Improvements in the Manufacture and Production of Medicinal Compounds from Ethereal Oils.
Year: 1890

page_text: Date of Application, 24th Nov., 1890
Complete Specification Left, 15th Aug., 1891-Accepted, 19th Sept., 1891
PROVISIONAL SPECIFICATION.
Improvements in the Manufacture and Production of Medicinal
Compounds from Ethereal Oils.
I JAMES YATE JOHNSON of 47 Lincolns Inn Fields in the County of
Middlesex Gentleman do hereby declare the nature of this invention which has
been communicated to me from abroad by Dr. F. von Heyden (Nachfolger) of
Radebeul near Dresden in the Empire of Germany) to be as follows
The odouriferous constituent of most ethereal oils or ethers is known to consist of
oxygen containing bodies. Menthol, borneol, geranium oil, thymol, carvacrol
eugenol and gaultheria oil, may be mentioned as examples of these bodies which
contain the oxygen usually in the form of a hydroxyl.
It is known that these bodies or substances possess peculiar medicinal properties
and that they act as strong poisons to bacteria, but their clinical application has
heretofore been greatly restricted owing to their intensely strong taste and smell
and the corrosion and burning effect which they produce upon the mucous
membrane.
My foreign correspondent has now discovered that by converting these hydroxyl
containing bodies into their carbonates and carbamates as hereinafter described it
is possible to obtain therefrom useful medicinal products which are odourless,
tasteless and which do not injure the mucous membrane.
For this purpose the ethereal oils may be directly subjected to the reactions
hereinafter described, but it is preferable to employ the oxygen containing bodies
separated from the oils. The following are given as examples of the manufacture
of the new products obtained according to this invention, but I do not limit myself
as to the precise proportions or combinations of the ingredients.
This is effected by the action of one molecule of phosgene in the form of a gas or
in solution upon the hydroxyl compound according to either of two methods
namely:-
:-
(A) Upon two molecules of the hydroxyl containing material at an elevated
temperature the reaction taking place according to the known equation.
The following is given as an example of the process according to the first
method (A.).
Carvacrol and phosgene in the molecular proportion of two to one the phosgene
being dissolved in benzene are heated to about 150 degrees Centigrade in a vessel
capable of withstanding pressure. The benzene is driven off from the product of
the reaction by means of steam and the oily residue being distilled carvacrol
carbonate is obtained in the form of a colourless oil, boiling at a higher degree than
360° Centigrade.
The following are examples of the process according to the second method (B).
I. Equivalent quantities of eugenol and sodium hydroxide are dissolved in water
and phosgene gas is introduced until neutral reaction takes place. The separated

page_text: product of the reaction is recrystallized out of alcohol and eugenol carbonate is
obtained in the form of colourless tasteless and odourless crystals melting at from
about 93 to 94 degrees Centigrade. From guaiacol and creosol the corresponding
carbonates melting at 85 and 145 degrees Centigrade are obtained in like manner.
2. Menthol is dissolved in toluene and heated with one molecule of sodium in a
reflux cooler (Rückfluss Kühler) until all the sodium is taken up. Phosgene in
equal molecular proportion to the sodium is then introduced and the toluene is
distilled off with the aid of steam. The remaining menthol carbonate is washed
with alcohol. The product is white odourless and tasteless and melts at about
106 degrees Centigrade.
In like manner from dextro borneol can be obtained the ester carbornate melting
at 216 degrees Centigrade and from lævo borneol the ester carbonate melting at
225 degrees Centigrade.
Peppermint oil or menthon may be employed in place of the menthol and
camphor in place of the borneol. The yield in ester carbonates is somewhat less
than when borneol and menthol are employed.
II. The carbonates of the bodies hercinbefore referred to are manufactured as
follows for example :-
(A) By the action of phosgene amide CICONH, upon the substance selected
or a salt thereof in equal molecular proportions according to the following
equations.

