Phenol → 4-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-1-methyl-piperidin-4-ol

HRID 1264054Notes

Reaction equation

HRID 1264054 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:9]#[C:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][N:15]=[C:14]3OC2C=CC=CC=2)([OH:8])[CH2:4][CH2:3]1.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:33]=[CH:32]2.Cl.[NH+]1C=CC=CC=1.C1(O)C=CC=CC=1>CCOC(C)=O>[CH2:38]([N:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:14]3[C:13]4[C:18](=[CH:19][CH:20]=[C:11]([C:10]#[C:9][C:5]5([OH:8])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:12]=4)[N:17]=[CH:16][N:15]=3)=[CH:37][CH:36]=2)[CH:32]=[CH:33]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1

Participants

6

Reactant 4

HCID 996PhenolHCID 27946241-Benzyl-1H-indol-5-ylamineHCID 186164891-Methyl-4-(4-phenoxy-quinazolin-6-ylethynyl)-piperidin-4-olHCID 21584435Pyridinium hydrochloride

Product 1

HCID 694846844-[4-(1-Benzyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-1-methyl-piperidin-4-olYield 60.6%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

In a 1 mL Wheaton vial quinazoline 22 (80 mg, 0.22 mmol) was combined with 5-amino-1-benzylindole (54 mg, 0.24 mmol), pyridinium hydrochloride (5 mg, 0.04 mmol) and phenol (104 mg, 1.11 mmol). The vial was capped and heated at 100° C. for 16 hours. After cooling the contents of the Wheaton vial were solvated in a minimal amount of EtOAc and placed atop a silica gel (5 g) column. Elution of the column with 1:1:0.1 Hexanes:EtOAc/NEt3 removed high Rf impurities. The desired product 23 (Rf 0.05, 10:1 CH2Cl2:MeOH) was eluted off with 10:1 CH2Cl2:MeOH and gave a yellow solid (65 mg, 60%). 1H NMR (DMSO d6; 400 MHz): δ: 9.88 (s, 1H, NH), 8.67 (s, 1H), 8.45 (s, 1H), 7.92 (d, 1.7 Hz), 7.76 (d, 1H, J=8.5 Hz), 7.67 (d, 1H, J=8.5 Hz), 7.50 (d, 1H, J=3.1 Hz), 7.42 (d, 1H, J=8.9 Hz), 7.35 (dd, 1H, J=8.9 Hz, 1.9 Hz), 7.31-7.18 (m, 6H), 6.48 (dd, 1H, J+3.1 Hz, 0.8 Hz), 5.41 (s, 2H), 2.97 (br, 2H), 2.67 (br, 2H), 2.47 (s, 3H), 1.92 (br, 2H), 1.82 (br, 2H). LRMS: 488.2 (MH+), 126.1.

Workup

  1. customThe vial was capped
  2. temperatureAfter cooling the contents of the Wheaton vial
  3. washElution of the column with 1:1:0.1 Hexanes
  4. washThe desired product 23 (Rf 0.05, 10:1 CH2Cl2:MeOH) was eluted off with 10:1 CH2Cl2

Sources & evidence

ORD record
ord-a9301c6f44ae407d86e7d862600bb603
Source dataset
uspto-grants-2003_04
Patent number
US06541481B2

Reaction notes

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