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Патент USA US2409756

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2,409,755
Patented Oct. 22,‘ 1946
UNITED ' s-TArEs PATENT omen
METHOD FOR OBTAINING 5,5-‘DIARYIJ
‘
>HYDANTOINS'
.
Henry R. Henze, vAustin, Tex., assignor to Parke,‘
Davis & Company, Detroit, Mich, a corporation
of Michigan .
'
No Drawing. ‘Original application September 9,
1940, Serial No. 356,107. Divided and this ap- .
plication May 11, 194,4, Serial No. 535,211
10 Claims. (o1. race-309.5)
1
I have also found that the conditions of reac
‘ This invention‘ ‘relates to a method for obtain- '
ing hydantoins from ketones and more particu
larly to the preparation ‘of 5,5-diary1hydantoins
from diaryl ketones.
This application is a. division of my copend
ing application Serial No. 356,107, ?led Septem
her 9, 1940.
.
tion required for the formation of diarylhydan
toins from diaryl ketones determine the yield
which may be obtained. In general, the oper
ating temperature should be maintained within
1 the range of 50-150” C. and the time required for
‘ reaction proportionately varied from at least 20
.
An object of this invention is the preparation
of diarylhydantoins from diaryl ketones accord
ing-to .a new and novel method.
Other objects of this invention will be appar
ent on perusal of the speci?cation and the ap
hours for the lower temperatures to at least 1
hour for the higher temperatures, although
10 longer times of heating are in general helpful.
At the lower temperatures longer times of heat
ing are required to obtain the same ‘gross yield
that may be obtained at higher temperatures
with shorter reaction times.‘ For example, while
Hitherto diarylhydantoins have been prepared
from derivatives of benzil and similar compounds. 15 at least20 hours of heating at,55°, is necessary
pended claims.
‘
However, no method has been available. for the
preparation of 5,5-diarylhydantoins from the
.to get a substantial yield, the same yield can be
obtained at 110° by only a few hours of heating
corresponding diaryl ketones, despite the fact
in a closed vessel so as to retain the volatile com
that such ketones are frequently more readily
available, than the corresponding benzil deriva
ponents.
20
tives.
I have found that 5,5-diary1hydantoins can be
‘
l
.
r
,
In general, the diaryl ketone is not completely
converted into the diarylhydantoin. The yield
of diarylhydantoin calculated on the basis of the
amount of diaryl ketone originally introduced
‘prepared from diaryl ketones by heating the lat
into the reaction mixture is termed the gross
ter in fused acetamide or other lower aliphatic
amide as asolvent, with a water-soluble cyanide 25 yield while the yield of diarylhydantoin calcu
lated on the basis of the amount of diaryl ketone
and ammonium carbonate or an equivalent sub
actually used up, i. e. the difference between
stance capable of yieldingammonia and ‘car;
the amount of diaryl ketone originally introduced
and the amount recovered, istermed the net
so as to removeanyunreacted diaryl ketone and 30 yield. ‘While the gross yield is considerably di
minished by operating at lower temperatures and
,thlenthe hydantoin is‘isolated, for example, by
for shorter times of heating, the net yield is good
acidifying the alkaline solution.
under a11 conditions within the range indicated.
The reaction maybe illustrated ‘as follows for
the caseof the preparation of 5,5-diphenylhydan
vErrawmil'e 1.‘-Preparation‘ of ‘5-phenyl-5-(p-bro
bon dioxide under,v the conditions of reaction.
The reaction ‘mixture thus obtained is treated
35
mophenyl-(-hydantoin
-
26 g. of p-bromobenzophenone is dissolved in
125 g. of fused acetamide and then 28 g. of am
monium carbonate and 9 g. of potassium cyanide
40 are ‘added. ‘The mixture is heated in a steel
container at 110° C. for 6 hours. While still
liquid, the contents of the bomb are diluted with
water and acidi?ed with a, slight excess ‘of min
eral acid, such as sulfuric or hydrochloric‘ acid‘.
