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Патент USA US3028417

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United States Patent 0
B?ZBAW
Patented Apr. 3, 1962
1
2
3,028,407
example, alkyl amines especially lower alkyl amines as
rnethyl-, ethyl-, dimethyl- and diethylamines, as well as
hydroxyalkylamines also called alkanolarnines such as
SUBSTITUTED ETHYLENEDIAMHNE COMPOUNDS
HAVING AROMATIC RINGS
Martin Knell, Yorktown Heights, N.Y., and Harry Kroll,
Warwick, R.I., assignors to Geigy Chemical Corpora
tion, a corportaion of Delaware
No Drawing. Filed Apr. 18, 1958, Ser. No. 729,263
15 Claims. (Cl. 260-439)
the lower alkanolamines as mono-, di- or trialkanolamines
illustrated by mono-, di- or triethanolarnine, or diamines
such as ethylenediamine, as well as heterocyclic amines
as morpholine.
So also, a still further type of salt embraced by the
invention is the alkali metal (e.g. sodium or potassium)
This invention is that of ethylene bis(alpha-imino~ 10 phenolate type. This type, in addition to the possibility
orthohydroxyphenylacetic acid)-monoamide, and its di
of having alkali cation carboxylate, and possibly also
hydrochloride, and derivatives of both thereof wherein
sulfonate, groups as described above, also has the hydro
(a) at least one of the hydrogens on either or both of the
gen in at least the ortho-hydroxy group on at least one,
ethylene carbons is replaced by (i) an alkyl group espe
and preferably both, of the benzene nuclei replaced by
cially a lower alkyl such as vmethyl or ethyl, or (ii) a 15 an alkali metal.
hydroxyalkyl group particularly a lower hydroxylalkyl
group such as the ethanol or hydroxyethyl group
In this speci?cation and the appended claims, lower
allcyl, lower allroxy, and lower hydroxyalkyl (which lat
ter is also called lower alkanol) are those groups wherein
the alkyl group has from one to six carbon atoms. The
methylene group, —CH2.CH2.CH2.CH2--, and simulta 20 alkyl group that can replace a hydrogen on either or both
of the benzene nuclei more often may not exceed ten
neously linked to both of the ethylene carbons by replac
carbon atoms.
ing a hydrogen on each of them respectively and thereby
Accordingly, the free bases of the various dihydrochlo
forming with both of them a saturated six carbon ring
(—C2H4OI-l), or (iii) a divalent lower alkylene group,
such as a lower alkylene group as the divalent tetra
ride products of the invention, including as well their
havingthe two imino nitrogens still linked respectively
separately to adjacent carbons, and the relative position 25 various types of above indicated salts, are represented by
the general formula
of these nitrogens with respect to each other may be cis
or trans; or (b) at least one of the four other hydrogens
on at least one, and preferably both, of the benzene
nuclei is replaced by a substituent group that is inert to,
i.e. does not react with, a primary amine, that is to say
a substituent group that is free of a functional carbonyl
group such as is in the keto and aldehyde groups, for
example, alkyl (having less than eleven carbon atoms)
and especially lower alltyl, lower hydroxyalkyl, lower 35 wherein R, R1, R2 and R3 are separately selected from
hydrogen, an alkyl group and especially a lower alkyl
alkoxy, carbonyl, alkali metal or ammonium carboxylate,
group or a hydroxyalkyl group and especially a lower
hydroxyl, O-alkali metal (i.e. the hydroxyl group with
hydroxyalkyl group, or R and R1 or R2 and R3 respec
its hydrogen replaced by an alkali metal), sulfo, alkali
tively jointly are a divalent polyalkylene group forming
cation suifonate, nitro, amino, or a cyano group, or a
halogen radical; and especially with both of the benzene 40. a saturated ring with both of the ethylene carbons, all
as described in the opening paragraph of this speci?ca
nuclei ‘being identically substituted; or (c) both types of
tion; X1, X2, X3, X4, X5, X6, X7 and X8 are independently
the substitutions (a) and (b) are present at the same time
individually selected from hydrogen and a snbstituent
in the compound.
group that does not react with a primary amine, as de
Certain of the substituent groups that can replace one
or more of the hydrogens of the benzene nuclei may be 45 ?ned in the ?rst paragraph of this speci?cation, and pref
erably with X1, X2, X3 and X4 being respectively the same
referred to in classes, for example, the alkyl and hydroxy
alkyl groups can be referred to as a substituent containing
a lower alkyl group; the carboxyl and alkali cation car—
boxylate groups can be referred to as a substituent con
taining the carbonyloxy group
as X3, X7, X6 and X5; and wherein M is independently
selected from hydrogen and an alkali cation, that is to
say an alkali metal or an ammonia-derived cation of the
type described above and with its nitrogen atom linked
50 to the oxygen of the carboXyl group; and wherein M2 and
M3 are independently individually selected from hydro
gen and an alkali metal, ‘and generally preferably with
M2 and M3 being the same.
'
the sulfo and alkali cation sulfonate groups can be re
The free ‘bases of the dihydrochloride compounds of
ferred to as a sub-stituent containing the group or radical 55
—SO3—-; the hydroXyl, alkoxy, and O-alkali metal can be
the invention, that is those wherein M, M2 and M3 in the
refer-red to as a substituent containing an oxy group; and
the nitro, amino, and cyano groups can be referred to
general formula are hydrogen, are water-soluble. How
ever, the derivatives wherein M is a mono-, di- or tri
ethanolamine cation is water-soluble. So also are those
wherein M is an alkali cation, as de?ned hereinabove,
as a substituent containing nitrogen or a substituent com
posed of nitrogen and only one other element.
