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Патент USA US2504984

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2,504,984
Patented Apr. 25, 1950 ‘
UNITED. STATES PATENT OFFICE
_
2,504,984
METHOD FOR OBTAINING AMIDES 0F
POLYHYDROXY ACIDS CONTAINING A
SUGAR GROUP
Horace S. Isbell and Harriet L. Frush, Washing
ton, D. 0., assignors to the United States of
America as represented by the Secretary of
Commerce
No Drawing. Application August 31, 1948,
Serial No. 47,136
11v Claims. (01. 260-333)
(Granted under the act of March 3, 1883, as
amended April 30, 1928; 3'70 0. G. 757)
1
The invention described herein may be manu
factured and used by or ‘for the Government of
the United States for governmental purposes
without the payment to us of any royalty there
on in accordance with the provisions of the act
of April 30, 1928 (Ch, 460, 45 Stat. L. 467) .
2
Suitable aminoglycuronic amides for purposes
of this invention can be prepared by the methods
disclosed in the aforementioned co-pending ap
plication of Isbell and Frush and include 1
aminomannuronic amide, l-aminoglucuronic
amide, l-aminogalacturonic amide, and other
aminoglycuronic amides.
The hydrolysis of such amino-glycuronic
amides can be carried out by treating the amino
This invention relates to ammonia derivatives
of the uronic acids. Particularly, the invention
relates to a new series of compounds, the glycu
roni-c amides and a method for producing the 10 amide with an acid which may be organic or in
organic. However, for reasons of economy and
same. Still more particularly the invention re
simplicity of operation, acids such as sulfuric
lates to the production of the aldohexuronic
and hydrochloric acid are presently preferred.
amides: mannuronic amide, glucuronic amide,
In order to prevent the hydrolysis of the amide
galacturonic amide, and like derivatives.
In the co-pending Isbell and Frush application, 15 group it is necessary to limit the quantity of acid
used to not more than one molecular equivalent
Serial No. 47,135, ?led August 31, 1948, there is
per mole of amino-amide being hydrolyzed. The
disclosed a method for the preparation of a new
hydrolysis reaction of the aminoglycuronic amide
series of ammonia derivatives of the uronic acids;
results in the formation of an ionic ammonium
the aminoglucuronic amides. These compounds
are produced by reacting an ester of uronic acid 20 salt such as the sulfate or chloride.
The by-product ammonium salt can be sepa
with an amine reagent such as ammonia, alkyl
amines, aryl amines, and the like, whereby -—NH2
groups are attached to the glycosidic carbon and
the carboxylic carbon to produce aminoglycu
ronic amides such as l-aminomannuronic amide,
l-aminogalacturonic amide, l-aminoglucuronic
rated from the hydrolysis reaction mixture by
various methods. A convenient method involves
forming an insoluble compound with the anionic
constituent present and volatilization of the ni
trogen base. For example, when sulfuric acid is
amide, l-aminolyxuronic amide, and the like. In
used to hydrolyze the amino-amide, precipitating
one embodiment thereof mannuronic lactone is
suspended in methanol and reacted with an
hydrous ammonia, and on completion of the re
action the excess solvent and ammonia are sep
earth metal followed by distillation to remove
the ammonia; or if 01- is present, as where hy
drochloric acid is employed to effect the hydroly
arated from the crystalline l-aminomannuronic
amide.
the S04: as an insoluble sulfate of an alkali
sis, the 01* can be removed as an insoluble chlo
ride such as silver chloride. Another method for
removing the ionic constituents involves passing
Heretofore attempts to prepare crystalline
amides of polyhydroxy acids containing a poten 35 the mixture through or contacting the mixture
with a cation exchange resin to remove the cation
tial aldehyde group have been unsuccessful.
constituents and then with an anion exchange
Accordingly, it is an object of this invention to
resin to neutralize the regenerated acid. Suit
produce a new series of solid crystalline ammonia
able cation exchange resins include sulfonic acid
derivatives of the uronic acids; the glycuronic
high polymers, the sulfonated coals, and resins
amides. It is another object of this invention to 40 containing carboxyl groups. The anion exchange
provide a method for the production of the
resins include the condensation products of phe
aldohexuronic amides: glucuronic amide, galac
nol and formaldehyde, modi?ed by amination, or
turonic amide, and mannuronic amide. Other
by copolymerization with a suitable diamine. In
objects and advantages will be apparent or will 45 such procedure it is possible to completely hy
drolyze the glycosidic amino group with less than
appear hereinafter.
