JPWO2009044707A1 - ニトロトリアゾール誘導体、およびそれを用いる化合物の製造方法 - Google Patents
ニトロトリアゾール誘導体、およびそれを用いる化合物の製造方法 Download PDFInfo
- Publication number
- JPWO2009044707A1 JPWO2009044707A1 JP2009536043A JP2009536043A JPWO2009044707A1 JP WO2009044707 A1 JPWO2009044707 A1 JP WO2009044707A1 JP 2009536043 A JP2009536043 A JP 2009536043A JP 2009536043 A JP2009536043 A JP 2009536043A JP WO2009044707 A1 JPWO2009044707 A1 JP WO2009044707A1
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- general formula
- μmol
- synthesis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 106
- YXFWFUSVDJIVIV-UHFFFAOYSA-N 4-nitro-2h-triazole Chemical class [O-][N+](=O)C=1C=NNN=1 YXFWFUSVDJIVIV-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 238000004519 manufacturing process Methods 0.000 title claims description 14
- 238000000034 method Methods 0.000 claims abstract description 89
- 125000001424 substituent group Chemical group 0.000 claims abstract description 50
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 13
- 125000005553 heteroaryloxy group Chemical group 0.000 claims abstract description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 9
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 327
- 239000011541 reaction mixture Substances 0.000 claims description 40
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000007810 chemical reaction solvent Substances 0.000 claims description 16
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000001769 aryl amino group Chemical group 0.000 claims description 8
- 125000005110 aryl thio group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 156
- 230000015572 biosynthetic process Effects 0.000 abstract description 155
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 14
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 abstract description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 150000001721 carbon Chemical class 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 93
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 74
- 239000002904 solvent Substances 0.000 description 66
- -1 Alkyl Chloroformate Chemical compound 0.000 description 64
- 239000000047 product Substances 0.000 description 60
- 239000000203 mixture Substances 0.000 description 58
- 239000000243 solution Substances 0.000 description 40
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 229920006395 saturated elastomer Polymers 0.000 description 39
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 37
- 235000017557 sodium bicarbonate Nutrition 0.000 description 37
- 239000007787 solid Substances 0.000 description 30
- 239000011734 sodium Substances 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 239000012230 colorless oil Substances 0.000 description 18
- KUEFXPHXHHANKS-UHFFFAOYSA-N 5-nitro-1h-1,2,4-triazole Chemical compound [O-][N+](=O)C1=NC=NN1 KUEFXPHXHHANKS-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 12
- BHTJYIDOVYPNKR-UHFFFAOYSA-N 2-trimethylsilylethyl 3-nitro-1,2,4-triazole-1-carboxylate Chemical compound C[Si](C)(C)CCOC(=O)N1C=NC([N+]([O-])=O)=N1 BHTJYIDOVYPNKR-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229940125904 compound 1 Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 8
- 229940126086 compound 21 Drugs 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 0 *Nc1ccccc1 Chemical compound *Nc1ccccc1 0.000 description 7
- XFSAQXHAIMAZTD-CYBMUJFWSA-N benzyl n-[(1r)-1-phenylethyl]carbamate Chemical compound N([C@H](C)C=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 XFSAQXHAIMAZTD-CYBMUJFWSA-N 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- 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 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 229940126142 compound 16 Drugs 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 4
- OZXKTSRNLSDQTO-UHFFFAOYSA-N C1C(C)OC(C)CN1C(=O)OCC1=CC=CC=C1 Chemical compound C1C(C)OC(C)CN1C(=O)OCC1=CC=CC=C1 OZXKTSRNLSDQTO-UHFFFAOYSA-N 0.000 description 4
- SJMQGKILXSLHOT-UHFFFAOYSA-N CC1CN(CC(C)O1)C(=O)OCC(Cl)(Cl)Cl Chemical compound CC1CN(CC(C)O1)C(=O)OCC(Cl)(Cl)Cl SJMQGKILXSLHOT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126208 compound 22 Drugs 0.000 description 3
- 229940125878 compound 36 Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000013076 target substance Substances 0.000 description 3
- ALIYGTDWTPWSDQ-UHFFFAOYSA-N tert-butyl 4-phenylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC=C1 ALIYGTDWTPWSDQ-UHFFFAOYSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- 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 2
- 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
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- 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 2
- MWBAZBLBRUONAU-UHFFFAOYSA-N 2,2,2-trichloroethyl (4-methoxyphenyl)sulfanylformate Chemical compound COC1=CC=C(SC(=O)OCC(Cl)(Cl)Cl)C=C1 MWBAZBLBRUONAU-UHFFFAOYSA-N 0.000 description 2
- GHFRNBCWUZUIKV-UHFFFAOYSA-N 2,2,2-trichloroethyl 3-nitro-1,2,4-triazole-1-carboxylate Chemical compound [O-][N+](=O)C=1N=CN(C(=O)OCC(Cl)(Cl)Cl)N=1 GHFRNBCWUZUIKV-UHFFFAOYSA-N 0.000 description 2
- PAVDVFNMTYTIEG-UHFFFAOYSA-N 2,2,2-trichloroethyl n-phenylcarbamate Chemical compound ClC(Cl)(Cl)COC(=O)NC1=CC=CC=C1 PAVDVFNMTYTIEG-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- ZQOLCGZSRGITGA-AXFHLTTASA-N C(OCC(Cl)(Cl)Cl)(O[C@@H]1[C@H](CC[C@@H](C1)C)C(C)C)=O Chemical compound C(OCC(Cl)(Cl)Cl)(O[C@@H]1[C@H](CC[C@@H](C1)C)C(C)C)=O ZQOLCGZSRGITGA-AXFHLTTASA-N 0.000 description 2
- FJYSQFJNXFJJRA-UHFFFAOYSA-N C(OCC(Cl)(Cl)Cl)(SCCC)=O Chemical compound C(OCC(Cl)(Cl)Cl)(SCCC)=O FJYSQFJNXFJJRA-UHFFFAOYSA-N 0.000 description 2
- BGRDBZKVJYDFHW-UAGQMJEPSA-N C(OCC1=CC=CC=C1)(O[C@@H]1[C@H](CC[C@@H](C1)C)C(C)C)=O Chemical compound C(OCC1=CC=CC=C1)(O[C@@H]1[C@H](CC[C@@H](C1)C)C(C)C)=O BGRDBZKVJYDFHW-UAGQMJEPSA-N 0.000 description 2