60
While also each of M2 and M3 is an alkali metal. Other
Thus, the invention includes also various types of
water-soluble salts of the various derivatives are those
alkali cation salts of ethylene bis(alpha-imino-ortho
wherein any of the substituents X1 through X8 is an alkali
hydroxyphenylacetic acid)-rnonoamide and of any of its
type sulfonate, i.e. an alkali metal sulfonate or a sul
various above described derivatives. Among these vari
ous types of salts are those formed with the sole acetic
acid carbonyl group or with any carboxyl and/ or sulfonic
acid group on either or both of the benzene rings. These
several types of salts include those with an alkali cation
which is intended to include the alkali metal salts as the
fonate of an ammonia-derived cation of the type de
scribed in the third paragraph of this speci?cation.
The derivatives wherein M is an alkylamine or alka
nolamine cation having a higher alkyl chain, i.e. over
about six carbon atoms, as in the long chain primary
sodium and potassium salts, and also the ammonia 70 amines which can be straight chain amines such as lauryl
amine, or branched chain, are soluble in organic solvents,
derived salts such as the ammonium salt and amine salts
for example, the lower aliphatic alcohols, and show some.
as those of primary, secondary and tertiary amines, for
.
8,028,4=07
3
4
generally slight, solubility in hydrocarbon solvents such
tion of the dinitrile was completed, the temperature of the
reaction was increased to 40° C. A few minutes there
after a solid separated out from the homogeneous mixture.
as solvent naphtha, benzene, toluene, and hexane, and in
ethyl ether and other ethers.
The compounds of the invention are prepared by con
The heating of the mixture then was continued at 40-45 °
for four hours. The ethylene bis(alpha-ortho-hydroxy
phenyl acetic acid)-monoamide dihydrochloride that sepa_
densing one mole of an ethylenediamine with two moles
of ortho-hydroxyzenzaldehyde otherwise unsubstituted or
having on the benzene nucleus any such other substituent
or substituents as is desired in the end product to be made
from it, and under operating conditions to eliminate two
moles of water for each mole of the ethylenediarnine, 10
and thereby to form the corresponding disalicylidene
rated out then was ?ltered oil and washed with acetone
until the ?ltrate was free of color, and dried under vacuum.
163.6 grams of the dihydrochloride product were obtained
(87% yield).
Analysis for C13H230‘5N3C121
ethylenediimine either further unsubstituted on the hen
zene ring or having on it the other particularly selected
N (amide)
N(l;otal)
O1
substituent or substituents that it was desired to have in
the end product. The thus obtained particular disalicyli 15
deneethylenediimine then is treated with sufficient hy
drogen cyanide to convert it to the corresponding ethylene
bis(alpha-imino-orthohydroxyphenyl acetonitrile) which
latter, after removal from its reaction medium, then is
hydrolyzed under hydrolysis conditions that convert one 20
of its nitrile groups to a carboxyl group and the other
calculated ______ __' ____________________ __
3. 2
9. 7
l6. 4
found _________________________________ __
3. 4
9. 4
l6. 6
Neutral equivalent (in dimethyl formamide using
KOH) found 108 (calculated is 108).
Example 2
Tetra — methylene ethylene bis(alpha - imino - ortho to the carboxamide group (i.e. —CONH2).
hydroxyphenylacetic acid) -m0noamia"e dihydrochloria‘e.-—
The separated dinitrile is hydrolyzed by mixing it with
Tetra-methylene ethylenediamine was condensed with
concentrated hydrochloric acid, advantageously by add
ing the dinitrile with stirring to the required amount of 25 salicylaldehyde, in the ratio of one mole of the former
to two moles of the latter, in known manner under con
that acid, to strongly acidity it, and controlling the heat
ditions to eliminate two moles of water for each mole
ing up of the reaction mixture for its temperature not to
of tetra-methylene ethylenediamine. One mole of the
exceed about 40° C., and preferably initially not to ex
resulting disalicylidenetetra-methylene ethylenediimine
ceed about 30° C.; and after completing the mixing of the
dinitrile, raising the temperature to about 40° 'C., or, be 30 (or disalicylidene 1,2-cyclohexanediamine) was placed in
a three liter three-necked ?ask as in the preceding exam
tween about 40 and 45° C., and continuing the heating
ple. A mixture of seven hundred milliliters of liquid
at about 40° to about 45° C. for a time suficient for
hydrogen cyanide cantaining one hundred and eighty mil
the desired monoamide-monoacid to be formed (as its di~
liliters of water and two and one-half milliliters of con
hydrochloride). Such time can ‘be about four hours, for
centrated hydrochloric acid was added, rapidly with stir
example, with the product of Example 1. The time can
ring, to convert the diimine to tetra-methylene ethylene
be correspondingly increased if the heating is conducted
bis(alpha-imino-ortho~hydroxyphenyl acetonitrile). The
at any temperature under 40° C. It is the heating within
temperature was maintained at 20-25" C. for six hours.
this controlled range that enables the conversion to the
monoamide. The completion of the conversion can be
The excess hydrogen cyanide was evaporated off, and the
checked readily by simply analyzing for the content of 40 oily dinitrile residue then was added, with stirring, por
tionwise to a volume of concentrated hydrochloric acid
amide nitrogen. This method including the controlled
equal to about ?ve times its weight, and the heating up
heating conditions for producing monoamide as dihydro
of the reaction medium was controlled to keep it below
30° C. After the addition of the dinitrile was completed,
the temperature of the reaction mixture was raised to 40°
chloride is also part of the invention.
