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

HRID 1842802Notes

Reaction equation

HRID 1842802 reaction equation
F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][N:34]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]([CH3:27])[CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[C:4]([O:28][CH3:29])[CH:3]=2)[CH2:33]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 7019156(3S)-(-)-3-(Dimethylamino)pyrrolidineHCID 71239058N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine2×

Product 1

HCID 71270238N-[4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amineYield 64.3%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 295 mg, 0.75 mmol), ((3S)—N,N-dimethylpyrrolidin-3-amine (103 mg, 0.90 mmol) and DIPEA (0.196 mL, 1.13 mmol) were dissolved in DMA (3 mL) and sealed into a microwave tube. The mixture was heated to 100° C. for 45 minutes in a microwave reactor, then cooled to r.t., diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and then eluted with 1:1 methanolic ammonia in CH2Cl2. Fractions containing the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 2-7% methanolic ammonia in CH2Cl2 gave the title compound (235 mg, 64%) as a red solid; 1H NMR: 1.83 (1H, m), 2.17 (1H, m), 2.22 (6H, s), 2.72-2.86 (1H, m), 3.17 (2H, m), 3.26 (1H, m), 3.47 (1H, m), 3.88 (3H, s), 3.97 (3H, s), 6.58 (1H, s), 7.12 (1H, t), 7.19 (1H, d), 7.21-7.31 (1H, m), 7.52 (1H, d), 8.01 (1H, s), 8.23-8.33 (2H, m), 8.36 (1H, d), 8.58 (1H, s); m/z: ES− MH+ 488.35.

Workup

  1. customsealed into a microwave tube
  2. temperaturecooled to r.t.
  3. customabsorbed onto an SCX column
  4. washThe column was washed with CH3OH
  5. washeluted with 1:1 methanolic ammonia in CH2Cl2
  6. additionFractions containing the desired product
  7. concentrationconcentrated in vacuo
  8. customPurification by FCC
  9. washeluting with 2-7% methanolic ammonia in CH2Cl2

Sources & evidence

ORD record
ord-443dd59cb22b4f96a1c8c8616d6e2bf2
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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