Note: Descriptions are shown in the official language in which they were submitted.
~`
1(~47~a~7 .
1 ~ ~his inven~ion relates to a novel process
for preparing quinazoline derivatives.
More particularly, this.invention rela-tes to
a novel process for preparing quinazo]ine derivatives
o~ the formula,
R2 ~ R~ -
' `'~
wherein Rl, R2 and R3 are independently a hydrogen
atom, a halogen atom, a tri~luoromethyl group, a nitro
group, a lower alkylsul~onyl group, a Iower alkyl
-- group, a lower alkoxy group or a lower alkylthio ~ :
15 group; and R4 is a hydrogen atom, a lower alkyl group, :.:
.
an~aralkyl group, a lower alkanoyloxyalkyl groupj a
lower alkoxyalkyl group, a polyhaloalkyl group, a
. cycloalkyl group, a cycloalkylalkyl group, a tetra- ~ ~
hydrofurfuryl group, a tetrahydropyranylmethyl group, ~:
a pyridylmethyl group, a furylmethyl group or a thien~
methyl group.
In the compounds o~ the above ~ormula
the term "halogen" includes all.halogen atoms, i.
fluorine~ chlorine, bromine and iodine, the term
25 "alkyl" meanS both straight and branched chain aliphatic ..
hydrocarbon radicals, and lower alkyl i5, ~or example, ;~
Cl_4~alkyl ~7hich includes such groups as methyl, ethyl, ~ . .
. .
n-propyl, isopropyl, n-butyl, isobutyl and tertiary-
butyl; the term "lower alkoxy" is 9 for example, C~
~0 alkoxy which includes such ~roups as methoxy, ethoxy, ~. ;
.'.
1~7967
1 n-propoxy, isopropoxy, n-butoxy and tertiary-butoxy;
the term "aralkyl" is, for example, benæyl, phenethyl,
phenylpropyl, chlorobenzyl or fluorobenzyl group; the -
- term "lower alkylsulfonyl~ i3, f~r example, Cl_4 alkyl-
5 sulfonyl which includes such groups as methylsulfonyl, : :~
ethylsulfonyl, propylsulfonyl, etc.; the term "iower
alkanoyloxyalkyl" is, for example, (C2_3 alkanoyloxy)-
Cl_4 alkyl in which the C2_3 alkànoyloxy moiety in-
cludes such groups as acetoxy and propionyloxy, and
10 the Cl_4 alkyl moiety is as defined above; the term ;
"lower alkoxyalkyl" is, ~or example, (Cl_~ alkoxy)-
al_4 alkyl in which both moieties are as de~ined
- above; the term "polyhaloalkyl" is, for example, a
trichloromethyl, trifluoromethyl, trichloroethyl, :
trifluoroethyl or pentafluoropropyl group; the term
"cycloalkyl" i~, for examnle, C~ 6 cycloalkyl which
includes such groups as cyclopropylj cyclobutyl, cyclo-
pentyl, cyclohexyl, methylcyclopropyl, dimethylcyclo- .
propyl, etc.; the term "cycloalkylalkyl" is, for
20 example, (C3_6 cycloalkyl)-Cl_~ alkyl in which both . .
moieties are as defined above; and the term "alkyl-
thio" is, ~or example, Cl_4 alkylthio which includes
~uch ~roups as methylthio, ethylthio, propylthio and :~
butylthio. ~: :
~here are some well-known methods for pre- ~ .
paring the quinazoline derivatives represented by the
formula [I), and one of the most common methods among
them is disclosed in Japanese Patent Publication No. ;~
48396/1972 in ~hich the quinazoline derivatives ~
~0 are obtained by reactin~ a dihydroquinazolinone derivative
~47967
1 of the formula [II~,
R4
Rl ~ NH ; (II)
5R2 ~ R3
.
wherein Rl, ~2, R3 and R4 are as defined above, with
an oxidizing agent such as potassiwn permangana~e.
The above-mentioned method is, however,
relatively troublesome in the operation after the
reaction and further includes treatment of the oxidiz-
ing agent as waste matter.
