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Патент USA US2408098

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Patented Sept. 24, 1946
_
2,408,096
UNITED STATES PATENT‘I'QFFICE
POLYHYDROXYAIHINO COMPOUNDS
John ‘S. Pierce, Richmond,‘ Va., and John H.
Wotiz, Pittsburgh, Pa.; said Wotiz, assignor to
said Pierce
No Drawing.v Application May 1, 1944,
Serial'No. 533,644
5 Claims. (01. 2sd-5s4.)
2
The present invention relates to new chemical
compounds and to their'methods of manufacture.
following examples. It is understood that these
. one object of-this invention is to provide a.
the invention in any way.
examples are illustrative only and do not limit ,
means of holding bismuth in neutral solution, in
high concentration. This is extremely important .
from a therapeutic standpoint.
I
'
>
, panol dihydrochlorz‘de
Another object of this invention is to provide
a means of holding iron salts in solution, par
ticularly ferric salts in alkaline solution.
Another object is to hold in solution'a‘high
concentration of various metallic salts with a low
concentration of the cation of the salt. Such a
- (HOCHQSCNHCHZCHOHCHZNHC(CHBOHMBHCI
amino-methaneiloi moles) and 92.5 grams of
epichlorohydrin‘ (1.0' mole) and 200 ml. of 95%
alcohol'was heated on a boiling water bath under
reiiux' for '5 hours. The reaction mixture thus
formedvwas treated with 100 ml. of concentrated
hydrochloric acidjwith stirring. A heavy pre
cipitate was" formed. The mixture was cooled
and ?ltered withgsuction'. ‘The precipitate was
ceutical applications as is shown in the discussion
our
invention.
..
>
'
4'
'
-'
Y
"
v
‘ A mixture of 242 grams of tris(hydroxymethyl) -
property has important industrial and pharma
of
" 'ExAMPnE '1‘
1,3-ln's [iris (hydroazymethyl) methylamino] -2-pro- '
,
Another object is to furnish intermediates for
the dye industry, for detergents and for pharma
recrystallized from an alcohol-water solution.
In general, our invention relates to polyhydroxy
There was obtained 190 grams (51% of theory) of
compounds containing two amino groups and four s29 1‘,3-'bi's [tris(hydroxymethyl) methylamino] -2-pro
ceuticals.
‘
.
or more hydroxyl groups and to means of pro
panol dihydrochloride, ‘melting at 185-1879. On
further puri?cation, the product'melted at 186
188} Calculated for CiiHzaovClzNzt Cl, 19.13%‘.
ducing these compounds. More speci?cally, it
relates to polyhydroxy amino alcohols made up
of two groups, one containing an aminov group
Found,
and three hydroxyl groups and the other contain
'
ing one or more hydroxyls, these groups ‘being
atoms.~
,
.
‘
'
‘
"
'
‘
'
EXAMPLE
‘
2
'
‘
'
’
1,3-bz's [trz‘s (hydroxymethyl) methylaminol ~2-pro
panel dihydrochloride
connected by linkage of amino nitrogens through
carbon
19.07%.
'
‘
One phase of this invention in which wjev are
particularly interested is the class of compounds
,
l
l
(HOCHQgCNHCHgCHOHCHgNHC(CH2OH)a.2HC1
Glyceroldichlorohydrin was heated with‘ two
containing two tris(hydroxymethyl) ,methylamino
molar quantities of tris(hydroxymethyl)amino- '
groups, linked by alkylene or 'alkylene and hy
droxylated methylene groups. A speci?c com
pound which may be used to illustrate ourv inven
tion has the following structure:
methane at 100° for 3 hours with no solvent and
with. frequent ‘ stirring. The yellow glue thus
formed was dissolved in hot alcohol and the solu
tion was acidi?ed with hydrochloric acid. The
precipitatev which formed on cooling was recrys
stallized from aqueous alcohol. (For constants,
see Example 1'.)
