Note: Descriptions are shown in the official language in which they were submitted.
1046Q63
1 ~his invention relates to a novel process for
preparing 2(lH)-quinazolinone derivatives.
There has heretofore been known a process
for converting a 3,4-dihydro-2(1H)-quinazolinone
derivative to a corresponding 2(1H)-quinazolinone deri-
vative-having excellent pharmacological properties,
such as anti-inflammatory, analgesic, uricosuric and/or
- anti-viral activities, by using a heavy metal oxidizing
agent such as a manganese compound, chromium compound
or salt thereof (e.g. potassium permanganate, manganese `
dio~ide or chromium trioxide) as described in our Canadian
Patent No. 949,570.
These oxidizing agents employed in the prior
process are relatively expensive and moreover, they
may cause difficult problems of the waste treatment
and disposal in terms of environmental pollution,
especially in case of adopting large scale manufacture.
In order to improve such inconvenience of
the known process, the present inventors have studied
earnestly, and have found that 3,4-dihydro-2(1H)-
quinazolinone derivatives can readily be converted to
the corresponding 2(lH)-quinazolinone derivatives with
high purity by the action of chlorine or bromine.
This~invention provides a novel process for
preparing a compound of t-he formula,
~ ~ (I)
d~
-
1046~63
1 wherein Rl and R2 are individually hydrogen, halogen,
lower alkyl, lower alkoxy, lower alkylthio, lower
alkylsulfonyl, nitro,-trifluoromethyl, di-lower alkyl-
amino, or when taken together Rl and R2 form methylene-
5. dioxy; R3 is phenyl, halophenyl, nitrophenyl, loweralkylphenyl, lower alkoxyphenyl or pyridyl; and R is
lower alkyl, lower cycloalkyl, lo~er cycloalkyl-lower
. : alkyl, aralkyl, lower alkoxy-lower alkyl or lower
haloalkyl; or pharmaceutically acceptable acid addition
salts thereof, which comprises reacting a ~,4-dihydro-
2(1H)-quinazolinone of the formula,
R
R2 ~
~ ~ ~ (II)
1 i O
wherein R, Rl, R2 and R3 are as defined above, wi.th
chlorine or bromine in the presence or absence of an
alkali in an inert solvent.
In the compound of the above formula (I)
and elsewhere in the specification, the term "alkyl"
means both straight or branched chain saturated aliphatic
hydrocarbon radicals, and the term "lower alkyl" may
be methyl, ethyl, n-propyl, isopropyl, n-butyl or
isobutyl; the term "lower alkoxy" may be methoxy, ethoxy,
- n-propoxy, isopropoxy, n-butoxy or isobutoxy; the term
"lower cycloalkyl" may be cyclopropyl, cyclobutyl,
cyclopentyl, cyclohcxyl, cycloheptyl or cyclooctyl;
the term "aralkyl" may, for example, be benzyl,
.
~og6063
1 halobenY.yl or lower alkylbcnzyl; t~le term "halot~en"
may be fluorine, chlorine, bromine or iodine; and the
term "lower haloalkyl" may, for example, be 2-chloro-
ethyl, 2,2-dichloroethyi, 2-bromoethyl, 2-fluoroethyl,
2,2-di~luoroethyl, 2,2,2-trifluoroethyl or 2,2,3,3,3-
pentafluoropropyl.
- In carrying out the process of the present
invention, the reaction may be preferably carried out
at a temperature in the range of from room temperature
to the boiling point of the solvent employed.
. Examples of the alkali include sodium
- hydroxide, potassium hydroxide, sodium carbonate,
. . potassium carbonate, sodium bicarbonate, potassium
bicarbonate, sodium acetate, potassium acetate, sodium
methoxide, sodium ethoxide, potassium tert-butoxide
.and the like.
Suitable inert solvents include, for example,
methanol, ethanol, n-propanol, isopropanol, n-butanol,
tert-butanol, methoxyethanol, ethoxyethanol, tetra-
hydrofuran, dioxane, water, chloroform, carbon tetra-
chloride, 1,2-dichloroethane, l,l,l-trichloroethane,
benzene, toluene or a mixture thereof.
Chlorine or bromine is used in at least
equimolar amount, more specifically a few.molar
amount to the 3~4-dihydro-2(1H)-quinazolinone of
the formula (II). For the reaction, chlorine or
bromine may be also employed in the form of a
hypohalogenous acid derivative such as sodium
hypochlorite, sodium hypobromite, potassium hypobromitc
or tert-butyl hypochlorite, which can be readily
. 104f~63
1 prep~red by adding chlorine or bromine to a coolcd solu-
tion of sodium hydroxide or potassium hydroxide according
to a known procedure.
In certain conditions, 3-halosubstituted
3,4-dihydro-2(1H)-quinazolinone derivative may be obtain-
ed as an intermediate of this reaction. The intermediate
is relatively unstable and can be easily converted to
: the end product by heating or treating with an inorganic
or organic base such as alkali metal hydroxide, alkali
metal alkoxide, ammonia, triethylamine, pyridine or
the like.
