加倍。1H NMR (500 MHz,CDC13): δ 7·88 (s3 1H)5 7.55 (app t, J=7.5 Hz, 1H), 7.22-7.28 (m5 2H),6.99, 6.95 (d,J=2.5 Hz,1H),6.92, 6.90 (sm 1H),4.52 (m,1H),3.70 (s5 3H),2.90 (七重峰,J=7 Hz,1H),2.81 (m, 1H),2.60-2.70 (m,2H),1.23-1.28 (m,6H)。 步驟D : 5-[5、異丙基-2,-甲氧基-4-(三氟甲基)聯苯基-2_ 基】-1,3-噁唑烷-2-酮 向一 〇·44克2 -胺基異丙基- 2’-甲氧基-4-(三I甲基) 102763.doc -94- 1299991 聯苯基-2-基]乙醇溶於15毫升CH2C12的〇°C溶液中添加 0.241克二異丙基乙基胺,然後添加〇·185克三光氣。該混 合物於0°C下攪拌30分鐘,然後用30毫升EtOAc與20毫升飽 和NaHC〇3稀釋。分相並用20毫升鹽水洗滌有機相,乾燥 (Na2S〇4) ’ 並濃縮。殘留物在一 Biotage Horizon,40S 管 柱上藉由快速層析法純化、用1 CV溶於己烷之5% EtOAc洗 提、之後用一超過10 CV之溶於己烷之EtOAc的自5至100% 線性梯度洗提以提供標題化合物。質譜(ESI)380.2(M+1)。 , 4 NMR信號由於滯轉對映異構現象而加倍。1h NMR (500 MHz,CDCI3) : 5 7·90, 7·86 (s,1H),7.66 (d5 J=8 Hz,1H), 7.35 (d, J=8 Hz, 1H), 7.27 (dd5 J=2.5 Hz, 8.5 Hz 1H), 7.03 (d,J=2.5 Hz,0.5H),6.87-6.93 (m,1.5H),5.65, 5.50 (t,J=8 Hz,lH),5.23,5.09 (s,1H),3.75 (s,1.5H),3.69 (s,1.5H), 3.68, 3.51 (t,J=9 Hz,1H),3·31,3·19 (t,J=8.5 Hz,0·5Η), 2.90 (七重峰,J=7 Hz,1H),1·25, 1·24 (d,J=7 Hz,6H)。 在一 Chiralpak AD 2x25公分管柱上藉由HPLC進一步純 _ 化、用溶於庚烷之10%異丙醇按9毫升/分鐘之速度洗提可 提供兩種對映異構體:對映異構體A,tR=1分鐘;對映 異構體B,tR=17.4分鐘。 實例52
3·苄基-5-[5’-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基-2-基]- 102763.doc -95· 1299991 1,3_德嗤烧-2·嗣
2-基]-1,3-噁唑烷-2-酮溶於1毫升DMF的〇。〇溶液中添加1〇 毫克氫化納。將該混合物於室溫下攪拌1〇分鐘,然後添加 24毫克苄基溴。該混合物於室溫下攪拌過夜,然後用15毫 升EtOAc與5毫升水稀釋。分相並用水與鹽水各5毫升洗滌 有機相,乾燥(Na2S〇4),並濃縮。殘留物在一 Biotage Horizon,25S管柱上藉由快速層析法純化、用丄cv己烷洗 • 提、之後用一超過10 cv溶於己烷之Et0Ac的自0至50〇/〇之 線性梯度洗k以提供標題化合物。質镨(Esi)47〇.i (M+1)。1H NMR (500 MHz,CDC13):占 7.86,7·76 (s, 1Η),7.62 (d,J=8 Ηζ,1Η),7·14_7·40 (m,7Η),7_01,6.77 (d, J=2.5 Hz,1H),6.87, 6.83 (d,J= 8·5 Hz,1H),5·45, 5·53 (m, 1H)5 4.30-4.53 (m, 2H), 3.73, 3.55 (s, 3H), 3.48, 3.30 (m, 1H),3·10, 2·96 (t,J〜8·5 Hz,1H),2.89, 2.82 (七重峰,J=7 Hz,1H),1·24, 1·16 (m,6H)。 實例53
3-[3,5-雙(三氟甲基)苄基】_5-[5,_異丙基甲氧基_心(三氟 甲基)聯苯基-2-基卜ι,3-噁唑烷酮(外消旋) 遵循實例50中所述程序,43毫克5-[5’-異丙基-2,-甲氧基· 102763.doc -96- 1299991 4-(二I曱基)聯苯基-2-基]-1,3-11 惡°坐烧-2__與43毫克3,5 -德 (三氟曱基)苄基溴可生成標題化合物。質胃 (ESI)606.1(M+1)。lH NMR信號由於滯轉對映異構現象而 加倍。1H NMR(500 MHz,CDC13) : 5 7.58-7.88 (m5 5H) 7.34 (d,J=8 Hz,1H),7·23 (m,1H),7.02, 6·79 (d,卜2 Hz, 1H),6.88,6·85 (d,8·5 Hz,1H),5.45,5.42 (m,1H), 4.52-4.64 (m,1·5Η),4·36 (d,J=15.5 Hz,0·5 H),3.74,3 57 (s,3H),3.49,3.34 (m,1H), 3.09,2·99 (t,J〜8·5 Hz,1H), _ 2·89, 2.81 (七重峰,Hz,1H),1.24, 1·12 (m,6H)。 實例54
3-[3,5-雙(三氟甲基)苄基卜5-[5,_異丙基甲氧基_4_(三氟 甲基)聯苯基-2_基]-1,3_噁唑烷_2-酮(對映異構體A) • 遵循實例50中所述方法,43毫克5-[5,-異丙基-2,-甲氧基-心(三氣甲基)聯苯基基]·(對映異構體A) 與43毫克3,5-雙(三氟甲基)节基漠可生成標題化合物。在 Chiralpak AS 4.6x250^米管柱上採用分析型HpLC、用溶 於庚烧之5%異丙醇按〇·5毫升/分鐘洗提· tR=99分鐘 實例55 102763.doc -97- 1299991
CF3 氟 甲基)聯苯基_2-基】噁唑烷_2_酮(對映異構體b) 遵循實例5〇中戶斤述方法,44毫克5-[5、異丙基-2,-甲氧基-4-(三氟甲基)聯笨基!基卜u“惡唑m同⑽映異構體B) /、43毫克3,5·雙(二氟甲基)苄基溴可生成標題化合物。在 ehuralpak AS 4·6χ250毫米管柱上採用分析型HpLC、用溶 於庚烷之5%異丙醇按〇·5毫升/分鐘洗提:tR=u,〇分鐘 實例56
0H
1-(4-氟苯基)-1-經基丙酿J 將一粉碎LaCl〆%毫克,〇·1〇4毫莫耳)溶於無水thf(78 φ 毫升)的懸浮液於N2下冷卻至-78°C並攪拌15分鐘。添加一 正-BuLi(浴於己烧之ι·6 ]y[溶液,195微升,0.312毫莫耳) 溶液並持續攪拌15分鐘。將該反應物加溫至〇i並攪拌3〇 分鐘。添加三曱基甲矽烷基氰化物(31毫克,42微升, 0.312毫莫耳)且將該反應物於〇°c下攪拌3〇分鐘並經3〇分鐘 加溫至室溫。藉由套管添加醯基三甲基矽烷(Cunico, r. F.,
Kuan,C· -P·,J· Org. CTzem·,1985,50,5410-5413)(121 毫 克,1·〇4毫莫耳)與4-氟苯甲醛(142毫克,1.14毫莫耳)溶於 無水THF(19毫升)之溶液,並將該反應物於室溫下攪拌2小 102763.doc -98- 1299991 時。此時間之後,添加1 N HC1(24毫升)並將該反應物攪拌 1小時。添加Et2〇(25毫升),且分出有機層並用Η2〇(2χ:25 毫升)洗滌。經合併之水性層用Et20(3x50毫升)萃取。經合 併之有機萃取物經乾燥(MgS〇4)並在真空下濃縮以生成粗 產物。此產物藉由快速層析法(Si,25x160毫米,溶於己 烧中之EtOAc的梯度為0至50%)純化以生成一無色固體狀1-(4-氟笨基)-1-羥基丙酮。R,= 〇·31 (20% EtOAc/己烷)。1H NMR (CDC13, 500 ΜΗζ)δ 7.29 (m, 2H), 7.08-7.04 (m, 2H), 5.06 (d, J = 3.6 Hz3 1H), 4.35 (t3 J = 6.5 Hz, 1H), 2.05 (s, 3H)。 實例57
赤型-與蘇型-1-(4-氟苯基)-2-({[5’-異丙基-2,-甲氧基-4-(三 氟甲基)聯苯基-2-基]甲基}胺基)丙-1-醇 於室溫下,向一 {[5* -異丙基-2^甲氧基-4-(三氟甲基)聯 苯基-2·基]甲基}胺(67毫克,0.204毫莫耳)與二氣苯 基)-1-經基丙酮(45毫克,0.204毫莫耳)溶於MeOH的溶液 中添加NaCNBH3(19毫克,0.306毫莫耳),之後添加乙酸(2 滴)。將該反應物於室溫下攪拌5小時。反應混合物用 EtOAc(20毫升)、H2〇(20毫升)以及鹽水(5毫升)稀釋。水 性層用EtOAc(2x20毫升)萃取。經合併之有機萃取物經乾 102763.doc -99- 1299991 燥(Na2S〇4)並在真空下濃縮以生成粗產物。此產物藉由快 速層析法(Si,12x160毫米,溶於己烷中之玢〇八〇的梯度為 0至50%)純化以生成兩種可能之無色油狀非對映異構體, 赤型-1-(4-氟苯基)-2_({[5’_異丙基_2,_甲氧基-4-(三氟甲基) 聯本基-2-基]甲基}胺基)丙_1_醇(68.4亳克)與蘇型_ι_(4_氟 苯基)-2-( {[5f-異丙基-2’-甲氧基-4-(三氟甲基)聯苯基基] 甲基}胺基)丙-1-醇(48.9毫克)。赤型-非對映異構體:R/ = 0.40(20% EtOAc/己烷)。LCMS計算值=476.22 ;試驗值= | 476.2 (M+l)+。巾 NMR (500 MHz,CDC13)3 7.72 (s5 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.36 (m5 1H), 7.27 (dd, J = 8.5, 2.3 Hz, 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 = 8·0 Hz,6H),0·64 (t,/ = 5·4 Hz,3H)。蘇型-非對映異 構體:R/ = 0·20 (20% EtOAc/ 己烷)。LCMS 計算值= 476.22 ;試驗值=476·2 (M+l)+。4 NMR (500 MHz, CDC13)5 7.73 (d, 9.0 Hz, 1H), 7.58 (d, 7.9 Hz? 1H), • 7.32 (m,1H),7·24 (m,3H),7.07-6.97 (m,3H),6·92 (d,/ = 8.5 Hz,1H),4.05 (d,7·9 Hz,1H),3·82·3·70 (m,5H), 3.59 (d, 13 Hz, 1H), 3.51 (d5 J - 13 Hz, 1H)5 2.90 (m, 1H),2·51 (m,1H),1.25 (m,6 H),0·73 (d,/ = 6.4 Hz, 3H) 〇 實例58 102763.doc -100 - 1299991 聯 苯基-2·基]甲基卜
同實例7之步 算值=502.20
3_{[5’_異丙基_2’_甲氧基_4-(三氟甲基) 4-甲基-1,3-噁唑烷-2-酮 驟 3。R/= 〇·3 8(20% EtOAc/己烷)。LCMS計 ;試驗值=502.2 (M+l)+。lH NMR (500
