Diisopropylethylamine → 5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine

HRID 1842773Notes

Reaction equation

HRID 1842773 reaction equation
Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:7]3[CH2:8][CH:5]([N:4]([CH3:9])[CH3:3])[CH2:6]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 22121220N,N-Dimethylazetidin-3-amine--hydrogen chloride (1/2)2×HCID 712408945-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine2×

Product 1

HCID 712408905-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amineYield 93.7%

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Conditions

Temperature
140 °C

Procedure

N,N-dimethylazetidin-3-amine (Intermediate 26, 144 mg, 0.83 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 312 mg, 0.75 mmol) and DIPEA (0.460 mL, 2.64 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 (347 mg, 93%) as an orange solid after trituration with diethyl ether; 1H NMR: 2.14 (6H, s), 3.09-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.01-4.11 (2H, m), 6.28 (1H, s), 6.98 (1H, t), 7.13-7.20 (1H, m), 7.46 (1H, d), 8.15 (1H, s), 8.23 (1H, d), 8.37 (1H, s), 8.47 (1H, s), 8.49 (1H, s), 11.84 (1H, s); m/z: ES+ MH+ 494.16.

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-9db1c51b92614a048e9fae68e9797de7
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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