TWI450890B - 用於製備胺甲醯吡啶酮hiv整合酶抑制劑之方法及中間體 - Google Patents
用於製備胺甲醯吡啶酮hiv整合酶抑制劑之方法及中間體 Download PDFInfo
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- TWI450890B TWI450890B TW098142599A TW98142599A TWI450890B TW I450890 B TWI450890 B TW I450890B TW 098142599 A TW098142599 A TW 098142599A TW 98142599 A TW98142599 A TW 98142599A TW I450890 B TWI450890 B TW I450890B
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- 238000000034 method Methods 0.000 title claims description 51
- 239000000543 intermediate Substances 0.000 title claims description 11
- OHEKQGOBJIKKIF-AWEZNQCLSA-N (12as)-n-[(4-fluorophenyl)methyl]-7-hydroxy-6,8-dioxo-3,4,12,12a-tetrahydro-2h-pyrido[5,6]pyrazino[2,6-b][1,3]oxazine-9-carboxamide Chemical compound C([C@@H]1OCCCN1C(=O)C1=C(C2=O)O)N1C=C2C(=O)NCC1=CC=C(F)C=C1 OHEKQGOBJIKKIF-AWEZNQCLSA-N 0.000 title 1
- 229940099797 HIV integrase inhibitor Drugs 0.000 title 1
- 239000003084 hiv integrase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 107
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims description 36
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 30
- 125000003342 alkenyl group Chemical group 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 125000003107 substituted aryl group Chemical group 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 9
- 241000872931 Myoporum sandwicense Species 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 230000001335 demethylating effect Effects 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 10
- 239000000203 mixture Substances 0.000 description 91
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 239000000243 solution Substances 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000013078 crystal Substances 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 37
- -1 VI Chemical compound 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 22
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 19
- 239000002244 precipitate Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000002002 slurry Substances 0.000 description 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000008367 deionised water Substances 0.000 description 7
- 229910021641 deionized water Inorganic materials 0.000 description 7
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- KQIGMPWTAHJUMN-VKHMYHEASA-N 3-aminopropane-1,2-diol Chemical compound NC[C@H](O)CO KQIGMPWTAHJUMN-VKHMYHEASA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 229940125898 compound 5 Drugs 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 4
- QDZZDVQGBKTLHV-UHFFFAOYSA-N (2,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1F QDZZDVQGBKTLHV-UHFFFAOYSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 4
- 229940126657 Compound 17 Drugs 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 4
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 230000032683 aging Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000005561 phenanthryl group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- NMMIHXMBOZYNET-UHFFFAOYSA-N Methyl picolinate Chemical compound COC(=O)C1=CC=CC=N1 NMMIHXMBOZYNET-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DODOHUTYOAEFNY-UHFFFAOYSA-N [Li].CC(CCCCCCCCCN)(C)C.CC(CCCCCCCCCN)(C)C Chemical compound [Li].CC(CCCCCCCCCN)(C)C.CC(CCCCCCCCCN)(C)C DODOHUTYOAEFNY-UHFFFAOYSA-N 0.000 description 2
- 125000005011 alkyl ether group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
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- BKMMTJMQCTUHRP-VKHMYHEASA-N (S)-2-aminopropan-1-ol Chemical compound C[C@H](N)CO BKMMTJMQCTUHRP-VKHMYHEASA-N 0.000 description 1
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- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
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- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
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- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
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- 238000002441 X-ray diffraction Methods 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
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- WXMZPPIDLJRXNK-UHFFFAOYSA-N butyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CCCC)C1=CC=CC=C1 WXMZPPIDLJRXNK-UHFFFAOYSA-N 0.000 description 1
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- 229910052801 chlorine Inorganic materials 0.000 description 1
