Note: Descriptions are shown in the official language in which they were submitted.
~$1~ 7
Preparation of Quinazoline Derivatives
This invention relates to a process for the prep-
aration of 4-aryl-quinazoline-2(lH)-ones, in particular a
compound of formula I,
R4 IRl
R3 R~ I
in which Rl signifies a (Cl-C8) hydrocarbon
radical optionally mono-, di or tri-
substituted with fluoro, chloro or bromo,
R2 signifies monocyclic aryl, and
R3 and R4, which may be the same or different, each
signifies a hydrogen atom, a (Cl-C
alkyl or alkoxy radical, or fluorine,
chlorine, bromine or trifluoromethyl,
or R3 and R4 together signify 6,7-
methylenedioxy,
by dehydrogenating a corresponding 4-aryl-5,6,7,8-tetra-
hydro-2(1H)-quinazolinone, in particular a compound of
X - 1 -
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formula II, R
R4
~ N`C = O II
R3
R2
in which Rl, R2, R3 and R4 are as defined above,
with sulphur, in an inert organic solvent, characterised
in that the dehydrogenation is effected in the presence of
an inorganic metal compound which is an oxide, hydroxide
or salt of a metal, other than magnesium, aluminium,
beryllium or an alkali metal, and which forms a metar-
sulphide under the reaction conditions.
The process of the invention is suitably effec-
ted at temperatures in the range of from 125 to 250C,
preferably 130 to 200C and more preferably in the range
135 to 200C.
The reaction is carried out in an organic solvent
inert under the reactive conditions. Preferred solvents
include ethylene glycol, propylene glycol, ethoxyethoxy-
ethanol, dioxane, toluene, xylene and ~-cymeme. It is
generally preferred to employ a solvent boiling at the
desired reaction temperature in order to utilise reflux
conditions, e.y. ~-cymene under the more preferred
temperature conditions.
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The mol ratio of sulphur to the quinazolinone
starting material may vary fairly widely but is suitably
at least 1.7 : 1. The upper limit is not particularly
critical, but it is unnecessary and inefficient to employ
the sulphur in an amount exceeding a mol ratio of 6 : 1.
More suitably, the mol ratio will be in the range of from
1.9 : l to 4 : 1, preferably in the range of 2 : 1 to 3 : 1.
The metal compound to be employed is, as indicated,
one which forms a sulphide under the reaction conditions. In
addition to the alkali metals and magnesium and aluminium,
as a practical matter the rare earth metals and metals with
an atomic number of 84 or greater are not preferred. Pref-
erred metals include calcium, titanium, zirconium, chro~ium,
lead, molyb~enum, mangane~e, iron, tin, cobalt, nickel,
palladium, copper, silver, zinc, cadmium, mercury, antimony
and bismuth, more preferably calcium, iron or zinc. The
metal compound may be a salt, for example a salt of a strong
acid, such as a halide, e.g. chloride, sulphate or nitrate,
but is preferably an oxide or hydroxide, pa:rticularly an
oxide. The preferred metal compounds include calcium oxide,
~inc oxide and, in particular,ferric oxide. A number of the
metal compounds which may be used, e.g. calcium chloride,
react with hydrogen sulphide to form an acidic medium and
the resulting metal sulphides tend to be unstable or soluble
in such medium. In such cases, it is preferred to include
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in the reaction mixture a hydroxide base, e.g. an alkali
metal hydroxide or alkaline earth metal hydroxide, or an
excess of the metal compound when this is a hydroxide base.
Preferably, an alkali metal hydroxide, e.g. potassium or
sodium hydroxide, is used.
The mol ratio of metal compound to the quinazolin-
one starting material is suitably at least 1 : 1, preferably
at least 1.5 : 1. The upper limit is not critical but mol
ratios in excess of 10 : 1 offer no additional advantage.
More suitably, the mol ratio will be in the range of from
1.8 : 1 to 6 : 1, preferably 2 : 1 to 4 : 1 and more pref-
erably in the range of from 2.1 : 1 to 3 : 1.
Where employed, the hydroxide base is conveniently
present in a mol ratio relative to the quinazolinone
starting material, of at least 1 : 1, suitably at least
1.5 : 1, preferably 1.8 to 6 : 1, more pre~erably 2 to 3 : 1.
The process of the present invention may be effec-
ted under sub- or super-atmospheric pressure but is most
suitably carried out under atmospheric pressure. A blanket
or constant flow of a yas, inert under the reaction con-
ditions, e.g. nitrogen, over the reaction mixture is pref-
er~ed.
The reaction may typically be run from about 1 to
15 hours.
