The Manufacture of Diquinolyline Derivatives.
Year: 1890

page_text: Date of Application, 15th Apr. 1890
Complete Specification Left, 15th Jan., 1891-Accepted, 21st Feb., 1891
PROVISIONAL SPECIFICATION.
The Manufacture of Diquinolyline Derivatives.
I, BENJAMIN WILLCOX, of 47, Lincoln's Inn Fields, in the County of Middlesex,
Patent Agent, do hereby declare the nature of this invention (which has been
communicated to me from abroad by The Farbenfabriken vormals Friedrich Bayer &
Co., of Elberfeld, in the Empire of Germany), to be as follows:-
Amido phenyl quinoline aceto acctic ester or amido phenyl alkyl oxy quinoline
aceto acctic ester are obtained according to this invention by treating amido phenyl
quinoline or amido phenyl alkyl oxy quinoline with aceto acetic ester without the
application of heat and are converted into two isomeric oxy methyl diquinolylines
or alkyl oxy methyl diquinolylines by heating to from 200 to 250 degrees Centi-
grade with or without the employment of condensing agents.
Diquinolyline derivatives with one hydroxyl are produced according to this
invention in the following manner.
Amido phenyl quinoline such for example as that described on page 1904 of the
Berliner Berichte Vol. XVIII is treated preferably according to Conrad's process
(Berl. Ber. 20, 948) with aceto acetic ester without the application of heat.
The resulting substituted aceto acetic ester is heated with or without condensing
agents and converted by the resulting condensation into a mixture of two isomeric
methoxy diquinolylines which result in almost equal quantities and may be termed
alpha and beta oxymethyl diquinolylines. The alpha oxymethyl diquinolyline
crystallises without water of crystallisation becomes brown at about 340 degrees
Centigrade without melting and its hydrochloric acid salt or hydrochlorate contains
three molecules of water of crystallisation. Under the action of cold water it turns
yellow and decomposes immediately into hydrochloric acid and basic salt.
The beta oxymethyl diquinolyline on the other hand crystallises with one mole-
tule of water of crystallisation and melts anhydrous at 312 degrees Centigrade. The
hydrochloric acid salt contains three molecular proportions of water of crystallisation
and does not dissociate.
The condensation to oxy diquinolyline derivatives by means of aceto acetic ester
can be produced with the meta amido phenyl para methoxy quinoline described in
page 1920 of Vol. XX of the Berliner Berichte and the bases thus obtained and
the exact conditions of their production may be illustrated by the following example.
The meta amido phenyl para methoxy quinoline and aceto-acetic-ester are brought
together in equal parts and the mixture being allowed to stand for a few days at
a temperature of 40 degrees Centigrade the water separates and can be mechani-
cally removed. A crystalline mass is thus obtained which being separated from
the brown mother lye and covered with alcohol is almost white. This substance
at a temperature of from about 200 to 250 degrees Centigrade changes with genera-
tion of alcohol into a crystal mass which being separated from the adhering syrup
by cold alcohol represents a mixture of two isomeric substances. Thus two com-
binations can be separated by the aid of their sulphuric acid salts thus obtaining
one salt more readily soluble in hot diluted sulphuric acid and one less readily
soluble. The latter salt soluble with difficulty contains a base whose melting
point is above 320 degrees Centigrade and which appears to constitute a methoxy
oxymethyl diquinolyline.
This compound being reduced with tin and hydrochloric acid or other suitable
educing agent (solium and ethyl or amyl alcohol or the like) yields after
eparation of the tin and other hydro products a tetra hydro product which can
be separated from the amorphous products by the aid of heated alcohol into which the
aid products pass. The crystalline base or beta combination forms shining tablets

