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Патент USA US3098866

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3,998,853
United States Patent () rice
Patented July 23, 19563
1
2
amine to yield the mixed anhydride, which is treated
with 4~arnino-3-methyl-2-phenylmorpholine in a suitable
3,098,853
@ARBQCYCLKI-3-METHYLMORPHOLINES
N-AtCYLATED DERIVATIVES 0F 4-AMiN0-Z
sol-vent medium, resulting in 3-methyl-4~(5’-methylisoxa
zole -3 '-carb oxamido ) -2-phenylmorpholine.
Reaction of the aforementioned substituted 4-amino
morpholines with the appropriate isocyanates results in
the corresponding instant substituted morpholin-4-yl
ureas. Typically, a solution of 4-arnino<3-methyld2
Max Ii. Kalm, Skokie, Ill, assignor to G. D. Searle & C0,,
‘Chicago, Iii, a corporation of Delaware
No Drawing. Filed June 14, 1961, Ser. No. 116,975
‘r
9 Claims.
(Ql. 260—-2=i7.1)'
'
The present invention is concerned with novel acyl
phenylmonpholine and p-chlorophenyl isocy-anate in
derivatives of heterocyclic hydrazines and, more particu 10 ether is heated at the re?ux temperature to afford N-(2
larly, with N-acyl derivatives of 4-amino-2-carbocyclic
3-methylmorpholines of the structural formula
phe ny1-3 -1nethylmorpho1in-4-yl ) -N’-p-chlorophenylurea.
The compounds of this invention exhibit valuable anti
bacterial and anti-fungal properties as is evidenced, for
example, by their inhibitory action on the growth of
15 Diplococcus pneumoniae and Trichophyton menta'gro
R
CH3
phytes. In addition, the instant substituted morpholin-4
ylureas and substituted carboxarnidomorpholines display
wherein R is a 6-membered carbocycle, R’ is selected
from the group consisting of pyridyl, 5-methyl-3-isox
azolyl, and hydrocarbon radicals of less than 9 carbon
valuable pharmacological properties. They are, for ex
ample, anorectic, hypotensive, anti-in?ammatory, and
atoms optionally substituted by halo, lower alkoxy, and 20 cholesterol synthesis inhibitory agents.
(lower alkanoyl)amido groups, X is a carbonyl or sul
The invention will appear more fully from the ex
ttonyl group, {and n is 0 or 1.
The hydrocarbon radicals which R’ represents are
amples which follow. These examples are set forth by
way of illustration only and it will be understood that
exempli?ed by methyl, ethyl, propyl, ibutyl, pentyl, hexyl,
the invention is not to be construed as limited in spirit
the branched-chain isomers thereof, phenyl, benzyl, 25 or in scope by the details contained therein, as many
phenethyl, tolyl, and icyclohexyl.
modi?cations in materials and methods will be apparent
Suitable starting materials for the manufacture of the
compounds of this invention are the substituted 4-a-mino
morpholine-s of the structural formula
from this disclosure to those skilled in the art. ‘In these
examples temperatures are given in degrees centigrade
(° C.). Quantities of materials are expressed in parts by
30 weight unless otherwise noted.
Example 1
R
To a solution of 1.92 parts of 4-amino-3-methyl-2
CH3
phenylmorpholine and 1.36 parts of phenylacetic acid in
wherein R is ‘as identi?ed supra, which are prepared
‘67 parts of methylene chloride is added a solution of 2.27
by nitrosation of the corresponding substituted morpho
lines followed by reduction of the resulting N-nitroso
parts of dicyclohexylcarbodiimide in 26.8 parts of meth
ylene chloride, and the resulting mixture is allowed to
compounds, ‘as is described in my copending applica
stand at room temperature for about one hour.
tion, Serial No. 104,217, ?led April 20, 1961. Acyla
The
tion of these intermediates with a carboxylic acid chlo 40 precipitate of dicyclohexylurea is removed by ?ltration,
and the ?ltrate is evaporated to dryness to afford a yellow‘
ride or sulfonic acid chloride affords the carboxamido
solid. Recrystallization of this solid from absolute etha
and sulfonamidomorpholines of the present invention.
