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

HRID 513045

반응식

HRID 513045 반응식
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]

참가 물질

7

반응물 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

생성물 1

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

시약·촉매·용매 2

HCID 167845palladium(II) acetate촉매HCID 312751,4-Dioxane용매

반응 조건

온도
140 °C

실험 절차

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)+.

후처리

  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

출처 및 근거

ORD 기록
ord-9a77622444d94b209be9a12a0e9ff566
출처 데이터셋
uspto-grants-2015_08
특허 번호
US09102671B2

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