The Manufacture and Production of New Pharmaceutical Preparations.
Year: 1896

page_text: Date of Application, 5th Mar., 1896
Complete Specification Left, 29th Oct., 1896-Accepted, 12th Dec., 1896
PROVISIONAL SPECIFICATION.
The Manufacture and Production of New Pharmaceutical
Preparations.
I, JAMES YATE JOHNSON, of 47 Lincoln's Inn Fields, in the County of London,
Gentleman, do hereby declare the nature of this invention, (which has been com-
municated to me from abroad by the Firm or Company, trading under the title of,
Vereinigte Chininfabriken Zimmer & Co., of 46. Darmstaedter Landstrasse,
Frankfort-on-the-Main, in the German Empire,) to be as follows:-
A problem, the solution of which has hitherto been unsuccessfully attempted, is
the obtainment of tasteless preparations of cinchona alkaloids. The bitter taste
of these alkaloids and their salts has hitherto been a great objection to their use
as medicines for internal absorption and in certain cases such as that of infants it
has rendered their employment impossible for this purpose. The means which
have hitherto been tried to counteract this bitter taste have consisted in the
addition of syrups, saccharine, glycyrrhizin, and the like or in the employment of
certain salts of the cinchona alkaloids, either soluble with difficulty, or totally
insoluble, such as tannate of quinine. The former plan has not been successful
because no preparation has hitherto been found to be capable of neutralizing or
concealing the intensely bitter taste which is the characteristic of the cinchona
alkaloids, while although by the latter method, it is feasible, to obtain tasteless, or,
but moderately bitter preparations these are attended with the drawback that,
owing to their insolubility, they are too slowly absorbed by the system and do not,
therefore, allow the alkaloids to act in a sufficiently prompt and certain manner.
My foreign correspondents have succeeded in preparing derivatives of quinine,
as well as of other cinchona alkaloids, which are entirely free from any taste, and
are also dissolved in the stomach rapidly enough to ensure a prompt absorption by
the system, these preparations being at the same time derivatives of carbonic acid,
i.e. bodies in which for instance the quinine-rest has been introduced into one
hydroxyl group of the hypothetical carbonic acid

page_text: (1) The preparation belonging to the first series is obtained by the action of
phosgen (carbon-oxychloride, gas upon quinine in accordance with the following
equation:-
COCI, +2 C2HN₂O, CO
=
+CHNO,HCI
OC H.NO.
wherein the quinine-rest has passed into the hydroxyl group and in that case, it
may be described as "chloro carbonyl quinine."
In preparing this compound the following course is adopted.
Phosgen, either in the gaseous condition, or dissolved in benzol, toluene, or some
other suitable solvent, is caused to act upon quinine, which may be either in the
solid state or suspended, or dissolved, in a suitable medium or vehicle and should
preferably be dehydrated. The reaction will proceed most smoothly at a low
temperature, and the development of heat which would otherwise occur while the
reaction is in progress, may be counteracted by cooling. The required combination
will take place also where the normal or a higher temperature prevails, but then at
the same time more or less coloured bye-products will form more readily. Or, in
some cases, it may be advisable to operate under pressure, say in a closed vessel
fitted with a stirrer, when the temperature may be either lowered, or raised,
according to circumstances.
The following will serve as an example to illustrate how the process can be
carried out.
6.5 kilogrammes of anhydrous quinine, are gradually introduced into 30 kilogrammes
of benzol solution containing 12 per cent. of phosgen gas which solution is maintained
at a low temperature by cooling with cold water or ice. The mixture undergoing
reaction presently assumes the form of a yellowish magma. After the whole of the
quinine has been incorporated in it, and when the reaction is completed, the mixture
is allowed to rest for a time, after which the phosgen gas, which has not been taken
up by the reaction, is removed by suction, evaporation, or, if preferred, by distillation
or by any other suitable means. Whilst it is not absolutely necessary to employ
such a large quantity of phosgen gas in excess, it is expedient to do so in practice
owing to the great volatility of that gas.
Upon the completion of the foregoing operations, the crystalline mass is filtered,
washed with benzol, dried and digested with water, for the purpose of eliminating
the muriate of quinine which has formed. The residue which dissolves in water
with difficulty, is crystallized out of strong alcohol, or any other suitable solvent.
Further small quantities of the body may be extracted upon allowing the benzol
mother liquor to evaporate, and treating the residue, remaining after evaporation,
in the manner hereinbefore described.
The analysis of chloro-carbonyl quinine led to the following result:-

