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Description  |
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This invention relates to the preparation of
1-substituted4-cyclosubstituted tetrahydro quinazolinones and
intermediates and to certain novel compounds thereby.
The compounds of this invention include compounds of the formula I:
##STR3##
wherein: R.degree. is lower alkyl, preferably containing 1 to 3 carbon
atoms,
n is 0, 1 or 2,
R is lower alkyl, preferably containing 1 to 5 carbon atoms, e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl and sec butyl,
R' is a radical of the formula
##STR4##
in which Y and Y' are the same or different and represent hydrogen, halo
of atomic weight of 19 to 36, lower alkyl, preferably containing from 1 to
2 carbon atoms, e.g., methyl or ethyl, lower alkoxy, preferably containing
from 1 to 2 carbon atoms, e.g., methoxy or ethoxy, or one of Y and Y' is
trifluoromethyl while the other is hydrogen, or a radical of the formula
##STR5##
in which Y" is hydrogen, fluorine, chlorine or alkyl of 1 to 3 carbon
atoms.
This invention also comprises:
A. PREPARING A COMPOUND OF THE FORMULA I, above, by cyclizing a compound of
formula II
##STR6##
in which R, R', R.degree. and n are as defined above, with phosgene, and
B. PREPARING A COMPOUND OF THE FORMULA Ia
##STR7##
IN WHICH R', R.degree. and n are as defined above, and R" has the same
significance as R, defined above, except that it may not signify a
tertiary alkyl group in which the tertiary carbon atom is directly
attached to the ring nitrogen atom, by cyclizing a compound of formula IIa
##STR8##
wherein R.degree., R', R" and n are as defined above with a carbonic acid
derivative selected from the group of
i. a C.sub.1-2 alkyl chlorocarbonate and
ii. a 1,1'-carbonyldiimidazole.
Process (a) is suitably carried out at a temperature of from -30.degree. C.
to +50.degree. C., preferably -5.degree. C. to 30.degree. C. The reaction
may be carried out in an organic solvent which is inert under the reaction
conditions, suitably an aromatic hydrocarbon, e.g., benzene, toluene or
xylene, preferably toluene. Other suitable solvents include dioxane. The
mole ratio of the phosgene to the compound of formula II is not
particularly critical, but a substantial excess of the phosgene is
preferably employed. The process may optionally be carried out in the
presence of an acid-binding agent such as an inorganic base, e.g. a
trialkylamine or pyridine, preferably triethylamine. The reaction time may
range for 1/2 to 10 hours, more usually 1 to 4 hours.
Process (b) (i) is suitably carried out at a temperature of from
-30.degree. C. to 100.degree. C., preferably -0.degree. C. to +30.degree.
C. The reaction may be carried out in an organic solvent which is inert
under the reaction conditions, suitably an aromatic hydrocarbon, e.g.,
benzene, toluene or xylene, preferably toluene. Other suitable solvents
include dioxane or the alkyl chlorocarbonate. The mole ratio of the
chlorocarbonate to the compound of formula IIa is not particularly
critical, but a substantial excess of the alkyl chlorocarbonate is
preferably employed. The process may optionally be carried out in the
presence of an acid-binding agent such as an inorganic base, e.g., a
trialkylamine or pyridine, preferably triethylamine. The reaction time may
range for 1/2 to 10 hours, more usually 1 to 4 hours.
Process (b) (ii) is suitably carried out at a temperature of from 0.degree.
C. to 120.degree. C., preferably 40.degree. C. to 90.degree. C. The
reaction is preferably carried out in an organic solvent which is inert
under the reaction conditions, suitably an aromatic hydrocarbon, e.g.,
benzene, toluene or xylene, especially benzene. An excess of
1,1'-carbonyldiimidazole is preferably employed.
The compounds of the formula I and Ia can be isolated from the reaction
mixtures by working up by conventional procedures.
