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

HRID 513045

反応式

HRID 513045 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.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:65]1([F:79])[CH2:69][NH:68][C@@H:67]([C:70]2[CH:71]=[C:72]([CH:75]=[C:76]([F:78])[CH:77]=2)[C:73]#[N:74])[CH2:66]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:73]([C:72]1[CH:71]=[C:70]([C@H:67]2[CH2:66][C:65]([F:79])([F:64])[CH2:69][N:68]2[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)[CH:77]=[C:76]([F:78])[CH:75]=1)#[N:74]

参加物

7

反応物 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 53249841Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylateHCID 66691400(R)-3-(4,4-difluoropyrrolidin-2-yl)-5-fluorobenzonitrile

生成物 1

HCID 60171438(R)-ethyl 5-(2-(3-cyano-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

試薬・触媒・溶媒 2

HCID 167845palladium(II) acetate触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
140 °C

実験手順

A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (100 mg, 0.37 mmol), palladium acetate (1.7 mg, 7 μmol), xantphos (7 mg, 11 μmol), cesium carbonate (170 mg, 0.52 mmol), 1,4-dioxane (0.5 mL) and (R)-3-(4,4-difluoropyrrolidin-2-yl)-5-fluorobenzonitrile (I-24) (84 mg, 0.37 mmol). The contents were heated to 140° C. for 1 hour under microwave irradiation. 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 (R)-ethyl 5-(2-(3-cyano-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-8). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=7.6 Hz, 1 H), 8.24 (s, 1 H), 7.38 (s, 1 H), 7.33-7.29 (m, 1 H), 7.25-7.21 (m, 1 H), 6.93 (d, J=2.8 Hz, 1 H), 6.19 (dd, J=2.8, 7.6 Hz, 1 H), 5.14 (dd, J=4.4, 9.2 Hz, 1 H), 4.34-4.25 (m, 2 H), 4.25-4.16 (m, 1 H), 4.05-3.93 (m, 1 H), 3.14-2.98 (m, 1 H), 2.53-2.42 (m, 1 H), 1.34 (t, J=7.2 Hz, 3 H). MS m/z 415.1 (M+1)+.

後処理

  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

出典と根拠

ORDレコード
ord-9a77622444d94b209be9a12a0e9ff566
出典データセット
uspto-grants-2015_08
特許番号
US09102671B2

関連ノート

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