Diisopropylethylamine → N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine

HRID 1842800Notes

Reaction equation

HRID 1842800 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.Cl.Cl.[CH3:32][N:33]1[CH2:40][CH2:39][CH2:38][C:34]21[CH2:37][NH:36][CH2:35]2.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:29][O:28][C:4]1[CH:3]=[C:2]([N:36]2[CH2:37][C:34]3([N:33]([CH3:32])[CH2:40][CH2:39][CH2:38]3)[CH2:35]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[CH:19]=2)[CH:15]=[CH:14][N:13]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 71239058N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine2×HCID 717431205-Methyl-2,5-diazaspiro[3.4]octane dihydrochloride2×

Product 1

HCID 71239536N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amineYield 55%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 300 mg, 0.76 mmol), 8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 115 mg, 0.92 mmol), DIPEA (0.158 mL, 0.92 mmol) and DMA (4 mL) was heated at 100° C. for 1 h. The mixture was then absorbed onto an SCX column, and the column was washed with CH3OH. The column was then eluted with 1:1 methanoic ammonia in CH2Cl2 and fractions containing the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 1.5% CH3OH in CH2Cl2 gave the title compound (209 mg, 55%) as an orange solid; 1H NMR: 1.71 (2H, dt), 2.00-2.10 (2H, m), 2.40 (3H, s), 2.67 (2H, t), 3.74 (2H, d), 3.88 (3H, s), 3.96 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.12 (1H, t), 7.20 (1H, d), 7.25 (1H, dd), 7.52 (1H, d), 8.02 (1H, s), 8.28-8.34 (2H, m), 8.36 (1H, d), 8.63 (1H, s); m/z: ES+ MH+ 500.6.

Workup

  1. customThe mixture was then absorbed onto an SCX column
  2. washthe column was washed with CH3OH
  3. washThe column was then eluted with 1:1 methanoic ammonia in CH2Cl2 and fractions
  4. additioncontaining the desired product
  5. concentrationconcentrated in vacuo
  6. customPurification by FCC
  7. washeluting with 1.5% CH3OH in CH2Cl2

Sources & evidence

ORD record
ord-16b64eebe8344092b8df44370e749e7d
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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