Improvements in the Manufacture and Production of Pharmaceutical Compounds.
Year: 1891

page_text: Date of Application, 11th July, 1881
Complete Specification Left, 30th Mar., 1882-Accepted, 7th May,
1892
PROVISIONAL SPECIFICATION.
Improvements in the Manufacture and Production of
Pharmaceutical Compounds.
I BENJAMIN WILLCOX of 47 Lincoln's Ten Fields in the County of Middlesex
Patent Agent do hereby declare the nature of this invention which has been
communicated to me from abroad by Farbenfabriken vormals Friedrich Bayer
& Company of Elberfeld in the Empire of Gerinany to be as follows:-
This invention relates to new products which can be advantageously employed
as substitutes for salol (salicylic acid phenolether). In the year 1886 Sahli intro-
duced this substance and subsequently it was found to exercise secondary detrimental
effects, owing to the phenol which is disengaged in the organism so that in soine
cases it could not be employed.
My foreign correspondents have now found that such detrimental effects are not
incidental to the acetylamido-derivatives of the salol and of analogous compounds
which are hereinafter mentioned for example the so-called acetylamidosalol
(salicylic acid paraacetyl amidophenylester) according to the equation:
is changed into salicylic acid, paraamido-phenol and acetic acid and which matters
are perfectly 'harmless the paraamido phenol not having the detrimental effects of
the phenol.
Of the acetylamido salols, which in general are obtained by the reaction of
aromatic acids (benzoic acid, toluylic acid, oxybenzoic acids alkyloxybenzoic acids,
cresol carbon acids) upon nitrophenols by reducing the nitrophenylethers and by
changing the so formed amido compounds into their acetyl derivatives, that product
is of especially high value which results from the action of salicylic acid upon
paranitrophenol, the paranitrophenylester thus produced being further reduced and
the amidophenylsalicylic ether being then changed into its acetyl-derivative. The
formation of this compound called acetylamidosalol may be carried out in the
|following manner the parts being by weight.

page_text: be purified by crystallisation from its solution in alcohol or benzene in which
solvents it is readily soluble. It is thereby obtained in alınost colourless glittering,
flat tablets that melt at 151 to 152 degrees centigrade.
This amido. product is then suspended in glacial acetic acid and mixed with
the theoretical quantity of acetylchloride, or acetic acid anhydride. Under
spontaneous heating a clear solution results, from which the acetylamido compound
formed separates causing the whole liquid to become of a pap-like consistency.
The acetylderivative is almost insoluble in cold water and only sparingly soluble in
hot water but in alcohol and benzene it dissolves more readily and it separates out
from such hot solutions in small, white, glittering lamina melting at 187 degrees
centigrade.
The aforesaid new compound may advantageously be employed instead of salol
(salicylic acid phenylester) as it does not exercise the secondary detrimental effect of
the latter.
D
1
T
J. H. JOHNSON & Co.,
47, Lincoln's Inn Fields, London, W.C., Agents.
COMPLETE SPECIFICATION.
Improvements in the Manufacture and Production of
Pharmaceutical Compounds...
I BENJAMIN WILLCOX of 47 Lincoln's Inn Fields in the County of Middlesex
Patent Agent do hereby declare the nature of this inventioni (which has been
communicated to me from abroad by the Farbenfabriken vormals Friedrich
Bayer & Co. of Elberfeld in the Empire of Germany) and in what manner the
same is to be performed to be particularly described and ascertained in and by the
following statement :-
This invention relates to new products which can be advantageously employed
as substitutes for salol (salicylic acid phenol ether).
In the year 1886 Sahli introduced this substance and subsequently it was found
to exercise detrimental effects owing to the phenol becoming disengaged in the
organism so that in some cases it could not be employed..
My foreign correspondents have discovered that such detrimental effects are not.
incidental to the use of the acetylamido derivatives of salol and of analogous
compounds which are hereinafter mentioned. Thus, for example, the socalled
acetylamido salol (para acetylamidophenyl salicylate) undergoes change, in. the
manner represented by the equation.

