Potassium Carbonate → tert-butyl (2S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

HRID 1412989ノート

反応式

HRID 1412989 の反応式
[CH3:1][O:2][C:3](=[O:50])[NH:4][CH:5]([CH:46]([O:48][CH3:49])[CH3:47])[C:6]([N:8]1[CH2:12][CH:11]([CH2:13][O:14][CH3:15])[CH2:10][CH:9]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32](B1OC(C)(C)C(C)(C)O1)=[CH:31][CH:30]=2)=[O:7].I[C:52]1[NH:56][C:55]([C@@H:57]2[CH2:61][CH2:60][CH2:59][N:58]2[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[N:54][CH:53]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([NH:4][C@H:5]([C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]1[C:29]2[C:34]([CH2:35][O:36][C:23]=1[CH:22]=3)=[CH:33][C:32]([C:52]1[NH:56][C:55]([C@@H:57]3[CH2:61][CH2:60][CH2:59][N:58]3[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[N:54][CH:53]=1)=[CH:31][CH:30]=2)=[O:7])[C@@H:46]([CH3:47])[O:48][CH3:49])=[O:50]

参加物

8

反応物 3

HCID 11430Potassium CarbonateHCID 58498756(S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 178494459HCID 178494459、化合物

生成物 1

HCID 178495661tert-butyl (2S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate収率 7.4%

試薬・触媒・溶媒 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 178418397HCID 178418397、化合物触媒HCID 679Dimethyl Sulfoxide溶媒HCID 312751,4-Dioxane溶媒

反応条件

温度
90 °C

実験手順

To a solution of methyl(1-{4-(methoxymethyl)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methoxy-1-oxobutan-2-yl)carbamate (0.15 g, 0.22 mmol) in a mixture of DMSO (2.0 mL) and dioxane (2.0 mL) was added (S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.15 g, 0.40 mmol), tetrakis(triphenylphosphine)palladium (0.028 g, 0.024 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.018 g, 0.025 mmol), and aqueous potassium carbonate (2M, 0.35 mL, 0.70 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 90° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The remaining solution was basified with aqueous bicarbonate and extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide tert-butyl(2S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.013 g, 7%).

後処理

  1. customThe solution was degassed with argon for 5 min
  2. temperatureheated
  3. temperatureThe solution was cooled to room temperature
  4. additiondiluted with EtOAc
  5. washThe organic layer was washed with water and brine
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. customThe crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA)
  9. concentrationconcentrated under reduced pressure
  10. customto remove volatile organics
  11. extractionextracted with CH2Cl2 (3×)
  12. dry with materialThe combined organic layers were dried over Na2SO4
  13. concentrationconcentrated under reduced pressure

出典と根拠

ORDレコード
ord-51dbc6143af74c12a8c3e12b4eddef4b
出典データセット
uspto-grants-2014_12
特許番号
US08921341B2

反応ノート

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