110cm
'
7
onion
,
nocHroNnomoHoHomNno-piimii
‘7
noon,
‘
'
cmon
‘
This compound, like all other compounds covered 4.0
by this invention is extremely soluble in water
and also forms very soluble salts; as the dihydro
"
EXAMPLE 3
71.3-61.9 [tris (hydroxymethyl) methyldminol -2-proi
,
,
panol
_
chloride. Due to its high solubility and tothe
;(H0cH2)scNncrigcnoncnzNncwmon),
hydroxyl groups and the secondary amino groups,
’ ‘The ‘free base,v ~1,3'-bis[tris(hydroxymethyl)
by this inventiom may be combined with other
Idium chloride, was prepared by treatment of the
:dihydrochloride, in‘ methyl alcohol, with the cal-.
this compound, like the other compounds covered 1 45
- methylaminole2-propanol, mixed with a little so
less soluble substances to form new products of
intermediate
solubility.
-
‘
'
'
'
'culated quantity'of sodium methylate, re?uxing,
' As illustrative of the methods used to prepare 50 cooling; and-‘?ltering off the sodium chloride and
jevaporatingto a'syrup. Also, the free base was
compounds covered by our invention, we give the
I
2,408,096
3
4
prepared for analysis from the dihydrochloride
by prolonged heating with excess silver carbonate,
removal of dissolved silver with hydrogen sul?de,
and removal of colored impurities by repeated
at 160.5-162°. Calculated for C14H3406BI‘2N2: Br,
32.87%. Found 32.10%.
EXAMPLE 7
1 -diethanoZamino-3-tris (hydroxymethyl) meth
solution in absolute alcohol and treatment with
ylamino-Z-propanol dihydrochloride
anhydrous acetone. Finally, by evaporation of
the oily lower layer, the free base was obtained
as an oil. Calculated for CnHzvOqNz: N, 9.40%.
(HOCHZCHZ) 2NCH2CHOHCH2NHC (CI-120E) 3.2HC1
A mixture of 10.5 grams of diethanolamine (0.1
Found, 9.41%.
mole) and 9.3 grams of epichlorohydrin (0.1
10 mole) was stirred well, the temperature being
EXAMPLE 4
1,2-bis [ tris (hydroxymethyl) methylcminol ethane
kept around 30°. After the initial exothermic re
dz'hydrobromz'de
'
action ceased the mixture was left over night at
room temperature. The clear viscous liquid was
extracted with ether. The ether insoluble prod
A mixture of 12 grams of tris(hydroxymethyl) - 15
uct was added to 12 grams of tris(hydroxymeth
aminomethane and 20 ml. of freshly distilled
yl) aminomethane (0.1 mole) and 50 ml. of ethyl
ethylene bromide was heated in a round bottom
alcohol and the mixture was heated under re
flask equipped with an air condenser, on an oil
?ux on a water bath for 6 hours. The reaction
bath at 180° for 4 hours. A light brown colored
mixture then was acidi?ed with concentrated hy
glue resulted. The excess ethylene bromide was 20 drochloric acid. An oil was thrown out by the
removed by extraction with ether. The residue
addition of absolute alcohol, acetone and ether.
was puri?ed by recrystallization from alcohol.
This oil was converted to a semi-solid by solution
The product, 1,2-bis[tris(hydroxymethyl) methyl
in aqueous alcohol, treatment with anhydrous
aminolethane dihydrobromide, melted at 205
acetone and allowing the lower layer, after evap
206°. Calculated for C10H26O6BI'2N2Z Br, 37.16%. 25 oration, to stand in a vacuum desiccator. Final
Found, 37.09%.
ly, puri?cation was eii’ected by extraction with
EXAMPLE 5
hot absolute alcohol. Melting point, 139441".
1,3-bis [trz‘s (hydromymethyl) methyZamino-l pro
Calculated for C'uI-IzaOeClzNz: Cl, 19.96%. Found,
' pane dihydrobromide
(HOCHZMCNHCHZCHQCHZNHC(CH2'OH).Q.2HBr
30
A solution of 24 grams‘ of tris(hydroxymethyl) -
19.55%.