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The process of the invention results in substanti-
ally higher yields than the corresponding known process,
which does not employ a metal compound, and which usually
results in a mixture of the desired quinazolin-2(1~)-or.e
and the corresponding 3,4-dihydro derivative.
The compounds II are either known ~ se or may
be prepared from kno~m materials by methods described in the
literature.
In the compounds of the formulae I and I~ the
(Cl-C8) hydrocarbon radical of Rl may for example be (Cl-C6)
alkyl, (C3-C7) cycloalkyl, (C4-C7~ cycloalkylalkyl, having
a (C3-C6) cycloalkyl and a (Cl-C2) alkyl portion, phenyl,
benzyl or phenethyl. Examples of halo-substituted hydro-
carbon radicais for Rl include (Cl-C6) alkyl, mono~, di-
or tri-substituted by fluorine, chlorine or bromine and
phenyl, benzyl or phenethyl, mono- or di-substituted by
fluorine, chlorine or bromine. Di- or tri-halogen substit-
uted radicals are preferably substituted by the same
halo~en atoms.
In the compounds of the formula I ~ d II, R2 is
more preferably a rad~cal of formula III or IV,
~ lll or ~ y IV
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in which Y and Yl may be the same or different, each
signifies a hydrogen, fluorine, chlorine
or bromine atom, a (Cl-C3) alkyl or alkoxy
radical, or a trifluoromethyl group,
provided that when one of Y and Yl signi-
fies a trifluoromethyl group, the other
signifies a hydrogen atom, and
Y2 signifies a hydrogen, fluorine, chlorine
or bromine atom, or a (Cl-C3) alkyl or
alkoxy radical.
The compounds of formula I are known for their
anti-inflammatory activity and in this regard R1 is prefer-
ably (Cl-C6) alkyl or cyclopropylmethyl, more preferably
(Cl-C6) alkyl, especially isopropyl. R2 is preferably a
phenyl radical optionally mono- or di-substituted as indic-
ated above, and is more preferably phenyl or ~-fluorophenyl.
R3 and ~4 may each be hydrogen. Preferably, however, at
least one is Cl 3-alkyl, in particular methyl, for example
in the 7-position, or Cl 3-alkoxy, e.g. methoxy, for example
in the 6-position.
Compounds that are most preferably prepared are
7-methyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone and
l-isopropyl-4-~-fluorophenyl-7-methyl-2(lH)-quinazolinone.
The following Examples llustrate the process of
~he invention.
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EX~IPLE 1: 7-Methyl-l-isopropyl-4-~henvl-2(~ g~uina
.
inone
A mixture of 200 ml of ~-cymene, 40 g of ferric
oxide and 7 g of sulphur is heated to reflu~ (ca. 175C),
and there is then added thereto dropwise over a period of
40 minutes a hot (130C) solution of 28.2 g of 7-methyl-
l-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1Il)-quinazolin-
one in 200 ml of ~-cymene. The resulting solution is
refluxed for 3.5 hours duriny which time 1.8 ml of water
are collected in a Dean Stark separator. The reaction
solution is then cooled to 28C and filtered through a
Celite pad which is then ~7ashed 4 times each with 25 ml
of toluene. Th~ toluene washings are extracted with
50 ml of 4N hydrochloric acid and the ~-cymene filtrate
is extracted with 350 ml of 4N hydrochloric acid. T~e
ac~d extracts are combined and extracted with 100 ml
of toluene~ and such toluene extracts discar~ed. The
acid solution remaining after such tolue~e extraction is
treated by addition of 350 ml of toluene and 110 g of
50~ aqueous sodium hydroxide solution. The phases are
separated and the toluene phase washed twice each with
100 ml of water, followed by drying over sodium sulphate,
filtering and evaporation in vacuo. The solid residue is
crystallised ~rom ethyl acetate to obtain 7 methyl-l-
isopropyl-4-pher.yl-quinazolin-2(1H~-one, m.p. 139-141C.
. ,~.
r ~ '~ .
,
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EX~PLE 2~ sopro~yl-4-p-fluoro~henyl-7-methyl-2(lH)
quinazolinone
A mixture of 67 ml of xylene, 13.3 g of ferric
oxide and 2.5 g of sulphur is heated under a nitrogen
5 atmosphere to reflux and there is then added thereto, ;
over a period of 20 minutes drop~Jise, a hot ~100-110C)
solution of 10 g of 7-methyl-1-isopropyl-4-~-fluoro-
phenyl-5,6,7,8-tetrahydro-2(lH)-quinazolinone in 100 ml
of Yylene. The resulting solution is refluxed for 10
hours, during which time water is collected in a Dean
Stark separator. The reaction mixture is then cooled to
80C and filtered through a Cellte~iad.