page_text: J. H. JOHNSON & Co.,
47, Lincoln's Inn Fields, London, Agents.
COMPLETE SPECIFICATION.
Improvements in the Manufacture and Production of Medicinal
Compounds from Ethereal Oils.
I, JAMES YATE JOHNSON of 47 Lincolns Inn Fields, in the County of
Middlesex Gentleman, do hereby declare the nature of this invention, which has
been communicated to me from abroad by Dr. F. von Heyden (Nachfolger) of
Radebeul near Dresden 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 :-
The odouriferous constitutent of most ethereal oils or ethers is known to consist
of oxygen containing bodies. Menthol, borneol, geraniol, thymol, carvacrol,
eugenol, and gaultheria oils may be mentioned as examples of these bodies which
contain the oxygen usually in the form of hydroxyl. It is known that these
bodies or substances possess peculiar medicinal properties and that they act as
strong poisons to bacteria but their clinical application has heretofore been greatly
restricted owing to their intensely strong taste and smell and the corrosive and
burning effect which they produce upon the mucous membrane.
My foreign correspondent has now discovered that by converting these hydroxyl
containing bodies into their carbonates or carbamates or alkyl carbonates as herein-
after described, it is possible to obtain therefrom useful medicinal products which
are odourless, tasteless, and which do not injure mucous membrane.
With the object of effecting the aforesaid conversions the ethereal oils may
be directly subjected to the reactions hereinafter described but it is preferable
to employ the oxygen containing bodies separated from the oils. The following

page_text: This is effected by the action of one molecule of phosgene in the form of a
gas or in solution upon the hydroxyl compound according to either of two methods
namely
:-
(A.) Upon 2 molecules of the hydroxyl containing material at an elevated
temperature the reaction taking place according to the known equation :-
method (A).
Carvacrol and phosgene in the molecular proportion of two to one the phosgene
being dissolved in benzene are heated to about 150 degrees Centigrade in a vessel
capable of withstanding pressure.
The benzene is driven off from the product of the reaction by means of steam
and the oily residue being distilled carvacrol carbonate is obtained in the form of
a colourless oil boiling at a temperature exceeding 360 degrees Centigrade.
The following are examples of the process according to the second method (13).
1. Equivalent quantities of eugenol and sodium hydroxide are dissolved in water
and phosgene gas is introduced until neutral reaction takes place. The separated
product of the reaction is recrystallised out of alcohol and eugenol carbonate is
obtained in the form of colourless, tasteless, and odourless crystals melting at from
about 93 to 94 degrees Centigrade. From guaiacol and creosol the corresponding
carbonates melting at 85 and 145 degrees Centigrade are obtained in like manner.
2. Menthol is dissolved in toluene and heated with one molecule of sodium in a
reflux cooler until all the sodium is taken up. Phosgene in equal molecular
proportion to the sodium is then introduced and the toluene is distilled off with
the aid of steam. The remaining menthol carbonate is washed with alcohol.
The product is white odourless and tasteless and melts at about 106 degrees
Centigrade.
In like manner from dextro borneol can be obtained the ester carbonate melting
at 216 degrees Centigrade and from lævo borneol the ester carbonate melting at
225 degrees Centigrade.
Feppermint oil or menthon may be employed in place of the menthol and
camphor in place of the borneol but the yield in ester carbontes is somewhat less
than when borneol and menthol are employed.

page_text: (A) By the action of phosgene amide, CICONH,, upon the substance selected or
a salt thereof in equal molecular proportions according to the following known
5.equations.
(B) By the action of one of the hydroxyl containing bodies or of a salt thereof
upon phosgene in equal molecular proportions and subsequent treatment with
10 ammonia according to the following equation.
method (A).
Thymol is dissolved in dry ether and an equi-molecular quantity of phosgene
amide is added. The mixture sets or solidifies with escape of chloride of hydrogen
and forms a crystalline paste of thymol carbamate whose melting point when
crystallized out of alcohol is 133 degrees Centigrade.
SECOND METHOD (B).
1. To a solution of phosgene in benzene, dry sodium guaiacol is gradually added
in equal molecular proportions with energetic stirring and ammonia is then
introduced until the mass gives a strong ammoniacal odour. The benzene is then
distilled off, the residue is washed with water and recrystallised out of alcohol.
The melting point of the product is 125 degrees Centigrade.
2. Guaiacol and phosgene in the proportion of one molecule of guaiacol to from
one to two molecules of phosgene are heated to 120 degrees Centigrade with or
without a diluent in a tightly closed vessel. The excess of phosgene is then
distilled off the product of the reaction saturated with ainmonia as in the preceding
example and then treated with water and recrystallised out of alcohol. The
melting point of the product is 125 degrees Centigrade.
By means of methods of treatment such as those herein before described it is
possible to obtain from the ethereal oils or from the hydroxyl yielding bodies
separated therefrom a variety of useful combinations or compounds such for
example as the following namely-