EXAMPLE 8
1 - 'ethylethanolamino - 3 -'t1‘2's (hydroxymethyl) -
aminomethane (0.2 mole) and 10 grams of tri
methylene bromide (0.05 mole) in 150 ml. of alco
methylammo-z-propanol dihydrochloride
HOOHZOHACZHQNCHQGHOHCHzNHC(CHgOH)3.2HCl
hol was heated under re?ux ‘on a water bath for 35
Ethylaminoethanol was reacted with an equi
6 hours. On standing over night, needle like
molar quantity of epichlorohydrin at a temper-,
crystals of (HOCHz) 3CNI-I2.HB1‘ were formed.
ature below 30°. The condensation product thus
These were ?ltered off and the ?ltrate was made
formed was heated with an equimolar amount of
distinctly acidic with hydrobromic acid. The
acidic solution was evaporated to low volume to 40 tris(hydroxymethyl) aminomethane for 8 hours
remove most of the water. The gummy residue - on a water bath and the mixture was acidi?ed
with hydrochloric acid. Repeated attempts to
was dissolved in hot absolute alcohol and treated
recrystallize from alcohol failed to yield a solid
with an equal volume of anhydrous acetone. Two
but the light pink colored glue analyzed fairly
layers were formed. The lower layer was sepa
rated and triturated with a mixture of equal vol 45 satisfactorily. Calculated for C11H28O5C12N2! Cl,
20.90%. Found, 19.74%.
umes of absolute alcohol and anhydrous acetone,
until crystalline. The solid, 1,3-bis[tris(hydroxy
EXAMPLE 9
methyl) methylamino] propane
dihydro'bromide,
on three recrystallizations from alcohol, melted
at 170-171°. Calculated for C11H2806B1‘2N22 Br,
at
35.98%. Found, 35.25%.
EXAMPLE 6
1,6-bis [iris (hydromymethyl) methylaminlo ] hexane
wy’ -Bis [trz‘s(hydro:cymethyl) methylaminol 41m
pyl ether dih'ydrochloride
(HOOHz) aCNHCHzCHzCHzO CHzCHaOHzNHC (CHZOH) 3.2K C
A mixture of 17 grams of rm1’-dichloropropyl
ether (01 mole) and 24 grams of tris(hydroxy
methyDmethylamine (0.2 mole) in 100 ml. of al
dihydrobromide
55 cohol was heated over night at 110°. The alco
holic solution was acidi?ed with hydrochloric acid
and the precipitated tris(hydroxyrmethyl) methyl
A mixture of 48.4 grams of tris(hydroxy
amine hydrochloride was ?ltered off. Repeated
methyl) aminomethane (0.4 mole) and 24.4 grams
evaporations, solution in absolute alcohol, treat
of hexamethylene bromide (0.1 mole) was re 60 ments with anhydrous acetone and ?nally treat
?uxed with mechanical stirring until a homo
ments with anhydrous ether were necessary to
geneous mixture'was obtained. The brown glue
remove all of the unreacted amino-alcohol hy
thus formed was dissolved by re?uxing with 300
drochloride. Finally, the product 'y,'y'-bis[tris
ml. of 95% alcohol. ‘The alcoholic solution was
(hydroxymethyl) methylamino] -propyl ether hy
made strongly acidic with hydrobromic acid and 65 drochloride was obtained as an oil, slightly im
most of the alcohol was evaporated off. The
pure. Calculated for C14H34O7C12N22 chlorine
residue was treated with absolute alcohol and
17.16%.
anhydrous acetone to yield crystals of impure
(HOCHz)3C1\II-I2.H1Br, melting at 128-132°. The
An attempt to prepare [ELK-bis [tris(hydroxy
methyl) -methylaminol -ethyl ether dihydrochlo
?ltrate was treated with three volumes of anhy 70
drous acetone. An oily layer was formed. This
lower layer was triturated with absolute alcohol
and anhvdrous acetone, yielding a solid melting
at 150-155". On recrystallization from 95% al-,
ride in a similar way from B,B'-dichloroethyl
ether and tris(hydroxymethyl)l-methylamine was
cohol and anhydrous acetone, the product melted
Found 16.30%.