The invention is illustrated by, but not restricted to,
the following examples:
and the hydrolysis of the dinitrile completed by heating
Example 1
at 40—45° for several hours as in Example 1, and the
Preparation of ethylene bis(alpha-imino-ortho-hydroxy
resulting monoamide dihydrochloride similarly was ?l
tered, washed and dried.
phenylacetic acid )-m0n0amide dihydrochloride from eth
ylene bis(alpha-imino-ortho-hydroxyphenyl acezonizrile). 50
Example 3
—One mole of disalicylidene ethylenediimine, obtained
Methylethylene bis(alpha - im‘ino - ortho - hydroxy
from condensing two moles of salicylaldehyde and one
mole of ethylenediamine, was placed in a three-liter three
phenylacetic acid) - monoamide dihydrochloride.-Pro
necked ?ask ?tted with a stirrer, re?ux condenser (cooled
panediamine-l,2 was condensed with salicylaldehyde, in
with ice water) and thermometer. A mixture of seven 55 a ratio of one mole of the former to two moles of the
latter, in known manner under conditions to eliminate
hundred milliliters of liquid hydrogen cyanide, one hun
two moles of water for each mole of methyethylene
dred and eighty milliliters of water and two and one
diamine. The resulting disalicylidenemethylethylenedi
half milliliters of hydrochloric acid was added rapidly
imine then was treated in a three-necked ?ask as in the
while stirring the ‘reaction mixture. Stirring was con
preceding example with a mixture of liquid hydrogen
tinued for three hours during which in place of the
cyanide, water and hydrochloric acid to convert it to
methylethylene bis (alpha-imino-ortho-hydroxyphenyl ace
tonitrile). The dinitrile produced then was ?ltered off,
initially suspended golden yellow solid there was sus
pended in the reaction medium a light tan solid, namely,
the ethylene bis(alpha-imine-ortho-hydroxyphenyl ace~
washed well with water, and air dried. The dried dinitrile
tonitrile). This dinitrile then was ?ltered off. A sam
ple, washed well with water and air dried, showed a 65 was added portionwise with stirring to concentrated hy
drochloric acid and hydrolyzed in the same manner as
melting point of l13~1l5° C. and neutral equivalent of
163 (calculated is 161) on titration with perchloric acid
in glacial acetic acid; percent nitrogen found 17.17; c?~
was the dinitrile in Examples 1 and 2. The resulting de
culated 17.38.
washed and dried as in the other examples.
sired monoamide dihydrochloride then ,was separated‘,
Hydrolysis of the nitrile.—0ne hundred and forty 70
grams (0.434 mole) of ethylene bis(alpha-imino-ortho
hydroxyphenyl acetonitrile) were added with stirring por
tionwise to seven hundred milliliters of concentrated hy
drochloric acid and the heating up of the reaction medium
was controlled to keep it below 30° C. After the addi
Example 4
Ethylene bis( alpha - imino-Z-hydroxy-S-methyl-phenyI
acetic acid) -m0n0amide dihyclrochlorida-Five hundred
and forty-four grams (4 moles) of Z-hydroxy-S-methyl
75 benzaldehyde and eight hundred milliliters of ethylene‘
3,028,407
6
dichloride were placed in a four-liter three-necked ?ask
yielding two hundred and forty grams of ethylene
equipped with a strirrer, reflux condenser, and dropping
bis(alpha-imino-2~hydroxy-5~chlorophenylacetonitrile) .
funnel.
One hundred and ninety-?ve grams of this foregoing
dinitrile then were added portionwise with stirring to
seven hundred and ?fty milliliters of concentrated hydro
To the mixture was added one hundred and
twenty grams (2 moles) of anhydrous ethylenediamine
at a rate to maintain the temperature of 30° C. After
the addition was completed, the mixture was re?uxed to
chloric acid, while maintaining the temperature below
30° C. After the addition was completed, the stirring
remove by azeotropic distillation the Water formed dur
ing the reaction. The reaction mixture then was cooled
to 20° C. To the agitated reaction mixture there was
was continued for several hours while maintaining the
concentrated hydrochloric acid while stirring and keeping
By replacing the Z-hydroxy-S-chlorobenzaldehyde of
temperature below 30° C., during which time, from the
added two hundred and forty grams of liquid hydrogen 10 homogeneous mixture there precipitated out the dihydro
chloride of ethylene bis(alpha-imino-Z-hydroxy-S-chloro
cyanide. After eight hours, a light yellow solid that had
phenylaoetic acid)-monoamide which was ?ltered oif.
separated out was ?ltered off, and dried under vacuum
The yield of this dihydrochloride was increased by con
at room temperature. Yield: four hundred and forty
centrating the ?ltrate solution under vacuum while keep
grams of ethylene bis(alpha-imino-Z-hydroxy-5-methyl~
ing the temperature below 30° C. The additional amount
phenyl acetonitrile). ‘
'
of the dihydrochloride was added to the part which was
Three hundred and ?fty parts of this dinitrile then
?rst ?ltered off.
were added portionwise to ?fteen hundred milliliters of
example 5 by its stoichiometric equivalent of ‘any other
the temperature below 30° C. Stirring was continued for
several hours during which time the dihydrochloride of 20 suitable Z-hydroxy-(rnono- or poly-)halobenzaldehyde
and following the procedure of that example, there is
the monoamide separated out from the homogeneous mix
obtained respectively the corresponding other ethylene
ture. The yield of this monoamide dihydrochloride was
bis(alpha-imino-Z-hydroxy-(mono- or poly-)halophenyl
increased by concentrating the ?ltrate solution under
acetic acid)-monoamide dihydrochloride. For example,
vacuum and keeping the temperature below 30° C.