page_text: Lævo borneol
Carvacrol
وو
"
NH COOCH,
Guaiacol
Creosol
"
د"
Eugenol
Thymol
Geraniol
* "
"
NH COOCH OCH
NH COOCH
NH.CO
2
NHCOOCHOCH,
NH COOCHOCH,
129
10: 17
23
وو
"
"
120
13
"
"
"
,,
125
33
"
"
35
140
,,
"
"
"
124
"
"
"
"
133
"
NH COOCH
"
""
"
"
124
"
"
"
"
13
17
On being incorporated with the organism or living body these new medicinal
preparations split up into carbonic acid (or ammonia) and active hydroxyl bodies
which are immediately absorbed so that they exert no more poisonous action than
does the phenol separating from the salol in the organism.
In the application of these principles in practice it is likewise possible to convert
into the carbonate the ethyl salicylate in place of the methyl salicylate (gaultheria
oil) and the iso eugenol in place of the eugenol as follows:
Ethyl salicylate carbonate (C.H.COOC,H.) CO. Melting point 98 degrees
Centigrade.
Iso eugenol carbonate CO(OC,H,OCH₁), Melting point from 112 to 113
degrees Centigrade.
In place of employing guaiacol and creosol creosote may be directly converted
into the carbonate. Of course no chemical formula can be given for the creosote
carbonate obtained, creosote being a mixture of guaiacol creosol and other phenols.
The creosote carbonate is a corresponding mixture containing other phenol
carbonates along with guaiacol carbonate and creosol carbonate. Its chemical and
physical properties vary according to the nature of the creosote employed.
The creosote carbonate is obtained in a liquid or semi solid condition and in
other respects resembles guaiacol carbonate being insoluble in water, soluble in
spirit and in ether and regenerating the free creosote in the living body or organism.
Compared to creosote the creosote carbonate presents the general advantages
hereinbefore specified.
The hydroxyl containing bodies hereinbefore specified can likewise be converted
into the alkyl carbonates in place of into the carbonates or carbamates. For
example eugenol can be converted into eugenol methyl carbonate
The products thus obtained are liquid at medium temperature and on this account
are suitable for injections which are performed with difficulty with the solid
carbonates and carbamates.
In carrying out this manufacture the following products may be obtained for
example

page_text: and gaultheria oil of products that are odourless, tasteless, neutral and innocuous to
mucous membrane the said materials being converted into carbonates by (I) allowing
them or their salts to be acted on by phosgene in the molecular proportions of
1 of phosgene to 2 of the other substance, or (II) by allowing either (a) one
molecular proportion of phosgene amide to act upon one molecular proportion of
borneol, menthol, creosol, eugenol, thymol, carvacrol or geraniol or the salts
thereof or (b) by treating one molecular proportion of borneol, menthol, guaiacol,
creosol, eugenol and carvacrol or the salts thereof first with one molecular pro-
portion of phosgene and afterwards with ammonia.
2. In the manufacture of odourless, tasteless and neutral products, innocuous to
mucous membrane as hereinbefore described and claimed the substitution of creosote
in place of the guaiacol and creosol, the substitution of ethyl salicylate in place of
the methyl salicylate (gaultheria oil) and the substitution of iso eugenol in place
of the eugenol 2 molecular proportions of these substances or their salts being
treated with one molecular proportion of phosgene for the purpose of forming the
carbonate.
3. In place of converting the hydroxyl containing bodies referred to in the
preceding claiming clauses namely eugenol, iso eugenol, guaiacol, creosol, creosote,
carvacrol, gaultheria oil and ethyl salicylicate into their carbonates and carbamates
the conversion of the said bodies into the methyl carbonates and ethyl carbonates
by treating one molecular proportion of the said bodies or of the salt thereof with
one molecular proportion of methyl chloro carbonate or ethyl chloro carbonate.
Dated this 15th day of August 1891
J. H. JOHNSON & Co.