Sodium bis(trimethylsilyl)amide → N-(2-chloro-5-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide

HRID 1812371

反応式

HRID 1812371 の反応式
F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.[NH2:32][C:33]1[CH:34]=[C:35]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:36]([Cl:39])=[N:37][CH:38]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:39][C:36]1[C:35]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:34][C:33]([NH:32][C:2]2[C:3]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:38][N:37]=1

参加物

5

反応物 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 665998534-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholineHCID 71480920N-(5-amino-2-chloro-3-pyridinyl)methanesulfonamide

生成物 1

HCID 86647079N-(2-chloro-5-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide収率 73.1%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
0 °C

実験手順

To a stirred solution of 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (0.157 g, 0.368 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330 step 2, 0.103 g, 0.462 mmol) in THF (2 mL) in 20 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.47 mL, 1.47 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The mixture was partitioned between a mixture of saturated aqueous sodium chloride (10 mL)/buffer (pH 5.0, citric acid/NaOH) (10 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: iPrOH in CHCl3 0% to 10%) to afford N-(2-chloro-5-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(1-morpholinoethyl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (0.169 g, 73% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 13.18 (s, 1H) 9.78 (d, J=1.96 Hz, 1H) 8.83 (d, J=2.54 Hz, 1H) 8.63 (d, J=2.54 Hz, 1H) 8.36 (d, J=2.35 Hz, 1H) 8.31 (s, 1H) 6.76 (br. s., 1H) 5.85-5.90 (m, 1H) 4.17-4.24 (m, 1H) 3.79-3.88 (m, 1H) 3.73 (t, J=4.50 Hz, 4H) 3.51-3.59 (m, 1H) 3.14 (s, 3H) 2.94 (s, 3H) 2.45-2.62 (m, 4H) 2.01-2.22 (m, 3H) 1.66-1.93 (m, 3H) 1.48 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 628.0 (M+H)+.

後処理

  1. customThe mixture was partitioned between a mixture of saturated aqueous sodium chloride (10 mL)/buffer (pH 5.0, citric acid/NaOH) (10 mL) and EtOAc (20 mL)
  2. extractionThe aqueous phase was extracted with EtOAc (2×20 mL)
  3. dry with materialThe combined organic phases were dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by silica gel column chromatography (50 g, eluent: iPrOH in CHCl3 0% to 10%)

出典と根拠

ORDレコード
ord-bbe0f82100bc42e3aa2c41183cce3336
出典データセット
uspto-grants-2013_01
特許番号
US08362241B2

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