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2,403,633
Patented Oct. 1, 1946
S PATENT. QFFICEJ
* UNITED ‘STATE
2,408,633 1 '
PRODUCTION ‘OF SUBSTITUTED QUINAZO
LONES FROM ORGANIC PHOSPHAZO COM‘
POUNDS
Alfred Guenther, Riegelsville, Pa., and Jack F.
Morgan, Phillipsburg, N. .L, ,assignors to Gen
:eral Aniline & Film Corporation, New York,
_
N. Y., a corporation of Delaware ,
.
NoDrawing. Application April '1, 1945,
Serial No. 587,213
'
10 Claims. (01. zoo-+251)
l
2
The present invention relates to the prepara-'
ethyl,’ propyl, butyl, amyl, lauryl and the like,
tion of substituted quinazolones and to such
alkoxy such as methoxy, ethoxy, propoxy and the
like, X is alkyl as above and Y is an aliphatic
It has been suggested that quinazolones be pre
pared by the interaction of acylanthranils with
amines. While this method can be operated to
give good yields, it nevertheless requires the em
ployment of intermediates which are highly un
stable with respect to moisture. Consequently, '
considerable care must be exercised in the han 10
radicalsuch as alkyl as above and alkylamino
such as methylamino, ethylamino and the like,
quinazolones.
dling of the intermediates if satisfactory yields
are to be obtained.
-
' Most of the other methods‘which have been
employed for the production of quinazolones re
an aromatic radical such as phenol, tolyl, anisyl,
phenetyl, m-nitrophenyl, p-chlorophenyl, naph
thyl, phenylamino and the like, cycloaliphatic
such as cyclopentyl, cyclohexyl and the like, or a
heterocyclic nitrogenous nucleus such as Pyri-,
dyl, quinolyl, and the like. Where Y is alkyl
amino or phenylamino, the alkyl or phenyl rad-,
ical will be separated from the quinazolone nitro
gen by an —NH—, group. The aromatic or het
15 erocyclic nucleus represented by the character R
quire the use of such high temperatures as nec
essarily cause some decomposition of the react
may be benzene, naphthalene, anthracene, an
ants. For example, 2-methyl-3-phenyl-4-quinaz
olone has been prepared by heating o-acet
thraquinone, dibenzofurane, carbazole, diphenyl
amide benzanilide to temperatures of 175 to 210°
Thereaction is effected by heating N-acyl-o
amino-cyclic carboxylic acid with the organic
phosphazo compound in a suitable solvent there
for. The degree of heating required depends on
the’ nature of the reactants and may vary consid
ene sul?de and the like.
C. These procedures suffer fromthe disadvan
tages that the decomposition involved not only
lowers the yield but through .by-product forma
tion decreases the purity of the desired end prod- V
.
erably. While it is preferred to eifect the reac
uct.
It has now been discovered that substituted 25 tion by re?uxing the reaction mixture, it should
be borne in mind that it is possible to carry out
quinazolones can be prepared while avoiding the
the reaction by heating to a temperature below
disadvantages of the prior art by heating an or
the boiling point of the reactants.
ganic phosphazo compound with an N-acyl-o
The N-acyl aminocyclic carboxylic acids em
amino carboxylic acid in an organic solvent.
These products react together smoothly at mod 30 ployed may be represented by the following for
eratelyelevated temperatures to produce the de
mula:
‘
sired quinazolones in a pure condition and in
H
NCOZ
good yields. The organic phosphazo compounds
are prepared by the reaction of phosphorus tri
R
\COOH
chloride and primary amines, which are common
stable materials. The preparation of substituted
in which Z is alkyl such as methyl, ethyl, proe
quinazolones by the reaction of organic phos
phazo compounds and N-acyl-o-amino carbox
pyl, .butyl, amyl, octyl, decyl and the like, and
R has the values given above, the amide group
stitute the purposes and objects of the present 40 and the carboxylic acid group being in o-posi
tion of the nucleus represented by R. Exam
ylic acids and the quinazolones so obtained con
invention.
1
'
ples of such compounds are:
The quinazolones, the production of which is
contemplated herein, have the following structural
formula:
.