‘
These objects and advantages are accom- one mole equivalent of acid.
plished in accordance with this invention by the
If such a method is used to remove the cati
' method for the production of glycuronic amides
onic constituent, a very small quantity of acid
which comprises hydrolyzing the glycosidic
is preferably added to the material before pass
ing it over the cation exchange resin. The resin
amino group of an amino glycuronic amide by
reacting said amino-amide with an acid, sepa
decomposes the initially formed ammonium salt,
regenerates the acid, which in turn reacts with
rating the thus produced ammonium salt from
and hydrolyzes more of the aminoglycuronic
saidreaction mixture, and. recovering the glycu
55 amide and concurrently reforms the ammonium
ronic amide.
2,504,984
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*
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salt which in turn reacts with the cationic ex
change resin. Thus, a small quantity of acid is
sufficient toe?ect the hydrolysis of a large quan
tity of an aminoglycuronic amide. The small
quantity of acid which remains after such treat
acid in turn reacts with more of the l-aminoman
nuronic amide reforming ammonium chloride
which reacts again with the resin. Thus, a
small quantity of hydrochloric acid is suf?cient
to effect the decomposition of a large quantity of
the aminog-lycuronic amide. The eiliuent is neu
tralized by passing, it through a column ?lled with
soluble salt or by ?ltration through an anion .
anion exchange resin, Amberlite IR-ll-B, a modi
exchange resin. The resulting. salt-free, neutral
?ed amine resirn The resulting neutral solution
solution contains a substantially pure glycuronic
amide.
10, is evaporated to a syrup from which mannuronic
amide crystallizes-in. good yield.
The glycuronic amide can be recovered from
If it is desired; to remove the loosely bound
the solution in crystalline form by concentration
amino group without recourse to ion exchange
of the solution to a syrup from which crystals
resins, the following procedure may be used.
of the amide will separate. It is possible to in
crease the yield by the addition to- the syrup of 15
Example III
an organic solvent in which the glycuronic amide
Ten
grams
of
l-aminomannuronic
amide are
is relatively insoluble. Filtration‘or other suit
dissolved in 100 ml. of water and the solution is
able solid-liquid separating means can be- em,
treated with a molecularly equivalent quantity
ployed to recover the crystalline; product.
of dilute sulfuric acid added drop by drop, fol
The glycuronic amide can be recrystallized by
lowed by a molecularly equivalent quantity of
dissolving it in water. concentrating the. solution
barium hydroxide solution. The barium sulfate
at a low temperature. as in a vacuum still, until
is separated‘ and the solution is evaporated to a
it hasformed a syrup, from which crystals of the
thick syrup ‘from which mannuronic amide crys
amide separate. The addition of an organic
tallizcd in good. yield.
solvent, say, methanol, in portions to the syrup
as crystallization proceeds. facilitates crystalliza
Example IV
tion.
l-aminoglucuronic amide is dissolved in water
The followingv examples ‘will, show how the in
and the loosely bound amino group is hydrolyzed
vention may be carried out; the invention, how
ever,v is not to be construed as limited thereto.
3O by reacting the amino-amide with 0.1 equivalent
of hydrochloric acid, followed by ?ltration
Example I
ment can be removed by precipitation as an in
Crude l-aminomannuronic amide is dissolved
in IOparts of‘ water and 0.2 N-hydrochloric acid
is, added dropwise. until the solution has a pH of
5, ten. minutes after the addition of the last por
tion of acid. This requires substantially one mole
of acid per mole of l-amino-mannuronic amide.
The solution is then passed ?rst over a cation
exchange resin, Amberlite IR-IGO-H (a sulfonic
acidhigh polymer) to. remove the ammonium ion,
and then over an anion exchange resin, Amber
lite IR..--¢l-Bv (‘an amino phenolic resin) to remove
regenerated acid. The solution so obtained is
concentrated at about 40° centigrade to a thick
syrup from which mannuronic amide crystallizes.
