The Manufacture and Production of Carbonic Ethers, of Quinine and other Cinchona Alkaloids.
Year: 1898

page_text: The Manufacture and Production of Carbonic Ethers, of Quinine
and other Cinchona Alkaloids.
I, GEORGE WILLIAM JOHNSON, of 47, Lincoln's Inn Fields, in the County of London,
Chartered Patent Agent, do hereby declare the nature of this invention (which has
been communicated to me from abroad by Vereinigte Chininfabriken Zimmer & Co.,
Gesellschaft mit beschraenkter Haftung, of 46, Darmstaedter Landstrasse, Frankfort-
on-Main, in the German Empire) to be as follows:-
My foreign correspondents have produced the chlorocarbonic ether of quinine by
the action of phosgene gas on quinine, according to the equation
this being most conveniently effected in practice by allowing excess of phosgene to
O act on quinine. They have further found that by limiting the quantity of phosgene,
it is possible to obtain a preparation in which the second chlorine atom of the
phosgene appears to be replaced by the quinine rest.
For this purpose, gaseous phosgene, or phosgene dissolved in some convenient
solvent, is allowed to act on a double proportion of quinine, the quantity relations
5 expressed by the equation
being adhered to as nearly as possible, or at most a slight excess of phosgene over the
above proportion, being employed.
The new compound thus obtained can be referred to as diquininecarbonic ether,
carbonyl-quinine, or quinine carbonate, the last of these names, however, rendering it
necessary to distinguish the substance from the compound of the same name obtained
from quinine and carbonic acid, and therefore constituting a salt of quinine.
The following is a convenient method of performing the invention.
One kilogram of anhydrous quinine is dissolved in 4 kilograms of chloroform,
76-4 grams of phosgene gas being passed into the cooled solution. The product of the
reaction remains liquid, because quinine hydrochloride, produced by the reaction is
also readily soluble in chloroform. In order to remove this substance, together with
small quantities of quinine remaining unchanged, the product of the reaction is
agitated with water containing one per cent. acetic acid until the extracts no longer
37

page_text: taste bitter. The diquininecarbonic ether is then removed from the chloroform
solution by agitation with water containing one per cent. sulphuric acid, small
quantities of the chlorocarbonic ether of quinine, which is almost always produced,
remaining dissolved in the chloroform. The new compound can be isolated from the
sulphuric acid solution by treatment with alkalis and agitation with ether, which is
then evaporated, or allowed to stand, depositing the substance in the form of white,
crystalline crusts, which may be purified by recrystallisation from -alcohol or
benzene.
TU
It
Diquininecarbonic ether melts at 186.5° Centigrade and is insoluble in water and
benzene, and also in ether excepting when freshly precipitated by alkalis; it dissolves
readily in alcohol, benzene chloroform and acids, reacts neutral, and is tasteless.
appears to be stable when boiled with water, but changes into quinine when heated
with dilute alkalis, or still more readily when warmed with acids, an acid solution
undergoing this change even on standing. The sulphuric acid solution exhibits a
greenish-blue fluorescence. The compound does not give the herapathite
reaction, but gives the thalleioquine reaction. With acids it yields well
characterised, beautifully crystalline salts, which frequently separate with water
of crystallisation. When dry, these salts are exceedingly stable, but are
distinguished by the instability of their aqueous solutions, as already mentioned,
yielding the corresponding salts of quinine on standing, and still more readily on
heating.
The salts are obtained by the action of the corresponding acid on a molecular
proportion of diquininecarbonic ether; among others, the following have been pre-
pared and analysed:
The neutral sulphate, of the composition

