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Патент USA US2404299

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Patented July 16,1946
I 2,404,299
UNITED STATES PATENT OFFICE
-
2,454,299 7
SUBSTITUTED IMIDAZOLJES
Lucas P. Kyrides, Webster Groves, Mo., assignor
' to Monsanto Chemical Company, St. Louis, Mo.,
a‘ corporation of Delaware
No Drawing. Application March 3, 1944,
Serial No. 524,929
7 Claims. (Cl. 2.60—309)
>
The present invention relates to the produc
tion of new therapeutic agents and insecticide
,
2
during the synthesis of the imidazole derivative
or immediately thereafter and before the product
\According to the present invention, generally
is isolated from the reaction mixture.
The products of the present invention have "also.
been found to possess utility as insecticides and
toxicants for insecticide compositions; such ‘as
sprays and powders in which the compounds are
stated, new products which are of outstanding
value as active agents against micro-organisms
vents, adhesives, coating agents; repellents'and
toxicants which are substituted lmidazole com
pounds, and comprises the method of producing
the compounds as well as the new products them- .;
selves.
.
blended with suitable wetting agents; ?llers, ‘s01
are made by preparing substituted imidazoles of .10 other ingredients employed in ‘compounding in
the type represented by the formula:
The products of the present invention may be
prepared by reacting ethylene diamine with a
molecular'equivalent or less of an acylating agent
16 ‘comprising an aliphatic‘monocarboxylic acid have
ing as-its alkyl or‘alkenyl residue one of the radi
secticides.
‘
<
'
'
ca'ls described hereinbefore" in the de?nition of
in which R representsan acyclic‘ hydrocarbon
R1 ‘withfrespect to the ‘formula. , The acid thus
dodecyl, tridecyl, tetradecyl, pentadecyl and hex
adecyl radicals, or a straight chain alkenyl radi
acid, the alkyl e'stensuch as the butyl ester, or
‘employedwill be composed "of an alkyl oralker'iyl
radical having'from- lOYto 16 carbon atoms in its
structure and ‘R1 represents an acyclic hydrocar $20 residue “o‘ffthe proper chain length or withv the
proper branchedchain components together with
bon radical having from 1 to 5 carbon atoms in
a carboxylic acid group, the carbon atom of which
its structure. The acyclic hydrocarbon radical
is not included in the contemplation of the‘cha'in
represented by R may be composed of a straight
length hereinbefore described. In place of the
chain alkyl radical such as the decyl, undecyl,
desirably thetm'ethyl' or ethyl ester, maybe‘cm
cal, such as decenyl, undecenyl, dodecenyl, tri
ployed, or the acyl halide such as the acyl chlo
decenyl, tetradecenyl, pentadecenyl and hexade
ride, or the acid anhydride.
cenyl radicals in which one or more double bonds
may be located in various positions in the chain. '
_
I
The resulting mono-acyl amino derivative is
then condensed with the aid of a suitable mild
R1 may be a straight chain alkyl radical such
as the methyl, ethyl, propyl, butyl and amyl radi
cals, or a branched chain alkyl radical such as
dehydrating agent, such .as powdered calcium
oxide, to form the 2-alkyl (or 2-alkenyl) imidaz
oline. The derivative thus prepared is then re
the isopropyl, tertiary butyl and is‘oamyl radi
acted with an alkylating agent having as its alkyl
35
cals._ Likewise, R1 may be an alkenyl radical hav
residue one of the residuesdescribed hereinbe
ing from 1 to 5 carbon atoms in its straight or
fore in the de?nition of R with‘ respect to the
branched chain structure, for example, the pro“
formula. The alkylating agent may be an alkyl
penyl, butenyl and isobutenyl radicals. The wa-_
halide, such as lauryl ‘chloride or tride'c'yl bromide.
ter-soluble salts of these compounds may be pre
pared and are also valuable‘ as active agents :40 The derivative thus prepared is then dehydrogé'n;
ated- with the aid of a suitable dehydrogenation
against micro-‘organisms and‘as insecticide toxi
cants. For example, the hydrochlorides, hydro
bromides and acetates and other salts may be
‘employed: ‘
The new products and their water-‘soluble salts
may be administered orally orparenterally and
have been found to be unusually e?ective against
catalyst, such as nickel, to form the l-alkyl (or
alkenyl)-2-alkyl (or all?senyl). imidazole.