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- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- HQFQTTNMBUPQAY-UHFFFAOYSA-N cyclobutylhydrazine Chemical compound NNC1CCC1 HQFQTTNMBUPQAY-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- ATBKVKDEMSGMTQ-UHFFFAOYSA-N hydrazine triphenylphosphane Chemical compound NN.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 ATBKVKDEMSGMTQ-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
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- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- JUVSRACZYLMJQD-UHFFFAOYSA-N methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-phenylmethoxypyridine-2-carboxylate Chemical compound O=C1C=CN(CC(O)CO)C(C(=O)OC)=C1OCC1=CC=CC=C1 JUVSRACZYLMJQD-UHFFFAOYSA-N 0.000 description 1
- BQCJQVPKXUQHNJ-UHFFFAOYSA-N methyl 5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-phenylmethoxypyridine-2-carboxylate Chemical compound O=C1C(Br)=CN(CC(O)CO)C(C(=O)OC)=C1OCC1=CC=CC=C1 BQCJQVPKXUQHNJ-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
本發明包括合成具有HIV整合酶抑制活性之化合物之習知方法的修改形式。
2006年11月2日公開之WO 2006/116764闡述各種化合物及用於其製備的詳細合成方案,其全部內容以引用方式併入本文中。具體而言,第16、27、及32步涉及使用可包含四氧化鋨之試劑自雙鍵產生-CHO基團。
本發明提供產生連接至6員環之雜原子之醛亞甲基、或水合或半縮醛亞甲基的方法,該等方法不經由烯基團且無需使用鋨試劑。
本發明包含製備式(I)化合物之方法:
其中R係-CHO、-CH(OH)2
或-CH(OH)(OR4
);P1
係H或羥基保護基團;P3
係H或羧基保護基團;R3
係H、鹵素、羥基、視需要經取代之低碳烷基、視需要經取代之環烷基、視需要經取代之低碳烯基、視需要經取代之低碳烷氧基、視需要經取代之低碳烯氧基、視需要經取代之芳基、視需要經取代之芳氧基、視需要經取代之雜環基團、視需要經取代之雜環氧基及視需要經取代之胺基;R4
係低碳烷基;Rx
係H、鹵基或R2
-X-NR1
-C(O)-;R2
係視需要經取代之芳基;X係單鍵、選自O、S、SO、SO2
、及NH之雜原子基團或其中每一者可雜有雜原子之低碳伸烷基或低碳伸烯基;且R1
係H或低碳烷基;其包括以下步驟:
i) 使式(II)之化合物:
與式(III)或(IV)之胺反應:
其中R5
及R6
獨立地係低碳烷基或R5
及R6
可為烷基並連接形成5-、6-、或7-員環,
以分別製得式(V)或(VI)之中間體:
及
ii) 對(V)或(VI)實施再官能化以製得(I)。
術語「低碳烷基」單獨或與任一其他術語之組合係指含有1至6個碳原子之直鏈或具支鏈飽和脂肪族烴基團。烷基之實例包含(但不限於)甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、正己基及諸如此類。
術語「低碳環烷基」係指在任一化學穩定構型中由3-6個碳組成的飽和或部分飽和碳環。適宜碳環基團之實例包含環丙基、環丁基、環戊基、環己基、及環庚基。
術語「低碳烯基」單獨或與任一其他術語之組合係指具有一或兩個碳-碳雙鍵的直鏈或具支鏈烷基。烯基之實例包含(但不限於)乙烯基、丙烯基、異丙烯基、丁烯基、異丁烯基、戊烯基、己烯基、己二烯基及諸如此類。
術語「低碳伸烷基」係指直鏈或具支鏈之二價烴基,較佳具有1至6個碳原子,除非另有定義。本文所用「伸烷基」之實例包含(但不限於)亞甲基、伸乙基、伸丙基、伸丁基、伸異丁基及諸如此類。
術語「低碳伸烯基」係指具有一或兩個碳-碳雙鍵之直鏈或具支鏈二價烴基。
術語「低碳烷氧基」係指烷基醚基團,其中術語「烷基」如上所定義。適宜烷基醚基團之實例包含(但不限於)甲氧基、乙氧基、正-丙氧基、異丙氧基、正-丁氧基、異丁氧基、第二-丁氧基、第三-丁氧基及諸如此類。
術語「鹵素」係指氟(F)、氯(Cl)、溴(Br)或碘(I)。
術語「芳基」單獨或與任一其他術語之組合係指含有6個碳原子、且更佳含有6-10個碳原子之碳環芳族部分(例如苯基或萘基)。芳基之實例包括(但不限於)苯基、萘基、茚基、甘菊藍基、茀基、蒽基、菲基、四氫萘基、茚滿基、啡啶基及諸如此類。除非另有所指,否則術語「芳基」亦包含芳烴基團之各個可能的位置異構體,例如1-萘基、2-萘基、5-四氫萘基、6-四氫萘基、1-啡啶基、2-啡啶基、3-啡啶基、4-啡啶基、7-啡啶基、8-啡啶基、9-啡啶基及10-啡啶基。芳基之實例包括(但不限於)苯基、萘基、茚基、甘菊藍基、茀基、蒽基、菲基、四氫萘基、茚滿基、啡啶基及諸如此類。術語「芳烷基」係指經芳基取代之烷基。芳烷基之實例包含(但不限於)苄基及苯乙基。
本文所用術語「雜環基團」及「雜環」係指3-至7-員單環雜環或8-至11-員雙環雜環系統,其任一環係飽和、部分飽和或不飽和,且若為單環,其可視需要發生苯并稠合。每一雜環皆由一或多個碳原子及1至4個選自由N、O及S組成之群的雜原子組成,且其中氮及硫雜原子可視需要氧化,且氮原子可視需要四級銨化,且包括其中任一上述雜環與苯環稠合形成之任一雙環基團。可在任一碳或雜原子上連接雜環,只要此連接可產生穩定結構即可。較佳之雜環包含5-7員單環雜環及8-10員雙環雜環。在雜環具有取代基時,應理解,取代基可連接至環中無論雜原子還是碳原子之任一原子上,只要產生穩定化學結構即可。「雜芳族化合物」或「雜芳基」包括於上述雜環中,且通常係指其中環系統係含有5至20個碳原子,較佳含有5至10個碳原子之芳族單環或多環基團的雜環,其中一或多個環碳,較佳1至4個環碳被諸如N、O、S及P等雜原子置換。較佳之雜芳基包含5-6員單環雜芳基及8-10員雙環雜芳基。亦包括於術語「雜環」範圍內的「雜環系」或「雜環基」係其中含雜原子之非芳族環與一或多個芳族環稠合形成之基團,如二氫吲哚基、苯并二氫吡喃基、啡啶基或四氫喹啉基,其中連接基團或連接點係位於含雜原子之非芳族環上。除非另有所指,否則術語「雜環」、「雜環系」或「雜環基」亦包括雜環基團之每一可能的位置異構體,例如1-二氫吲哚基、2-二氫吲哚基、3-二氫吲哚基。雜環之實例包含咪唑基、咪唑啉基、咪唑啶基、喹啉基、異喹啉基、吲哚基、吲唑基、吲唑啉基(indazolinolyl)、全氫嗒嗪基、嗒嗪基、吡啶基、吡咯基、吡咯啉基、吡咯啶基、吡唑基、吡嗪基、喹喔啉基、六氫吡啶基、吡喃基、吡唑啉基、六氫吡嗪基、嘧啶基、噠嗪基、嗎啉基、硫嗎啉基、呋喃基、噻吩基、三唑基、噻唑基、咔啉基、四唑基、噻唑啶基、苯并呋喃基、硫嗎啉基碸、噁唑基、噁二唑基、苯并噁唑基、側氧基六氫吡啶基、側氧基吡咯啶基、側氧基氮呯基、氮呯基、異噁唑基、異噻唑基、呋呫基、四氫吡喃基、四氫呋喃基、噻唑基、噻二唑基、間二氧環戊烯基、二氧己環基、氧硫雜環戊烯基(oxathiolyl)、苯并間二氧環戊烯基、二硫雜環戊烯基(dithiolyl)、苯硫基、四氫噻吩基、環丁碸基、二噁烷基、二氧戊環基、四氫呋喃并二氫呋喃基、四氫吡喃并二氫呋喃基、二氫吡喃基、四氫呋喃并呋喃基及四氫吡喃并呋喃基。
可選之取代基係羥基、鹵素、胺基及低碳烷基。
保護基團可選自彼等熟習此項技術者所習知之基團,包含揭示於以下中之保護基團:Greene,Theodora W.;Wuts,Peter G. M..Protective Groups in Organic Synthesis.第二版,(1991),第473頁或Kocienski,Philip J. Protecting Groups.第三版,2005,(2005),第679頁。
本發明描述如上所述之方法,其中在該式(I)化合物中R3
係H。
本發明描述如上所述之方法,其中在該式(I)化合物中R係-CHO。
本發明描述如上所述之方法,其中在該式(I)化合物中R係-CH(OH)2
。
本發明描述如上所述之方法,其中在該式(I)化合物中R係-CH(OH)(OR4
)。
本發明描述如上所述之方法,其中在該式(I)化合物中,R3
係H、鹵素、羥基、視需要經取代之低碳烷基、視需要經取代之環烷基、視需要經取代之低碳烯基、視需要經取代之低碳烷氧基。
本發明描述如上所述之方法,其中該式(I)化合物具有式(VII):
本發明描述如上所述之方法,其中該式(I)化合物具有式(Ia):
本發明描述如上所述之方法,其中該式(I)化合物具有式(VIII):
本發明描述如上所述之方法,其中該式(I)化合物具有式(IX):
本發明描述如上所述之方法,其中式(II)之該化合物具有式(IIa):
本發明包含製備式(I)化合物之方法:
其中R係-CH(OH)(OR4
);P1
係羥基保護基團;P3
係H;R3
係H;R4
係低碳烷基;Rx
係R2
-X-NR1
-C(O)-;R2
係視需要經取代之芳基;X係低碳伸烷基;且R1
係H;其包括以下步驟:
iii) 使式(II)之化合物:
與式(III)之胺反應:
其中R5
及R6
獨立地係低碳烷基,以製得式(V)之中間體
