Cesium carbonate → 6-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(5-fluoropyridin-3-ylamino)nicotinamide

HRID 84855

반응식

HRID 84855 반응식
Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:5]([F:23])=[CH:4][C:3]=1[C:24]#[N:25].[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1.C(=O)([O-])[O-:35].[Cs+].[Cs+]>CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].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].C1(C)C=CC=CC=1>[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]1[NH:8][C:6]1[C:5]([F:23])=[CH:4][C:3]([C:24]([NH2:25])=[O:35])=[C:2]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=2)[N:7]=1.[C:24]([C:3]1[CH:4]=[C:5]([F:23])[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:2]=1[NH:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1)#[N:25]

참가 물질

8

반응물 3

HCID 10796Cesium carbonateHCID 5744505-Fluoro-3-pyridinamineHCID 86666159HCID 86666159, 화합물

생성물 2

HCID 573361096-((1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-(5-fluoropyridin-3-ylamino)nicotinamideHCID 86666158HCID 86666158, 화합물

시약·촉매·용매 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium촉매HCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzene촉매HCID 1140Toluene용매

실험 절차

To a clean 100 mL flask were added to following reagents: (tert-butyl (1S,2R)-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (100 mg, 0.27 mmol), 3-amino-5-fluoropyridine (61 mg, 0.54 mmol), fine-powder cesium carbonate (264 mg, 0.81 mmol), Q-Phos (1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (40 mg, 0.054 mmol; Aldrich #675784) and Pd(dba)2 (bis(dibenzylideneacetone)palladium(0)) (64 mg, 0.11 mmol; Aldrich #227994). To the mixture was then added 15 mL toluene. The resulting slurry was degassed using argon stream gently for 3 min. It was then sent to 110° C. bath with an air-cooled condenser on top and stirred under argon for overnight. The mixture was then cooled to RT and concentrated on rotovap to remove all the solvent. To the residue were added 300 mL EtOAc and 100 mL water. After vigorously stirring for 15-30 min, the organic phase was separated, and the aq phase and the black junks between org and aq phases were all discarded. The EtOAc phase was then washed with brine twice. The organic phase was dried over MgSO4, concentrated and subjected to flash column with 0%-35% EtOAc in DCM to isolate the desired product, tert-butyl (1S,2R)-2-(5-cyano-3-fluoro-6-(5-fluoropyridin-3-ylamino)pyridin-2-ylamino)cyclohexylcarbamate. It was added 4 mL TFA at RT. After stirring for 3 min, 1 mL conc. H2SO4 was added. The mixture was then sent to pre-heated 80° C. bath and stirred for 90 min. It was then cooled to RT. To it was added 10 mL water. The mixture was stirred for 10 min, filtered and directly subjected to prep HPLC (running with 3 mM HCl in water as solvent A and neat acetonitrile as solvent B) in two injections to isolate the title compound as HCl salt (lyophilized). Yield: 58 mg, 59% yield for Step 2. UV: 258, 330 nm. M+H found for C17H20F2N6O: 363.3. NMR (CD3OD): 8.56 (1H, m), 8.20 (1H, dd, J=11.2; 2.0 Hz), 8.06 (1H, m), 7.82 (1H, d, J=11.6 Hz), 4.42 (1H, m), 3.86 (1H, m), 1.93-1.63 (8H, m) ppm.

후처리

  1. additionTo a clean 100 mL flask were added
  2. customThe resulting slurry was degassed
  3. customwas then sent to 110° C.
  4. concentrationconcentrated on rotovap
  5. customto remove all the solvent
  6. additionTo the residue were added 300 mL EtOAc and 100 mL water
  7. stirringAfter vigorously stirring for 15-30 min
  8. customthe organic phase was separated
  9. washThe EtOAc phase was then washed with brine twice
  10. dry with materialThe organic phase was dried over MgSO4
  11. concentrationconcentrated

출처 및 근거

ORD 기록
ord-14bdc556421d4637afd27efc62123dfd
출처 데이터셋
uspto-grants-2014_09
특허 번호
US08846928B2

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