Nitrogen → 3-{5-[4-(4-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

HRID 2039168Notes

Reaction equation

HRID 2039168 reaction equation
[CH3:1][O:2][C:3](=[O:29])[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]2[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:30]([O:34][C:35]([N:37]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=3)=[CH:46][N:47]=2)[CH:41]2[CH2:55][CH:38]1[CH2:39][CH2:40]2)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C.N#N>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.CO.CCOC(C)=O>[C:30]([O:34][C:35]([N:37]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:28]#[C:27][C:24]4[CH:25]=[CH:26][C:21]([C:18]5[NH:17][C:16]([CH:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:29])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:22][CH:23]=4)=[CH:50][CH:49]=3)=[CH:46][N:47]=2)[CH:41]2[CH2:55][CH:38]1[CH2:39][CH2:40]2)=[O:36])([CH3:33])([CH3:31])[CH3:32]

Participants

9

Reactant 4

HCID 947NitrogenHCID 8471TriethylamineHCID 596109073-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterHCID 72338228(1-{2-[4-(4-ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Product 1

HCID 666207333-{5-[4-(4-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterYield 54%

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 21584119Ethylacetate methanolSolvent

Conditions

Temperature
80 °C

Procedure

A solution of (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (500 mg, 1.27 mmol), 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (530 mg, 1.27 mmol), and triethylamine (531 □L, 3.81 mmol) in DMF (6.4 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (150 mg, 0.13 mmol) and CuI (25 mg, 0.13 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was quenched with AcOH then purified by reverse phase preparative HPLC (10-70% MeCN—H2O; 0.1% formic acid modifier) then silica gel chromatography (0-10% MeOH-EtOAc gradient) to afford 3-{5-[4-(4-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (500 mg, 0.68 mmol, 54% yield). LCMS-ESI+: calc'd for C42H50N7O5: 732.4 (M+H+); Found: 732.2 (M+H+).

Workup

  1. customThe pressure flask was sealed
  2. temperatureAfter cooling to room temperature
  3. customthe reaction was quenched with AcOH
  4. customthen purified by reverse phase preparative HPLC (10-70% MeCN—H2O; 0.1% formic acid modifier)

Sources & evidence

ORD record
ord-c959231e8df94b168b39de1193bd2ce6
Source dataset
uspto-grants-2013_11
Patent number
US08575118B2

Reaction notes

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