V
_
,
r
i
I
,
'
/ \c-x ‘
R
N-acetyl-o-amino naphthoic acid
l
‘/N---Y
C
II
o
'
N-acetyl anthranilic acid
N-acetyl-5-chloro anthranilic acid
45 N-propionyl anthranilic acid
N-butyryl anthranilic acid
,
..
' to
in which R is an aromatic or heterocyclic ‘nu
cleus which may be substituted by monovalent
groups, “for example, nitro, halogen,_such as ch10.
' rine, bromine and the like, alkyl such as’methyl, 55
N -acetyl-5-nitro anthranilic acid
N-acetyl-?-methyl anthranilic acid
N-acetyl-5-ethoxy anthranilic acid and the like.
The organic phosphazo compounds, the reac
tion of which is contemplated herein, have the
following general formula:
(a-n-gr-nrnm
>
'
2,408,633
4
a
lone. While the quantities of the reactants may
be varied from that indicated in the equation, it
is found that for best results the molar propor
in which n is 1 or 2 and R represents an
aliphatic chain such as methyl, ethyl, propyl,
butyl, amyl, octyl, dodecyl, stearyl, and the
tions designated’ should beresorted'to;
The substituted quinazolones of the present
like, an alicyclic nucleus such as cyclopentyl,
cyclohexyl or the like,
an aromatic nucleus
such as phenyl naphthyl, anthracyl and the
invention may be utilized as intermediates in the
like, or a heterocyclic nucleus such as pyridyl,
formation of dyestuffs.
quinolyl, carbazolyl, diphenylene oxide, diphen
The following examples serve to further illus
trate the invention‘. but it is to be understood
that these examples are illustrative and not lim
itative in nature‘. The parts are by weight.
ylene sul?de and the like. The radical rep"
resented by R may also be sub‘stitut'e'd‘by such"
substituent groups
as halogen
such
as chlo
rine, bromine and the 1ike,.alk'yl such asethyl,
Example: I. '—‘ 2=m'ethyZ-3-phenyZ-4-quinazolone
methyl,
as methoxy,
propyl,
ethoxy,
butylpropoxy
and the’
and
like,’
thealkoxy;
like; amino‘;~
such
substituted amino such as alkylated amino,- iiv e.,v
150 :parts' of a toluene solution containing 10.7
- parts'of‘ crude“phenylphosphazoanilide
dimethylamino, diethylamino and the~like,'and
sulfo.
,
l
is’ treated with 17.9 parts of N-acetylanthranilic
The organic phosphazo compounds are read
ily produced by the reaction of an organic'prih
mary amine with phosphorous trichloride, pref
acid.. The‘ mixture is agitated, heated to the
reflux temperature, and agitation thereof main
tained at this temperature-for 1 to 2-hours. The
erably'in the ratio'of 5:1, and in the presence-of
anlorg'a'nic solvent. The organic primary amine
suspension is treated WlthBOO parts‘of- 5% sodium
carbonate solution and the toluene ‘removed’ by
which? is" employedv may be aliphatic such as
steam distillation.
methylamine', ethylamine, propylamine, _butyl—
amine, octylamine, dodecylamine and the like,
water and dried.
an‘ alicyclic amine such as. cycl'opentylamine,
cyclohexylamine, and the like, an aromatic
There is thus obtained 19.3 parts of a crude
product melting at 138 to 140° C. This» quan
tity represents 82% of- the theoretical yield. By
amine such as aniline, o-toluidine, m-toluidine,
p-toluid'ine, m-chloraniline, o-anisidine, m.
nitro aniline, p-amino diphenylamine, ni
phenylen'e diamine, p-phenylene diamine, ben
zidine, 4.4’-diaminodlphenyl methane,v alpha
naphth-ylamine, sulfanilicv acid or a heterocyclic
amine such as 2-amino pyridine, 2-amino‘ quino
line, 2'-amin0 diphenylene oxide,‘ and the like.
The amine should in no case contain in the 0
or p-position' to the amino nitrogen,‘ a nitro or
carbonyl group. When amines of the ‘latter constitution are employed, either no'reaction ensues
The white solid- which re
mains is separated’ by ?ltration, washed with
re'crystallizing from alcohol, pure 2-methyl-3
phenyl-4-quinazolone meltingat 147 to 148° C. is
obtained.