MHz,笨-d/; ! 滯轉異構體混合物)δ 7.96 (s,0·5Η),7.75 (s,0·5Η),7 3W… •Μ (d,7.7 Ηζ,1Η),7.10-7.06 (m,2Η),6·94 (d’ / 一 2·1 Ηζ,〇·5Η),6.88 (d,J = 2.1 Ηζ,0·5Η),6.69-6.62 (m’ 4·5Η),6,55 (d,J= 8·4 Ηζ,0.5Η),4.95 (d,15.9 Ηζ, 〇·5Η), 4.86 (d, j = 15.8 Ηζ5 0.5Η), 4.80 (d, J = 7.9 Ηζ5 〇·5Η),4.7G (d,/ = 7·8 Ηζ,〇·5Η),4』4 (d,J = 15.8 Ηζ, 〇·5Η),3·93 (d,ι5·9 Ηζ,0.5Η),3·36 (s,1.5Η),3·22 (s, 1.5Η),3·14 (m,〇·5Η),3·05 (m,0·5Η),2.79-2.71 (m,1Η), 1.18 (m, 6Η), 0.02 (d, J = 6.5 Hz, 1.5H), -0.04 (d5 J = 6.5 Hz,1.5H)。使用對掌性HPLC(AD管柱,20x250毫米,溶 於庚烷之3% EtOH)可將該化合物分成其兩種對映異構體 (4i?,5iS)-5-(4-氣苯基)-3-{[5’-異丙基-2’-甲氧基-4·(三象甲 基)聯苯基-2-基]甲基}-4-甲基-1,3-噁唑烷-2-_與(4&5幻_ 5-(4-氟苯基)-3-{[5,-異丙基-2,-曱氧基-4-(三氟甲基)聯苯 基·2·基]曱基卜4-曱基-1,3-噁唑烷-2-酮。 102763.doc -101- 1299991 遵循實例58中概述之程序來製備列於表2之化合物: 表2
實例 R LCMS (M+l)+ 59 〇 乂)..,〃(^F 502.2 60 °、消旋 502.2 61 。叫 CI 552.2 62 CI 552.2 63 Cl外消旋 552.1 實例64 102763.doc 102- 1299991
MeO, F3C, % l-{[5f-異丙基-2’-甲氧基-4_(三氟甲基)聯苯基-2-基]甲基卜 4-苯基β比洛唆-2-嗣 於室溫及Ν2下,將雙(三甲基甲矽烷基)醯胺鈉(114微升 溶於THF之1 Μ溶液,0.114毫莫耳)添加至一經攪拌之4-苯 基吡咯啶-2-酮(Winans,C. F·,Adkins,Η·,丄 乂所· C/2em. 5W·,1933,55,4167-4176)(17 毫克,0.103 毫莫耳)溶於無 水THF(1毫升)的溶液中。攪拌該反應物5分鐘,並藉由套 管添加2-(溴甲基)-5’-異丙基-2^甲氧基-4-(三氟甲基)聯苯 基(20毫克,0.0516毫莫耳)溶於無水THF(2毫升)的溶液。 將該反應物於室溫下攪拌3天。反應物用飽和NH4C1(10毫 升)猝滅並用EtOAc(3><20毫升)萃取。經合併之有機萃取物 用鹽水(10毫升)洗滌,經乾燥(Na2S〇4)並在真空下濃縮以 生成粗產物。此產物藉由快速層析法(Si,丨2x160毫米, 溶於己烷中之EtOAc的梯度為〇至9〇%)純化以生成一無色 油狀1-{[5’·異丙基-2’-曱氧基_4-(三氟甲基)聯苯基-2-基]甲 基卜4-苯基吼咯啶酮。R, = m (2〇% Et〇Ac/己烷)。 LCMS計异值=468.22 ;試驗值=468.2 (M+l)+。lH NMR (600 MHz,苯-d6,1:1之滯轉異構體混合物)δ 7.79 (s, 0.5Η),7.73 (s,0·5Η),7·33 (d,J = 7.7 Ηζ,1Η),7.08-7.04 102763.doc -103- 1299991 6·88 (s,0.5H),6.76 ^ 8.5, 3.1 Hz, 1H)5 13.9 Hz, 1H), 3.29 3H), 2.63-2.57 (m, 叫,1.20-1.16 (m, (m,4H),6.99 (m,1H),6.92 (s,0·5Η), (dd? J = 16.0, 7.4 Hz, 2H)? 6.60 (dd, j 4.58 (d,/ = 15.4 Hz,1H),4·38 (t, (s,1.5H),3.26 (s,1.5H),2.85-2.73 (m, 1H),2.38-2.28 (m,1H),2.21-2.11 (m, 6H) 〇 實例65
二氣苯基)小狀·異丙基·2,_甲氧基(三氣甲基)聯 本基-2-基]甲基比洛咬_2__ 藉由一類似於實例64之方法,以/ 二氟苯基比咯 淀-2-酮(藉由一類似於Marivet,M. 〇 t·,Bourguignon, J.
J· ; Lugnier,C·,Mann,A·,Stoclet,J • l·,Wermuth,C. -G· J. Md. C心m·,1989, 32, 1450-1457中之方法製備)起始來 製備。LCMS計算值=504.20 ;試驗值=504·2(Μ+1)+。 實例66
102763.doc 104- 1299991 5-[3,S-雙(三氟甲基)苯基】-3·[2-碘-5-(三氟甲基)苄基】1>3_ 噁唑烷_2-酮 在一 N2氣氛中,用溶於THF(1毫升)之5_[3,5·雙(三敗甲 基)苯基]-1,3_σ惡吐烧-2-酮(500毫克,1.67毫莫耳)於〇°c下 處理一經攪拌之氫化鈉溶於THF(5毫升)之懸浮液(6〇%,於 油中,167毫克,4· 18毫莫耳)。攪拌該反應物20分鐘,並 逐滴滴加2-(漠、曱基)-1 -破-4-(三氟曱基)苯(610毫克,;[· 67 毫莫耳)溶於THF (1毫升)的溶液。將該反應物於室溫下擾 拌18小時。該反應物用H2〇(l毫升)猝滅並分配在EtOAc(80 毫升)與H2〇(25毫升)之間。水相用EtOAc(2x20毫升)重新 萃取,且經合併之有機萃取物用鹽水(3〇毫升)洗滌,經乾 燥(MgS〇4)並在真空下濃縮以生成粗產物。此產物藉由快 速矽膠層析法(溶於己烷中之EtOAc的梯度為0至30%)純化 以生成5-[3,5_雙(二氟甲基)苯基]_3-[2-埃-5-(三氯1甲基)节 基]1,3-噁嗤烷-2·酮。R/= 0.55 (515% EtOAc/己烷)。LCMS 584 (M+l)+。lH NMR (CDC13, 500 ΜΗζ) δ 8.05 (d,/= 8.2 Hz,1H),7.95 (br s,1H),7.85 (br s,2H),7.51 (br s,1H), 7.32 (m, 1H), 5.72 (t, J = 8.0 Hz, 1 H), 4.74 (d, J = 15.5 Hz,1H),4.64 (d,/ = 15·3 Hz),4.14 (t,J = 7.1 Hz,1H), 3.47 (dd,J = 7.1,1.6 Hz) 〇 實例67 102763.doc -105- 1299991
_4H3都,_異丙基_2’_甲氧基_4_(三氟甲基)聯苯基_ 2-基]甲基卜1,3_噁唑烷酮 步驟A : (4外4-节基_3_[2冬5(三氣甲基)节基】^•嚼唾 - 2 - 8¾ 在一 N2氣氛中,用溶於THF〇毫升)之(3)_4_苄基_2-噁唑 烷酮(49毫克,〇·27毫莫耳)在〇它下處理一經攪拌之氫化鈉 溶於THF(3毫升)的懸浮液(60。/〇,於油中,27毫克,〇·68毫 莫耳)。授拌該反應物20分鐘,並逐滴滴加2-(溴曱基)_卜 埃-4-(二氟甲基)苯(1〇〇毫克,〇·27毫莫耳)溶於thf(1毫升) 的溶液。於室溫下攪拌該反應物ί8小時。該反應物用 Η2〇( 1宅升)猝滅並分配在EtOAc(80毫升)與Η2〇(25毫升)之 間。水相用EtOAc(2x20毫升)重新萃取,且經合併之有機 萃取物用鹽水(30毫升)洗滌,經乾燥(MgS〇4)並在真空下 濃縮以生成粗產物。此產物藉由快速石夕膠層析法(溶於己 烷中之EtOAc的梯度為0至30%)純化以生成(45>4-苄基-3-[2-蛾-5_(三氟曱基)苄基]1,3-。惡。坐烧-2-酮。R/ = 〇·45 (15% EtOAc/己烷)。LCMS 462 (M+l)+。1H NMR (CDC13,500 MHz) δ 8.04 (d, J= 8.2 Hz5 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,16.0
Hz, 1H)5 4.49 (d5 J = 16.1 Hz), 4.28 (t, J = 8.7 Hz5 1H)3 102763.doc -106- 1299991 4.25 (t? J = 9.1, 4.8 Hz, 1H), 3.94 (m, 1H)5 3.16 (dd? J = 13.5, 4·8 Hz,1H),2·73 (dd,/= 9.1,4·4 Hz,1H)。 步驟8:(45>4_苄基-3-{[5’-異丙基-2,_甲氧基-4_(三氟甲 基)聯苯基-2-基]甲基}-1,3_。惡嗤烧_2-酮 將一經攪拌之(45)-4-苄基-3-[2-峨-5-(三氟甲基)苄 基]1,3-噁唑烷-2-酮(63毫克,0.137毫莫耳)、2-甲氧基-5-異丙基苯基硼酸(52毫克,0.274毫莫耳)、K2C〇3(47毫 克’ 0.34毫莫耳)與Pd(〇Ac)2(9 2毫克,〇 〇137毫莫耳)溶於 _ 丙綱:H2〇(5:1) (6毫升)中的懸浮液加熱至回流並維持!小 牯。在真空下濃縮該反應混合物,用h2〇(15毫升)稀釋並 用EtOAC(3x3〇毫升)萃取。經合併之有機萃取物用鹽水(3〇 笔升)洗滌,經乾燥(MgS〇4),過濾並濃縮。所得粗產物藉 由矽膠快速層析法(溶於己烷中之EtOAc的梯度為〇至20%) 、、’屯化成(4*S) ‘苄基·3·( [5’_異丙基_2’_曱氧基-4-(三氟曱基) 聯苯基_2_基]甲基噁唑烷-2-酮。R/ = 0.35(15% _ Et〇Ac/己烷)。LCMS 484(M+1)+。1H 丽R(CDC13,500 MHz)(存在滯轉異構體;於lH NMR中觀察到一些峰加倍) δ 7.72 (br s 1Η),7·65 (br s,1Η),7·42 (m,lH),mm (m,3H),7·08 (d,2.3 Hz,1H),6.90-6.84 (m,3H),4.80 (d5 J = 15.8 ih), 4.35 (d, J = 15.8 Hz)? 4.28 (t, J = 8.7 Hz, 1H)5 3.96^3.92 (m5 3H), 3.78 (s5 3H)5 3.62-3.52 (m5 1H),2·94·2·86 (m,1H),2·82 (dd,9.4, 3·9 Hz,1H),2.42 (dd,9.6, 3.9 Hz),1.26 (s,3H),1.10 (s,3H)。 實例68 102763.doc -107- 1299991
2-碘-5-(三氟甲基)苯甲酸
將氫氧化鉀(3.78克;〇·0673莫耳)添加至一經攪拌之2_ 碘-5-(二氟甲基)苯甲腈(實例2 ; 4克;〇.〇135莫耳)溶於1:1 異丙醇· Η20溶液(60毫升)的溶液中。將該反應物加熱至 回流並維持14小時,然後其分配在Η2〇(5〇毫升)與 EtOAc(50毫升)之間。水性層用Et〇Ac(5〇毫升)萃取並用6 N HC1酸化至pH 5。水性層進一步用Et〇Ae(4x5〇毫升)萃 取,且經合併之萃取物用鹽水(5〇毫升)洗滌,經由Μ0〇4 乾燥’經過濾並在真空下濃縮以生成一黃色固體狀2_碘_5_