The reaction may be usually effected with-
out isolation of the intermediate. In this reaction,
the compounds of the formula (I) may be substantially
prepared as a hydrochloride or hydrobromide, which
easily liberates the hydrogen halide by contacting with
an alkali.
This invention is further disclosed in the
following Examples of more preferred embodiments there-
of, which are presented for the purpose of illustrationand it is not intended to limit the scope of the inven-
tion.
~xample 1
To a solution of 3.13 g of l-cyclopropylmethyl-
4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone in
60 ml of hot methanol was added dropwise 3 g of bromine
at 60 - 65C, and the stirred mixture was gently re-
fluxed for 1 hour. The solvent was then removed under
- reduced pressure to give the hydrobromide of the
~046~63
1 product as orange residue. To the residue was added
50 ml of ammonia water and the resulting suspension
was well stirred. The colorless precipitate was
collected by filtration, washed with water and dried
to give 3.06 g of 1-cyclopropylmethyl-4-phenyl-6-
chloro-2(1H)-quinazolinone, m.p. 174 - 175C.
: Example 2
To a suspension of 3.13 g of l-cyclopropyl-
methyl-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone
and 3.2 g of sodium methoxide in 60 ml of methanol was
added dropwise a solution of 5 g of bromine in 20 ml
of methanol, and the mixture was refluxed for 6 hours
with stirring. The solvent was then removed undér
reduced pressure and the residue was triturated with
aqueous sodium bicarbonate solution. The precipitate
was collected by filtration, washed with water and
- dried to give 3.06 g of 1-cyclopropylmethyl-4-phenyl-
6-chloro-2(1H)-quinazolinone, m.p. 172 - 173C.
Example 3
To a solution of 3.13 g of l-cyclopropyl-
methyl-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone
in 20 ml of ch~oroform was added dropwise 3.8 g of
bromine, and the mixture was stirred at room temperature
for 10 hours. The solvent was then removed under re-
duced pressure and the residual orange crystals was
washed with isopropanol-isopropyl ether and dried to
give 3.94 g of 1-cyclopropylmethyl-4-phenyl-6-chloro-
- 2(1H)-quinazolinone hydrobromide, m.p. 187 - 189C.
1~)4f~Q63
1 Example 4
To a solution of 3.08 g of l-cyclopropyl-
methyl-4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quinazoli-
none in 15 ml of hot dioxane was added dropwise 2.3 g
of bromine, and the mixture was stirred at 75 - 80C
for 6 hours. After cooling, the precipitate was filter-
ed, washed with ethanol-n-hexane and dried to give
-I 3.8 g of 1-cyclopropylmethyl-4-phenyl-6-methoxy-2(lH)-
quinazolinone hydrobromide as orange crystals, which
were recrystallized from methanol-isopropanol to give -
orange needles, m.p. 196.5 - 197C. (decomp.).
~xample 5
. To a solution of 3.08 g of l-cyclopropyl-
methyl-4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quina-
zolinone in 30 ml of ethanol was added dropwise at
75C a solution of 4.8 g of bromine in 15 ml of ethanol~ -
The resulting mixture was stirred at 75C for 2 hours.
To the reaction mixture was then added portionwise ~ g
of sodium ethoxide at 60 - 70C with stirring. Then,
most of the ethanol was distilled off and 50 ml of
water was added to the residue to dissolve the in-
organic salt and crystallize the product. The result-
ing yellow precipitate was collected by filtration,
washed with water and dri~d to give 3.02 g of l-cyclo-
propylmethyl-4-phenyl-6-methoxy-2(lH)-quinazolinone,
- m.p. 114 - 115C.
,
Example 6
To ~ solution of 3.0~ g of l-cyclopropylmcthyl-
- 6 -
- ~04~63
.
1 4-phenyl-6-methoxy-3,4-dihydro-2(lH)-quinazolinone and
0.8 g of sodium hydroxide in 30 ml of hot methanol was
added gradually at 65 - 70~ 15 g of sodium hypo-
chlorite solution (12% available chlorine) prepared from
chlorine and aqueous sodium hydroxide according to a
known procedure. The stirred mixture was heated at 70C
for additional 1 hour. After cooling, 30 ml of water
was added with stirring ~o the react-ion mixture, and
the resulting mixture was cooled in ice water. The
precipitate was filtered with suction, washed with water,
and dried to give 2.9 g of 1-cyclopropylmethyl-4-phenyl-
6-methoxy-2(lH)-quinazoiinone, m.p. 114 - 115C.
,
Example 7
To a solution of 3.41 g of 1-(2,2,2-trifluoro-
ethyl)-4-phenyl-6-chloro-3,4-dihydro-2(lH)-quinazolinone
in 20 ml of hot methanol was added dropwise at about
60C a solution of 4.0 g of bromine in 5 ml of methanol.
The mixture was heated at 60C for 2 hour with stirring.
~o the reaction mixture was then added gradually 40 g
of lO~o aqueous sodium carbonate solution at 50 - 60C.