及
iv) 對(V)實施再官能化以製得(I)。
用於本發明方法中之特定化合物包含彼等用於各實例中且具有下式(IIa)、(VIa)、(VIb)及(Ia)者:
可將本發明合成順序之產物(Ia)與胺(例如式H2
NCH2
CH2
CH2
OH)縮合,溴化(若Rx
係H),羰基化且醯胺化並最終脫苄基以產生WO 2006/116764第240頁中示為(I-7)之化合物,其中(R)m
係4-F且Ra
係H。或者,此一化合物可根據本發明藉由以(I)開始來合成,其中Rx
係對-F-苯基-CH2
-NH-C(O)-,R3
係H,P1
係苄基(Bn)且P3
係羧基保護基團。
此外,可藉由本發明方法製得之式(I)化合物包含彼等具有下式(VII)、(VIII)及(IX)者:
更具體而言,步驟i)可在約50-150℃之溫度下於質子性或非質子性溶劑(例如EtOH、THF或DMF)中實施約1-10小時。
更具體而言,步驟ii)可藉由使二醇起始材料(VI)與氧化劑(例如NaIO4
、RuO4
或Pb(OAc)4
)在環境溫度下於溶劑(例如H2
O、MeOH或CH3
CN)中實施一或多個小時來達成。對於縮醛型起始材料(例如(V))而言,反應可視需要於諸如HCl、CF3
COOH或HCO2
H等酸中加熱進行。
步驟ii)亦可涉及在Rx
位置實施再官能化,例如將Rx
=H轉化成Rx
=Br,視需要進一步再官能化成Rx
=R2
-X-NR1
-C(O)-。步驟ii)亦可涉及P3
之再官能化。例如P3
=H至P3
=Me。
本發明描述如上所述之方法,其中該再官能化步驟ii)包括將式(V)之中間體去甲基化以製得式(I)化合物。
本發明描述如上所述之方法,其中該再官能化步驟ii)包括使式(VI)之中間體與NaIO4
反應以製得式(I)化合物。
本發明描述下式(V)之化合物:
其中P1
係H或羥基保護基團;P3
係H或羧基保護基團;R3
係H、鹵素、羥基、視需要經取代之低碳烷基、視需要經取代之環烷基、視需要經取代之低碳烯基、視需要經取代之低碳烷氧基、視需要經取代之低碳烯氧基、視需要經取代之芳基、視需要經取代之芳氧基、視需要經取代之雜環基團、視需要經取代之雜環氧基及視需要經取代之胺基;Rx
係H、鹵基或R2
-X-NR1
-C(O)-;R2
係視需要經取代之芳基;X係單鍵、選自O、S、SO、SO2
、及NH之雜原子基團或其中每一者可雜有雜原子之低碳伸烷基或低碳伸烯基;R1
係H或低碳烷基;且R5
及R6
獨立地係低碳烷基或R5
及R6
可為烷基並連接形成5-、6-、或7-員環。
本發明描述具有上式(V)之化合物,其中R3
係H。
本發明描述下式(Va)之化合物:
其中P1
係H或羥基保護基團;P3
係H或羧基保護基團;R3
係H、鹵素、羥基、視需要經取代之低碳烷基、視需要經取代之環烷基、視需要經取代之低碳烯基、視需要經取代之低碳烷氧基、視需要經取代之低碳烯氧基、視需要經取代之芳基、視需要經取代之芳氧基、視需要經取代之雜環基團、視需要經取代之雜環氧基及視需要經取代之胺基;Rx
係H、鹵基或R2
-X-NR1
-C(O)-;R2
係視需要經取代之芳基;X係單鍵、選自O、S、SO、SO2
、及NH之雜原子基團或其中每一者可雜有雜原子之低碳伸烷基或低碳伸烯基;且R1
係H或低碳烷基。
本發明描述具有上式(V)之化合物,其中R3
係H。
本發明描述下式(VI)之化合物:
其中P1
係H或羥基保護基團;P3
係H或羧基保護基團;R3
係H、鹵素、羥基、視需要經取代之低碳烷基、視需要經取代之環烷基、視需要經取代之低碳烯基、視需要經取代之低碳烷氧基、視需要經取代之低碳烯氧基、視需要經取代之芳基、視需要經取代之芳氧基、視需要經取代之雜環基團、視需要經取代之雜環氧基及視需要經取代之胺基;Rx
係H、鹵基或R2
-X-NR1
-C(O)-;R2
係視需要經取代之芳基;X係單鍵、選自O、S、SO、SO2
、及NH之雜原子基團或其中每一者可雜有雜原子之低碳伸烷基或低碳伸烯基;且R1
係H或低碳烷基。
本發明描述具有上式(V)之化合物,其中R3
係H。
本發明描述下式(I)之化合物:
其中R係-CH(OH)(OCH3
);P1
係-Bn;P3
係-CH3
;R3
係-H;且Rx
係Br。
本發明描述下式(14)之化合物:
本發明描述下式(15)之化合物:
本發明描述下式(I)之化合物:
其中R係-CH(OH)2
;P1
係H或羥基保護基團;P3
係H或羧基保護基團;R3
係H、鹵素、羥基、視需要經取代之低碳烷基、視需要經取代之環烷基、視需要經取代之低碳烯基、視需要經取代之低碳烷氧基、視需要經取代之低碳烯氧基、視需要經取代之芳基、視需要經取代之芳氧基、視需要經取代之雜環基團、視需要經取代之雜環氧基及視需要經取代之胺基;R1
係H或低碳烷基;Rx
係H、鹵基或R2
-X-NR1
-C(O)-;R2
係視需要經取代之芳基;且X係單鍵、選自O、S、SO、SO2
、及NH之雜原子基團或其中每一者可雜有雜原子之低碳伸烷基或低碳伸烯基。
在下列實例及整個本說明書中,可使用下列縮寫:Me(甲基)、Bn(苄基)、Aq(水溶液)、Et(乙基)、C(攝氏度)。
下列實例僅意欲具有闡釋作用且並不意欲以任何方式限制本發明範圍。
實例1e之起始材料係本發明方法中式(IIa)之化合物,其亦如下文化合物5及WO 2006/116764中第113頁之101號化合物所示。本發明方法之產物如下文中化合物8所示,其具有本發明方法之式(I)。下文展示為化合物13之最終產物係WO 2006/116764中第240頁之式(I-7)化合物,其中(R)m
係2,4-二-F且Ra
係H,然而,前提條件係在第65頁式(XXVI)中指定為R16
之位置處具有α甲基。
因此,在實例1之上文順序中,化合物5與WO 2006/116764中第113頁之化合物101及本發明方法之式(IIa)相同;上文之化合物6與本發明方法之式(VIa)相同;上文之化合物7與本發明方法之式(VIb)相同;且化合物8與本發明方法之式(Ia)相同。本發明方法之步驟i)係上文之5至6而步驟ii)係6至8。
向存於14.0L MeCN中之2000g化合物1(1.0當量)的漿液中添加2848g苄基溴(1.05當量)及2630g K2
CO3
(1.2當量)。將混合物在80℃下攪拌5h並冷卻至13℃。過濾沉澱物並使用5.0L MeCN洗滌。濃縮濾液並向殘餘物中添加3.0L THF。濃縮THF溶液以獲得3585g油狀粗製化合物2。未經進一步純化,將化合物2用於下一步驟中。
1
H NMR(300MHz,CDCl3
)δ7.60(d,J=5.7Hz,1H),7.4-7.3(m,5H),6.37(d,J=5.7Hz,1H),5.17(s,2H),2.09(s,3H)。
向904g粗製化合物2中添加5.88L THF且將溶液冷卻至-60℃。將存於THF中之5.00L 1.0M的雙(三甲基矽烷基胺)鋰(1.25當量)在-60℃下經2h逐滴添加至化合物2之溶液中。然後,在-60℃下添加存於800mL THF中之509g苯甲醛(1.2當量)的溶液且將反應混合物在-60℃下陳化1h。將THF溶液在小於2℃下倒入1.21L濃HCl、8.14L冰水及4.52L EtOAc之混合物中。使用2.71L鹽水洗滌有機層(兩次)且使用3.98L EtOAc萃取水層。濃縮合併之有機層。向混合物中添加1.63L甲苯且濃縮(兩次)以提供化合物3之甲苯漿液。過濾,使用0.90L冷甲苯洗滌並乾燥以獲得955g化合物3之晶體(自化合物1之產率為74%)。
1
H NMR(300MHz,CDCl3
)δ7.62(d,J=5.7Hz,1H),7.5-7.2(m,10H),6.38(d,J=5.7Hz,1H),5.16(d,J=11.4Hz,1H),5.09(d,J=11.4Hz,1H),4.95(dd,J=4.8,9.0Hz,1H),3.01(dd,J=9.0,14.1Hz,1H),2.84(dd,J=4.8,14.1Hz,1H)。
在小於30℃下向存於8.82L THF中之882g化合物3(1.0當量)之溶液中添加416g Et3
N(1.5當量)及408g甲磺醯氯(1.3當量)。確認化合物3消失後,在小於30℃下向反應混合物中添加440mL NMP及1167g DBU(2.8當量)且將反應混合物陳化30min。使用1.76L 16%硫酸中和混合物並使用1.76L 2% Na2
SO3
水溶液洗滌有機層。濃縮有機層後,添加4.41L甲苯并濃縮混合物(三次)。添加4.67L己烷後,使用冰浴冷卻混合物。過濾,使用1.77L己烷洗滌並乾燥以提供780g化合物4之晶體(產率為94%)。
1
H NMR(300MHz,CDCl3
)δ7.69(d,J=5.7Hz,1H),7.50-7.25(m,10H),7.22(d,J=16.2Hz,1H),7.03(d,J=16.2Hz,1H),6.41(d,J=5.7Hz,1H),5.27(s,2H)。
在小於25℃下向存於2.47L MeCN、2.47L EtOAc及2.47L H2
O中之822g化合物4(1.0當量)及11.2g RuCl3
‧nH2
O(0.02當量)的混合物中添加2310g NaIO4
(4.0當量)。陳化1h後,在小於25℃下向混合物中添加733g NaClO2
(3.0當量)。陳化1h後,過濾沉澱物並使用8.22L EtOAc洗滌。向濾液中添加1.64L 50% Na2
S2
O3
水溶液、822mL H2
O及630mL濃HCl。使用4.11L EtOAc萃取水層且合併有機層並濃縮。向殘餘物中添加4L甲苯且濃縮混合物並使用冰浴冷卻。過濾,使用1L甲苯洗滌並乾燥以提供372g化合物5之晶體(產率為56%)。
1
H NMR(300MHz,CDCl3
)δ7.78(d,J=5.7Hz,1H),7.54-7.46(m,2H),7.40-7.26(m,3H),6.48(d,J=5.7Hz,1H),5.6(brs,1H),5.31(s,2H)。
將存於1.53L EtOH中之509g化合物5(1.0當量)及407g 3-胺基-丙烷-1,2-二醇(2.5當量)的混合物在65℃下攪拌1h且在80℃下攪拌6h。添加存於200mL EtOH中之18.8g 3-胺基-丙烷-1,2-二醇(0.1當量)後,將混合物在80℃下攪拌1h。添加存於200mL EtOH中之18.8g 3-胺基-丙烷-1,2-二醇(0.1當量)後,將混合物在80℃下攪拌30min。冷卻並添加509mL H2