- PYEOMZCJLJGRRX-UHFFFAOYSA-N C1(=CC=CC=C1)N1CCN(CC1)C(=O)OCC(Cl)(Cl)Cl Chemical compound C1(=CC=CC=C1)N1CCN(CC1)C(=O)OCC(Cl)(Cl)Cl PYEOMZCJLJGRRX-UHFFFAOYSA-N 0.000 description 2
- UCDRFWYJRSTBNC-MRVPVSSYSA-N C1(=CC=CC=C1)[C@@H](C)NC(OCC(Cl)(Cl)Cl)=O Chemical compound C1(=CC=CC=C1)[C@@H](C)NC(OCC(Cl)(Cl)Cl)=O UCDRFWYJRSTBNC-MRVPVSSYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- BGRANJBPDGNANZ-UHFFFAOYSA-N OCCCNC(OCC(Cl)(Cl)Cl)=O Chemical compound OCCCNC(OCC(Cl)(Cl)Cl)=O BGRANJBPDGNANZ-UHFFFAOYSA-N 0.000 description 2
- NZLOBYFLOQJJKW-ZJUUUORDSA-N O[C@@H]1Cc2ccccc2[C@@H]1NC(=O)OCC(Cl)(Cl)Cl Chemical compound O[C@@H]1Cc2ccccc2[C@@H]1NC(=O)OCC(Cl)(Cl)Cl NZLOBYFLOQJJKW-ZJUUUORDSA-N 0.000 description 2
- PJHDVFVGPKCGQX-CVEARBPZSA-N O[C@H]1[C@H](C2=CC=CC=C2C1)NC(OCC1=CC=CC=C1)=O Chemical compound O[C@H]1[C@H](C2=CC=CC=C2C1)NC(OCC1=CC=CC=C1)=O PJHDVFVGPKCGQX-CVEARBPZSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- GXCUEAGUTCCVRZ-GTPIUPDVSA-N [Si](C)(C)(C(C)(C)C)[C@@]1([C@@H](O[C@@H]([C@]1(O)[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)N1C(=O)N=C(NC(=O)OCC[Si](C)(C)C)C=C1)O Chemical compound [Si](C)(C)(C(C)(C)C)[C@@]1([C@@H](O[C@@H]([C@]1(O)[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)N1C(=O)N=C(NC(=O)OCC[Si](C)(C)C)C=C1)O GXCUEAGUTCCVRZ-GTPIUPDVSA-N 0.000 description 2
- PLGFQWGBIYWVAB-NMYSLYKMSA-N [Si](C)(C)(C(C)(C)C)[C@@]1([C@@H](O[C@@H]([C@]1(O)[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)N1C=NC=2C(=O)NC(NC(=O)OCC[Si](C)(C)C)=NC12)O Chemical compound [Si](C)(C)(C(C)(C)C)[C@@]1([C@@H](O[C@@H]([C@]1(O)[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)N1C=NC=2C(=O)NC(NC(=O)OCC[Si](C)(C)C)=NC12)O PLGFQWGBIYWVAB-NMYSLYKMSA-N 0.000 description 2
- PNZLWPYFFGGLOZ-FPGGFNBJSA-N [Si](C)(C)(C(C)(C)C)[C@@]1([C@@H](O[C@@H]([C@]1(O)[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)N1C=NC=2C(NC(=O)OCC[Si](C)(C)C)=NC=NC12)O Chemical compound [Si](C)(C)(C(C)(C)C)[C@@]1([C@@H](O[C@@H]([C@]1(O)[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)N1C=NC=2C(NC(=O)OCC[Si](C)(C)C)=NC=NC12)O PNZLWPYFFGGLOZ-FPGGFNBJSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000005427 anthranyl group Chemical group 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- CCQYQRMFLKGSGU-UHFFFAOYSA-N benzotriazol-1-yl carbamate Chemical compound C1=CC=C2N(OC(=O)N)N=NC2=C1 CCQYQRMFLKGSGU-UHFFFAOYSA-N 0.000 description 2
- WMUCDKZHFUDTBZ-UHFFFAOYSA-N benzyl 2,2,2-trichloroethyl carbonate Chemical compound ClC(Cl)(Cl)COC(=O)OCC1=CC=CC=C1 WMUCDKZHFUDTBZ-UHFFFAOYSA-N 0.000 description 2
- QSDUPHSUBRKHKC-UHFFFAOYSA-N benzyl 3-nitro-1,2,4-triazole-1-carboxylate Chemical compound N1=C([N+](=O)[O-])N=CN1C(=O)OCC1=CC=CC=C1 QSDUPHSUBRKHKC-UHFFFAOYSA-N 0.000 description 2
- LWHOQQGVABCHHR-UHFFFAOYSA-N benzyl 4-phenylpiperazine-1-carboxylate Chemical compound C1CN(C=2C=CC=CC=2)CCN1C(=O)OCC1=CC=CC=C1 LWHOQQGVABCHHR-UHFFFAOYSA-N 0.000 description 2
- WXQCFKYWSKKNKY-UHFFFAOYSA-N benzyl n-(3-hydroxypropyl)carbamate Chemical compound OCCCNC(=O)OCC1=CC=CC=C1 WXQCFKYWSKKNKY-UHFFFAOYSA-N 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- SGZWYNUJLMTSMJ-UHFFFAOYSA-N benzyl n-phenylcarbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1=CC=CC=C1 SGZWYNUJLMTSMJ-UHFFFAOYSA-N 0.000 description 2
- 125000006267 biphenyl group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- WOIRCKJMSPMDAM-SNVBAGLBSA-N tert-butyl n-[(1r)-1-phenylethyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C)C1=CC=CC=C1 WOIRCKJMSPMDAM-SNVBAGLBSA-N 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- 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 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- LFOIDLOIBZFWDO-UHFFFAOYSA-N 2-methoxy-6-[6-methoxy-4-[(3-phenylmethoxyphenyl)methoxy]-1-benzofuran-2-yl]imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=C2SC(OC)=NN2C=C1C(OC1=CC(OC)=C2)=CC1=C2OCC(C=1)=CC=CC=1OCC1=CC=CC=C1 LFOIDLOIBZFWDO-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 1
- HCCNBKFJYUWLEX-UHFFFAOYSA-N 7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)-3-(pyrazin-2-ylmethylamino)pyrido[3,4-b]pyrazin-2-one Chemical compound O=C1N(CCOCCC)C2=CC(C=3C=NC(OC)=CC=3)=NC=C2N=C1NCC1=CN=CC=N1 HCCNBKFJYUWLEX-UHFFFAOYSA-N 0.000 description 1
- MTHGKAXXBPZMAJ-UHFFFAOYSA-N CC(c1ccccc1)NC(/[O]=C/c1ccccc1)=O Chemical compound CC(c1ccccc1)NC(/[O]=C/c1ccccc1)=O MTHGKAXXBPZMAJ-UHFFFAOYSA-N 0.000 description 1
- MFZDURZHQJBEIU-UHFFFAOYSA-N CCCSC(OCCCl)=O Chemical compound CCCSC(OCCCl)=O MFZDURZHQJBEIU-UHFFFAOYSA-N 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- AXMWDEAXOHFHRO-UHFFFAOYSA-N O(C1=CC=CC=C1)C(=O)N1N=C(N=C1)[N+](=O)[O-].O(C1=CC=CC=C1)C(=O)N1N=C(N=C1)[N+](=O)[O-] Chemical compound O(C1=CC=CC=C1)C(=O)N1N=C(N=C1)[N+](=O)[O-].O(C1=CC=CC=C1)C(=O)N1N=C(N=C1)[N+](=O)[O-] AXMWDEAXOHFHRO-UHFFFAOYSA-N 0.000 description 1
- GQHPUDHZJKXLBT-UHFFFAOYSA-N O(C1=CC=CC=C1)CC(=O)N1N=C(N=C1)[N+](=O)[O-].O(C1=CC=CC=C1)CC(=O)N1N=C(N=C1)[N+](=O)[O-] Chemical compound O(C1=CC=CC=C1)CC(=O)N1N=C(N=C1)[N+](=O)[O-].O(C1=CC=CC=C1)CC(=O)N1N=C(N=C1)[N+](=O)[O-] GQHPUDHZJKXLBT-UHFFFAOYSA-N 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 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
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 1
- KLQPZMVZPDIKBV-UHFFFAOYSA-N [O-][N+](C1=NNC=CC=C1)=O Chemical compound [O-][N+](C1=NNC=CC=C1)=O KLQPZMVZPDIKBV-UHFFFAOYSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- FIMJSWFMQJGVAM-UHFFFAOYSA-N chloroform;hydrate Chemical compound O.ClC(Cl)Cl FIMJSWFMQJGVAM-UHFFFAOYSA-N 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940126540 compound 41 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229940126545 compound 53 Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002004 n-butylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004888 n-propyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 125000005029 naphthylthio group Chemical group C1(=CC=CC2=CC=CC=C12)S* 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003395 phenylethylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/14—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