The yield of crystalline mannuronic amide from
10 grams of mannuronic lactone is about 5 grams.
Additional product is obtained by working up the
mother liquor.
,
Crystalline mannuronic. amide, the product of
the present invention, has the formula CsI-IiiOeN.
When heated in a meltingv point tube it decom
poses at 145° to 150° centigrade. The freshly
prepared solution exhibits mutarotation with the
through a column of a cation exchange resin, Am
berlite IR-C-50‘, a carboxylic acid. type cation ex
changer. The residual acid in the effluent is re
moved by ?ltration through an anion exchange
resin., Amberlite IR-Ll-B, and the solution is con
centrated under vacuum at a temperature below
40° centigrade to a thick syrup from which glu
curonic amide crystallizes
Crystalline glucuronic amide, a product of the
present invention. is the hydrate of the alpha
pyranose modi?cation. It has the formula
C6H1iOsN'I-I2O and melts at l12°-117°, resolidify
ing, and then melting with decomposition above
150° centigrade. The freshly prepared solution
exhibits mutarotation. Thus, the speci?c rota
tion, M11320, changes from +78“ (‘3 minutes) to
+3l.6° (18»v hours after dissolution). The muta
rotation indicates that the substance is the alpha
pyranose modi?cation and in water solution es
tablishes an equilibrium state with other modi?
cations.
Ewample V
Ten grams of 1~aminogalacturonic amide are
speci?c rotation, [0011120, changing from +2.4° (1.4 55 dissolved in. 200 ml. of water and 1 ml. of acetic
acid is added. The solution is passed in the
minutes) to —10.4° ('30'rninutes after dissolution).
course of 90 minutes through a column contain
The optical rotation shows. that the compound is
ing a cation exchange resin, Amberlite IR-lOO-H.
the alpha pyranose. modi?cation and that in wa
The effluent is then concentrated at a tempera
ter solution it establishes an equilibrium with
60 ture of less than 40° Centigrade to a syrup.
other modi?cations.
Methanol is added nearly to saturation and the
If it is desired to e?ect conversion of the amino
syrup is kept at a temperature of 50° centigrade
glycuronic amide to the free amide with only a
for several hours. During this‘ time, galacturon
small quantity of, acid,- the procedure in the fol
ic amide crystallizes from the solution. After
lowing Example II is effective.
65 separation of‘ the crystals from solution, they are
Example II‘
puri?ed bydissolving in water, ?ltering the solu
tion with the aid of a decolorizing carbon and
Ten grams of 1-aminomannuronic amide are
concentrating it at a low temperature in a vacu
dissolved in 100 ml. of water and 1 ml. of 0.2 N
um still. Methanol is added and the syrup is
hydrochloric- acid is added. The solution is al 70 kept at a temperature of 50° centigrade while
lowed to percolate slowly through a column of ca
crystallization occurs. Crystalline galacturonic
tion. exchange resin, Amberlite IR-.l00-I-I, a phe
amide thus prepared has the formula CGI‘IIIOSN
nol-formaldhyde, resin with, w-sulfonic acid
groups. The resin decomposes the ammonium
and melts at 172°—178° centigrade.
The freshly
prepared solution has a. speci?c rotation, [1111320
chloride andregenerates hydrochloric acid,v the 75 of +80°, which changes in the courseof 19 hours
2,504,984
r
5
to +15.7°. This mutarotation is characteristic
of alpha pyranose modi?cations.
If galacturonic amide is crystallized under dif
ferent conditions, it separates from solution as
the monohydrate of the beta pyranose modi?ca
tion. Thus, if galacturonic amide is dissolved
in an equal weight of water at 40° centigrade
and the solution is allowed to stand for two
hours at room temperature to e?ect conversion
to the alpha-beta equilibrium mixture,v and
ethanol is added to the point of incipient tur
bidity, the crystals which separate have the for
mula c?nno?u-nzo. [111D2o equals —21° (3 min
utes), which changes to +14.6° (22 hours after
from the reaction mixture, and recovering the
aldohexuronic amide.
