Reacción #660601

Ecuación de reacción

4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine

1,4-dioxane

1-((S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid

N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate

N,N-diisopropylethylamine

→

1-((S)-2,3-Dihydroxypropyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide

Disolventes

EtOAc

hydrogen chloride

N,N-dimethylformamide

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.STIRRINGstirred overnight
2. 2
   Lavadowashed with 1N Na2CO3, water and brine
3. 3
   Secadothen dried over MgSO4
4. 4
   Concentraciónconcentrated
5. 5
   workup.ADDITIONMeOH was added (1 mL)
6. 6
   Otroa solid separated
7. 7
   workup.STIRRINGstirred for 2 h
8. 8
   Concentraciónconcentrated
9. 9
   workup.ADDITIONTo this product was added MeOH
10. 10
    Otrothe precipitate collected
11. 11
    Otroto give a white solid

Procedimiento

1-((S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.0446 g, 0.122 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.0466 g, 0.122 mmol) in N,N-dimethylformamide (2.00 mL) was added N,N-diisopropylethylamine (0.0388 mL, 0.223 mmol) and stirred at rt for 15 min. 4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (0.035 g, 0.11 mmol) was added and stirred overnight. The solution was diluted with EtOAc, washed with 1N Na2CO3, water and brine then dried over MgSO4 and concentrated. MeOH was added (1 mL) and a solid separated. This material was dissolved in 4 M of hydrogen chloride in 1,4-dioxane (2 mL, 8 mmol), stirred for 2 h and then concentrated. To this product was added MeOH and the precipitate collected to give a white solid. mp=165-6° C.; LCMS m/z=621 (M+1); 1H NMR (DMSO) δ: 11.0 (s, 1H), 8.72 (s, 1H), 8.48 9 d, 1H, J=5.4 Hz), 8.01, 7.98 (dd, 1H, J=2.4, 13.5 Hz), 7.52-7.55 (j, 1H), 7.34-7.46 (m, 6H), 6.47 (d, 1H, J=5.4 Hz), 6.17 (d, 1H, J=5 Hz), 4.78 (t, 1H, J=5.7 Hz), 4.22 (d, 1H, J=10 Hz), 3.94 (d, 6H), 3.75-3.78 (m, 2H), 3.3 (m, 2H).

Fuente