The Manufacture or Production of Acid Derivatives of Alkylic Salts of Paramidophenyl-carbonic Acid.
Year: 1894

page_text: Date of Application, 11th Aug., 1894
Complete Specification Left, 30th Apr., 1895-Accepted, 15th June, 1895
PROVISIONAL SPECIFICATION.
[Communicated from abroad by THE FARBENFABRIKEN, vormals FRIEDRICH
BAYER & Co., of Elberfeld, Germany.]
The Manufacture or Production of Acid Derivatives of Alkylic Salts
of Paramidophenyl-carbonic Acid.
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 :-
Mering (see Therapeutische Monatshefte of December of the year 1893) states,
that the more or less favourable action of the diverse derivatives of paramido
phenol, depends on the manner in which the substitution radicles contained in the
said derivatives of paramido phenol are split off, when the latter are taken up by
the body.
My foreign correspondents have made further chemical and physiological
researches with derivatives of paramido phenol, and they have found that the acid
derivatives of the alkylesters of paramidophenyl carbonic acid, having the general
formula:
are valuable products, as they possess a favorable action similar to that of
phenacetine. My foreign correspondents mean by the expressions Ac and Ac₁ in
the above formulæ, any organic acid radicles such as, for instance, COCH,
or-CO.OCH, or the like, and they understand by the expression Alkyl in the
above given formulæ, any alkyl radicle of the fatty or aromatic series.
According to the researches of my foreign correspondents, such acid derivatives
of alkylesters of paramido phenyl carbonic acid can be obtained, for example,
either by treating alkylesters of paramido phenyl carbonic acid having the
following formula
with acid anhydrides, or acid chlorides, or agents acting in a similar manner
(Method A), or by acting with esters of chloro carbonic acid, or other halogen
carbonic acids, on such derivatives of paramido phenol as contain acid radicles in
place of hydrogen in the amido group (Method B), or by treating with acid
chlorides, or acid anhydrides, or the like, those of the alkylesters of paramido
phenyl carbonic acid which result from the aforesaid Methods A or B, and contain
but one acid radicle in place of hydrogen in the amido group (Method C).

page_text: In order to illustrate the said Method A, my foreign correspondents give the
following example, starting from the hitherto unknown alkylesters of paramido
phenyl carbonic acid, which, according to the researches of my foreign corre-
spondents, can be prepared, for instance, by acting with the sodium salt of para
nitro phenol in watery solution on the esters of chloro carbonic acid, and
subsequently reducing the so-formed alkylesters of para-nitro phenyl carbonic
acid. When using the sodium salt of para-nitro-phenol, and the ethylester of
chloro carbonic acid, a so-called mixed ester is obtained, which has the
formula :-
:-
It melts at 68 degrees Centigrade, and is converted by reduction into the corre-
sponding ethylester of paramido phenyl carbonic acid, the hydro chloride of
which crystallizes in needles. The other alkylesters of pyramido phenyl carbonic
acid can be obtained in an analogous manner.
PRODUCTION OF THE ETHYLESTER OF MONO-ACETYLATED PARAMIDO
PHENYL CARBONIC ACID.
10 parts (the parts are by weight) of the said hydrochloride of the ethylester of
paramido phenyl carbonic acid are mixed with 5 parts of sodium acetate and
15 parts of acetic acid anhydride (or 20 parts of glacial acetic acid). The
resulting mixture is boiled, during one hour, in a vessel provided with a reflux
condenser, and the mass thus obtained is poured into water. The crude mono
aceto compound which separates is subsequently crystallized from hot water.
possesses the following formula :-
It
This ethylester of mono acetylated paramido phenyl carbonic acid exhibits
nearly the same degree of solubility in water as phenacetine, and, when crystallized
from water, forms beautiful glass-like needles, which melt at 122 degrees Centigrade,
and are decomposed by boiling with alkalies, paramido phenol being split off.
The above named Method B is illustrated by the following Examples Two and 3
Three, the parts being by weight.
PRODUCTION OF THE ETHYLESTER OF MONO-ACETYLATED PARAMIDO
PHENYL CARBONIC ACID.
150 parts of mono aceto-paramido phenol are dissolved, at ordinary temperature,
in 500 parts of water and 50 parts of sodium hydroxide. Under cooling and
energetic stirring, 110 parts of the ethylester of chlorocarbonic acid are introduced
into the said solution. After a short time, a granular precipitate is separated,
which is the ethylester of monoacetylated paramido phenyl carbonic acid, having
the properties as above mentioned.
If, according to the Method B, a carbonic acid derivative of the alkylester of
paramido phenyl carbonic acid is to be prepared, the production of the carbonic
acid derivative of paramido phenol (so-called para-hydroxy phenylurethane) can be