page_text: In an analogous manner the carbonic ethers of other cinchona alkaloids, as for
instance, cinchonidine, may be prepared.
Dated this 29th day of July 1898.
JOHNSONS & WILLCOA,
47, Lincoln's Inn Fields, London, W.C., Agents.
The Manufacture and Production of Carbonic Ethers of Quinine
and other Cinchona Alkaloids.
I, GEORGE WILLIAM JOHNSON, of 47, Lincoln's Inn Fields, in the County of
London, Chartered Patent Agent, do hereby declare the nature of this invention
(which has been communicated to me from abroad by Vereinigte Chininfabriken
Zimmer & Co., Gesellschaft mit beschraenkter Haftung, of 46, Darmstaedter Land-
strasse, Frankfort-on-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 :-
My foreign correspondents have produced the chlorocarbonic ether of quinine by
the action of phosgene gas on quinine, according to the equation
this being most conveniently effected in practice by allowing excess of phosgene to
20 act on quinine. They have further found that by limiting the quantity of phosgene,
it is possible to obtain a preparation in which the second chlorine atom of the phos-
gene appears to be replaced by the quinine rest.
For this purpose, gaseous phosgene, or phosgene dissolved in some convenient
solvent, is allowed to act on a double proportion of quinine, the quantity relations
25 expressed by the equation.
being adhered to as nearly as possible, or at most a slight excess of phosgene over
the above proportion being employed.
The new compound thus obtained can be referred to as diquininecarbonic ether,
carbonyl quinine, or quinine carbonate the last of these names, however rendering it
necessary to distinguish the substance from the compound of the same name obtained
from quinine and carbonic acid, and therefore constituting a salt of quinine.
The following is a convenient method of performing the invention.
One kilogram of anhydrous quinine is dissolved in 4 kilograms of chloroform, 76-4
grams of phosgene gas being passed into the cooled solution. The product of the
reaction remains liquid, because quinine bydrochloride, produced by the reaction is
also readily soluble in chloroform. In order to remove this substance, together with
small quantities of quinine remaining unchanged, the product of the reaction is
agitated with water containing one per cent. acetic acid until the extracts no longer

page_text: taste bitter. The diquininecarbonic ether is then removed from the chloroform
solution by agitation with water containing one per cent., sulphuric acid, small
quantities of the chlorocarbonic ether of quinine, which is almost always produced,
remaining dissolved in the chloroform. The new compound can be isolated from the
sulphuric acid solution by treatment with alkalis and agitation with ether, which is
then evaporated, or allowed to stand, depositing the substance in the form of white,
crystalline crusts, which may be purified by recrystallisation from alcohol or benzene.
Elementary analysis gave
Пустодеп
Diquininecarbonic ether melts at 186.5° Centigrade and is insoluble in water and
ligroine, and also in ether excepting wher. freshly precipitated by alkalis, it dissolves
readily in alcohol, benzole, chloroform and acids, reacts neutral, and is tasteless. It
appears to be stable when boiled with water, but changes into quinine when heated
with dilute alkalis, or still more readily when warmed with acids, an acid solution
undergoing this change even on standing. The sulphuric acid solution exhibits a
greenish-blue fluorescence. The compound does not give the herapathite reaction but
gives the thalleioquine reaction.
With acids it yields well characterised, beautifully crystalline salts which frequently
separate with water and crystallisation.
When dry these salts are exceedingly stable but are distinguished by the
instability of their aqueous solutions, as already mentioned yielding the corresponding
salts of quinine on standing, and still more readily on heating.
The salts are obtained by the action of the corresponding acid on a molecular
proportion of diquininecarbonic ether; among others, the following have been
prepared and analysed.
The neutral sulphate of the composition

page_text: 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 and production of carbonic ethers of quinine and other cinchona
alkaloids by causing phosgene gas to act upon quinine or the other cinchona
alkaloid of which the carbonic ether is to be formed.
2. The manufacture and production of carbonic ethers of quinine and other
cinchona alkaloids by causing one molecular proportion of phosgene to act upon
four molecular proportions of quinine or the other cinchona alkaloid of which the
carbonic ether is to be formed.
Dated this 17th dor of March 1900
JOHNSONS & WILLCOX,
47, Lincoln's Inn Fields, London, W.C., Agents.