Improvements in the Manufacture of Fine Chemical Products for Use in Pharmacy and other Purposes.
Year: 1898

page_text: Improvements in the Manufacture of Fine Chemical Products for
Use in Pharmacy and other Purposes.
We, HENRY SOLOMON WELLCOME, of Snow Hill Buildings, Holborn Viaduct,
London, E.C., Manufacturing Chemist, and SAMUEL BARNETT SCORYVER, of 27,
Arundel Gardens, Kensington Park, in the County of Middlesex, Doctor of Science,
do hereby declare the nature of this invention to be as follows:-
The preparation of certain acid phenolic salts of dibasic acids by the action of the
anhydride of the acid on the sodiuin compound of the phenol. For this purpose the
sodium is suspended, preferably in wire form in a liquid such as xylol or benzol
which has no chemical action either on the sodium compound of the phenol or upon
the anhydride of the acid. The liquid chosen should preferably be capable of
dissolving either the anbydride or the sodium salt. The phenol is then added the
reaction proceeding in some cases at the ordinary temperature, in other cases on
the application of heat. When this reaction is complete, the anhydride is added and
the mixture is allowed to stand, or is in certain cases warmed. The two bodies react
according to the following general equation.-
Improvements in the Manufacture of Fine Chemical Products for
Use in Pharmacy and other Purposes.
We, HENRY SOLOMON WELLCOME, of Snow Hill Buildings, Holborn Viaduct,
London, E.C., Manufacturing Chemist, and SAMUEL BARNETT SCORYVER, of 27,
Arundel Gardens, Kensington Park, in the County of Middlesex, Doctor of Science,
do hereby declare the nature of this invention to be as follows:-
:-
The preparation of certain acid phenolic salts of dibasic acids by the action of the
anhydride of the acid on the sodiuin compound of the phenol. For this purpose the
sodium is suspended, preferably in wire form in a liquid such as xylol or benzol
which has no chemical action either on the sodium compound of the phenol or upon
the anhydride of the acid. The liquid chosen should preferably be capable of
dissolving either the anhydride or the sodium salt. The phenol then added the
reaction proceeding in some cases at the ordinary temperature, in other cases on
the application of heat. When this reaction is complete, the anhydride is added and
the mixture is allowed to stand, or is in certain cases warmed. The two bodies react
according to the following general equation.―
CO
COONa
R
0 + XONa == R
CO
\COOX.
(X is here intended to represent a phenylic radical or substituted phenylic radical,
not merely the group (CH)).
The acid phenolic salt can be prepared from the sodium salt thus formed in various
ways. The mixture in xylol, benzol, etc., can be washed with water, and the sodium
salt thus dissolved out. The acid phenolic salt can be precipitated from this solution
by the addition of acid. In other cases the sodium salt is too readily hydrolysed in
presence of water. The benzol, etc., can then be distilled off and the sodium salt left
as residue dried and decomposed by acid in presence of other liquids than water.
The above reaction does not appear to be capable of universal application. In the
case of certain substituted phenols containing a negative group such as nitrophenol,
the phenol seems to exert too acid a reaction and to form too stable a sodium salt to
split up the anhydride ring. In other cases it is difficult to find a liquid capable of
dissolving either the anhydride of the acid, or the sodium salt of the phenol.
As examples of the substances produced by the specified reaction which is claimed
to be the essential feature of this invention may be mentioned
Phenol hydrogen camphorate
Guaiacol hydrogen camphorate
Thymol hydrogen camphorate
Thymol hydrogen succinate
Thymol hydrogen phthalate