page_text: profitably united in one operation with the conversion of the said carbonic acid
derivative into the corresponding alkylester of the carbonic acid derivative of
paramido phenylcarbonic acid, that is to say, two molecular proportions of the
ester of chloro carbonic acid are allowed to act at once on one molecular
proportion of paramido-phenol, as becomes evident from the following example :
PRODUCTION OF THE ETHYLESTER OF PARAMIDO PHENYL-CARBONIC
CONTAINING THE GROUP COOCH, IN PLACE OF
AMIDO GROUP.
ACID
HYDROGEN IN THE
150 parts (the parts are by weight) of paramido phenol are dissolved in 500 parts
of water and 100 parts of sodium hydroxide. On carefully cooling and energetically
stirring, 220 parts of the ethylester of chloro carbonic acid are then added taking care
that the liquid remains alkaline. When the reaction is finished, the crumbling mass is
filtered off, and crystallized from dilute alcohol (50 per cent.). It forms needles not
readily soluble in water, and melting at 108 degrees Centigrade. It is insoluble in
acids and alkalies, and is decomposed by boiling with acids or alkalies, paramido
phenol being split off. It possesses the following formula:
Naturally, salts of paramidophenol can likewise be used in the process illustrated
by the foregoing last example, in place of free amidophenol, in which case, a
greater quantity of alkali must be employed.
The product obtainable as described in the last example, can also be prepared
by first treating, in a solution containing sodium carbonate, paramidophenol with
the alkylester of chloro carbonic acid, in order to obtain the so-called parahydroxy-
phenylurethane having the formula:
and by subsequently allowing another molecular proportion of the ester of chloro-
carbonic acid to act, in alkaline solution, on the parahydroxyphenyleurethane
thus formed.
In order to illustrata the aforesaid Mothad ( the following fourth example is
PRODUCTION OF THE ACETO DERIVATIVE OF THE COMPOUND OBTAINABLE
AS DESCRIBED IN THE FOREGOING THIRD/EXAMPLE :—
The carbonic acid derivative obtainable as described in the foregoing Third
Example, is mixed with acetic acid anhydride aud a small quantity of zinc
chloride. The resulting liquid is then boiled until the reaction is complete. A
product is thus formed which, when crystallised from alcohol, melts at 65 degrees
Centigrade, and possesses the following formula :-

page_text: In order to produce the products hereinbefore defined, my foreign correspondents
do not limit themselves to the directions above given, as these can be varied. For
instance, the ethylester of chloro-carbonic acid used in the preceding examples
can be replaced by the corresponding quantities of analogous esters, such as methyl
or propyl or butyl, or the like esters, products being thus obtained which, in their
physiological action, are similar to the compounds derived from the ethylester of
chloro carbonic acid. Other acid anhydrides, or acid chlorides, can also be used
in place of acetic acid anhydride or acetyl chloride used in the above described
processes. The acetylated paramido-phenol used in the foregoing Example Two,
can be replaced by corresponding quantities of analogous acid derivatives of
paramido phenol, and other paramido-phenol compounds, or acid derivatives
thereof, can be used in place of paramido phenol, or its acid derivatives, which
are employed as mentioned in the aforesaid processes.
The chemical compounds obtainable by means of the processes hereinbefore
defined are suitable for being employed for therapeutical purposes.
Dated this 11th day of August 1894.
NEWTON & SON,
Agents for the Applicant.
The Manufacture or Production of Acid Derivatives of Alkylic Salts
of Paramidophenyl-carbonic Acid.
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 :-
Mering (see Therapeutische Monatshefte, of December of the year 1893) states,
that the more or less favourable action of the various derivatives of paramido-
phenol depends on the manner in which the substituted radicles contained in the
said derivatives of paramidophenol are split off, when the latter are taken up in
the body.
My foreign correspondents have made further chemical and physiological
researches with derivatives of paramidophenol, and they have found, that the acid
derivatives of the alkylic salts of paramidophenyl-carbonic acid of the general
formula
are valuable products, inasmuch as they exert a favorable action similar to that
of phenacetine. My foreign correspondents mean by the expressions Ac and Ac
in the above formulæ, any organic acid radicles, such as, for instance, COCH,,
or—CO.OC₂H, or the like, and they understand by the expression Alkyl in the 40
above formulæ any alkyl radicle of the fatty series.
According to the researches of my foreign correspondents, such acid derivatives
of alkylic salts of paramido phenyl carbonic acid can be obtained, for example,