45 The mixture is then chilled and the precipitated
crude 5-pheny1-5e (p-br0mopheny1-) S-hydantoin
is ?ltered off. It is then treated with an aqueous
solution of dilute sodium hydroxide'to' dissolve
the hydantoin from the solid unreacted 'p-bromo
benzophenone. After ?ltration, the alkaline ex
tract is then acidi?ed to cause the separation of
solid
pure . 5-phenyl-5-(p-bromophenyl-) -hy
dantoin which is ?ltered ad and dried. The melt
ing point is 239° C. and the yield is 28 g.,(_85‘.2%
55
vnet
yield.)
,
,
H
g
_
~ 1
2,409,755
3
4
Instead of working up the reaction mixture as
described above, the reaction mixture may be
dissolved in water and acidi?ed. The precipi
tate is collected and leached with 5% sodium hy
droxide solution to dissolve the diphenylhydan
toin. The undissolved benzophenone is separated
rendered somewhat more alkaline and then any
unreacted benzophenone removed by extraction
with a water-immiscible organic solvent such as
and the alkaline solution is acidi?ed with acetic
benzene, ether, or the like. Then the alkaline
layer may be acidi?ed to precipitate the diaryl
acid to precipitate the 5,5-diphenylhydantoin.
The precipitate is collected, dried and recrystal
hydantoin which may be puri?ed by recrystalli-. ,
lized from methanol. Thus there is obtained an
zation as for example from alcohol.
83.5% gross yield of the hydantoin; since 1.2
of benzophenone 15’ recovered’ the net meld
Example 2.—-Preparation of 5-phenyl-5-(p-chlo- 10
rophenyz')'hydantom
The following table summarizes the results of
A mixture of 21-6 g. of p-chloro-benzophenone,
125 g. acetamide, 28 g- of ammonium carbonate
Egg?‘
Reactants
1 ______ _.
9.1g.benzophenone,4.5g.potasslumcyanlde,15.01;.
a number of experiments in which the conditions
of reaction'and the solvents are varied.
Solvent
.
Conditions
$21
.
Per cent
100cc.water ________________________ __
ammonium carbonate.
100° 0.; 14hr _____ ..
0
5 ___________ “g8 ............................................. _. 115 gdoacetamide 20 cc. water ........ ._
.
...
>__
4.
__d
5.
-413...
I
____ _.
"55.;
____________________________________ _.
115
.
"
.D
_
. 100 g. gggtggiggj _____________ __
____ _.
'
95
6 ______ __
'
9.1 g. benzophenone, 2.45 g. sodium cyanide, 4.8 g.
ammonium carbonate.
_._._do ________________________ __
7 ______ __
9.1 g. benzopheno, 3.4 g. potassium cyanide, 4.8 g.
_.___do _______________________________ __
__
ammonium carbonate.
83.5
96
85
____ ..
~
110° 0.; 6 hrs ____ __
85
____ __
e ____________ .do ________________________________________ -.do ......... _.
8 ........... _.do ____________________ .......-
50 g. acetamide._
110° 0.; 4 hrs ____ -_
s5
.... ..
10 _____ __ ‘18.2 g. benzophenone, 9.0 g. potassium cyanide, 28 g.
90° 0.; 2 hrs _____ __
100 g. acetamide.
ammonium carbonate.
5. l
79
and 9 g. of potassium cyanide isheated inabomb 30
Instead of using acetamide in this example,
for 4 hours at 110° 0. While still hot, the reacother lower aliphatic amides such as propion
tion mixture is diluted with water and then
amide, butyramide and the like may also be em
cooled. The solution is acidi?ed, the precipiployed.
tated crude 5-phenyl-5-(p-chloro-phenyl-) -hyIn view of the foregoing examples it will be ap
dantoin is collected and puri?ed as in Example 1. 35 parent that numerous variations can be employed
The yield of this product, melting point 243° C.
in my process without departing from the spirit of
is 27 g.
my invention.
_
_
v_
For example, I may employ any diaryl ketone
Example 3-—P_Tepamt?m 0f 5,5-dZ-‘(p-d2methylammophenyl-)-hydantom
_
containing in the aromatic nucleus no groups
.10 which are attacked by cyanides or ammonium
_
carbonate or the combination of the two.
To 115 g. of fused acetamide is added 18 g- Of
Mlchler 5 ketone (bis-Pip '(_d1methy1?mm°)'ben'
ggphenogfiil
31-5‘3'giqgéngitassrllag
057F213: 15an?eZaiegd
amm
e’
mix
atldelg infill 1453315551‘.
witgflgfzilnés
o
a
_
a
_ '
e
_
'
,
,
diaryl ketones, on ring-amino substituted diaryl
-
tone, di-p-tolyl ketone, anisyl phenyl ketone, etc.
Instead of using sodium cyanide or potassium
Eh‘; pgeclgltated??-tdg<p-glmqth-
y ammo!) em’ ' ' 1y an 0”} 0° e‘? e
an
ketones,Such
ring-alkylated
diaryl ketones and the
ketones include p-bromobenzophe
none’ p'amimbenzophemne Xenyl phenyl ke
a‘ like.
1 J
The alkaline layer is carefully neutrahzed with
afetlP 9mg
Thus
I may practice my invention on ring-halogenated
cyanide in the practice of my invention, I may
dlged' 5U employ other water-soluble cyanides such as cal
The yield of product melting point 276-230 C-
cium cyanide or lithium cyanide.
15 6g-
usually prefer to use alkali metal cyanides, be
.
.
cause of their availability.
Example {tr-P“M33211”, 0%: 5 (dwhenylene_> '
y .
However, I
Instead of using ammonium carbonate in the
5;, practice of my invention, I may use other equiva
of fused acetamide.
18 gramsof ?uorenone
is dissolved in .100 grams
Then 9 grams of potassium
1251f’r $215131 i oafmcli'gggg
‘$2223 g’glfllooi’lnalgglgé
.
'
. .
cyanideand 28.8 grams of ammonium carbonate
gas may, be pumped into the autoclave cont'fumng
are added and ‘the mixture heated in a Steel bomb
the rmxture of the dlaryl ketone, the orgamc sol
at 110.. C_ for 10 hours_ The reaction mixture 50 vent and the water-soluble cyanide, and the mix
is diluted With 150 cc. of water, and then the
We heated?“ w°rked_up to Obtain the ewe“
mixture is acidi?ed with hydrochloric acid and
spenduig d1ary1hydant9m'. {mother sf’urce of
the precipitated solid collected.
The yield of
ammma and can)“ dloXlde 15* ammOmum car
diphenyleneehydantoin of melting point 324° 7C.
is 215 grams (86% gross yield) _
'
Example 5.--Prepardtion of 5,5.-diphenylhydan_
bamate' ,
65
,
,
_
Where 1n the speci?cation and claims the term
ammonium carbonate is used, it is to be under
stood that it refers to the article of commerce
tot-n using acetamide as a solvent
designated by that name, which however is con
sldered to be in reality a mixture of ammonium
100 grams of acetamide is melted in a steel 70 bicarbonate and ammonium Carbamate. See
bomb and to it is added 9.1 grams of benzofurther F- Ephraim In0rganic Chemistry (third
phenone, 2.45 grams of sodium cyanide and 4.8
ed. translated by P. C. L. Thorne and A. M. Ward,
grams of ammonium carbonate. The bomb is
closed and heated at 110° C. for 4 hours. Then,
Nordeman Publishing Company, New York, 1939),
page 801.
while still liquid, the contents of the ‘bomb are 75 Since the invention may be practiced not only
2,409,755
5
‘
6
.
.
agent derived from the system NHa-CO2-—Aq ca
from the system NHa—COz-—Aq capable of re
generating all of these latter components under
the conditions of the reaction, in the presence
of a lower aliphatic amide, acidifying the reac-‘
tion mixture, and separating the 5,5-diphenyl
pable of regenerating all of these components
hydantoin thus produced.
under the conditions of reaction.”
What I claim as my invention is:
1. Process for the preparation of a diaryl hy
6. Process for the preparation of 5,5-diphenyl
hydantoin which comprises heating together in
with ammonium carbonate, as above de?ned, but
also with other equivalent sources of carbon di
oxide and ammonia in the presence of water, I
have used as a generic expression the phrase “re
dantoin which comprises heating together at tem
peratures above 90° C. and for a time, at least a
few hours, permitting accumulation of appreci
a closed system preventing loss of volatile react
ants at temperatures above 90° C. and for a time,
at least a few hours, permitting accumulation
of appreciable reaction product, benzophenone,
a water-soluble inorganic cyanide, and a re
able reaction produot, a diaryl ketone, a water
agent derived from the system NI-Ia—CO2-—Aq
soluble inorganic cyanide, and a reagent derived
from the system NH3—COz-—Aq capable of re 15 capable of regenerating all of these latter com
ponents under the conditions of the reaction, in
generating all of these latter components under
the presence of a lower aliphatic amide, acidify
the conditions of the reaction, in the presence
ing the reaction mixture, and separating the
of a lower aliphatic amide, acidifying the reac
5,5-diphenyl hydantoin thus produced.
tion mixture, and separating the diaryl hydantoin
V20 '7. Process for the preparation of 5,5-diphenyl
thus produced.