page_text: Chloro-carbonyl quinine crystallizes out of alcohol in delicate, colourless, and
perfectly tasteless needles, melting at from 187° to 188° Centigrade, and soluble
with difficulty in water, ether, and cold alcohol, but readily soluble in chloroform
and boiling alcohol. It is far less basic than quinine, its aqueous solution being of
perfectly neutral reaction though it does dissolve in acids, in combining with which
it forms salts. From these solutions, the alkaloid is separated again by means of
alkalies.
The solution in diluted sulphuric acid has a blue fluorescence and-like quinine-
this body gives the thalleiochin reaction.
(II) The bodies appertaining to the second group are best obtained by causing
alkyl-ethers of chloro carbonic acid or chloro-formic acid as such, or dissolved in a
suitable solvent, to act upon quinine, which may or may not be anhydrous, and may
be either dissolved, or suspended, in a suitable medium.
The reaction takes place in accordance with the following equation :-
OC,H
VOC,H,
2 C2H,N,O, + Co
CO
+CH,N,O,HCI
CL
OC HNO
or on corresponding lines if instead of chloro-formic ethyl-ether, chloro-formic
methyl-ether or any of the other ethers of chloro-formic acid be used. The
preparations obtained may be considered as ethers of quinine-carbonic acid. The
following directions may, with advantage, be observed in the preparation of, say,
the ethyl-ether of quinine carbonic acid.
5 kilogrammes of anhydrous quinine are gradually added to a solution of
1.8 kilogrammes of chloro-formic ethyl-ether in 20 kilogrammes of benzol. The
reaction takes place without any application of external heat. The mixture is
then allowed to stand for several hours. Then the crystalline mass is filtered, the
muriate of quinine is eliminated by means of water, and the residue is crystallized
out of diluted alcohol. After the evaporation of the benzol, a further supply of
the body may be extracted from the benzul mother lye.
The quinine carbonic ether may be obtained also at a higher temperature than
that indicated and, if desired, under pressure, or with the addition of a surplus of
chloro-formic ether.
The formation of muriate of quinine, in the course of the reaction defined above,
may be obviated and the entire quantity of quinine may be caused to pass into the
novel combination, a quantity of a base, equivalent to that of the quinine employed,
being allowed to participate in this reaction:-
VOC,H,
OC,H
CHNO, + NaOH + CO
= CO
+ H₂O + NaCl.
CI
CHNO
For this purpose, 5 kilogrammes of quinine are dissolved in 10 kilogrammes of
strong alcohol, and to this solution 0.62 kilogrammes of pure caustic soda, dissolved
in their own weight of water are added. Theu, while the mixture is being
energetically stirred, and cooled, 1.8 kilogrammes of the chloro-formic ethyl-ether
are added.
When the reaction is completed, the sodium-chloride which has separated, is
filtered off, and the alcoholic solution is either distilled off, or mixed with water
whereby the quinine-carbonic ether is precipitated and finally crystallized out of
diluted alcohol.
The ethyl-ether of quinine-carbonic acid forms delicate white needles, having
their point of fusion at 95° Centigrade, and dissolving with difficulty in water, but
being readily soluble in alcohol, ether, and chloroform. The substance is not bitter