- C07C329/02—Monothiocarbonic acids; Derivatives thereof
- C07C329/04—Esters of monothiocarbonic acids
- C07C329/06—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C329/00—Thiocarbonic acids; Halides, esters or anhydrides thereof
- C07C329/02—Monothiocarbonic acids; Derivatives thereof
- C07C329/04—Esters of monothiocarbonic acids
- C07C329/10—Esters of monothiocarbonic acids having sulfur atoms of thiocarbonic groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
-
- 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 System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Abstract
Description
更に本発明は、前記ニトロトリアゾール誘導体を使用し、保護基導入、医薬品合成のための試薬等として有用な化合物を製造する方法に関する。
カルバメート(carbamate)、カーボネート(carbonate)、チオカーボネート(thiocarbonate)は、合成化学において保護基導入のために多用される化合物であり、医薬品の合成中間体としても有用な化合物であるため、その需要は多い。現在、これらの合成のためには、Alkyl Chloroformate系の試薬、Succinimidyl/Benzotriazol-1-yl Carbamate系の試薬が主に使用されている(例えばWuts, P. G. M.; Greene, T. W. "Greene's PROTECTIVE GROUPS in ORGANIC SYNTHESIS 4th Ed." WILEY-INTERSCIENCE, New Jersey, 2007.参照、その全記載は、ここに特に開示として援用される。)。
上記以外の試薬として、脱離基にアジドを有するものも知られているが、化合物の特性からスケールが大きくなるにしたがい取り扱いに注意を要する。
そこで本発明の目的は、合成化学上有用なカルバメート、カーボネートおよびチオカーボネートを簡便な工程により合成するための合成試薬として有用な化合物を提供することにある。
で表される化合物と反応させることにより、下記一般式(III):
で表される化合物を製造する方法に関する。
更に、本発明のニトロトリアゾール誘導体は、上記目的物の合成において副生される3-nitro-1H-1,2,4-triazoleを回収・再利用することができるため、資源の再利用の面からも優れた試薬である。
以下、本発明のニトロトリアゾール誘導体について、更に詳細に説明する。
以下に、前記アリール基およびヘテロアリール基の具体例を示す。
本発明は、一般式(I)で表されるニトロトリアゾール誘導体を、下記一般式(II):
で表される化合物と反応させることにより、下記一般式(III):
で表される化合物を製造する方法に関する。
反応溶媒中、一般式(I)で表されるニトロトリアゾール誘導体を一般式(II)で表される化合物と攪拌し、析出してきたニトロトリアゾールをろ別し、溶媒を留去することで一般式(III)で表される目的化合物を得る。ここで、一般式(I)で表されるニトロトリアゾール誘導体と一般式(II)で表される化合物の混合比は、モル比で1:1とする。また、反応溶媒の量は、一般式(I)で表されるニトロトリアゾール誘導体の濃度で0.1〜1M程度とすることができる。
反応溶媒中、一般式(I)で表されるニトロトリアゾール誘導体を一般式(II)で表される化合物と攪拌した後、洗浄および乾燥し、溶媒を留去することで一般式(III)で表される目的化合物を得る。ここで、反応溶媒としてジクロロメタンおよび/もしくはクロロホルムを使用すること、ならびに/または、一般式(I)で表されるニトロトリアゾール誘導体と一般式(II)で表される化合物との反応混合物へジクロロメタンおよび/もしくはクロロホルムを添加することが、副生物である3-nitro-1H-1,2,4-triazoleを反応系外に除去しながら、迅速かつ定量的に反応を進行させることができるため好ましい。具体的には、一般式(I)で表されるニトロトリアゾール誘導体をジクロロメタンおよび/またはクロロホルム中に添加し、一般式(II)で表される化合物を加え攪拌した後、更にジクロロメタンを加え、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を留去することで目的物を得る。または、ジクロロメタンおよび/またはクロロホルム以外の反応溶媒を使用する場合は反応混合物へジクロロメタンおよび/またはクロロホルムを添加した後、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を留去することで目的物を得ることもできる。一般式(I)で表されるニトロトリアゾール誘導体と一般式(II)で表される化合物との混合比および添加量については、方法Aについて前述した通りである。
反応溶媒中、一般式(I)で表されるニトロトリアゾール誘導体、一般式(II)で表される化合物および塩基を加え、攪拌する。次いで、洗浄および乾燥した後、溶媒を留去することで一般式(III)で表される目的化合物を得る。具体的には、一般式(I)で表されるニトロトリアゾール誘導体をジクロロメタンおよび/またはクロロホルム中に添加し、一般式(II)で表される化合物および塩基(例えばトリエチルアミン、2,6−ルチジン等)を加え攪拌した後、更にジクロロメタンを加え、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を留去することで目的物を得る。一般式(I)で表されるニトロトリアゾール誘導体と一般式(II)で表される化合物との混合比および添加量については、態様Aについて前述した通りである。また塩基の使用量は、例えば1〜10当量程度とすることができる。
方法Bにおいて、溶媒を留去し、残渣をカラムクロマトグラフィーで分離精製することにより、目的化合物を得る。ただし、一般式(I)で表されるニトロトリアゾール誘導体と一般式(II)で表される化合物の混合比は、モル比で、例えば1:1〜5:1程度とする。
方法Cにおいて、溶媒を留去し、残渣をカラムクロマトグラフィーで分離精製することにより、目的化合物を得る。ただし、一般式(I)で表されるニトロトリアゾール誘導体と一般式(II)で表される化合物の混合比は、モル比で、例えば1:1〜5:1程度とする。
反応溶媒中、一般式(I)で表されるニトロトリアゾール誘導体、一般式(II)で表される化合物および塩基を加え、攪拌する。次いで、洗浄および乾燥した後、溶媒を留去することで一般式(III)で表される目的化合物を得る。具体的には、一般式(I)で表されるニトロトリアゾール誘導体を5% NaHCO3水溶液とジクロロメタン混合溶媒中に添加し、一般式(II)で表される化合物を加え攪拌した後、更にジクロロメタンを加え、飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を留去することで目的物を得る。一般式(I)で表されるニトロトリアゾール誘導体と一般式(II)で表される化合物との混合比および添加量については、方法Aについて前述した通りである。
以下に、本発明を実施例により更に説明する。ただし、本発明は実施例に示す態様に限定されるものではない。また、以下において「NT」とは、3-nitro-1H-1,2,4-triazoleを示す。
Benzyl 3-nitro-1H-1,2,4-triazole-1-carboxylateの合成
NaH(60質量% in paraffin liquid)411.2 mgをAr雰囲気下、ヘキサン(10 ml×3)で共沸乾燥後、減圧乾燥し、NaH 249.6 mg(10.4 mmol)を得た。これに対し、Ar雰囲気下、ピリジン(5 ml×3)、トルエン(5 ml×3)で共沸乾燥したNT 1.19 g(10.4 mmol)のTHF溶液(30 ml)を加え、0 ℃で10分間攪拌した。溶液を0 ℃で攪拌しつつ、Z-Cl 1.48 ml(10.4 mmol)を加え、0 ℃で30分間攪拌後、室温で12時間攪拌した。塩をろ別し、溶媒を留去した後、EtOAcより再結晶を行い、目的化合物(収率95%。針状結晶。薄黄色)を得た。同定結果を以下に示す。
mp: 112-113 ℃ (dec.); 1H NMR (400 MHz, CDCl3) δ 8.99 (1H, s), 7.55-7.42 (5H, m), 5.54 (2H, s); 13C NMR (125 MHz, CDCl3) δ 163.1, 147.1, 146.0, 132.4, 129.9, 129.4, 129.0, 72.5; Anal. calcd for for C10H8N4O4・1/4H2O: C, 47.53; H, 3.39; N, 22.17. Found: C, 47.37; H, 3.32; N, 22.04.
2,2,2-Trichloroethyl 3-nitro-1H-1,2,4-triazole-1-carboxylateの合成
出発物質を変更した点を除き、合成例1と同様の方法により、2,2,2-Trichloroethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate(以下、「Troc-NT」という)を合成した(収率92%、角柱状結晶、薄黄色)。合成スキームおよび同定結果を以下に示す。
9H-Fluorenylmethyl 3-nitro-1H-1,2,4-triazole-1-carboxylateの合成
出発物質を変更した点を除き、合成例1と同様の方法により、9H-Fluorenylmethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate(以下、「Fmoc-NT」という)を合成した(収率95%、針状結晶、薄黄色)。合成スキームおよび同定結果を以下に示す。
2-(Trimethylsilyl)ethyl 3-nitro-1H-1,2,4-triazole-1-carboxylateの合成
出発物質を変更した点を除き、合成例1と同様の方法により、2-(trimethylsilyl)ethyl 3-nitro-1H-1,2,4-triazole-1-carboxylate(以下、「Teoc-NT」という)を合成した(収率96%、針状結晶、薄黄色)。合成スキームおよび同定結果を以下に示す。
Anisoyl 3-nitro-1H-1,2,4-triazoleの合成
NaH(60質量% in paraffin liquid)398.3 mgをAr雰囲気下、ヘキサン(10 ml×3)で共沸乾燥後、減圧乾燥し、NaH 202.0 mg(8.4 mmol)を得た。これに対し、Ar雰囲気下、ピリジン(5 ml×3)、トルエン(5 ml×3)で共沸乾燥したNT 958 mg(8.4 mmol)のTHF溶液(20 ml)を加え、0 ℃で10分間攪拌した。溶液を0 ℃で攪拌しつつ、Anisoyl chloride 1.14 ml(8.4 mmol)を加え、0 ℃で10分間攪拌後、室温で12時間攪拌した。塩をろ別し、溶媒を留去した後、EtOAcより再結晶を行い、目的化合物(収率92%。針状結晶。薄黄色)を得た。同定結果を以下に示す。
1H NMR (400 MHz, CDCl3) δ 9.10 (1H, s), 8.36 (2H, d, J = 9.0 Hz), 7.06 (2H, d, J = 9.0 Hz), 3.95 (3H, s); 13C NMR (100 MHz, CDCl3) δ 165.3, 162.5, 161.4, 146.7, 134.7, 119.3, 114.3, 55.7.