O後,濃縮混合物。向殘餘物中添加2.54L H2
O及2.54L AcOEt。分離後,使用1.02L EtOAc洗滌水層。在小於12℃下向水層中添加2.03L 12%硫酸以獲得化合物6之晶體。過濾,使用1.53L冷H2
O洗滌並乾燥以提供576g化合物6之晶體(產率為83%)。
1
H NMR(300MHz,DMSO-d6
)δ7.67(d,J=7.5Hz,1H),7.5-7.2(m,5H),6.40(d,J=7.5Hz,1H),5.07(s,2H),4.2-4.0(m,1H),3.9-3.6(m,2H),3.38(dd,J=4.2,10.8Hz,1H),3.27(dd,J=6.0,10.8Hz,1H)。
向存於2.88L NMP中之576g化合物6(1.0當量:含有5.8%之H2
O)之漿液中添加431g NaHCO3
(3.0當量)及160mL碘代甲烷(1.5當量)且將混合物在室溫下攪拌4h。冷卻至5℃後,在小於10℃下向混合物中添加1.71L 2N HCl及1.15L 20% NaCl水溶液以獲得化合物7之晶體。過濾,使用1.73L H2
O洗滌並乾燥以提供507g化合物7之晶體(產率為89%)。
1
H NMR(300MHz,DMSO-d6
)δ7.59(d,J=7.5Hz,1H),7.40-7.28(m,5H),6.28(d,J=7.5Hz,1H),5.21(d,J=5.4Hz,1H),5.12(d,J=10.8Hz,1H),5.07(d,J=10.8Hz,1H),4.83(t,J=5.7Hz,1H),3.97(dd,J=2.4,14.1Hz,1H),3.79(s,3H),3.70(dd,J=9.0,14.4Hz,1H),3.65-3.50(m,1H),3.40-3.28(m,1H),3.26-3.14(m,1H)。
向存於5.07L MeCN、5.07L H2
O及9.13g AcOH(0.1當量)中之507g化合物7(1.0當量)之混合物中添加390g NaIO4
(1.2當量)且將混合物在室溫下攪拌2h。添加1.52L 10% Na2
S2
O3
水溶液後,濃縮混合物並冷卻至10℃。過濾,使用H2
O洗滌並乾燥以提供386g化合物8之晶體(產率為80%)。
1
H NMR(300MHz,DMSO-d6
)δ7.62(d,J=7.5Hz,1H),7.42-7.30(m,5H),6.33(d,J=6.0Hz,2H),6.29(d,J=7.5Hz,1H),5.08(s,2H),4.95-4.85(m,1H),3.80(s,3H),3.74(d,J=5.1Hz,2H)。
藉由加熱將378g化合物8(1.0當量)之混合物溶於3.78L MeOH中後,濃縮溶液。向殘餘物中添加1.51L甲苯并濃縮混合物。向殘餘物中添加1.89L甲苯、378mL AcOH及137g(R)-3-胺基-丁-1-醇(1.3當量)且將混合物加熱至90℃,在90℃下攪拌2.5h並濃縮。向殘餘物中添加1.89L甲苯并濃縮混合物。使用3.78L及1.89L CHCl3
萃取殘餘物且使用2×1.89L H2
O洗滌。合併有機層並濃縮。向殘餘物中添加1.89L EtOAc並濃縮混合物。添加1.89L EtOAc後,過濾,使用1.13L EtOAc洗滌並乾燥以提供335g化合物9之晶體(產率為83%)。
1
H NMR(300MHz,CDCl3
)δ7.70-7.58(m,2H),7.40-7.24(m,3H),7.14(d,J=7.5Hz,2H),6.47(d,J=7.5Hz,1H),5.35(d,J=10.2Hz,1H),5.28(d,J=10.2Hz,1H),5.12(dd,J=3.9,6.3Hz,1H),5.05-4.90(m,1H),4.07(dd,J=3.9,13.5Hz,1H),4.00-3.86(m,3H),2.23-2.06(m,1H),1.48(ddd,J=2.4,4.5,13.8Hz,1H),1.30(d,J=6.9Hz,3H)。
向存於1.66L NMP中之332g化合物9(1.0當量)之漿液中添加191g NBS(1.1當量)且將混合物在室溫下攪拌2h。添加1.26L H2
O後,將混合物攪拌30min。添加5.38L H2
O且將混合物在10℃下陳化30min並在5℃下陳化1h後,過濾,使用1.33L冷H2
O洗滌並乾燥以提供362g化合物10之晶體(產率為89%)。
1
H NMR(300MHz,CDCl3
)δ7.69-7.63(m,2H),7.59(s,1H),7.38-7.24(m,3H),5.33(d,J=10.2Hz,1H),5.25(d,J=9.9Hz,1H),5.12(dd,J=3.9,5.7Hz,1H),5.05-4.90(m,1H),4.11(dd,J=3.9,13.2Hz,1H),4.02-3.88(m,3H),2.21-2.06(m,1H),1.49(ddd,J=2.4,4.5,14.1Hz,1H),1.31(d,J=6.9Hz,3H)。
在一氧化碳氣氛下,將存於335mL DMSO中之33.5g化合物10(1.0當量)、34.8mL i-Pr2
NEt(2.5當量)、14.3mL 2,4-二氟苄胺(1.5當量)及4.62g Pd(PPh3
)4
(0.05當量)的混合物在90℃下攪拌5.5h。冷卻後,過濾沉澱物且使用50mL 2-丙醇洗滌。向濾液中添加502mL H2
O及670mL AcOEt後,使用335mL 0.5N HCl水溶液及335mL H2
O洗滌有機層且使用335mL AcOEt萃取水層。合併有機層並濃縮。向殘餘物中添加150mL 2-丙醇並濃縮混合物。添加150mL 2-丙醇後,濃縮、冷卻至20℃並過濾,獲得化合物11之粗製晶體。藉由加熱將粗製晶體溶於380mL丙酮中後,過濾沉澱物並濃縮濾液。添加200mL EtOH後,濃縮,添加150mL EtOH,濃縮,冷卻並過濾,獲得化合物11之粗製晶體。藉由加熱將粗製晶體溶於450mL丙酮中後,濃縮溶液。向殘餘物中添加150mL 2-丙醇並濃縮混合物(兩次)。冷卻殘餘物後,過濾,使用2-丙醇洗滌並乾燥以提供34.3g化合物11之晶體(產率為84%)。
1
H NMR(300MHz,CDCl3
)δ10.40(t,J=6.0Hz,1H),8.35(s,1H),7.66-7.58(m,2H),7.42-7.24(m,5H),6.78-6.74(m,2H),5.30(d,J=9.9Hz,1H),5.26(d,J=10.2Hz,1H),5.15(dd,J=3.9,5.7Hz,1H),5.05-4.90(m,1H),4.64(d,J=5.4Hz,2H),4.22(dd,J=3.9,13.5,1H),4.09(dd,J=6.0,13.2Hz,1H),4.02-3.88(m,2H),2.24-1.86(m,1H),1.50(ddd,J=2.4,4.5,14.1Hz,1H),1.33(d,J=7.2Hz,3H)。
在氫氣氣氛下,將存於252mL THF及28mL MeOH中之28.0g化合物11(1.0當量)及5.6g 10% Pd-C的混合物攪拌1h。在過濾沉澱物(Pd-C)並使用45mL THF洗滌後,添加5.6g 10% Pd-C且將混合物在氫氣氣氛下攪拌1.5h。過濾Pd-C且使用150mL CHCl3
/MeOH(9/1)洗滌,濃縮濾液。藉由加熱將殘餘物溶於1.38L EtOH中後,將溶液逐漸冷卻至室溫。過濾後,濃縮濾液並冷卻。過濾,使用EtOH洗滌並乾燥以提供21.2g化合物12之晶體(產率為92%)。
1
H NMR(300MHz,DMSO-d6
)δ12.51(s,1H),10.36(t,J=5.7Hz,1H),8.50(s,1H),7.39(td,J=8.7,6.3Hz,1H),7.24(ddd,J=2.6,9.5,10.8Hz,1H),7.12-7.00(m,1H),5.44(dd,J=3.9,5.7Hz,1H),4.90-4.70(m,1H),4.65-4.50(m,1H),4.54(d,J=5.1Hz,2H),4.35(dd,J=6.0,13.8Hz,1H),4.10-3.98(m,1H),3.96-3.86(m,1H),2.10-1.94(m,1H),1.60-1.48(m,1H),1.33(d,J=6.9Hz,3H)。
藉由加熱將18.0g化合物12(1.0當量)溶於54mL EtOH中後,隨後過濾,在80℃下向溶液中添加21.5mL 2N NaOH水溶液(1.0當量)。將溶液逐漸冷卻至室溫。過濾,使用80mL EtOH洗滌並乾燥以提供18.8g化合物13之晶體(產率為99%)。
1
H NMR(300MHz,DMSO-d6
)δ10.70(t,J=6.0Hz,1H),7.89(s,1H),7.40-7.30(m,1H),7.25-7.16(m,1H),7.06-6.98(m,1H),5.22-5.12(m,1H),4.87-4.74(m,1H),4.51(d,J=5.4Hz,2H),4.35-4.25(m,1H),4.16(dd,J=1.8,14.1Hz,1H),4.05-3.90(m,1H),3.86-3.74(m,1H),2.00-1.72(m,1H),1.44-1.32(m,1H),1.24(d,J=6.9Hz,3H)。
實例1m展示製備化合物13之一水合物形式:結晶化合物13b的方法。
在30℃下將30.0g化合物13(1.0當量)溶於600mL THF-水溶液(8:2)中後,向溶液中添加36.0mL 2N NaOH水溶液(1.0當量)。將混合物在室溫下攪拌2小時。過濾沉澱,使用150mL THF-水溶液(8:2)、150mL THF洗滌。在85℃及潮濕條件下乾燥以提供30.4g化合物13b之晶體(化合物13之一水合物形式,產率為93%)。
向存於14.0L MeCN中之2000g化合物1(1.0當量)的漿液中添加2848g苄基溴(1.05當量)及2630g K2
CO3
(1.2當量)。將混合物在80℃下攪拌5h並冷卻至13℃。過濾沉澱物並使用5.0L MeCN洗滌。濃縮濾液並向殘餘物中添加3.0L THF。濃縮THF溶液以獲得3585g油狀粗製化合物2。未經進一步純化,將化合物2用於下一步驟中。