page_text: to the taste, its reaction upon litmus paper being decidedly basic, whilst it has the
property of forming salts by combining with acids. The fluorescence of the
sulphuric acid and nitric acid solutions, like that of quinine, is blue. These
solutions, when brought into contact with the several alkaloid reagents yield
precipitates; and the body obtained has the property of producing the thalleiochin
reaction.
If the chloro-formic ethyl-ether be replaced by the corresponding methyl-ether,
quinine-carbouic methyl-ether will be obtained, which closely resembles the first
mentioned ethyl derivative, but which will melt at 123° Centigrade.
(III) Bodies constituted exactly like the quinine derivatives referred to in the
preceding paragraphs I and II may be obtained also by means of cinchonidine, if,
in the course of the processes herein before described, an equivalent quantity of
cinchonidine be substituted for the quinine.
Chloro-carbonyl cinchonidine is obtained by the action of phosgen gas upon
cinchonidine in accordance with the following equation :-
The method of proceeding to be adopted can be exactly the same as that
described in paragraph I, but, taking into account the minor equivalent weight of
cinchonidine, 5-9 kilogrammes of this alkaloid only will be used."
Chloro-carbonyl-cinchonidine forms colourless needles, when crystallized out of
alcohol, and is absolutely free from taste. Its point of fusion is 191° Centigrade.
It is only soluble with great difficulty in water and ether, and it is difficult to
dissolve it in cold alcohol, but it will readily dissolve in hot alcohol and chloroform.
The reaction of chloro-carbonyl-cinchonidine is neutral, though it will dissolve
in acid. The sulphuric acid solution thereof does not present any fluorescence or
give rise to the thalleiochin reaction.
Cinchonidine-carbonic ethers are obtained, like the analogons quinine prepara-
tions, by the action of chloro-formic ethers upon cinchonidine say, for instance, as
expressed by the following equation:-
VOC₂H
OC,H,
2 C1,HN,O+CO3
=== CO
+ C₁, H2, N₂OHCI
CI
OC,H
OC₂H,
C₁,H,N,O + NaOH + CO
= C
+H₂O+NaCl.
NaCl.
CI
In preparing these ethers, the methods described in paragraph II, will answer
the purpose very well, the only modification required being the substitution of
4-5 kilogrammes of cinchonidine for 5 kilogrammes of quinine.
Cinchonidine-carbonic-ethyl-ether forms delicate white crystals having their
melting point at 85° Centigrade. They dissolve with difficulty in water, but
readily in alcohol, chloroform and ether; and they are also easily soluble in acids,
yielding non-fluorescent solutions. No thalleiochin reaction is obtainable with
this body; it is not bitter to the taste, and its reaction upon litmus paper is
alkaline.
Both chloro-carbonyl-quinine and chloro-carbonyl-cinchonidine, as well as the

page_text: quinine-carbonic, and cinchonidine-carbonic ethers (respectively) and the salts
thereof are suitable for use for medicinal purposes.
Dated this 5th day of March 1896.
JOHNSONS & WILLCOX,
47 Lincoln's Inn Fields, London, W.C., Agents.
The Manufacture and Production of New Pharmaceutical
Preparations.
I, JAMES YATE JOHNSON of 47 Lincoln's Inn Fields in the County of London
Gentleman, do hereby declare the nature of this invention (a communication
from the Firm or Company trading under the title of Vereinigte Chininfabriken
Zimmer & Co., of 46 Darmstaedter Landstrasse, Frankfort-on-the-Main in the
German Empire) and in what manner the same is to be performed to be
particularly described and ascertained in and by the following statement :-
A problem, the solution of which has hitherto been unsuccessfully attempted,
is the obtainment of tasteless preparations of cinchona alkaloids. The bitter
taste of these alkaloids-and their salts has hitherto been a great objection to their
use as medicines for internal absorption and in certain cases such as that of infants
it has rendered their employment impossible for this purpose. The means which
have hitherto been tried to counteract this bitter taste have consisted in the addition
of syrups, saccharine, glycyrrhizin and the like or in the employment of certain
salts of the cinchona alkaloids either soluble with difficulty or totally insoluble, such
as tannate of quinine. The former plan has not been successful because no prepara-
tion has hitherto been found to be capable of neutralizing or concealing the
intensely bitter taste which is the characteristic of the cinchona alkaloids, while
although by the latter method, it is feasible, to obtain tasteless, or, but moderately
bitter preparations these are attended with the drawback that, owing to their
insolubility, they are too slowly absorbed by the system and do not, therefore,
allow the alkaloids to act in a sufficiently prompt and certain manner.
My foreign correspondents have succeeded in preparing derivatives of quinine,.
as well as of other cinchona alkaloids, which are entirely free from any taste, and
are, also dissolved in the stomach rapidly enough to ensure a prompt absorption
by the system, these preparations being at the same time derivatives of carbonic
acid, i.e. bodies in which for instance the quinine-rest has been introduced into one
hydroxyl group of the hypothetical carbonic acid
(I)
CO
OC2H2N₂O

