A New Anti-pyretic and Anti-neuralgic Chinolin Derivative and Process for the Production of the same.
Year: 1891

page_text: Date of Application, 14th Oct., 1391-Accepted, 23th Nov., 1891
[Communicated from abroad by GUSTAV ADOLF DAHL, of the firm of Dahl and
Company, of Barmen, in the Kingdom of Prussia, Dye-stuff Manufacturers.]
A New Anti-pyretic and Anti-neuralgic Chinolin Derivative and
Process for the Production of the same.
I ADOLF BANG of Basinghall Street Leeds in the County of York Dye-stuff
Merchant do hereby declare the nature of this invention and in what manner the
same is to be performed, to be particularly described and ascertained in and by the
following statement:―
produced by Fischer and Renouf (B B XVII 759). If this æthylæther is treated
with nitric acid, or with nitric sulphuric acid, in addition to a dinitro product,
(insoluble in dilute acids), a mono-nitro-ortho-oxyethylchinolin, (melting point
128° C.), is produced; in which as my communicator has proved, the ana-position
must be ascribed to the nitro group. The mono-nitro æther, precipitated from
the acid solution, forms yellow microscopic needles, which are insoluble in water,
readily soluble in hot alcohol, and difficultly soluble in cold alcohol. In acidulated
water it dissolves forming a salt.
chloric acid, stannous chloride and hydrochloric acid, iron filings and other reducing
agents, the corresponding ortho-oxyethyl-ana-amido-chinolin, (melting point 80° C.).
The same forms small yellow needles, which are scarcely volatile with low pressure
steam, readily soluble in alcohol, difficultly soluble in cold water, and pretty
difficultly soluble in æther.
On longer boiling with anhydrous (glacial) acetic acid or in the form of the

page_text: from the amido body.
The acetyl derivative dissolves pretty easily in hot water, and separates out on
cooling in white needles. It is very readily soluble in alcohol. It still possesses
basic properties, and dissolves with facility in dilute acids, forming salts. It is
distinguished by anti-pyretic and anti-neuralgic effects.
The following directions will serve as examples of the production, with regard
to which I would expressly remark, that I by no means bind myself to the exact
proportions given, since such can be varied at pleasure in ways well known to
chemists.
A. PRODUCTION OF THE ÆTHER.
100 grammes of commercial ortho-oxychinolin are dissolved in 500 grammes of
alcohol, and to this solution 40 grammes of caustic soda, dissolved in 40 grammes
of water, are added. After cooling, 110 grammes of æthyl-bromide are added,
and next carefully warmed, afterwards more vigorously on the return flow cooler
of the steam bath. The alcohol is then distilled off, and under the introduction of
carbonic acid, (in order to transform the unchanged caustic soda into the
carbonate), is heated on the steam bath in an open saucer to remove the water.
The mass is hereupon extracted with æther, and the æther extract distilled.
The æther first passes off, then some water, and lastly between 282° and 290° C.
the ortho-oxychinolin-ethyl-æther.
B. PRODUCTION OF THE NITRO-PRODUCT.
One volume of oxy-chinolin-æthyl-æther is slowly entered, under cooling with
water, into four volumes of nitric acid, (spec. grav. 1.52), the mixture warmed for
a short time on the water bath until nitrous acid is given off, and poured into
three times its volume of water. The still warm solution is at once filtered off
from the precipitated di-nitro product, (about 4%), and the filtrate partly
neutralized with caustic soda. The by far greater portion of the mono-nitro-
chinolin-ethyl-æther then separates out in the form of the nitric acid salt on
cooling. This when drained, dissolved in a little water and precipitated
with ammonia, furnishes the ortho-oxy-ethyl-ana-nitro chinolin (melting point
128° C.).
A little of the nitro product may yet be obtained from the mother liquor of the
nitric acid salt, by precipitation with ammonia and recrystallization of the precipitate
in alcohol.
C. REDUCTION OF THE NITRO-ÆTHER.
The reduction of the nitro æther can be carried out as well with tin and
hydrochloric acid as with stannous chloride and hydrochloric acid, or with iron, or.
other reducing agents, in the ways well known to chemists. In the first cases
one employs ten per cent. more than is required according to theory. After the
precipitation of the tin with sulphuretted hydrogen, the resulting hydrochloric acid
salt is at once pure. The fluid is evaporated almost to dryness, and the hydrochloric
acid salt drained off, and dried at 100° C. in the drying closet,

