Reacción #69775

Ecuación de reacción

sodium hydrogencarbonate

terephthalic acid monomethyl ester chloride diisopropylethylamine

terephthalic acid monomethyl ester chloride

[4-(3-aminophenyl)-6,7-dimethoxyquinazolin-2-yl]methylamine

→

crystals

Rendimiento 93.9%

methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid

Rendimiento 93.9%

Disolventes

ethyl acetate

ethyl acetate

tetrahydrofuran

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.ADDITIONTo the suspension was added dropwise over 1 hour
2. 2
   workup.STIRRINGThe mixture was then stirred at 0° C. for 11 hours
3. 3
   OtroThe reaction mixture was transferred into a separatory funnel
4. 4
   ExtracciónAfter extraction
5. 5
   Otrothe organic layer was separated
6. 6
   Lavadowashed with 190 g of a 5% sodium chloride solution and 190 mL of water (twice) in this order
7. 7
   ConcentraciónThe organic layer was concentrated under reduced pressure at 40° C
8. 8
   workup.ADDITIONTo the residue was added 143 mL of methanol
9. 9
   workup.STIRRINGthe mixture was stirred
10. 10
    Temperaturawhile heating to 40° C
11. 11
    workup.STIRRINGThirty-three minutes after initiation of stirring
12. 12
    Otrothe temperature of an oil bath was set at 75° C
13. 13
    Otro30 minutes
14. 14
    Otrohad exceeded 60° C.
15. 15
    Otrowas set at 50° C
16. 16
    Otrowas decreased to 55° C.
17. 17
    workup.ADDITION143 mL of 2-propanol was added dropwise
18. 18
    TemperaturaSubsequently, the internal temperature was gradually cooled to 27.3° C.
19. 19
    workup.STIRRINGthe mixture was then stirred at 20° C. for 17 hours
20. 20
    FiltraciónThe precipitated crystals were filtered
21. 21
    Lavadorinsed with a mixed solution of 14.3 mL of methanol and 14.3 mL of 2-propanol
22. 22
    Otroto yield 15.72 g of a crude target product (wet body

Procedimiento

Subsequently, a suspension of 9.50 g (30.00 mmol) of [4-(3-aminophenyl)-6,7-dimethoxyquinazolin-2-yl]methylamine in 380 mL of tetrahydrofuran was stirred, while it was cooled at 0° C. To the suspension was added dropwise over 1 hour, 80.71 g of the above mixed solution consisting of [terephthalic acid monomethyl ester chloride/diisopropylethylamine] (the content of terephthalic acid monomethyl ester chloride: 6.55 g; 33.00 mmol). The mixture was then stirred at 0° C. for 11 hours. Thereafter, 190 mL of ethyl acetate was added to the reaction mixture at 0° C., and 380 g of a 5% sodium hydrogencarbonate solution was then added dropwise. The reaction mixture was transferred into a separatory funnel, and 190 mL of ethyl acetate was added. After extraction, the organic layer was separated, and washed with 190 g of a 5% sodium chloride solution and 190 mL of water (twice) in this order. The organic layer was concentrated under reduced pressure at 40° C. To the residue was added 143 mL of methanol, and the mixture was stirred while heating to 40° C. Thirty-three minutes after initiation of stirring, the temperature of an oil bath was set at 75° C. Thereafter, 30 minutes after the internal temperature had exceeded 60° C., the oil bath was set at 50° C. When the internal temperature was decreased to 55° C., 143 mL of 2-propanol was added dropwise. Subsequently, the internal temperature was gradually cooled to 27.3° C., and the mixture was then stirred at 20° C. for 17 hours. The precipitated crystals were filtered, and rinsed with a mixed solution of 14.3 mL of methanol and 14.3 mL of 2-propanol to yield 15.72 g of a crude target product (wet body; the content of the target compound: 13.31 g) as pale yellow crystals (yield: 93.9%).

Fuente