page_text: (I) The preparation belonging to the first series is obtained by the action of
phosgen (carbon-oxychloride) gas upon quinine in accordance with the following
equation :-
Cl
CO
OH
wherein the quinine-rest has passed into the hydroxyl group, and in that case, it
may be described as "chloro carbonyl quinine.'
In preparing this compound, the following course is adopted.
Phosgen, either in the gaseous condition or dissolved in benzol, toluene, or some
other suitable solvent, is caused to act upon quinine, which may be either in the
solid state, or suspended, or dissolved, in a suitable medium or vehicle and should
preferably be dehydrated. The reaction will proceed most smoothly at a low
temperature, and the developement of heat which would otherwise occur while the
reaction is in progress, may be counteracted by cooling. The required combination
will take place also where the normal or a higher temperature prevails, but then
at the same time more or less coloured bye-products will form more readily. Or,
in some cases, it may be advisable to operate under pressure, say in a closed vessel
fitted with a stirrer, when the temperature may be either lowered, or raised,
according to circumstances.
The following will serve as an example to illustrate how the process can be
carried out.
6.5 kilogrammes of anhydrous quinine, are gradually introduced into 30 kilo-
grammes of benzol solution containing 12 per cent. of phosgen gas, which solution
is maintained at a low temperature by cooling with cold water or ice. The mixture
undergoing reaction presently assumes the form of a yellowish magma. After the
whole of the quinine has been incorporated in it, and when the reaction is completed,
the mixture is allowed to rest for a time, after which the phosgen gas, which has
not been taken up by the reaction, is removed by suction evaporation, or, if
preferred, by distillation, or by any other suitable means. Whilst it is not
absolutely necessary to employ such a large quantity of phosgen gas in excess, it is
expedient to do so in practice owing to the great volatility of that gas.
Upon the completion of the foregoing operations, the crystalline mass is
filtered, washed with benzol, dried, and digested with water, for the purpose of
eliminating the muriate of quinine which has formed. The residue which dissolves
in water with difficulty is crystallized out of strong alcohol, or any other suitable
solvent. Further small quantities of the body may be extracted, upon allowing the
benzol mother liquor to evaporate, and treating the residue, remaining after
evaporation in the manuer hereinbefore described.

page_text: 240
Calculated for
C 65-20 per cent.
H 5.95
CI 9-18
N 7-24
"
""
"
"
وو
/C₂H, N, O,
CO
CI
Found.
C 65-22 per cent.
H 5.96 "
Cl 9.12 33
"
33
N 7.34 35 39
Chloro-carbonyl quinine crystallizes out of alcohol in delicate, colourless and
perfectly tasteless needles, melting at from 187° to 188° Centigrade, and soluble
with difficulty in water, ether, and cold alcohol, but readily soluble in chloroform
and boiling alcohol. It is far less basic than quinine, its aqueous solution being of
perfectly neutral reaction though it does dissolve in acids, in combining with which
it forms salts. From these solutions, the alkaloid is separated again by means of
alkalies.
The solution in diluted sulphuric acid has a blue fluorescence and-like
quinine-this body gives the thalleiochin reaction.
(II) The bodies appertaining to the second group are best obtained by causing
alkyl-ethers of chloro-carbonic acid or chloro-formic acid as such, or dissolved in
a suitable solvent, to act upon quinine, which may, or may not be anhydrous, and
may be either dissolved, or suspended, in a suitable medium.
The reaction takes place in accordance with the following equation :-
CI
\OCHN₂O
or on corresponding lines if instead of chloro-formic ethyl-ether, chloro-formic
methyl-ether or any of the other ethers of chloro-formic acid be used. The
preparations obtained may be considered as ethers of quinine-carbonic acid. The
following directions may with advantage be observed in the preparation of, say,
the ethyl-ether of quinine-carbonic acid.
5 kilogrammes of anhydrous quinine are gradually added to a solution of
1.8 kilogrammes of chloro-formic ethyl-ether in 20 kilogrammes of benzol. The
reaction takes place without any application of external heat. The mixture is then
allowed to stand for several hours. Then the crystalline mass is filtered, the
muriate of quinine is eliminated by means of water, and the residue is crystallized
out of diluted alcohol. After the evaporation of the benzol, a further supply of the
body may be extracted from the benzol mother lye.
The quinine-carbonic ether may be obtained also at a higher temperature than
that indicated and, if desired, under pressure, or with the addition of a surplus of
chloro-formic ether. The formation of muriate of quinine, in the course of the
reaction defined above, may be obviated and the entire quantity of quinine may be
caused to pass into the novel combination, a quantity of a base, equivalent to that
of the quinine employed, being allowed to participate in this reaction :-
OC,H,
CH,N,O,+ NaOH + CO
= CO
OC,H
+H,O + Na Cl.
INO

