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

HRID 1509677ノート

反応式

HRID 1509677 の反応式
[CH3:1][CH:2]([CH3:47])[C@H:3]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:4]([N:6]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][C@H:7]1[C:12]1[NH:16][C:15]2[C:17]3[C:22]([CH:23]=[CH:24][C:14]=2[N:13]=1)=[CH:21][C:20]1[C:25]2[C:30]([CH2:31][O:32][C:19]=1[CH:18]=3)=[CH:29][C:28](B1OC(C)(C)C(C)(C)O1)=[CH:27][CH:26]=2)=[O:5].Br[C:49]1[NH:53][C:52]([C@@H:54]2[CH2:58][CH2:57][CH2:56][N:55]2[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[N:51][CH:50]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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]>[CH3:45][O:44][C:43]([NH:42][C@H:3]([C:4]([N:6]1[CH2:10][C@@H:9]([CH3:11])[CH2:8][C@H:7]1[C:12]1[NH:16][C:15]2[C:17]3[C:22]([CH:23]=[CH:24][C:14]=2[N:13]=1)=[CH:21][C:20]1[C:25]2[C:30]([CH2:31][O:32][C:19]=1[CH:18]=3)=[CH:29][C:28]([C:49]1[NH:53][C:52]([C@@H:54]3[CH2:58][CH2:57][CH2:56][N:55]3[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[N:51][CH:50]=1)=[CH:27][CH:26]=2)=[O:5])[CH:2]([CH3:1])[CH3:47])=[O:46]

参加物

7

反応物 3

HCID 11430Potassium CarbonateHCID 56605192tert-Butyl (2S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylateHCID 178502425Methyl [(2S)-3-methyl-1-{(2S,4S)-4-methyl-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}-1-oxobutan-2-yl]carbamate

生成物 1

HCID 178502427tert-butyl (2S)-2-[5-(2-{(2S,4 S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-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 24%

試薬・触媒・溶媒 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)触媒HCID 178418397HCID 178418397、化合物触媒HCID 80711,2-Dimethoxyethane溶媒

反応条件

温度
85 °C

実験手順

Methyl [(2S)-3-methyl-1-{(2S,4S)-4-methyl-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}-1-oxobutan-2-yl]carbamate (298 mg, 0.47 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (443 mg, 1.4 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), PdCl2(dppf)2 (36 mg, 0.05 mmol), and K2CO3 (2M in H2O, 0.78 mL, 1.55 mmol) were combined in DME (5 mL). The mixture was degassed with bubbling N2 for 10 min then heated to 85° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tert-butyl (2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (84 mg, 24%).

後処理

  1. customThe mixture was degassed with bubbling N2 for 10 min
  2. temperatureAfter cooling
  3. additionthe reaction mixture was diluted with EtOAc
  4. washwashed successively with saturated aqueous NaHCO3 and brine
  5. dry with materialThe organics were dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc)

出典と根拠

ORDレコード
ord-5b9eb1cfe0a4470fb0a9435ee7737d20
出典データセット
uspto-grants-2015_12
特許番号
US09221833B2

反応ノート

読み込み中…