The filtrate and the filter cake are washed 3
times each with 50 ml of toluene. The filtrates are com-
bined and then extracted successively with 200, 100 and50 ml of 4N hydrochlorlc acid. The acid extracts are
combined and washed with 100 ml of toluene, the toluene
extracts being discarded. To the acid solution, remaining
after such toluene extraction,aré added 200 ml of toluene
and 115 g of 50% aqueous sodium hydroxide solution ~;hilc
stirring and cooling. TAe phases are separated and the
aqueou~ phase washed twice each with 100 ml of toluene.
~''~' ' .
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The toluene phases are combined, wached twice
each with 100 ml of water, followed by drying over
anhydrous magnesium sulphate, filtering through Celite ~
and concentrating to yield 8.8 g (90%) of yellow crystals.
. 5 Recrystallisation occurs from ethylacetate to obtain the
title compound with m.p. 175-176.5C.
EX~MPLE 3: 1-Iso~ro~vl-4-Dhenvl-7-methvl-2(1~)-auinazolinone
A mixture of 28.2 g of 7-~.ethyl-1-isopropyl-4-
phenyl-5,6,7,8-tetrahydro-2(lH)-quinazolinone, 9.6 g of
10 sulphur, 10 g of sodium hydroxide, 20 g of calcium
chloride and 200 ml of carbitol (2-[2-ethoxyethoxy]ethanol~
~s heated under a nitrogen blanket at 150C for 2 hours.
The resulting miY.ture is then cooled to 65C, 500 ml of
benzene added and the mixture cooled with stirring to 15C
15 and the liquid phase decanted. The organic phase is washed
with ~ater and evaporated to obtain an oil which is dissol-
ved in a mixture of 100 ml of benzene and 100 ml of 50~
aqueous hydrochloric acid. The xesultiny mixture is stirred
for one hour at room temperature, tr.e phases separated and
20 the acid phase treated with 50 ml of benzene~ The acid
phase is neutralised with 50~ sodium hydroxide solution,
extracted with 150 ml o~ benzene and the benzene extracts
washed with water until neu~ral. ~fter drying over sodium
sulphate, the benzene sclution is evapcra~ed to obtain the
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crude product which is recrystallised from ethyl acetate
to obtaln l-isopropyl-4-phenyl-7-methyl-2(lH)-quinazolinone,
m.p. 141-142C.
EXAMPL~ 4: 7-Methyl-l-isopro~yl-4-(p-fluorophenvl)-quin
azolin-2-(lH)-one
To a stirred mixture of 4.3 g of sulphur, 6.8 g
of zinc oxide and 67 ml of a mixture of xylenes heated to
reflux (ca. 138C) under a nitrogen blanket is added a
pre-heated (100-115C) solution of 10.0 g of 7-methyl-1-
isopropyl-4-(~-fluorophenyl)-5,6,7,8-tetrahydro-2(1~)-
quinazolinone in 100 ml of a mixture of xylenes. After
addition'(ca. 20 m-nutes), the resulting ~ixture is refluxed
overnight, cooled and filtered through Cellte. The solids ~
are washed with toluene and the filtrate and washin~s ex-
tracted four times with 4N hydrochloric acid and the extractswashed with 100 ml of toluéne. The aqueous phase is treated
with 200 ml of toluene and treated portionwise with 115 g
of 50~ sodium hydroxide solution in an ice-bath. The
aqueous phase is extracted twice each with 100 ml of toluene
and the organic phase water washed and dried. The crude
yellow solid obtained on filtering and concentration in vacuo
is dissolved in 100 ml of ethyl acetate, filtered and
concentrated to a volume o, 50 ml and cooled to 0C to
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obtain a precipitate which is recrystallised from ethyl
acetate to yield 7-methyl-1-isopropyl-4~ fluorophenyl)-
quinazolin-2(lH)-one.
EXAMPLE 5:
The procedure of Example 4 is repeated employing
an equivalent molar amount of lead dioxide in place of
zinc oxide to yield the same product.
EXAMPLE 6:
In a manner analogous to any one of the preceding
Exampies and employing appropriate starting materials in
approximately equivalent amounts, the following compounds
may be obtained:-
5,7-dimethyl-1-isopropyl-4-phenyl-quinazolin-2~lH)-one;
l-isopropyl-7-methyl-4-(~-methylphenyl)-quinazolin-2(lH)-
one;l-isopropyl~7-methyl-4-(2-thienyl)-quinazolin-2(1H)-one;
l-cyciopropylme~hyl-6-methoxy-4-phenyl-quinazolin-2(lH)-one.