_
.
bons such as benzene, toluene and the like, the
chlor derivatives thereof, such‘ as monochlor
benzene; monochlortoluen'e and the like, normally
liquid aliphatc hydrocarbons such as octane,
solvent naphtha, kerosene and their chlor deriva
tives such as- ethylene chloride,,butyl chloride,
N,
on a.
/ \C/
or the reaction takes place with vigorous decom 40
position resulting in a tarry, unidenti?able mass.
The solvents used should be‘ inert to the re
act‘ants and should be normally liquid. Suitable
solvents are normally liquid aromatic hydrocar
,
A benzo-substitutedv quinazolone of the follow
ing formula is obtainedv by replacing the N
acetylanthranilic acid-by. 25.5 parts of Z-N-acetyl
35
amino-3-naphthoic acid.
(l
The phenylpho'sphaz‘oanili'de' employed in this re
action is obtained by heating 260 parts of toluene
4' and'186 parts‘ of aniline't'o‘ 50° C‘. and adding in the
course of one-half hour 55' parts of phosphorus
trichlo'ri‘de and 43 parts of toluene". The mix
ture is agitated during the‘ addition of the‘ phos
phorus‘ tri'chloride'and for one hour thereafter.
50 Thev aniline‘ hydrochloride which is' formed is
octyl chloride and ohlor kerosene and normally
?ltered o? andthe'?ltrate'used'directly or‘ evapo
liquid nitrogenous heterocyclic bases such as _
r‘a‘te‘d‘a'nd' dried“ to is'ola‘te'th‘e crude phenylphos
pyridine, quinoline and the like.
phazoanilide.
'
‘
The reaction by which the substituted quin
azolones are produced, assuming that the N
acyl-o-amino carboxylic acid is N-acetyl anthra
nilic acid and the organic. phosphazo compound
is phenyl phosphazo anilide, may be graphically
represented as follows:
' Example
II. — 2-methyle3'ep-chlorophenyk4
quz'nazolone
.
.
The procedure is thefsame as in' Example" I ex‘
cept‘ that there are used as the organic phospha'zb
compound‘ 14.6 parts of‘ 4'.4"-dichlorphenylphos
O
phazoanilide.
The
4.4’ - dichlo'rpheiiylphos
phazoanilide is obtained in a manner similar“ to
that utilized to producethe'uns'ubstitut‘ed .ph‘e'riyl
phosphaz'oanilide.
Example
N
CH"
/ \ l/
C
2
-
l.
N
\/
C
Y
n
0
It Will be observed that according to this formula
1 mol of the phosphazocompound is reacted for
each 2 mols of the N-acyl-o- amino carboxylic
acid to yield 2 mols ofthe‘sub'stituted quinazo
'
. '
III. -— 2-methyZ-3-phenyl-6-chloro-4
quinazolone
The procedure is the same as in Example I ex
cept that there is used in lieu of N-acetyl-anthra
nilic acid 21.35 parts of N-acetyl-5-ch1oro
anthranilic acid.
|
Example v IV. - 2-methyZ-3-p-methyZphenyZ-4-
qui'hazolone
The ‘procedure isf the same as in Example-1; ex- ‘
cept thatthere is3 used
lieu~ofetheipheny-lphbse-l
2,408,633
phazoanllide 12.11 parts of p-toluylphosphazo
p’-toluidide.
Analysis
This phosphazo compound is prepared in a
manner similar to that utilized in preparing the
phenylphosphazoanilide.
Example V.—2-methyl-3-butyl-4-quinlczolone
N
Calculated
Found
Percent
Percent
9.
C ________________________________________ __
12. 36
9. 60
12. 15
A solution of 73 parts of N-butylamine and 130
parts of toluene is agitated and treated drop
Various modi?cations of the invention will oc
wise with a solution of 27.5 parts of phosphorus 10 cur to persons skilled in the art and we there?
fore do not intend to be limited in the patent
trichloride and 22 parts of toluene. The sus
granted except as required by the prior art and
pension thus obtained is agitated and heated
at the re?ux temperature for one hour. The hot
the appended claims.