'
unsuccessful but 4-tris(hydroxymethyl) methyl
morpholine hydrochloride, melting at 184-185°
was obtained.
15.57%,
Calculated for CsHiaO4ClN: Cl,
Found, 15.59%.
A
’ '
'
2,408,096
6
5
The compounds to which our invention ‘relates
TABLEI'
possess certain novel properties respecting the
solubilizing action on-various cations, in alkaline
solution.
'
r
'
_
,
_
.
I
4
_
Cation solubtlization vwith 1,3-bis 'tris'mydroryé
methyl) methylamino-z-propanol
~
As is well known, ferric hydroxide and some
I '
- basic salts of the ferricion'are ‘extremely insolu;
ble. Aqueous solutions containing'ierrous com; .
Molar concentrations
.
mine
Gabon
pounds, in contact with air or‘dissolve'd oxygen‘,
.0 mm
alcohol
'
y roxl e
(and results)1
readily form insoluble ferric compounds, even
0.5
0. 5
0. 5
when
rate ofthe
oxidation
solutionsincreases
are distinctly
as the‘acidic
alkalinity
and the
in-.
creases. Thus the clogging of iron pipes with
rust is a serious industrial problem. Certain
polyhydroxy compounds, such as the sugars, tend
to hold iron in solution in alkaline medium, but
V 0.5 0.5+
0. 5 30. 5-}
0. 5 0. 5+
0. 5
0.15
0. 25
0. 5
0.5
8.0£
8. 0+
4 8. 0d:
50. 5:1:
ll2.51 ..... __
0. 5* 0. 5+
O. 5 0. 5+
2. 5+ 2 8. 0+
2. 5+
8. 0+
0.5
00.5
.......
__
O. 25
0. 5
0. 5+
2. 5+
8. 0+
0. 5
0. 5
0. 5+ - 2. 5+
7 8. 0d;
Cd++ ______________ . .
these sugars, due to their reactivity, decompose
,
2.5+
2. 5+
2. 5+
in alkali, particularly when warmed. Our poly-i
1 Failure to precipitate after approximately two hours is indicated
hydroxyamines are much more stable toward al—'
kali than are the sugars and alkaline solutions
is used to_indicate initial solubilization but the formation of a pre
by “+”. Immediate precipitation is indicated by “—-" and “:l:"
cipitate within twohours, usually within a few minutes.
of these compounds have high solvent action on
1 Precipitates within a few minutes;
ferric hydroxide. For example, ferric hydroxide
did not precipitate when alkali in excess was
added to a solution approximately 0.1 molar in
5 It‘ air is present, a wine color starts to form almost as soon as the
amino alcohol and Mn++ are mixed. When the air was displaced
by Pyrofax gas, a clear solution was obtained which gradually be
Fe+++ and 0.5 molar in 1,2-bis [tris(hydroxy
came wine colored and ?nally purple. Also, a precipitate formed
fairly readily, particularly in the solution containing excess alkali. '
methyl) -methylaminol ethane. Also, under ap
9 Bluish colored precipitate in deep blue solution.
proximately the same' conditions, 1,3-bis [tris
(hydroxymethyl)methylamino] propane, 1,6-bis
'[tris(hydroxymethyl)methylaminol hexane, 1
tris(hydroxymethyl) methylamino-B-diethylami
no-2-propanol and 1-tris(hydroxymethyl)meth
‘ 7 Precipitate, on standing.
Since all of the polyhydroxyamines listed
above proved to have solubilizirig action on cer
:30 tain cations," in ‘alkaline solution, several ‘more
derivatives of trislhydroxyme'thyl) aminomethane
ylamino-3-ethylethanolamino -V2 - propanol gave
no precipitate of ferric hydroxideQ
_
r
were
V
1,3-bis [tris(hydroxymethyl)methylaminol - 2 -
hours at 100° there was a slight silicious precipi
tate but none of ferric hydroxide.
,
and
tested
as
solubilizing
1,6-bis [tris(hydroxymethyl) methylami
no]-23,4,5~tetrahydroxyheirane
chosen arbitrarily to illustrate the solvent action
propanol gave no precipitate when treated with
an equal volume of 10 molar sodium hydroxide.