t-Butoxy 3-nitro-1H-1,2,4-triazole-1-carboxylate の合成
出発物質を変更した点を除き、合成例5と同様の方法により、t-butoxy 3-nitro-1H-1,2,4-triazole-1-carboxylate(以下、「Boc-NT」という)を合成した(収率55%、薄黄色)。合成スキームおよび同定結果を以下に示す。
Phenoxyacetyl 3-nitro-1H-1,2,4-triazoleの合成
出発物質を変更した点を除き、合成例5と同様の方法により、Phenoxyacetyl 3-nitro-1H-1,2,4-triazole(以下、「Pac-NT」という)を合成した(収率65%、板状結晶、薄黄色)。合成スキームおよび同定結果を以下に示す。
Phenoxycarbonyl 3-nitro-1H-1,2,4-triazoleの合成
出発物質を変更した点を除き、合成例5と同様の方法により、Phenoxycarbonyl 3-nitro-1H-1,2,4-triazole(以下、「Px-NT」という)を合成した(収率87%、結晶、薄黄色)。合成スキームおよび同定結果を以下に示す。
Palmitoyl 3-nitro-1H-1,2,4-triazoleの合成
出発物質を変更した点を除き、合成例5と同様の方法により、Palmitoyl 3-nitro-1H-1,2,4-triazole(以下、「Pal-NT」という)を合成した(収率95%、針状結晶、薄黄色)。合成スキームおよび同定結果を以下に示す。
Benzyl (R)-1-phenylethylcarbamate (2)の合成(方法A)
1H NMR (400 MHz, CDCl3) δ 7.46-7.23 (10H, m), 5.13 (1H, d, J = 12.2 Hz), 5.04 (1H, d, J = 12.2 Hz), 5.09 (1H, br), 4.93-4.81 (1H, m), 1.49 (3H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 155.1, 143.1, 136.1, 128.3, 128.2, 127.8, 127.0, 125.6, 66.5, 50.6, 22.4; MS (MALDI TOF) m/z calcd for C16H17NNaO2 [M+Na]+ 278.12, found 277.99.
2,2,2-Trichloroethyl (R)-1-phenylethylcarbamate (3)の合成
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物1(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物3)を得た(定量的(4%のNTを含む)、白色固体)。
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物1(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物3)を得た(収率88%、白色固体)。
1H NMR (300 MHz, CDCl3) δ 7.46-7.20 (5H, m), 5.28 (1H, brs), 4.88 (1H, dq, J = 7.0, 7.0 Hz), 4.75 (1H, d, J = 11.7 Hz), 4.67 (1H, d, J = 11.7 Hz), 1.53 (3H, d, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 153.5, 142.6, 128.6, 127.4, 125.8, 95.5, 74.5, 51.1, 22.4; MS (FAB) m/z calcd for C11H13Cl3NO2 [M+H]+ 296.00, found 296.06.
(9H-Fluoren-9-yl)methyl (R)-1-phenylethylcarbamate (4)の合成
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物1(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物4)を得た(定量的(NTを含む)、白色固体。)。
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物1(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物4)を得た(収率96%、白色固体)。
1H NMR (400 MHz, CDCl3) δ 7.74 (2H, d, J = 7.3 Hz), 7.57 (2H, d, J = 7.3 Hz), 7.48-7.12 (9H, m), 5.04 (1H, brs), 4.85 (1H, brs), 4.40 (2H, brd, J = 6.8 Hz), 4.18 (1H, brs), 1.47 (3H, brd, J = 5.6 Hz); 13C NMR (100 MHz, CDCl3) δ 155.3, 143.7, 141.1, 128.5, 127.5, 127.2, 126.9, 125.8, 124.9, 124.8, 119.8, 66.5, 50.7, 47.4, 22.5; MS (MALDI TOF) m/z calcd for C23H21NNaO2 [M+Na]+ 366.15, found 366.12.
2-(Trimethylsilyl)ethyl (R)-1-phenylethylcarbamate (5) (方法F)
1H NMR (400 MHz, CDCl3) δ 7.36-7.22 (5H, m), 4.91 (1H, brs), 4.91-4.76 (1H, m), 4.20-4.08 (2H, m), 1.47 (3H, d, J = 6.8 Hz), 0.96 (2H, t, J = 8.5 Hz), 0.02 (9H, s); 13C NMR (100 MHz, CDCl3) δ 155.7, 143.5, 128.4, 127.1, 125.8, 63.0, 50.5, 22.6, 17.9, -1.3; MS (MALDI TOF) m/z calcd for C14H23NNaO2Si [M+Na]+ 288.14, found 288.18.
Benzyl 2,6-dimethylmorpholine-4-carboxylate (7)
合成例1で得たZ-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物6(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物7)を得た(定量的(2%のNTを含む)、白色固体)。
合成例1で得たZ-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物6(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物7)を得た(収率89%、白色固体)。
1H NMR (300 MHz, CDCl3) δ 7.48-7.24 (5H, m), 5.14 (2H, s), 3.98 (2H, brs), 3.55 (2H, brs), 2.55 (2H, brs), 1.17 (6H, d, J = 5.9 Hz); 13C NMR (100 MHz, CDCl3) δ 154.8, 136.4, 128.4, 127.9, 127.8, 71.6, 67.2, 49.2, 18.8; MS (MALDI TOF) m/z calcd for C14H19NNaO3 [M+Na]+ 272.13, found 271.99.
2,2,2-Trichloroethyl 2,6-dimethylmorpholine-4-carboxylate (8)の合成
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物6(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物8)を得た(定量的(NTを含む)、白色固体)。
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物6(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物8)を得た(収率92%、白色固体)。
1H NMR (300 MHz, CDCl3) δ 4.78 (1H, s), 4.76 (1H, s), 3.99 (2H, brd, J = 13.2 Hz), 3.60 (2H, m), 2.67 (1H, t, J = 12.1 Hz), 2.58 (1H, t, J = 12.1 Hz), 1.20 (3H, d, J = 6.2 Hz); 13C NMR (100 MHz, CDCl3) δ 153.0, 95.5, 75.0, 71.7, 71.7, 49.6, 49.4, 18.8; MS (FAB) m/z calcd for C9H15Cl3NO3 [M+H]+ 290.01, found 290.07.
(9H-Fluoren-9-yl)methyl 2,6-dimethylmorpholine-4-carboxylate (9)の合成
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物6(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物9)を得た(定量的(NTを含む)、無色オイル)。
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物6(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物9)を得た(定量的、無色オイル)。
1H NMR (400 MHz, CDCl3) δ 7.75 (2H, d, J = 7.3 Hz), 7.55 (2H, d, J = 7.3 Hz), 7.39 (2H, t, J = 7.3 Hz), 7.31 (2H, t, J = 7.3 Hz), 4.64-4.32 (2H, m), 4.24 (1H, t, J = 6.5 Hz), 3.95 (1H, brs), 3.71 (1H, brs), 3.47 (1H, brs), 3.37 (1H, brs), 2.50 (2H, brs), 1.14 (6H, brs); 13C NMR (100 MHz, CDCl3) δ 154.7, 143.8, 141.2, 127.5, 126.9, 124.7, 119.8, 71.6, 67.2, 49.5, 49.1, 47.5, 18.7; MS (MALDI TOF) m/z calcd for C21H23NNaO3 [M+Na]+ 360.16, found 360.14.
2-(Trimethylsilyl)ethyl 2,6-dimethylmorpholine-4-carboxylate (10)の合成(方法A)
1H NMR (400 MHz, CDCl3) δ 4.22-4.12 (2H, m), 4.08-3.80 (2H, m), 3.58-3.48 (2H, m), 2.54-2.42 (2H, m), 1.17 (6H, d, J = 6.1 Hz), 1.04-1.96 (2H, m), 0.04 (9H, s); 13C NMR (100 MHz, CDCl3) δ 155.2, 71.7, 63.7, 49.1, 18.8, 17.9, -1.3; MS (FAB) m/z calcd for C12H25NNaO3Si [M+Na]+ 282.15, found 282.22.
Benzyl (1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-ylcarbamate (12)の合成(方法A)
1H NMR (300 MHz, CDCl3) δ 7.44-7.12 (9H, m), 5.56-5.36 (1H, m), 5.20-5.04 (3H, m), 4.55 (1H, bs), 3.10 (1H, dd, J = 16.5, 4.8 Hz), 2.88 (1H, dd, J = 16.5, 1.7 Hz), 2.29 (1H, br); 13C NMR (100 MHz, CDCl3) δ 156.6, 140.3, 139.5, 136.1, 128.4, 128.1, 128.0, 128.0, 127.0, 125.2, 124.3, 73.5, 67.1, 59.3, 39.5; MS (MALDI TOF) m/z calcd for C17H17NNaO3 [M+Na]+ 306.11, found 306.02.