After cooling, the colorless precipitate was filtered
with suction, washed with water, and dried to give
3.35 g of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-chloro-
2(lH)-quinazolinone, m.p.-183.5 - 184.5C.
Example 8
Using a proccdurc similar to that describcd
in Examples 1 - 7, and starting with a corresponding
3,4-dihydro-2(1H)-quin~zolinone derivative, there wcre
.
-- 7 --
-
~04~Q63
1 obtained the follo.~ing compounds in excellent yields.
l-Cyclopropylmethyl-4-phenyl-2(1H)-quinaæoli-
none, m.p. 154 - 155C.
l-Cyclopropylmethyl-4-phenyl~6-bromo-2(lH)-
quinazolinone, m.p. 163 - 164C.
l-Cyclopropylmethyl-4-phenyl-7-methyl-2(11I)-
quinazolinone, m.p. 126 - 127C.
l-Cyclopropylmethyl-4-phenyl-7-methoxy-2(1H)-
quinazolinone, m.p. 169 - 170C.
101-Cyclopropylmethyl-4-phenyl-6-methylthio-
2(lH)-quinazolinone, m.p. 133 - 134C.
l-Cyclopropylmethyl-4-phenyl-6-nitro-2(lH)-
quinazolinone, m.p. 172 - 173C.
l-Cyclopropylmethyl-4-phenyl-6-trifluoromethyl-
152(lH)-quinazolinone, m.p. 166 - 167C.
l-Cyclopropylmethyl-4-phenyl-6,8-dichloro-
2(lH)-quinazolinone, m.p. 158 - 159C.
l-Cyclopropylmethyl-4-phenyl-7,8-methylene-
dioxy-2(1H)-quinazolinone, m.p. 228 - 229C.
201-Cyclopropylmethyl-4-(o-fluorophenyl)-6-
chloro-2(1H)-quinazolinone, m.p. 168 - 169C.
l-Cyclopropylmethyl-4-(p-methoxyphenyl)-6-
methoxy-2(1H)-quinazolinone, m.p. 148 - 149C.
l-Cyc-lopropylmethyl-4-(p-nitrophenyl)-6-
25methoxy-2(1H)-quinazolinone, m.p. 147 - 149C.
l-Cyclopropylmethyl-4-(o-tolyl)-6-chloro-
2(lH)-quinazolinone, m.p. 204 - 205C.
l-Cyclopropylmethyl-4-(p-tolyl)-6-methoxy-
2(1H)-quinazolinone, m.p. 136 - 1~8C.
1~)46Q63
1 1-Cyclopropylmethyl-4-(2-pyridyl)-6-chloro-
2(lH)-quinazolinone, m.p. 120 - 121C.
l-Cyclohexyl~ethyl-4-phenyl-6-nitro-2(lH)-
quinazolinone, m.p. 201 - ~202C.
1-Cyclohexyl-4-phenyl-6-nitro-2(lH)-
quinazolinone m.p. 186 - 187C.
l-Methyl-4-phenyl-6-chloro-?(lH)-quinazolinone,
,. m.p. 220 - 221C.
l-Ethyl-4-phenyl-6-chloro-2(lH)-quinazolinone,
m.p. 167 - 168C.
l~Isopropyl-4-phenyl-6-methoxy-2(1H)-quinazoli-
none, m.p. 140 - 142C.
l-Isopropyl-4-phenyl-7-methoxy-2(lH)-quina-
zolinone m.p. 134 - 136C.
1-Isopropyl-4-phenyl-7-methyl-2(lH)-quinazoli-
none, m.p. 141 - 142C.
i-Isopropyl-4-phenyl-6-dimethylamlno-2(lH)-
quinazolinone, m.p. 167 - 168C.
l-~enzyl-4-phenyl-6-nitro-2(lH)-quinazolinone,
m.p. 173 - 174C.
l-(o-Methylbenzyl)-4-phenyl-6-nitro-2(lH)-
quinazolinone, m.p. 200 - 201C.
l-Methoxymethyl-4-phenyl-6-chloro-2(lH)-quina-
zolinone, m.p. 165 - 166C.
1-(2-Ethoxyethyl)-4-(o-fluorophenyl)-6-
chloro-2(1H)-quinazolinone, m.p. 146 - 147C.
1-(2-Chloroethyl)-4-phenyl-6-nitro-2(lH)-
quinazolinone m.p. 190 - 191C.
1-(2,2-Difluorocthyl)-4-phenyl-6-nitro-2(1H)-
quinazolinone, m.p. 197 - 198C.
1046a~63
1 1-(2,2,2-Trifluoroethyl)-4-phenyl-6-methoxy-
2(lH)-quinazolinone, m.p. 157 - 158C.
1-(2,2,2-Trifluoroethyl)-4-phenyl-6-methyl-
2(1H)-quinazolinone, m.p. 178 - 179C.
1-(2,2,3,3,3-Pentafluoropropyl)-4-phenyl-6-
methyl-2(lH)-quinazolinone, m.p. 175 - 176C.
-- 10 -
.. . .
_ ~
