Dimethyl-p-toluidine → 5-chloro-9-fluoro-4H-1,3,3a,6-tetraaza-benzo[e]azulene

温度

65 °C

To a suspension of 9-fluoro-6H-1,3,3a,6-tetraaza-benzo[e]azulen-5-one (4.40 g, 20 mmol) in chloroform (250 mL) were added N,N-dimethyl-p-toluidine (12 mL) and phosphorus oxychloride (5.7 mL, 60 mmol), and the resulting mixture was stirred for 20 h at 65° C. Further N,N-dimethyl-p-toluidine (1.2 mL) and phosphorus oxychloride (0.6 mL, 6.3 mmol) were added, and stirring was continued for 1 h at 65° C. After cooling to ambient temperature the reaction mixture was poured onto aqueous sodium hydrogencarbonate (sat., 1 L), and the resulting mixture was stirred vigorously for 45 min. The layers were separated and the aqueous layers was extracted with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated. Purification by chromatography (SiO2, hexane:ethyl acetate=100:0 to 40:60) and recrystallisation from diisopropyl ether afforded 5-chloro-9-fluoro-4H-1,3,3a,6-tetraaza-benzo[e]azulene (3.85 g) as a brown solid which was dissolved in DMF (65 mL) and cooled to −55° C. 1-Chloro-3-isocyanomethyl-benzene (4.00 g, 26.4 mmol), and a solution of potassium tert-butylate (3.15 g, 27.3 mmol) in DMF (15 mL) were added at −50° C. to −55° C. The reaction mixture was stirred for 1 h at −40° C. to −50° C. before allowing to warm to ambient temperature. Acetic acid (1.1 mL) was added, and the mixture was poured onto aqueous sodium hydrogencarbonate (sat., 2 L) and extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium hydrogencarbonate (sat.) and dried over sodium sulfate. Purification by chromatography (SiO2, dichloromethane:ethanol=100:0 to 98.5:1.5) afforded the title compound (1.25 g, 18%) as a white crystalline solid. MS: m/e=352.2 [M+H]+.

1. stirringstirring
2. waitwas continued for 1 h at 65° C
3. temperatureAfter cooling to ambient temperature the reaction mixture
4. stirringthe resulting mixture was stirred vigorously for 45 min
5. customThe layers were separated
6. extractionthe aqueous layers was extracted with chloroform
7. dry with materialThe combined organic layers were dried over magnesium sulfate
8. concentrationconcentrated
9. customPurification
10. customby chromatography (SiO2, hexane:ethyl acetate=100:0 to 40:60) and recrystallisation from diisopropyl ether

ORDレコード

ord-92ca05c690ca45bb9f11fac3aa9322e4

出典データセット

uspto-grants-2008_10

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07432256B2