On being heated in av sealed Pyrex tube‘ for 2
synthesized
agents.
The above‘ concentration of 0.1 molar Fe+++
is not necessarily the limit of solubility, but is
of our amino alcohols on ferric hydroxide. In
some cases much higher concentrations of
Fe+++ can be held in alkaline solution. For
example‘, a solution 1 molar in Fe+++ and in
-
7
3 The precipitate at this point may be partly due to some hydro
chloride of the amino alcohol, present as an impurity.
l cloudiness, initially. Increased precipitate, on standing.
’
I
'
'
-
(HOCHc) sCNHCI-Iz (CHOH) 4CH2NHC (CHzOI-I) a
formed (as the dihydrobromide) by heating man;
nitol dibromide with‘ slightly over four molar
‘quantities of tris(hydroxymethyl) aminomethane
at
in alcoholsolution in a sealed tube at 138° for '
15 hours, had a solubilizing action on Fe+++,
Bi+++, Mn++, Ni++, Co++, Cu++ and
Cd++, when the molar concentration of cation,
amino alcohol and-‘sodium hydroxide were re
45 spectively 0.l,-0.25 and 3.5. ‘This is not neces
sarily the limit of the solubilizinglpower of the
In the solubilization tests described above and
in the tests which immediately follow, the amino . ' amino alcohol for Fe(Ol-I)s did not precipitate
when Fe+++,‘ the above amino alcohol and ex
alcohols were used as salts, the dihydrochloride
cess sodium hydroxide were mixed in molar con
or dihydrobromide, and were treated with excess
centrations of 0.33, 0.25 and 3.5 respectively.
sodium hydroxide solution, to set free the amino '
alcoh'ols.
‘
Many useful applications of our novel solubil
izing agents will occur to those skilled in the,
'
Solubilization tests were run with each of the
amino alcohols listed above and with each oi.’ the
various arts. Illustrative examples of ‘a few uses
cations Bi+++, Mn++, Ni++, Co++, Cd++
are given.
and Cu++. The molar concentration of cation, 55
amino alcohol and sodium hydroxide were re
spectively 0.1, 0.5 and 3.0.
(Note: Actually, 4.0
"
The ability of the amino alcohols to hold fer
ric hydroxide in solution, as illustrated particu
larly with 1,3-bis [tris(hydroxymethyl) methylam
molar quantities of sodium hydroxide were used, 1 inol-Z-propanol, should ?nd many important in
. dustrial applications. One particularly useful
but 1.0 molar quantity was used up in setting free
the amino alcohol from its salt.) 7. In all cases, 60 application is in cleaning out boiler tubes. Not
only does the above amino alcoho1 have a ten
dency to‘ hold ferric hydroxide in ‘solution but a
hot alkaline solution of it slowly loosens rust.
As stated above, in the case of the solubilization
In a boiler tube, the loosening of rust so that it
of ferric hydroxide, the data given do notnec 65 may be blown out of the tube, is almost as much
essarily represent the limits of solubility, but are
value as its’dissolution.
clear solutions or at most very slight precipitates
were obtained.
7 ‘
given to show that solubilization of, certain cation
hydroxides is a characteristic of the series of
polyhydroxyamines covered by this patent appli
Another useful application may be in the treat
ment of syphilis. A solution of bismuth contain
ing approximately 60 mg. of bismuth per ml. was
cation.
70 prepared by warming freshly precipitated bismuth
Table I gives values obtained with various ca- . hydroxide with a solution which was'approxi
tions, using 1,3-bis [tris (hydroxymethyl) methyl-'
aminol-2-propanol as solubili'zing agent, with
various concentrations of cation, ‘amino alcohol
and sodium hydroxide.
'
mately 0.8 molar in 1,3-bis[tris(hydroxymeth
yl)methylaminol-Z-propanol and in sodium hy
‘ droxide and by neutralizing with tartaric acid to
75 approximately a pH of 7.4
This solution was
2,408,096
7
'74-21grams of 1,3-bis[_tris (hydroxymethyl) meth
ylaminol-Z-propanol dihydrochloride and 20
found to be stable to heatin a sealed tube at 125°
for _30 minutes.
