Citric Acid → HCID 57504615、化合物

HRID 1098132ノート

反応式

HRID 1098132 の反応式
[H-].[Na+].[CH2:3]([O:5][CH2:6][C@H:7]([OH:12])[C:8]([O:10][CH3:11])=[O:9])[CH3:4].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:22][C:15]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:29][C:28]1[C:23]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:12][C@@H:7]([CH2:6][O:5][CH2:3][CH3:4])[C:8]([O:10][CH3:11])=[O:9])[C:15]=3[CH:22]=[N:21]2)=[N:24][CH:25]=[CH:26][CH:27]=1

参加物

6

反応物 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 57438644methyl (2S)-3-ethoxy-2-hydroxypropanoateHCID 575044824-Chloro-1-(3-chloropyridin-2-YL)-1H-pyrazolo[3,4-D]pyrimidine2 回

生成物 1

HCID 57504615HCID 57504615、化合物収率 75.1%

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
0 °C

実験手順

60% sodium hydride in mineral oil (0.96 g, 24.1 mmol) was added portionwise to (S)-methyl 3-ethoxy-2-hydroxypropanoate (Intermediate G4) (2.97 g, 20.1 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (5.87 g, 22.1 mmol) in tetrahydrofuran (50 mL) was added dropwise over a period of 2 minutes. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hour. The reaction was cooled to ˜10° C., 1M citric acid (20 mL) added and the mixture was extracted with EtOAc (2×50 mL). The organic extracts were washed with water (25 mL) and saturated brine (25 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to give the methyl (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxypropanoate (5.7 g, 70% ee). This was further purified by chiral HPLC on Chiralcel OJ eluting with isohexane/isopropanol/triethylamine (70:30:0.1) at 60 mL/min. to give the enantiomerically pure product (3.8 g, 50%) as a colourless gum. 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.60-3.73 (2H, m), 3.79 (3H, s), 4.00-4.11 (2H, m), 5.85 (1H, dd), 7.45 (1H, dd), 8.00 (1H, dd), 8.42 (1H, s), 8.58 (1H, s), 8.61 (1H, dd), m/z (ESI+) (M+H)+=378; HPLC tR=1.84 min.

後処理

  1. temperatureto warm to ambient temperature
  2. stirringstirred for 2 hour
  3. temperatureThe reaction was cooled to ˜10° C.
  4. extractionthe mixture was extracted with EtOAc (2×50 mL)
  5. washThe organic extracts were washed with water (25 mL) and saturated brine (25 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customThe residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane

出典と根拠

ORDレコード
ord-6c7100277bfd4ca9b399e50d054a3b2a
出典データセット
uspto-grants-2012_03
特許番号
US08143263B2

反応ノート

読み込み中…