Hydrogen Peroxide → 2-Chloro-4-morpholino-6-fluoro-7-bromo-quinazoline

Participants

Reaction Steps

Scheme Ib provides the preparation of the compounds of the invention where R1 is F and R2 is morpholine following the synthetic route described in Scheme I. Specifically 3-bromo-4-fluoro-aniline 1b is reacted with chloral hydrate and hydroxylamine hydrochloride at about 90° C. to provide N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide 2b. In one embodiment, 3-bromo-4-fluoro-aniline 1b is reacted with about 1 equivalent of chloral hydrate and about 3 equivalents of NH2OH.HCl in the presence of Na2SO4 and hydrochloric acid. Addition of N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide 2b to sulfuric acid at about 50° C., followed by raising the temperature of the solution to about 90° C. provided 5-fluoro-6-bromo-1H-indolin-2,3-dione 3b. Conversion of 5-fluoro-6-bromo-1H-indolin-2,3-dione 3b to 3-fluoro-4-bromo-6-amino-benzoic acid 4b was performed using hydrogen peroxide. In one embodiment, the reaction is performed at about 0° C. In another embodiment, 3-fluoro-4-bromo-6-amino-benzoic acid 4b is prepared using about 1.5 volumes of H2O2 at about 0° C. in the presence of NaOH, such as 2N NaOH. Conversion of 3-fluoro-4-bromo-6-amino-benzoic acid 4b to 6-fluoro-7-bromo-quinazolin-2,4-dione 5b may be performed using urea at about 200° C. In one embodiment, 3-fluoro-4-bromo-6-amino-benzoic acid 4b is converted to 6-fluoro-7-bromo-quinazolin-2,4-dione 5b using an excess, i.e., about 10 equivalents, of urea. Replacement of the oxo groups of 6-fluoro-7-bromo-quinazolin-2,4-dione 5b with chlorine groups may be performed using a chlorinating agent such as POCl3. In one embodiment, the reaction is performed in the presence of DIPEA at about 130° C. The resultant 2,4-dichloro-6-fluoro-7-bromo-quinazoline 6b is then reacted with morpholine at about 0° C. to provide 2-chloro-4-morpholino-6-fluoro-7-bromo-quinazoline 7c. R3-substitution of 2-chloro-4-morpholino-6-fluoro-7-bromo-quinazoline 7c may be performed using R3B(OR)2. In one embodiment, R3-substitution is performed in the presence of a catalytic amount of PdCl2(PPh3)2. In another embodiment, the reaction is performed at about 90-95° C. in the presence of Na2CO3, ethanol and H2O. The 2-position of compound 8c is then substituted with a 2-(tert-butoxycarbonyl)amino)pyrimidine using (2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid to provide compound 9c. In one embodiment, the reaction is performed in the presence of a catalytic amount of PdCl2(PPh3)2. In another embodiment, the reaction is also performed in the presence of about 2 equivalents of Cs2CO3 and DMF at about 75° C. to provide compound 9c. Finally, deprotection of compound 9c is performed using TFA or HCl, such as 4N HCl in 1,4-dioxane at about 0° C. to room temperature.

Provenance & Evidence