page_text: From these compounds various metallic salts, neutral esters and other derivatives
can be formed.
Dated the 1th dav
Annuat 1809
HENRY S. WELLCOME.
SAMUEL BARNETT SCHRYVER.
Improvements in the Manufacture of Fine Chemical Products for
Use in Pharmacy and other Purposes.
We, HENRY SOLOMON WELLCOME, of Snow Hill Buildings, Holborn Viaduct, London,
Manufacturing Chemist, and SAMUEL BARNETT SCHRYVER, of 27, Arundel Gardens,
Kensington Park, in the County of Middlesex, Doctor of Science, 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 :-
The employment in pharmacy of various phenols in the form of salts of acids is
well known and widely extended. In almost all cases, however, neutral salts have
been employed. The invention which forms the subject of the present application
aims at forming by a new method, which will be described in detail below, acid salts
of organic dibasic acids. Such compounds will have in pharmacy the following
advantages:-
1. As they are capable of being very easily hydrolysed, the phenol can be very
readily set free, and thus absorbed in the system.
2. As they contain a free carboxyl group, they are capable of forming various salts,
metallic, alkylic, and phenylic. We thus have a new method for combining phenols
with metals.
The method consists essentially of allowing the sodium salts of phenols to act upon
the anhydrides of organic dibasic acids under certain conditions which will be specified
herein.
A reaction then takes place, which can be represented by the following general

page_text: When the phenol is entirely converted into its sodium salt, and preferably while the
mixture is still warm, the anhydride is added. An almost immediate reaction takes
place, and on standing the sodium phenolic salt separates out, generally in a gelati-
nous form. This is then in most cases washed out with water, and the acid phenolic
salt precipitated from the solution of the sodium salt by a dilute mineral acid. In a
few cases the sodium phenolic salt is exceedingly unstable; and readily hydrolysed
on standing, even with cold water. In these cases obviously another method of
isolating the acid phenolic salt must be adopted.
The falling
mnonude from whanols and wheral others were prevered
When the phenol is entirely converted into its sodium salt, and preferably while the
mixture is still warm, the anhydride is added. An almost immediate reaction takes
place, and on standing the sodium phenolic salt separates out, generally in a gelati-
nous form. This is then in most cases washed out with water, and the acid phenolic
salt precipitated from the solution of the sodium salt by a dilute mineral acid. In a
few cases the sodium phenolic salt is exceedingly unstable; and readily hydrolysed
on standing, even with cold water. In these cases obviously another method of
isolating the acid phenolic salt must be adopted.
The following compounds from phonels and phonel ethers were prop
Hydrogen phenol camphorate,
thymol succinate.
prepared
-
"
"9
"
د,
"
camphorate.
phthalate,
guaiacol camphorate.
"
"
"
»
"
succinate.
carvacrol camphorate.
Anaphthol camphorate.
PREPARATION OF HYDROGEN PHENOL CAMPHORATE.
One atomic equivalent of sodium is suspended in ten times as many litres of xylene
as kilogrammes are employed of phenol. One molecular equivalent of phenol is then
added, and the mixture gently heated to about 90° C., with continual stirring, until
the sodium has dissolved. One molecular equivalent of camphoric anhydride ground
into a paste with a little xylene is then added in small quantities at a time, the
mixture being vigorously shaken after each addition. A certain amount of heat is
evolved in the reaction. After standing for some time, and cooling, a gelatinous
mass separates, and is shaken out with about its own volume of water. The xylene
is separated from the aqueous solution. On adding ten per cent. sulphuric acid or
any other mineral acid the phenolic salt separates out as an oil. To prepare a pure
specimen for analysis it was dissolved in ether; the ethereal solution is dried over
calcium chloride and the residue, after distilling off the ether, allowed to stand in a
vacuum. After a few days the light yellow oil commences to solidify, forming hard
clusters of radiating needles, which can only be separated with some little difficulty
from the sides of the crystallising basin. These were then dried on a porous plate,
and were re-crystallised from chloroform and petroleum ether. They then melted
sharply at 100° C.
PREPARATION OF HYDROGEN THYMOL SUCCINATE.
Thymol in xylene solution was treated with sodium, the same relative proportions
being used as in the preparation of sodium phenate. The sodium dissolved with
great readiness, with considerable evolution of heat it being unnecessary to warm
until the sodium is nearly all dissolved. The sodium thymol compound is readily
soluble in xylene, and hence the reaction in the case of thymol compounds is always
very easy to carry out. The solution, however, darkens very readily on standing,
owing probably to oxidation by the air; the anhydride should therefore be added as
soon as possible. On addition of succinic anhydride the dark colour of the solution
of the sodium thymol derivative disappears, and the sodium thymol succinate
separates out in the form of a light yellow, gelatinous mass. It is dissolved out with
water and the acid thymol succinate precipitated by dilute sulphuric or hydrochloric
acid. It separates as an oil, which very readily solidifies to a mass of granular