25
Analysis
For ()2"lEIf"()5l\I3Cla
calculated _______________________________ ._
found ___________________________________ _.
N(total)
9.1
8.9
Gl(titratable)
15. 4
15. 7
by replacing the example 5 substituted benzaldehyde by
2-hydroxy-3,S-dichlorobenzaldehyde there is similarly ob‘
tained ethylene bis(alpha-imino~2-hydroxy-3,5-dichloro—
phenylacetic acid)-monoamide dihydrochloride; with
2-hydroxy-4,S-dichlorobenzaldehyde there is prepared
30 ethylene bis( alpha - imino-2-hydroxy-4,5-dichlorophenyl
acetic acid)-monoarnide dihydrochloride; with Z-hydroxy
5,6-dichlorobenzaldehyde there is obtained ethylene bis
By replacing the Z-hydroxy-S-methylbenzaldehyde of
Example 4 respectively by the stoichiometric equivalent
(alpha-imino-Z-hydroxy-S ,6 - dichlorophenylacetic acid)
of any other (mono- or poly-) alkyl, hydroxybenzalde 35
monoamide dihydrochloride; then with 2-hydroxy-3,5,6
trichlorobenzaldehyde there is prepared ethylene bis
hyde and following the procedure of that example, there
is similarly prepared with 2-hydroxy-3,S-dimethylbenzal
dehyde the corresponding ethylene bis(alpha-imino—2
monoamide dihydrochloride; similarly using Z-hydroxy
S-bromobenzaldehyde there results ethylene bis(alpha
(alpha-imino-2-hydroxy-3,5 ,?-trichlorophenylacetic acid) -
hydroxy-3,S-dimethylphenylacetic racid)-monoamide di
hydrochloride; and replacing it with 2-hydroxy-5-ethyl
benzaldehyde there is obtained ethylene bis(alpha-imino
imino-2-hydroxy-5-bromophenylacetic acid) - mo-noamide
40
2-hydroxy-5~ethylphenylacetic acid)-monoamide dihydro
chloride; and with Z-hydroxy-S-(tertlary)butylbenzalde
hyde there is prepared ethylene bis(alpha-irnino-2-hy
droxy-S-tertiary-butylphenylacetic acid)-rnonoamide di
hydrochloride; and with Z-hydroxy-S-octylbenzaldehyde
there is formed ethylene bis(alpha-imino-2-hydroxy-5
octylphenylacetic acid)-monoarnide dihydrochloride; and
dihydrochloride; and with 2-hydroxy-3,S-dibromobenzal
dehyde there is obtained ethylene bis(alpha-imino-2
hydroxy-3,S-dibromophenylacetic acid)-monoamide dihy
drochloride; then using 2-hydroxy-5-iodobenzaldehyde
there results ethylene bis(alpha-imino-2-hydroxy-5-iodo
phenylacetic acid)-mo~noamide dihydrochloride; and like
wise with 2-hydroxy-3,S-diiodobenzaldehyde there is ob
tained ethylene bis(alpha-imino — 2 - hydroxy-3,5-dii0do
ethylene bis(alpha-imino-Z-hydroxy-S-nonylphenylacetic
phenylacetic acid)-rnonoamide dihydrochloride; and simi
larly others.
By replacing the salicylaldehyde in Examples 2 and 3
acid)-monoamide dihydrochloride; and similarly others.
Similarly, when in place of the alkyl-Z-hydroxybenzal
by the stoichiometrically equivalent amount of a 2-hy
droxybenzaldehyde having linked to its benzene ring some
with Z-hydroxy-S-nonylbenzaldehyde there is formed
dehyde used in Example 4, ethylencdiamine is reacted
other substituent group or groups inert to (i.e. that does '
with a corresponding (mono- or poly-)halo-Z-hydroxy
or do not react with) a primary amine and which it is
benzaldehyde, there is obtained the corresponding ethyl 55 desired to have attached to the benzene ring in the end
enediamine derivative with halogen on the benzene rings,
product sought, and by repeating the combination of steps
as illustrated by, but not restricted to, the following:
of these several foregoing pertinent examples, there is
obtained the corresponding ethylene bis(alpha-irnino
Example 5
or-tho-hydroxyphenylacetic iacid)-monoamide dihydro
Ethylene bis(alpha-imin0 - 2 - hydrOxy-S-chlorophenyl
acetic acid)-m0noamizle dihydr0chl0ride.—A solution of
three hundred and thirteen grams of Z-hydroxy-S-chloro
benzaldehyde in four hundred milliliters of ethylene
chloride was placed in a two liter three-necked ?ask
equipped with stirrer, dropping funnel andDean-Stark 65
chloride with the corresponding additional substituent or
substituents on its benzene rings.
In the manner just indicated, with ethylenediamine:
Z-hydroxy, 3-sulfobenzaldehyde yields ethylene bis(alpha
imino - ortho - hydroxy-rneta-sulfophenylacetic ‘ acid)
rnonoarnide dihydrochloride; I
trap for azeotropic distillation of the water formed in the
2-hydroxy-3-rnethoxybenzaldehyde yields ethylene bis
reaction. To this solution was added sixty grams of
(alpha - imino -_ ortho - hydroxy-rneta-methoxyphenyl
anhydrous ethylenediarnine at a rate that maintained the
acetic acid)-rnonoamide dihydrochloride;
temperature at 30° C. After the addition was complete,
the mixture was re?uxed to remove by azeotropic dis 70 Z-hydroxy-S-hydroxyethylbenzaldehyde yields ethylene bis
(alpha - imino-ortho-hydroxy-meta-hydroxyethylphenyl
tillation the water formed. The reaction mixture then
was cooled to 20° C. and one hundred and twenty grams
of liquid hydrogen cyanide were added with agitation.
