Ethyl Acetate → N-(4-(Chlorodifluoromethoxy)phenyl)-5-(4-fluoro-1H-pyrazol-5-yl)-6-(3-(hydroxymethyl)azetidin-1-yl)nicotinamide

HRID 525771노트

반응식

HRID 525771 반응식
[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[F:28][C:29]1[CH:30]=[N:31][NH:32][C:33]=1[Sn](CCCC)(CCCC)CCCC.CCOC(C)=O>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16]([C:33]3[NH:32][N:31]=[CH:30][C:29]=3[F:28])[C:15]([N:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1

참가 물질

6

반응물 3

HCID 8857Ethyl AcetateHCID 111530444-fluoro-5-(tributylstannyl)-1H-pyrazoleHCID 89906278N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)azetidin-1-yl)-5-iodonicotinamide

생성물 1

HCID 89908146N-(4-(Chlorodifluoromethoxy)phenyl)-5-(4-fluoro-1H-pyrazol-5-yl)-6-(3-(hydroxymethyl)azetidin-1-yl)nicotinamide

시약·촉매·용매 2

HCID 178418397HCID 178418397, 화합물촉매HCID 679Dimethyl Sulfoxide용매

반응 조건

온도
100 °C

실험 절차

A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)azetidin-1-yl)-5-iodonicotinamide (Stage 92.1, 200 mg, 0.392 mmol), 4-fluoro-5-(tributylstannyl)-1H-pyrazole (147 mg, 0.392 mmol), Pd(PPh3)4 (22.67 mg, 0.02 mmol) in DMSO (2 mL) was stirred at 100° C. under argon atmosphere for 21 h. The RM was treated with EtOAc, washed with sat. aq. NaHCO3 and brine dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography on silica gel, dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg 1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was further purified by preparative SFC (Column Diol, from 21% to 26% in 6 min) to give the title product as a white solid. HPLC (Condition 7) tR=5.701 min, UPLC-MS (Condition 8) tR=0.95 min, m/z=468.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.58-2.73 (m, 1H) 3.43-3.51 (m, 2H) 3.51-3.60 (m, 2H) 3.75-3.85 (m, 2H) 4.68-4.77 (m, 1H) 7.30-7.38 (m, 3H) 7.83-7.91 (m, 2H) 7.99-8.07 (m, 1H) 8.73-8.83 (m, 1H) 10.21 (s, 1H) 12.92-13.18 (m, 1H).

후처리

  1. washwashed with sat. aq. NaHCO3 and brine
  2. dry with materialdried over Na2SO4
  3. customthe solvent was evaporated off under reduced pressure
  4. customThe residue was purified by flash chromatography on silica gel
  5. dissolutiondissolved in MeOH (3 mL)
  6. filtrationfiltered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg 1.5 mmol), the cartridge
  7. washwas washed with MeOH
  8. customthe solvent was evaporated off under reduced pressure
  9. customto give a residue which
  10. customwas further purified by preparative SFC (Column Diol, from 21% to 26% in 6 min)

출처 및 근거

ORD 기록
ord-cc5981ca759943f4bb81e39445e745e5
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09340537B2

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