.
The compounds to which our invention relates
have properties which indicate their usefulness
grams of sodium hydroxide per liter, did not de
posit free copper on a clean strip of iron metal
in calcium therapy for in the therapeutic use of
calcium it is desired to have a moderately low
concentration of Ca++ but to'have a relatively
immersed in it.
high concentration of combined calcium in a
the solution, with the iron strip as=cathocle, an
adherent coating of copper was deposited on the
However, when an electric cur
rent, with a voltage of 1.6 and a current density
of 0.14 ampere per sq. dec. was passed through
form in which it can be utilized by. the, body.
.
Calcium gluconate is likely the most generally 10 iron.
The ability of the polyhydroxyamines not only
used form of calcium for intravenous injection
to hold the copper in solution but also to prevent
and it also is used extensively for oral admin
the precipitation of. copper on iron and to hold
istration. It usually is given in 10 per cent solu
tion intravenously or intramuscularly. Since cal
iron and various other cations in solution should
cium gluconate contains approximately 9 per 15 prove of- great value in copper plating. The abil
ity of our amino alcohols to hold a low concen
cent of calcium, this corresponds to a content of
tration of various other cations should likewise
approximately 10 mg. of calcium per ml. of
solution.
prove of value in electroplating with other
i
metals.
In preparing calcium for therapeutic use we
The temperatures reported in this application
employed the following procedure: Freshly pre; 20
cipitated calcium hydroxide was warmed with an
are all on the centigrade scale.
equimolar quantity of 1,3-bisltris(hydroxymeth—
yl)methylaminol -2-propanol dihydrochloride in
some of the products remained as oils for a long
In our work with the polyhydroxyamine salts,
time and were crystallized with great di?‘iculty.
approximately 30 per cent solution. The aqueous
solution was filtered from a slight residue and 25 It is quite likely that some of the products
evaporated to a syrup.
which we reported as oils eventually may be
On neutralization to
crystallized to yield fairly high melting sol
physiological pH (7.4) with hydrochloric acid a
ids. The constants reported are those ob
clear solution was obtained with a relatively low
tained by careful experimentation but since
concentration of Ca++ and a total concentration
of approximately 40 mg. of calcium per ml. Ace 30 slight traces of impurities frequently prevent
the crystallization of a substance or lower the
tic acid also was used to neutralize the basic
melting point of a solid appreciably, we do not
solution containing calcium. A solution can be
limit our claims to substances with the exact
made by the methods just described appreciably
physical properties reported.
more concentrated than 40 mg. of Ca per ml.
A further use for which our compounds are 35
adapted is in the art of electroplating.v As is well
, known, elements high in the electromotive series
readily replace from solution the elements lower
in the series. Thus, iron displaces copper readily
We claim:
.
> 1. New compounds of the structure
(HOCI-Iz) sCNI-ICHz (CI-IX) ZCHZNHC (CI-120E) 3
where X is taken from the group H and OH and
40 2 represents a number from zero to four, in
and when it is desired to plate copper on iron, it
clusive.
,
is customary to use a bath containing potassium
2. Salts of the compounds in claim 1.
cyanide to lower the concentration of the copper
3. _A new compound of the structure
ion in solution. The toxicity of the cyanide solu
(HOCH2) sCNHCHzCHOHCI-IzNI-IC (CHzOH) 3
tion makes it desirable to use a substitute. In
alkaline solutions of our pc-lyhydroxyamines, the 45
4. Salts of the compound of claim 3.
concentration of Cu++ is extremely low. As il
5. The dihydrochloride of the compound of
lustrative of this low concentration and of an im
claim 3.
portant industrial application of these polyhy
droxyamines, We give the ‘following example:
Asolution containing 25 grams of CuSO4.»5I-IzO,
JOHN S. PIERCE. T
50 '.
JOHN H. WOTIZ. '
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