In carrying out‘the preparation of the N-acyl
ethylene diamine, it‘ is desirableito employ an
hydrous ethylene diamine; However, ethylene
micro-organisms such ‘as streptococcus in vitro
diamine that is not substantially anhydrous may
be employed. The anhydrous material facilitates
and in vivo; The organiciand inorganic acid salts '
the attainment of somewhat higher yields.
may be preparedv by dissolving the products in an
aqueous solution containing the; stoichiometrical
equivalent of a suitable acid, such as hydrochloric,
hydrobromic, acetic acids and'the like, and the
solution may be employed for parenteral adminis
tration.= Also, the .acid salts maybe prepared ”
‘The following examplesjillustrate the process
of the present ‘invention and the compounds re
sulting therefrom. These examples arewbe
construed‘ as merely illustrating and not as limit
ing the scope of the present invention.
2,404,299
24 grams of 50% sodium hydroxide solution with
agitation and ?ltered. The benzene layer of the
?ltrate was separated and distilled to remove the
benzene. The residue was distilled at reduced
pressure to recover the product. B. P. 151-155°
C./6 mm. Yield of 1-n-decyl-2-methyl-4,5-di
hydroimidazole, 41.3%. The material’ assayed
A mixture, 'oi264 grams of anhydrous ethyl
99.8%. This material was dehydrogenated ac
acetate (3 moles) and 540 grams of ethylene di
cording to the method of Example 1. Yield of
amine (9 moles) was heated in an autoclave at
100-110° C. for 36 hours. A pressure of about 10 1-n-decy1-2-methyl-imidazole, 90.5% of theory.
B. P. 153-160° C‘./5.5 mm.
20 pounds was developed. The mixture was
transferred to a still and the ethanoland excess
Example 3
ethylene diamine were distilled o? at about-100'
1-n-Tetradecyl-2-methyl-imidazole
mm. absolute pressure. The fractionation yield
i ' CH—N—-CHg-(OH2)1a~CHa
ed 203 grams (66.5%) . of partially _ crystallized 15v
N -acetyl ethylene diamine at 133-139° C./27 mm.
on
C-OHs
A mixture of 203 grams of N-acetyl ethylene
N
diamine and 560 grams of ?nely powdered cal
A mixture of 60.7 grams of 2-methyl-4,5-di
cium oxide was heated in'a ?ask immersed in an
oil bath at 225—235° C. for 14 hours. After cool 20 hydroimidazole prepared according to the method
ofExample 1, 83 grams of tetradecyl chloride‘ and
7 ing to 90—100° C., the mixture was extracted with
Y110 cc. of xylene was re?uxed 18 hours at 145°C.
three 500 cc. portions of alcohol. The alcohol
The mixture was cooled to room temperature and
_ was removed from‘ the extract by distillation and
diluted with 125 cc_‘of water. To this mixture,
the residue‘ was distilled at atmospheric ‘pressure.
13. P. 195—198° 0.- Yield of2-methyl-4,5-dihy 25 27.5 grams of 50% sodium hydroxide was added
with agitation. The resulting mixture was-‘?l
droimidazole, 88%. '
' I
tered and the xylene layerwas separated and dis
A mixture of 100.8 grams of 2-Inethyl-4,5-di
tilled to remove the xylene. The residue was
hydroimidazole,v 123.0 grams of n-dodecyl chlo
ride (0.6 mole) and’290 cc. of xylene was re?uxed
at 148° C. for 16 hours and then cooled to 25° C.
distilled at reduced pressure to recover the prod
B..P.j190~193°' C./6 mm. .Yield of 1-n
so
tetradecyl-2-methy1-4,5-dihydroimidazole, j 34%.
IA- solutionof 50 grams of 50% sodium ‘hydroxide
solutionv in .33 cc. of water was added with agita
The material assayed 97.4%.
This material was
dehydrogenated according to the method of Ex
tion; The l’mixture'was ?ltered and the xylene
layer was separated’ from the ?ltrate. vAfter 1'6‘.
ample 1.
The product was l-n-tetradecyl-2
moval‘of the xylene underreduced pressure‘, the "35 methyl-imidazole. B. P. 187-199° C./5.5 mm.
residue was distilled, B." 'P. 177-184°_C./>6. min.
The yie1d'Was’60.7f"g'raI_hs', 01‘ 40.2%, tialdulat'ed'on
n-dodecyl chloride " charged. The. preeue': as»
'droimidazole.
I
;
40
.
‘ 'In place of n-dodecyl chloride. n-dodecyl‘lbro
'mide'may'be employed.