nol a?ords white needles of 3-methyl#2-phenyl-4-phenyl
This process is exempli?ed by the reaction of 4-amino-3
acetamidomorpholine, Ml’. about l53—-l54.5°. This sub
methyl-l-phenylmorpholine with p-anisoyl chloride in
the presence of pyridine to atiord 4-(p~anisamido)-3 45 stance is represented by the formula
meth?-Z-phenylmorpholine as well as the reaction of
that substituted aminomorpholine with p-acetamido
benzenesulfony-l chloride and pyridine to yield 4-(peacet
amidobenzenesulfonamido) - 3-methyl-2-phenylrnorpho
line. An alternate process how the manufacture of these 50
compounds involves reaction of the free carboxylic or
sulfonic acid with the substituted aminomorpholine in
CH3
the presence of a dehydrating agent such as a disubsti
tuted car-bodiimide.
Typically,
Example 2
4-arnino-3-me’thyl-2
phenylmonpholine is allowed to react with phenylacetic
acid in the presence of dicychlohexylcarbodiimide to
To‘ a solution of 3.84 parts of 4-amino-3-methyl-2
phenylmorpholine and 3 parts of hydrocinnamic acid in
134 parts of methylene chloride is added a solution of 4.54
parts of dicyclohexylcarbodiimide in 67 parts of methylene
produce 3 - methyl-2~phenyl~4-phenyl=aoetamidomorpho
line. A third process particularly suitable for the n1=anu_
facture of the instant carboxamido-morpholines involves
chloride, and the reaction mixture is stored at room tem
reaction of the car-boxylic acid with ethyl chloroformate 60 perature for about 2 hours, then is ?ltered to remove the
in the presence of an acid acceptor such as triethyiarnine
precipitated dicyclohexylurea. The solvent is removed
to ‘afford the mixed anhydride, which is then treated with
the appropriate minomio-rpholine.
For example, 5
from the ?ltrate by evaporation on the steam bath. The
oily residue is dissolved in butanone and treated with iso
, propanolic hydrogen chloride, then with ether to afford
methyl-3-isoxazole carboxylic acid is allowed to react
With ethyl chloroformate in the presence of triethyl 65
3 - methyl-Z-phenyl ~ 4 - (p-phenylpropionamido)mor
3,098,853
3
4
pholine hydrochloride. Recrystallization from butanone
Example 6
The substitution of 1098 parts of m-bromobenzoyl chlo
ride for benzoyl chloride in the procedure of Example 3
results in 4-(m-bromobenzamido)-3-methyl-2-phenylmor
pholine. This product is recrystallized from absolute
ether produces the pure hydrochloride.
The aforementioned hydrochloride is dissolved in water
and treated with dilute aqueous sodium hydroxide. The
resulting aqueous mixture is extracted with chloroform,
and the organic layer is separated, dried over anyhdrous
sodium sulfate, and evaporated to dryness to yield the
ethanol to afford the pure material, which melts at about
214.5-216". It is represented by the formula
crystalline free base, 3-methyl-2-phenyl-4-(B-phenylpro
0
pionarnido)morpholine, M.P. about 119-121”, which is
represented by the formula
10
ll
CH3
OH:
Br
15
Example 7
By substituting 7.32 parts of cyclohexylcarbonyl chlo
ride and otherwise proceeding according to the processes
Example 3
20 of
Example
3,
4-cyolohexylcanboxamido-3-methyl-2
phenylrnorpholine is obtained. This substance is re
crystalized from absolute ethanol to yield white needles
To a solution of 9.6 parts of 4-amino-3-methyl-2-phenyl
morpholine in 49 parts of pyridine is added 7.02 parts of
benzoyl chloride. When the initial exothermic reaction
of the pure compound, which displays ‘a melting point
of about 209-2105". Its structural formula is illustrated
subsides, the reaction mixture is heated on the steam bath
for about 30 minutes, then is stripped of excess pyridine 25 below.
by ‘distillation at reduced pressure.