page_text: being energetically stirred, and cooled, 1.8 kilogrammes of the chloro-formic ethyl-
ether are added.
When the reaction is completed, the sodium chloride which has separated, is
filtered off, and the alcoholic solution is either distilled off or mixed with, water
whereby the quinine-carbonic ether is precipitated and finally crystallized out of
diluted alcohol.
The ethyl-ether of quinine-carbonic acid forms delicate white needles, having
their point of fusion at 95° Centigrade, and dissolving with difficulty in water, but
being readily soluble in alcohol, ether, and chloroform. The substance is not
bitter to the taste, its reaction upon litmus paper being decidedly basic whilst it
has the property of forming salts by combining with acids. The fluorescence of
the sulphuric acid and nitric acid solutions, like that of quinine, is blue. These
solutions, when brought into contact with the several alkaloid reagents, yield
precipitates; and the body obtained has the property of producing the thalleiochin
reaction.
If the chloro-formic ethyl-ether be replaced by the corresponding methyl-ether,
quinine-carbonic methyl-ether will be obtained, which closely resembles the first
mentioned ethyl derivative, but which will melt at 123° Centigrade.
(III) Bodies constituted exactly like the quinine derivatives referred to in the
preceding paragraphs I and II may be obtained also by means of cinchonidine, if,
in the course of the processes hereinbefore described, an equivalent quantity of
cinchonidine.be substituted for the quinine.
Chloro-carbonyl cinchonidine is obtained by the action of phosgen gas upon
cinchonidine in accordance with the following equation:-
COCI, +2 C₁, HN,O= CO
+ C₁,H,N,OHCI.
OCHN
The method of proceeding to be adopted can be exactly the same as that
described in paragraph I but, taking into account the minor equivalent weight of
cinchonidine, 5-9 kilogrammes of this alkaloid only will be used.
Chloro-carbonyl cinchonidine forms colourless needles, when crystallized out of
alcohol, and is absolutely free from taste. Its point of fusion is 191° Centigrade.
It is only soluble with great difficulty in water and ether, and it is difficult to
Jissolve it in cold alcohol, but it will readily dissolve in hot alcohol and
chloroform.
The reaction of chloro-carbonyl cinchonidine is neutral, though it will dissolve
in acid. The sulphuric acid solution thereof does not present any fluorescence or
give rise to the thalleiochin reaction.
Cinchonidine-carbonic ethers are obtained, like the analogous quinine pre-
parations, by the action of chloro-formic ethers upon cinchonidine say, for instance,
as expressed by the following equation:-
OC₂H
OC₂H
= CO
CI
OC₁,H,N₂
2 CH2N2O + CO
or according to this equation:-
+ C₁,H,N,OHCI.
OC₂H,
QC.H.
C₁,H,NO+NaOH + CO
CC
+ H2O + NaCl.
CI
\OCH,N,

page_text: the purpose very well, the only modification required being the substitution of
4.5 kilogrammes of cinchonidine for 5 kilogrammes of quinine.
Cinchonidine-carbonic-ethyl-ether forms delicate white crystals having their
melting point at 85° Centigrade. They dissolve with difficulty in water, but
readily in alcohol, chloroform, and ether; and they are also easily soluble in acids,
yielding non-fluorescent solutions. No thalleiochin reaction is obtainable with
this body; it is not bitter to the taste, and its reaction upon litmus paper is.
alkaline.
Both chloro-carbonyl-quinine and chloro-carbonyl-cinchonidine, as well as the
quinine-carbonic, and cinchonidine-carbonic ethers (respectively) and the salts
thereof are suitable for use for medicinal purposes.
Having now particularly described and ascertained the nature of this inven-.
tion and in what manner the same is to be performed, I declare that what I
claim is :-
1. The manufacture of new pharmaceutical preparations by acting upon quinine,.
or upon cinchonidine, with phosgen (carbon-oxy-chloride).
2. The manufacture of new pharmaceutical preparations by acting upon quinine,
or upon cinclonidine with an ether of chloro-formic acid with or without the
addition of alkalies.
3. As new articles of manufacture new pharmaceutical preparations such as.
can be prepared in the manners hereinbefore described and claimed.
Dated this 27th day of October 1896.
JOHNSONS & WILLCOX,
47 Lincoln's Inn Fields, London, W.C., Agents..