,
The inventors have studled to overcome the
disadvantages of those well-known methods, and found ;~
.
15 ~ that the dihydroquinazolinone derivatives of ~ormula l;
[I~ can be c~nv~rt,e~ t~ the ~uina~ol~none derivàtives
of formula [I3 in a high yield by the oxidation reaotion
which is caused when the dihydroqulnazolinone deriva~
tives are irradiated with light. In this method,
oxidizing agents such as potassium permanganate are
not necessary and operation after the reactian is very
easy.
Thus, an object of the present inventio~i
is to provide quina201ine derivatives o~ the formula
tI), which have excellent pharmacological properties.
.
Anothèr object of the present invention;is to provide
a novel process ~or producing such useful qui.nazoline
` derivatives. Other objects and~merits of the present
invention`will be apparent from the following descrip~
tion.
', ' ' ' .; ''''
- 3 ~
'~,. .
~ 7967
.
1 The method of the present invention is carried
out by exposin~ the dihydroquinazolinone ~erivatives
of the formula (II) to light.
As a light source, sun~i~ht, low-pressure
and high-pressure mercury lamps may be used.
The present reaction can advanta~eously be ~-~
carried out in the presence of a solvent. The solvent
includes alcohols such as methanol, ethanol an~ iso-
propanol, aromatic hydrocarbons such as benzene, ~ ~
10 toluene and xylene, chloroform, acetone, dioxane, ~ ~ '
tetrahydrofuran, dimethylsulfoxide or mixtures there- ~; ;
of. ~he reaction is generally carried out at room
temperature, but if necessary it may be carried out ~ ;~
under cooling or at the reflux -temperature o~ the
solvent used. The reaction easily proceeds by mere
cx~osure of the reaction solution to li~ht, but sol~e~
times it is promoted remarkably by passin~ air or
.. . .
oxygen gas into the solution. ~ `
~he quinazolinone derivatives of the formula ~
20 ~I~ obtained by the method of the present invention ` `
, . ~ .
are very use~ul as an anti-inflammatory agent, anti- ~`
viral agent, uricosuric agent and intermediates for ~ ;
other use~ul anti-inflammatory a~ents.
,
According to the process o~ the present
invention, thç following quinazoline derivat1ves, for
example, can be obtained.
4-Phenyl-2(1H)-quinazolinone, m.p. 251 - 252C ~
4-Phenyl-6-chloro-2(lH)-quinazo~inone, m.p. ; ;
> 3~0C
4-Phenyl-6-fluoro-2(1H)-quinazolinone,
. .
! ~
- : ~
1~47~67
1 m.p. ~ 300C
4-Phenyl 6-methyl-2(1H)-quinazolinone, m.p.
> 290~ :
4-Phenyl-6-methoxy-2(lH~-quinazolinone,
m.p. 287C
4-Phenyl-6-nitro-2(lH)-quinazolinone, m.p.
> 300C
4~Phenyl-6-trlfluoromethyl-2(1H)-quinazolinone,
m.p. 299C
,
1 Methyl-4-phenyl-6,7-dimethoxy-2(1H)- ~ `
quinazolinone, m.p. 197 - 198C . .
4-(o-Chlorophenyl)-6-nltro-2(lH)-quinazolinone,
m.p. > 300C
4-(o-Fluorophenyl)-6-chloro-2(~I)-quinazolinone, ~. ~
m.p. ~ 300C ~ ~::;`3.
l-Methyl-4-phenyl-2(1~)-quina301inone, m.p.
142 - 143C ~ ~
l-Methyl-4-phenyl-6-chloro-2(IE)-quinazolinone, ..
m.p. ~20 - 221C
1-Methyl-4-phenyl-6-iodo-2(1H)-quinazolinone,
m.p. 247 - 2~8C
l-Methyl-4-phenyl-6-methoxy-2(lH)-quinazolinone,
m.p. 166C :
l-Methyl-4-phenyl-6-nitro-2(lH)-quinazolinone,
m.p. 259 - 264C :
.
