Triethylamine → HCID 178502176, compound

HRID 71763Notes

Reaction equation

HRID 71763 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38](=[O:64])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][CH:53]=[C:54]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[CH:63])=[CH:58][CH:57]=2)[N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C(N(CC)CC)C>[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:63]#[C:62][C:59]4[CH:60]=[CH:61][C:56]([C:54]5[N:55]=[C:51]([CH:47]6[CH2:48][CH2:49][CH2:50][N:46]6[C:44](=[O:45])[CH:40]([NH:39][C:38]([O:37][CH3:36])=[O:64])[CH:41]([CH3:43])[CH3:42])[NH:52][CH:53]=5)=[CH:57][CH:58]=4)=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 72338228(1-{2-[4-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester2×HCID 178502207HCID 178502207, compound

Product 1

HCID 178502176HCID 178502176, compoundYield 35%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalyst

Conditions

Temperature
80 °C

Procedure

A mixture of 4-(4-bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (686 mg, 1.74 mmol), (1-{2-[4-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (800 mg, 1.45 mmol), copper(I) iodide (28 mg, 0.14 mmol), tetrakis(triphenylphosphine)palladium(0) (167 mg, 0.14 mmol), triethylamine (2.0 mL, 14.5 mmol) and degassed dimethylformamide (10 mL) was stirred at 80° C. for 1 hour. (1-{2-[4-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (200 mg, 0.57 mmol) was added. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (50 mL) and washed with water (10 mL), saturated ammonium chloride (2×10 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (439 mg, 0.50 mmol, 35%). C46H57N9O8 calculated 863.4 observed [M+1]+ 864.5; rt=1.91 min. 1H (DMSO-d6): δ=8.07 (m, 1H), 7.76 (m, 4H), 7.68 (m, H), 7.56 (d, J=7.6 Hz, 2H), 7.30 (d, J=8.8 Hz, 1H), 5.37 (m, 1H), 5.21 (m, 1H), 5.08 (m, 2H), 4.80 (m, 1H), 4.07 (t, J=7.2 Hz, 2H), 3.81 (m, 2H), 3.52 (s, 3H), 3.51 (s, 3H), 2.33 (m, 2H), 2.08 (m, 1H), 1.97 (m, 4H), 1.39 (s, 9H), 1.34 (m, 2H), 0.81 (m, 12H).

Workup

  1. customdegassed dimethylformamide (10 mL)
  2. customAfter 1 hour the solvent was removed under reduced pressure
  3. washwashed with water (10 mL), saturated ammonium chloride (2×10 mL)
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. customThe solvent was removed under reduced pressure
  7. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-5f469e8223574d94a0d4e928ede5ca88
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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