(二氟甲基)苯甲酸。LCMS = 317·0 (M+l)+。lH NMR (CDC13, 500 MHz) : 5 8.27 (d, / = ι.6 Hz, 1 H)5 8.25 (d,
f3c 實例69
OH
[2_蛾-5-(三氟甲基)苯基】甲醇 於〇C及N2下,將硼烷_THF(溶於THF之1.0 μ溶液;94 毫升;94毫莫耳)添加至一經攪拌之2_碘_5_(三氟甲基)苯甲 酸(2.97g ; 9.4毫莫耳)溶於THF(3〇〇毫升)的溶液中。將該 反應物加熱至回流並維持9〇分鐘,且然後小心地用6 N HC1猝滅直到不再有氣體產生為止。用H2〇(25〇亳升)稀釋 該反應物並用EtOAc(3x250毫升)萃取之。經合併之萃取物 102763.doc -108- 1299991 用鹽水(300耄升)洗滌,經由MgS〇4乾燥,過濾並在真空 下濃縮。粗產物藉由快速層析法(0至25% EtOAc/己烷梯 度)純化以生成白色固體狀[2-碘-5-(三氟甲基)苯基]甲醇。 LCMS = 285.0 (M _ 17)+。lH NMR (CDC13, 500 MHz) : (5 7·97 (d,8.3 Hz,1 H),7.79 (s,1 H),7.28 (d,8.4 Hz, 1 H),4·75 (s,2 H)。 一可選程序如下:向一溶於THF(100毫升)與水(i〇毫升) 之2-蛾-5-(三氟甲基)苯甲醛(實例8〇,步驟a,9克)的0°C溶 液中添加NaBH4(0.5克)。攪拌該反應物30分鐘。向該反應 混合物中添加稀釋的HC1水溶液(要謹慎)。用醚萃取該混 合物’且用水洗滌醚層,然後用鹽水洗滌之。然後,醚層 經由無水MgSCU乾燥,過濾並濃縮。該物質於Si〇2上進行 層析(使用一 1:3 CH2C12/己烷分級梯度,然後用1:1 CH2C12/ 己烷,然後再用100% CH2C12)以生成一白色固體狀[2-碘-5-(三氟甲基)苯基]甲醇。
f3c 實例70
2-(溴乙基)-1·碘-4_(三氟甲基)苯 於0°C及N2下,將四溴化碳(1.86克;5.6毫莫耳)與三苯 基膦(1.47克;5.6毫莫耳)相繼添加至一經攪拌之[2-碘-5-(三氟曱基)苯基]甲醇(1.13克;3.74毫莫耳)溶於CH2Cl2(25 毫升)的溶液中。將該反應物於室溫下授拌4 8小時。添加 一第二當量的四溴化碳(1.2克;3.74毫莫耳)與三苯基膦 102763.doc -109- 1299991 (0.98克’ 3.74¾莫耳)’ 將該反應物携拌額外η小時。 在真空下去除溶劑’且殘留物藉由快速層析法(〇至25%之 EtOAc/己院梯度)純化以生成一澄清油狀2韻乙基^ _蛾_ 4-(三氟甲基)苯。1H NMR (CDC13, 500 MHz): 6 8.02 (d, J = 8.2 Hz, 1 Η), 7.73 (d, J = 1.8 Hz, 1 H), 7.26 (dd, J = 8.3,1.8 Hz,1 H),4.64 (s,2 H)。 實例71
5_[3,5·雙(二敗甲基)苯基卜惡唾燒_2•酮
遵循實例13中所述程序,546克2_胺基—1-[3,5_雙(三氟 甲基)苯基]乙醇可生成一米黃色固體狀5^3,5-雙(三氟曱 基)本基]-1,3-福嗤烧 。LCMS = 300.1 (M+l)+。lH NMR (CDCI3,500 MHz) : δ 7·94 (s,1 Η),7·89 (s,2 Η), 5·81_5.77 (m,1 Η),5·29 (s,1 η),4.17-4.12 (m,1 Η),3.59腾 _ 3·55 (m,1 Η)。 實例72
5-[3,5-雙(三氟甲基)苯基卜3_{[4,_氟j,異丙基-2,_甲氧基_4- 102763.doc •110- 1299991 (三氟曱基)聯苯基-2-基】甲基}_1,3_噁唑烷-2_酮 將一存於5:1丙酮/水(6毫升)中之5-[3,5-雙(三氟甲基)苯 基]-3-[2-埃-5-(三氟甲基)苄基]-1,3-«惡吐院_2-_(60毫克; 0·103毫莫耳)、(4-氟-5-異丙基-2-甲氧基苯基)硼酸(27毫 克;0.129毫莫耳)、乙酸鈀(7毫克;0·0103毫莫耳)與碳酸 鉀(3 6毫克;0 · 2 5 7毫莫耳)的混合物加熱至回流並維持1小 時。在真空下去除丙酮,且殘留物用Η2〇( 10毫升)稀釋並 用CH2Cl2(3xlO毫升)萃取。經合併之萃取物用鹽水(1〇毫 φ 升)洗滌,經由Na2S〇4乾燥,經過濾並在真空下濃縮。殘 留物藉由快速層析法(0至25%之EtOAc/己烷梯度)純化以生 成一透明玻璃狀5-[3,5-雙(三氟曱基)苯基]-3-{[4,·氟-5,異 丙基-2^曱氧基-4-(三氟甲基)聯苯基-2-基]甲基卜1,3_嚼嗤 烷-2·酮。LCMS = 624·2(Μ+1)+。lH NMR (苯-d6,500 MHz,滞轉異構體之 1:1 混合物):δ 7·60 (s,1·5 H),7.45 (s, 0.5 H),7.31-7.25 (m,3 H),6.98-6.94 (m,1 H),6.87-6.82
(m, 1 H), 6.43-6.37 (m, 1 H), 4.54 (d5 J= 15.6 Hz, 0.5 H)? 修 4.40-4.36 (m5 1 H)5 4.47 (d5 J = 15.6 Hz5 0.5 H), 3.96 (d, J =15.5 Hz,0·5 H),3.80 (d,/= 15.8 Hz,0.5 H),3.24-3.15 (m,1 H), 3.02 (s,3 H),2.62-2.58 (m,0.5 h),2.53-2.48 (m? 0.5 H), 2.12-2.07 (m, 0.5 H)5 2.04^2.00 (m, 0.5 H)1.22-1.11 (m,6 H)。 藉由對掌性HPLC(使用15% IPA/庚烷以及一〇d管柱)可 將外消旋物質分成其兩種對映異構體。 (5i?)-5-[3,5-雙(三氟甲基)苯基]-3_{[4,_氟-5,異丙基_2,·甲 102763.doc -111- 1299991 氧基-4-(三氟曱基)聯苯基-2-基]甲基}-l,3-噁唑烷-2-酮: LCMS = 624·2(Μ+1)+。1H NMR (苯-d6, 500 MHz,滯轉異 構體之 1:1 混合物):δ 7.62 (s,1.5 H),7.47 (s,0.5 H),7.34- 7.27(m,3H),6.99-6.95 (m,lH),6.88-6.83 (m,lH),6.44· 6.39 (m,1 Η),4·54 (d,《/= 15·5 Ηζ,0·5 H),4.47-4.41 (m,1 H)? 4.33 (d, J = 15.6 Hz, 0.5 H)? 3.98 (d? J = 15.7 Hz, 0.5 H),3.82 (d,J = 15.8 Hz,0.5 H),3.24-3.15 (m,1 H), 3.05
(s? 3 H), 2.67-2.62 (m, 0.5 H)? 2.57-2.52 (m5 0.5 H)5 2.16-2.11 (m,0.5 H),2.09-2.04 (m,0.5 Η)1·22·1·11 (m,6 H)。 (55>5-[3,5_雙(三氟甲基)苯基]-3-{[4’-氟-5’異丙基·2’-Τ 氧基-4-(二氣甲基)聯苯基-2-基]甲基}· 1,3 - ^惡ϋ坐烧-2 -嗣: LCMS = 624·2(Μ+1)+。lH NMR(苯-d6,500 MHz,滯轉異 構體之 1:1 混合物):5 7.63(8,1.5 11),7.48(8,0.5 11),7.35· 7.27(m,3H),7.00-6.95 (m,lH),6.88-6.83 (m,lH),6.44-6.38 (m, 1 Η), 4.54 (d, J= 15.8 Hz, 0.5 H)5 4.48-4.42 (m? 1 H), 4.34 (d, J - 15.8 Hz, 0.5 H)5 3.99 (d? J = 15.8 Hz, 0.5 φ H),3.83 (d,/ = 15.8 Hz,0.5 H),3.25-3.15 (m,1 H),3.05 (s5 3 H)3 2.68-2.63 (m? 0.5 H)5 2.58-2.53 (m3 0.5 H)? 2.18-2.12 (m,0·5 H),2.10-2.05 (m,0·5 H),1.23-1.11 (m,6 H)。 實例73
102763.doc -112- 1299991 步驟1 : (4S,5i?)-5-[3,5-雙(三氟甲基)苯基卜3_[2-碘-5_(三氟 甲基)苄基]-4-甲基·1,3-噪嗅烧_2_酮 於0°C及Ν2下,將一經攪拌之氫化鈉存於thf(60毫升)中 之懸浮液(於礦物油中之60%分散液;1 _3克;0.0325莫耳) 逐滴滴加至一(4S,5i?)-5-[3,5-雙(三氟甲基)苯基]-4-甲基-1,3-噁唑烷-2-酮(實例17)(4.077克;0.013莫耳)溶於THF(50 毫升)的溶液中。觀察到有氣體產生。將所得混合物於〇°c 下攪拌30分鐘,然後添加一 2-(溴甲基)_1_碘-4-(三氟甲基) • 苯(4.754克;0.013莫耳)溶於THF(20毫升)的溶液。將該反 應物加溫至室溫並攪拌14小時。小心地用H20(15毫升)猝 滅該反應並且反應物分配在EtOAc (25 0毫升)與H2 0(75毫 升)之間。水性層用EtOAc(3xlOO毫升)萃取。經合併之有 機層用鹽水(100毫升)洗滌,經乾燥(MgS04),過濾並在真 空下濃縮。殘留物藉由快速層析法(0至20%之EtOAc/己烷 梯度)純化以生成6.4克(82.5%)白色固體狀5-雙(二氟曱基)苯基]-3-[2-蛾- 5-(三氟^甲基)节基]-4 -甲基-1,3_ • 惡唾烧-2-酮。LCMS = 598.1 (M+l)+。4 NMR (CDC13, 500 MHz) : δ 8.03 (d, J= 8.2 Hz, 1 H), 7.90 (s, 1 H), 7.79 (s,2 H),7.58 (s,1H),7.30 (dd,/ = 8.2 Hz,J = 2.0 Hz,1 H),5.76 (d,J = 8 Hz,1 H),4·88 (d,15.8 Hz,1 H),4·37 (d, J = 15.8 Hz, 1 H), 4.09-4.02 (m, 1 H)5 0.8 (d5 J = 6.6