1,6-Dimethyl-4-phenyl-2(IH3-quinazolinone, ~ ~ :
o
.p. 150 C : .
l-Ethyl-4-phenyl.-6-nitro-2(1H)-quinazolinone,
m.p. 176 - 178C .
1-Ethyl-4-(o-tolyl)-G-chloro-2(iII)-quin~æolinone,
r~ , ' '
. - ~. .... .
~ :
~1479~7
1 m.p. 138 - 139C
l-Isopropyl-~-phenyl-7-methyl-2(1H)~quinazolinone,
m.p. 140C
l-Isopropyl-4-phenyl-7~methoxy-2(lH)
quinazolinone, m.p. 1~7 - 1~8C
l-Isopropyl-4-phenyl-6-nitro-2(1H)-quinaæolinone,
m.p. 194 - 195C
l-Isobutyl-4-phenyl-6-chloro-2(lH)-quinazolinone,
m.p. 138 - 1~9C `
1-(2,2,2-Trifluoroethyl)-4-phenyl-6-chloro- ~
2(1H)-quinazolinone, m.p. 185 - 186C ~ "'
~ 1-(2,2,3,3,3-Pentafluoropropyl)-4-phenyl-6- ~"
;~ methyl-2tlH)-quinazolinone, m.p. 175.5 - 176.5C
~ l-Benzyl-4-phenyl-6-nitro-2(1H)-quinazolinone,
; ~ 15 m.p. 173 - 174C
l-~oetoxyethyl-~-phanyl-G-chloro-2(1H)-
quinazolinone, m.p. 139 - 140C i ~
~ l-Acetoxyethyl-4-phenyl-6-nitro-2(1H)- ; `~`
;~ quinazolinone, m.p. 158 - 159C ` ;~
1-(2-Ethoxyethyl)-4-phenyl-6-nitro-2(~I)-
quinazolinone, m.p. 128 - 129C
l-Cyclohexyl-4-phenyl-6-nitro-2(1H)-quinazolinone,
m.p. 186 - 187C
l-Cyclopropylmethyl-4-phenyl-6-chloro-2(1H)-
quinazolinone, m~p. 174 - 175C
,
l-Cyclopropylmethyl-4-phenyl-6-nitro-2(lH)-
quinazolinone, m.p. 172 - 173C
Cyclopropylmethyl-4-phenyl-6-trifluoro-
methyl-2(1~)-quinazolinone, m.p. 166 - 167C
1-Cyclopropylmethyl~4-phenyl-6-methyl-
,
- ~ G - -
~',
1~)47967
1 sul~onyl-2 ( lH )-quinazolinone, m.p. 186 - 187C
l-Cyclopropylmethyl-4-phenyl-6-bromo 2(~I)-
quinazolinone, m.p. 16~ - 164C `~
l-Cyclopropylmethyl~4-phenyl-6,~dichloro-
2(~I)-quinazolinone, m.p. 158 - 159C ~`
l-Cyclopropylmethyl-4-phenyl-6~methoxy-
2(1H)-quinazolinone, m.p. 115 ~ 116C
l-Cyclopropylmethyl-4-(o-fluorophenyl)-6
chloro-2tlH)-quinazolinone, m.p. 171 - 172C
1-Cyclopropylmethyl-4-phenyl-6-methylthio-
2(1H)-quinazolinone, m.p. 159 - 160C r~
l-Cyclohexylethyl-4-phenyl-6-chloro-2(lH)-
quinazolinone, m.p. 115 - 116C
l-Cyclopropylmethyl-4-(o-chlorophenyl)-6-
nitro-2(1H)-quinazolinone, m.p. 165 - 166C
l-Cyolop~nty:Lmethyl-4-phenyl-6-nitro-2(1H)- ,:
quinazolinone, m.p. 200 - 201C
l-Cyclohexylmethyl-4-phenyl-6-nitro-2(1H)-
quinazolinone, m.p. 201 - 202C
1-Tetrahydro~ur~uryl-4-phenyl-6-nitro-2(1H)-
quinazolinone, m.p. lq9 - 150C
~ 2-Tetrahydropyràr~ylmethyl)-4-phenyl-6-
nitro-2~I)-quinazolinone, m.p. 185 - 186C
1-(2-Pyridylmcth~1)-4-phenyl-6-nitro-2(1H)-
quinazolinone, m.p. 175 - 176C ~ ;
1-(2-Furylmethyl)-4-phenyl-6-nitro-2(1H~
quinaæolinon~, m.p. 190 - 190.5C ~ ~
1-(2-Thienylmethyl)-4-phenyl-6-nitro-2(~I)- ~ ~;
quinazolinone, m.p. 219 - 220C
The lnvent.on is lllustrated more particularly
- 7 -
.