2,2,2-Trichloroethyl (1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-ylcarbamate (13)の合成
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物11(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物13)を得た(収率95%(4%のNTを含む)、白色固体)。
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物11(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物13)を得た(収率92%、白色固体)。
1H NMR (400 MHz, CDCl3) δ 7.38-7.21 (4H, m), 5.73 (1H, brd, J = 8.3 Hz), 5.14 (1H, dd, J = 8.3, 5.0 Hz), 4.86 (1H, d, J = 12.0 Hz), 4.74 (1H, d, J = 12.0 Hz), 4.62 (1H, dt, J = 5.0, 2.0 Hz), 3.16 (1H, dd, J = 16.6, 5.0 Hz), 2.93 (1H, dd, J = 16.6, 2.0 Hz), 2.09 (1H, brs); 13C NMR (100 MHz, CDCl3) δ 154.8, 139.9, 139.4, 128.3, 127.2, 125.3, 124.4, 95.5, 74.7, 73.5, 59.4, 39.7; MS (MALDI TOF) m/z calcd for C12H12Cl3NNaO3 [M+Na]+ 345.98, found 345.94.
(9H-Fluoren-9-yl)methyl (1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-ylcarbamate (14)の合成
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物11(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物14)を得た(定量的(NTを含む)、白色固体)。
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物11(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物14)を得た(収率94%、白色固体)。
1H NMR (400 MHz, CDCl3) δ 7.76 (2H, d, J = 7.5 Hz), 7.62 (2H, d, J = 7.3 Hz), 7.40 (2H, t, J = 7.5 Hz), 7.31 (2H, t, J = 7.3 Hz), 7.22 (4H, brs), 5.39 (1H, brs), 5.12 (1H, brs), 4.62-4.48 (3H, m), 4.25 (1H, t, J = 6.6 Hz), 3.12 (1H, dd, J = 16.4, 4.6 Hz), 2.90 (1H, d, J = 16.4 Hz), 1.97 (1H, brs); 13C NMR (100 MHz, CDCl3) δ 156.6, 143.7, 141.2, 141.2, 140.2, 139.5, 128.1, 127.6, 127.1, 126.9, 126.9, 125.2, 124.9, 124.3, 119.9, 73.5, 66.8, 59.3, 47.4, 39.6; MS (MALDI TOF) m/z calcd for C24H21NNaO3 [M+Na]+ 394.14, found 394.16.
2-(Trimethylsilyl)ethyl (1S,2R)-2,3-dihydro-2-hydroxy-1H-inden-1-ylcarbamate (15)の合成(方法F)
1H NMR (400 MHz, CDCl3) δ 7.31-7.20 (5H, m), 5.34 (1H, brs), 5.17-5.05 (1H, m), 4.63-4.54 (1H, m), 4.23 (2H, t, J = 8.5 Hz), 3.12 (1H, dd, J = 16.6, 5.2 Hz), 2.91 (1H, dd, J = 16.6, 1.9 Hz), 2.40 (1H, br), 1.02 (2H, t, J = 8.5 Hz), 0.06 (9H, s); 13C NMR (125 MHz, CDCl3) δ 157.2, 140.6, 139.8, 128.2, 127.1, 125.3, 124.4, 73.5, 63.5, 59.1, 39.4, 17.7, -1.5; MS (MALDI TOF) m/z calcd for C15H23NNaO3Si [M+Na]+ 316.13, found 316.06.
Benzyl 4-phenylpiperazine-1-carboxylate (17) の合成
合成例1で得たZ-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物16(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物17)を得た(定量的(10%のNTを含む)、黄色オイル)。
合成例1で得たZ-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物16(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物17)を得た(収率91%、黄色オイル)。
1H NMR (300 MHz, CDCl3) δ 7.44-7.18 (6H, m), 6.96-6.84 (3H, m), 5.16 (2H, s), 3.66 (4H, t, J = 5.0 Hz), 3.14 (4H, brs); 13C NMR (100 MHz, CDCl3) δ 155.0, 151.0, 136.4, 129.0, 128.4, 127.9, 127.8, 120.3, 116.6, 67.2, 49.5, 43.8; MS (MALDI TOF) m/z calcd for C18H20N2NaO2 [M+Na]+ 319.14, found 319.08.
2,2,2-Trichloroethyl 4-phenylpiperazine-1-carboxylate (18)の合成(方法A)
1H NMR (400 MHz, CDCl3) δ 7.31-7.25 (2H, m), 6.96-6.87 (3H, m), 4.78 (2H, s), 3.72 (4H, brd, J = 18.8 Hz), 3.22-3.15 (4H, m); 13C NMR (100 MHz, CDCl3) δ 153.2, 150.8, 129.1, 120.5, 116.7, 95.6, 75.1, 49.5, 44.1; MS (MALDI TOF) m/z calcd for C13H16Cl3N2O2 [M+H]+ 337.03, found 336.98.
(9H-Fluoren-9-yl)methyl 4-phenylpiperazine-1-carboxylate (19)の合成
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物16(100μmol)を加え室温で5分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物19)を得た(定量的(NTを含む)、淡黄オイル)。
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物16(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物19)を得た(収率93%、淡黄オイル)。
1H NMR (400 MHz, CDCl3) δ 7.78 (2H, d, J = 7.6 Hz), 7.60 (2H, d, J = 7.1 Hz), 7.41 (2H, t, J = 7.6 Hz), 7.33 (2H, t, J = 7.1 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.28 (1H, d, J = 8.3 Hz), 6.93 (1H, d, J = 8.3 Hz), 6.92 (2H, t, J = 8.3 Hz), 4.49 (2H, d, J = 6.6 Hz), 4.27 (1H, t, J = 6.6 Hz), 3.62 (4H, brs), 3.12 (4H, brs); 13C NMR (100 MHz, CDCl3) δ 154.9, 150.9, 143.7, 141.1, 129.0, 127.5, 126.9, 124.8, 120.3, 119.8, 116.6, 67.3, 49.4, 47.4, 43.8; MS (MALDI TOF) m/z calcd for C25H25N2O2 [M+H]+ 385.19, found 385.19.
2-(Trimethylsilyl)ethyl 4-phenylpiperazine-1-carboxylate (20)の合成(方法A)
1H NMR (400 MHz, CDCl3) δ 7.27 (2H, dd, J = 7.6, 7.3 Hz), 6.93 (2H, d, J = 7.6 Hz), 6.89 (1H, t, J = 7.3 Hz), 4.22 (2H, t, J = 8.4 Hz), 3.63 (4H, t, J = 4.9 Hz), 3.14 (4H, t, J = 4.9 Hz), 1.03 (2H, t, J = 8.4 Hz), 0.05 (9H, s); 13C NMR (100 MHz, CDCl3) δ 155.4, 151.0, 129.0, 120.2, 116.6, 63.7, 49.5, 43.7, 17.9, -1.3; MS (MALDI TOF) m/z calcd for C16H27N2O2Si [M+H]+ 307.18, found 307.08.
Benzyl 3-hydroxypropylcarbamate (22)の合成
合成例1で得たZ-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物21(100μmol)を加え室温で30分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物22)を得た(定量的(NTを含む)、無色オイル)。
合成例1で得たZ-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物21(100μmol)を加え室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物22)を得た(収率94%、無色オイル)。
合成例1で得たZ-NT(100μmol)をジクロロメタン(500μl)に添加し、トリエチルアミン(200μmol)および化合物21(100μmol)を加え、室温で5分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物22)を得た(収率97%、無色オイル)。
1H NMR (400 MHz, CDCl3) δ 7.44-7.28 (5H, m), 5.12 (1H, brs), 5.11 (2H, s), 3.67 (2H, t, J = 5.8 Hz), 2.64 (1H, br), 3.35 (2H, q, J = 5.8 Hz), 1.70 (2H, quintet, J = 5.8 Hz); 13C NMR (100 MHz, CDCl3) δ 157.2, 136.3, 128.4, 128.0, 128.0, 66.9, 59.5, 37.8, 32.6; MS (MALDI TOF) m/z calcd for C11H15NNaO3 [M+Na]+ 232.09, found 231.90.
2,2,2-Trichloroethyl 3-hydroxypropylcarbamate (23)の合成
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物21(100μmol)を加え室温で30分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物23)を得た(定量的(2%のNTを含む)、無色オイル)。
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物21(100μmol)を加え室温で30分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物23)を得た(収率95%、無色オイル)。
1H NMR (400 MHz, CDCl3) δ 5.41 (1H, brs), 4.74 (2H, s), 3.73 (2H, t, J = 6.0 Hz), 3.41 (2H, q, J = 6.0 Hz), 2.41 (1H, brs), 1.76 (2H, quintet, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3) δ155.0, 95.3, 74.4, 59.7, 38.1, 32.2; MS (MALDI TOF) m/z calcd for C6H11Cl3NO3 [M+H]+ 249.98, found 249.81.