The solid residue is
o
treated with about 75 parts of water, then is made alkaline
by the addition of dilute aqueous sodium hydroxide. The
o
resulting solid product is collected by ?ltration, washed
N-NHG
CH3
with water, and dried to produce 4-benzamido-3-methyl-2 30
phenylmorpholine. Recrystallization from absolute etha
nol affords white needles of the pure product, melting at
about 211-213". This compound is represented by the
formula
0
/
\
O
Example 8
35
H
To a solution of 9.6 parts of 4-amino-3-methyl-2
phenylmorpholine in 49 parts of pyridine is added 8.5
—NHC-—
parts of o-anisoyl chloride. After the initial exothermic
reaction subsides, the reaction mixture is heated on the
40 steam bath for about 30 minutes, then is stripped of
excess pyridine at reduced pressure. The resulting resi
due is treated with about 75 parts of water, then with
dilute aqueous sodium hydroxide. The resulting viscous
CH3
Example 4
oily product is extracted with chloroform, and the organic
layer is separated, washed with Water, dried over anhy
By substituting 8.5 parts of p-anisoyl chloride in the 45 drous potassium carbonate, and treated with decolorizing
process of Example 3, 4- (p-anisamido)-3-methyl-2-phenyl
morpholine is obtained. Recrystallization of this prod
carbon. The decolorized organic solution is ‘stripped of
solvent at reduced pressure, and the residual oil is tri
turated with hexane to afford 4-(o-anisamido)-3-methyl
2-phenylmorpholiue as an oil. Its structure is illustrated
not from absolute ethanol affords white needles of the
pure substance melting at about 193.5—l194.5°. This sub
50 by the ‘following formula
stance is represented by the formula
0
0
ll
O
55
CH3
Example 5
60
The substitution of 8.7 parts of p-chlorobenzoyl chlo~
ride for benzoyl chloride in the process of Example 3 re
‘_\N—NH(LJ—
CH3
0 0 Ha
Example 9
A solution of 5.46 parts of 3-carboxy-5-methylisoxazole
in 241.2 parts of methylene chloride is cooled to about
—5‘’, then is treated successively, ‘by dropwise addition
sults in 4-(p-chlorobenzamid0)-3-methyl-2-phenylmor
with stirring, with 4.34 parts of triethylarnine and 5.15
pholine. This substance is recrystallized from benzene
to yield light tan needles of the pure material, M.P. about 65 parts of ethyl chloroformate over a period of about 22
minutes. The resulting mixture is stirred at —5° for
197—l99.5°. Its structure is represented by the formula
about 30 minutes, then is treated by dropwise addition
over a period of about 15 minutes with a solution of 8.25
0
/
0
\
ll
N-NHG-
CH3
—o1
parts of 4-amino-3-methy1-2-phenylmorpholine in 26.8
70 parts of methylene chloride. The resulting yellow reac
tron mixture is stirred at —5° for ‘about 30 minutes,
allowed to warm to room temperature, then stored at
room temperature for about 16 hours. The solvent is
removed by evaporation at reduced pressure, and the
75 yellow solid residue is triturated with ether, then col~
3,098,853
Example‘ 13
lected by ?ltration. This solid is extracted with benzene,
and the benzene extract is evaporated to dryness at re
duced pressure.
To a solution of 9.6 parts of 4-amino-3-methyl-2-phen
ylmorpholine in 49 parts of pyridine is added 8.84 parts
of benzenesulfonyl chloride, and the initial exothermic
reaction is allowed to subside, whereupon the reaction
mixture is heated on the steam bath for about 30 minutes,
This crude product is recrystallized
twice from absolute ethanol to afford white needles of
3-methyl-4-(5' - methylisoxazole-3'-carboxamido) -2-phen
ylmorpholine, melting at about 165—166°. It is repre
sented by the following structural formula
then stripped of excess pyridine at reduced pressure.
Treatment of the residue with about 75 parts of water and
su?icient dilute aqueous sodium hydroxide to render the
mixture basic results in separation of the oily product,
which is extracted into chloroform.
The chloroform
layer is separated, washed with water, dried over anhy
drous sodium sulfate, and treated with decolorizing car
15 bon.