1l~ 47 9 67 !~1 by way of the followin~ examples but, as will bc more
apparent, is not limited to the details thereof.
Example 1
In 10 ml of dimethylsulfoxide was dissolved
1.0 g of 1-cyclopropylmethyl-4-phenyl-6-chloro-~,4-
dihydro-2(1H)-quinazolinone and the resuIting solution -~`
was stirred for 50 hours while exposing the reaction
solution to the light of a low-pressure mercury lamp
used as a light source. After the reaction solution
was allowed -to stand, precipitated crystals were ;
filtered, washed with isopropyl alcohol and dried to
give 0.58 g of 1-cyclopropylmethyl-4-phenyl-6-chloro- ~;
2(1~)-quinazolinone, m.p. 171 - 174C.
The filtrate was diluted w1th 30 ml of water
and extracted with chloroform. The extract was dried ;
over anhydrous sodium slllfate and evaporated under ~ ;
reduced pressure. The residue obtained was recry~tallized
from isopropyl alcohol -to obtain 0.29 g of a second crop
of crystals.
,
Example 2 ~ `
In 20 ml of acetone was dissolved 0.5 g of
l-cyclopropylmethyl-4-phenyl-6-chloro-3,4-dihydro-
2(1H)-quinaæolinone and the resulting solution was
exposed to the light of a low-pressure mercury lamp
used as a light source for 57 hours. ~he reaction
solution was concentrated under reduced pressure and
the residue obtained was recrystallized from ~ ml
of isopropyl alcohol to obtain l-cyclopropylmethyl-
' ~
. ,. . - : ~ ~
~ -: , - . . . . .
1~7967
- , ' . ,': ::
1 4-phenyl-6-chloro-2(1II)-quin~zolinone, m.p. 170 -
172C. -
Exsmple 3 ` ~ . r `;
In 60 ml of acetone was dissolv~d 1.0 g o~
l-cyclopropylmethyl-4-phenyl-6-chloro-3,4-dihydro-
2(1H)-quinazolinone and the resulting solution was
exposed to the light of a low-pressure mercury lamp ;
used as a light source for 28 hours while passing air `
through the reaction solution with stirring. After
removing the solvent under reduced pressure from the
reaction solution, the residue obtained was recrystal-
lized from 4 ml o~ isopropyl alcohoI to obtain 0.68 g
of l-cyclopropylmethyl-4-phenyl-6-chloro-2(1M)- ~.
quinazolinone, m.p. 173 - 176C.
.... .... .
Example 4
The reaction solution obtained by the same
procedure as Example 1 was exposed to sunlight for 50
hours in place of the light of a low-pressure meroury
lamp. Operation a~ter the reaction was carried out
according to Example 1 to obtain l-cyclopropylmethyl- "
4-phenyl-6-chloro-2(1H)-quinazolinone, m.p. 171
173C.
Example 5 ;~
The prooess of Exampls 1 was repssted but
l-cyclopropylmethyl-4-phenyl-6-methoxy-3,4-dihydro- .
2(1H)-quina~olinone was used in place of l~cyclo-
prop~vImethyl-4~phenyl-6-chloro-3,4~dihydro-2(1H)- ~ ;~
:
~ . . .
s 9 `- s :
.~ ~
~47~;7 : ~
:
1 quinazoli~lone. Thus, l-cyclopropylmethyl-4-phenyl-6-
methoxy-2-(IH)-quinazolinone9 m.p. 115 - 116C, was
obtained. ~ .
.
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