The Manufacture or Production of New Pharmaceutical Compounds.
Year: 1897

page_text: Date of Application, 30th Apr., 1897
Complete Specification Left, 31st Jan., 1898-Accepted, 9th Apr. 1898
[Communicated from abroad by THE FARBENFABRIKEN, vormals FRIEDRICH
BAYER & Co., of Elberfeld, Germany.]
The Manufacture or Production of New Pharmaceutical Compounds.
I, HENRY EDWARD NEWTON, of the Office for Patents, 6, Bream's Buildings,
Chancery Lane, in the County of London, Patent Agent, do hereby declare the
nature of this invention to be as follows:-
The present invention relates to the manufacture of new condensation products
from hexamethylenetetramine and tannin, or the like materials
My foreign correspondents have found that, if hexamethylenetetramine be
allowed to act on tannin, two different chemical compounds are obtained, the one
containing three, and the other 6, molecular proportions of tannin, relatively
to one molecular proportion of hexamethylenetetramine. A good method to
obtain these bodies in a pure state, is to mix exactly such quantities of the two
ingredients as correspond with the above defined molecular proportions. Thus,
for instance, if the watery solution of one molecular proportion of hexamethy-
lenetetramine be added to a watery solution of three molecular proportions of
tannin, a white precipitate results, which represents the compound containing
one molecule of hexamethylenetetramine and three. molecules of tannin. In
an analogous manner, the other compound is obtained in a pure state, if 6 mole-
cules of tannin be allowed to act on one molecule of hexamethylenetetramine.
If more than three, but less than six, for instance, five molecules of tannin are
employed, precipitates are obtained, which most probably represent mixtures
of the two above described compounds. If, on the other hand, less than three
molecules of tannin are acting on 1 molecule of hexamethylenetetramine (for
instance, if the two ingredients are mixed in equimolecular proportions), always
the above mentioned product, containing 3 molecules of tannin to 1 molecule of
hexamethylenetetramine, is obtained, whilst the rest of the hexamethylenetetra-
mine remains dissolved in a free state.
The different precipitates obtainable in the manner hereinbefore described are
fairly soluble in water. Therefore, it is necessary to employ concentrated solu-
tions of the two ingredients, in order to get the reaction products precipitated,
which are likewise easily soluble in alcohol. The more tannin contained in the
precipitated products, the more easily they dissolve in water and alcohol, and
the lower is their melting point. All these products are of an astringent taste,
and therefore they cannot be employed for medicinal purposes. They can, how-
ever, as my foreign correspondents have found, be easily transformed into tasteless
insoluble compounds which melt with difficulty, if they be heated for a short
time, either by themselves or in the presence of an indifferent liquid. When
treated in this manner, they represent valuable internal astringents, as they
contain a large percentage of tannin.

page_text: In order to illustrate the new process, my foreign correspondents give the
following example, the parts being by weight.
EXAMPLE I.
A cold solution of 3.2 parts of tannin in 20 parts of water, is added, while being
stirred, to a cold solution of 1.4 parts of hexamethylenetetramine in 20 parts of
water. An amorphous white precipitate at once separates, which, after the
mixture has been stirred for some time, is filtered and pressed. The dry mass
thus obtained represents the soluble condensation product of one molecular
proportion of hexamethylenetetramine with 3 molecular proportions of tannin.
For the purpose of rendering this product insoluble and tasteless, several
methods can be adopted. One of these methods is to treat the aforesaid dry
mass, previously broken up, in a porcelain-pan. At first the product melts, and
the resulting liquid is well stirred. Heating is continued for from one half to one
hour, at from 90 to 100 degrees centigrade. The liquid thus becomes stiffer and
stiffer, and finally becomes a hard lump, which can be ground.
The same result is obtained if a concentrated watery solution of the above-
described white precipitate is heated for a while, the liquid becoming gradually
cloudy, and finally separating a resin-like mass, which, after further heating,
changes into a hard lump. Another method to render the soluble compound
insoluble, is to heat its solution in glycerine for a quarter of an hour at about
110° centigrade. On pouring this solution into water, a light brown amorphous
precipitate separates, which is the insoluble and tasteless compound. The same
amorphous precipitate can be obtained if the above given quantities of the two
ingredients are dissolved in glycerine, and the mixture of these solutions is heated,
say, for a quarter of an hour, at about 1050 centigrade. On subsequently pouring
this mixture into water, the amorphous compound is obtained; thus, the forma-
tion of the soluble compound, and its transformation into the insoluble body,
can be effected in one operation. The light brown powder thus obtained may
be purified, if desired, by washing with hot water, and subsequently drying, at
from 90 to 100 degrees centigrade.
The insoluble compound obtained in any of the above described manners is
tasteless and odourless, insoluble in water, alcohol, and ether. According to the
analytical researches of my foreign correspondents, it contains about 5 per cent.
of nitrogen, which percentage corresponds with that of the condensation product
formed from one molecular proportion of hexamethylenetetramine and three
molecular proportions of tannin.
Instead of using hexamethylenetetramine as above described, mixtures of the
corresponding quantities of formic aldehyde and ammonia (which, it is well
known, form hexamethylenetetramine when mixed) can be used with the same
result.
In order to illustrate the use of mixtures of formaldehyde and ammonia, the
following example is given. The parts are by weight.
EXAMPLE II.
4.8 parts of a 37.4 per cent. solution of formic aldehyde, are mixed with 2.8 parts
of a 24 4 per cent. solution of caustic ammonia (which quantities correspond with
1.4 parts of hexamethylenetetramine). This mixture, after being diluted with
12 parts of water, is cooled. A cold solution of 19.4 parts of tannin, in 50 parts
of water, is subsequently added while stirring. On allowing the reaction mixture
to stand at ordinary temperature for about one day, the greatest part of the
reaction product separates as a viscous mass at the bottom of the vessel. This
mass, when separated from the liquid, is dried at ordinary temperature, for
instance, by spreading it out on porous tiles or the like. When dry, the light
yellow mass can easily be pulverised.
By treating it in one of the manners described in the preceding example, it