1
H NMR(300MHz,CDCl3
)δ7.60(d,J=5.7Hz,1H),7.4-7.3(m,5H),6.37(d,J=5.7Hz,1H),5.17(s,2H),2.09(s,3H)。
向904g粗製化合物2中添加5.88L THF且將溶液冷卻至-60℃。將存於THF中之5.00L 1.0M的雙(三甲基矽烷基胺)鋰(1.25當量)在-60℃下經2h逐滴添加至化合物2之溶液中。然後,在-60℃下添加存於800mL THF中之509g苯甲醛(1.2當量)的溶液且將反應混合物在-60℃下陳化1h。將THF溶液在小於2℃下倒入1.21L濃HCl、8.14L冰水及4.52L EtOAc之混合物中。使用2.71L鹽水洗滌有機層(兩次)且使用3.98L EtOAc萃取水層。濃縮合併之有機層。向混合物中添加1.63L甲苯且濃縮(兩次)以提供化合物3之甲苯漿液。過濾,使用0.90L冷甲苯洗滌並乾燥以獲得955g化合物3之晶體(自化合物1之產率為74%)。
1
H NMR(300MHz,CDCl3
)δ7.62(d,J=5.7Hz,1H),7.5-7.2(m,10H),6.38(d,J=5.7Hz,1H),5.16(d,J=11.4Hz,1H),5.09(d,J=11.4Hz,1H),4.95(dd,J=4.8,9.0Hz,1H),3.01(dd,J=9.0,14.1Hz,1H),2.84(dd,J=4.8,14.1Hz,1H)。
在小於30℃下向存於8.82L THF中之882g化合物3(1.0當量)之溶液中添加416g Et3
N(1.5當量)及408g甲磺醯氯(1.3當量)。確認化合物3消失後,在小於30℃下向反應混合物中添加440mL NMP及1167g DBU(2.8當量)且將反應混合物陳化30min。使用1.76L 16%硫酸中和混合物並使用1.76L 2% Na2
SO3
水溶液洗滌有機層。濃縮有機層後,添加4.41L甲苯并濃縮混合物(三次)。添加4.67L己烷後,使用冰浴冷卻混合物。過濾,使用1.77L己烷洗滌並乾燥以提供780g化合物4之晶體(產率為94%)。
1
H NMR(300MHz,CDCl3
)δ7.69(d,J=5.7Hz,1H),7.50-7.25(m,10H),7.22(d,J=16.2Hz,1H),7.03(d,J=16.2Hz,1H),6.41(d,J=5.7Hz,1H),5.27(s,2H)。
在20℃下經2.5h向存於95mL MeCN及10mL水中之10.0g化合物4及13.6mg RuCl3
‧nH2
O之混合物中添加155mL水、7.2g氫硫酸、及15.5g NaIO4
的混合物。陳化1h後,分離有機層及水層且藉由30mL乙酸乙酯萃取水層。藉由30mL乙酸乙酯再次萃取水層併合併有機層。向合併之有機層中添加6mL 5% NaHSO3
溶液並分離各層。藉由添加4.0g 2M NaOH溶液將有機層調節至pH為6.0並分離水層。在添加60mL 5% NaHCO3
溶液及257mg TEMPO後,在25℃下經1h向反應混合物中添加25.9g NaClO溶液並攪拌30min以檢查反應完成。分離各層後,添加42.5mL 5% Na2
SO3
溶液及30mL AcOEt並分離。藉由30mL AcOEt萃取水層並分離。在20℃下經1h向反應混合物中添加12% H2
SO4
並將混合物冷卻至5℃。將混合物攪拌30min後,過濾混合物,使用30mL水洗滌兩次並乾燥以提供5.7g化合物5之晶體(產率為70%)。
1
H NMR(300MHz,CDCl3
)δ7.78(d,J=5.7Hz,1H),7.54-7.46(m,2H),7.40-7.26(m,3H),6.48(d,J=5.7Hz,1H),5.6(brs,1H),5.31(s,2H)。
將存於1.53L EtOH中之509g化合物5(1.0當量)及407g 3-胺基-丙烷-1,2-二醇(2.5當量)的混合物在65℃下攪拌1h且在80℃下攪拌6h。添加存於200mL EtOH中之18.8g 3-胺基-丙烷-1,2-二醇(0.1當量)後,將混合物在80℃下攪拌1h。添加存於200mL EtOH中之18.8g 3-胺基-丙烷-1,2-二醇(0.1當量)後,將混合物在80℃下攪拌30min。冷卻並添加509mL H2
O後,濃縮混合物。向殘餘物中添加2.54L H2
O及2.54L AcOEt。分離後,使用1.02L EtOAc洗滌水層。在小於12℃下向水層中添加2.03L 12%硫酸以獲得化合物6之晶體。過濾,使用1.53L冷H2
O洗滌並乾燥以提供576g化合物6之晶體(產率為83%)。
1
H NMR(300MHz,DMSO-d6
)δ7.67(d,J=7.5Hz,1H),7.5-7.2(m,5H),6.40(d,J=7.5Hz,1H),5.07(s,2H),4.2-4.0(m,1H),3.9-3.6(m,2H),3.38(dd,J=4.2,10.8Hz,1H),3.27(dd,J=6.0,10.8Hz,1H)。
向存於2.88L NMP中之576g化合物6(1.0當量:含有5.8%之H2
O)之漿液中添加431g NaHCO3
(3.0當量)及160mL碘代甲烷(1.5當量)且將混合物在室溫下攪拌4h。冷卻至5℃後,在小於10℃下向混合物中添加1.71L 2N HCl及1.15L 20% NaCl水溶液以獲得化合物7之晶體。過濾,使用1.73L H2
O洗滌並乾燥以提供507g化合物7之晶體(產率為89%)。
1
H NMR(300MHz,DMSO-d6
)δ7.59(d,J=7.5Hz,1H),7.40-7.28(m,5H),6.28(d,J=7.5Hz,1H),5.21(d,J=5.4Hz,1H),5.12(d,J=10.8Hz,1H),5.07(d,J=10.8Hz,1H),4.83(t,J=5.7Hz,1H),3.97(dd,J=2.4,14.1Hz,1H),3.79(s,3H),3.70(dd,J=9.0,14.4Hz,1H),3.65-3.50(m,1H),3.40-3.28(m,1H),3.26-3.14(m,1H)。
在17℃至14℃下向存於70.9g MeCN中之15.0g化合物7(1.0當量)之混合物中添加60mL H2
O、2.6g H2
SO4
及11.5g NaIO4
的混合物。將反應混合物攪拌1小時後,過濾沉澱物。將濾液添加至11.8g抗壞血酸鈉鹽、64g水及60mg H2
SO4
之溶液中。濃縮混合物後,冷卻至5℃,過濾,使用H2
O洗滌並乾燥以提供12.9g化合物8之晶體(產率為90%)。
1
H NMR(300MHz,DMSO-d6
)δ7.62(d,J=7.5Hz,1H),7.42-7.30(m,5H),6.33(d,J=6.0Hz,2H),6.29(d,J=7.5Hz,1H),5.08(s,2H),4.95-4.85(m,1H),3.80(s,3H),3.74(d,J=5.1Hz,2H)。
在60℃下向10.0g化合物8及33.3g二乙二醇二甲醚之混合物中添加存於4.7g二乙二醇二甲醚及1.0g乙酸中之3.3g(R)-3-胺基-丁-1-醇的溶液。將反應混合物在95℃下攪拌9小時後,將反應混合物冷卻至-5℃並過濾。洗滌濕晶體並乾燥以獲得8.3g化合物9(78%)。
XRD數據:1
H NMR(300MHz,CDCl3
)δ7.70-7.58(m,2H),7.40-7.24(m,3H),7.14(d,J=7.5Hz,2H),6.47(d,J=7.5Hz,1H),5.35(d,J=10.2Hz,1H),5.28(d,J=10.2Hz,1H),5.12(dd,J=3.9,6.3Hz,1H),5.05-4.90(m,1H),4.07(dd,J=3.9,13.5Hz,1H),.4.00-3.86(m,3H),2.23-2.06(m,1H),1.48(ddd,J=2.4,4.5,13.8Hz,1H),1.30(d,J=6.9Hz,3H)。
在室溫下向存於26.5g二氯甲烷中之5.7g NBS之漿液中添加存於92.8g二氯甲烷中之10g化合物9。攪拌反應混合物6.5h後,將反應混合物添加至2.0g Na2
SO3
及40.3g水之溶液中。使用稀NaOH溶液及水洗滌有機層,濃縮二氯甲烷並替換為甲醇。將混合物冷卻至-5℃並過濾,且洗滌濕晶體並乾燥以獲得10.3g化合物10(84%)。
1
H NMR(300MHz,CDCl3
)δ7.69-7.63(m,2H),7.59(s,1H),7.38-7.24(m,3H),5.33(d,J=10.2Hz,1H),5.25(d,J=9.9Hz,1H),5.12(dd,J=3.9,5.7Hz,1H),5.05-4.90(m,1H),4.11(dd,J=3.9,13.2Hz,1H),4.02-3.88(m,3H),2.21-2.06(m,1H),1.49(ddd,J=2.4,4.5,14.1Hz,1H),1.31(d,J=6.9Hz,3H)。
在一氧化碳氣氛下,將存於188mL DMA中之25.0g化合物10、11.6g i-Pr2
NEt、12.8g 2,4-二氟苄胺、335mg Pd(OAc)2
及1.9g 1,4-雙(二苯基膦基)丁烷的混合物在85℃下攪拌4h。冷卻後,分離反應混合物並將混合物之10/25用於下一步驟。在40℃下將6.6g AcOEt、29.9g水及3mg晶種添加至反應混合物中。攪拌7min後,添加29.9g水並冷卻至室溫。在室溫下過濾晶體並藉由47.2g乙醇進行洗滌以獲得10.1g化合物11之晶體(產率為83%)。
1
H NMR(300MHz,CDCl3
)δ10.40(t,J=6.0Hz,1H),8.35(s,1H),7.66-7.58(m,2H),7.42-7.24(m,5H),6.78-6.74(m,2H),5.30(d,J=9.9Hz,1H),5.26(d,J=10.2Hz,1H),5.15(dd,J=3.9,5.7Hz,1H),5.05-4.90(m,1H),4.64(d,J=5.4Hz,2H),4.22(dd,J=3.9,13.5,1H),4.09(dd,J=6.0,13.2Hz,1H),4.02-3.88(m,2H),2.24-1.86(m,1H),1.50(ddd,J=2.4,4.5,14.1Hz,1H),1.33(d,J=7.2Hz,3H)。