The compounds of formula II above can be prepared by reacting a compound of
formula III
##STR9##
in which R, R.degree. and n are as defined above with a suitable strong
base and a compound of formula IV
r'--c.tbd.n iv
in which R' is as defined above, in an inert solvent to form a solution of
the Salt A
##STR10##
in which R, R.degree., R' and n are as defined above, and X is a metal,
preferably lithium or magnesium, and quenching the solution with water.
Suitable strong bases are those which are capable of removing a hydrogen
atom from the methylene group in the cyclohexene ring adjacent to the
amine function of compound III to provide the desired anion for reaction
with the compound of formula IV. They include the alkali metal salts,
especially the lithium salt, of secondary amines such as diethylamine,
dimethylamine and diisopropylamine, as well as other bases such as methyl
magnesium iodide. Lithium diisopropylamide, because of its relatively
large size, is quite advantageous where there is an R.degree. group in the
meta position of the compound of formula III. One mol of the strong base
and up to about 1.2 mols can be used per mol of the compound of formula
III, preferably equimolar amounts are used.
The temperature of the reaction mixture is maintained at about 20.degree.
to 80.degree. C.
Generally, the compound of formula III in a suitable solvent such as
benzene, is added to a solution of the base in a suitable solvent and
allowed to react for about 10 to 60 minutes. The compound of formula IV,
neat or in a suitable inert solvent, is then added to the reaction mixture
of the base and compound III. The compounds III and IV and the strong base
may, however, be brought together simultaneously.
The resulting reaction mixture containing the salt of formula A can, at
this point, be treated by process (a) or (b) above to yield directly the
compound of formula I. Suitable temperature control should be exercised,
as this reaction is more exothermic than when compound II is employed.
However, the salt solution is advantageously quenched with water to obtain
the compound of formula II, which can be reacted in situ according to
process a) or b) to form compound I, but is preferably extracted and
washed first using conventional methods.
The compounds of formula III can be prepared by reacting a compound of
formula V
##STR11##
wherein R.degree. and n are as defined above, with a compound of formula
VI
r--nh.sub.2 vi
wherein R is as defined above,
to eliminate one molecule of water, conveniently in the presence of a
molecular sieve or a dehydrating agent, such as alumina, calcium chloride,
phosphorus pentoxide or mixtures thereof.
This reaction can be carried out at temperatures from 0.degree. to about
80.degree. C., conveniently 20.degree. to 30.degree. C. In cases where the
compound of formula VI is volatile, an excess is generally mixed with the
compound of formula V and the unreacted portion removed by vacuum
distillation after removal of the dehydrating agent. When the compound of
formula VI is nonvolatile, equimolar proportions of compounds of formulae
V and VI are mixed in suitable solvent such as benzene, the solvent then
being removed in vacuo after completion of the reaction and after
filtration of the dehydrating agent.
The compounds of formula V are known or can be produced in a known manner.
The compounds of formula I are useful because they possess pharmaceutical
activity in animals. In particular, the compounds I are useful as
anti-inflammatory agents as indicated by the Carrageenan-induced edema
test in rats. For the above-mentioned use, the dosage administered will,
of course, vary depending upon known factors such as the particular
compound and mode of administration. However, in general, satisfactory
results are obtained when administered at a daily dosage of from about 5
milligrams to about 200 milligrams per kilogram of body weight, preferably
given in divided doses 2 to 4 times a day, or in sustained release form.
For most mammals the administration of from about 300 milligrams to about
2000 milligrams of the compound per day provides satisfactory results and
dosage forms suitable for internal administration comprise from about 75
milligrams to about 1000 milligrams of the compound in admixture with a
solid or liquid pharmaceutical carrier or diluent.
The compounds of the formula I are also useful as analgesics as indicated
by application of pressure to yeast-inflammed foot of the rat (oral
administration). For such use, the compound may be administered to obtain
satisfactory results in modes and forms similar to those employed in the
treatment of inflammation and at dosages indicated above as applicable for
the use of the compound in the treatment of inflammation.