page_text: can be rendered insoluble. In this form, it is a light brown tasteless and odour-
less powder, insoluble in water, in alcohol, and in ether. According to the
analytical researches of my foreign correspondents, it contains 1 molecular propor-
tion of hexamethylenetetramine relatively to 6 molecular proportions of tannin.
It may be remarked that my foreign correspondents do not limit themselves
to the particulars given in the above examples, as these are merely typical, and
can be varied within wide limits. Thus, for instance, the extracts of all materials
containing tannic acids, such as the extracts from ratanhia catechu, oak-bark,
quebracho, or the like can be employed instead of tannin.
Dated this 20th day of Anil 1897
NEWTON & SON,
Agents for the Applicant.
The Manufacture or Production of New Pharmaceutical Compounds.
I, HENRY EDWARD NEWTON, of the Office for Patents, 6, Bream's Buildings,
Chancery Lane, in the County of London, Patent Agent, do hereby declare the
nature of this invention and in what manner the same is to be performed, to be
particularly described and ascertained in and by the following statement:
1
The present invention relates to the manufacture of new condensation products
from hexamethylenetetramine and tannin, or the like materials.
My foreign correspondents have found that, if hexamethylenetetramine be
allowed to act on tannin, two different chemical compounds are obtained, the one
containing three, and the other 6, molecular proportions of tannin relatively
to one molecular proportion of hexamethylenetetramine. A good method to
chtain these bodies in a pure state, is to mix exactly such quantities of the two
ingredients as correspond with the above defined molecular proportions. Thus,
for instance, if the watery solution of one molecular proportion of hexamethy-
lenetetramine is added to a watery solution of three molecular proportions of
tannin, a white precipitate results, which represents the compound as derived
from the one molecule of hexamethylenetetramine and three molecules of tannin.
In an analogous manner, the other compound is obtained in a pure state, if
6 molecules of tannin be allowed to act on one molecule of hexamethylenetetra-
mine. If more than three, but less than six (for instance, five molecules of
tannin), are employed, precipitates are obtained which most probably represent
mixtures of the two above described compounds, but if, on the other hand, less
than three molecules of tannin are used, on one molecule of hexamethylenetetra-
mine (for instance, if the two ingredients are mixed in equimolecular proportions),
the product containing 3 molecules of tannin to one molecule of hexamethylene-
tetramine, is always obtained, whilst the excess of the hexamethylenetetramine
remains dissolved in a free state.
The different precipitates obtainable in the manner hereinbefore described are
fairly soluble in water. Therefore, it is necessary to employ concentrated solu-
tions of the two ingredients, in order to get the reaction products precipitated
which are likewise easily soluble in alcohol. The more tannin contained in the
precipitated products, the more easily they dissolve in water and alcohol, and
the lower is their melting point. All these products are of an astringent taste,
and therefore they cannot be employed for medicinal purposes.
They can, however, as my foreign correspondents have found, be easily trans-
formed into tasteless insoluble compounds, which melt with difficulty if they
are heated for a short time, either by themselves, or in the presence of an indifferent