在氫氣氣氛下,將存於67.6mL THF及1.6mL H2
O中之4.0g化合物11及0.8g 50%濕5% Pd-C的混合物在50℃下攪拌1.5h。將80mg NaHSO3
及2.0mL純水之混合物添加至反應混合物且將反應混合物攪拌1h後,過濾沉澱物,使用20mL THF洗滌並將濾液濃縮至11.97g。經1h添加6.7mL乙醇及33.6mL純水後,將反應混合物冷卻至25℃。過濾,使用26.9mL EtOH洗滌並乾燥以提供2.33g化合物12之晶體(產率為82%)。
1
H NMR(300MHz,DMSO-d6
)δ12.51(s,1H),10.36(t,J=5.7Hz,1H),8.50(s,1H),7.39(td,J=8.7,6.3Hz,1H),7.24(ddd,J=2.6,9.5,10.8Hz,1H),7.12-7.00(m,1H),5.44(dd,J=3.9,5.7Hz,1H),4.90-4.70(m,1H),4.65-4.50(m,1H),4.54(d,J=5.1Hz,2H),4.35(dd,J=6.0,13.8Hz,1H),4.10-3.98(m,1H),3.96-3.86(m,1H),2.10-1.94(m,1H),1.60-1.48(m,1H),1.33(d,J=6.9Hz,3H)。
藉由加熱將18.0g化合物12(1.0當量)溶於54mL EtOH中後,隨後過濾,在80℃下向溶液中添加21.5mL 2N NaOH水溶液(1.0當量)。將溶液逐漸冷卻至室溫。過濾,使用80mL EtOH洗滌並乾燥以提供18.8g化合物13之晶體(產率為99%)。
1
H NMR(300MHz,DMSO-d6
)δ10.70(t,J=6.0Hz,1H),7.89(s,1H),7.40-7.30(m,1H),7.25-7.16(m,1H),7.06-6.98(m,1H),5.22-5.12(m,1H),4.87-4.74(m,1H),4.51(d,J=5.4Hz,2H),4.35-4.25(m,1H),4.16(dd,J=1.8,14.1Hz,1H),4.05-3.90(m,1H),3.86-3.74(m,1H),2.00-1.72(m,1H),1.44-1.32(m,1H),1.24(d,J=6.9Hz,3H)。
實例A之起始材料係化合物8,其與本發明方法之式(Ia)相同。因此,實例A描述了本發明方法在提供下文式17化合物之中間體中的用途,該中間體與Brian Johns等人之WO 2006/116764中第237頁的化合物ZZ-2係同分異構體。
藉由加熱將320g化合物8(1.0當量)之混合物溶於3.20L MeOH中後,濃縮溶液。向殘餘物中添加1.66L MeCN、5.72mL AcOH(0.1當量)及82.6g(S)-2-胺基-丙-1-醇(1.1當量)並將混合物加熱至70℃,在70℃下攪拌4h並濃縮。向殘餘物中添加1.67L 2-丙醇並濃縮混合物(兩次)。冷卻殘餘物後,過濾,使用500mL冷2-丙醇洗滌並乾燥以提供167g化合物14之晶體(產率為52%)。
1
H NMR(300MHz,CDCl3
)δ7.61-7.55(m,2H),7.40-7.20(m,4H),6.53(d,J=7.2,1H),5.46(d,J=10.5Hz,1H),5.23(d,J=10.2Hz,1H),5.20(dd,J=3.9,9.6Hz,1H),4.46-4.34(m,1H),4.31(dd,J=6.6,8.7Hz,1H),4.14(dd,J=3.9,12.3Hz,1H),3.79(dd,J=9.9,12.3Hz,1H),3.62(dd,J=6.9,8.7Hz,1H),1.38(d,J=6.3Hz,3H)。
向存於780mL NMP中之156g化合物14(1.0當量)的漿液中添加93.6g NBS(1.1當量)並將混合物在室溫下攪拌2.5h。將反應混合物添加至3.12L H2
O中。過濾,使用8.0L H2
O洗滌並乾燥以提供163g化合物15之晶體(產率為84%)。
1
H NMR(300MHz,DMSO-d6
)δ8.37(s,1H),7.55-7.50(m,2H),7.42-7.25(m,3H),5.34(dd,J=3.6,9.9.Hz,1H),5.18(d,J=10.8Hz,1H),5.03(d,J=10.5Hz,1H),4.53(dd,J=3.6,12.0Hz,1H),4.40-4.20(m,2H),3.99(dd,J=9.9,11.7Hz,1H),3.64(dd,J=5.7,8.1Hz,1H),1.27(d,J=6.3Hz,3H)。
在一氧化碳氣氛下,將存於816mL DMSO中之163g化合物15(1.0當量)、163mL i-Pr2
NEt(2.5當量)、68.4mL 2,4-二氟苄胺(1.5當量)及22.5g Pd(PPh3
)4
(0.05當量)的混合物在90℃下攪拌7h。冷卻後,去除沉澱物,使用50mL DMSO洗滌並添加11.3g Pd(PPh3
)4
(0.025當量),再次將反應混合物在一氧化碳氣氛及90℃下攪拌2h。冷卻後,去除沉澱物並添加2.0L AcOEt及2.0L H2
O,使用1.0L 1N HCl水溶液及1.0L H2
O(兩次)洗滌有機層並使用1.0L AcOEt萃取水層。合併有機層並濃縮。殘餘物之矽膠管柱層析提供184g化合物16之發泡體(產率為96%)。
1
H NMR(300MHz,CDCl3
)δ10.38(t,J=6.3Hz,1H),8.39(s,1H),7.75-7.25(m,7H),6.90-6.70(m,2H),5.43(d,J=10.2Hz,1H),5.24(d,J=10.2Hz,1H),5.19(dd,J=3.9,9.9Hz,1H),4.63(d,J=6.0Hz,2H),4.50-4.25(m,3H),3.86(dd,J=9.9,12.3Hz,1H),3.66(dd,J=6.9,8.4Hz,1H),1.39(d,J=6.0Hz,3H)。
在氫氣氣氛下,將存於3.31L THF及0.37L MeOH中之184g化合物16(1.0當量)及36.8g 10% Pd-C的混合物攪拌3h。過濾沉澱物(Pd-C)後,使用THF/MeOH(9/1)洗滌並添加36.8g 10% Pd-C,將混合物在氫氣氣氛下攪拌20min。過濾沉澱物(Pd-C)並使用THF/MeOH(9/1)洗滌後,濃縮濾液。向殘餘物中添加200mL AcOEt後,過濾以獲得粗製固體化合物17。合併沉澱物並使用4.0L CHCl3
/MeOH(5/1)萃取。濃縮CHCl3
/MeOH溶液並向殘餘物中添加250mL AcOEt後,過濾以獲得粗製固體化合物17。合併粗製固體並藉由加熱將其溶於8.2L MeCN/H2
O(9/1)中。過濾後,濃縮濾液。向殘餘物中添加1.5L EtOAc並濃縮混合物(三次)。冷卻殘餘物後,過濾並乾燥以提供132g化合物17之晶體(產率為88%)。
1
H NMR(300MHz,DMSO-d6
)δ11.47(brs,1H),10.31(t,J=6.0Hz,1H),8.46(s,1H),7.40(td,J=8.6,6.9Hz,1H),7.24(ddd,J=2.6,9.4,10.6,1H),7.11-7.01(m,1H),5.39(dd,J=4.1,10.4Hz,1H),4.89(dd,J=4.2,12.3Hz,1H),4.55(d,J=6.0Hz,2H),4.40(dd,J=6.8,8.6Hz,1H),4.36-4.22(m,1H),4.00(dd,J=10.2,12.3Hz,1H),3.67(dd,J=6.7,8.6Hz,1H),1.34(d,J=6.3Hz,3H)。
藉由加熱將16.0g化合物17(1.0當量)溶於2.56L EtOH及0.64L H2
O中後,隨後過濾,在75℃下向溶液中添加39mL1N NaOH水溶液(1.0當量)。將溶液逐漸冷卻至室溫。過濾,使用80mL EtOH洗滌並乾燥以提供13.5g化合物18之晶體(產率為80%)。
1
H NMR(300MHz,DMSO-d6
)δ10.73(t,J=6.0Hz,1H),7.89(s,1H),7.40-7.30(m,1H),7.25-7.16(m,1H),7.07-6.98(m,1H),5.21(dd,J=3.8,10.0Hz,1H),4.58(dd,J=3.8,12.1Hz,1H),4.51(d,J=5.4Hz,2H),4.30-4.20(m,2H),3.75(dd,J=10.0,12.1Hz,1H),3.65-3.55(m,1H),1.27(d,J=6.1Hz,3H)。
此實例B使用一種方法在吡喃酮環中插入環氮來代替氧並藉由雙鍵之鋨氧化來產生醛等效物。因此,此實例並不屬於本發明範圍內且經提供以顯示根據本發明方法所製得之中間體的用途。具體而言,下文化合物F係本發明方法之最終產物(VIII)且在此處使用其以獲得下文之產物I,產物I在WO 2006/116764第240頁的結構(I-7)(其中(R)m
係4-F且Ra
係H)之範圍內。
向化合物A(23.8g,110mmol)之溴苯(238ml)溶液中添加二氧化硒(24.4g,220mmol)。將反應混合物在140℃下攪拌13小時,同時藉由Dean-Stark捕集器去除水。冷卻後藉由過濾去除不溶性顆粒,且蒸發溶劑。向殘餘物中添加甲苯并過濾掉沉澱物。在真空中濃縮後,藉由矽膠管柱層析(己烷/乙酸乙酯)純化殘餘物。獲得黃色油狀化合物B(16.5g,65%)。
1
H-NMR(CDCl3
)δ: 5.51(2H,s),6.50(1H,d,J=5.4Hz),7.36(5H,s),7.75(1H,d,J=5.4Hz),9.88(1H,s)。
向亞氯酸鈉(38.4g,424mmol)及胺基磺酸(54.9g,566mmol)之冰冷水(465ml)溶液中添加化合物B(46.5g,202mmol)之丙酮(465ml)溶液並將混合物在室溫下攪拌40分鐘。在真空中去除丙酮後,藉由過濾收集沉澱物並使用冷水洗滌。獲得化合物C之無色晶體(42.8g,86%)。
1
H-NMR(DMSO-d6
)δ: 5.12(2H,s),6.54(1H,d,J=5.6Hz),7.33-7.46(5H,m),8.20(1H,d,J=5.6Hz)。
