Potassium Carbonate → HCID 178502435, compound

HRID 1625517Notes

Reaction equation

HRID 1625517 reaction equation
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]

Participants

10

Reactant 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, compoundHCID 178502434HCID 178502434, compoundHCID 178502451HCID 178502451, compound

Product 1

HCID 178502435HCID 178502435, compound

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-4d1d18a28067417696f2c0d6d504d5c2
Source dataset
uspto-grants-2014_07
Patent number
US08779156B2

Reaction notes

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