The Manufacture and Production of New Derivatives of Quinine- carbonic Aoid.
Year: 1899

page_text: Date of Application, 7th Nov., 1899
Complete Specification Left, 7th Aug., 1900-Accepted, 8th Sept., 1900
PROVISIONAL SPECIFICATION.
The Manufacture and Production of New Derivatives of Quinine-
carbonic Aoid.
I, JAMES YATE JOHNSON, of 47, Lincoln's Inn Fields, in the County of London,
Gentleman, do bereby declare the nature of this invention (which has been com-
municated to me from abroad by Vereinigte Chiniufabriken Zimmer & Co., of Frank-
furt-on-Maine, in the German Empire) to be as follows:-
In the Specification of Letters Patent No. 4991, of 1896, I have described prepara-
tions from quinine which may be regarded as derivatives of quinine-carbonic acid.
These were the chlorocarbonie ether of quinine, or the chloride of quiniue carbonic
acid and the alkyl ethers of quinine carbonic acid with the corresponding derivatives
of cinchonidine. All these compounds have the cominon property of being either
devoid of bitter taste, or of having it only to a slight extent, and as they possess the
medicinal characteristics of quinine in more or less high degree, they are fitted to
take a prominent place in therapeutics.
My foreign correspondents have now succeeded in preparing new derivatives of
quininecarbonic acid which are not only tasteless, but are composed of quinine-
carbonic acid in union with compounds which themselves bave pronounced inedicinal
qualities.
The substances under consideration may be divided into two groups, firstly, those
preparations which are, generally speaking, the phenol-ethers of quinine carbonic
acid, and secondly, derivatives of the amnide of quinine carbonic acid.
The phenol ethers are best prepared by the action of quinine on the corresponding
phenol carbonates, with or without the addition of a suitable solvent but a quinine
salt such as inuriate of quinine can also be employed.
While still warni, the reaction mixture is dissolved in benzene, the quinine carbonic
phenol-ether produced being then taken up by sulphuric or some other diluted acid,
0 and precipitated with alkali. It can be purified by recrystallisation, for example,
from ether and ligroine. The new compound is a white, crystalline powder alınost
tasteless and very readily soluble in alcohol, ether, and chloroform and less readily
soluble in ligroine.

page_text: It melts at 120° Centigrade. The substance forms salts with acids, and the
salicylate of quiuinecarbonic phenol-ether inay be prepared by dissolving 60 grams
of the ether (1 molecular proportion) and 51 grams of salicylic acid (2 molecular
proportions) in warm alcohol, and adding water until the clear solution becomes
slightly turbid. As the liquid cools, the salt separates in white leaflets which can be 5
purified by recrystallisation from dilute alcohol. It is tasteless, dissolves readily in
alcohol, benzene, and chloroform, but with difficulty in ether, ligroine and water; it
melts at 166° Centigrade. Analysis gave.
CH₂N,O.OII+CH¸‹
20'
O.CH., N.O
CO=CO
OCH OH
Quininecarbonic pyrocatechol-ether forms slender white needles, which are tasteless
and readily soluble in alcohol, ether, benzene, and chloroform, and melt at 184-185°
Centigrade.
This compound also forms salts. The sulphate is obtained by adding excess of 20
dilute sulphuric acid to a solution of the ether in alcohol. The crystalline mass
which separates is recrystallised from dilute alcohol. The sulphate forms white
needles, dissolving with difficulty in alcohol, but readily in water. Analysis gave
Quininecarbonic pyrocatechol-ether forms slender white needles, which are tasteless
and readily soluble in alcohol, ether, benzene, and chloroform, and melt at 184-185°
Centigrade.
This compound also forms salts. The sulphate is obtained by adding excess of 20
dilute sulphuric acid to a solution of the ether in alcohol. The crystalline mass
which separates is recrystallised from dilute alcohol. The sulphate forms white
needles, dissolving with difficulty in alcohol, but readily in water. Analysis gave
1,50 = 21*30 per cent.
21 29,
"
Other phenol ethers can likewise be readily obtained, for example, quinine-carbonic
paranitrophenol-ether, quininecarbonic-para-ethyl-ainido-phenol-ether, and, quinine-
carbonic-thymol-ether can be prepared by heating quinine with excess of the respective
phenolcarbonate, either alone or dissolved in a neutral solvent.
In certain cases, the preparation of quinine-carbonic phenol ethers inny proceed in
such a way that quinine is acted upon by the corresponding phenol-ether of chloro-
carbonic acid instead of by the phenol-carbonate.
The derivatives of the amide of quinine carbonic acid, mentioned at the commence.