將烯丙胺(13.2g 231mmol)之乙醇(17ml)溶液添加至化合物C(17.2g,70mmol)之乙醇(69ml)懸浮液中,然後將混合物在50℃下攪拌4.5小時且在75℃下攪拌3小時。向冷卻之反應混合物中添加2N鹽酸及冰並藉由過濾收集沉澱物。獲得化合物D之無色晶體。
1
H-NMR(CDCl3
)δ: 4.37(2H,brs),4.95(2H,s),5.26-5.39(2H,m),5.81-5.94(1H,m),6.32(1H,dd,J=0.8,7.2Hz),7.29-7.37(3H,m),7.48-7.51(2H,m),7.99(1H,dd,J=0.8,7.6Hz),8.11(1H,brs)。
向化合物D(14.6g,51mmol)之乙腈(146ml)懸浮液中添加1,8-二氮雜雙環[5.4.0]十一-7-烯(15.5g,102mmol)及碘代甲烷(18.2g,128mmol)並將混合物在室溫下攪拌15小時。蒸發溶劑後,藉由矽膠管柱層析(氯仿/甲醇)純化殘餘物。獲得化合物E之無色固體(14.2g,93%)。
1
H-NMR(CDCl3
)δ: 3.75(3H,s),4.40(2H,d,J=5.7Hz),5.16-5.35(2H,m),5.29(2H,s),5.81-5.94(1H,m),6.62(1H,d,J=7.5Hz),7.27-7.42(6H,m)。
向化合物E(13.3g,44mmol)之乙醚(390ml)溶液中添加二水合鋨酸鉀(VI)(1.62g,4.4mmol)及高碘酸鈉(28.1g,132mmol)。將混合物在室溫下攪拌2.5小時並藉由過濾收集沉澱物。將所收集之固體溶於氯仿-甲醇中並過濾掉不溶性顆粒。在真空中濃縮以獲得化合物F之粗製產物(14.3g)。
1
H NMR(DMSO-d6
)δ: 3.23(3H,s),3.82(3H,s),3.87(2H,t,J=4.4Hz),4.62(1H,dd,J=11.7,4.8Hz),5.11(2H,s),6.31(1H,d,J=7.5Hz),6.78(1H,d,J=6.6Hz),7.33-7.40(5H,m),7.64(1H,d,J=7.5Hz)。
向化合物F(11.7g,粗製產物)之氯仿(108ml)及甲醇(12ml)溶液中添加3-胺基丙醇(2.77g,36.9mmol)及乙酸(1.2ml)並將混合物在70℃下攪拌90分鐘。在真空中濃縮後,藉由矽膠管柱層析(氯仿/甲醇)來純化殘餘物。獲得化合物G之無色晶體(8.48g,2個步驟之產率為72%)。
1
H-NMR(CDCl3
)δ: 1.54-1.64(1H,m),1.85-2.01(1H,m),3.00(1H,dt,J=3.6,12.9Hz),3.74(1H,dt,J=2.7,12.3Hz),3.93(1H,dd,J=5.1,13.5Hz),4.07-4.21(2H,m),4.63-4.69(1H,m),4.94(1H,t,J=4.8Hz),5.25(2H,dd,J=10.2,24.6Hz),6.56(1H,d,J=7.5Hz),7.22-7.38(5H,m),7.63-7.66(2H,m)。
在15分鐘內向化合物G(6.1g,18.7mmol)之乙酸(93ml)溶液中逐滴添加溴(1.44ml,28.0mmol)之乙酸(31ml)溶液。將混合物在室溫下攪拌3小時。添加5%之亞硫酸氫鈉(8ml)水溶液後,在20分鐘內逐滴添加2N的氫氧化鈉(500ml)。藉由過濾收集沉澱物並使用二氯甲烷及二異丙醚之混合物進行洗滌。獲得化合物H之無色晶體(6.02g,79%)。
1
H-NMR(DMSO-d6
)δ: 1.55-1.74(2H,m),3.12(1H,dt,J=3.0,12.3Hz),3.84(1H,dt,J=2.7,11.7Hz),4.00-4.05(1H,m),4.20-4.26(1H,m),4.40-4.46(2H,m),5.03(2H,s),5.15-5.17(1H,m),7.31-7.40(3H,m),7.56-7.58(2H,m),8.39(1H,s)。
向化合物H(71mg,0.175mmol)及肆(三苯基膦)鈀(0)(25mg,0.035mmol)之二甲基亞碸(1.42ml)溶液中添加4-氟苄胺(0.06ml,0.525mmol)及二異丙胺(0.15ml,0.875mmol),然後將混合物在一氧化碳氣氛及80℃下攪拌5小時。冷卻後,添加飽和氯化銨水溶液並用乙酸乙酯萃取混合物。使用水洗滌萃取物並使用無水硫酸鈉進行乾燥。在真空中去除溶劑並使用矽膠管柱層析(乙酸乙酯/甲醇)來純化殘餘物。獲得化合物I之無色晶體(74.5mg,89%)。
1
H-NMR(DMSO-d6
)δ: 1.58-1.74(2H,m),3.10-3.18(1H,m),3.80-3.88(1H,m),4.02-4.07(1H,m),4.43-4.59(5H,m),5.05(2H,s),5.20(1H,t,J=3.9Hz),7.13-7.19(2H,m),7.32-7.40(5H,m),7.56-7.59(2H,m),8.61(1H,s)。
合成5-溴-1-[2-羥基-2-(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯(與相應醛平衡)
此實例C顯示如上文實例1中所示之化合物6(式(VI))的再官能化,其包含在Rx
位置溴化以產生本發明之最終產物20及21(式(I))。在Rx
位置具有Br之該等化合物可如實例1及2中一般發生反應以添加R2
-X-NR1
-C(O)-側鏈。
1-(2,3-二羥丙基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯
向反應器中裝填1-(2,3-二羥丙基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸6(4.302kg,13.47mol),隨後裝填NaHCO3
(1.69kg,20.09mol)及242g去離子水。向此反應器中添加21.4kg NMP且攪拌混合物並將溫度調至28-35℃。經由加料漏斗經1-3個小時向反應混合物中逐滴添加硫酸二甲酯(2.34kg,18.30mol)同時將溫度保持在28-33℃。將漿液在此溫度下攪拌14h。在認為完成時,將反應混合物冷卻至5℃或更低,且藉由添加HCl(存於2806g去離子水中之561mL濃HCl)將混合物中和至pH為6。在最高溫度為10℃下向反應容器中緩緩裝填由8.7kg NaCl、20kg去離子水及14.8kg冰組成的20%冷鹽水溶液。將混合物在0-10℃下攪拌2.5h。在真空下過濾漿液並使用15kg去離子水洗滌濾餅兩次。在45-55℃及真空下乾燥濕固體產物直至獲得恆定重量。獲得期望產物1-(2,3-二羥丙基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯7,其為淺黃色固體(3.77kg,藉由HPLC獲知純度為99.42%,產率為84%)。1
H NMR(300MHz,DMSO-d6
)δ7.60(d,J=7.5Hz,1H),7.36(m,5H),6.28(d,J=7.5Hz,1H),5.23(d,J=5.4Hz,1H),5.10(Abq,J=10.8Hz,2H),4.85(m,1H),3.98(dd,J=14.3,2.4Hz,1H),3.79(s,3H),3.70(dd,J=14.3,9.0Hz,1H),3.58(m,1H),3.23(m,1H)。
5-溴-1-(2,3-二羥丙基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯。
向反應器中裝填1-(2,3-二羥丙基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯7(3.759kg,11.27mol)及18.8L DMF。在18-20℃下經20分鐘經由漏粉鬥向此經攪拌混合物中添加N-溴琥珀醯亞胺(2.220kg,12.47mol)。將所得混合物在室溫下攪拌16h。此時藉由HPLC發現存在小於1%之起始材料。藉由冷卻至10℃來處理半批混合物且添加冰/水混合物(存於35kg去離子水中之12kg冰)並攪拌混合物,然後過濾。對第二半批料重複此過程。使用14L水洗滌合併之濾餅並在真空箱中乾燥以提供4.033kg 5-溴-1-(2,3-二羥丙基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯19(91.6%),其係具有99.2% HPLC純度之灰白色粉末。1
H NMR(300MHz,甲醇-d4
)δ8.21(s,1H),7.41-7.33(m,5H),5.16(s,2H),4.17(dd,J=14.3,2.4Hz,1H),3.90(dd,J=14.3,9.0Hz,1H),3.81(s,3H),3.78(m,1),3.52(dd,J=11.3,4.8Hz,1H),3.41(dd,J=11.3,6.3Hz,1H)。
5-溴-1-[2-羥基-2-(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯(與相應醛平衡)
向反應器中裝填高碘酸鈉(1.67kg,7.8mol)及44L去離子水。向經攪拌混合物中添加8.5kg冰。攪拌此混合物直至所有冰皆融化且混合物溫度為1.4℃。經由粉末加料漏斗向此混合物中添加5-溴-1-(2,3-二羥丙基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯19(2.73kg,6.62mol)。將混合物升溫至室溫並將漿液攪拌16h。藉由1
H NMR監測試樣且顯示起始材料消失。過濾混合物並使用20kg去離子水洗滌濾餅。重複此過程直至獲得陰性澱粉/碘化物試紙結果(4×20L洗滌)。在45-55℃下於真空箱中乾燥固體以提供5-溴-1-(2,2-二羥乙基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯20(2.176kg,88%)與相應醛形式21之混合物。藉由HPLC測得純度為99.5%。1
H NMR(300MHz,丙酮-d6
