Water → (1-{2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 417545Notes

Reaction equation

HRID 417545 reaction equation
[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:43][C:42]2[CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=3)[CH:46]=[CH:47][C:41]=2[N:40]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.O>CN(C=O)C.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.[Cu]I>[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:43][C:42]2[CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:22]#[C:21][C:18]4[NH:17][C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=4)=[CH:50][CH:49]=3)[CH:46]=[CH:47][C:41]=2[N:40]=1)=[O:33])[CH:29]([CH3:31])[CH3:30]

Participants

8

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 66620819(1-{2-[6-(4-Bromo-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 76818854{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

Product 1

HCID 49848172(1-{2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterYield 11.2%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (62 mg, 0.195 mmol), (1-{2-[6-(4-Bromo-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (73 mg, 0.146 mmol), Pd(PPh3)4 (11 mg, 0.00975 mmol), CuI (4 mg, 0.0195 mmol) and triethylamine (0.271 mL, 1.95 mmol) were suspended in DMF (2 mL). The reaction mixture was stirred at 80° C. for 3 hours then 1 mL of water was added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (12 mg, 11%). 1H NMR (MeOH-d4, 400 MHz) 7.66-7.64 (m, 2H), 7.59-7.50 (m, 4H), 7.24 (s, 1H), 6.98 (m, 1H), 5.28 (m, 1H), 5.12 (m, 1H), 4.28-4.19 (m, 2H), 4.04-3.82 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 2.43-2.01 (m, 10H), 0.99-0.87 (m, 12H); MS (ESI) m/z 737 [M+H]+.

Workup

  1. customthe mixture was purified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-65baaa7e4c084a839203a0ad20ed9ae6
Source dataset
uspto-grants-2012_01
Patent number
US08088368B2

Reaction notes

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