Hz,3 H)、 步驟2 : (4S,5i?)-5-【3,5_雙(三氟曱基)苯基]-3-{【4,-氟_5,異 丙基-2f -曱氧基- 4-(三氟甲基)聯苯基-2-基]甲基}-4_曱基_ 102763.doc -113- 1299991 1,3-福峻烧_2_酮 將一經攪拌之存於C6H6/EtOH/H2O(120毫升/17毫升/51毫 升)之(4*S,5i?)-5-[3,5-雙(三氟曱基)苯基]-3-[2-碘-5_(三氟曱 基)苄基]-4-甲基-1,3-噁唑烷-2-酮(4.29克;7.19毫莫耳)、 • (4-氟-5-異丙基-2-甲氧基苯基)硼酸(實例78)(4.57克; 21.57毫莫耳)、四(三苯基膦)鈀(〇)(1·〇克;0.86毫莫耳)與 碳酸鈉(6.35克)的混合物於N2下加熱至回流(100°C )並維持 14小時。該反應物分配在EtOAc(200毫升)與H20(100毫升) 赢 之間。水相用EtOAc(3x200毫升)萃取。合併之有機相用鹽 水(100毫升)洗滌,經乾燥(MgS04),過濾並在真空下濃 縮。殘留物藉由矽膠快速層析法(0至25%之EtOAc/己烷梯 度)純化以生成一黃色固體狀(45\5/?)-5-[3,5·雙(三氟甲基) 苯基]-3-{[4*-氟-5’異丙基-2’-甲氧基-4-(三氟甲基)聯苯基_ 2-基]甲基甲基-1,3-°惡嗤烧_2-_。為去除黃色雜質,將 2.7克溶於165毫升EtOH中並添加275毫克脫色焦碳(活性 碳,Daixo,G-60,100篩目粉末,Alddch)。將該混合物 • 於室溫下攪拌40分鐘,過濾並在真空下濃縮。用約25毫升 己烷研磨後生成一白色固體狀2.46克標題化合物。ιΗ NMR指示有微量雜質,其可藉由矽膠快速層析法(〇至15% 之EtOAc/己烷梯度)去除。殘留溶劑藉由自乙腈低壓凍乾 去除。LCMS - 638.3 (M+l)+。4 NMR (苯-d6,500 MHz, • 滞轉異構體之 1:1 混合物):δ 7.82 (S,〇·5 H),7.60 (s,0·5 Η), 7.57 (s, 1 Η), 7.33 (d, J = 8 Hz, 1H), 7.27 (d, J = 9.9 Hz3 2 H)? 7.02-6.98 (m5 1 H)? 6.89 (d, J = 8.5 Hz, 0.5 H)5 102763.doc -114· 1299991 6.82 (d,/ = 8.5 Ηζ,0·5 H),6.45 (d,/ = 12·1 Ηζ,〇·5 H), 6.35 (d,/= ΐι·9 Hz,0·5 H),4.94 (d,/=ι6·〇 Hz,〇·5 H), 4.87 (d, J = 15.8 Hz, 0.5 H), 4.54 (d5 J = 8.0 Hz, 0.5 H), 4.50 (d,/= 7.8 Hz,0.5 H),3.74-3.66 (m,1 H),3.23-3.15 (m,1 H),3·12 (s,1·5 H),2.99 (s,1·5 H),2.97-2.92 (m,〇·5 H), 2.89-2.84 (m, 0.5 H), 1.21-1.09 (m, 6 H), -0.27 (d, / = 6.7 Hz,1.5 H),-0·40 (d,/= 6.7 Hz,1·5 H)。 用於生成(45,51?)-5-[3,5_雙(三氟甲基)苯基卜異 • 丙基_2,_甲氧基_4-(三氟甲基)聯苯基-2-基]甲基}-4-甲基- 1,3-噁唑烷-2-酮之可選方法: 將一存於5:1丙酮/水(6毫升)之(4S,5i?)_5-[3,5-雙(三氟甲 基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-i,3-噁唑烷-2-酮(50毫克;0.084毫莫耳)、(4-氟-5-異丙基-2-甲氧基苯基) 硼酸(實例78,22毫克;〇.1〇5毫莫耳)、乙酸鈀(6毫克; 0.0103毫莫耳)與碳酸鉀(29毫克;0.257毫莫耳)的混合物 加熱至回流並維持1小時。在真空下去除丙酮,且殘留物 馨 用H2〇(l〇毫升)稀釋並用CH2Cl2(3xlO毫升)萃取。經合併 之萃取物用鹽水(10毫升)洗滌,經由Na2S〇4乾燥,經過渡 並在真空下濃縮。所得殘留物藉由快速層析法(〇至25%之 丑1〇八〇/己烷梯度)純化以生成一透明玻璃狀(4&5及)_5-[3,5-雙(三氟曱基)笨基]-3-{[4’-氟-5’異丙基_2’_甲氧基_4_(三氟 甲基)聯苯基-2-基]甲基卜4-甲基-1,3-噁唑烷-2-酮。 實例74 102763.doc -115- 1299991
(47?,Μ)-4-[3,5_雙(三氟甲基)苯基卜1-{[5,異丙基_2,甲氧 基-4-(三氟曱基)聯苯基_2-基]甲基卜5-甲基咪唑啶_2_酮 步驟A : (45,5呙_5_[3,5-雙(三氟甲基)苯基卜3{[5,_異丙基_ 2’-甲氧基-4_(三氟甲基)聯苯基基】甲基卜仁甲基-•噁 唑烷-2-酮 將((4&56>5-[3,5-雙(三氟曱基)苯基]-4-甲基-u•噁唑 烷-2-酮)(46.2毫克,〇·148毫莫耳)置於一乾燥燒瓶中並添 加DMA(3毫升)。添加NaHMDS(296微升溶於THF之1 Μ溶 液,0.296毫莫耳),且攪拌該反應物5分鐘。此時,藉由套 管將2*-(溴甲基)-5-異丙基-4,-(三氟甲基)聯苯基-2-基甲醚 (80.0毫克,0.207毫莫耳)添加於DMA(2毫升)中。30分鐘 φ 後,用飽和NH4C1(2毫升)猝滅該反應物。用EtOAc(40毫 升)稀釋此混合物。有機層用水(15毫升)與鹽水(15毫升)洗 滌,經由Na2S〇4乾燥,過濾並濃縮。殘留物使用25% EtOAc/己烷藉由快速層析法純化生成(4&55>5-[3,5-雙(三 氟甲基)苯基]-3-{[5’-異丙基-2*-甲氧基-4-(三氟曱基)聯苯 基-2-基]甲基}-4-甲基-1,3-噁唑烷-2-酮。R/ = 0.27(25% EtOAc/己烷)。LCMS = 620.2(M+1)+。1H NMR(CDCl3,500 MHz ;存在滯轉異構體)δ 6.90-7.88 (m,9H),4.04-5.05 (m, 102763.doc -116- 1299991 3H),3.25-3.74 (m,4H),2.88 (m,1H),1·19-1·24 (m,6H), 0.99-1.07 (m,3H)。 步驟B : (l&2S)-l-[3,5-雙(三氟甲基)苯基】-2·({[5,-異丙基-2f-甲氧基-4-(三氟甲基)聯苯基-2-基】甲基}胺基)丙-i-醇 向一(45,55>5-[3,5_雙(三氟甲基)苯基]_3-{[5,-異丙基_2,-甲氧基-4-(三氟甲基)聯苯基_2·基]甲基}·4-甲基-1,3-喔嗤 烷-2-酮(147.7毫克,0.239毫莫耳)溶於EtOH(7.5毫升)的溶 液中添加Η2〇(1·5毫升)與KOH(150毫克,2.67毫莫耳)。將 此溶液加熱至7 5 °C並保持3 0小時,然後冷卻至室溫。添加
EtOAc(75毫升)並用H2〇(15毫升)與鹽水(2x15毫升)洗滌有 機層。有機層經由Na2S〇4乾燥,過濾並濃縮。所得殘留 物藉由快速層析法純化以生成(1S,2S)-1_[3,5·雙(三氟甲基) 苯基]-2-({[5’-異丙基-2,-甲氧基_4-(三氟甲基)聯苯基_2-基] 曱基}胺基)丙小醇。R/= 0.44 (40% EtOAc/己烷)。LCMS = 594·2 (M+l)+。1H NMR (CDC13, 500 ΜΗζ)δ 6.93-7.78 (m, 9H),3.51-4.20(m,6H),2.91(m,lH),2.49(m,lH),1.22- 1.26 (m,6H),〇·79__0·81 (m,3H)。 步驟c :第三丁基{(15,25)_2_[3,5_雙(三氟曱基)苯基】_2_羥 基-i-曱基}{[s,_異丙基_2,_甲氧基(三氟甲基)聯苯基_2_ 基]甲基}胺基甲酸醋 ° ( ’之^)· 1 _[3,5·雙(二氟^甲基)苯基]-2-({[5’_異丙基_ 2甲氧基4-(二氟甲基)聯苯基_2_基]甲基丨胺基)丙-卜醇 (135.5¾克,〇·228毫莫耳)溶於CH2Ci2(5毫升)的溶液中添 加BOC2〇(49.7毫克,〇·228毫莫耳)。將該反應物於室溫下 102763.doc -117- 1299991 攪拌2天;在此期間,添加2份額外之b〇C2〇(各25毫克)。 2天後’ ?農縮此反應物,且殘留物使用2〇% EtOAc/己烧藉 由快速層析法純化以生成第三丁基{(1&2幻-2-[3,5-雙(三氟 甲基)苯基]-2-羥基_1_甲基}{[5’_異丙基_2,_甲氧基-4-(三氟 曱基)聯苯基-2-基]甲基}胺基曱酸酯。R/ = 0.41(40%
EtOAc/己烷)。LCMS = 594.2(M+l-BOC)+。 步称D :第三丁基{(1&2/?)_2-疊氮基_2-[3,5_雙(三氟甲基) 苯基】-1_甲基}{[5,-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基-Φ 2-基】甲基}胺基甲酸酯 向一乾燥燒瓶中裝入THF(1毫升)、二氮二甲酸二乙酯 (DEAD)(11微升,〇〇698毫莫耳)與二苯基磷醯基疊氮化物 (DPPA)(15微升,〇.〇698毫莫耳)。藉由套管將第三丁基 {(15,25>2-[3,5_雙(三氟甲基)苯基羥基小甲基乙 基}{[5’-異丙基_2’-曱氧基_4_(三氟曱基)聯苯基I基]曱基} 胺基甲酸酯(20·7毫克,0.0698毫莫耳)添加於THF(1毫升) 中。接下來添加Ph3P(18.3毫克,〇·〇698毫莫耳)。將該反 _應物於至溫下攪拌30分鐘,且然後添加額外之DEAD(11微 升,0.0698毫莫耳)、DPPA(15微升,〇〇698毫莫耳)與 Ph3P(18.3毫克,0·0698毫莫耳)。經額外3〇分鐘後,用 EtOAc(40毫升)稀釋該反應物並用水與鹽水(各15毫升)洗 滌。所得有機層經由Na2S〇4乾燥,過濾並濃縮。所得殘 留物使用15% Et〇Ae/己烧藉由快速層析法純化生成第三丁 基{(1㈣)-2-疊氮基-2-[3,5-雙(三氟f基)苯基]小甲基乙 基}{[5’-異丙基-2,-甲氧基_4_(三氟甲基)聯苯基_2_基]甲基} 102763.doc -118 - 1299991 胺基甲酸酯。R,= 0.60(25% EtOAc/ 己烷)。LCMS = 619.3(M+l-BOC)+ ο 步驟Ε : (li?,2S)_l-疊氮基_ΐ_[3,5-雙(三氟甲基)苯基】-TV- {[5’-異丙基-2’-甲氧基_4-(三氟甲基)聯苯基-2-基】甲基}丙-2-胺 向一第三丁基{(1&2及)_2_疊氮基_2-[3,5-雙(三氟甲基)苯 基]-1_甲基乙基}{[5,·異丙基-2,-甲氧基-4-(三氟甲基)聯苯 基-2-基]甲基}胺基甲酸酯(2毫克,0.030毫莫耳)溶於 • CH2Cl2(2毫升)的溶液中添加TFA(2〇〇微升)。將該反應物 於室溫下攪拌1小時,然後用CH2Cl2(25毫升)稀釋。用1 N NaOH(15毫升)洗滌此CH2C12溶液,且水相用CH2Cl2(25毫 升)重新萃取。合併有機萃取物,用鹽水(2〇毫升)洗滌之, 經由Na2S〇4乾燥,經過濾並濃縮。所得殘留物使用15〇/〇 EtOAc/己烷藉由快速層析法純化以生成疊氮基_ 1-[3,5-雙(三氟甲基)苯基異丙基·2,_曱氧基_‘(三 氟曱基)聯苯基-2-基]甲基}丙-2-胺。R/: 0.45(15% EtOAc/ Φ 己烷)。LCMS = 619·2(Μ+1).。 步驟F ·· (1Λ,25)_1_[3,5_雙(三氟甲基)苯基卜τν2-{[5,_異丙 基-2’-甲氧基-4-(三氟甲基)聯苯基_2_基]甲基}丙烷 二胺 向一(1足2幻-1_疊氮基-1-[3,5-雙(三氟曱基)苯基]_#_{[5,_ 異丙基-2’-甲氧基_4-(三氟甲基)聯苯基_2_基]甲基}丙_2_胺 (17.8毫克’ 0.0288毫莫耳)溶於THF(3毫升)的溶液中添加 Pt〇2(12毫克,〇·〇53毫莫耳)。將該反應物置於氫氣氣氛中 102763.doc -119- 1299991 並於室溫下攪拌3小時。藉由過濾去除觸媒並濃縮據液。 使所得殘留物通過一含〇至10% MeOH/CH2Cl2之短發膠检 塞以生成(1及,25)-1-[3,5-雙(三氟曱基)苯基]_#入{[5,_異丙 基_2、曱氧基-4-(三氟甲基)聯苯基-2-基]甲基}丙烷-1ϊ2•二 胺。LCMS = 619·2(Μ+1)+。 步驟G : (4i?,5S)-4-[3,5-雙(三氟甲基)苯基】q-us,·異丙基_