The resulting solution is concentrated at reduced
pressure to afford a dark brown oil, which is triturated
Example 10
with hexane to yield the solid product. Recrystallization
To a suspension of 8.9 parts of isonicotinoyl chloride
of this crude solid from benzene results in light tan crystals
hydrochloride in 49 parts of pyridine is added a solution
of 4 - benzenesulfonamido - 3 - methyl - 2 - phenylmor
of 9.6 parts of 4-amino-3-methyl-Z-phenylmorpholine in
pholine, M.-P. about 164—166‘’ (dec.). This product is
49 parts of pyridine. The initial exothermic reaction is 20 illustrated by the structural formula
allowed to subside, and the reaction mixture is heated
on the steam bath for about 30 minutes, then stripped of
pyridine by distillation at reduced pressure. The residue
is suspended in about 75 parts of water, and this mixture
is made alkaline by the addition of ‘dilute aqueous sodium 25
hydroxide. The resulting product is extracted with
chloroform, and the organic layer is separated, washed
with water, then dried and decolorized with a mixture of
anhydrous potassium carbonate and decolorizing carbon.
The resulting solution is evaporated to dryness at reduced 30
pressure, and the solid product is triturated with hexane
Example 14
Re
By substituting 9.56 parts of p-toluenesulfonyl chloride
crystallization of this crude product from benzene pro
duces white ?akes of 4-isonicotinamido-B-methyl-Z-phen
for benzenesulfonyl chloride in the process of Example
to remove small amounts of residual pyridine.
1 3, 3-methyl-2-phenyl-4-(p-toluenesulfonamido) morpho
ylmorpholine, M.P. about 209-‘211°, which is represented 35 line is obtained. Recrystallization from benzene affords
white needles of the pure substance melting at about
'by the structural formula
153-154°. ‘Its structure is represented by the following
formula
40
0
N—NHSOz—®'OH3
CH3
45
The reaction of 14.85 parts of 4-amino-2-cyclohexyl-3
Example 15
methylmorpholine and 13.35 parts of isonicotinoyl chlo
ride hydrochloride by the procedure of Example 10
The substitution of 11.7 parts of p-acetamidobenzene
results in 2-cyclohexyl-4-isonicotina:mido-3-methylmor 50 sulfonyl
chloride for benzenesulfonyl chloride in the pro
‘pholine, which melts at about 155—157°. This substance
cedure of Example 13 results in 4-(p-acetamidobenzene
is represented by the following formula
sulfonamido)-3-methy1-2-phenylmorpholine. The prod
not can be recrystallized from absolute ethanol to yield
white needles of the pure substance, which melts at about
Its structure is rep
55 208° with immediate decomposition.
resented by the following formula
60
By substituting 9.08 parts of o-ethoxybenzoyl chloride
and otherwise proceeding according to the processes of
Example 8, 4—(o-ethoxybenzamido)-3-methyl-2-phenyl
morpholine is obtained. Its structure is represented by
the following formula
65
Example 16
A solution of 5 parts of 4-arnino-3-methyl-2-phenyl
morpholine and 3.21 parts of phenyl isocyanate in 237
parts of anhydrous ether is heated at re?ux for about one
hour, then cooled to room temperature. The resulting
crystalline precipitate is collected by ?ltration, washed
with ether, and dried to yield N-(3-methyl-2-phenylmor
75 tpholin~4-yl)-N'-phenylurea as a white crystalline solid,
3,098,853
8
melting at about 191-194".
about 11/2 .hours.
Its structural formula is illus
The reaction mixture is cooled to
room temperature and the resulting crystalline product is
trated as follows
0
collected by ?ltration, then extracted with hot benzene.
ll
The benzene extract is concentrated at reduced pressure
to afford N - (2-phenyl-3-methylmorpholin-4-yl)-N’-p
chlorophenylurea as a white crystalline solid, melting at
about 191-194°. Its structural formula is shown below
CH3
0
ll
Example 17
CH3
The substitution of 4.15 parts of o-chlorophenyl iso
cyanate for phenyl isocyanate in the process of Example
16 results in N-(3-methyl-2-phenylmorpholin-4~y1)-N'-o
chlorophenylurea, obtained as a white crystalline solid. 15
It displays a melting point of about 180—181.5°, and is
Example 21
A solution of 5 parts of 4-amino-3-methyl-2—phenyl
morpholine and 1.92 parts of ethyl isocyanate in 158 parts
of anhydrous ether is heated at re?ux for about 2 hours.
represented by the structural formula
20 The solvent is removed by distillation on the steam bath,
CH3
and the residual oil crystallizes upon standing. Tritura
tion of this solid with hot hexane affords N-(3-methyl-2
01
25
phenylnrorpholin-4-yl)-N'-ethylurea as a white crystal
line solid, M.P. about 154—157°. Its structure is repre
sented by the following formula
Example 18
A solution of ‘5 parts of 4-amino-3-methyl-2-phenyl
morpholine and 5.35 parts of p-bromophenyl isocyanate
in 237 parts of anhydrous ether is heated at re?ux for 30
CH3
about 2 hours, then concentrated at reduced pressure.
