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Патент USA US2406892

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Patented Sept. 3, 1946
Joseph B. Niederl, Victor Niederl; and Martin E.
McGreal, Brooklyn," N. Y.
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' '
No Drawing. Continuation of application Serial.
No. 393,672, May 15, 1941. This application
January 1, 1943, Serial No‘. 4712024,‘
1 Claim. (01. 260F241)
This invention» relates. to. N-benzyl-Nealkyl
morpholinium compounds and particularly to
such- -benzyl-N-alhy1 morpholinium compounds
as diethyi and diisopropyl ethers; and lilre inert
solvents,‘ In a special embodiment of the inv‘en-i
tioh, the reaction carried out in the “presence
of a‘solvent which dissolves the reactants but pre‘;
(imitates out the‘ reaction ' products,‘ especially if
the solvent is @001.‘ Wheh operating in this man
having‘ from 12" to 18, carbon atoms in the. alkyl
radical. More specifically, the invention relates
to potent bactericidal agents, such as, N-benzyl
N-cetyl morpoholinium chloride.
ner, " ‘the "N-f-benZyl-N-alkyl v‘morpholiniurn salts
may be separated" out in a purified form without
This application is a continuation of applica
the'necessity of removing the solvent.‘ Various
tion Serial No. 393,672, ?led: May 15, 19.4.1.
The. N-benzyl-N-alkyl» morpholinium come 10 solvents may serve this dual purpose as a homo
genizing and a crystallizing‘ medium. For prac
pounds of this invention. may. be prepared by sev
eral methods. Most. conveniently when prepar
ing N-benzyl-N-alkyl morp-holinium halides, the '
tical reasons‘, ethyl acetate seems to be the most
peraturesand in. the presencev or in the absence
of an'inertsolvent. Thus, any. of the lower. mo
lecular. N-alky-lated morpholines, such as‘, N
l ' In accordance with one embodiment of the in
appropriate solvent of this type. It should be
N-‘alkylated morpholine is. treated with a benzyl
understood, therefore; that claims directed to re
halide. Generally. speaking, the reaction may be 15 actions taking place in the presence of ethyl ace
tate encompass such equivalents.
carried to completion at roomor at elevated tem
vention; temperatures are ‘regulated in such a
manner that the reactants are retained in a liq
methyl,'N~ethy»1, N-prop-yl, N-butyl, or. N-amyl 20 uid phase during thé're'action. ' Generally speak
ing, water or. steam baths provide su?iciently
morpholine; or any of the. higher‘ molecular
high temperatures'for such a purpose. ' ‘
alkylated morpholines, such as, N~.lauryl, N-my
When the reactants are mixed together with
ristyl, N-cetyl or N-octadecyl morpholine, de
out diluents “of solvents; suitable concentrated
scribed in 'patent‘application Serial 'No. 435,638,,
?led March 21, 1942, may be subjected to the 25 aqueous solutions of the reaction productmay
be‘ formed merely by the addition of water with
action of benzyl chloride or benzyl bromide to
out the necessity of expensive separatory, crystal
yield the respective N-benZyl-N-alkyl morpho
lizing or purifying'steps.
linium halides.
In another method for preparing the N-benzyl
N -alkyl~ morpholinium halides, N -benz7yl ‘morpho
considered a limitation upon it.