(9H-Fluoren-9-yl)methyl 3-hydroxypropylcarbamate (24)の合成
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物21(100μmol)を加え室温で30分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物24)を得た(定量的(NTを含む)、白色固体)。
合成例3で得たFmoc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物21(100μmol)を加え室温で30分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物24)を得た(収率93%、白色固体)。
1H NMR (400 MHz, CDCl3) δ 7.75 (2H, d, J = 7.6 Hz), 7.57 (2H, d, J = 7.6 Hz), 7.39 (2H, t, J = 7.6 Hz), 7.30 (2H, t, J = 7.6 Hz), 5.06 (1H, brs), 4.42 (2H, d, J = 6.6 Hz), 4.20 (1H, t, J = 6.6 Hz), 3.72-3.52 (2H, m), 3.40-3.28 (2H, m), 2.60 (1H, brs), 1.80-1.58 (2H, m); 13C NMR (100 MHz, CDCl3) δ 157.1, 143.7, 141.1, 127.5, 126.9, 124.8, 119.8, 66.6, 59.5, 47.3, 37.7, 32.6; MS (MALDI TOF) m/z calcd for C18H19NNaO3 [M+Na]+ 320.13, found 320.06.
2-(Trimethylsilyl)ethyl 3-hydroxypropylcarbamate (25)の合成(方法A)
1H NMR (400 MHz, CDCl3) δ 4.99 (1H, brs), 4.17 (2H, t, J = 8.4 Hz), 3.69 (2H, t, J = 5.9 Hz), 3.34 (2H, q, J = 5.9 Hz), 1.71 (2H, quintet, J = 5.9 Hz), 0.99 (2H, t, J = 8.4 Hz), 0.04 (9H, s); 13C NMR (100 MHz, CDCl3) δ 157.6, 63.3, 59.4, 37.5, 32.8, 17.9, -1.3; MS (MALDI TOF) m/z calcd for C9H21NNaO3Si [M+Na]+ 242.12, found 242.10.
Benzyl phenylcarbamate (27)の合成(方法E)
1H NMR (400 MHz, CDCl3) δ 7.42-7.25 (9H, m), 7.05 (1H, t, J = 7.3 Hz), 6.72 (1H, brs), 5.18 (2H, s); 13C NMR (100 MHz, CDCl3) δ 153.1, 137.6, 135.9, 128.9, 128.5, 128.2, 128.1, 123.4, 118.6, 67.0; MS (MALDI TOF) m/z calcd for C14H13NNaO2 [M+Na]+ 250.08, found 249.91.
2,2,2-Trichloroethyl phenylcarbamate (28)の合成
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物26(100μmol)を加え室温で15分間攪拌した。析出したニトロトリアゾールをろ別し、溶媒を留去することで目的物(化合物28)を得た(定量的(4%のTroc-NTを含む)、白色固体)。
合成例2で得たTroc-NT(100μmol)をジクロロメタン(500μl)に添加し、次いで化合物26(100μmol)を加え室温で15分間攪拌した。反応混合物にジクロロメタン4mlを加えた後、飽和炭酸水素ナトリウム水溶液(5ml×3)で洗浄し、無水硫酸ナトリウムで乾燥した。次いで、溶媒を留去し目的物(化合物28)を得た(収率97%、白色固体)。
1H NMR (400 MHz, CDCl3) δ 7.45-7.29 (4H, m), 7.14-7.08 (1H, m), 6.95 (1H, brs), 4.82 (2H, s); 13C NMR (100 MHz, CDCl3) δ 151.3, 136.8, 129.0, 124.0, 118.8, 95.2, 74.5; MS (FAB) m/z calcd for C9H8Cl3NNaO2 [M+Na]+ 289.95, found 290.00.
2-(Trimethylsilyl)ethyl phenylcarbamate (29)の合成(方法E)
1H NMR (400 MHz, CDCl3) δ 7.40-7.24 (4H, m), 7.05 (1H, t, J = 7.3 Hz), 6.59 (1H, brs), 4.29-4.23 (2H, m), 1.08-1.02 (2H, m), 0.06 (9H, s); 13C NMR (100 MHz, CDCl3) δ 153.5, 137.8, 128.8, 123.1, 118.5, 63.5, 17.9, -1.3; MS (FAB) m/z calcd for C12H19NNaO2Si [M+Na]+ 260.11, found 260.16.
2,2,2-Trichloroethyl 4-(phenylthio)phenylcarbamate (31)の合成(方法D)
1H NMR(400MHz, CDCl3) δ 7.42-7.34 (4H, m), 7.30-7.17 (5H, m), 6.93 (1H, brs), 4.82 (2H, s); 13C NMR(100MHz, CDCl3) δ 151.2, 136.5, 136.4, 133.0, 130.0, 129.0, 126.5, 119.5, 95.1, 74.5.
Dibenzyl carbonate (33)の合成(方法C)
1H NMR (400 MHz, CDCl3) δ 7.44-7.24 (10H, m), 5.16 (4H, s); 13C NMR (100 MHz, CDCl3) δ 154.7, 134.8, 128.2, 128.2, 128.0, 69.5; MS (FAB) m/z calcd for C15H14NaO3 [M+Na]+ 265.08, found 265.13.
Benzyl 2,2,2-trichloroethyl carbonate (34)の合成(方法C)
1H NMR (400 MHz, CDCl3) δ 7.48-7.32 (5H, m), 5.24 (2H, s), 4.77 (2H, s); 13C NMR (100 MHz, CDCl3) δ 153.7, 134.3, 128.7, 128.5, 128.3, 94.3, 76.8, 70.7; MS (FAB) m/z calcd for C10H9Cl3NaO3 [M+Na]+ 304.95, found 305.02.
Benzyl 2-(trimethylsilyl)ethyl carbonate (35)の合成(方法C)
1H NMR (400 MHz, CDCl3) δ 7.41-7.30 (5H, m), 5.15 (2H, s), 4.27-4.21 (2H, m), 1.09-1.03 (2H, m), 0.04 (9H, s); 13C NMR (100 MHz, CDCl3) δ 155.1, 135.4, 128.5, 128.3, 128.2, 69.3, 66.6, 17.6, -1.5; MS (FAB) m/z calcd for C13H20NaO3Si [M+Na]+ 275.11, found 275.17.
Benzyl (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl carbonate (37)の合成(方法E)
1H NMR (400 MHz, CDCl3) δ 7.44-7.28 (5H. m), 5.15 (1H, s), 5.14 (1H, s), 4.53 (1H, dt, J = 10.0, 4.4 Hz), 2.11-2.05 (1H, m), 1.95 (1H, doublet of quintet, J = 7.0, 2.7 Hz), 1.71-1.64 (2H, m), 1.54-1.40 (1H, m), 1.40 (1H, tt, J = 12.0, 3.2 Hz), 1.05 (2H, q, J = 11.8 Hz), 0.91 (3H, d, J = 6.6 Hz), 0.88 (3H, d, J = 6.6 Hz), 0.88-0.81 (1H, m), 0.78 (3H, d, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 154.7, 135.3, 128.4, 128.2, 128.0, 78.6, 69.3, 47.1, 40.8, 34.2, 31.5, 26.1, 23.4, 22.1, 20.9, 16.4; MS (FAB) m/z calcd for C18H26NaO3 [M+Na]+ 313.18, found 313.18.
2,2,2-Trichloroethyl (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl carbonate (38)の合成(方法E)
1H NMR (400 MHz, CDCl3) δ 4.79 (1H, d, J = 11.9 Hz), 4.76 (1H, d, J = 11.9 Hz), 4.60 (1H, dt, J = 11.0, 4.5 Hz), 2.12-2.05 (1H, m), 1.98 (doublet of quintet, J = 6.9, 2.7 Hz), 1.75-1.65 (2H, m), 1.55-1.43 (2H, m), 1.12 (1H, q, J = 11.8 Hz), 1.12-1.00 (1H, m), 0.93 (3H, d, J = 6.4 Hz), 0.91 (3H, d, J = 7.1 Hz), 0.91-0.85 (1H, m), 0.80 (3H, d, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 153.6, 94.7, 80.0, 76.5, 47.0, 40.6, 34.1, 31.6, 26.3, 23.5, 22.1, 20.8, 16.4; MS (MALDI TOF) m/z calcd for C13H22Cl3O3 [M+H]+ 331.06, found 331.16.