For the above usage, oral administration with pharmaceutically acceptable
carriers may take place in such conventional forms as tablets, dispersible
powders, granules, capsules, syrups and elixirs. Such compositions may be
prepared according to any method known in the art for the manufacture of
pharmaceutical compositions, and such compositions may contain one or more
conventional adjuvants, such as sweetening agents, flavoring agents,
coloring agents, and preserving agents, in order to provide an elegant and
palatable preparation. Tablets may contain the active ingredient in
admixture with conventional pharmaceutical excipients, e.g., inert
diluents such as calcium carbonate, sodium carbonate, lactose and talc,
granulating and disintegrating agents, e.g., starch and alginic acid,
binding agents, e.g. magnesium stearate, stearic acid and talc. The
tablets may be uncoated or coated by known techniques to delay
disintegration and adsorption in the gastro-intestinal tract and thereby
provide a sustained action over a longer period. Similarly, suspensions,
syrups and elixirs may contain the active ingredient in admixture with any
of the conventional excipients utilized for the preparation of such
compositions, e.g. suspending agents (methylcellulose, tragacanth and
sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and
polyoxyethylene sorbitan monooleate) and preservatives
(ethyl-p-hydroxy-benzoate). Capsules may contain the active ingredient
alone or admixed with an inert solid diluent, e.g. calcium carbonate,
calcium phosphate and kaolin. The preferred pharmaceutical compositions
from the standpoint of preparation and ease of administration are solid
compositions, particularly hard-filled capsules and tablets.
A representative formulation is a capsule prepared by conventional
techniques and containing the following ingredients:
______________________________________
Ingredient Parts by Weight
______________________________________
Compound of formula I, e.g. 7-methyl-
1-isopropyl-4-phenyl-5,6,7,8-tetra-
hydro-2(1H)-quinazolinone
50
Inert solid diluent e.g. kaolin
200
______________________________________
Preferred compounds of formula I, from the point of view of pharmacological
activity, are those in which R signifies an isopropyl radical.
The compounds of formula I are also useful as intermediates in the
preparation of compounds of the formula VII
##STR12##
wherein R, R.degree., R' and n are as defined above.
The preparation of compounds VII from compounds I is effected by
dehydrogenating the latter. This reaction can be carried out in the
presence of a dehydrogenating agent, such as sulfur, selenium, a
benzoquinone such as 2,3,5,6-tetrachloro-1,4-benzoquinone and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetracyanoethylene or
triphenylmethyl perchlorate or a dehydrogenation catalyst, such as
palladium on charcoal or nickel.
Where a dehydrogenating agent such as sulfur or a benzoquinone is used, at
least 2 mols per mol of the compound I are employed, with the preferred
amount being about 2 to 2.5 mols. Where a dehydrogenation catalyst is
used, a catalytic amount sufficient to cause removal of two molecules of
hydrogen per mole of compound of formula I is employed. Temperatures in
the range of about 60.degree. to 180.degree. C., are employed. The
particular temperatures, as well as the reaction time will depend upon the
particular dehydrogenating agent or catalyst and the ease with which the
starting material surrenders hydrogen, this in turn depending somewhat on
the nature and location of R.degree. and the value of n. A solvent is also
used, such as xylene or other organic liquid having a sufficiently high
boiling point. When a dehydrogenation catalyst is used, a hydrogen
scavenger, such as nitrobenzene, is employed in place of or in addition to
other solvents. The product can be isolated from the reaction mixture by
working up by conventional methods.
When a dehydrogenation catalyst is used without a hydrogen scavenger,
compounds of the formula VIII
##STR13##
wherein R, R.degree., R' and n are as defined above, are obtained.
Compounds VII and VIII are known and are useful as anti-inflammatory and
analgesic agents.
The following examples illustrate the invention. Percentages are by weight
and temperatures are in degrees Centigrade. Unless otherwise specified,
the reactants are brought together under substantially ambient temperature
and pressure conditions and no control of the reaction temperature is
exercised.