‘ ‘
" ‘
One mole, 311 grams, of N-cetyl morpholine
_ having
halides prepared in accordance'with the previ
E. fgf 23°‘ c. and a B; P. of 184° C. at 4
pressurerié P184351
‘a one liter round-bot
tonied iiasl; and"l(‘2§ grams of freshly distilled
benjzlyl ‘chloride are added. The flash is sealed
N-benzyl-N-methyl morpholinium halides
-N-benzyl-N-ethyl morpholinium halides
N-benzyl-yN-n-propyl morpholinium halides
N-benzyl-N-n-butyl morpholinium halides“
Emmrle icNrbrnzyzeN-qlh? morrholmium
Briana-“WW1. and ‘evamyl. iodides or léllllT'yli {mi
ristyl, cetyl and octadecyl bromides andthe it:
ously discussed. processes are:
30 embodiments of‘ the invention but are not to be
line having a boiling-point of 160°.- to 1615’ .C.‘ is
reacted with a lower- molecular orhigher molecé
ular alkyl halide, such as, ethyl, ‘methyl, n-pro
Among the‘ Nrbenzyl-N-alkyl IEIQFPEQ
The following examples disclose illustrative
N-benzyl-N-n-amyl morpholinium halides
N-ber'izyl-N-laur'yl morpholinium halides’? “
li-benzyl-N-inyristyl,mprpholinium halides "
N-benzyl-N-cetyl ‘morpholinium halides?“ ‘
N-benzyl-N-octadecyl morpholinium halides
N'Pb§§ZXlTN.-PI1§UYI marnholmium halides
>W~hi1e itis not necessary to 'use solvents in car
rying out the reactions of this'inventioihsql‘veilts
or diluents may be used, including esters, such as,
_ y
dtomforin a concentrated aqueous
solution of
en‘zlyl-N-cetyl morpholiniuni chlo
ride, water 18 added directly ‘to the reaction prod
ue‘p. F‘ofinstancéf,‘ the Nebenzy1-N-cety1 mor
pholiniumhhloride derived ‘from the previously
describedhreaction ‘may be transferred to ‘an ‘ap
propriate vessel and mixed with 1748 ml. of water
to ‘form’ a 20% aqueous solution. In a like man
ethyl acetatef hydrocarbons,‘ such‘ as, benzene,
ner, aqueous solutions having a concentration of
toluene, petroleum ether, and thédlkeyalcohols,
such as, ethyl and methyl alcoholj ethers, such 55 5% to 50% of N-benzyl-N-cetyl morpholim'um
chloride, may be prepared by dissolving the re
action product in the appropriate volume of
Such concentrated aqueous solutions of N-ben
zyl-N-cetyl morpholinium chloride are very val
uable and convenient for preparing desired disin
ether, benzene, toluene, or the like. Preferably,
the N-benzyl-N-alkyl morpholinium chloride is
then recrystallized from hot ethyl acetate.
When aqueous solutions are desired, the reac
tion mixture is merely distilled with an appropri
ate amount of water to yield, for example, con
centrations of 50%, 30% or 20%. The reaction
mass may be pre-treated with suitable adsorbents
or subjected to ?ltration, to increase its purity,
fecting and sterilizing solutions merely by fur
ther addition of water.
Similarly, one-tenth mole of freshly distilled N
cetyl morpholine and one-tenth mole of freshly 10 before being diluted with the water.
distilled benzyl chloride may be reacted in an
appropriate tube having a capacity of 50 to 60 cc.
After the introduction of the reactants into the
tube they are thoroughly mixed and the tube is
sealed and placed in a boiling water bath. After 4
hours, the contents of the tube will solidify upon
Example 2.-—N-benzyl-N-allcyl morpholinium
One mole of freshly distilled N-alkyl morpho
line is diluted with about 2 parts per volume of
ethyl acetate and introduced into a suitable glass
vessel. Thereafter, one mole of freshly distilled
benzyl bromide is introduced into the reaction
vessel. The reaction mass is thoroughly shaken
cooling. After 12 hours, the reaction is completed
and the reaction product is soluble in water in all
proportions. In order to crystallize out the N
benzyl-N-cetyl morpholinium chloride, the con 20 and allowed to stand at room temperature. After
tents of the tube are transferred to a ?ask, such
about 12 hours, a nearly quantitative yield of the
as, a 250 cc. Erlenmeyer ?ask, and boiled with
reaction product, N-benzyl-N-alkyl morpholinium
100 cc. of ethyl acetate. The boiling is continued
bromide, is obtained. Thereupon, the crystals are
until the entire contents of the tube are dissolved.
?ltered off and recrystallized from ethyl acetate.
Then, the resulting solution is allowed to stand at
The mother liquor, upon concentration under re
room temperature for one hour, whereupon 31
duced pressure, yields additional crystals of N
grams of N-benzyl-N-cetyl morpholinium chlo
benzyl-N-alkyl morpholinium bromides.
ride crystallize out. The crystals are ?ltered off
For example, one-tenth mole, 31 grams, of N
and the mother liquor is concentrated to yield
cetyl morpholine is diluted with 50 ml. of ethyl
additional crystals of the quaternary ammonium
acetate and introduced into a 250 ml. Erlenmeyer
?ask. Thereupon, one-tenth mole, 17 grams, of
The N-benzyl-N-cetyl morpholinium chloride
freshly distilled benzyl bromide is slowly intro—
produced as described hereinbefore begins to sin
duced into the ?ask. After the completion of the
ter at 85° C. and is completely melted at 150° C.
addition of the benzyl bromide, the mixture is
In a similar manner, by using appropriate N
thoroughly shaken, closed with a stopper and set
alkyl morpholines, the following N-benzyl-N-al
aside at room temperature for at least 12 hours.
kyl morpholinium chlorides are produced:
At the end of this period of time, 40 grams~ of N
benzyl-N-cetyl bromide have crystallized out.