)δ8.12(s,1H),7.49-7.30(m,5H),5.56(dd,J=6.0,2.4Hz,1H),5.23(m,1H),5.20(s,2H),3.97(d,J=5.1Hz,2H),3.87(s,3H)。
5-({[(2,4-二氟苯基)甲基]胺基)羰基)-1-[2-羥基-2-(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯(與相應醛平衡)
此實例展示在根據本發明方法製備式(I)化合物時步驟i)中式(II)化合物5與(III)之一者之反應及式(V)化合物(化合物22、23、24及25)的再官能化步驟ii)。
1-[2,2-雙(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸
向裝填500mL無水乙醇之燒瓶(1L)中添加49.2g(0.2mol)4-側氧基-3-[(苯甲基)氧基]-4H-吡喃-2-甲酸5。將懸浮液緩慢加熱至55~60℃然後添加2-胺基-乙醛-二甲基乙縮醛(84.1g,0.8莫耳)。然後將反應物升至65℃並進一步攪拌18小時。在減壓下去除溶劑以製得褐色油狀物1-[2,2-雙(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸22(粗製物),其可直接用於下一步驟。
1-[2,2-雙(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯
將所獲得之上述粗製1-[2,2-雙(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸22溶於DMF(500mL)中。向此溶液中添加NaHCO3
(50.5g,0.6莫耳)。使用機械攪拌儀劇烈攪拌懸浮液同時藉由加料漏斗經30分鐘引入存於TBME中之CH3
I(2.0M,300mL)。添加後,將反應物於室溫下攪拌過夜。然後使用EtOAc(約1.5L)稀釋反應混合物且用水及鹽水洗滌。藉由無水Na2
SO4
乾燥有機層。蒸發溶劑以獲得褐色油狀物1-[2,2-雙(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯23,其可直接用於下一步驟。
1-[2,2-雙(甲氧基)乙基]-5-溴-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯
向配備有機械攪拌儀之2L燒瓶中裝填如上文所獲得之1-[2,2-雙(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯23及500mL二氯甲烷。向此燒瓶中逐份添加NBS(30g,0.17莫耳)。在室溫下攪拌反應物直至反應完成(藉由TLC監測,約6小時)。然後使用二氯甲烷稀釋混合物並使用NaHCO3
(ss)洗滌。藉由Na2
SO4
乾燥有機相然後蒸發溶劑。藉由管柱層析(矽膠,EtOH/DCM: 0-40%)純化粗製產物以獲得淺褐色固體1-[2,2-雙(甲氧基)乙基]-5-溴-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯24(50g,經三個步驟之產率為60%)。1
H NMR(400MHz,氯仿-d)δppm 7.7(s,1H),7.4(m,2H),7.3(d,J=7.9Hz,3H),5.3(s,2H),4.4(s,1H),3.8(d,J=4.8Hz,2H),3.8(s,3H),3.4(s,6H)。LC-MS(M+H+
):計算值426,觀測值426。
1-[2,2-雙(甲氧基)乙基]-5-({[(2,4-二氟苯基)甲基]胺基}羰基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯
向壓力容器中裝填1-[2,2-雙(甲氧基)乙基]-5-溴-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯24(6.4g,15mmol)、2,4-二氟苄胺(3.2g,22.5mmol)、K3
PO4
(9.45g,45mmol)、Pd(OCOCF3
)2
(398mg,1.2mmol)、Xantophos(694mg,1.2mmol)及甲苯(200mL)。藉由CO(4X)吹掃混合物然後在CO氣氛(60psi)下加熱至100℃保持22小時。冷卻至室溫後,經由矽藻土過濾出固體並使用EtOAc洗滌。濃縮濾液並藉由管柱層析(矽膠,EtOAc/己烷0~80%)純化殘餘物以獲得淺褐色油狀物1-[2,2-雙(甲氧基)乙基]-5-({[(2,4-二氟苯基)甲基]胺基}羰基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯25(4.7g,61%)。1
H NMR(400MHz,氯仿-d)δppm 10.4(m,1H),8.4(s,1H),7.4(m,6H),6.8(d,J=9.3Hz,2H),5.3(s,2H),4.6(d,J=5.7Hz,2H),4.5(s,1H),4.0(d,J=4.8Hz,2H),3.8(s,3H),3.4(s,6H)。LC-MS(M+H+
):計算值517,觀測值517。
5-({[(2,4-二氟苯基)甲基]胺基)羰基)-1-[2-羥基-2-(甲氧基)乙基]-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯(與相應醛平衡)
在40℃下使用90%蟻酸(250mL)將1-[2,2-雙(甲氧基)乙基]-5-({[(2,4-二氟苯基)甲基]胺基}羰基)-4-側氧基-3-[(苯甲基)氧基]-1,4-二氫-2-吡啶甲酸甲酯25(11.6g)處理約12小時(藉由LC-MS監測)。在<40℃下蒸發溶劑後,將殘餘物再次溶於EtOAc(約1L)中並使用NaHCO3
及鹽水洗滌所得溶液。然後藉由Na2
SO4
乾燥有機相。蒸發溶劑後,獲得標題化合物26及27,其為約80/20之平衡混合物(10.57g)。1
H NMR(400MHz,DMSO-d6
)δppm 10.3(m,1H),9.47(s,乙醛-H,約0.2H),8.4(m,1H),7.3(s,6H),7.2(m,1H),7.0(m,1H),6.3(m,2H),5.1(s,3H),4.9(m,1H),4.5(m,3H),3.9(m,2H),3.8(s,3H)。LC-MS,對於26(M+H+
),計算值503,觀測值503;對於27(M+H2
O+H+
),計算值489,觀測值489。
Claims (23)
- 一種製備式(I)化合物之方法,
- 如請求項1之方法,其中在該式(I)化合物中,R係-CHO。
- 如請求項1之方法,其中在該式(I)化合物中,R係-CH(OH)2 。
- 如請求項1之方法,其中在該式(I)化合物中,R係-CH(OH)(OR4 )。
- 如請求項之2方法,其中該式(I)化合物具有式(VII):
- 如請求項之3方法,其中該式(I)化合物具有式(Ia):
- 如請求項之4方法,其中該式(I)化合物具有式(VIII):
- 如請求項之4方法,其中該式(I)化合物具有式(IX):
- 如請求項之1方法,其中式(II)之該化合物具有式(IIa):
- 如請求項1之方法,其中在該式(I)化合物中,R3 係H、鹵素、羥基、視需要經取代之低碳烷基、視需要經取代之環烷基、視需要經取代之低碳烯基、視需要經取代之低碳烷氧基。
- 一種製備式(I)之化合物之方法,
- 如請求項1之方法,其中該再官能化步驟ii)包括將其中R5 或R6 為甲基之式(V)之中間體去甲基化,製得該式(I)化合物。
- 如請求項1之方法,其中該再官能化步驟ii)包括使式(VI)之中間體與NaIO4 反應,製得該式(I)化合物。
- 如請求項1之方法,其中R3 係H。
- 一種具有下式(V)之化合物,
- 如請求項15之化合物,其具有下式(Va):
- 一種具有下式(VI)之化合物,
- 一種具有下式(I)之化合物,
- 如請求項16、17或18之化合物,其中R3 係-H。
- 一種具有下式(14)之化合物,
- 一種具有下式(15)之化合物,
- 一種具有下式(I)之化合物,
- 一種製備如請求項20或21之化合物之方法,其包含如請求項6之方法所界定之步驟。
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PT2376453T (pt) | 2020-01-14 |
WO2010068262A1 (en) | 2010-06-17 |
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CN107011260A (zh) | 2017-08-04 |
US8552187B2 (en) | 2013-10-08 |
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ES2763540T3 (es) | 2020-05-29 |
EP3617194A1 (en) | 2020-03-04 |
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CN104788367A (zh) | 2015-07-22 |
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EP2376453B1 (en) | 2019-11-20 |
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EP3617194B1 (en) | 2023-11-08 |
US20140005405A1 (en) | 2014-01-02 |
US20110263855A1 (en) | 2011-10-27 |
KR101678563B1 (ko) | 2016-11-22 |
KR20160127179A (ko) | 2016-11-02 |
TW201029973A (en) | 2010-08-16 |
ES2964383T3 (es) | 2024-04-05 |
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