曱氧基-4-(三氟甲基)聯苯基-2-基]曱基卜5-甲基咪唑唆胃 2-fi^J ,將一(1及,2$)-1-[3,5-雙(三氟甲基)苯基]-iV2_{[5’_異丙基_ 2、甲氧基-4-(三氟甲基)聯苯基-2-基]曱基}丙烷-1,2-二胺 (8.0毫克,〇·〇135毫莫耳)溶於CH2Cl2(2毫升)的溶液冷卻 至〇°C並添加DIPEA(14微升,0.081毫莫耳),之後添加三 光氣(2毫克,0.00657毫莫耳)。將該反應物於〇°C下攪拌30 分鐘,然後用EtOAc(30毫升)稀釋。用飽和NaHC〇3(10毫 升)與鹽水(10毫升)洗條該反應物。所得有機層經由 Na2S〇4乾燥,過濾並濃縮。殘留物使用40% EtOAc/己烷 馨藉由快速層析法純化生成(4i?,5*S)-4-[3,5-雙(三氟甲基)苯 基]-1-{[5*-異丙基-21-甲氧基-4-(三氟曱基)聯苯基_2_基]曱 基}-5-甲基咪唑啶-2-酮。R/ = 0.24(40% EtOAc/己烷)。 LCMS = 619·2(Μ+1)+。lH NMR(CD2Cl2,600 MHz ;存在 滯轉異構體)δ 6·91-7·84 (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) 〇 實例75 I02763.doc -120- 1299991
(35,41〇-4_[3,5-雙(三氟甲基)苯基卜2][5,_異丙基-2,_甲氧 基二氟曱基)聯苯基-2-基】甲基}-3_甲基-1,2,5-嗟二嗤咬 1,1-二氧化物 將(1/?,25)-1-[3,5-雙(三氟甲基)苯基]_#2-{[5,-異丙基-2,-修 甲氧基-4-(三氟甲基)聯苯基-2-基]甲基}丙烷_1,2_二胺(15.9 毫克’ 0.0269毫莫耳)、磺醯胺(4毫克,0.0403毫莫耳)與吡 咬(600微升)裝入一玻璃反應管中。用n2沖洗該管,將其 密封後加熱至120°C並維持2小時。然後將該反應物冷卻至 室溫,用EtOAc(40毫升)稀釋並用H2〇、1 N HC1與鹽水(各 !〇毫升)洗滌。有機層經由Na2S〇4乾燥,過濾並濃縮。使 用25% EtOAc/己烷藉由快速層析法純化殘留物生成 (35,4/?)-4_[3,5-雙(三氟甲基)苯基]_2-{[5,-異丙基_2,_甲氧 ^ 基-4-(三氟曱基)聯苯基-2-基]甲基}-3-甲基-1,2,5-噻二唑咬 1,1-二氧化物。R,= 0.27 (25% EtOAc/ 己烷)。LCMS = 65 5·2 (M+l)+。lH NMR (C6D6,500 MHz ;存在滯轉異構 體)δ 6.51-8.19 (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)。 實例76
I
102763.doc -121 - 1299991 2 -敗-1-異丙稀基-4-甲氧基苯 步驟A : 2-(2-氟-4-甲氧基苯基)丙-2-醇 向一 2,-氟-4,-甲氧基苯乙酮(4·45克,26·5毫莫耳)溶於 THF(5〇毫升)的〇°C溶液中添加2·4 M MeMgBr(11.6毫莫 耳,27.8毫莫耳)溶液。於0°C下攪拌該混合物,然後在室 溫下授拌4小時。該反應物用飽和氯化錢溶液猝滅。有機 物用乙酸乙酯(3x50毫升)萃取。經合併之乙酸乙酯層用鹽 水洗滌並經由硫酸鈉乾燥。通過快速管柱(使用EtOAc:己 φ 烧=2:8作為洗提液)後獲得一油狀醇。 步驟B : 2_氟-i_異丙烯基曱氧基苯 向一 2_(2_氟_4·曱氧基苯基)丙-2_醇(來自步驟a)(3.89 克’21·14毫莫耳)溶於二氯甲烷(5〇毫升)的溶液中添 加1^(:1(1.95毫升,25.4毫莫耳)與三乙胺(6」2毫升,46.5 耄莫耳)。於0 °C下授拌該溶液,然後在室溫下攪拌2小 時。用二氣甲烷00毫升)稀釋此溶液,用水洗滌並經由硫 酸鈉乾燥。通過快速管柱(使用Et〇Ac:己烧=1:9作為洗提 _液)後獲得一油狀標題化合物。lH NMR (CDC13, 500 MHz) δ 7.25 (t,/= 9.0 Hz,1H),6.68 (dd,8.5, 2·5 Hz,1H), 6.63 (dd, 13, 2·5 Hz,1H) ’ 5.20 (d,/ = 17.0 Hz,2H), 3.82 (s,3H),2.18 (s,3H)。 生成2-氟-1_異丙烯基甲氧基苯之可選途徑·· 將一溶於四氫呋喃(714毫升,〇·714莫耳)之1() “雙(三 甲基甲矽烷基)醯胺鈉的溶液添加至溴化甲基三苯基鱗(255 克,0.714莫耳)(2·5〇公升)在THF中的懸浮液(經冰浴冷卻) 102763.doc -122- 1299991
80毫升)蘇滅,其Fal可觀家$丨丨銘名& i ^
縮至一漿液,用7:2己烷:乙酸乙酯稀釋, )。將混合物濃 並使其靜置過 夜。藉由過濾去除固體並將濾液濃縮成黃色油。經快速管 _ 柱(使用9 · 1己烧·乙基作為洗提液)後得到標題化合物。 實例77
1-氟-4·碘-2-異丙基-5-甲氧基苯 在1大氣壓並存在催化量Pd/C的情況下向一 2-氟_1βι異丙 烯基-4-曱氧基苯(實例76,1.96克,11.81毫莫耳)溶於 MeOH(30毫升)的溶液充入氫氣。將該混合物於室溫下授 拌1小時。通過矽藻土過濾該混合物。然後將濾液添加至 存於1\^〇11(10耄升)之硫酸銀(3.68克,11_81毫莫耳)與埃 (3 ·00克’ 11 · 8 1毫莫耳)的混合物中。將該混合物於室溫下 授拌3小時直到溶液顏色變為淺黃色。過濾該混合物並濃 縮渡液。通過快速管柱(使用EtOAc:己烷5:95(作為洗提 液))後得到標題化合物。lH NMR (CDC13,500 ΜΗζ) δ 7.61 (d,8.0 Ηζ,1Η),6.56 (d,/= 12.5 Hz, 1Η),3.90 (s, 3H),3.18 (m,1H),1.28 (m,6H)。 102763.doc •123- 1299991 實例78
(4-氟-5-異丙基-2-甲氧基苯基)硼酸 向一 1_氟-4-峨-2-異丙基_5 -甲氧基苯(實例77,2.61克, 8.88毫莫耳)溶於THF的-78°C溶液中逐滴滴加正_BuLi(4.26 毫升,10·65毫莫耳,2·5 Μ)。將該溶液於_78°C下攪拌30 分鐘。添加三曱基硼酸酯(2.98毫升,26.6毫莫耳)。然 • 後,將該溶液於_78°C攪拌3小時。在_78。(:下用飽和氯化銨 猝滅該反應物’並將此混合物加溫至室溫。所得有機物用 乙酸乙酯(3x50毫升)萃取。經合併之乙酸乙酯層用鹽水洗 滌並經由硫酸鈉乾燥。得到一固體狀標題化合物,其純度 足以用於下一步。用石夕膠進一步純化會造成產物分解。i Ή NMR (CDC13, 500 MHz) δ 7·74 (d,10.0 Ηζ,1Η),6.62 (d, J= 12.5 Hz, 1H), 5.65 (br s, 2H), 3.92 (s, 3H), 3.20 (m, 1H),1·22 (m,6H)。 ⑩ 實例79
I
(45,5i?)-5-[3,S-雙(三氟甲基)笨基]_3_[(扣氣_4,-氟_5,_異丙 基_2,_甲氧基聯苯基-2-基)甲基卜‘甲基_ι,3-噁唑燒酮 102763.doc -124- 1299991 步驟A: 1-溴-2-(溴曱基)-4-氣苯 將一存於四氯化碳(50毫升)之2-溴-5-氯-甲苯(2·〇〇克, 9.75毫莫耳)、>^8(2.08克,11.7毫莫耳)與催化量八13;^的 混合物於回流條件下攪拌4小時。TLC(EtOAc··己烷=5:95) 顯示無起始材料。將該混合物過濾並將濾液濃縮。通過快 速管柱(使用EtOAc:己烷=5:95作為洗提液)後得到一白色 固體狀標題化合物。1H NMR (CDC13, 500 ΜΗζ) δ 7.53 (d, J = 9.0 Hz, 1H), 7.47 (d, J =2.5 Hz5 1H), 7.18 (dd, J = 8.5, I 2·5 Hz,1H),4.60 (s,2H)。 步驟B.(4S,5i?)_5_[3,5-雙(三氟甲基)苯基】_3_(2_溴_5_氣节 基)-4-甲基-1,3-嚼嗤烧-2-酮 向一(4S,5R)-5-[3,5-雙(三氟甲基)苯基卜4_甲基4,3_噁唑 烷-2-酮(0.050克,〇·16毫莫耳)溶於THF(1毫升)的〇。〇溶液 中添加ΝαΗ(7·6毫克,〇·19毫莫耳,60%)。將該混合物於〇 C下授拌30分鐘。添加來自步驟a的標題化合物(〇 〇59 克’ 0·2 1毫莫耳)。將全部混合物於〇〇c下攪拌1小時並加溫 籲至室溫維持4小時。用飽和氣化銨猝滅該反應。用乙酸乙 酯(3 X 15毫升)萃取有機物。經合併之乙酸乙酯層用鹽水洗 滌並經由硫酸鈉乾燥。經製備型TLC(使用Et〇Ac:己烷= 2.8作為洗提液)純化後得到標題化合物。ih NMR (CDC13, 500 ΜΗζ) δ 7.92 (s3 1H), 7.82 (s, 2H)5 7.55 (d5 J = 8.5 Hz5 1H), 7.43 (d, J = 2.5 Hz3 1H)5 7.23 (dd5 J = 8.5? 2.5 Hz3 1H),5.77 (d,/ = 8.0 Hz,1H),4.86 (d,《7 = 16·0 Hz,1H), 4.36 (d5 16.0 Hz, 1H)? 4.11 (m, 1H), 0.82 (d5 6.5 Hz, 102763.doc -125- 1299991 步驟C.(4S,5i〇-5-[3,5•雙(三氟f基)苯基】_M⑷氣4 ι 5’-異丙基-2’-甲氧基苯基_2_基)甲基卜‘甲基噁唑烷_2_ 將一存於丙酮/水(4:1)混合物中之(4&5及卜5_[3,5•雙(三氟
