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

HRID 513052

反应方程式

HRID 513052 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.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O.[F:62][C:63]1[CH:64]=[C:65]([C@@H:69]2[NH:73][CH2:72][C@@H:71]([C:74]#[N:75])[CH2:70]2)[CH:66]=[CH:67][CH:68]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(O)(C)C>[C:74]([C@@H:71]1[CH2:72][N:73]([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:69]([C:65]2[CH:66]=[CH:67][CH:68]=[C:63]([F:62])[CH:64]=2)[CH2:70]1)#[N:75]

参与物

7

反应物 4

HCID 10796碳酸氢铯HCID 162179852-二环己基磷-2',6'-二异丙氧基-1,1'-联苯HCID 53249841乙基5-溴吡唑并[1,5-A]吡啶-3-甲酸酯HCID 66691683(3S,5R)-5-(3-fluorophenyl)pyrrolidine-3-carbonitrile 2,2,2-trifluoroacetate

产物 1

HCID 60171691ethyl 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

试剂、催化剂与溶剂 2

HCID 167845palladium acetate催化剂HCID 6386叔丁醇溶剂

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 (30 mg, 0.11 mmol), palladium acetate (1.0 mg, 5 μmol), RuPhos (5 mg, 10 μmol), cesium carbonate (65 mg, 0.20 mmol), tBuOH (0.5 mL) and (3S,5R)-5-(3-fluorophenyl)pyrrolidine-3-carbonitrile 2,2,2-trifluoroacetate (I-31) (30 mg, 0.10 mmol). The contents were heated to 120° C. overnight in an oil bath. Upon cooling to room temperature the reaction was filtered through celite and concentrated. The crude product was purified by column chromatography on silica gel with an EtOAc/hexane gradient as eluant to yield ethyl 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-19). 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1 H), 8.22 (d, J=7.6 Hz, 1 H), 7.40-7.32 (m, 1 H), 7.07-6.96 (m, 3 H), 6.88 (d, J=9.4 Hz, 1 H), 6.24 (dd, J=2.7, 7.6 Hz, 1 H), 5.10 (dd, J=2.5, 8.0 Hz, 1 H), 4.39-4.29 (m, 2 H), 4.23-4.14 (m, 1 H), 3.95-3.78 (m, 1 H), 3.42-3.29 (m, 1 H), 2.92-2.78 (m, 1 H), 2.50-2.39 (m, 1 H), 1.36 (t, J=7.1 Hz, 3 H). MS m/z 379.1 (M+1)+. Further elution with MeOH/DCM gradient afforded ethyl 5-((2R,4S)-4-carbamoyl-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-20). MS m/z 397.1 (M+1)+.

后处理

  1. temperatureUpon cooling to room temperature the reaction
  2. filtrationwas filtered through celite
  3. concentrationconcentrated
  4. customThe crude product was purified by column chromatography on silica gel with an EtOAc/hexane gradient as eluant

来源与证据

ORD记录
ord-6a36a33b3d9f48b58a37cc466935123c
来源数据集
uspto-grants-2015_08
专利号
US09102671B2

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