page_text: crystals, and these can be filtered off from the mother liquor. For analysis a part was
twice recrystallised from a mixture of chloroform and petroleum-ether, separating in
aggregates of well defined crystals, melting at 121°-122° C.
Analysis:-
0.1145 g. substance gave 0·0780 g. H₂O and 0·2809 g. CO₂.
Found H
--
7.56 %
0
H
C = 66.89%
7.20 % C
=
67.20 %
Caled. C14 His
=
It forms
This body was prepared in exactly the same way as the corresponding succinate.
The acid salt is likewise precipitated from the sodium salt solution by dilute
sulphuric acid or hydrochloric acid as an oil which readily solidifies.
aggregates of well defined crystals when precipitated from the ethereal solution by
light petroleum. The specimen analysed was twice recrystallised in this way.
Analysis:-
=
=
0.1267 g. substance gave 0.0669 g. H₂O and O 3.3371 g. CO₂.
Found H 5.82 %
C 72.55 %
Caled. C18 H18 0
H
-
6.04 % C 72.47 %
=====
The same method was adopted as for the other thymol compounds.
The hydrogen thymol camphorate is precipitated from the solution of the sodium 2
salt by sulphuric acid as an oil, which often does not solidify until it has stood for
several days. It then forms a yellow coloured mass which is easily soluble in ether,
chloroform and light petroleum ether. For analysis it was twice recrystallised from
the last named solvent, from which it separates out in the form of hard nodular
masses melting at 89° C. It has a slight local anesthetic action, producing a feeling 2
of numbness when placed on the back of the tongue.
The sodium salts of all the above thymol derivatives are very readily hydrolysed
by warm water, although the free acids are fairly stable.
THE PREPARATION OF HYDROGEN GUAIACOL CAMPHORate.
12-4 parts of guaiacol are dissolved in about 124 parts of xylene, 2-3 parts of
sodium, either in the form of wire or cut up into thin slices, are then added to the
mixture, which is gradually heated, care being taken that the temperature does not
exceed about 95° C. (the melting point of sodium). The sodium guaiacol compound
thus formed is fairly soluble in warm xylene. As soon as the sodium has dissolved,
18.2 parts of camphoric anhydride are added to the still warm liquid, and a reaction
takes place almost immediately. After cooling and standing for some time the
sodium guaiacol camphorate thus formed separates out in the form of a white,
somewhat gelatinous mass. This is then dissolved out with 120 parts of water, the
xylene separating out on the top of the aqueous solution of the sodium salt. To this
aqueous solution an excess of a mineral acid is added, when hydrogen guaiacol
camphorate separates as an oil which almost immediately commences to crystallise,
and forms after standing a short time a mass of hard crystals which can be readily
powdered and are already nearly pure. A further purification can be effected by
dissolving the substance in about half its weight of acetone, and throwing the syrupy
solution into a large quantity of cold water with continual stirring. For a final

