Diisopropylethylamine → N-{4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

HRID 1842786Notes

Reaction equation

HRID 1842786 reaction equation
CCN(C(C)C)C(C)C.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[CH:28]=[N:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.[CH3:38][N:39]1[CH2:43][C@@H:42]2[NH:44][CH2:45][CH2:46][C@@H:41]2[CH2:40]1>FC(F)(F)CO>[CH3:38][N:39]1[CH2:40][C@@H:41]2[C@@H:42]([N:44]([C:11]3[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]4[N:26]=[C:25]([C:27]5[CH:28]=[N:29][N:30]6[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=56)[CH:24]=[CH:23][N:22]=4)=[C:13]([O:36][CH3:37])[CH:12]=3)[CH2:45][CH2:46]2)[CH2:43]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 44221716(3aR,6aR)-5-Methyloctahydropyrrolo[3,4-b]pyrrole2×HCID 71240760N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine2×

Product 1

HCID 71269945N-{4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amineYield 61%

Reagents, catalysts & solvents 1

HCID 64092,2,2-TrifluoroethanolSolvent

Conditions

Temperature
140 °C

Procedure

DIPEA (0.583 mL, 3.35 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 515 mg, 1.34 mmol) and (3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole (Intermediate 37, 186 mg, 1.47 mmol) in 2,2,2-trifluoroethanol (5 mL) and the mixture was heated in a microwave at 140° C. for 1 h. After cooling, the mixture was part-purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia, and then concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (400 mg, 61%) as an orange/red foam; 1H NMR (CDCl3): 1.87 (1H, dd), 1.90-1.98 (2H, m), 2.03-2.14 (3H, m), 2.20 (3H, s), 2.28 (1H, dd), 2.45 (2H, ddd), 2.60-2.67 (1H, m), 2.97-3.07 (1H, m), 3.18-3.34 (3H, m), 3.48-3.58 (1H, m), 3.96 (3H, s), 4.20 (2H, t), 4.40 (1H, ddd), 6.43 (1H, s), 6.86 (1H, d), 7.35 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.92 (1H, s); m/z: ES+ MH+ 491.15.

Workup

  1. temperatureAfter cooling
  2. customthe mixture was part-purified by ion exchange chromatography
  3. washeluting with 7M methanolic ammonia
  4. concentrationconcentrated in vacuo onto silica
  5. customPurification by FCC
  6. washeluting with 0-5% 7N methanolic ammonia in CH2Cl2

Sources & evidence

ORD record
ord-301f6b10f8a04dfb9c002464dc4636c1
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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