2-(Trimethylsilyl)ethyl (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl carbonate (39)の合成(方法E)
1H NMR (500 MHz, CDCl3) δ 4.50 (1H, dt, J = 11.0, 4.6 Hz), 4.25-4.16 (2H, m), 2.10-2.04 (1H, m), 1.97 (doublet of quintet, J = 6.9, 2.8 Hz), 1.71-1.64 (2H, m), 1.54-1.43 (1H, m), 1.40 (1H, tt, J = 11.5, 3.2 Hz), 1.10-1.00 (4H, m), 0.91 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6.8 Hz), 0.91-0.83 (1H, m), 0.79 (3H, d, J = 6.9 Hz), 0.05 (9H, s); 13C NMR (125 MHz, CDCl3) δ 155.0, 78.0, 66.0, 47.0, 40.8, 34.1, 31.4, 26.0, 23.3, 22.0, 20.7, 17.5, 16.2, -1.6; MS (FAB) m/z calcd for C16H32NaO3Si [M+Na]+ 323.20, found 323.21.
O-2,2,2-Trichloroethyl S-4-methoxyphenyl carbonothioate (41)の合成(方法C)
1H NMR (400 MHz, CDCl3) δ 7.46 (2H, d, J = 9.8 Hz), 6.93 (2H, d, J = 9.8 Hz), 4.81 (2H, s), 3.83 (2H, s); 13C NMR (100 MHz, CDCl3) δ 169.7, 160.9, 136.6, 114.9, 94.3, 75.7, 55.5; MS (FAB) m/z calcd for C10H9Cl3NaO3S [M+Na]+ 336.92, found 336.95.
O-2,2,2-Trichloroethyl S-propyl carbonothioate (43)の合成(方法C)
1H NMR (400 MHz, CDCl3) δ 4.83 (2H, s), 2.91 (2H, t, J = 7.3 Hz), 1.71 (2H, tq, J = 7.3, 7.3 Hz), 1.01 (3H, t, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 170.5, 94.5, 75.4, 33.3, 23.1, 13.3.
2',3',5'-O-Tris-t-butyldimethylsilyl-4-N-[2-(trimethylsilyl)ethoxycarbonyl]-cytidine (44)の合成(方法D)
1H NMR (400 MHz, CDCl3) δ 8.53 (1H, d, J = 7.3 Hz), 7.58 (1H, brs), 7.17 (1H, d, J = 7.3 Hz), 5.79 (1H, brs), 4.32-4.25 (2H, m), 4.17-4.08 (3H, m), 4.07-4.02 (1H, m), 3.80 (1H, d, J = 11.2 Hz), 1.10-1.03 (2H, m), 0.97 (9H, s), 0.92 (9H, s), 0.89 (9H, s), 0.24 (3H, s), 0.16 (3H, s), 0.14 (3H, s), 0.13 (3H, s), 0.06 (9H, s), 0.05 (6H, s); 13C NMR (100 MHz, CDCl3) δ 162.0, 154.8, 152.3, 144.5, 93.9, 90.8, 83.0, 76.2, 68.9, 64.8, 60.7, 26.2, 26.0, 26.0, 18.7, 18.2, 17.6, -1.3, -3.9, -4.0, -4.9, -5.0, -5.0, -5.4; MS (MALDI TOF) m/z calcd for C33H67N3NaO7Si4 [M+Na]+ 752.40, found 752.60.
2',3',5'-O-Tris-t-butyldimethylsilyl-6-N-[2-(trimethylsilyl)ethoxycarbonyl]-adenosine (47)の合成(方法D)
1H NMR (300 MHz, CDCl3) δ 8.74 (1H, s), 8.32 (1H, s), 8.25 (1H, brs), 6.08 (1H, d, J = 5.2 Hz), 4.67 (1H, dd, J = 5.2, 4.5 Hz), 4.43-4.28 (3H, m), 4.19-4.12 (1H, m), 4.03 (1H, dd, J = 11.4, 3.9 Hz), 3.80 (1H, dd, J = 11.4, 2.8 Hz), 1.17-1.05 (2H, m), 0.96 (9H, s), 0.94 (9H, s), 0.79 (9H, s), 0.15 (3H, s), 0.14 (3H, s), 0.11 (6H, s), 0.07 (9H, s), -0.04 (3H, s), -0.26 (3H, s); 13C NMR (100 MHz, CDCl3) δ 152.6, 150.9, 150.8, 149.2, 141.4, 122.1, 88.3, 85.6, 75.9, 72.0, 64.5, 62.5, 26.2, 26.0, 25.8, 18.7, 18.2, 18.0, 17.8, -1.3, -4.2, -4.5, -4.5, -4.9, -5.2, -5.2; MS (MALDI TOF) m/z calcd for C34H67N5NaO6Si4 [M+Na]+ 776.41, found 776.60.
2',3',5'-O-Tris-t-butyldimethylsilyl-2-N-[2-(trimethylsilyl)ethoxycarbonyl]-guanosine (49)の合成(方法E)
1H NMR (400 MHz, CDCl3) δ 11.30 (1H, brs), 8.04 (1H, s), 7.47 (1H, brs), 5.86 (1H, d, J = 5.4 Hz), 4.38-4.32 (3H, m), 4.26 (1H, dd, J = 4.4, 3.4 Hz), 4.09 (1H, ddd, J = 3.4, 3.2, 2.2 Hz), 3.92 (1H, dd, J = 11.5, 3.2 Hz), 3.78 (1H, dd, J = 11.5, 2.2 Hz), 1.12-1.05 (2H, m), 0.96 (9H, s), 0.94 (9H, s), 0.81 (9H, s), 0.14 (3H, s), 0.13 (3H, s), 0.11 (3H, s), 0.10 (3H, s), 0.08 (9H, s), -0.02 (3H, s), -0.21 (3H, s); 13C NMR (100 MHz, CDCl3) δ 155.3, 153.1, 148.2, 146.2, 136.8, 120.7, 87.3, 85.6, 76.9, 72.1, 66.0, 62.7, 26.2, 25.9, 25.7, 18.6, 18.2, 18.0, 17.7, -1.4, -4.2, -4.4, -4.5, -4.9, -5.2, -5.3. HRMS (FAB+) m/z calcd for C34H67N5NaO7Si4 [M+Na]+ 792.4015, found 792.4020.
Benzyl (R)-1-phenylethylcarbamate (2)の合成(方法B)
Benzyl (R)-1-phenylethylcarbamate (2)の合成(方法B)
1H NMR (400 MHz, CDCl3) δ 7.48-7.16 (5H, m), 4.80 (2H, brs), 1.64-1.20 (12H, brs).
t-Butyl 4-phenylpiperazine-1-carboxylate (52)の合成(方法B)
1H NMR (400 MHz, CDCl3) δ 7.31-7.23 (2H, m), 6.96-6.85 (3H, m), 3.58 (4H, t, J = 5.0 Hz), 3.13 (4H, t, J = 5.0 Hz), 1.48 (9H, s).
N,N'-Bispalmitoyl-L-lysine ethyl ester (54)の合成(方法F)
1H NMR (400 MHz, CDCl3) δ 6.20 (1H, d, J = 7.8 Hz), 5.76-5.70 (1H, m), 4.56 (1H, dt, J = 8.1, 4.4 Hz), 4.19 (2H, q, J = 7.2 Hz), 3.27-3.20 (2H, m), 2.23 (2H, t, J = 7.6 Hz), 2.16 (2H, t, J = 7.7 Hz), 1.89-1.78 (1H, m), 1.73-1.48 (7H, m), 1.40-1.19 (53H, m), 0.88 (6H, t, J = 6.8 Hz); 13C NMR (125 MHz, CDCl3) δ 173.2, 173.0, 172.4, 61.5, 51.7, 38.9, 36.9, 36.7, 32.3, 32.0, 29.8, 29.8, 29.6, 29.5, 29.5, 29.5, 29.4, 28.9, 26.0, 25.8, 22.8, 22.5, 14.3, 14.3.
