Ammonium Chloride → Mutated EGFR-IN-1

HRID 1842754Notes

Reaction equation

HRID 1842754 reaction equation
[CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][N:5]([CH3:34])[C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:32][CH3:33])[CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:34])[C:6]1[C:11]([NH2:12])=[CH:10][C:9]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)[CH:19]=[CH:18][N:17]=2)=[C:8]([O:32][CH3:33])[CH:7]=1

Participants

6

Reactant 2

HCID 25517Ammonium ChlorideHCID 71239349N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)-2-nitro-1,4-benzenediamine2×

Product 1

HCID 78358313Mutated EGFR-IN-1Yield 85.4%

Reagents, catalysts & solvents 3

HCID 23925IronCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

A mixture of N′-(2-dimethylaminoethyl)-2-methoxy-N′-methyl-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine (Intermediate 101, 220 mg, 0.46 mmol), iron (155 mg, 2.78 mmol) and NH4Cl (17.32 mg, 0.32 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 2 h. The crude mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (175 mg, 85%) as a beige foam; 1H NMR: 2.17 (6H, s), 2.36 (2H, t), 2.63 (3H, s), 2.88 (2H, t), 3.74 (3H, s), 3.88 (3H, s), 4.58 (2H, br s), 6.76 (1H, s), 7.12-7.19 (2H, m), 7.21-7.27 (1H, m), 7.48 (1H, s), 7.51 (1H, d), 7.78 (1H, s), 8.27 (1H, d), 8.30 (1H, s), 8.42 (1H, d); m/z: ES+ MH+ 446.32.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 2 h
  3. customThe crude mixture was purified by ion exchange chromatography
  4. washThe desired product was eluted from the column
  5. concentrationconcentrated in vacuo onto silica
  6. customPurification by FCC
  7. washeluting with 0-5% 7N methanolic ammonia in CH2Cl2

Sources & evidence

ORD record
ord-0d3b14c7ba2b4ec4a14984501ac774e8
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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