page_text: liquid. When treated in this manner, they represent valuable internal astrin-
gents, as they contain a large percentage of tannin.
In order to illustrate the new process, my foreign correspondents give the
following example, the parts being by weight.
EXAMPLE I.
A cold solution of 3.2 parts of tannin in 20 parts of water is added, while being
stirred, to a cold solution of 1.4 parts of hexamethylenetetramine in 20 parts of
water. An amorphous white precipitate at once separates, which, after the
mixture has been stirred for some time, filtered and pressed. The nearly dry
mass thus obtained represents the soluble condensation product from one mole-
cular proportion of hexamethylenetetramine and 3 molecular proportions of
tannin.
For the purpose of rendering this product insoluble and tasteless, several
methods can be adopted. One of these methods is to heat the aforesaid nearly
dry mass, previously broken up in a porcelain pan. At first, the product melts,
and the resulting liquid is well stirred. Heating is continued for from one half
to one hour at from 90 to 100 degrees centigrade. The liquid thus becomes
stiffer and stiffer, and finally becomes a hard lump, which can be ground.
The same result is obtained if a concentrated watery solution of the above-
described white precipitate is heated for a while, the liquid becoming gradually
cloudy, and finally separating a resin-like mass, which, after further heating,
changes into a hard lump. Another method to render the soluble compound
insoluble, is to heat its solution in glycerine for a quarter of an hour at about
110° centigrade. On pouring this solution into water, a light-brown amorphous
precipitate separates, which is the insoluble and tasteless compound. The same
amorphous precipitate can be obtained if the above given quantities of the two
ingredients are dissolved in glycerine, and the mixture of these solutions is heated,
say, for a quarter of an hour, at 105° centigrade. On subsequently pouring
this mixture into water, the amorphous compound obtained; thus, the forma-
tion of the soluble compound, and its transformation into the insoluble body,
can be effected in one operation. The light-brown powder thus obtained may
be purified, if desired, by washing with hot water, and subsequently drying at
from 90 to 100 degrees centigrade.
The insoluble compound obtained as above described is tasteless and odourless,
and insoluble in water, alcohol, and ether. According to the analytical researches
of my foreign correspondents, it contains about 5 per cent. of nitrogen, which
percentage corresponds with that of the condensation product formed from one
molecular proportion of hexamethylenetetramine and three molecular proportions
of tannin.
Instead of using hexamethylenetetramine, mixtures of the corresponding quan-
tities of formic aldehyde and ammonia (which, it is well known, form hexamethy-
lenetetramine, when mixed) can be used with the same result.
In order to illustrate the use of mixtures of formaldehyde and ammonia, the
following example is given. The parts are by weight.
EXAMPLE II.
4.8 parts of a 37.4 per cent. solution of formic aldehyde, are mixed with 2.8 parts
of a 24.4 per cent. solution of caustic ammonia (which quantities correspond with
1.4 parts of hexamethylenetetramine). This mixture, after being diluted with
12 parts of water, is cooled. A cold solution of 19.4 parts of tannin, in 50 parts
of water is subsequently added, while stirring. On allowing the reaction mixture
to stand at ordinary temperature for about one day, the greatest part of the
reaction product separates as a viscous mass at the bottom of the vessel. This
mass, when separated from the liquid, is dried at ordinary temperature, for
instance, by spreading it out on porous tiles or the like. When dry, the light
yellow mass can easily be pulverised.

page_text: By treating it in either of the ways described in the preceding example, it can
be rendered insoluble. In this form, it is a light-brown tasteless and odourless
powder, insoluble in water, in alcohol, and in ether. According to the analytical
researches of my foreign correspondents, it contains molecular proportion of
hexamethylenetetramine relatively to 6 molecular proportions of tannin.
It may be remarked that my foreign correspondents do not limit themselves
to the particulars given in the above examples, as these are merely typical, and
can be varied within wide limits. Thus, for instance, the extracts of all materials
containing tannic acids, such as the extracts from ratanhia, catechu, oak-bark,
quebracho, or the like, can be employed, instead of tannin.
Having now particularly described and ascertained the nature of the said inven-
tion and in what manner the same is to be performed, as communicated to me
from abroad, I declare that what I claim is:
1. The process for producing a new condensation product from three molecules
of tannin and one molecule of hexamenthylenetetramine, by allowing one mole-
cule of hexamethylenetetramine to act on quantities of tannin varying up to
three molecules, substantially as herein before described.
2. The production of the new condensation product from 3 molecules of tannin
and one molecule of hexamethylenetetramine, by allowing 1 molecule of
hexamethylenetetramine to act on three molecules of tannin, substantially as
hereinbefore described.
3. The manufacture of a new condensation product from 6 molecules of tannin,
and one molecule of hexamethylenetetramine, by acting with 6, or more than 6,
molecules of tannin, on one molecule of hexamethylenetetramine, substantially
as herein before described.
4. Producing products representing probably mixtures of a condensation pro-
duct, from 3 molecules of tannin and 1 molecule of hexamethylenetetramine, with
a condensation product from 6 molecules of tannin and 1 molecule of hexamethy-
lenetetramine, which process consists in allowing more than 3, and less than 6,
molecules of tannin to act on 1 molecule of hexamethylenetetramine, substantially
as hereinbefore described.
5. In the process claimed in the above Claims 1 to 4, the use of mixtures of
formic aldehyde and ammonia, instead of hexamethylenetetramine.
6. In the process claimed in the above Claims 1, 2, 3, and 4, the use of the
extracts of materials containing tannic acids, such as the extracts of ratanhia,
catechu, oak-bark, quebracho, or the like, instead of tannin.
7. The transformation of the products obtained according to the above
Claims 1, 2, 3, 4, 5, or 6, into tasteless insoluble compounds which melt with
difficulty, by heating the said products in or without the presence of suitable
solvents or diluents, substantially as herein before described.
8. The formation of the compounds referred to in Claim 7, by first producing
the soluble condensation products, and then transforming the same into the
insoluble compounds, in one operation, substantially as hereinbefore described.
9. As new articles of manufacture, the new products hereinbefore defined.
10. The use of the new products obtainable according to the above Claims 7
and 8, for medicinal purposes.