After eight hours, the light yellow solid that formed was
?ltered off and dried under vacuum atroom temperature, 75
acetic acid)-monoamide dihydrochloride;
2,4-dihydroxybenzaldehyde yields ethylene bis(alpha
imino-Z,4-dihydroxyphenylacetic acid)-monoamide di
hydrochloride;
3,028,407
8
2,=6-dihydroxybenzaldehyde yields ethylene bis(alpha
are obtained the corresponding derivatives wherein each
of at least two or more of X1, X2, X3 and X4 and also
X8, X7, X6 and X5 is a substituents group rather than
three or" each of these two groups X’s being hydrogen.
Likewise, by replacing the ethylenediamine or tetra
rnethylene ethylene-diamine or methylethylenediamine by
some other-differently substituted ethylenediarnine, for
example, where a hydrogen on each of the carbon atoms
of the ethylene radical is replaced by a lower alkyl or
imino—2,6-dihydroxyphenylacetic acid)-monoamide i
hydrochloride;
2-hydroxy-3-nitrobenzaldehyde yields ethylene bis(-alpha
imino ~ ortho - hydroxy - meta-nitrophenylacetic
acid)
monoamide dihydrochloride;
2-hydroxy-3~aminobenzaldehyde yields ethylene bis(alpha
imino - ortho - hydroxy-meta-aminophenylacetic
acid)
monoamide dihydrochloride;
2-hydroxy-3-carboxybenzaldehyde yields ethylene bis
(alpha - imino~ortho-hydroxy-meta-carboxyphenylacetic
acid)-monoamide dihydrochloride; and
2-hydroxy-S-carboxybenzaldehyde yields ethylene bis
(alpha-imino--ortho - hydroxy - 5 - carboxyphenylacetic
acid)-monoamide dihydrochloride.
10
lower alkanol (i.e., hydroxyalkyl such as hydroxy (lower)
alkyl) group ora hydrogen on one of the ethylene car
bons is replaced by an alkanol (i.e. hydroxyalkyl) group,
and reacting one mole of such substituted ethylenediamine
with two moles of any of the mono- or poly-further sub
15 stituted ortho-hydroxybenzaldehydes and completing the '
procedures of any of the preceding applicable several ex
amples, there result the corresponding other derivatives
wherein R, R1, R2 and R3 of the general formula are
placed by an alkyl group e.g. methylethylenediarnine, 20 other substituents than those already described in relation
to the speci?c examples.
octylethylenediamine or dodecylethylenediamine, respec
While the general description, in the ninth paragraph
tively separately with two moles of each of the different
of
this speci?cation, of the preparation of the monoamide
further substituted Z-hydroxybenzaldehydes included in
dihydrochlorides of the invention, and the illustrative ex
the various preceding paragraphs, and following the steps
of the corresponding preceding Examples 2 and 3 respec 25 amples, show the reaction ?rst between the particular
ethylenediamine and the selected substituted salicylal
tively, there are obtained respectively the corresponding
dehyde and then converting the resulting diimine to its
individual tetra-methylene ethylene or methylethylene
corresponding dinitrile, this order is not ?xed. Thus,
bis(alpha - imino-ortho'hydroxyphenylacetic acid)-mono
the selected salicylaldehyde may be reacted ?rst with hy
amide dihydrochlorides having respectively the cor
drogen cyanide to form the nitrile, two moles of which
responding additional substituents on the phenyl nucleus
then can be reacted with one mole of the ethylenediamine
as speci?cally shown in Examples 4 and 5, and by the
to give the corresponding ethylene bis(alpha-imino—ortho- ,
replacement of the particular substituted benzaldehydes
hydroxyphenyl
acetonitrile). Then also, the hydrogen
used respectively in these examples by any other of the
cyanide can be replaced by the equivalent quantity of an
substituted benzaldehydes disclosed above as suggested
replacements for any of the speci?c substituted benzal 35 alkali metal cyanide such as sodium cyanide and the pH
of the reaction mixture adjusted to provide the hydrogen
dehydes used in any of these examples. All of these addi
cyanide equivalent.
tional speci?c derivatives are incorporated herein by ref
For adjusting the pH in that step in the method as
erence as if each of them was correspondingly separately
illustrated
in the several examples, there can be used
actually individually set forth in full herein.
any suitable and compatible acid such as hydrochloric
Any S-alkyl, or S-alkoxy, or S-hydroxyalkyl (such 40
acid.
as hydroxyethyl or hydroxypropyl), -2 - hydroxybenzal
The free base of the dihydrochloride of each of the
dehyde which may not be readily available for synthesizing
speci?c examples was prepared by stirring one-tenth of a
Similarly, by using one mole of tetra-methylene ethyl
enediarnine, or of a substituted ethylenediarnine wherein
a hydrogen linked to one of the ethylene carbons is re
a desired end product ethylene bis(alpha - imino, sub
stituted-phenylacetic acid) - monoamide dihydrochloride,
readily can be prepared from the corresponding 5 - alkyl
or 5 - alkoxy or 5 - hydroxyalkyl phenol to the corre
sponding 2. -1 hydroxy 5 - alkyl or - alkoxy or - hydroxy
alkyl benzaldehyde by the Reirner-Tieman process de
scribed at page 37 of the fourth edition of Houben
Weyl “Methoden der organischen Chemie” (1954), Georg
Thieme Verlag, Stutgart, Germany.