耄克,0.085毫莫耳)、(4-氟-5-異丙基甲氧基苯基)硼酸 (只例78 ’ 23毫克’ 0·11宅莫耳)、破酸鉀⑺毫克,〇18毫 _ 莫耳)與催化里Ac的混合物加熱至回流並維持1小時。 去除丙酮並添加水。所得有機物用二氣曱烷(3><15毫升)萃 取。經合併之二氣甲烷層用鹽水洗滌並經由硫酸鈉乾燥。 經製備型反相HPLC純化後得到一固體狀標題化合物。i H NMR (CDCI3,500 MHz)—旋轉異構體 ι:ι 混合物 g7.9〇 (s, 1H),7·73 (s,2H),7.49 (m,1H),7.40 (m,1H),7·20 (m,1H), 7.00 (m, 1H), 6.68 (dd5 12.0, 3.0 Hz, 1H), 5.63 (d, J = 8·0 Hz,% H),5.44 (d,/ = 8.0 Hz,% H),4.85 (d,J = 1〇·〇 • Hz,% H),4.82 (d,/ = 10.0 Hz,% H),4.03 (d,J = 16.0 Hz, % H),3.84 (m,11/2 H),3.80 (s,3H),3.20 (m,1H),1·20 (m, 6H)5 0.56 (d5 J = 6.5 Hz, 3/2 H)5 0.38 (d, J = 6.5H, 3/2 H)。LC-MS (M+l) ·· 604.3, 4.61 分鐘。 實例80
〇H 102763.doc -126- 1299991 5-[2-蛾-5-(三氟甲基)苯基]-1,3-”惡嗤燒-2-酮 步驟A : 2-碘-5-(三氟甲基)苯甲醛 經30分鐘向一 2-碘-5-(三氟甲基)苯甲腈(實例2 , 42克)溶 於CH2C12(300耄升)的_78 °C溶液中添加一 DIBAL溶於 CH2C12(175毫升,1 M)的溶液。形成一沉澱。將該反應物 加溫至0 C。經30分鐘逐滴滴加額外25毫升之DIBAL·溶 液。將該反應物倒入200毫升2 N HC1水溶液中,用醚稀釋 並攪拌1小時。TLC分析指示亞胺仍存在,再添加額外1〇〇 • 毫升之2 N HC1水溶液且將該反應物攪拌過夜。藉由τιχ分 析顯示亞胺仍舊存在,再添加2〇〇毫升2 n HC1水溶液並將 混合物攪拌2小時。分層並用醚反萃取水性層。合併醚萃 取物,用鹽水洗滌,經由無水MgS〇4乾燥,過濾並濃縮。 產物藉由矽膠層析法(用95:5己烷/EtOAc洗提)純化以生成 白色固體狀埃_5-(三氟甲基)苯曱醛。iH NMR (5〇〇 MHz, CDCls): δ 10.00 (s5 1Η)5 8.12 (s5 1Η), 8.11 (d, J=8 Hz, 1H),7.53 (dd,J=2 Hz,8 Hz,1H)。 •步驟B : 5_[2-蛾_5_(三氟甲基)苯基卜l,3-嚼唑烷-2_酮 向一 〇·2克2-碘-5-(三氟曱基)苯甲醛溶於3毫升]^〇11的〇 °C溶液中添加〇·13毫升硝基甲烷,然後添加〇·28毫升2·5 ν •Na〇H/谷液。將該混合物於0°C下攪拌3小時,然後藉由添 加2.1¾升〇.33 N Ac〇H水溶液來中和。此混合物分配在⑺ 笔升水與10毫升Et0Ac之間。水相用2x5毫升EtOAc萃取。 。併之有機物用1〇毫升鹽水洗滌,經由Na2S〇4乾燥,並 濃縮。將所得殘留物溶解於4毫升Me〇Ht並添加〇.5毫升 102763.doc -127- 1299991 88%甲酸水溶液。添加約200毫克阮内鎳漿液並用&吹掃 此混合物,且在一 H2氣氛下攪拌4小時。通過一矽藻土墊 層過濾此混合物(用MeOH洗滌)並將濾液濃縮。殘留物分 配在10毫升10% NH40H水溶液與20毫升EtOAc之間。水相 用2xlO毫升EtOAc萃取。合併之有機物用1〇毫升鹽水洗 務,經由Na2 S〇4乾燥,並濃縮之。使所得殘留物溶解於2 毫升CH2C12中。向此溶液中添加〇·ιΐ4毫升二異丙基乙基 胺,然後添加0.065克三光氣。將該混合物於下攪拌3〇 _ 为鐘’然後用1 〇宅升EtOAc與10宅升飽和NaHC〇3稀釋。 水相用2x 10毫升EtOAc萃取。合併之有機物用1〇毫升鹽水 洗務’經由Na2S〇4乾無,並?農縮之。在一 Biotage Horizon 25S管柱上藉由快速層析法、用溶於己烷之1 cv 4% EtOAc 洗提、之後用超過10 CV之溶於己烧之EtOAc自4至100%線 性梯度洗提來純化殘留物以提供標題化合物。質譜 (ESI)350.0(M+1) 〇 1H NMR (500 MHz,CDC13) : δ 8.00 (d, J=8 Hz,1H),7.74 (br s,1H),7·33 (br d,J=8 Hz,1H),5·80 鲁(dd,J=7 Hz,9 Hz 1H),5·05-5·50 (br,1H),4.28 (t,J=9 Hz, 1.5H),3.36 (dd,7 Hz,9 Hz,1H) 〇 實例8 1
5-[5’-異丙基-2’-甲氧基-4-(三氟甲基)聯苯基基】-1,3-噁 嗅烧-2-酮 102763.doc •128- 1299991 向一 65毫克5-[5,-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基_ 2·基]-1,3-噁唑烷-2-酮、45毫克(5-異丙基-2-甲氧基苯基) 獨酸與66毫克碳酸鉀溶於6毫升丙酮與1.5毫升水的溶液中 添加約5毫克乙酸把。將此混合物力^熱至回流並於此溫度 下攪拌1.5小時。藉由旋轉蒸發去除丙酮並用1〇毫升Et〇Ac 與10毫升水稀釋殘留物。水相用10毫升EtOAc萃取。合併 之有機物用10毫升鹽水洗滌,經由Na2S〇4乾燥,並濃 縮。在一 Biotage Horizon 25S管柱上藉由快速層析法、用工 • CV溶於己烷之10% Et0Ac洗提、之後用一超過1〇 cv之溶 於己烧之EtOAc自10至1〇〇%的線性梯度洗提來純化殘留物 以提供標題化合物。波譜數據提供於實例49中。 遵循實例52中概述之程序製備列於表2中之化合物: 表3
實例 R LC/MS 數據(M+1) 82 488.1 對映異構體A 83 Η Cl 對映異構體A 504.1 102763.doc -129- 1299991
實例90
84 NC 對映異構體A 495.1 85 對映異構體A 476.2 86 m 對映異構體A,非對映異構體A 484.2 87 m 對映異構體A,非對映異構體B 484.2 88 m 對映異構體B,非對映異構體A 484.2 89 對映異構體B,非對映異構體B 484.2 5-[2-碘-5-(三氟曱基)苯基]-4-甲基-1,3-噁唑烷-2-酮 遵循實例80中所述程序並使用硝基乙烷、0.2克2-碘-5-(三氟甲基)苯曱醛可提供0.102克期望之產物,其藉由快速 層析Biotage Horizon 25S管柱、用1 CV溶於己烷之10% EtOAc洗提、之後用一超過10 CV之溶於己烷之EtOAc自10 至100%線性梯度洗提可分離為順式與反式非對映異構 102763.doc -130- 1299991 體0 反式-5-[2-碘-5-(三氟曱基)苯基]_4_甲基-1,3-噁唑烷-2-_ :質譜(ESI)372.1 (M+1)。lH NMR (500 MHz, CDC13) : 5 8.02 (d,J=8 Hz,1H),7.61 (d,J=1.5 Hz,1H), 7·32 (dd,J=2 Hz,8 Hz,1H),6.16 (s,1H),5·39 (d,J=4 Hz, 1H),3.76 (dq,J= 6 Hz,4.5 Hz,1H),1.62 (d, J=6 Hz,3H)。 順式-5-[2-碘-5-(三氟甲基)苯基]-4-甲基-1,3·噁唑烷-2-酉同:質譜(ESI)372.1 (Μ+1)。lH NMR (500 ΜΗζ, CDC13) : δ 7·98 (d,J=8 Ηζ,1Η), 7·6〇 (br s,1Η),7.33 (dd, j=le5 Hz,8 Hz,1H),6·25 (s,1H),5.85 (d,J=8 Hz,1H), 3.76 (dq,J= 8 Hz,7 Hz,1H),0.81 (d,J=7 Hz, 3H)。 實例91
反式-5-[5,-異丙基-2’-甲氧基-4-(三氟甲基)聯苯基-2_基卜4-• 甲基-1,3-噁唑烷-2-酮(外消旋) 向-^0.036克反式-5-[2-峨-5-(三氣甲基)苯基]·4_甲基_ 1,3-噁唑烷-2-酮、〇·〇24克(5-異丙基-2-甲氧基苯基)硼酸與 0.04克碳酸鉀溶於2毫升丙酮與0.5毫升水的溶液中添加約2 宅克乙酸把。將此混合物加熱至回流並於此溫度下擾掉 I5小時。藉由旋轉蒸發去除丙酮並用10毫升EtOAc與10毫 升水稀釋殘留物。水相用10毫升EtOAc萃取。合併之有機 物用10毫升鹽水洗滌,經由Na2s〇4乾燥,並濃縮。在_ 102763.doc -131 - 1299991
Biotage Horizon 25S管柱上藉由快速層析法、用1 CV溶於 己烷之10% EtOAc洗提、之後用一超過1〇 CV之溶於己烷 之EtOAc自10至100%的線性梯度溶洗提來純化殘留物以提 供標題化合物。質譜(ESI)394.2(M+1)。lH NMR信號由於 滯轉對映異構現象而加倍。1H NMR (500 MHz,CDC13): δ 7.80,7.78 (s,1Η),7.64,7.63 (d,J〜8 Ηζ,1Η),7·35 (d, J=7.5 Hz,1H),7.27,7·26 (d,J〜8 Hz 1H),7.00,6.95 (d, J=2.5 Hz,1H),6.93,6.92 (d,J〜8 Hz,1H),5.87,5.81 (s, • 1H),5.16, 5.10 (d,J〜5 Hz,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=6.5 Hz,3H)。 實例92
順式-5-[5’-異丙基-2,-甲氧基-4-(三氟甲基)聯苯基_2_基卜4一 甲基-1,3-噁唑烷-2-酮(外消旋) 遵循實例91中所述程序,0·〇46克順式_5-[2-埃-5-(三氟 甲基)苯基]-4-甲基-1,3-噁唑烧-2-酮可提供期望之產物。質 譜(ESI)394.2(M+1)。1H NMR信號由於滯轉對映異構現象 而加倍。lH NMR (500 MHz,CDCI3) : 57.89,7.88 (s,lH), 7.65,7.64 (d,J〜7·5 Hz,1H),7·34,7.32 (d,J〜8 Hz,1H), 7.26 (d,J=8.5 Hz,1H),6.98,6.86 (d,J=2.5 Hz,1H),6.91, 6.89 (d,J〜8 Hz,1H ),5·83, 5·75 (s,1H),5.69, 5·61 (d,J〜8 102763.doc -132- 1299991 Ηζ,1Η),3.75 (s,1·8Η),3.58-3.70 (m,2H),3·32 (m,〇·6Η), 2·88 (m,1H),1.23 (m,6H),0·89, 0·71 (d,J=6.5 Hz,3H)。 實例93
φ 反式_3-[3,5_雙(三氟甲基)苄基】_5-[5,_異丙基_2,_甲氧基-4-(二氟甲基)聯苯基-2-基】-4-甲基-1,3-嚼嗤烧-2-酮(外消旋) 向一 30毫克反式-5_[5,-異丙基-2,-甲氧基-4-(三氟曱基)聯 苯基-2-基]-4-甲基-1,3-噁唑烷-2-酮溶於1毫升DMF的〇。(:溶 液中添加8毫克氫化鈉。將該混合物於室溫下攪拌丨〇分 鐘,然後添加32毫克3,5-雙(三氟甲基)苄基溴。將該混合 物於室溫下攪拌過夜,然後用10毫升EtOAc與10毫升水稀 釋。分相並用5毫升EtOAC萃取水相。合併之有機物用5毫 φ 升鹽水洗滌,乾燥(Na2S〇4),並濃縮。在一 Biotage Horizon 25S管柱上藉由快速層析法、用1 CV溶於己烧之 4% EtOAc洗提、之後用一超過1〇 CV之溶於己烷之Et〇Ac 自4至1 〇〇%的線性梯度洗提來純化殘留物以提供標題化合 物。質譜(ESI)620.2(M+1)。1H NMR信號由於滯轉對映異 構現象而加倍。1H NMR (500 MHz,CDC13) : δ 7.53-7.80 (m,5Η),7.33 (d,J=8 Ηζ,1Η),7.21-7.29 (m,1Η),7.00, 6.76 (d,J=2.5 Hz,1H),6.91,6.86 (d,J= 8·5 Hz,〇·4Η), 102763.doc -133- 1299991