page_text: with acid anhydrides, or acid chlorides, or agents acting in a similar manner
(Method A); or by acting with alkylic-salts of chlorocarbonic acid, or other
haloid carbonic acids, on derivatives of paramidophenol containing acid radicles
in place of hydrogen in the amido group (Method B); or by treating with acid
chlorides or acid anhydrides, or the like, the alkylic salts of paramidopheny!
carbonic acid, such as are formed by the aforesaid Methods A or B, and
containing but one acid radicle in place of hydrogen in the amido group
(Method C).
In order to illustrate the said Method A, my foreign correspondents give the
following example, starting from the hitherto unknown alkylic salts of paramido
phenyl carbonic acid. According to the researches of my foreign correspondents,
these alkylic salts of paramido phenyl carbonic acid can be prepared, for instance,
by acting with the sodium salt of paranitrophenol, dissolved in water, on the
alkylic salts of chloro carbonic acid, and subsequently reducing the so-formed
alkylic salts of para-nitro-phenylcarbonic acid. When using the sodium salt of
para nitrophenol, and the ethylic salt of chlorocarbonic acid, a mixed salt is
obtained, which has the formula:-
It melts at 68 degrees Centigrade, and is converted by reduction into the
corresponding ethylic salt of paramidophenyl carbonic acid, the hydro chloride
of which crystallizes in needles. The other alkylic salts of paramidophenyl-
carbonic acid can be obtained in an analogous manner.
PRODUCTION OF THE ETHYLIC SALT OF
MONACETYLATED
PHENYLCARBONIC ACID.
PARAMIDO
10 parts (the parts are by weight) of the said hydrochloride of the ethylic salt
of paramido phenylcarbonic acid are mixed with 5 parts of sodium acetate and
15 parts of acetic anhydride (or 20 parts of glacial acetic acid). The mixture
boiled during one hour in a vessel provided with a reflux condenser, and the mass
thus obtained is poured into water. The crude monaceto compound which
separates is subsequently crystallized from hot water. It is represented by the
following formula:
This ethylic salt of monacetylated paramido phenyl carbonic acid is nearly as
soluble in water as phenacetine. When crystallized from water, it forms
beautiful vitreous needles, which melt at 122 degrees Centigrade. It is decomposed
O by boiling with alkalies, paramidophenol being formed.
The above named Method B is illustrated by the following Examples B and C,
the parts being by weight.

page_text: PRODUCTION OF THE ETHYLIC SALT
MONACETYLATED PARAMIDOPHENYL-
CARBONIC ACID.
151 parts of monaceto paramidophenol are dissolved at ordinary temperature
in 500 parts of water and 50 parts of sodium hydroxide. 110 parts of the ethylic
salt of chloro carbonic acid are introduced into the said solution, care being taken
to cool and to stir the mixture well. After a short time, a granular precipitate
separates, which is the ethylic salt of mon acetylated paramidophenyl carbonic
acid, having the properties above mentioned.
If, according to the Method B, a carbonic acid derivative of the alkylic salt of
paramido phenylcarbonic acid is to be prepared, two molecular proportions of the
chlorocarbonic salt are allowed to act on one molecular proportion of paramido
phenol, or a salt thereof, in the presence of alkali lye. This process is illustrated
by the following example :-
PRODUCTION OF THE ETHYLIC SALT OF
PARAMIDO PHENYLCARBONIC ACID
CONTAINING THE GROUP-COO₁₂H, IN PLACE OF IIYDROGEN IN THE
AMIDO GROUP.
109 parts (the parts are by weight) of paramido phenol are dissolved in
500 parts of water and 100 parts of sodium hydroxide. 220 parts of the ethylic
salt of chlorocarbonic acid are then added, taking care to cool and stir well, and
that the liquid remains alkaline. When the action is at an end, the product is
filtered off and crystallized from dilute alcohol (50 per cent.). It forms needles,
melting at 108 degrees Centigrade, which are not readily soluble in water. It is
insoluble in acids and alkalies, and is decomposed by boiling with acids or alkalies,
paramidophenol being formed. It is represented by the following formula :-
Naturally, salts of paramidophenol can also be used in the process illustrated by
the foregoing last example, in place of free amidophenol, in which case a greater
quantity of alkali must be taken. In place of sodium hydroxide used in the
preceding Third Example, other alkaline hydroxides, such as potassium hydroxide,
can be used.
On using sodium carbonate, or some other alkaline carbonate in place of alkali
hydroxide, the process proceeds in a somewhat different manner, and in this case
the product obtained, as described in the preceding Third Example, is prepared by
first treating paramido phenol dissolved in a solution containing sodium carbonate,
or another alkaline carbonate, with the alkylic salt of chlorocarbonic acid, in order
to obtain the so-called para-hydroxyphenylurethane having the formula :-