The crystalline product which separates is collected by ?l
tration and extracted with hot benzene. Removal of ben
zene from the ?ltrate by distillation at reduced pressure
produces the white crystalline product, N-(3-methyl-2
phenylmorpholin-4-yl) -'N'-p-bromophenylurea, melting at
35
about 202-205 °. Its structure is represented by the for
Example 22
The substitution of 2.3 parts of n-butyl isocyanate in
the procedure of Example 21 results in N-(3-mcthyl-2
phenylmorpholin-4-yl)-N’ - n - butylurea, which is repre
sented 'by the structural formula
v40
CH3
CH3
.45
Example 19
Example 23
The substitution of 5.05 parts of 3,4-dichlorophenyl
isocyanate in the process of Example 19 results in N-(3—
A solution of 5 parts of 4-amino-3-methyl-2-phenyl
morpholine and 4.15 parts of m-chlorophenyl isocyanate
in 237 parts of anhydrous other is heated at re?ux for
methyl-2-phenylmorpholin-4-yl) - N'-3,4-dichlorophenyl
urea of the structural formula
about 11/2 hours, then allowed to stand at room tempera
ture for about 16 hours. The solvent is evaporated to
afford a yellow oil, which is ?rst triturated with hexane,
then crystallized from absolute ether.
The resulting 55
White solid is extracted with a mixture of benzene and
chloroform, and the extract is evaporated to dryness at
reduced pressure to yield an oil, which crystallizes on
standing. This crystalline product, N-(3-methyl-2-phen
ylmorpholin-4-yl) - N’ - Iii-chlorophenylurea, exhibits a 60
melting point of about 134-151° and is represented by '
the following formula
By substituting 10.24 parts of o-ethyl-benzenesulfonyl
0
o
\T\I_NH<Il-NH_C_>
CH3
chloride and otherwise proceeding according to the
processes of Example 13, 4-(o-ethylbenzenesulfonamido)
65 S-mcthyl-Z-phenylmorpholine of the structural formula
0 Hz C Ha
01
/T“'\
O
70
Example 20
A solution ‘of 5 parts of 4-amino-3~methyl-2-phenyl
morpholine and 4.15 parts of p-chlorophenyl isocyanate
in 237 parts of anhydrous ether is heated at re?ux for 75 is obtained.
N-NHS 02
0 H3
3,098,853
1O
9
What is claimed is:
1. A compound of the formula
3. A compound of the formula
CH3
wherein R is selected from ‘the group of radicals consist
ing ‘of phenyl and cyclohexyl, R’ is selected from the 10
wherein A is ‘selected from the group of radicals consist~
group of radicals consisting of phenyl, phenyl-(lower
alkylene), halophenyl, ‘(lower allooxy)phenyl, cyclohexyl,
ing of phen-yl, (lower alkyD-phenyl, and lower alkanoyl)
pyridyl, and 5-methyl-3-isoxazolyl, and n is selected from
the group of integers consisting of 0 and 1.
2‘ A compound of ‘the formula
Z-phenyLrnorpholine.
amidophenyl.
4. 3 - methyl-4-(5'-methylisoXazole-3'-carboxamido)
5. 4-isonicotinairnido-3-methyl-2-phenylmorpholine.
6. 4—benzamid:o-3-methyl~2-phenylmorpholine.
7. N - (3-methyI-Z-phenylmorpholine-4-yl)-N’-phenyl
urea.
CH3
8. N - (3-methyl-2-phenylmorpholin-4-yl)-N'-o-chloro
phenylurea.
9. N - (3 - methyl-2-phenyhn0rpholin~4-yl)-N’-ethyl
urea
No references cited.
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