5·15, 5·10 (d,J==4·5 Hz,1H),4.80, 4·74 (d,J=16 Hz,1H) 4·25, 4·21 (d,16 Hz,1H),3.76 (s,2H),3.49 (s,1H),3.43 (m,〇·4Η),3·18 (m,0·5Η),2.77_2·98 (m,1H),1.24 (m,3H), 實例94
順式-3·[3’5_雙(三氟甲基)节基】-5-[5,-異丙基-2、曱氧基+ (一氣甲基)聯笨基基】_4_曱基-1,3-口惡嗤燒_2酮(外消旋) 遵循貫例93中所述程序,40毫克順式-5-[5,-異丙基甲 乳基4 (一氟甲基)聯苯基-2-基]-4_曱基-1,3-噁嗤烧與 42毫克3,5_雙(三氟甲基)苄基溴可生成標題化合物。質譜 (ESI)620.2(M+1)。lH NMR信號由於滯轉對映異構現象而 Φ 加倍。lH NMR (500 MHz,CDC13) ··占 7.82-7.94 (m,2h) 7·62-7·74 (m,3H),7·39,7.37 (d,J〜8 Hz,1H),7·25,7·17 (br d,J=8.5 Hz,1H),7.00, 6.78 (s,1H),6.87, 6.84 (d, 8.5 Hz,1H),5.59, 5.56 (d,J=4.5 Hz,1H),4.96 (d,J=16 Hz, 1H),4.22, 4·11 (d,J=16 Hz,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=7 Hz,3H),1·〇6 (m,3H),0.88, 0.69 (d,J=6.5 Hz,3H)。 實例95 102763.doc -134- 1299991
(41?’5及)_5-[2-碟_5_(三氟甲基)苯基】-4-甲基-1,3-'|惡嗤娱*· 2_酮 步驟A : (45>4_苄基_3_{(2及,35)-3-羥基-3_[2-碘_5-(三氟甲 基)苯基]-2-甲基丙醯基卜13-噁唑烷_2_酮
Ph
將一存於10毫升EtOAc之1.8克5,-異丙基-2、甲氧基-4-(三 氟甲基)聯苯基-2_曱醛(實例80,步驟A)、1.16克(45>4-苄 基-3-丙酿基_1,3-噁唑烷-2-酮、0.048克氯化鎂、1.40毫升 三乙胺與0·91毫升三甲基氣矽烷的混合物在室溫下攪拌24 小時’然後通過一 l〇x10公分矽膠栓塞過濾,用400毫升 Et2〇洗提。濃縮濾液,並添加1〇毫升MeOH以及2滴三氟乙 φ 酸。將此溶液於室溫下攪拌30分鐘並濃縮成一淺黃色油。 在一 Biotage Horizon 65i管柱上藉由快速層析法、用15 CV 溶於己烧之10%丙_洗提來純化殘留物以提供1 42克(53%) 標題化合物。質譜(ESI)516.2 (M_OH)。lH NMR (500 MHz,CDCI3) ·· δ 8·00 (d,J=8.5 Hz,1H), 7·76 (d,J=2 Hz, 1H),7.22-7.32 (m· 4H),7.07 (br d,J=6.5 Hz,2H),5.18 (dd, J=6.5 Hz,7·5 Hz,1H),4·67 (m,1H),4.46 (dq,J= 6.5 Hz, 7.5 Hz,1H),4.17 (t,J=9 Hz,1H),4.11 (dd,J=3 Hz,9 Hz, 102763.doc -135- 1299991 ⑽,㈠.5 ΗΖ,13.5 Ηζ,1Η),1.34 (d,J=7.5 Ηζ,3Η)。 步驟^⑽,寧基)苯基 唑烷_2-酮 ’向-〇·65克(4外4-节基⑽將3-經基_3仆破^三 氟甲基)苯基]-2-甲基丙酸基卜1,3“惡唾烧_2_綱溶於6毫升 3/四虱呋喃-水的(TC溶液中添加〇1〇2克溶於15毫升水之 氫氧化m後添加〇·554毫㈣%過氧域水溶液。將此 籲溶液在代下㈣1小時,此時,LC/MS分析顯示無起始材 料。將一 1·5 Μ亞硫酸鈉溶液(37毫升)添加至冷溶液中, 然後將其倒入一分液漏斗中並用2χ1〇毫升CH2Cl2萃取。 經合併之CH2C12萃取物用20毫升3:1水-飽和NaHC〇3水溶 液反萃取。經合併之水性層用6 N HC1酸化(pH〈 U並用 4x10毫升EtOAc萃取。經合併之Et〇Ac萃取物用1〇毫升鹽 水洗滌,經由Na2S〇4乾燥,並濃縮。將殘留物溶解於1〇 毫升甲苯中。添加二苯基磷醯基疊氮化物(〇·315毫升)與 _ 耄升二乙胺並將此混合物在1〇〇°c擾拌過夜,然後冷 卻並濃縮。在一 Biotage Horizon 40S管柱上藉由快速層析 法、用1 CV溶於己烷之5% EtOAc洗提、之後用一超過10 CV之溶於己烷之EtOAc自5至100%的線性梯度洗提來純化 殘留物以提供0.302克(67%)標題化合物。質譜 (ESI)372.1(M+1)。lH NMR (500 MHz,CDC13) : δ 8.02 (d, J=8 Hz,1H),7·61 (d,J=1.5 Hz,1H),7.32 (dd,J=2 Hz, 8 Hz,1H),6.16 (s,1H),5.39 (d,J=4 Hz,1H),3·76 (dq,J= 6 102763.doc -136- 1299991
Ηζ,4·5 Hz,1H),U2 (d,J=6 Hz,3H)。在 Chiralpak AD 4·6Χ250*米管柱上藉由分析型HPLC、用溶於庚烷之4%乙 醇按〇·75毫升/分鐘(對於足及,怳=2156分鐘;對於怂$, 叹=1 8.00分鐘)洗提顯示98%以。 實例96
(4及,51〇-3-[3,5_雙(三氟甲基)苄基卜5-[2-蛾_5_(三氟甲基)苯 基]-4-甲基-1,3-β惡嗤烧-2-酮 向一95宅克(47?,5及)-5-[2_峨-5-(三敦甲基)苯基]_4-甲基-1,3-噁唑烷-2-酮溶於1毫升DMF的0°C溶液中添加20毫克氫 化鈉。將該混合物於0°C下攪拌10分鐘;然後添加94毫克 3,5-雙(三氟甲基)苄基溴。將該混合物於〇。〇下攪拌1〇分 鐘,然後用1 〇耄升EtO Ac與10毫升水稀釋。分相並用1〇毫 升EtOAc萃取水相。經合併之有機相用10毫升鹽水洗滌, 經由Na2S〇4乾無’並濃縮。在一 Biotage Horizon 25M管 柱上藉由快速層析法、用1 CV溶於己烧之2% EtOAc洗 提、之後用一超過1〇 CV之溶於己烷之EtOAc自2至100%的 線性梯度洗提純化殘留物以提供0.121克(79%)標題化合 物。質譜(ESI)598.1 (M+1)。lH NMR (500 MHz, CDCI3) : δ 8.00 (d,J=8.5 Hz,1H),7·77 (s,1H),7·58 (br s, 102763.doc -137- 1299991 3H),7·34 (紙 J=i.5 Hz,8 Hz,1H),5.36 (d,J=4 Hz, 1H), 4·89 (d,J:"16 Hz,1H),4.31 (d,J=16 Hz,1H),4.48 (dq,J= 6 Hz,4 Hz,1H),ι·55 (d,J=6 5 Hz,3H)。 實例97
❿ F3C cf3 (4及,5及)-3-[3,5-雙(三氟甲基)节基】_5]5,_異丙基·2,_甲氧 IJ- 二氟甲基)聯苯基-2-基]-4-甲基-1,3-噁唑烷-2-酮 遵循貫例81中所述程序,41毫克(4i?,5i?)-3_[3,5-雙(三氟 甲基)节基卜5-[2-碘-5-(三氟曱基)苯基]-4-甲基-1,3-噁唑烷-與17毫克(5-異丙基-2-甲氧基苯基)硼酸可生成39毫 克標題化合物(95%)。質譜(ESI)620.4(M+1)。1HNMR信號 _ 由於滯轉對映異構現象而加倍。1H NMR (500 MHz, CDCl3):3 7.53-7.80 (m,5H),7.33(d,J=8Hz,lH),7.21-7.29 (m,1H), 7·〇〇, 6.76 (d,Hz,1H),6.91,6·86 (d,J= 8·5 Hz,0.4H),5.15, 5.10 (d,J=4.5 Hz,1H), 4_80, 4·74 (d, J=16 Hz,1H),4.25, 4.21 (d,16 Hz,1H),3·76 (s,2H),3·49 (s,1H),3·43 (m,0.4H),3.18 (m,0.5H),2.77-2.98 (m,1H), 1.24 (m,3H), 1.16 (m,3H),0.78,0.61 (d,J=6.5 Hz,3
Hz) 〇 102763.doc -138- 1299991 實例98
(4i?,5i〇_3_[3,5-雙(三氟甲基)苄基】-5_[4,-氟-5,-異丙基-2,-| 甲氧基-4-(三氟甲基)聯苯基-2-基卜4-甲基-1,3-噁唑烷-2-酮 遵循實例81中所述程序,38.5毫克(4i?,5i〇-3-[3,5-雙(三 It甲基)节基]_5-[2 -蛾- 5- (三氟^曱基)苯基]-4 -曱基-1,3 -°惡唾 烷-2-酮與18毫克(4_氟-5·異丙基-2-曱氧基苯基)硼酸(實例 78)可生成27毫克標題化合物(66%)。質譜 (ESI)638.3 (M+1)。4 NMR信號由於滯轉對映異構現象而加倍。1Η NMR (500 MHz,CDC13) : δ 7·55·7·80 (m,5Η),7·29 (d,J=8 Hz,1H),7.00, 6.77 (d,J= 8.5 Hz,1H),6·68, 6.63 (d,J〜12 # Hz,1H),5.08, 5·04 (d,J〜5 Hz,1H),4.81,4.75 (d,J=16 Hz, 1H),4.26, 4·23 (d,15.5 Hz,1H),3.75 (s,2H),3.50 (s,1H), 3.43 (m,0.5H),3.12-3.24 (m,1·5Η),1·24, 1.22 (d,J〜5 Hz, 3H),1.17,1.06 (d,J=7 Hz,3H),0.84,0.70 (d,J=6 Hz, 3H)。 實例99 102763.doc -139- 1299991
(4S,SS)-S- 2-酮
步驟A
[2
續-S-(二故甲基)苯基卜4_曱基4,3-噁唑烷_ 基)苯基;甲 :]_2 卞土 -3气(2$,3及)-3-羥基-3-[2·碘-5-(三氟甲 基丙醯基M,3-噁唑烷-2-酮
Ph
遵循實例9Stb 〇Η 0 0 步驟八所述程序,〇·72克5,-異丙基-2,-甲氧 二氣甲其 土)聯苯基-2-曱醛(實例8〇,步驟Α)、〇·466克 (4及)_4_节基j : ^ 一 丙醯基-1,3·噁唑烷-2-酮、〇.〇2克氯化鎂、 毫升一乙胺與〇·3 8毫升三甲基氯矽烷可提供〇·554克 (52%)標題化合物。質譜(esi)5162 (μ_〇η)。⑴ nmr