page_text: PRODUCTION OF THE ACETYL DERIVATIVE OF THE COMPOUND OBTAINABLE
AS DESCRIBED IN THE FOREGOING THIRD EXAMPLE.
The carbonic acid derivative obtainable as described in the foregoing Third
Example is mixed with a sufficient quantity of acetic anhydride and a small
quantity of zinc chloride. The liquid mixture is then boiled until the action is
complete. A product is thus formed which, when crystallized from alcohol, melts
at 65 degrees Centigrade, and is represented by the following formula :-
In order to produce the products herein before defined, my foreign correspondents
do not limit themselves to the directions above given, as these can be varied. For
instance, instead of the ethylic salt of chlorocarbonic acid used in the preceding
examples, the corresponding quantities of analogous salts, such as methyl or propyl
or butyl or the like salts can be used, products being thus obtained which are
similar to the compounds derived from the ethylic salt of chloro carbonic acid.
Other acid anhydrides, or acid chlorides, can also be used in place of the acetic
anhydride, or acetyl chloride, used in the above described processes. The acetylated
paramidophenol used in the foregoing Example B can be replaced by corresponding
quantities of analogous acid derivatives of paramidophenol."
The process hereinbefore termed Process B, and illustrated by the preceding two
Examples B and C, can also be carried out, though less cheaply, in alcoholic
solution, using, for instance, ethylalcohol as solvent or diluent. In this case, the
corresponding alkaline alcoholate may be used in place of an alkaline hydroxide.
For instance, an equivalent quantity of sodium ethylate is then substituted for
sodium hydroxide.
Such or similar modifications do not alter the nature of this invention, which in
general relates to the production of certain derivatives of paramidophenol, having
the above given general formulæ, either from alkylic salts of paramidophenyl-
carbonic acid, or from paramidophenol containing an acid radicle in place of one
hydrogen of the amido group, or from paramidophenol itself, or from alkylic salts
of such paramidophenyl carbonic acids as contain an acid radicle in place of one
hydrogen of the amido group.
The chemical compounds obtainable by means of the processes herein before
defined, are suitable for use for therapeutical purposes.
Having now particularly described and ascertained the nature of this 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 derivatives of paramidophenol, represented by
the general formula:-
(in which formula any acid radicles, such as-COCH, or-COOC,H,, or the
like, are represented by the term Ac, and alkyl groups of the fatty series by the
expression Alkyl), which process consists―
(a) in treating alkylic salts of paramido phenyl carbonic acid with acid

page_text: anhydrides, acid chlorides, or other agents acting in the same or a similar
manner; or
(b) in allowing salts of chlorocarbonic acid to act in the presence of an
alkaline hydroxide, or the like, on paramidophenol containing an acid
radicle (such as-COCH, or-COOC,H,, or the like) in place of one
hydrogen atom of the amido group; or
(c) in treating a molecular proportion of paramidophenol, or a salt thereof, in
the presence of an alkaline bydroxide, or the like, with two molecular
proportions of an alkylic salt of the chlorocarbonic acid.
The process for producing derivatives of paramidophenol represented by the
ral formula
(in which formula any acid radicle, such as-COCH-COOCH, or the like,
are represented by the terms Ac and Ac,, and any alkyl radicle of the fatty series
by the expression Alkyl), which process consists in treating with acid anhydrides,
acid chlorides, or other suitable agents acting in the same or a similar manner, the
derivatives of paramidophenol which correspond with the formula given in the
preceding first claim.
3. As new products of manufacture, the new derivatives of paramidophenol
produced by the processes hereinbefore defined, or by any other means affording
the same result.
4. The use of the new products hereinbefore defined for pharmaceutical
purposes.
NEWTON & SON,
Agents for the Applicant.