Any halogenated 2-hydroxybenzaldehyde which may not
’ be readily available for synthesizing a desired end product
mole of the dihydrochloride with one-?fth of a mole of
sodium hydroxide dissolved in two hundred milliliters of
water. The resulting free base showed good solubility in
water. The corresponding free base of any other dihy
drochloride produced by replacing the salicylaldehyde
of any of the examples by some other substituted salicyl
aldehyde, or by replacing the ethylenediamine or sub
stituted ethylenediamine by some other substituted ethyl
enediamine, is similarly prepared.
Any such resulting ‘free base is converted to its alkali
cation salt, especially to its carboxylate salt, such as its
ethylene bis(alpha - imino, halo — substituted - phenyl
alkali metal, for example, sodium carboxylate, by adding
acetic acid) ~ monoamide dihydrochloride can be prepared
to the aqueous solution of such free base one equivalent
of an alkalizing agent, such as an alkali metal hydroxide,
as sodium hydroxide.
readily from the corresponding halogenated phenol, for
example, the corresponding 4-halo or 2,4-dihalophenol,
by converting the such required halogenated phenol to
the desired halogenated Z-hydroxybenzaldehyde by either
Thus, by reacting any of these monoamide dihydro
chloride covered by ‘the invention with the required
the above-mentioned Reimer-Tieman reaction or Gatter 60 equivalent amount of the corresponding alkalizing agent
man aldehyde synthesis as described in A. R. Surrey’s
such as an alkali metal or ammonium hydroxide or amine
“Name Reactions in Organic'Chemistry.”
of the type described in the third paragraph of this speci
?cation, there is obtained the corresponding salt wherein
Thus, the various Z-hydroxybenzaldehydes having some
M of the general formula is ‘an alkali cation of the type
other substitutents on the benzene ring, as illustrated by
those in the full paragraph in column 6, lines 62 to 75 and 65 above de?ned for M. For example, ?ve grams of ethylene
bis ( alpha-imino-ortho~hydroxyphenylacetic acid) -mono
column 7, lines l-lS, yield ‘corresponding derivatives
amide 'dihydrochloride, brie?y called “Compound I,”
wherein three of X1, X2, X3 and X4 andthree of X3,
was added to ?fteen milliliters of 6 normal ammonium
X7, X6 and X5 of the general formula in the sixth para
hydroxide and forty milliliters of water and stirred. When
graph of this speci?cation are hydrogen. Then, by re
acting one mole vof the ethylenediamine, or the ethylene 70 all of the Compound I was dissolved, the solution con~
tained the ammonium salt of Compound 1. Similarly,
diamine with lower alkyl or alkanol (i.e. hydroxyalkyl)
substituents on any of its ethylene carbon atoms, with
two moles of an ortho-hydroxyben2aldehyde having
on itsv benzene ring two or more other substituents of
?ve grams ‘of Compound I was added to a solution of
seven and one-half milliliters of triethylamine in ?fty mil
liliters of water and stirred. ‘When all ‘of the Compound I
the type disclosed anywhere in this speci?cation, there 75 was dissolved, the solution contained the triethylam
3,028,407
9
1a
sented by any of X1 through X8 of the general formula
the hydrogen of the carboxyl group of the acetic acid
residue of the compound, but also of the hydro-gen of the
can be converted simultaneously to the corresponding
phenolic ortho-hydroxyl group.
alkali cation salt ‘by employing su?icient of the selected
Preparation of the chelate complexes as embraced by
the invention, is illustrated by, but not restricted to, the
monium salt of Compound I. Any carboxyl group repre
alkalizing agent.
following example.
In any of the derivatives wherein any of X1 through
X8 is the sulfonic acid radical, addition of the alkalizing
agent will convert it to the corresponding sulfonate group
before any carboxyl group is changed to carboxylate.
Then if carboxylates are also desired, su?icient alkalizing 10
agent must be included to neutralize the carboxyl groups
after the sulfonate groups are formed.
Then to form
phenolates by neutralization of the ortho hydroxyls,
enough alkalizing agent must be added to make the pH
Example 6
Ferric chelate of ethylene bis(alpha-imin0-0rth0hy
droxyphenylacetic acid)-m0n0amide.—Two hundred and
twenty-one grams (0.5 mole) of ethylene bis(alpha-imino—
ortho-hydroxyphen-ylacetic acid)-monoarnide dihydro-
chloride were stirred up in one liter of water. While stir
, ring that slurry, there was added one hundred and thirty
?ve grams (0.5 mole) of powdered ferric chloride (hexa
15 hydrate), which immediately produced a deep reddish
greater than 10.
The various products of the invention are effective
purple color. Then there was added two hundred grams
metal complexing agents in aqueous and non-aqueous
of a ?fty percent solution of sodium hydroxide (2.5v
media. The resulting complexes, especially iron (particu
moles), and the exothermic reaction was cooled by im
larly ferric) chelates of the various products of the in—
mersing the reaction vessel in a cold-water-bath.
20
vention, are stable in strongly alkaline solutions.