'
l
‘
'
'
mixture of 427.7 gramsof anhydrous methyl
'
' For the. dehydrogenation of 1-n-dedecy1-2
caproateand 592 grams of anhydrous ethylene
diamine
was reacted according to the method
45
was prepared by heating nickel formate in a
of Example 1. The N-caproyl-ethylene diamine
mineral oil until decomposition of the formate
obtained was condensed with the aid of anhy
occured. - The nickel catalyst may be prepared
drous calcium oxide according to the method
by other methods, for'example, the method dis
of Example 1. The product was identi?ed as 2
closed in U. S. Patent 1,378,736, issued May 17,
amyl-4,5_-dihydroimidazole. B. P. l50-l57° C./34
1921, to Ellis. Other suitable dehydrogenation
methyl-4,5-dihydroimidazole, a nickel catalyst
mm. The yield of this material was 56.8%, based
catalysts, such as Raney nickel catalysts, may be
employed. A mixture of.3.2 grams .ofjhe cata
lyst thus preparedwand 60.7 grams of l-n-do
on methyl ,caproate. The M. P. of the material
was 53-54:.6" C.
.
decyl-2-methyl-4,5-dihydroimidazole was heated
>
V
r’
Amixture of 168 grams
with agitation to 225°-235°_C. until hydrogen was
imidazole, 123 grams of n-dodecyl chloride, and
no. longer evolved. The reaction mixture was
cooled to 125° C. and 1/2 gram of the nickel cata
Heating was resumed and con
method ofExampleLand thejresulting' reaction
mixture was treated with 50 grams of 50% sodium
The'distilled product was 1-n-dodecyl-2-methyl
'layerand distillation of the residue, the material
lyst was added.
200 ,cc. of xylene was reactedaccording to the
solution in 300 cc. of Water. ' After ‘?l;
tinued until ,the evolution of hydrogen‘ ceased. .60 hydroxide
tration, removalofjxylene from the'non-aqueous
The reaction mixture was then distilled in vacuo'.
imidazole.
V‘
e
'
.
,
'
'
'
"
recovered ‘was identi?ed as l-n-dodecyl-2-n
,
amyl-4,5-dihydroimidazole. ' This material was
Example 2
'dehydrogenated ‘according to the method of Ex
ample I 1.
The‘ product was. l-n-dodecyle2éamyl
‘ . 0% 707cm .. .j.
. N’.
r - Armix'tu're of150.4 grams (0.6 mole) of 2i-meth'yli- '
' 4,5-dihydroimidazole, prepared according to'i'the ’
method 'of’Example 1, 52.8 grams "(0.3 mole) of
decyl chloride and ‘100 ‘cc. of benzene was re?uxed
' for 7 hours and :cooled to ‘room temperature.
' The mixture was vtreated with ‘150 cc. of water and
‘
eemptuna may bélpreparea by reeetilsee
$735 mixture‘ or- 101 grams or 2-n'iethyli4',5-dihydro
t
imidazole. This latter'may then .be reacted ‘with
n-dodecyl chloride according to the method of
Example 2' with the resultant production of l-n
grams of h'exadeoyl chloride and 110 'cci'of xylene
and processing the reaction mixture according to
the method of Example 2. The resulting mate
dodecyl- 2-isopropyl-4,5-dihydroimidazole. This
rial, 1 - n - hexadecyl-2-methyl-4,5-dihydroimid
material may then be deh'ydrogenated according
to the method of Example 1 to form l-n-dodecyl
azole, may then be dehydrogenated according to
the method of Example 1 to produce l-n-h'exa
2-isopropyl-imidazole.
decyI-Z-methyI-imidazole.
Example 6
1-n-Tridecyl-Z-methyl-imidazole
Example 10
10
l-'Dodecyl-z-isobutenyl-imidazole
(?H-—N-V-CH‘2- (CH2)11' CH3
V‘
CH
‘
-omv
N
I
“
_
according to the method of Example 2, and'dehy
'
.
‘
N
_
\CHa
r.
~
This compound may be prepareid‘by reactingya
mixture of anhydrous methyl dimethacrylate and
drogenating the resulting l-n-tridec‘yl-Z-methyl
4,5-dihydroimidazole according to the method of
_
20H:
CH
This product was prepared by reacting 2-meth
an excess of anhydrous ethylene diamine accord
ing to the method of Example 1. The product
recovered from the reaction mixture, N-dimeth
,
Example 7
acroyl ethylene diamine, is then condensed with
calcium oxide withwthe resultant production ‘of
l-n-Dodecyl-Zcthyl-imidazole
2-isobutenyl-y4,5-dihydroimidazole.
