Potassium Carbonate → HCID 178502435, Verbindung

HRID 1625517Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1625517
I[C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([C@@H:15]([NH:19][C:20](=[O:23])[O:21][CH3:22])[CH:16]([CH3:18])[CH3:17])=[O:14])[NH:5][CH:6]=1.I[C:25]1[CH:50]=[CH:49][C:28]2[NH:29][C:30]([C@@H:32]3[CH2:36][C@H:35]([CH3:37])[CH2:34][N:33]3[C:38]([C@@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[CH:41]([CH3:43])[CH3:42])=[O:39])=[N:31][C:27]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:59]2[S:63][C:62]3[CH:64]=[C:65](B4OC(C)(C)C(C)(C)O4)[S:66][C:61]=3[CH:60]=2)O1.C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=C(S(O[Na])(=O)=O)C=CC=2OC)CCCCC1>C(O)(C)C.O.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:47][O:46][C:45]([NH:44][C@@H:40]([CH:41]([CH3:43])[CH3:42])[C:38]([N:33]1[CH2:34][C@@H:35]([CH3:37])[CH2:36][C@H:32]1[C:30]1[NH:29][C:28]2[CH:49]=[CH:50][C:25]([C:65]3[S:66][C:61]4[CH:60]=[C:59]([C:2]5[N:3]=[C:4]([C@@H:7]6[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]6[C:13]([C@@H:15]([NH:19][C:20](=[O:23])[O:21][CH3:22])[CH:16]([CH3:18])[CH3:17])=[O:14])[NH:5][CH:6]=5)[S:63][C:62]=4[CH:64]=3)=[CH:26][C:27]=2[N:31]=1)=[O:39])=[O:48]

Komponenten

10

Edukt 5

HCID 11430Potassium CarbonateHCID 588254992,5-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]thiopheneHCID 178492906HCID 178492906, VerbindungHCID 178502434HCID 178502434, VerbindungHCID 178502451HCID 178502451, Verbindung

Produkt 1

HCID 178502435HCID 178502435, Verbindung

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 167845palladium(II) acetateKatalysatorHCID 962WaterLösungsmittelHCID 3776IsopropanolLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
90 °C

Versuchsvorschrift

To a degassed (vacuum/nitrogen flush) mixture of methyl N-[(1S)-1-[(2S,4S)-2-(4-iodo-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (153.5 mg, 0.3347 mmol), methyl N-[(1S)-1-[(2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (162.1 mg, 0.3347 mmol), 4,4,5,5-tetramethyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]thiophen-2-yl]-1,3,2-dioxaborolane (125 mg, 0.3188 mmol) and K2CO3 (220.3 mg, 1.594 mmol) in degassed isopropanol (3.750 mL) and H2O (1.250 mL) are added [3-(2-dicyclohexylphosphanylphenyl)-2,4-dinnethoxy-phenyl]sulfonyloxysodium (VPHOS) (13.07 mg, 0.02550 mmol) and Pd(OAc)2 (1.431 mg, 0.006376 mmol). After degassing twice, reaction mixture is heated at 90° C. for 16 hours, then diluted with ethyl acetate (30 mL). The aqueous solution is discarded, and the organic solution is washed with water, brine, dried (Na2SO4) and concentrated. The residue is purified by silica gel chromatography using ethyl acetate to 8% MeOH-EtOAc as eluent to afford a mixture of products (160 mg) as yellow solid. The desired compound is isolated by reverse phase preparative HPLC to afford methyl N-[(1S)-1-[(2S,4S)-2-[4-[5-[2-[(2S,4S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]thieno[3,2-b]thiophen-2-yl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (34.4 mg) as yellow solid.

Aufarbeitung

  1. customTo a degassed
  2. customAfter degassing twice
  3. customreaction mixture
  4. washthe organic solution is washed with water, brine
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe residue is purified by silica gel chromatography
  8. customto afford

Quellen und Nachweise

ORD-Eintrag
ord-4d1d18a28067417696f2c0d6d504d5c2
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08779156B2

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