碳酸氢铯 → ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

HRID 513041

反应方程式

HRID 513041 反应方程式
Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:64][C@@H:65]1[CH2:69][NH:68][C@@H:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[CH:71]=2)[CH2:66]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:64][C@@H:65]1[CH2:69][N:68]([C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[CH:3]=2)[C@@H:67]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[CH:71]=2)[CH2:66]1

参与物

7

反应物 4

HCID 10796碳酸氢铯HCID 6360444,5-双二苯基膦-9,9-二甲基氧杂蒽HCID 53249841乙基5-溴吡唑并[1,5-A]吡啶-3-甲酸酯HCID 66684522(2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidine

产物 1

HCID 60165028ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

试剂、催化剂与溶剂 2

HCID 9811564三(二亚苄基丙酮)二钯催化剂HCID 312751,4-二氧六环溶剂

反应条件

温度
120 °C

实验过程

A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (27 mg, 0.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 2 μmol), xantphos (5 mg, 8 μmol), cesium carbonate (46 mg, 0.14 mmol), 1,4-dioxane (0.5 mL) and (2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidine (I-6) (18 mg, 0.1 mmol). The contents were heated to 120° C. for 12 hours. Upon cooling to room temperature the reaction was partitioned with EtOAc and water. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield ethyl 5-((2R,4S)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-1). 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1 H), 8.16 (d, J=7.6 Hz, 1 H), 7.31 (td, J=5.6, 7.6 Hz, 1 H), 7.05 (d, J=7.6 Hz, 1 H), 6.98 (d, J=2.8 Hz, 1 H), 6.96-6.91 (m, 2 H), 6.24 (dd, J=2.8, 8.0 Hz, 1 H), 5.39 (d, J=52.8 Hz, 1 H), 5.04 (dd, J=7.2, 9.2 Hz, 1H), 4.34-4.26 (m, 2 H), 4.17-3.90 (m, 2 H), 2.93-2.81 (m, 1 H), 2.11 (dddd, J=3.6, 9.2, 13.2, 40.8 Hz, 1 H). MS m/z 372.1 (M+1)+.

后处理

  1. temperatureUpon cooling to room temperature the reaction
  2. customwas partitioned with EtOAc and water
  3. washThe organic layer was washed with water, brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. customThe crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant

来源与证据

ORD记录
ord-cd37d316d9d8428d95597e21b332dd68
来源数据集
uspto-grants-2015_08
专利号
US09102671B2

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