After the reaction was completed, the precipitated
Derivatives of the invention are also useful as fungi
(solid) chelate was ?ltered o?', washed to remove water—
soluble salts of the reaction and dried. Because of the
cides and germ-icides, as oxidation inhibitors in hydro
carbons, in metal deactivation and in some solvent ex
proportion of sodium hydroxide used, the end product
traction applications. To illustrate: among the amine
was the ferric chelate of ethylene bis(alpha-imino-ortho
salts of the invention are substances effective for liquid 25 hydroxyphenylacetic acid)-monoamide.
extractions. For example, some such salts after sequester
The corresponding ferrous chelate is similarly pre
ing a metal from an aqueous solution, form with it a
pared, but due to its ready oxidation to the ferric chelate,
complex that is soluble in an organic solvent that may not
it is best prepared in an inert atmosphere (using, for
be soluble in water. Thus, such metal can be removed
example, carbon dioxide or nitrogen). Instead of the iron
30
from an aqueous phase to an organic phase. Manganese
chloride, any other water-soluble iron salt (either ferric
in water solutions, for example, will form with an amine
of ferrous depending on the particular chelate desired)
salt of ethylene bis(alpha-i-mino—ortho-hydroxy-phenyl~
can be used, such as the sulfate, nitrate, or acetate. Any
acetic acid)-monoamide dihydrochloride a complex that
of them can be added in powdered form or dissolved in
is soluble in chloroform. That enables the removal or
water.
extraction of manganese from water into an organic sol 35
The corresponding chelate with any other polyvalent
vent. The presence of higher alkyl groups (i.e. seven
metal is prepared by using a corresponding water-soluble
or more carbons) on the benzene groups of a derivative
salt of it and following the same or similar procedure.
of the invention enhances its solubility and that of its
The iron chelate, particularly ferric, can be used by
metal chelates in organic solvents, thereby increasing the
40
being applied on calcareous soils to overcome an iron
scope of their utility.
de?ciency in growing-plants susceptible to such de?ciency,
Where seen to be applicable and compatible, suitable
for example, chlorosis. The ?nely divided chelate can be
mixtures of any of the free bases, dihydrochlorides, and
dusted over the soil around the plant, or admixed with
alkali cation salts of the invention can be used jointly in
plant food chemicals.
various applications of them. Metal complexes or chelates
Thereby such iron chelate can be used to overcome an
made with derivatives of the invention are soluble in 45 iron de?ciency'in a growing plant by a method which
aliphatic and aromatic hydrocarbons and other organic
comprises administering to the plant an iron chelate, ad
solvents, for example, lower aliphatic alcohols, ketones,
lower alkyl esters of lower alkyl alcohols, and acyclic
ethers as ethyl ether, or cyclic ethers such as dioxane.
The derivatives of this invention, particularly as their
water-soluble salts as described herein, very readily form
metal complexes with divalent and other polyvalent
metals, in addition to iron (ferric) and manganese al
ready mentioned.
Thus, the invention embraces also such chel‘ate com 55
plexes of polyvalent metals with the various monoamides
vantageously the ferric, chelate of ethylene bis(alpha
imino-ortho-hydroxyphenylacetic acid)-monoamide and
in a quantity suf?cient to overcome such de?ciency.
Accordingly, the invention includes also the method
of overcoming an iron de?ciency in a growing plant by
administering to the plant an iron chelate of any of the
monoamide compounds of this invention and at a regimen
sui?cient to overcome the de?ciency in relation to the
particular soil wherein the plant is growing.
‘ In addition to administering the chelate complex in
powdered form or admixed with some plant food chem—
hydrochloride or any of the herein mentioned salts of .
ical or chemicals, it may be incorporated in any other
either form of them.
vehicle innocuous to the plant, for example, a plant fer
Embraced among such chelates of these various se 60 tilizer composition. Alternatively, the iron chelate can
questering agents of this speci?cation are those of divalent
be incorporated in an inert carrier or vehicle, for ex
metals such as the alkaline earth metals as barium, cal
ample, any innocuous sand such as vermiculite or others,
escribed herein, whether taken as the free base or di
cium, strontium, with magnesium included among them,
and the iron group metals iron, nickel, and cobalt, and
or a liquid vehicle such as water.
For use in dry form, a mixture can be prepared con
others such as copper, zinc, and manganese as well as 65
taining one part of the iron chelate of the monoamide of
Example 1 with ten parts of a balanced fertilizer such as
than divalent metals are not ‘only those with metals such
other divalent metals. The chelate complexes of higher
as iron, cobalt, and manganese and others like them that
also exist in the divalent state, but also those with metals
the 13-—0—13 (N—P-—K) analysis fertilizer. That composi~
tion can be used, for example, on citrus trees to the ex
that are only trivalent such as aluminum, as well as those 70 tent of ?ve pounds per tree.
Instead of the dihydrochloride of any of the mono
of metals of any other valence. It is possible to have
amides of this invention, some other dihydrohalide, such
the chelate complex of any of the metals so long as it is
as the dihyclrobromide, or any other compatible acid ad
divalent or higher.
dition salt, is prepared by adding the stoichiometric equiv
In these chelate complexes with ‘a polyvalent metal,
the linkage of that metal is ‘by replacement not only of 75 alent quantity of the particular acid to the ‘free base (pre
’
8,028,407
11
12
pared, for example, as described in column 8, lines 41
M2, X8, X7, X6, and X5 is correspondingly in sequence
51, inclusive, above). Alternatively, the dihydrobromide
the same as M3, X1, X2, X3 and X4 respectively.
3. An acid addition salt or ethylene bis(alpha-imino
can be prepared by using concentrated hydrobromic acid
in place of the concentrated hydrochloric acid in the pro
cedure for hydrolyzing the dinitrile (for example, column
3, line 70 above).
ortho-hydroXy-phenyla-cetic acid)-monoamide.
4. A dihydrohalide of ethylene bis(alpha-imino-ortho
hydroxy-phenylacetic acid)-rnonoamide.
While the invention has been described in relation to
5. A dihydrochloride of ethylene bis(alpha-imino-or
various speci?c embodiments of it, many modi?cations
tho-hydroxy-phenylacetic acid)-monoarnide.
