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

Temperature

0 °C

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%).

1. additionTo the suspension was added dropwise over 1 hour
2. stirringThe mixture was then stirred at 0° C. for 11 hours
3. customThe reaction mixture was transferred into a separatory funnel
4. extractionAfter extraction
5. customthe organic layer was separated
6. washwashed with 190 g of a 5% sodium chloride solution and 190 mL of water (twice) in this order
7. concentrationThe organic layer was concentrated under reduced pressure at 40° C
8. additionTo the residue was added 143 mL of methanol
9. stirringthe mixture was stirred
10. temperaturewhile heating to 40° C
11. stirringThirty-three minutes after initiation of stirring
12. customthe temperature of an oil bath was set at 75° C
13. custom30 minutes
14. customhad exceeded 60° C.
15. customwas set at 50° C
16. customwas decreased to 55° C.
17. addition143 mL of 2-propanol was added dropwise
18. temperatureSubsequently, the internal temperature was gradually cooled to 27.3° C.
19. stirringthe mixture was then stirred at 20° C. for 17 hours
20. filtrationThe precipitated crystals were filtered
21. washrinsed with a mixed solution of 14.3 mL of methanol and 14.3 mL of 2-propanol
22. customto yield 15.72 g of a crude target product (wet body

ORD record

ord-7eac46160f2542ada9e1b1d68461f495

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08530654B2