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Citric Acid → (2S)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)-2-(1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide

HRID 1098011
ノート
印刷プレビュー

反応式

HRID 1098011 の反応式
[H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:29]=[CH:30][C:23]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:3]1([O:7][CH2:8][C@H:9]([O:20][C:22]2[N:27]=[CH:26][N:25]=[C:24]3[N:28]([C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)[N:29]=[CH:30][C:23]=23)[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

6

反応物 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 575045064-chloro-1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine2 回HCID 57504623HCID 57504623、化合物

生成物 1

HCID 59279464(2S)-3-cyclobutoxy-N-(5-methylpyrazin-2-yl)-2-(1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide収率 41.6%

試薬・触媒・溶媒

1
HCID 8028Tetrahydrofuran溶媒

反応条件

温度
0 °C

実験手順

Sodium hydride (19.54 mg, 0.49 mmol) was added to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (102 mg, 0.41 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-methylpyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate V5) (100 mg, 0.41 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 5% MeOH in DCM to afford the product (78 mg, 41.6%). 1H NMR (400 MHz, DMSO) δ 1.23-1.36 (m, 1H), 1.38-1.51 (m, 1H), 1.60-1.75 (m, 2H), 1.96-2.07 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 3.71-3.87 (m, 2H), 3.89-3.98 (m, 1H), 5.71-5.78 (m, 1H), 7.28-7.34 (m, 1H), 7.75 (d, 1H), 8.15 (s, 1H), 8.39 (s, 1H), 8.45-8.51 (m, 2H), 8.93 (s, 1H), 11.01 (s, 1H), m/z (ESI+) (M+H)+=461.48; HPLC tR=1.75 min

後処理

  1. temperatureto warm to room temperature
  2. stirringstirred for 1 hour
  3. customthe majority of the THF removed in vacuo
  4. additionThe reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL)
  5. customThe organic layer was separated
  6. extractionthe aqueous layer re-extracted with ethyl acetate (2×50 mL)
  7. washThe combined organics were washed with saturated brine (25 mL)
  8. dry with materialdried (MgSO4)
  9. customevaporated
  10. customThe crude product was purified by flash silica chromatography
  11. washeluting with 0 to 5% MeOH in DCM

出典と根拠

ORDレコード
ord-42787f34b76c4b0a8e2479458f0bc85a
出典データセット
uspto-grants-2012_03
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08143263B2

反応ノート

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