Water → N-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

Temperature

50 °C

A mixture of potassium tert-butoxide (5.42 g) and THF (30 ml) was added to a solution of 4-hydroxytetrahydropyran (1.53 ml) in THF (30 ml) and the resultant mixture was stirred for 20 minutes. A slurry of 4-(6-chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline hydrochloride salt (6 g) in THF (30 ml) was added and the resultant mixture was heated to reflux for 1.75 hours. A second portion (1.81 g) of potassium tert-butoxide was added and the mixture was heated to reflux for an additional 2 hours. A second portion (0.15 ml) of 4-hydroxytetrahydropyran and a third portion (0.45 g) of potassium tert-butoxide were added and the mixture was heated to reflux for 0.5 hours. A fourth portion (0.9 g) of potassium tert-butoxide was added and the mixture was heated to reflux for a further 20 minutes. The resultant reaction mixture was allowed to cool to 50° C. and brine (60 ml) and water (30 ml) were added in turn. The layers were separated and the aqueous solution was extracted in turn with THF (30 ml) and with isopropyl acetate (30 ml). The organic extracts were combined and washed with brine (30 ml). The organic solution was evaporated. The residual solid was stirred for 1 hour under a mixture of methyl tert-butyl ether (24 ml) and isohexane (12 ml). The solid was isolated, washed with a 1:1 mixture of methyl tert-butyl ether and isohexane and dried in vacuo overnight at 40° C. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (5.02 g, 93% HPLC purity using Method A, retention time 4.61 minutes). A portion (3 g) of the material so obtained was dissolved in hot ethyl acetate (54 ml). The hot solution was filtered. The filtrate was allowed to cool to ambient temperature and was stirred for 3 hours. The resultant solid was isolated by filtration, and dried in vacuo at ambient temperature. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (1.61 g, 99.2% HPLC purity using Method A, retention time 4.51 minutes); NMR Spectrum: (DMSOd6) 1.9-2.0 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 6.95 (d, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 7.3 (d, 1H), 8.4 (s, 1H), 9.3 (s, 1H).

1. temperatureto reflux for 1.75 hours
2. temperaturethe mixture was heated
3. temperatureto reflux for an additional 2 hours
4. temperaturethe mixture was heated
5. temperatureto reflux for 0.5 hours
6. temperaturethe mixture was heated
7. temperatureto reflux for a further 20 minutes
8. customThe resultant reaction mixture
9. customThe layers were separated
10. extractionthe aqueous solution was extracted in turn with THF (30 ml) and with isopropyl acetate (30 ml)
11. washwashed with brine (30 ml)
12. customThe organic solution was evaporated
13. customThe solid was isolated
14. washwashed with a 1:1 mixture of methyl tert-butyl ether and isohexane
15. customdried in vacuo overnight at 40° C

ORD record

ord-19e5e390b63d488cb66b8a9aa16b0d40

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08304417B2