page_text: purification for the purpose of analysis the camphorate was twice recrystallised from
chloroform and light petroleum. It then melts at 112° C.
purification for the purpose of analysis the camphorate was twice recrystallised from
chloroform and light petroleum. It then melts at 112° C.
01018 a substance gave 0:0675 α. H.O. and 0·2476 α. CO.
ARAT
Owing to the readiness with which the sodium salt hydrolyses a different method
was adopted for preparing this body. Benzene was used as the liquid medium for
carrying out the reaction instead of xylene, otherwise the first part of the operation
was carried out in the same way as with the other compounds. After the sodium
guaiacol succinate had been formed it was filtered off from the benzene, in which it
is only very slightly soluble. It was then well pressed, dried and powdered, and the
dry powder then thrown into ten per cent, sulphuric acid containing a layer of ether
on the top, the acid guaiacol camphorate thus set free being dissolved up by the .
ether. On evaporating off the ether and allowing the residue to stand in a vacuum
for some days a mass of crystals was formed, which were then dried on a porous
plate. For analysis the crystals were then dissolved in ether, the ethereal solution
filtered off from a small amount of undissolved matter, and a small amount of
petroleum ether was then added to the solution. A small quantity was precipitated,
but as this was likely to contain some succinic acid it was filtered off from the
remainder of the solution, the mixture of ether and petroleum ether was then
evaporated off and the residual crystals finally recrystallised from chloroform and
light petroleum, from which they separated in the form of beautiful stellate aggregates
of needles, inelting at 75° C.
2
0.1070 g. substance gave 0·0504 g. H₂O, 0.2301 g. CO₂
Found H =
5.23% C = 58.65%
Caled. for CH₁₂05 H = 5.35%
C = 58.93%
Sodium dissolves on heating in a xylene solution of carvacrol and the sodium
carvacrol compound separates out in a crystalline form on cooling the solution. The
hydrogen carvacrol camphorate was prepared in the ordinary way, and forms a syrup
which does not crystallise, even when surrounded by a cooling mixture.

page_text: deposited from the mixture of solvents, it separates out in radiating stallate group
of somewhat thick crystals which were not obtained perfectly white M.P. 111° C.
Analysis
:―
0-2421 g. substance gave by Carius' method 0·1303 g. AgBr.
As stated above camphoric anhydride does not act even in a sealed tube at 180°
on the 2-6 dibromphenol, or on the 2-4-6 tribromphenol. The experiments on these
bodies were also carried out in the presence of xylene.
ACTION OF CAMPHORIC ANHYDRIDE ON THE NITROPHENOLS.
PREPARATION OF HYDROGEN META NITROPHENOL CAMPHORATE.
The sodium salts of ortho and meta nitrophenols for these experiments were made
by the action of an alcoholic solution containing the theoretical quantity of sodium
ethoxide or methoxide on the alcoholic solution of the phenol. From this solution
the sodium salt was precipitated by adding ether. Both the ortho and meta com-
pounds have a bright scarlet colour. On adding the ortho compound to a solution
of camphoric anhydride in xylene, no reaction took place even after heating for
several hours at 100° C. and continuing the heating for 3 or 4 hours longer at
180° C. The meta compound however readily dissolved on heating the corresponding
mixture on a water-bath (molecular proportions of sodium salt and anhydride, in
10 times as much xylene as anhydride). After standing the sodium metanitrophenol
camphorate separated out as a light yellow gelatinous mass. The acid salt was
separated in the usual way and only completely solidified after standing for some
time. This compound is insoluble in petroleum ether, only very slightly soluble in
chloroform, but readily soluble in benzene. From a solution in the latter solvent a
sample was precipitated for analysis by petroleum ether. It began to melt at 115° C.
but was not completely molten till some degrees higher.
0.2243 g. substance gave 8'6 c.c. moist N at 15° C. and 767 m.in.

page_text: The para-nitrophenol sodium salt was made by the direct action of sodium on the
xylene solution of para-nitrophenol. Like the ortho-nitrophenol sodium salt it is
without action on camphoric anhydride.
Succinic anhydride is also without action on ortho-nitrophenol sodium salt.
Having now particularly described and ascertained the nature of the said
invention, and in what manner the same is to be performed, we declare that what we
claim is :-
(1) The preparation of acid phenolic salts of organic dibasic acids by the action
of the sodium phenol compound upon the anhydride of the acid in the presence of
a chemically inactive liquid and the decomposition of the sodium phenolic salt thus
obtained by mineral acids substantially as described. The reaction is generally
although not universally applicable to substituted phenols certain exceptions having
been specified herein.
(2) The application of these acid phenolic salts made according to the process
herein described and the metallic, alkylic, and phenylic salts derivable therefrom, to
therapeutic and other uses.
Dated this Twelfth day of April Eighteen hundred and ninety-nine.
HENRY S. WELLCOME.
SAMUEL BARNETT SCHRYVER.