page_text: ment of this Specification, can be obtained in two ways, by the action of quinine or
quinine salts on substituted iso-cyanates or on substituted carbamie chlorides.
The following are examples of both methods.
PREPARATION OF THE ANILIDE OF QUININECARBONIC ACID (IHENYLCARBAMIC
ETHER OF QUININE).
Anhydrous quinine is heated, with slight excess of phenylic isocyanate, for a short
time at 190° Centigrade, dissolving to a brownish liquid which, on cooling, solidifies
to an amorphous mass. This is crushed fine, and treated with dilute acid (for
example, sulphuric acid) which dissolves the anilide of quinine-carbonic acid produced
according to the equation
Instead of heating the quinine alone with isocyanate, the operation can be per-
formed in a neutral solvent, such as benzene or toluene in which case a reflux
condenser is used, in order that the reaction may be complete. The benzene is
distilled off, and the anilide treated as aforesaid.
Alkalies precipitate it from the acid solution as a white powder, which dissolves
very readily in alcohol, ether, chloroform, and benzene, but is sparingly soluble in
ligroine and water. The melting point is not definite, but the compound is com-
pletely fused at about 100° Centigrade. The preparation is tasteless, but a slightly
bitter aftertaste is perceptible. Analysis gave
PREPARATION of the puenetidide of quininECARBONIC ACID. (PARAETHOXYPHENYL-
CARBAMIC ETHER OF QUININE).
A solution of paraethoxyphenylcarbamic chloride in benzene is first prepared by
adding 1 molecular proportion of phosgene dissolved in benzene to a well cooled
solution of 2 molecular proportions of phenetidine in benzene.
carbamic chloride is produced in accordance with the equation
Paraethoxyphenyl-
2CH,(O.C,H,).NH, + COCl = C,H, (O.C.Hạ).NH.COC). + CII, (O.C,H,)NH.HCI
and remains dissolved whilst phenetidine hydrochloride is precipitated. This is
filtored and to the filtrate are added 2 molecular proportions of quinine, which
dissolves on warming and forms the required compound according to the equation
+CHNO,.HCI.
П JU
NUCU
3..03
13,
00 = 0³N"H" & + 100Ɔ'HNˆ(³Ƒ³OO)*H*O

page_text: by filtration. The filtrate is agitated first with water and then with dilute acid (for
example, sulphuric acid) which takes up the phenetidide. It can be precipitated
from the acid solution by aminonia. It forms a white almost tasteless powder which
dissolves very readily in alcohol ether chloroform and benzene but very sparingly in
ligroine and water. It is somewhat stable towards acids, but may be completely
resolved into quinine and phenetidine by warm alcoholic caustic soda. Analysis
CAVA
נ'
The Manufacture and Production of New Derivatives of Quinine-
carbonic Acid.
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-

page_text: municated to me from abroad by Vereinigte Chininfabriken Zimmer & Co., of Frank-
furt-on-Maine, 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:-
In the Specification of Letters Patent No. 4991 of 1896 I have described prepara-
tions from quinine which may be regarded as derivatives of quinine-carbonic acid.
These were the chlorocarbonio ether of quinine, or the chloride of quinine-carbonic
acid, and the alkyl ethers of quinine carbonic acid with the corresponding derivatives
of cinchonidine. All these compounds have the common property of being either
devoid of bitter taste, or of having it only to a slight extent, and as they possess the
medicinal characteristics of quinine in more or less high degree, they are fitted to
take a prominent place in therapeutics.
.
My foreigu correspondents have now succeeded in preparing new derivatives of
quininecarbonic acid which are not only tasteless, but are composed of quininecarbonic
acid in union with compounds which themselves have pronounced medicinal qualities.
The new substances under consideration may be divided into two groups, firstly,
those preparations which are, generally speaking, the phenol-ethers of quinine-
carbonic acid, and secondly, derivatives of the amide of quininecarbonic acid.
The phenol-ethers are best prepared by the action of quinine on the corresponding
phenol-carbonates, with or without the addition of a suitable solvent but a quinine
salt such as inuriate of quinine can also be employed.
While still warm, the reaction mixture is dissolved in benzene, the quininecarbonic
phenol-ether produced being then taken up by sulphuric or some other diluted acid,
and precipitated with alkali. It can be purified by recrystallation, for example, from
ether and ligroine. The new compound is a white, crystalline powder almost taste-
less and very readily soluble in alcohol, ether, and chloroform and less readily soluble
in ligroine.
It melts at 120° Centigrade. The substance forms salts with acids, and the
salicylate of quinine-carbonic phenol-ether may be prepared by dissolving 60 grams
of the ether (1 molecular proportion) and 51 grams of salicylic acid (2 molecular
proportions) in warm alcohol, and adding water until the clear solution becomes
slightly turbid. As the liquid cools, the salt separates in white leaflets which can be
purified by recrystallisation from dilute alcohol. It is tasteless, dissolves readily in
alcohol, benzene, and chloroform, but with difficulty in ether, ligroine and water, it
melts at 166° Centigrade. Analysis gave

