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

HRID 1098265ノート

反応式

HRID 1098265 の反応式
[H-].[Na+].[Si:3]([O:10][CH:11]1[CH2:14][N:13]([CH2:15][C@H:16]([OH:27])[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]2[N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[Cl:44])[N:36]=[CH:37][C:30]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(OCC)(=O)C>[Si:3]([O:10][CH:11]1[CH2:12][N:13]([CH2:15][C@H:16]([O:27][C:29]2[N:34]=[CH:33][N:32]=[C:31]3[N:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[Cl:44])[N:36]=[CH:37][C:30]=23)[C:17]([NH:19][C:20]2[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[O:18])[CH2:14]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]

参加物

8

反応物 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 112655704-Chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-D]pyrimidineHCID 57504705(S)-3-(3-(tert-butyldimethylsilyl-oxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide

生成物 1

HCID 57504564(2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamide収率 82%

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
0 °C

実験手順

Sodium hydride (87 mg, 2.18 mmol) was added to (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB2) (400 mg, 1.09 mmol) in anhydrous tetrahydrofuran (15 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (318 mg, 1.20 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and then diluted with water (30 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 40 to 100% ethyl acetate in isohexane followed by 0-20% methanol in ethyl acetate to afford the product (532 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.83 (9H, s), 2.45 (3H, s), 3.61-3.90 (4H, m), 4.47-4.60 (2H, m), 4.69 (1H, m), 6.22 (1H, m), 7.36-7.48 (3H, m), 7.51-7.57 (1H, m), 8.03 (1H, s), 8.38 (1H, s), 8.50 (1H, s), 9.27 (1H, s), 10.31 (1H, s); m/z (ES+) (M+H)+=595; HPLC tR=2.63 min.

後処理

  1. temperatureto warm to room temperature
  2. stirringstirred for 2 hours
  3. customThe organic layer was separated
  4. extractionthe aqueous layer re-extracted with ethyl acetate (50 mL)
  5. washThe combined organics were washed with saturated brine (75 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customevaporated
  9. customThe crude product was purified by flash silica chromatography
  10. washeluting with 40 to 100% ethyl acetate in isohexane

出典と根拠

ORDレコード
ord-858462fc89d54fc0a8355eab5ced4f64
出典データセット
uspto-grants-2012_03
特許番号
US08143263B2

反応ノート

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