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

HRID 513052

反応式

HRID 513052 の反応式
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]

参加物

7

反応物 4

HCID 10796Cesium carbonateHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 53249841Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylateHCID 66691683(3S,5R)-5-(3-fluorophenyl)pyrrolidine-3-carbonitrile 2,2,2-trifluoroacetate

生成物 1

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

試薬・触媒・溶媒 2

HCID 167845palladium(II) acetate触媒HCID 6386tert-Butanol溶媒

反応条件

温度
120 °C

実験手順

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)+.

後処理

  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

出典と根拠

ORDレコード
ord-6a36a33b3d9f48b58a37cc466935123c
出典データセット
uspto-grants-2015_08
特許番号
US09102671B2

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