Process for production of 4(3H)-quinazolinone derivative
The present invention provides a process for producing a 4(3H)-quinazolinone derivative, which is useful as a medicinal substance, with better efficiency in an industrial scale. The process comprises the steps of reacting 4-hydroxy-N-tert-butoxycarbonylpiperidine with 4-fluoro-1-nitrobenzene in the presence of sodium hydride, reacting the resulting product with cyclobutanone, reducing the resulting product to give 4-(1-cyclobutyl-4-piperidinyl)oxyaniline, and reacting this compound with 2-methyl-5-trifluoromethyl-4H-3,1-benzoxazin-4-one to give 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone.
1 - 7 . (canceled)
8 . A process for producing 3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]-phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone, which comprises reacting 2-methyl-5-trifluoromethyl-4H-3,1-benzoxazin-4-one with 4-(1-cyclobutyl-4-piperidinyl)oxyaniline or its acid-addition salt in the presence of an acid.
9 . The process of claim 8 wherein the acid is acetic acid.
10 . The process of claim 9 which further comprises the addition of sodium acetate.
11 . The process of claim 8 wherein 4-(1-cyclobutyl-4-piperidinyl)oxyaniline or its acid-addition salt is prepared by:
(1) reacting 4-hydroxy-N-tert-butoxycarbonylpiperidine with 4-fluoro-1-nitrobenzene in the presence of a base to produce 4-(4-piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene,
(2) deprotecting 4-(4-piperidinyl)oxy-N-tert-butoxycarbonyl-1-nitrobenzene to produce 4-(4-piperidinyl)oxy-1-nitrobenzene,
(3) reacting 4-(4-piperidinyl)oxy-1-nitrobenzene with cyclobutanone in an inert solvent to produce 4-(1-cyclobutyl-4-piperidinyl)oxy-1-nitrobenzene, and
(4) reducing 4-(1-cyclobutyl-4-piperidinyl)oxy-1-nitrobenzene in an inert solvent.
12 . The process of claim 8 wherein 4-(1-cyclobutyl-4-piperidinyl)oxyaniline or its acid-addition salt is prepared by:
(1) reacting 4-hydroxypiperidine with cyclobutanone in an inert solvent to produce 1-cyclobutyl-4-hydroxypiperidine,
(2) reacting 1-cyclobutyl-4-hydroxypiperidine with 4-fluoro-1-nitrobenzene in the presence of a base to produce 1-cyclobutyl-4-(4-nitro-phenoxy)-piperidine, and
(3) reducing 1-cyclobutyl-4-(4-nitro-phenoxy)-piperidine in an inert solvent.
13 . The process of claim 8 wherein 2-methyl-5-trifluoromethyl-4H-3,1-benzoxazin-4-one is prepared by reacting 2-amino-6-trifluoromethylbenzoic acid or its salt with acetic anhydride in an inert solvent.
14 . The process of claim 8 wherein the acid-addition salt of 4-(1-cyclobutyl-4-piperidinyl)oxyaniline is 4-(1-cyclobutyl-4-piperidinyl)oxyaniline p-toluenesulfonate.