E1H—N—CH2- (CH2) 1o- CH3
CH
' OH———N;-CH:~-(CH2) 10- CH:
v
yl-4,'5- dihydroimidazole with ,tridecyl bromide
Example 1.
"6'
"Example '1‘ to ‘produce 2-isopropyl-4i5-dihydro-‘
"imidazole ‘prepared according to Example v1,144 7
This latter
product may then be reacted with n-dodecyl chlo
ride according vto the method of Example 2 to
o-om-cm
form l-n-dodecyl-2-is0butenyl-4,5-dihydroimid
N
azole. This material may then be dehydrogen
ated according to the method of Example 1 to
form 1-dodecyl-2-isobutenyl-imidazole.
This compound may be prepared by reacting
a mixture of anhydrous methyl propionate and an
excess of anhydrous ethylene diamine according
to the method of Example 1 to form N-epro'pionyl
ethylene diamine.
This product may; be - con
densed with calcium oxide according to the meth
od of Example 1 to form 2-ethyl-4,5-dihydroimid- ‘
azole. This latter product'may be reacted with '
' 011
n-dodecyl chloride according to the method of
0-035
%
Example :‘2 to form 1-n-dodecyl-2-ethyl-4,5-di
hydroimidazole. _ This material may thenlqe‘ de
vThis compound may be prepared by reacting a
hydrogenated according ‘to themethod of'Exam
mixture of 101 grams of 2-methyl-4,5-dihydro-'
ple 1 to form 1-n-dodecyl-2-ethylgimidaaole.
'
‘
Example 8
x
l-n-Dodecy1-2-propenyl-imidazole
‘
‘imidazole, prepared according to Example'l; 122
grams of ll-n-dodecenyl chloride and 200cc. of
'
xylene according to the method of Example 1,
and treating resulting reaction mixture as in Ex
ample 1 to recover the product. This product
may then be dehydrogenated according to the
method of Example ,1 to form l-(n-dodecen-ll
>C‘H—-N—-CH2-‘(QH2)m-CHa I‘ I
OH
G—CH=CH-CHB‘
\
V
.
.
yl-l) -2-methyl-imidazole.
Thisv compound may beprepared by reacting
Example 12
a mixture of anhydrous methyl crotonate and an
excess of anhydrous ethylene ‘diamine according "60
to'the method of Example 1' to produceNecro
tonyl ethylene diamine, This product may be
1- (n-Tetradecen-12-y1-1) -2-propenyl-imidaz ole
condensed with calcium oxide according to the
method of Example 1 ‘to produce 2-propenyl-4,5'- _v ‘_
diliydroimidaz'ole'. This latter product may then
be reacted with n-dodecylchloride according to
the method of Example 1 with the resultant pro
duction of l-n-,dodecyl42‘-'propenyl-4,5-dihydro
imidazole.
l
N/
,
'
.
.c
v
This compound may be prepared by ‘reacting a
mixture of 132 grams of 2-propenyl—4,5-dihydro;
imidazole, prepared as in Example 8 according to
the method of Example 1, 138 grams of 12-tetra
This material may then be dehydro
decenyl chloride and 200 cc. of xylene according ,
genated according to the method of Example 1 60 to the method of Example 1, and treating result
to form 1-n-dodecyl-2-propenyl-imidazole.
ing reaction mixture as in Example 1 to recover
Example 9
l-n-Dodecyl-2-isopropyl-imidazo1e
CH-N-CHz- (CH2)10- CH:
l
the product.
05
CH3
0% % -oH--o/‘
N
’
v
Example 13
CH3
This compound may be prepared by reacting a 70
mixture of anhydrous methyl isobutyrate and an
excess of anhydrous ethylene diamine according
to the method of Example 1. The resulting prod
uct, N-isobutyryl ethylene diamine, is condensed
with calcium oxide according to the method'of 75
1-n-Decy1-2-amy1-imidazole
CE C-CHa-(CHzh-CHa
N
A mixture of 2 mols of 2-amyl-4,5-dihydroimid
azole, prepared according to the method of Ex
ample 4, and one mol of n-decyl chloride was
heated at 144-150° C. for 15 hours. The reaction
product was diluted with Water, treated with a
5% excess of 50% sodium hydroxide, and extract
2,404,299
'7
ediwith'. n-butyl ' alcohol.