EXAMPLE 1
1-Isopropyl-4-Phenyl-5,6,7,8-Tetrahydro-2(1H)-Quinazolinone.
Step A: 1-Methyl-N-(cyclohexylidene)-ethylamine
To a mixture of 600 g. cyclohexanone and 1 l. isopropylamine are added 500
g. Linde Type 3A molecular sieves. The mixture is allowed to stand
overnight at room temperature, after which the isopropylamine is removed
in vacuo at room temperature. The oily residue is
1-methyl-N-(cyclohexylidene)-ethylamine.
Step B: 1-Isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone
n-Butyl lithium (15% in hexane, 0.1 mole) is added to 100 ml. benzene. To
this stirred solution dimethylamine is passed until excess had been added.
A stream of dry nitrogen, saturated with benzene vapour, is then passed
through the solution to remove excess amine. After 15 minutes, 13.9 g.
1-methyl-N-(cyclohexylidene)-ethylamine is added during about 2 minutes
producing a pale yellow solution. After a further 15 minutes, 10.3 g.
benzonitrile is added during about 2 minutes, producing a dark red/brown
solution of the lithium salt of
2-isopropyl-amino-.alpha.-phenyl-1-cyclohexene-1-methyleneimine. After one
hour, the solution is cooled to 0.degree. and 10.8 g. ethyl chloroformate
is added dropwise during about 15 minutes. After one hour, water is added
to the reaction mixture and the organic layer washed. The organic layer is
extracted with 2NHCl and the acid extracts then basified. Extraction of
this basic mixture with methylene chloride, followed by drying and
evaporation of the extracts, gives an oil which crystallizes from acetone
as 1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone, m.p.
176-177.
EXAMPLE 2
1-Isopropyl-4-Phenyl-5,6,7,8-Tetrahydro-2(1H)-Quinazolinone
To 5.05 g. diisopropylamine in 50 ml. dry benzene is added butyl lithium
(31.5 ml. of a 1.6N solution in hexane). After 15 minutes, 7.65 g. of
1-methyl-N-(cyclohexylidene)-ethylamine prepared as in Example 1 is added
during about 2 minutes. 5.5 g. benzonitrile is added after 10 minutes to
give a deep red solution, and after a further 10 minutes about 5 ml. of
water are added, causing the color to change to pale yellow. After 30
minutes, 5 g. of phosgene in a 12.5% solution in benzene is added dropwise
to this mixture at 0.degree.. After 1 hour, the reaction was worked up as
in Example 1 to give the same product.
EXAMPLE 3
6-Methyl-1-Isopropyl-4-Phenyl-5,6,7,8-Tetrahydro-2-(1H)-Quinazolinone.
Step A: 1-Methyl-N-(4-methyl cyclohexlidene)-ethylamine
To a mixture of 600 g. 4-methyl cyclohexanone and 1l. isopropylamine are
added 500 g. Linde Type 3A molecular sieves. The mixture is allowed to
stand overnight at room temperature, after which the sieves are removed by
filtration and the excess of isopropylamine is removed in vacuo at room
temperature. The residual oil is 1-methyl-N-(4-methyl
cyclohexylidene)-ethylamine.
Step B: 0.3 moles n-butyl-lithium (in a 1.6N solution of hexane) is added
to a solution of 30.3 g. diisopropylamine in 300 ml. benzene. After 15
minutes, there is added, during about 2 minutes, 45 g. of
1-methyl-N-(4-methyl cyclohexylidene)-ethylamine and after a further 15
minutes 30.9 g. benzonitrile are added during about 2 minutes, producing a
solution of the lithium salt of
5-methyl-2-isopropylamino-.alpha.-phenyl-1-cyclohexene-1-methylenimine.
After 30 minutes, 500 ml. water is added to the reaction mixture and the
organic layer washed several times with water. The organic layer is then
dried and evaporated to yield a yellow oil.