N-benzyl-N-methyl morpholinium chloride, M. P.
The crystals then may be ?ltered off and recrys
' 229° C.
N-benzyl-N-ethyl morpholinium chloride, M. P. 40 tallized from hot ethyl acetate. If the mother
liquor is concentrated under reduced pressure,
150° C.
additional crystals of the N-benzyl-N-cetyl mor
N-benzyl-N-lauryl morpholinium chloride, M, P.
pholinium bromide will form.
120° C.
_N - benzyl - N- myristyl morpholinium chloride,
M. P. 135° C.
The N-benzyl-N-cetyl morpholinium bromide
N-benzyl-N-cetyl morpholinium chloride, M. P.
150° C.
N-benzyl-N-octadecyl morpholinium chloride,
M. P. 165° C.
The previously described processes for produc
ing N-benzyl-N-alkyl morpholinium chlorides are
generally applicable. Normally, one mole of
freshly distilled N-alkyl morpholine is placed in a
suitable reaction vessel which can be sealed or
otherwise closed, such as in an autoclave, or in-'
troduced into a reaction vessel provided with a
re?ux condenser having a drying tube attached
to ensure thoroughly anhydrous conditions.
This operation
may be repeated until all the quaternary mor
we Cr pholinium salt is isolated.
begins to sinter at about 85° C. and is completely
melted at about 130° C.
In a similar manner, the following N-benzyl-N
alkyl morpholinium bromides have been prepared
by reacting appropriate N-alkyl morpholines with
benzyl bromide.
N-benzyl-N-methyl morpholinium bromide, M. P.
251° C.
N-benzyl-N-ethyl morpholinium bromide, M. P.
175° C.
N-benzyl-N-lauryl morpholinium bromide, M. P.
102° C.
Thereafter, one mole of freshly distilled benzyl 60 N-benzyl-N-myristyl morpholinium bromide, M.
P. 117° C.
chloride is added.
The two reactants are mixed
thoroughly and the reaction vessel closed. Then
the reaction mixture preferably is heated to about
106° C. and the heating continued until the reac
N-benzyl-N-cetyl morpholinium bromide, M. P.
130° C.
N-benzyl-N-octadecyl morpholinium bromide,
v ,
tion mixture becomes solid on cooling and until 65 M. P. 145° C.
N-benzyl-N-phenyl morpholinium bromide, M. P,
it becomes completely soluble in water. This re
146° C.
action usually requires from 4 to 12 hours.
After the reaction is completed, further work
The previous examples disclose reactions in
ing up of the reaction product depends upon
volving molar ratios. An excess of either of the
whether the product is to be used as a crystalline 70 reagents may be present, however, without dele
solid or in concentrated aqueous solutions. When
teriously affecting the results since the reactions
the crystallized product is desired. it is either crys
will take place in equimolar proportions. 7'
tallized out of the reaction mixture or is precipi
The N-benzyl-N-alkyl morpholinium halides
tated out by the addition of a suitable diluent,
prepared as previously described may be used for
such as, ethyl acetate, diethyl ether, petroleum 75 the preparation of other N-benzyl-N-alkyl mor
pholinium salts. For instance, N-benzyl-N-alkyl
morpholinium sulfates, including the alkyl sul
fcetyl morpholinium nitrate, N-benzyl-N-cetyl
morpholinium sulfate, N-benzyl-N-cetyl morpho
linium ethosulfate, N-benzyl-N-cetyl morpholini
fates, such as, metho- and ethosulfates, or nitrates
and the like, are obtained by treating the halides
um methosulf ate, and the like.
with silver, sodium or potassium salts of the ap U!
It will be understood that the embodiments of
propriate mineral or organic acids or mono esters.
my invention described in the speci?cation and
Thus, the sulfates and nitrates are prepared by
illustrated by the examples are only illustrative
of the compounds and the processes by which
treating the chlorides or bromides, respectively,
with silver sulfate or silver nitrate. The alkyl
they are produced. Various modi?cations can
sulfates are best prepared by re?uxing a halide 10 be made without departing from the principles
with sodium or potassium salts of the respective
of the invention.
mono alkyl sulfates, such as, sodium methosul
We claim:
N-benzyl-N-cetyl morpholinium ethosulfate.
fate or potassium ethosulfate, and the like, dis
solved in an alcoholic solution. Compounds pro
duced in this manner include N-benzyl-N-alkyl
morpholinium salts having from 12 to 18 carbon
atoms in the alkyl radical, such as, N-benzyl-N
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