Claims (5)
- 一般式(I)中、Rは、置換基を有するメトキシ基もしくはエトキシ基、または置換基を有していてもよい炭素数3〜30のアルキルオキシ基を表す請求項1に記載のニトロトリアゾール誘導体。
- 前記反応は、反応溶媒としてジクロロメタンおよび/またはクロロホルムを用いて行われる請求項3に記載の製造方法。
- 請求項1または2に記載のニトロトリアゾール誘導体と、上記一般式(II)で表される化合物との反応混合物へ、ジクロロメタンおよび/またはクロロホルムを添加することを含む請求項3または4に記載の製造方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009536043A JP5227965B2 (ja) | 2007-10-03 | 2008-09-29 | ニトロトリアゾール誘導体、およびそれを用いる化合物の製造方法 |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007260255 | 2007-10-03 | ||
JP2007260255 | 2007-10-03 | ||
JP2007338931 | 2007-12-28 | ||
JP2007338931 | 2007-12-28 | ||
JP2009536043A JP5227965B2 (ja) | 2007-10-03 | 2008-09-29 | ニトロトリアゾール誘導体、およびそれを用いる化合物の製造方法 |
PCT/JP2008/067662 WO2009044707A1 (ja) | 2007-10-03 | 2008-09-29 | ニトロトリアゾール誘導体、およびそれを用いる化合物の製造方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2009044707A1 true JPWO2009044707A1 (ja) | 2011-02-10 |
JP5227965B2 JP5227965B2 (ja) | 2013-07-03 |
Family
ID=40526136
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009536043A Active JP5227965B2 (ja) | 2007-10-03 | 2008-09-29 | ニトロトリアゾール誘導体、およびそれを用いる化合物の製造方法 |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP5227965B2 (ja) |
WO (1) | WO2009044707A1 (ja) |
Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008520744A (ja) | 2004-11-19 | 2008-06-19 | ザ・レジェンツ・オブ・ザ・ユニバーシティ・オブ・カリフォルニア | 抗炎症性ピラゾロピリミジン |
CA2647391C (en) | 2006-04-04 | 2015-12-29 | The Regents Of The University Of California | Kinase antagonists |
WO2009046448A1 (en) | 2007-10-04 | 2009-04-09 | Intellikine, Inc. | Chemical entities and therapeutic uses thereof |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
US8703777B2 (en) | 2008-01-04 | 2014-04-22 | Intellikine Llc | Certain chemical entities, compositions and methods |
US8637542B2 (en) | 2008-03-14 | 2014-01-28 | Intellikine, Inc. | Kinase inhibitors and methods of use |
US8993580B2 (en) | 2008-03-14 | 2015-03-31 | Intellikine Llc | Benzothiazole kinase inhibitors and methods of use |
WO2010006086A2 (en) | 2008-07-08 | 2010-01-14 | Intellikine, Inc. | Kinase inhibitors and methods of use |
WO2010006072A2 (en) | 2008-07-08 | 2010-01-14 | The Regents Of The University Of California | Mtor modulators and uses thereof |
CA2738429C (en) | 2008-09-26 | 2016-10-25 | Intellikine, Inc. | Heterocyclic kinase inhibitors |
EP2358720B1 (en) | 2008-10-16 | 2016-03-02 | The Regents of The University of California | Fused ring heteroaryl kinase inhibitors |
US8476431B2 (en) | 2008-11-03 | 2013-07-02 | Itellikine LLC | Benzoxazole kinase inhibitors and methods of use |
JP5789252B2 (ja) | 2009-05-07 | 2015-10-07 | インテリカイン, エルエルシー | 複素環式化合物およびその使用 |
US8980899B2 (en) | 2009-10-16 | 2015-03-17 | The Regents Of The University Of California | Methods of inhibiting Ire1 |
JP5951600B2 (ja) | 2010-05-21 | 2016-07-13 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | キナーゼ調節のための、化合物、組成物および方法 |
CA2817577A1 (en) | 2010-11-10 | 2012-05-18 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US8809349B2 (en) | 2011-01-10 | 2014-08-19 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
TWI592411B (zh) | 2011-02-23 | 2017-07-21 | 英特爾立秦有限責任公司 | 激酶抑制劑之組合及其用途 |
AR088218A1 (es) | 2011-07-19 | 2014-05-21 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos utiles como inhibidores de pi3k |
AU2012284088B2 (en) | 2011-07-19 | 2015-10-08 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
EP2751093A1 (en) | 2011-08-29 | 2014-07-09 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
JP6342805B2 (ja) | 2011-09-02 | 2018-06-13 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 置換ピラゾロ[3,4−d]ピリミジンおよびその用途 |
US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
BR112015006828A8 (pt) | 2012-09-26 | 2019-09-17 | Univ California | composto, ou um sal farmaceuticamente aceitável do mesmo; composição farmacêutica; uso do composto; e método para modular a atividade de uma proteína ire1 |
US9481667B2 (en) | 2013-03-15 | 2016-11-01 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
PE20160685A1 (es) | 2013-10-04 | 2016-07-23 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos y usos de los mismos |
SG10201808053XA (en) | 2014-03-19 | 2018-10-30 | Infinity Pharmaceuticals Inc | Heterocyclic compounds for use in the treatment of pi3k-gamma mediated disorders |
WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US9708348B2 (en) | 2014-10-03 | 2017-07-18 | Infinity Pharmaceuticals, Inc. | Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof |
WO2017048702A1 (en) | 2015-09-14 | 2017-03-23 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same |
WO2017161116A1 (en) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors |
WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
CN109640999A (zh) | 2016-06-24 | 2019-04-16 | 无限药品股份有限公司 | 组合疗法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SU1689477A1 (ru) * | 1988-06-20 | 1991-11-07 | Le I Textilnoi | Komпoзиция для hизkotemпepatуphoгo otбeлиbahия xлoпчatoбуmaжhыx tkaheй |
-
2008
- 2008-09-29 JP JP2009536043A patent/JP5227965B2/ja active Active
- 2008-09-29 WO PCT/JP2008/067662 patent/WO2009044707A1/ja active Application Filing
Also Published As
Publication number | Publication date |
---|---|
WO2009044707A1 (ja) | 2009-04-09 |
JP5227965B2 (ja) | 2013-07-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5227965B2 (ja) | ニトロトリアゾール誘導体、およびそれを用いる化合物の製造方法 | |
ES2685621T3 (es) | Procesos para preparar intermedios para la fabricación de inhibidores NEP | |
RU2564024C2 (ru) | Промежуточные продукты для получения ингибиторов нейтральной эндопептидазы и способ их получения | |
KR101401118B1 (ko) | 바이아릴 치환된 4-아미노-부티르산 또는 그의 유도체의 제조 방법, 및 nep 억제제의 생성에서 그의 용도 | |
US5599994A (en) | Amino acid-derived diaminopropanols | |
EP3333173A1 (en) | Methods for preparing anti-viral nucleotide analogs | |
EP3481200B1 (en) | Processes for the preparation of 4-alkoxy-3-(acyl or alkyl)oxypicolinamides | |
Avenoza et al. | Enantioselective synthesis of (S)-and (R)-α-methylserines: application to the synthesis of (S)-and (R)-N-Boc-N, O-isopropylidene-α-methylserinals | |
AU2011312599B2 (en) | Method for preparing 2-amino-N-(2,2,2-trifluoroethyl) acetamide | |
EP2760848B1 (en) | Processes for the preparation of cabazitaxel involving c(7)-oh and c(13)-oh silylation or just c(7)-oh silylation | |
WO2020158687A1 (ja) | 光応答性ヌクレオチドアナログの製造方法 | |
JP7109056B2 (ja) | S-icaリボシルホモシステインの製造方法 | |
JPH07116126B2 (ja) | 2,3‐ジアミノアクリロニトリル誘導体 | |
JP2005075734A (ja) | 光学活性ホモクエン酸の製法 | |
KR102559870B1 (ko) | 카르밤산염 화합물의 제조방법 | |
US11358937B2 (en) | Reagents based on a tertiary amine backbone to introduce chemical functionality in nucleic acids and sequence-controlled polymers | |
CN115028661A (zh) | 一种4-氨基哌啶-1-甲基磷酸酯及其制备方法 | |
SU642299A1 (ru) | Способ получени трицина | |
WO2002012186A1 (en) | Optically active aziridine-2-carboxylate derivatives and a process for preparing them | |
JP3526606B2 (ja) | N−置換ピラジンカルボキシアミドの製造方法 | |
KR100650207B1 (ko) | 글루타릴 7-아미노-3-비닐-세팔로스포란산 유도체와 이의 제조방법 | |
CN113527178A (zh) | 对称二杂二硫类化合物及其合成方法和应用 | |
JP3669726B2 (ja) | 光学活性3−(p−アルコキシフェニル)グリシッド酸エステル誘導体の製造方法 | |
RU2203284C1 (ru) | Способ получения n-замещенных алкил-(2-диалкоксифосфорил)алкилимидатов | |
CN111410622A (zh) | L-胱硫醚盐酸盐的合成方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110916 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130305 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130318 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5227965 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20160322 Year of fee payment: 3 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |