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Патент USA US2403723

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Patented July 9, 1946 1
2,403,723
_ UNITED ‘ STATES
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OFFICE ,
2,403,723
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' “PREPARATION 0F1,2,4-0XADIAZOLES I
Donald
Kaisegrl'tiverside, 00ml, assignor to
American Cyanamld Company, New York,
N. Y.,acorporation ollltialn'e.
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No Drawing. Application June 23, 1944,
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Serial N0. 541,845
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57 Claims.’ (01. zoo-307i ' '
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“as solution Willtake Place a "Short time after the
pounds, nove11'reaction. products thereof, and to
methods ofpreparingthesamle.
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#I'his invention. relates tov new organic com
a
reaction has started-
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'The 3-a1ky1,’ cycloalkyl, and ,aryl-B-ureido
1.
I I'h'ave discoveredlthatewhen3-alkyl, cycloalkyl,
1,2,fl-oxadiazoles which are used as intermedi
. ates injthe present invention can be prepared-by
' heating together an acyl dicyandiamide and ‘hy
and!aryl-s-ureido-1,2,4;oxadiazoles are hydro
lyz'ed-byheating with anacid or. alkali in-a suit-.
able‘v liquid reaction-medium containing at 1 least
a:--small amount of water, a reaction takes place
iii-accordance with the vfollowing.“ equation: i .,
Y droxylamine, as shown, in Example 1,.
The acyl v '
dicyandiamides are in turn prepared bysimply
. '10.
mixingdicyandiamide with a desired acyl halide
oranhydride in a water-soluble alkali metal hy
‘ droxide in the presence of, a small amount of
water and a nonehydroxylated solvent such as‘
acetone.
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.Agreatnumber of 3-alkyl, cycloalkyl, and aryl
5-.ureido-1,2,4-oxadiazoles can be employed in
is the.
reaction describedherein to ‘produce the new
compounds 1 of the. , present, invention.
Among
these. may be speci?cally mentioned: 3-methyl
5-ureido-1,2,4-oxadiazole,
In; the formulas R; is analkyl, .cycl'oalkyl, or. aryl 20' 1,2,4-oxadiazole,
radical; The products of . the reaction, .3-alky1,
cycloalkyl,
’ 3-n-butyl-5-ureido
3-isoamyli5-ureido-1,2,4soxa
diazole, .3=dodecyle5-ureidoe1,2,4-oxadiazole, ,3
and‘ aryl-S-amino-1,2,4-oxadiazoles, '
are Knew; compounds and form .the .principalsube
iect 'matterlof the I present invention. 1 The- 5
aminolgroup'i-si very. easily hydrolyzed to a, .—‘OH 25
group, and". the resulting compounds, ..3-'alkyl,‘
oxadiazole,
oxadiazole, 3.-(p-hy_dr0xypheny1) -5-ureido-1,2,4
the purview of the present invention- .These' lat
hydrolysis‘ofthe reaction mixture. .
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,
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TI’h‘eI hydrolysis of-3'-'alkyl, cycloalkyl, and aryl
5-'ureid'o-1~,2,4-oxadiazoles may. take place.‘ at
3=phenyl-5-ureido-1,2,4
.. 3-(p-nitropheny1)-5—ureido-1,2,4
oxadiazole, 3- (o-carboxyphen'yl) -5-.ureido-1,2,4
are also new compounds and are included ‘within
ter' compounds are easily formed upon. continued
3- (wrhydroxydecyl) :5-ure
ido,1,2,4-oxadiazole,.
oxadiazole, .
3-cyclohexyl-5-ureidor1,2,4-oxadi
30 azole, and otheralkyl, cycloalkyl, and aryl-5
ureido-1,2,4-oxadiazo1es.
‘ L-Almost any commonly used acidic or alkaline ,
hydrolyzing agent may be used in the process des
temperatures between about»'25°~~C'.: and 125? C. ., scribed herein; Among such conventional hy
in_ an? alkaline ior acidic reaction‘. medium com 35 drolyzing agents are sodium. hydroxide, potas
prising water. A convenient'meth'od ofconduct;
sium. hydroxide, ammonium hydroxide, sodium
carbonate, potassium carbonate, barium hydrox
ide; etc, and sulfuric acid, hydrochloric acid,
acetic acid, nitric acid, phosphoric acid, etc.
ing the reaction is to mix the reactantsfin‘a suit
able solvent or diluent and heat thevreaction'mix
ture under a re?ux condenser until the reaction
is complete. This may-fbe determined by trap 40 Since the use “of acidic and alkaline hydrolyzing
ping the ammonia evolved from the reaction mix
ture and determining the amount so evolved until
a theoretical quantity has been liberated. This
procedure is illustrated in one :of the‘sp'eci?c ex
ampleshereinafter described.
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’ The time required-to complete’ the reaction may
be vfrom about 1 hour to about 30 hours‘or more
depending upon the utemperature‘ofthe reaction
and the nature of the acid or alkaliemployed ‘as
the hydrolyzing agent.
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A suitable solvent for the “reactants may be
water alone or ethanol, methanol, butanol, di
agents is well understood. by thosein the ‘art, lure
ther'de'soription thereof would. appear to be un
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necessary.
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The. 3'-alkyl,i' cycloalkyl, ; and. >ary1-5-amino
45
1,2,4-oxadiazoles of the present inventionrare
generally characterized as being basic, white
crystalline, solids, easily to slightly soluble in
‘Water depending upon the nature of the 3-sub
stituent. In general, they are not easily soluble
in organic solvents but may be dissolved in small
amounts in Cellosolve, aliphatic alcohols, pyr
idine, dloxane, etc, ; They melt or decompose at
oxane, Cellosolve, or’ otherwater-miscible sol
highv temperatures, their melting points being
vent, or a mixture ‘or-these solvents with each
somewhat, dependent upon themanner in which
other or with water.-» It will be understood, of,
they are determined; The 3-alky1, cycloalkyl, and
course-that, enoughwater is present to enable '
4aryl:5-amino-l,2,¢l-oxadiazoles are useful for _,a
the; hydrolysis to take place; as indicated. byithe
variety of purposes including: as ,dyestuif inter
mediates,» in the ‘preparation of'ch'emothera
peuticuagents, in. the, preparation of 1 quaternary
ammonium-compounds, and the like...
equation: above. : Althoughll usually, dissolve the
reactants before heating the reaction mixture,itf
isinot necessary that they becompletely dissolved,
2,403,723
4
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The 3-a1kyl, cycloalkyl, and aryl-5-hydroxy
’
1,2,4-oxadiazoles are somewhat similar in physi
cal properties to the 5-amino-oxadiazoles ‘but are‘
.
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‘Example
3;
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"A solution of 32.5 g. of 97 %v barium hydroxide
octahydrate in 250 cc. of hot water was ?ltered
characterized as being slightly more soluble in , ' ‘and added to 24.4 g. of 3-methyl-5-ureido-1,2,4
: oxadiazole in a 1-liter ?ask ?tted with a stirrer,
water and having a higher melting or decompo
sition point.
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nitrogen bubbling tube, and a condenser leading
As previously stated, the 5-amino-oxadiazoles
‘to .a,-,safety bottle ‘and ?nally to an absorption
are easily converted to the correspondingb-hye # ?ask containing 80cc. of 2.5 N hydrochloric acid.
droxy-oxadiazoles upon continued 'hydrolysis;
A stream of nitrogen was passed into the reaction
and care must be exercised in the initial hydroly .10. mixture as the mixture was re?uxed gently. The
sis if good yields of the 5-amino oxadiazoles; are 3 rate and extent of reaction was followed by titrat~
to be obtained. Also, as previously mentioned,
ing the acid solution to determine the amount
the
stopped
course
at of
thethe
required
reaction
point
mayby
be observing
followed‘ and
the ‘ ' of ammonia evolved and by weighing the barium
carbonate precipitated during the reaction. The
amount of ammonia evolved from the reaction
reaction was completed in 14 hours and.15_ ‘min
mixture. Continued hydrolysis results in elimi
utes. The reaction mixture'rwasf?ltered .and
nation of an additional mole of ammonia through.
cooled in an ice bath to precipitate awhite‘solid.
replacement of the 5-amino'group-by-a hydroxy
By continuous .‘ether, vextractionv of this'solid" ‘and
group iii the presence or water; '
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I’ g .
the'mother liquor "a total‘ of 11.2 g; ofgla‘ssy
My invention will now be illustratedin greater}
needles melting at 160-162“ C.‘ wasv obtained; ,By
detail by means of the following specific examples
recrystallizing a sample of 1. g.‘ of this'product
which are given for purposes of illustration. and
from 200 ‘cc. .of ether, a sample, meltingiat
163-164“ C." was obtained which analyzed ‘cor-,1
are not'to be ‘considered as limiting my inven
tion to the particular details described therein.» '
Example}
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rectly for 3-methyl-5-amino-1,2,4-oxadiazole.
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To a suspension of. 131.6 g. of‘benzoyl dicyan
A mixture of 20.4 g. (0.10 mol).-of,3-.phenyl-5
diamide in 1500 cc. of water was added a solution
ureido-1,2,4-oxadiazole, 60 g. (0.60 mol) of con
of 59 g. of hydroxylamine hydrochloride in .1500
( centrated hydrochloric acid, 250 cc. of water, and
100 cc. of dioxane‘was heated to re?ux. The
mixture foamed, and more dioxane and some bu
cc. of water. i The mixture was stirred and heated
and anadditional 500 cc. of water added. ' iAfteir‘
re?uxing 30 minutes, the mixture was cooled and
the colorless solid filtered. washed with ‘water,
tanol wereradded, After an hour’s heating, solu
tion occurred.
and dried. On analysis itproved to be 3—phenyl
Re?uxing was continued 4 hours
longer. The. brown solutioniwas clari?edxwith'.
351 Nuchar,
and the ?ltrate evaporated on a ‘steam
- .To'a solution-of 33 g. (0.50 mol) of 85%potase
bath; “ Arresidue-of brown‘liquid and .solidre
sium hydroxide in 250 cc. of water was added
mained. Concentrated. hydrochloric acid .was
40.8 g. - (0.20 mol) of 3-phenyl-5-ureido-1,2,4
added andthe solid ?ltered, washed-with more.
oxadiazole. On heating to re?ux, solution oc-.
acid,
and allowedto'dry. The material weighed
curred, and ammonia began to be evolved. ‘After.
5-ureido-1,2,4-0xadiazole.
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2 hours of heating, Nuchar was‘ added tothe light
yellow solution, and it was then ?ltered. Cooling
of the nearly colorless ?ltrate gave a small quan
tity of long needles which melted at 160-162“ C.
Crystallization from a'large volume of hot water
gave slender, beautiful needles which .meltedat
164-165" C. and which analyzed correctly. £011.3
40 6.0. g. and decomposed at 188-'190° C. : Crystal-l
lization from hot water raised the decomposition
point to 197-198“ C., and fusion-with the prey
viously isolated 3-pheny-5-hydroxy-1,2;4eoxadi
phenyl - 5 1 amino-1,2,4-oxadiazole. .~ Thisjlzcom-é
pound was soluble in acid,.rreprecipitated .by
alkali, and insoluble in excess alkali. When; 1a
portion was dissolved inwater which contained
silver nitrate, addition‘ of a drop‘of ammonia pre
cipitated a light, yellow, amorphous, silver salt,
azole‘of the samemelting'point gave no depres_sion of the melting temperature. .In. this exame
ple the hydrolysis was more drastic,'the starting
material being converted ?rst into 3-phenyl-5
amino-l,2,4,-oxadiazole and then , to, 3-phenyl-5
hydroxy-1,2,4eoxadiazole without isolationv or the
former
-Iclaim:'
1. A~,method,of
as in,,
Examples
preparing
1 Jand3.
.' compounds
, . l
1' having.
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thefollowing structural formula; .
which decomposed at 192° C.
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Addition of acetic acid to the original alkaline 65
?ltrate, obtained from the reaction immediately
above, precipitated, 20 g. of colorless solid which
decomposed at 188~190° C. Crystallization from
in which
‘ R I’
is I amember
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_'N=
¢or the‘
it—'X._‘
‘group; consisting of
a large volume of water which contained alittle
alkyl,
cycloalkyl,
and
arylradicals,
and
a
methanol raised the decomposition . point to 60
member ofthe group "consisting of aminoand
19'l—198° C. The material was alkali soluble,
1
reprecipitated by acids, andinsolublezin excess
acid.
Analysis wasin good agreement vfor. 3
phenyl-5-hydroxy-1,2,4-oxadiazole.
Example 2 ‘
In a further experiment using barium hydroxi
ide in place of» potassium hydroxide the mixture
was re?uxed for 17'hours. After separating the
barium carbonate which had formed'in the vre 70
action mixture, 3-phenyl-5-amino-1,2,440Xadi-v
azole ~ was recovered.
No." 3-phenyl-5-hydrbxy
1,2,4-oxadiazo1e- was’ obtained when using'lthis
mild hydrolyzing- agent under- the conditions of
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this experiment.~~¥- '
1
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4-?“ '
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N-O
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hydroxy radicals which comprisesthe. step, of
heating in the presence of a hydrolyzing agent a,
compound having the formula I}
~ ' ;
‘I
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N-o
% l
_
\Ng simian.
in whichR-is as de?ned above. . I
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2. A method }of» preparing 3-alkyl-5-amino
1,2},4-oxadiazoles which comprises heating‘. in the
presence of a'hydrolyzing agent a 3'-alkyl~5-'ur'ei
doe1,2,4-'Joxadiazole.-
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a. 'Am'ethodb! preaaaféiiatslgmaatga
5
2,403,723
oxadiazoles which comprises heating in the pres
ence of a hydrolyzing agent a 3-ary1-5-ureido
6
6. A method of preparing 3-ary1-5-amino-1,2,4
oxadiazoles which comprises heating at a tem
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perature within- the range of 25-125° C. in the
4. A method of preparing 3-e1ky1-5-amino
presence of water and an alkali a 3-ary1-5-ureido
1,2,4-oxadiazo1es which comprises heating at a 5 1,2,4-oxadiazo1e.
temperature within the range of 25-125° C. in
7 . A method of preparing 3-ary1-5-amino-L2A
the presence of water and an alkali a 3-a1ky1-5
.oxadiazoles which comprises heating at’ a, tem
ureido-1,2,4-oxadiazo1e.
‘
perature
the range of 25-125° C. in the
5. A method for preparing 3-a1ky1-5-amino
presence of water and barium hydroxide a 3-ary1
1,2,4-oxadiazole.
1,2,4-oxadiazo1es which comprises heating at a 10 S-ureido-1,2,4-oxadiazo1e.
temperature within the range of 25-125° C. in
the presence of water and an acid a. 3-a1ky1-5
ureido-1,2,4-oxa»diazo1e. '
DONALD W. KAISER.
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