Dichloromethane → N-{2-[2-(2-Methoxy-4-piperidin-4-yl-phenylamino)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide

HRID 1262338Notes

Reaction equation

HRID 1262338 reaction equation
O[C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:23])[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.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.C(OC([N:61]1[CH2:66][CH2:65][CH:64]([C:67]2[CH:72]=[CH:71][C:70]([NH2:73])=[C:69]([O:74][CH3:75])[CH:68]=2)[CH2:63][CH2:62]1)=O)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>CN(C)C=O>[CH3:75][O:74][C:69]1[CH:68]=[C:67]([CH:64]2[CH2:63][CH2:62][NH:61][CH2:66][CH2:65]2)[CH:72]=[CH:71][C:70]=1[NH:73][C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:23])[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

Participants

8

Reactant 6

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 142176Phenyl triflimideHCID 57416157Tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylateHCID 178422626HCID 178422626, compound

Product 1

HCID 66711462N-{2-[2-(2-Methoxy-4-piperidin-4-yl-phenylamino)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Into a 8-dram vial, N-[2-(2-Hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (210 mg, 0.63 mmol), N,N-Dimethylformamide (2.33 mL), N,N-Diisopropylethylamine (0.247 mL, 1.42 mmol), and N-Phenylbis(trifluoromethanesulphonimide) (0.276 g, 0.773 mmol) were added. The reaction was stirred at room temperature for 30 minutes. 4-(4-Amino-3-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.434 g, 1.42 mmol) was then added. The reaction mixture was heated at 120° C. for 4 hours. The solvent was removed under vacuum overnight. The resulting solid was treated with Methylene chloride (3.50 mL, 54.6 mmol) and Trifluoroacetic Acid (1.17 mL, 15.1 mmol) and stirred at room temperature overnight. The solvent was removed under vacuum. 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 N-{2-[2-(2-Methoxy-4-piperidin-4-yl-phenylamino)-5-methyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide a yellow solid (0.135 g, 41%). LCMS (E/I+) 521.13 (M+H). NMR 1H (DMSO-d6)-8.96 (s, 1H), 8.47-8.62 (m, 1H), 8.15-8.33 (m, 1H), 7.88-8.00 (m, 2H), 7.46-7.68 (m, 4H), 6.84 (s , 1H), 6.82 (s, 1H), 6.66 (d, 1H, J=8.11 Hz), 3.86 (s, 3H), 3.39 (d, 2H, J=12.75), 3.07 (s, 3H), 2.90-3.04 (m, 2H), 2.88 (s, 3H), 2.72-2.84 (m, 1H), 1.95 (d, 2H, J=13.48 Hz), 1.68-1.84 (m, 2H).

Workup

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

Sources & evidence

ORD record
ord-9fb5aa1dac1c41b7b4c37b9d336014d4
Source dataset
uspto-grants-2013_06
Patent number
US08471005B2

Reaction notes

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