page_text: Instead of this, the reduction of the ana-nitro-ortho-oxyethylchinolin may also
be proceeded with, with the double quantity of the stannous chloride as calculated
for the reduction, whereby a crystallized compound of the amido-derivative
with tin separates out, which can be readily filtered and dried at 80° C. It is just
this compound which is excellently suited for further treatment.
The hydrochloric acid salt dissolved in water and treated with carbonate of soda,
until the reaction is alkaline, splits up, with the separation of the free amido.
product, which is drained off and washed with a little water.
D. PRODUCTION OF THE ACETYL-PRODUCT.
One part of the amido product is boiled for four hours with three parts of
radical vinegar on the return flow cooler. It is then poured into water and
neutralized with ammonia, the acetyl-product separates out and is obtained pure
by recrystallization in water. Or one may also boil the hydrochloric acid salt,
resulting from the reduction with tin, resp. stannous chloride and hydrochloric
acid, for two hours on the return flow cooler with double the quantity of acetate
of soda and the threefold quantity of acetic acid anhydride, whereby on
pouring out into water and neutralizing with ammonia, the mono-acetyl product
separates out.
If the double tin salt described under C is to be acetylized directly, which is
specially to be recommended, one proceeds as follows. The finely powdered double
tin salt is stirred in about double the quantity of acetic acid, about 0-75 (4) parts
of the water-free sodic acetate is added, whereby the mixture becomes of a deep
red colour, and is then heated to boiling; afterwards allowed to cool somewhat,
and then add slowly yet about 0.30 parts of acetic acid anhydride and under active
stirring. When sufficient acetic acid anhydride is added, the previous deep red
colour changes to brown, whilst a yellow mass floats in the liquid. When the
acetylizing is completed, it is poured into about fifteen parts of water, boiled up,
whereon the tin in the form of a basic salt completely separates out; which is
filtered off and washed; whilst the filtrate is made very weakly alkaline with soda.
The acetyl-product hereby separated out is dissolved by boiling, and then allowed
to cool down, whereupon it crystallizes out in long needles. To purify it, it is
recrystallized out in water.
As basic chinolin derivative, the acetyl-ana-amido-orthooxyethyl-chinolin,
brought into contact with acids, furnishes salts, which are all more or less yellow
in colour. Salicylic acid serves as an example of the production. This crystallizes
out from the mixed alcoholic solutions of the molecular mass of the acetyl-product
and salicylic acid. The same is only weakly coloured, and decomposes at about
173° C. The salts from the acids soluble in water are readily obtained, by dis-
solving the acetyl product in the calculated quantity of the warm acidulated water
solution and subsequent crystallization.
The salts of the mineral acids are split up directly on steaming, gradually by
slow crystallization.
The body possesses according to experiments carried out therewith, very prominent
anti-pyretic and anti-neuralgic properties, and is intended to be produced for the
purpose of medicinal application.
Having now particularly described and ascertained the nature of my 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 production of the ana-nitro-ortho-oxyethyl-chinolin
by nitrification of the ortho-oxyethylchinolin with strong nitric acid, or nitric
sulphuric acid.
2° The production of the ana-amido-ortho-oxyethylchinolin by the reduction
of the ans-nitro-ortho-oxyethylchinolin with stannous chloride, tin and hydro-
chloric acid, iron filings and hydrochloric acid, or other reducing agents.

page_text: 3° The transformation of the ana-amido-ortho-oxyethylchinolin into the corre
sponding mono-acetyl derivative, by heating the same with anhydrous (glacial)
acetic acid, anhydrous (glacial) acetic acid and acetic acid anhydride; or the
hydrochloric acid salt of the ortho-oxyethyl-ana-amido-chinolin with acetate of
soda and acetic acid anhydride; or the double tin salt of the ana-amido-ortho-
oxyethylchinolin (resulting from the reduction with double the theoretical
quantity of stannous chloride), anhydrous (glacial) acetic acid, sodic acetate and
acetic acid anhydride.
4° The production of the hydrochloric, sulphuric, and salicylic acid salt of
the acetyl-ana-amido-ortho-oxyethylchinolin by the action of the corresponding
acids on the base, according to the above described methods.
5° The acetyl-ana-amido-ortho-oxyethylchinolin-called "analgen," and its
employment as medicament.
6° The hydrochloric, sulphuric, and salicylic acid salt of the acetyl-ana-amido-
ortho-oxyethylchinolin and its employment as medicaments.
Dated this 13th day of October 1891.
J. CLARK JEFFERSON,
2, East Parade, Leeds, Agent for Applicant.