(3R)-(+)-3-(Dimethylamino)pyrrolidine → N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine

HRID 1842740Notes

Reaction equation

HRID 1842740 reaction equation
[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:23]([CH3:36])=[CH:22][N:21]=2)=[C:12]([O:37][CH3:38])[CH:11]=1>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)[C:23]([CH3:36])=[CH:22][N:21]=3)=[C:12]([O:37][CH3:38])[CH:11]=2)[CH2:4]1

Participants

4

Reactant 2

HCID 2758521(3R)-(+)-3-(Dimethylamino)pyrrolidineHCID 71239199N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine2×

Product 1

HCID 71269904N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amineYield 65%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
140 °C

Procedure

(3R)—N,N-dimethylpyrrolidin-3-amine (255 mg, 2.24 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, 414 mg, 1.02 mmol) in DMA (4 mL) and the mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). Purification by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia provided semi-purified material after concentration of appropriate fractions in vacuo. Purification by FCC, eluting with 1-8% CH3OH in CH2Cl2 gave the title compound (330 mg, 65%) as an orange dry film; 1H NMR: 1.75-1.86 (1H, m), 2.13-2.19 (1H, m), 2.21 (6H, s), 2.37 (3H, s), 2.75 (1H, s), 3.10-3.20 (2H, m), 3.21-3.27 (1H, m), 3.46 (1H, td), 3.90 (3H, s), 3.94 (3H, s), 6.56 (1H, s), 7.03 (1H, t), 7.21-7.26 (1H, m), 7.49 (1H, d), 7.94 (1H, s), 8.05 (1H, s), 8.23 (1H, s), 8.37 (1H, d), 8.39 (1H, s); m/z: ES+ MH+ 502.33.

Workup

  1. concentrationThe mixture was then concentrated in vacuo
  2. dissolutionthe residue was dissolved in EtOAc (50 mL)
  3. customPurification by ion exchange chromatography
  4. washeluting with 0.35M methanolic ammonia provided semi-purified material after concentration of appropriate fractions in vacuo
  5. customPurification by FCC
  6. washeluting with 1-8% CH3OH in CH2Cl2

Sources & evidence

ORD record
ord-0ba3a640dd814c2d85a8fc7976e36872
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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