The butyl . alcohol and
' 5._The
some :‘unreacted 2 - amyl - 4,5_-'. dihydroimidazole
1-n+tetradecyl-2-methyl-imidazolev of
the‘formula:
'
,
‘
"
‘
'
Were removed from the vextract by distillation.
i
The residue was distilled, B. P. 143-174.5°/3.5
mm., and thereafter redistilled, B. P. 157-17073};
*'
‘
I
'
'
'
-
GH—yN—CHz-(CH2)12~CH:
0H" '
—CHzV
I
mm. This material was dehydrogenated accord
ing to the method of Example 1. The product
prepared for use as a therapeutic agent.
was 1-n-decyl-2-amyl-imidazole. Yield 93.8%;
6. A process for preparing compoundsT'of‘the
B. P. 149-176" O./3.5 mm.‘
formula type:
v‘ c c ,1
The present invention is a continuation-in-part 10’
a
N
of my copending application S. N; 498,583, ?led
August 13, 1943, which discloses the 4,5-dihydro
- ,CH-if-R
imidazole derivatives from which the novel thera
peutic agents‘ of the present invention may be
'
7
_
_
N%
,
.
v
in which R represents an acyclic hydrocarbon
15 radical having from 10' to 16 carbon atoms in its
derived as explained hereinbefore.
I claim:
}
,
structure and R1 represents an acyclic ‘hydrocar
bon'radical having from 1 to 5 carbon atoms ‘in
_ 1. _A compound of the group consisting of. sub
stituted imvidazoles'of the formula type:
its structure, said process comprising reacting
v ethylene diamine with an alkyl ester of va mono
20 carboxylic acid in which a carboxylic group' is
attached to a radical selected from the group of
radicals de?ned hereinbefore as R1, heating the
in which R represents an acyclic hydrocarbon
ethylene diamine derivative thus formed in the
radical having from 10 to 16 carbon atoms in its
presence of a mild dehydrating agent, reacting
structure‘ and Rrrepresents an acyclic hydrocar 25 the derivative thus formed with an alkyl halide
bon radical having from 1 to 5 carbon atoms in
having an alkyl radical selected from the group
its structure andacid salts thereof,_preparedfor
of radicals defined hereinbefore as R, heating
useas therapeutic agents.
;
V '
the derivative thus formed with a dehydrogena
_- 2. Substituted imidazoles of the formula type:
tionycatalyst and distilling oif the dehydrogena
'30
.
'
,
1(|_‘|;H___N_RI
'
_
J 7.?A process for preparing compounds of the
tion product;
1911:: Crew
formula type:
‘
'
.
'
'
" -
‘
'
J
in which Rrepresents a straight chain alkyl rad
ical‘uhaving from 10 to 16'carbon atoms in its
structure and R1 represents an acyclic hydrocar
bon radical having from 1 to 5 carbon atoms in
its structure, prepared for use as therapeutic
agents.v
I
‘r
3. .The V1-n-decyl-2-methyl-imidazole of’ the
formula:
‘
we‘
__
v
j
.
inl'which‘R represents a straight chain ‘alkyl
i radicalhaving from '10 to, '16 carbon atoms in
40 its structure and R1 represents anacyclic hydro- '
carbon radical having from 1 to 5 carbon atoms
in its structure, said process comprising reacting
V
ethylene diamine with an alkyl ester of a mono- .
'
uH_N—oH2-(c11i)tom
CH
.
‘
c-on,
'
‘
carboxylic acid in which a carboxylic group is
"
attached to a radical selected ‘from the group of
.45
radicals de?ned hereinbefore as R1, heating the
ethylene diamine derivative thus formed in the
N.
prepared for use as a therapeutic agent.
4. The 1-n-dodecyl-2-methyl-imidazole of the
formula:
V
.
'
_
-
-
-CH;—N—.—CH2-(OH2)in-,CH3>
on
'
'
-
O-CHa
N
‘e
presence of a mild dehydrating agent, reacting
the derivative thus formed with an’ alkyl halide
":50 having an alkyl‘ radical selected from the group
a of ‘radicals de?ned hereinbefore as R, heating the
derivative thus?formed with a dehydrogenation
catalyst and distilling off the dehydrogenation
product,
'
"
'
'
.
7 prepared for use as a therapeutic agent.
45,5 <
~
‘
, LUcAs P; KYRIDES.
'
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