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

HRID 513044

반응식

HRID 513044 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[CH:66]=[C:67]([CH:70]=[C:71]([C@H:73]2[CH2:77][C@H:76]([F:78])[CH2:75][NH:74]2)[CH:72]=1)[C:68]#[N:69]>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>[C:68]([C:67]1[CH:70]=[C:71]([C@H:73]2[CH2:77][C@H:76]([F:78])[CH2:75][N:74]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:72]=[C:65]([F:64])[CH:66]=1)#[N:69]

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 666849673-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile

생성물 1

HCID 60171437ethyl 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 312751,4-Dioxane용매

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온도
140 °C

실험 절차

A N2 purged flask was charged with ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (36 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg, 2 μmol), xantphos (6 mg, 8 μmol), cesium carbonate (61 mg, 0.19 mmol), 1,4-dioxane (0.5 mL) and 3-fluoro-5-((2R,4S)-4-fluoropyrrolidin-2-yl)benzonitrile (I-15) (28 mg, 0.13 mmol). The contents were heated to 140° C. for 25 minutes 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 ethyl 5-((2R,4S)-2-(3-cyano-5-fluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (X-7). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1 H), 8.21 (d, J=7.6 Hz, 1 H), 7.39 (s, 1 H), 7.31-7.27 (m, 1 H), 7.26-7.21 (m, 1 H), 6.94 (d, J=2.4 Hz, 1 H), 6.24 (dd, J=2.8, 7.6 Hz, 1 H), 5.40 (d, J=52.4 Hz, 1 H), 5.07 (dd, J=7.2, 9.6 Hz, 1 H), 4.35-4.26 (m, 2 H), 4.23-4.08 (m, 1 H), 4.05-3.93 (m, 1 H), 2.97-2.85 (m, 1 H), 2.17-1.99 (m, 1 H), 1.35 (t, J=7.2 Hz, 3 H). MS m/z 397.1 (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-c327336f6d3c451497593c4e39bdec5f
출처 데이터셋
uspto-grants-2015_08
특허 번호
US09102671B2

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