2. Process for the preparation of a diaryl hy
dantoin which comprises heating together in a
closed system preventing loss of volatile react
ants at temperatures above 90° C. and for a time,
at least a few hours, permitting accumulation of
appreciable reaction product, a diaryl ketone, a
water-soluble inorganic cyanide, and a reagent
derived from the system NH3-—C‘O2-Aq capable
of regenerating all of these latter components
I under the conditions of the reaction, in the pres
ence of a lower aliphatic amide, acidifying the
reaction mixture, and separating the diaryl hy
dantoin thus produced.
3. Process for the preparation of a diaryl hy
dantoin which comprises heating together at
temperatures above 90'’ C. and for a time, at least
a few hours, permitting accumulation of appre
ciable reaction product, a diaryl ketone, a water
hydantoin which comprises heating together at
temperatures above 90° C. and for a time, at least
a few hours, permitting accumulation of appre
ciable reaction product, benzophenone, a water
soluble inorganic cyanide, and a reagent derived
from the system NH3—CO‘2—Aq capable of re
generating all of these latter components under
the conditions of the reaction, in the presence
of fused acetamide, acidifying the reaction mix
ture, and separating the 5,5-diphenyl hydantoin
thus produced.
8. Process for the preparation of 5,5-diphenyl
hydantoin which comprises heating together in
a closed system preventing loss of volatile re
actants at temperatures above 90° C. and for a
time, at least a few hours, permitting accumula
tion of appreciable reaction product, benzophe
none, a water-soluble inorganic cyanide, and a
reagent derived from the system NH3--CO2—Aq
soluble inorganic cyanide, and a reagent derived 40 capable of regenerating all of these latter com—
from the system N'I-I3—-COz-'—Aq capable of re
ponents under the conditions of the reaction, in
generating all of these latter components under
the presence of fused acetamide, acidifying the
the conditions of the reaction, in the‘presence
reaction mixture, and separating the 5,5-diphenyl
of fused acetamide, acidifying the reaction mix
hydantoin thus produced.
ture, and separating the diaryl hydantoin thus 45
9. Process for preparing 5,5-diphenyl hydan
produced.
toin which comprises heating together at tem
4. Process for the preparation of a diaryl
peratures above 90° C. for several hours, benzo
hydantoin which comprises heating together in
phenone, a water-soluble inorganic cyanide, and
a closed system preventing loss of volatile re
a reagent derived from the system NH3—-COe-Aq
actants at temperatures above 90° C. and for a
capable of regenerating all of these latter com
time, at least a few hours, permitting accumu
ponents under the conditions of the reaction, in
lation of appreciable reaction product, a diaryl
the presence of fused acetamide, adding an acidi
ketone, a water-soluble inorganic cyanide, and
?ed aqueous solution, and separating the di
a reagent derived from the system NH3—-—CO2——Aq
phenyl hydantoin thus produced.
a
capable of regenerating all of these latter com
10. Process for preparing 5,5-diphenyl hydan
ponents under the conditions of the reaction, in
toin which comprises heating together in a closed
the presence of fused acetamide, acidifying the .
system preventing loss of volatile reactants at a
reaction mixture, and separating the diaryl hy
temperature about 110° C. for several hours, ben
dantoin thus produced.
zophenone, an alkali cyanide, and ammonium
5. Process for the preparation of 5,5-diphenyl
carbonate, in the presence of fused acetamide,
hydantoin which comprises heating together at
adding an acidi?ed aqueous'solution, and sep
temperatures above 90° C. and for a time, at least
arating the diphenyl hydantoin thus produced.
a few hours, permitting accumulation of appre
HENRY R. HENZE.
ciable reaction product, benzophenone, a water
soluble inorganic cyanide, and a reagent derived
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