Step C: 6-Methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahyro-2(1H)-quinazolinone
The oily product of Step B is dissolved in 400 ml. toluene together with
60.6 g. triethylamine and the solution added dropwise during about 30
minutes to a stirred solution of 60 g. phosgene in 1l. toluene at
0.degree.. The mixture is stirred for a further 1 hour at room temperature
and then water is added. Work-up as in Example 1 and recrystallization
from acetone/ether yields crystals of
6-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone, m.p.
175.degree.-177.degree..
EXAMPLE 4
7-Methyl-1-Isopropyl-4-Phenyl-5,6,7,8-tetrahydro-2(1H)-Quinazolinone.
Step A: Preparation of 1-methyl-N-(3-methylcyclohexylidene)-ethylamine
To a mixture of 112 g. 3-methyl cyclohexanone and 120 g. isopropylamine are
added 100 g. Linde Type 3A molecular sieves. The mixture is allowed to
stand overnight at room temperature, after which the sieves are removed by
filtration and the excess of isopropylamine is removed in vacuo at room
temperature. The oil residue is 1-methyl-N-(3-methyl
cyclohexylidene)-ethylamine, b.p. 36 to 0.5 mm.
Step B:
4-Methyl-2-isopropylamino-.alpha.-phenyl-1-cyclohexene-1-methylenimine
2.0 moles of n-butyl lithium (in a 1.6N solution in hexane) are added to a
solution of 202 g. of diisopropylamine in 2l. benzene. After 15 minutes
306 g. of 1-methyl-N-(3-methyl cyclohexylidene)-ethylamine are added while
stirring. After a further 30 minutes, 206 g. benzonitrile are added to the
mixture stirred for 45 minutes, producing a solution of the lithium salt
of 4-methyl-2-isopropylamino-.alpha.-phenyl-cyclohexene-1-methylenimine.
The reaction is then swamped with water and the organic layers washed 3
times with water. The organic layer is then dried and evaporated. The
yellow oily residue is then distilled and
4-methyl-2-isopropylamino-.alpha.-phenyl-1-cyclohexene-1-methylenimine
collected at 155.degree./0.7 mm.
Step C:
7-Methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone
A solution of 239 g.
4-methyl-2-isopropylamino-.alpha.-phenyl-1-cyclohexene-1-methylenimine and
172 g. triethylamine in 1l. toluene is added dropwise during 30 minutes to
a solution of 170 g. phosgene in 2 l. toluene at 0.degree.. After 1 hour
stirring water is added and the resulting mixture worked up as in Example
1 to give
7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone, m.p.
150.degree.-153.degree..
The following examples illustrate various methods of dehydrogenating the
tetrahydro compounds produced by the process of this invention.
EXAMPLE A
To 14 g. of 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro
2(1H)-quinazolinone in 280 ml. xylene is added 0.35 g. palladium on
charcoal catalyst (10%) and the mixture refluxed for 24 hours. The
catalyst is then removed by filtration and the filtrate evaporated to
leave a crystalline residue which crystallizes from ethyl acetate to yield
7-methyl-1-isopropyl-4-phenyl-4,5-dihydro 2(1H)-quinazolinone.
EXAMPLE B
To 14 g. of
7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone in
280 ml. xylene is added 0.70 g. palladium on charcoal catalyst (10%) and
3.5 ml. nitrobenzene and the mixture refluxed for 24 hours. The catalyst
is then removed by filtration and the filtrate evaporated. The residue
crystallized from ethyl acetate is a mixture of
7-methyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone and
7-methyl-1-isopropyl-4,5-dihydro-2(1H)-quinazolinone in a ratio of
approximately 2:1.
EXAMPLE C
To 50 ml. of xylene are added 1.35 g. of
7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinazolinone and
0.32 g. sulfur. The mixture is boiled overnight (about 16 hours). The
resulting solution is evaporated under pressure and the catalyst
crystalline residue is recrystallized from ether/petroleum ether to give
7-methyl-1-isopropyl-4-phenyl-2(1H)-quinazolinone.
* * * * *
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