Reacción #307301

Ecuación de reacción

hydrochloric acid

4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-quinazoline-6-carboxylic acid methoxy methyl amide

n-BuLi hexane

2-bromo-1-propene

N,N-diisopropylamine

→

4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline

Disolventes

tetrahydrofuran

tetrahydrofuran

tetrahydrofuran

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.ADDITIONAfter completion of addition
2. 2
   Otrowas elevated to 0° C.
3. 3
   Temperaturacooled again to −78° C
4. 4
   workup.STIRRINGthe mixture was stirred at −78° C. for 2 hours
5. 5
   workup.ADDITIONafter completion of addition
6. 6
   Otrowas elevated to 0° C.
7. 7
   workup.STIRRINGby stirring for 3 hours
8. 8
   OtroAfter completion of the reaction
9. 9
   Extracciónextracted with ethyl acetate
10. 10
    SecadoThe organic layer was dried over sodium sulfate
11. 11
    Concentraciónthe filtrate was concentrated
12. 12
    Lavadothe resulting crystalline residue was washed with methylene chloride

Procedimiento

To a solution of 4.22 ml of N,N-diisopropylamine in tetrahydrofuran (25 ml) cooled to −78° C. was added dropwise 18.8 ml of 1.6 mol/L n-BuLi hexane solution. After completion of addition, a temperature was elevated to 0° C., and the mixture was stirred at 0° C. for 20 minutes, and cooled again to −78° C. 1.33 ml of 2-bromo-1-propene in tetrahydrofuran (25 ml) was added, and the mixture was stirred at −78° C. for 2 hours. To the mixture was added dropwise a solution of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-quinazoline-6-carboxylic acid methoxy methyl amide (XI-1, 2.33 g) in tetrahydrofuran (50 ml) and, after completion of addition, a temperature was elevated to 0° C., followed by stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 2 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the filtrate was concentrated, and the resulting crystalline residue was washed with methylene chloride to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (VII-4, 1.71 g) as a yellow solid.

Fuente