(500 MHz,CDCI3) : δ 8.00 (d,J=8.5 Hz,1H),7.76 (d,J=2 Hz,1H),7.22-7.32 (m· 4H),7.07 (br d5 J=6.5 Hz, 2H),5.18 (dd,J-6.5 Hz,7.5 Hz,1H),4.67 (m,1H),4.46 (dq,J= 6.5
Hz,7.5 Hz,1H),4.17 (t,J=9 Hz,1H),4·11 (dd,J=3 Hz,9
Hz,1H),3.97 (d,J=8 Hz,1H),3.19 (dd,J=7 Hz,13.5 Hz, 1H),2.57 (dd,J=9.5 Hz,13.5 Hz,1H),1.34 (d,J=7.5 Hz, 3H)。 步驟3:(4&56>5-[2-硬-5-(三氟甲基)苯基]_4_甲基-1,3-噁 嗤烧-2 -調 -140- 102763.doc 1299991 遵循實例95中步驟B所述程序,〇·214克(4及)-4-节基-3-{(2&3Λ)_3-羥基-3_[2-破-5-(三氟甲基)苯基]_2_甲基丙醯 基}-1,3-喔嗤烧-2_酮、0.034克氫氧化鐘、〇·ΐ6毫升30%過 氧化氫水溶液、0.1毫升二苯基磷醯基疊氮化物與〇 072毫 升三乙胺可提供0.118克(79%)標題化合物。質譜 (ESI)372.1 (M+l) 〇 lH NMR (500 MHz, CDCI3) : δ 8.02 (d, J=8 Hz,1H),7.61 (d,J=1.5 Hz,1H),7.32 (dd,J=2 Hz,8 Hz,1H),6.16 (s,1H),5.39 (d,J=4 Hz,1H),3·76 (dq,J= 6 • Hz,4·5 Hz,1H),1.62 (d,J=6 Hz,3H)。於 Chiralpak AD 4.6x250毫米管柱上藉由分析型HPLC、用溶於庚烷之4%乙 醇按0.75毫升/分鐘(對於足及,iR=21.56分鐘;對於5^, 叹=18.00分鐘)洗提顯示99%6.6。 實例100
(4S,55>3_[3,5-雙(三氟甲基)苄基卜5-[2-碘-5_(三氟甲基)苯 基】-4-甲基-1,3-^惡嗤燒 遵循實例96中所述程序,〇1〇8克(4&5幻-5_[2-鐵-5_(三 氣甲基)苯基]-4-曱基-i,3-噁唑烷_2_酮、23毫克氫化鈉與 107毫克3,5-雙(三氟甲基)苄基溴可提供〇.151克(87%)標題 化合物。質譜(ESI)598.1 (M+l)。lH NMR (500 MHz, 102763.doc -141 - 1299991 CDCI3) : δ 8 πα δ·00 (d,J=8.5 Hz, 1H),7.77 (s,1H),7·58 (br s, 3H)5 7.34 (dd t 1 、Q,J=l.5 Hz,8 Hz,lH),5.36 (d,J=4 Hz, lH), 4.89 (d, J-i6 u 0 Hz,ih),4.31 (d,J=16 Hz,lH),4·48 (dq,J= 6
Hz5 4 Hz, lH^ 1 . 叫,1.55 (d,J=6.5 Hz,3H)。 實例101
(45,55)-3-f3 c ^ 雙(三氟甲基)苄基卜5-[5,-異丙基-2,-甲氧基- 4 (一敗甲基)聯笨基-2·基卜4·甲基-1,3-噁唑烷-2-酮
4盾Y歹丨 ί R 貝丨』81中所述程序,40毫克(4&55>3-[3,5-雙(三氟 甲基)节基a L2-峨_5-(三氟甲基)苯基]_4_甲基·1,3_噁唑烷-2-酮與17毫吉μ w 兄異丙基-2-曱氧基苯基)硼酸可生成39毫克 &題化合物(95%)。質譜(ESI) 620.4 (M+1)。lH NMR信號 由於/ηΓ轉對映異構現象而加倍。1H NMR (500 MHz, CDCI3) ·* δ 7 51 7 ca •J>’.8〇(rn,5H),7.33(d,J=8Hz,lH),7.21- 7.29 (m,1H),7·〇〇, 6 76 (d,J=2.5 Hz,1H),6 91,6 86 (d,J= 8·5 Hz,0.4H),5.15, 5 1〇 (d,J=4 5 Hz,ih)5 4.80, 4.74 (d, J一 16 Hz,1H),4.25, 4 21 (d,16 Hz,1H),3·76 (s,2H),3.49 (s, 1H), 3.43 (m5 0.4H), 3.18 (m, 0.5H), 2.77-2.98 (m, 1H), i·24 (m,3H),hl6 (m,3H),0.78,0.61 (d,J=6.5 Hz,3 102763.doc -142- 1299991
Hz) 〇 實例l〇2
(4及,5Λ)·5-[4,·15,·異丙基_2,_甲氣基基-2_基]-4-甲基nn惡唾烧_2__ -4_(三 氟甲基)聯苯
/循實例81中所述程序,毫克㈣將5·[24Ι (三 氣甲基)苯基卜心甲基十3“惡哇烧-2,與171毫克(4-氟-5-異 丙基I甲乳基苯基)爛酸(實例78)可生成241毫克標題化合 (〇)夤 (ESI)412.3(M+1)。In NMR信號由於滯轉對 、-構現象而加倍。lH NMR (5〇〇 MHz,CDCl3) ·· § 7 79, (s,叫,7.64, 7.62 (dd,J〜2.5 Ηζ,8 Ηζ,1Η),7·32, 7·31 (,J 8 ΗΖ,1Η),7·00, 6·95 (d,J=8.5 Ηζ,1Η),6.70, 6·67 (d, J —- 1 τ 丁 ζ,1Η),6.47, 6·43 (s,1Η),5.08, 5·04 (d,J=5 Ηζ, Η)’ 3·68-3·80 (m,3·5Η),3.53 (m,〇·5Η),3·21 (m,1Η), (ηι,6Η),〇·95, 〇·77 (d,Ηζ,3Η)。 美1循實例96中概述之程序可自(4i?,5i〇-5-[4,-氟-5,-異丙 土 _甲虱基_心(三氟甲基)聯苯基-2-基]-4-甲基_1,3_噁唑 烷_2’製備列於表4之化合物: 表4 102763.doc * 143 - 1299991
實例 R LC/MS數據(M+l) 103 F 520.3 104 F 520.3 105 520.3 106 538.4 / F 107 (K 非對映異構體A 516.4 108 m 非對映異構體B 516.4 109 <> 503.3 110 Cl 木 571.4 實例111 102763.doc 144- 1299991
((4i?,5S)-4_[3,5-雙(三氟曱基)苯基]-1·{[5,_異丙基_2,_甲氧 基-4-(三氟甲基)聯苯基-2-基】甲基}-5-曱基咪唑啶_2-亞基) 氰醯胺 向一(1兄25>1-[3,5-雙(三氟甲基)苯基]_妒-{[5,-異丙基_ 2^甲氧基-4-(二氟甲基)聯苯基-2-基]甲基}丙烧_1,2 -二胺 (25.1毫克,0.0424毫莫耳)溶於二氯乙烷(ι·5毫升)的溶液 中添加三乙胺(15微升,0.105毫莫耳)與二苯基氰基碳醯亞 胺酯(13毫克,0.053毫莫耳)。將該反應物加熱至60°C,過 夜,冷卻至室溫,經過濾並直接上樣至一矽膠管柱上用10 至40% EtOAc/己烷藉由快速層析法純化以生成21.6毫克 (79%) ((4及,56>4_[3,5_雙(三氟曱基)苯基]小{[5,·異丙基- 2^甲氧基-4-(三氟甲基)聯苯基-2-基]甲基}-5-甲基咪唆啶- 2-亞基)氰酸胺。& = 〇·2〇 (25〇/〇 EtOAc/ 己烷)。LCMS = 643.3 (M+l)+。iH nmR (C6D6,500 MHz;存在滯轉異構 體’ 一些峰加倍)δ 6.53-8.83 (m,10H),3.61-4.91 (m,3H), 3·28-2·70 (m,5H),1.14-1.25 (m,6H),-0.39一 -0·26 (m, 3H)。 102763.doc -145-
Claims (1)
12 197號專利申請案 r———一―,——_ 中文申請專利範圍替換本(96年3月)I依 μ 十、申請專利範圍: 1· 一種選自由具有式If、Ig及Ih之化合物組成之群的化合物 或其醫藥上可接受之鹽,
If f
A2係選自由苯基、環己基以及吡啶基組成之群,其中 視丨月况由1至2個獨立選自_素、-CH3、-CF3以及-CN 之取代基取代; 各R獨立選自由Η與-CH3組成之群; 各1^皆係獨立選自由弋”與^組成之群; 各^皆係獨立選自由-C卜C3烷基、-OCH3以及F組成 之群; 、 102763-960322.doc 1299991 Rl與R2各係獨立選自由Η與-C卜C2烷基組成之群; X係選自由-0-、-NH-、-N(CH3)-以及-CH2-組成之 群; Z係選自由-C(=0)-、-S(0)2-以及-C(=N-CN)-組成之 群; η為0或1 ; ρ為1 ;且 q為2或3。 _ 2.如請求項1之具有式Ii之化合物或其醫藥上可接受之鹽, 其中:
R7係選自由C1與-CF3組成之群; RC係選自由鹵素、-CH3、-CF3以及-CN組成之群;且 t為自0至2之整數。 3.如請求項1之具有式Ij之化合物或其醫藥上可接受之鹽, 其中: 102763-960322.doc 1299991
R7係選自由組成之群; RC係選自由鹵素、-CH3、CF3以及-CN組成 t為自0至2之整數。 ,且 4. :種如請求項】之化合物或其醫藥上可接受之鹽於製& 以在需要此治療之患者中提高HDL_C之藥劑之用途。用 5. y種如請求項i之化合物或其醫藥上可接受之鹽於製造用 以治療動脈粥樣硬化之藥劑之用途。 6. :種用以治療動脈粥樣硬化之醫藥組合物,丨包括如請 求項1之化合物或其醫藥上可接受之鹽,以及醫藥上可接 受之載劑。 7·如明求項1之化合物,其係選自下列化合物或其醫藥上可 接受之鹽:
102763-960322.doc 1299991
-4- 102763-960322.doc 1299991
102763-960322.doc 1299991
8.如請求項1之化合物或其醫藥上可接受之鹽
102763-960322.doc 1299991 其中R係選自由下列組成之群:
102763-960322.doc 1299991
102763-960322.doc 1299991
102763-960322.doc -9- 1299991
• 9.如請求項1之化合物或其醫藥上可接受之鹽,
其中R係選自由下列組成之群:
102763-960322.doc •10- 1299991
其中R係選自由下列組成之群:
-11 - 102763-960322.doc 1299991
Cl 11.如請求項1之具有如下結構之化合物或其醫藥上可接受之 鹽:
12.如請求項1之具有如下結構之化合物或其醫藥上可接受之
13.如請求項1之具有如下結構之化合物或其醫藥上可接受之 鹽: 102763-960322.doc 12- 1299991
14.如請求項1之具有如下結構之化合物或其醫藥上可接受之 鹽:
15.如請求項1之具有如下結構之化合物或其醫藥上可接受之 鹽:
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