6. Ethylene
bis(alpha-imino-ortho-hydroxy-phenyl
and substitutions in them can be made within the scope of
the appended claims which are intended also to cover 10 acetic acid)-monoamide.
V 7. Ethylene
' equivalents of them and the many variations indicated to
This application is a continuation-in-part of our co
8. Ethylene bis(alpha-irnino-ortho-hydroxy - 5 - methyl
phenylacetic acid)-monoamide dihydrochloride.
pending application Serial No. 682,580, ?led October 10,
1955, which in turn is a continuation-in-part of our then 15
co-pending application Serial No. 358,558 ?led May 29,
9. An iron chelate of ethylene bis(alpha-imino-'ortho
hydroxyphenylacetic acid)-monoamide.
1
10. The ferric chelate of ethylene bis(alpha~imino
1953, now abandoned.
What is claimed is:
l. A member of the class consisting of (a) a mono
amide having the indicated general formula
bis(alpha-i111lno~ortho-hydroxy-(lower)
alkylphenylacetic acid)-monoamide dihydrochloride.
be possible.
ortho~hydroxy~phenylacetic acid) -rnonoamide.
11. The method of hydrolyzing an ethylene bis(alpha
20
imino-ortho-hydroxyphenyl acetonitrile) to its correspond
ing ethylene bis(alpha-imino-ortho-hydroxyphenylacetic
acid)-monoamide, which method comprises mixing the
acetonitrile in a concentrated hydrohalide acid and con
trolling the heating of the reaction mixture to avoid ex
25 ceeding about 40° C. while the acetonitrile and the acid
are being admixed, and thereafter heating the mixture at
between about 40 to about 45° for ti e several hours suf
wherein any of R through R3 is separately a member of
the class consisting of hydrogen, an allryl group having 30
under 13 carbon atoms, a hydroxy (lower) allryl grou ,
and a divalent lower polyalkylene group having under 5
?cient for the hydrolysis to the monoamide dihydrohalide
to be completed.
12. The method as claimed in claim 11, wherein the
hydrohalide acid is hydrochloric acid.
13. The method as claimed in claim 12, wherein the
heating up of the reaction mixture is controlled below
30° C. while the acetonitrile and the acid are being ad—
:1 member of the class consisting of hydroge- , an alkyl 35
mixed, and thereafter the temperature is raised to about
group with one through ten carbon atoms, a lower alkoxy,
40° C. and continued between about 40° and 45° until
carbon atoms substituted for one of the pairs of R and R1
and of R2 and R3; and any of X1 through X3 is separately
lower hydroxyallryl, carbonyl, alkali cation carboxylate,
hydroXyl, alkali metal-oxy, nitro, free amino, cyano,
sulfo, alkali metal sulfonate group, and a halogen; and
the hydrolysis is completed.
14. A dihydrohalide of ethylene bis(alpha-imino-ortho
hydroxy~5-chlorophenyl-acctic acid)-monoamide.
M is independently selected from the class consisting of 40
15. A dihydrochloride of ethylene bis(alpha-imino-or
hydrogen and an alkali cation; and any of M2 and M3
tho-hydroxy-S-chlorophenyl-acetic
acid)-monoamide.
is independently selected from hydrogen and an alkali
metal (11) an acid addition salt of said rnonoamide; and
References Cited in the ?le of this patent V
(c) a polyvalent metal chelate of a member of the class
UNITED STATES PATENTS
45
consisting of (a) and (b); and wherein the alkali cation is
a'member of the class consisting of an alkali metal, am
monium, morpholino, and the radicals —NH2Q, —~NHQ2,
—NQ3, wherein Q is a member of the class consisting
of a lower alkyl and a (lower)alkylenediamino group.
2. A substance as claimed in claim 1, wherein each of
2,655,532
2,683,658
Hop? et a1. __________ __ Oct. 13, 1953
Saunders et al. ________ __ July 13, 1954
2,772,151
2,824,128
Niketin _______________ __ Feb. 20, 1956
Dexter ______________ __ Feb. 18, 1958
2,921,847
Knell et a1. __________ __ Jan. 19, 1960
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent No. 3,028,407
April 3, 1962
Martin Knell et a1.
It is hereby certified that error appears in the above numbered pat
ent requiring correction and that the said Letters Patent should read as
corrected below.
.
Column 1, line 11, for "orthohydroxyphenylacetic" read
-- ortho-hydroxyphenylacetic ——; lines 51 and 52, after
the formula insert a semicolon’; column 2, lines 27 to 33,
extreme right-hand portion of the formula, for "—Y2" read
-—- —-—X
--; column 3, line 6%, for "’ortho—hydroxyzenzaldehyde"
read —— ortho-Wdroxybenzaldehyde ——; column 4, line 33, for
"cantaining" read —- containing —-; lines 56 and 57, for
"methyethylenediamine" read ——- methylethylenediamine --;
column 5, in the table, heading to column 1 thereof, tor
...
For C 20 H 27 O 5 N 3 Cl‘2. ' read
__
For C2OH27O5N3Cl2
___
‘
, column
8,
line 3,‘ for “substituents" read —— substituent ——; line 4, after
"groups" insert —— of --—3 column 10, line 8, for "iorthohyJ',
in italics,
line 3,
read -- —0rtho—hy— —-,
in italics; column 12,
for "or" read —— of ——.
Signed and sealed this 4th day of September 1962.
(SEAL)
Attest:
ERNEST W. SWIDER
‘DAVID L. LADD
Attesting Officer
Commissioner of Patents
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