4. The method for the production of aldohex
uronic amides which comprises treating an
aqueous solution of an aminoaldohexuronic amide
with not more than one molar equivalent of
an acid, forming an insoluble salt with the
anionic constituent of the thus formed am
monium salt, separating said insoluble salt from
the mother liquor, concentrating said mother
liquor to a syrup whereby the excess ammonium
hydroxide is driven off and a solution of pure
aldohexuronic amide is obtained, and separating
the crystalline aldohexuronic amide which
dissolution).
In the event that it is desired to 15 forms in said syrup.
5. The treatment of l-aminomannuronic amide
by the method of claim 1, whereby mannuronic
solution obtained after removal of the ammonium
salts from the hydrolyzate of l-aminogalacturon
amide is produced.
6. The treatment of l-aminoglucuronic amide
ic amide, it is necessary to concentrate the aque
ous solution to a density corresponding to ap 20 by the method of claim 1, whereby glucuronic
proximating 30 per cent dry substance and then
amide is found.
add several volumes of an organic solvent which
'7. The composition of matter: mannuronic
dissolves in the syrup and renders the product
amide; CeHuOsN; melting with decomposition
separate p-galacturonic amide hydrate from the
less soluble. Methyl alcohol, ethyl alcohol, isO
at about 145° to 150° centigrade; [a]D2° changing
propyl alcohol, acetone, and dioxane are suitable 25 from +2.4° (1.4 minutes) to —'10.4° (30 minutes
for this purpose. Crystallization of p-galactu
after dissolution).
ronic amide monohydrate ordinarily begins spon
8. The composition of matter: glucuronic
taneously but may be facilitated by the addition
amide monohydrate; CsI-InOsNl-IzO, melting
of seed crystals.
point 112° to 117° centigrade, and after resolidi
From the foregoing description and examples, 30 fying, melting with decomposition above 150°
it is apparent that a new series of crystalline
centigrade; [@11320 changes from +78° (3 min
ammonia derivatives of the uronic acids has been
utes) to +31.6° (18 hours after dissolution).
produced and various methods have been shown
9. The composition of matter: galacturonic
for their production.
amide, CGHllOGN melting with decomposition at
Since many widely differing embodiments of
172° to 178° centigrade; [a]D2°=+80° (3 min
the invention will occur to one skilled in the art,
utes); +'15.7° (19 hours after dissolution).
the invention is not limited to the speci?c de
10. The composition of matter: galacturonic
tails illustrated and described, and various
amide monohydrate, CsH11O6N.H2O melting at
changes can be made therein without departing
113°Vto 116° centigrade, and after resolidifying,
from the spirit and scope thereof.
40 melting with decomposition at 172° to ‘178° centi
What is claimed is:
grade. [e]D2° changes from -2l° (3 minutes)
1. The method for the production of glycuronic
to +14.6° (22 hours after dissolution).
amides having the formula CsHiiOeNJlHzO where
n is 1 and 0 which comprises hydrolyzing the
glycosidic amino group of an amino-aldohex
uronic amide by reacting said amide with not
more than one molar equivalent of an acid, sep
arating the thus produced ammonium salt from
said reaction mixture, and recovering the gly
curonic amide.
2. The method for the production of aldohex
uronic amides which comprises reacting an
aminohexuronic amide with not more than one
11. The method for the production of aldo
hexuronic amide which comprises treating an
aqueous solution of an aminoaldohexuronic
amide with less than one equivalent of acid pass
ing the solution successively over a cation ex
change resin and then over an anion exchange
resin, concentrating the e?iuent to a syrup and
separating the crystalline aldohexuronic amide
which forms in said syrup.
HORACE S. ISBELL.
HARRIET L. FRUSH.
molar equivalent of an acid, separating the thus
REFERENCES CITED
formed ammonium salt from the reaction mix 55
ture, and recovering the aldohexuronic amide.
The following references are of record in the
3. The method for the production of aldohex
?le of this patent:
uronic amides which comprises treating an
UNITED STATES PATENTS
aqueous solution of an aminoaldohexuronic amide
Name
Date
Number
with not more than one molar equivalent of an 60
acid, separating the thus formed ammonium salt
2,380,739
Evans et al _______ __ July 31, 1945
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