page_text: PRODUCTION OF ACETYLAMIDOPHENYLIC SALICYLATE (ACETYL
AMIDOSALOL).
4 parts of nitrophenylic salicylate (which may be obtained in the known manner
from salicylic acid and paranitrophenol by means of dehydrating agents such as
phosphoroxychloride or the like) are introduced into a mixture of 5 parts of tin,
10 parts of alcohol and 15 parts of fuming muriatic acid. As soon, as the nitro
compound is dissolved the alcohol is evaporated, and then muriatic acid is added
which causes the tin salt of the amidophenylic salt to separate in the form of small
colourless needles. This is filtered off and dissolved in hot water and the tin is
precipitated which can best be effected by means of sulphuretted hydrogen gas.
On subsequently adding sodium carbonate to the liquid free from tin the amido-
phenylic salicylate is precipitated it being almost insoluble in water. It may be
purified by crystallisation from alcohol, or benzene, in which liquids it is readily
soluble. It is thus obtained in almost colourless glittering, flat tablets melting at
150 to 152 degrees centigrade. Iron, or other reducing agents, can be employed
instead of tin with good results. This amido product is then suspended in glacial
acetic acid and mixed with the theoretical quantity of acetyl chloride or acetic
anhydride. Heat is spontaneously evolved and a clear solution is formed' from
which the acetylamido compound soon separates causing the whole liquid to become
of a pap-like consistency. The acetyl derivative is almost insoluble in cold water
and only sparingly soluble in hot water, but it dissolves more readily in hot alcohol,
and benzene separating from such solutions in small, white, glittering lamina melting
at 187 degrees centigrade.
The aforesaid new compound may be advantageously employed instead of salol
(phenylic salicylate) as it does not exercise the detrimental secondary effect of the
latter.
If instead of the paranitrophenylic salicylate of the preceding example, the
analogous para-nitro-phenylic salts of ortho- meta- or para-cresolcarboxylic acid be
used similar results are obtained. Of these acetylamido-phenylic cresolcarboxylates
the ortho compound which is obtained by using ortho cresol carboxylic acid and
subjecting its parauitrophenylic salt to the treatment hereinbefore described
crystalizes from its solution in alcohol in white thin lamine which melt at 181 degrees
centigrade. The analogous meta-compound derived from the paranitrophenylic
salt of meta-cresol-carboxylic acid separates from its solution in alcohol in white
needles which are of silky lustre and which melt at 198 degrees centigrade whilst
the para-compound forms white lamina when crystallised from alcohol and melts at
167 degrees centigrade. With regard to the other properties, these cresol-
carboxylic derivatives in general are similar to the acetyl-amido-phenylic salt of
salicylic acid above described.
Having now particularly described and ascertained the nature of the said
invention and in what manner the same is to be performed I declare that what
I claim is―
1) The production of new pharmaceutical compounds by reducing the nitro-
-phenylic salts obtained from hydroxy carboxylic or alkylhydroxy carboxylic acids
and para-nitrophenols, with dehydrating agents such as phosphoroxychloride, or
the like, and converting the amidophenylic salts into the corresponding acetylamido-
phenylic salts by a subsequent treatment of the resulting amido compounds with
acetyl chloride, acetic anhydride, or other substances capable of displacing hydrogen
in an amido group by the acetyl group.

page_text: 2) As new products the acetylamido phenylic salts having chiefly the following
properties:
a) Acetylamido phenylic salicylate which crystallizes from its solution in
alcohol or benzene in small white glittering laminæ melting at 187 degrees
centigrade.
Acetylamidophenylic ortho cresol carboxylate crystallizing from its solution
in alcohol in white thin lamine which melt at 181 degrees centigrade.
c) Acetylamidophenylic meta cresol carboxylate separating from its solution
in alcohol in white lustrous needles melting at 198 degrees centigrade.
d) Acetylamidophenylic para cresol-carboxylate which crystallizes from-its
solution in alcohol in white lamine melting at 167 degrees centigrade.
Dated this 30th day of March 1892.
J. H. JOHNSON & Co.,
47, Lincoln's Inn Fields, London, W.C., Agents.