page_text: melting at 265 degrees Centigrade. This substance dissolves readily in hot
diluted sulphuric acid and when the solution is allowed to stand is precipitated in
the form of small whetstone shaped crystals. They have an intensely bitter
taste similar to that of sulphate of quinine. The salts of this beta base are
soluble with some difficulty in water. The salt represented by C20 H₁, N, O, being
more readily soluble in hot sulphuric acid contains a base which crystallises
in shining tablets whose water of crystallisation is discharged or separates at from
130 to 140 degrees Centigrade.
By reduction in like manner to the preceding compound there is obtained as
before together with higher hydrated products a base richer in hydrogen to the
extent of four atoms and representing the alpha compound and whose crystals melt
at 140 degrees Centigrade with separation of water and partial decomposition.
The salts of this combination are more readily soluble in water than are those
of the beta base but the hydrochloric acid salt dissolves with difficulty in diluted
hydrochloric acid.
The beta compound displays the same physiological properties as quinine in
the treatment of intermittent fevers but has no injurious secondary action.
:הנים
131 1
J
* 1000
J. H. JOHNSON & Co.,
Agents.
COMPLETE SPECIFICATION.
The Manufacture of Diquinolyline Derivatives.
I BENJAMIN WILLCOX of 47 Lincoln's Inn Fields in the County of Middlesex
Patent Agent do hereby declare the nature of this invention which has been
communicated to me from abroad by The Farbenfabriken vormals Friedrich
Bayer & Co. of Elberfeld 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:-
Amido- phenyl- quinoline- aceto- acetic-ether or amido- phenyl- alkyl- oxy-
quinoline- aceto- acetic-ether are obtained according to this invention by treating
amido- phenyl-quinoline or amido- phenyl- alkyl- oxy-quinoline with aceto- acetic-
ether without the application of heat and are converted into two isomeric-hydroxy-
methyl-diquinolylines or alkyl- oxy- hydroxy- methyl-diquinolylines by heating to
from 200 to 250 degrees Centigrade with, or without, the employment of condensing
agents.
These diquinolyline derivatives with one hydroxyl group are produced according
to this invention in the following manner.
Amido- phenyl-quinoline such for example as that described on page 1904 of the
Berliner Berichte. Volume XVIII is treated preferably according to Conrad's
process (Berliner Berichte 20; 948) with aceto- acetic-ether without the applica-
tion of heat. The resulting substituted aceto- acetic-ether is heated with, or
without, condensing agents and converted by condensation into a mixture of two
isomeric-hydroxy- methyl-diquinolylines which are produced in almost equal
quantities and may be termed alpha- and beta-hydroxy-methyl-diquinolylines.
The alpha-hydroxy- methyl-diquinolyline crystallises without water of crystal-
lization it becomes brown at about 340 degrees Centigrade without melting and its
hydrochloride contains three molecular proportions of water of crystallization.
Cold water turns it yellow and decomposes it immediately into hydrochloric acid
and basic salt.
The beta-hydroxy- methyl-diquinolyline on the other hand crystallises with one
molecular proportion of water and melts when anhydrous at 312 degrees
Centigrade.
The hydrochloride contains three molecular proportions of water of crystallization
and does not dissociate.
The condensation to hydroxy-diquinolyline derivatives by means of aceto-acetic-

page_text: ether can also be effected in the case of the meta- amido- phenyl- para- methoxy-
quinoline described in page 1920 of Volume XX of the Berliner Berichte and the
bases thus obtained and the exact conditions of their production may be illustrated by
the following example:-The meta- amido- phenyl- para- methoxy-quinoline and
aceto- acetic-ether are brought together in equal parts and the mixture is allowed to
stand for a few days at a temperature of 40 degrees Centigrade. Water then
separates and can be mechanically removed. A crystalline mass is thus obtained.
which after being separated from the brown mother liquor and covered with alcohol
is almost white. This substance gives off alcohol at a temperature of from about
200 to 250 degrees Centigrade changing into a crystalline mass which when
separated from the adhering syrup by cold alcohol is a mixture of two isomeric
substances. These two compounds can be separated by the aid of their sulphates
the one salt being more readily soluble in hot diluted sulphuric acid than
the other.
The salt which dissolves with difficulty affords a base which has a melting point
above 320 degrees Centigrade and which appears to be a methoxy-hydroxy-methyl-
diquinolyline.
This compound when reduced with tin and hydrochloric acid or other suitable
reducing agent (sodium and ethyl or amyl-alcohol or the like) yields after
separation of the tin and other products a hydride which can be separated from the
amorphous products by the aid of heated alcohol in which the said products are
soluble.
The crystalline base or beta combination forms shining tablets melting at
265 degrees Centigrade.
This substance dissolves readily in hot diluted sulphuric acid and when the
solution is allowed to stand is precipitated in the form of small whetstone shaped
crystals. They have an intensely bitter taste similar to that of sulphate of quinine.
The salts of this beta base dissolve with some difficulty in water.
The salt which is more readily soluble in hot sulphuric acid affords a base which
crystallises in shining tablets which lose water of crystallization at from 130
to 140 degrees Centigrade.
On reduction it yields together with higher hydrides a base richer in hydrogen
to the extent of four atoms the crystals of this alpha compound melting at
140 degrees Centigrade with separation of water and partial decomposition. The
salts of this compound are more readily soluble in water than are those of the beta
base. The hydrochloride dissolves with difficulty in diluted hydrochloric acid.
The beta compound displays the same physiological properties as quinine in cases
of intermittent fever but has no injurious secondary action.
Having now particularly described and ascertained the nature of the said inven-
tion and in what manner the same is to be performed, I declare that what I
claim is :-
1. The process for the manufacture of amido- phenyl-quinoline- aceto-acetic-ether
or amido- phenyl- alkyloxy- quinoline- aceto- acetic-ether by treating amido-
phenyl- quinoline or amido- phenyl- alkyloxy-quinoline with aceto- acetic-ether.
2. The process for the manufacture of diquinolyline derivatives by heating the
amido- phenyl- quinoline- aceto- acetic-ether or the amido- phenyl- alkyloxy-
quinoline- aceto- acetic-ether at a temperature of from about 200 to 250° degrees
Centigrade.
3. The process for the manufacture of hydrides by treating the diquinolyline
lerivatives claimed in the preceding claiming clause with reducing agents.
4. The new quinoline and diquinolyline derivatives hereinbefore described.
DL L
10011
J. H. JOHNSON & Co.,
Agents.