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

HRID 1842767

Reaction equation

HRID 1842767 reaction equation
CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[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.Cl.Cl.[CH3:42][N:43]([CH3:48])[CH:44]1[CH2:47][NH:46][CH2:45]1>CC(N(C)C)=O.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)[N:32]([CH3:39])[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:46]3[CH2:47][CH:44]([N:43]([CH3:48])[CH3:42])[CH2:45]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 22121220N,N-Dimethylazetidin-3-amine--hydrogen chloride (1/2)2×HCID 712392825-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine3×

Product 1

HCID 712408245-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amineYield 100%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

DIPEA (0.408 mL, 2.33 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine. 0.8 toluene-4-sulfonic acid salt (Intermediate 87, 330 mg, 0.58 mmol) in DMA (3 mL). N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 121 mg, 0.70 mmol) was then added in one portion. The mixture was heated in a microwave at 100° C. for 0.5 h then the mixture was cooled and diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated in vacuo. Further purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave the title compound (295 mg, 100%) as a brown gum; 1H NMR: (CDCl3) 2.18 (6H, s), 3.13-3.24 (1H, m), 3.67-3.75 (2H, m), 3.89 (3H, s), 3.96 (3H, s), 4.13 (2H, t), 6.04 (1H, s), 7.21-7.29 (1H, m, partially obscured by chloroform signal), 7.29-7.41 (3H, m), 8.22 (1H, s), 8.37 (1H, s), 8.46 (1H, d), 9.05 (1H, s); m/z: ES+ MH+ 508.

Workup

  1. temperaturethe mixture was cooled
  2. customabsorbed onto an SCX column
  3. washThe column was washed with CH3OH
  4. washeluted with 1:1 methanolic ammonia in CH2Cl2
  5. concentrationAppropriate fractions were concentrated in vacuo
  6. customFurther purification by FCC
  7. washeluting with 1-10% CH3OH in CH2Cl2

Sources & evidence

ORD record
ord-0d55d5f8cbc54b119d8746ba00ff3369
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Linked notes

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