Dimethylformamide → 2,2,2-Trifluoro-N-[1-(4-{7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-cyclobutyl]-acetamide

HRID 1262325Notes

Reaction equation

HRID 1262325 reaction equation
O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2([NH:69][C:70](=[O:75])[C:71]([F:74])([F:73])[F:72])[CH2:68][CH2:67][CH2:66]2)=[CH:61][C:60]=1[O:76][CH3:77]>>[F:72][C:71]([F:73])([F:74])[C:70]([NH:69][C:65]1([C:62]2[CH:63]=[CH:64][C:59]([NH:58][C:2]3[N:7]=[CH:6][C:5]4=[CH:8][CH:9]=[C:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[N:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH3:22])[N:4]4[N:3]=3)=[C:60]([O:76][CH3:77])[CH:61]=2)[CH2:66][CH2:67][CH2:68]1)=[O:75]

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 142176Phenyl triflimideHCID 86761893N-[1-(4-Amino-3-methoxy-phenyl)-cyclobutyl]-2,2,2-trifluoro-acetamideHCID 178482109HCID 178482109, compound

Product 1

HCID 867618922,2,2-Trifluoro-N-[1-(4-{7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-cyclobutyl]-acetamideYield 55.4%

Procedure

Into a 8-dram vial, N-[2-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (176 mg, 0.552 mmol), N,N-Dimethylformamide (2.00 mL, 25.8 mmol), N,N-Diisopropylethylamine (0.211 mL, 1.21 mmol), and N-Phenylbis(trifluoromethanesulphonimide) (0.236 g, 0.662 mmol) were added. The reaction was stirred at room temperature for 30 minutes. N-[1-(4-Amino-3-methoxy-phenyl)-cyclobutyl]-2,2,2-trifluoro-acetamide (0.350 g, 1.21 mmol) was then added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum overnight. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid. The solid was partitioned with NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2,2,2-Trifluoro-N-[1-(4-{7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-3-methoxy-phenyl)-cyclobutyl]-acetamide as a yellow solid (180 mg, 55%). LCMS (E/I+) 589.23 (M+H). NMR 1H (DMSO-d6)-9.98 (s, 1H), 8.96 (s, 1H), 7.93-8.00 (m, 1H), 7.90 (d, 1H, J=8.35 Hz), 7.77 (s, 1H), 7.60-7.68 (m, 1H), 7.48-7.56 (m, 2H), 7.04 (s, 1H), 7.02 (d, 1H, J=4.74 Hz), 6.95 (d, 1H, J=4.74 Hz), 6.87 (d, 1H, J=8.51 Hz), 3.84 (s, 3H), 3.03 (s, 3H), 2.09 (s, 3H), 2.54 (t, 4H, J=7.44 Hz), 1.70-2.00 (m, 2H).

Workup

  1. temperatureThe reaction mixture was heated at 120° C. for 4 hours
  2. customThe solvent was removed under vacuum overnight
  3. customThe reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN
  4. customto give a yellow solid
  5. customThe solid was partitioned with NaHCO3 and DCM
  6. customThe organic was separated
  7. washwashed with Brine
  8. dry with materialdried over Na2SO4
  9. filtrationThe solid was filtered
  10. washwashed with DCM
  11. customThe solvent was removed under vacuum

Sources & evidence

ORD record
ord-04455a0a085746ebbe30481b88df47f8
Source dataset
uspto-grants-2013_06
Patent number
US08471005B2

Reaction notes

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