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 2039168

Reaktionsgleichung

Reaktionsgleichung von HRID 2039168
[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]

Komponenten

9

Edukt 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

Produkt 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 esterAusbeute 54 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)KatalysatorHCID 178418397HCID 178418397, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittelHCID 21584119Ethylacetate methanolLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

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+).

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-c959231e8df94b168b39de1193bd2ce6
Quelldatensatz
uspto-grants-2013_11
Patentnummer
US08575118B2

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