I
reaction mixture is ?ltered and the solid amine
We claim:
1. The process of producing substituted quin
hydrochloride washed with 150 parts of hot tolu 15
azolones which comprises heating an organic
ene. About 48 parts (73% of the theoretical) of
phosphazo compound having the general formula
N-butylamine hydrochloride are thus recovered.
50 parts of the toluene ?ltrate, which contains
roughly about 9.2 parts of the butylphosphazo
butylamide are diluted with 100 parts of tolu 20 wherein n is selected from the class consisting
of 1 and 2, and R is selected from the class con
ene and to the resulting solution there are added
sisting of an aliphatic chain, an alicyclic nucleus,
17.9 parts of N-acetylanthranilic acid. The mix
an aromatic nucleus and a heterocyclic nucleus
ture is heated to the re?ux temperature and agi
and is free from nitro and carbonyl groups in
tated for a period of about 2 hours. To the re
o- and p-position to its linkage to the, remainder
action mixture there is then added a sui?cient
of
the molecule with an N-acyl-o-aminocyclic
amount of 5% sodium carbonate solution to ren
carboxylic acid selected from the class consist
der the reaction mixture alkaline and the tolu
ing of aromatic and heterocyclic carboxylic acids
ene is removed by steam distillation. The solid
in the presence of an inert, normally liquid or
remaining is separated by ?ltration, washed with
ganic solvent.
Water and recrystallized from alcohol.
30
2. The process as de?ned in claim 1 wherein
The product is pure Z-methyl-B-butyl-Il-quin
1 mol of the organic phosphazo compound is em
azolone.
ployed for each 2 mols of the N-acyl-o-amino
Example VI.—2-methyZ-3-lauryZ-4-quinazolone
carboxylic acid.
3. The process as de?ned in claim 1 wherein
The procedure is the same as in Example V 35
R is an aliphatic chain.
'
except that there are used 185 parts of lauryl
4. The process as de?ned in claim 1 wherein
amine in lieu of 73 parts of N-butylamine.
R is an aromatic nucleus.
Example VII.—~2-methyZ-3-cycZOhexyZ-4-quinazo
5. The process as de?ned in claim 1 wherein
Zone
R is a heterocyclic nucleus.
6. The process as de?ned in claim 1 wherein
99 parts of cyclohexylamine are dissolved in 40
the reactants are heated to the re?ux tempera
130 parts of toluene and while agitated treated
with a solution of 27.5 parts of phosphorus tri
chloride diluted with 22 parts of toluene. The
resulting suspension is re?uxed with agitation
for a period of 1 hour and ?ltered to remove
ture of the solvent.
7. The process as de?ned in claim 1 wherein
45
the N-acyl-o-amino cyclic carboxylic acid is of
the benzene series.
cyclohexylamine hydrochloride. 79.1 parts of the
8. The process of producing 2-methyl-3-phen
cyclohexylamine hydrochloride are recovered,
representing 97% of theory.
The solid is washed with 150 parts of hot tolu
yl-4-quinazolone which comprises re?uxing 1 mol
ene. 123 parts of the toluene ?ltrate, which con
tain roughly about 11.3 parts of the cyclohexyl
phosphazo cyclohexylamide, are diluted with 50
parts of toluene and there is then added 17.9
parts of N-acetylanthranilic acid. The mixture
is heated to re?ux until hydrogenchloride is no
of phenylphosphazoanilide with 2 mols of N-ace
tyl anthranilic acid in the presence of toluene.
9. The process of producing 2-methyl-3-lauryl
4-quinazolone which comprises re?uxing 1 mol
of lauryl phosphazo lauryl amide with 2 mols of
N-acetyl anthranilic acid in toluene.
10. The process of producing 2-methyl-3-a
pyridyl-4-quinazolone which comprises re?uxing
longer given off, whereupon the suspension is
1 mol of a-pyridylphosphazo pyridyl amide with
treated with su?icient 5% sodium carbonate so
2 mols of N-acetyl anthranilic acid in toluene.
lution to render the reaction mixture alkaline.
The toluene is removed by steam distillation leav 60
ing a light tan solid which upon treatment; with
hydrochloric acid yields pure white 2-methyl-3
cyclohexyl-4-quinazolone hydrochloride.
ALFRED GUENTHER.
JACK F. MORGAN.
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