Diisopropylethylamine → N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine

HRID 1842769Notes

Reaction equation

HRID 1842769 reaction equation
Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[CH:28]=3)[C:24]([CH3:37])=[CH:23][N:22]=2)=[C:13]([O:38][CH3:39])[CH:12]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:24]([CH3:37])=[CH:23][N:22]=3)=[C:13]([O:38][CH3:39])[CH:12]=2)[CH2:6]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 22121220N,N-Dimethylazetidin-3-amine--hydrogen chloride (1/2)2×HCID 71239199N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine2×

Product 1

HCID 71240800N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amineYield 71.6%

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Conditions

Temperature
140 °C

Procedure

N,N-dimethylazetidin-3-amine (Intermediate 26, 113 mg, 0.65 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)-pyrimidin-2-amine (Intermediate 79, 250 mg, 0.61 mmol) and DIPEA (0.374 mL, 2.15 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (213 mg, 71%) as an orange foam; 1H NMR: 2.13 (6H, s), 2.37 (3H, s), 3.09-3.16 (1H, m), 3.72 (2H, dd), 3.89 (3H, s), 3.93 (3H, s), 4-4.08 (2H, m), 6.27 (1H, s), 7.04 (1H, t), 7.20-7.26 (1H, m), 7.49 (1H, d), 7.90 (1H, s), 8.03 (1H, s), 8.23 (1H, s), 8.35 (1H, d), 8.46 (1H, s); m/z: ES+ MH+ 488.63.

Workup

  1. customThe cooled mixture was purified by ion exchange chromatography
  2. washeluting with 7M methanolic ammonia
  3. concentrationconcentrated in vacuo onto silica
  4. customFurther purification by FCC
  5. washeluting with 0-4% 7N methanolic ammonia in CH2Cl2

Sources & evidence

ORD record
ord-7702ee9afa9145df8ae81c11e14c6357
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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