page_text: PREPARATION OF QUININECARBONIO PYROCATECHIOL-ETHER.
The process is carried out exactly as in the case above given according to the
equation
Quininecarbonic pyrocatechol-ether forins slender white needles, which are tasteless
and readily soluble in alcohol, ether, benzene, and chloroform, and melt at 184-185°
Centigrade.
This compound also forms salts. The sulphate is obtained by adding excess of
dilute sulphuric acid to a solution of the ether in alcohol. The crystalline mass
which separates is recrystallised from dilute alcohol. The sulphate forms white 1
needles, dissolving with difficulty in alcohol, but readily in water. Analysis gave
N
-
H₂SO
=
50.2 per cent.
21.30,
33
-
5.3 per cent.
-
- 21.29
"
"
Other phenol ethers can likewise be readily obtained, for example, quininecarbonic
para-nitro-phenol-ether, quinine-carbonic-para-ethyl-amido-phenol-ether, and,quinine-
carbonic thymnol-ether can be prepared by heating quinine with excess of the respective
phenolcarbonate, either alone or dissolved in a neutral solvent.
In certain cases, the preparation of quinine-carbonic phenol ethers may proceed
in such a way that quinine is acted upon by the corresponding phenol-ether of chloro-
carbonic acid instead of by the phenol-carbonate.
The derivatives of the amide of quinine carbonic acid, mentioned at the commence.
ment of this specification, can be obtained in two ways, by the action of quinino or
quinine salts on substituted iso-cyanates, or on substituted carbamic chlorides.
The following are examples of both methods :—
PREPARATION OF THE ANILIDE OF QUININECARBONIC ACID.
OF QUININE.)
(PHENYLCARBAMIC ETHER
Anhydrous quinine is heated with slight excess of phenylic isocyanate, for a short
time at 190° Centigrade, dissolving to a brownish liquid which, on cooling solidifies
to nu ninorphous mass. This is crushed fine, and treated with dilute acid (for
example, sulphuric acid) which dissolves the anilide of quinine-carbonic acid produced
according to the equation
Instead of heating the quinine alone with isocyanate, the operation can be per- 3
formed in a neutral solvent, such as benzene or toluene in which case a reflux
condenser is used, in order that the reaction may be complete. The benzene is
distilled off, and the anilide treated as aforesaid.
Alkalies precipitate it from the acid solution as a white powder, which dissolves
very readily in alcohol, ether, chloroform, and benzene, but is sparingly soluble in 4

page_text: ligroine and water. The melting point is not definite, but the compound is
completely fused at about 100° Centigrade. The preparation is tasteless, but a
slightly bitter after-taste is perceptible.
Analysis gave
03
Coɔ =*0*NHº0 + 1000'HN' ('H³00) *H*
+ C H N.O.HC).
\NH.C.HOCH
The quinine hydrochloride which is produced separates on cooling and is removed
by filtration. The filtrate is agitated first with water and then with dilute acid (for
example, sulphuric acid) which takes up the phenetidide. It can be precipitated
from the acid solution by ammonia. It forms a white, almost tasteless powder which
5 dissolves very readily in alcohol, ether, chloroform and benzene but very sparingly in
ligroine and water. It is somewhat stable towards acids, but may be completely re-
solved into quinine and phenetidine by warm alcoholic caustic soda. Analysis
gave

page_text: from quinine. Phenetidide of cinchonidinecarbonic acid is a white crystalline taste
less powder inelting at 146° Centigrade which forms salts, and has the constitution
Analysis gave
found
/O.C₁HN,
21
CO
NH.CH.O.CH
/O.C₁₂H,N,
NH.C.H₂OCH
19
Calculated for CO.
C 73.52 per cent.
H = 6.78
"
دو
73.78 per cent.
7.02
""
39
The hereinbefore described compounds and their salts are capable of useful
application in medicine as they are not only tasteless, but unite in themselves the
good qualities of quinine with the antipyretic and antineuralgio action of phenol
derivatives such as paramidophenol.
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 manufacture and production of phenol ethers of quinine-carbonic acid
substantially as herein before described.
2. The manufacture and production of derivatives of the amide of quininecarbonic
acid substantially as herein before described.
3. The manufacture and production of new derivatives of quinine-carbonic acid
as herein before described under the several foregoing Examples.
Dated this 7th day of August 1900.
JOIINSONS & WILLCOX,
47, Lincoln's Inn Fields, London, W.C., Agents.