Improvements in the Manufacture, or Preparation, of Derivatives of (3) Hydroxycaffeine.
Year: 1899

page_text: Date of Application, 9th Aug., 1899-Accepted, 30th Sept., 1899
Improvements in the Manufacture, or Preparation, of Derivatives
of (3) Hydroxycaffeine.
I, GEORGE WILLIAM JOHNSON, of 47, Lincoln's Inn Fields, in the County of
London, Patent Agent, do hereby declare the nature of this invention (which has
been communicated to me from abroad by C. F. Boehringer & Soehne, of Waldhof,
near Mannheim, 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:—
As described in the Specification of the prior Patent No. 26261 of 12th.
December A.D. 1898 3¹: 8-dichlorocaffeine, obtained by the action of phosphorus
pentachloride on chlorocaffeine, is readily converted into chloroparaxanthine by
warming with water. The intermediate product 3'-hydroxy-8-chlorocaffeine, which
is unstable in the presence of water, is the first compound produced in this change.
Now derivatives of this hydroxychlorocaffeine are readily obtained by acting
on 31 8-dichlorocaffeine with alcohols, such as methylic, or ethylic, alcohol, instead
of water.
The alcohol ethers of hydroxychlorocaffeine, obtained in this way, are indifferent
to the action of water, and are readily isolated in consequence of the ease with
which they crystallize.
31-methoxy-8-chlorocaffeine, for example, is produced by the action of methylic
alcohol; its formation proceeds according to the equation

page_text: If, for instance, sodium methylate act on 31-methoxy-8-chlorocaffeine, obtained by
the action of methylic alcohol on 31: 8-dichlorocaffeine, 31; 8-dimethoxycaffeine is
readily produced, according to the equation

page_text: Reducing agents which work in alkaline solution are most appropriate for this
purpose, such as zinc dust and ammonia, as the action of acids on 31-methoxy-8-
chlorocaffeine eliminates the CH..O.CH-group too readily forming chloropara-
xanthine.
The following examples serve to explain the invention moro fulle The norte aun
:
In preparing 3-methoxy-8-chlorocaffeine it is unnecessary to employ crystallized
31 8-dichlorocaffeine, the syrup from which 31 8-dichlorocaffeine is obtained
according to the specification of the prior Patent No. 26261 of the 12th December
1898 being applicable to the purpose.
The said syrup is produced in the following manner 23 parts of dried chlorocaffeine
are heated, in an autoclave, with 30 parts of phosphorus pentachloride and 170 parts
of phosphorus oxychloride at froin 150° to 155° Centigrade, for from 8 to 9 hours.
After cooling a reddish-brown liquid is produced in which colourless needles are
suspended. The whole product is evaporated to a small bulk in vacuo, a tough
reddish-brown resin being obtained as residue.
For preparing 3-methoxy-8-chloracaffeine this syrup is boiled, in a reflux apparatus,
with about 20 parts of absolute methylic alcohol for from 5 to 6 hours.
The alcohol is completely removed by distillation, the residue taken up with ether
and washed with water to remove hydrochloric acid, the ether being then
evaporated; the syrupy residue is covered with a small quantity of methylic alcohol,
and, after a short time, becomes solid and crystalline.
The crystalline product is then dissolved in methylic alcohol, the 31-methoxy-8-
chlorocaffeine thus obtained in lustrous, slender, thread-like needles, resembling
asbestos. On analysis it gives numbers agreeing with the formula C₂HNO,Cl. and
has the constitution:
31-methoxy-8-chlorocaffeine melts at 129°-1300 Centigrade. It gives the
murexide test very distinctly with dilute nitric acid, or with chlorine water, and dis-
solves readily in boiling water, hot alcohol, benzene, acetone, ethylic-acetate, and
chloroform.
It also dissolves readily in fuming hydrochloric acid. On warming the solution for
some time on the water bath it undergoes decomposition, methylic chloride and
formaldehyde being eliminated with formation of chloroparaxanthine, which separates
in blunt, colourless prisms.

page_text: For the preparation of 31: 8-dimethoxycaffeine, 1 part of 31-methoxy-8-chloro-
caffeine is dissolved in 10 parts of methylic alcohol, and the solution boiled with
somewhat more than the calculated amount of sodium methoxide for about half an
hour, evaporated to remove alcohol, and the crystalline residue taken up with water.
The product thus obtained is dissolved in dilute alcohol, from which it separates in
concentric aggregates of small, slender needles, giving, on analysis, figures which
agree with the formula C₁HNO.
14
31 8-dimethoxycaffeine has the constitution formula
:
For the preparation of this substance, finely powdered 31: 8-dimethoxycaffeine is
warmed carefully on the water bath with 10 parts of 10 per cent. hydrochloric acid,
until it is dissolved. Copious evolution of methylic chloride takes place at the same
time.
When solution is complete, the liquid is cooled with ice-water, when colourless,
slender needles crystallize out, and after standing for several hours, they are removed
by filtration, and washed with a small quantity of ice-water.
The product is redissolved in methylic alcohol, and obtained from this medium in
blunt, colourless needles, which give numbers agreeing with the formula C₂H₁₂NO
31-methoxy-hydroxycaffeine has the constitutional formula.
It sinters at about 220° Centigrade when quickly heated, and melts at 228-229°
Centigrade; it dissolves readily in water, hot methylic and ethylic alcohols, very
readily in alkalies and in ammonia.
On treating the ammoniacal solution with silver nitrate, and boiling away the
ammonia, it yields a silver salt crystallising in small slender needles.
31-methoxyhydroxycaffeine gives the murexide test very distinctly.

page_text: IV. PREPARATION OF 3¹-METHOXYCAFFEINE,
On heating and agitating 1 part of 31-methoxy-8-chloro-caffeine with 2 parts of
zinc dust, 20 parts of water and 1 part of concentrated ammonia in closed vessels
at 105-110 Centigrade for from 4 to 5 hours, it becomes completely reduced to
5 31-methoxycaffeine. In order to isolate it, the zinc dust is filtered from the hot
solution and the concentrated filtrate repeatedly extracted with chloroform.
U
The residue obtained on evaporating the latter is dissolved in benzene, from which
31-methoxycaffeine is obtained in lustrous colourless prisms, or in slender thread-like
needles.
When dried at 105° Centigrade it has the composition C,H,NO, and the
tutional fanmaila
It melts at 121-123° Centigrade and sublimes partly undecomposed at higher
temperatures. It gives the murexide test with chlorine water. 31-methoxycaffeine
5 is readily soluble in cold water, alcohol, benzene, acetone and chloroforın, and is best
crystallised from warm ether or boiling petroleum.
It is precipitated in small slender needles from the aqueous solution by concen-
trated alkalies.
When heated with hydrochloric acid, 31-methoxycaffeine is converted into para-
anthine
For the preparation of this compound 1 part of 31-methoxy-8-chlorocaffeine is
heated with 10 parts of ammonia saturated at 0° in closed vessels for 8 hours at
130 135° Centigrade.
On cooling, the amino compound crystallises out almost completely in blunt,
colourless needles.
It is then pumped, washed with water, and redissolved in alcohol. The needles,
which melt at 253-255° Centigrade give numbers on analysis which agree with the
formula C,HNO, it has the constitution.
31-methoxy-8-aminocaffeine dissolves somewhat readily in boiling alcohol or water.
It dissolves however with great difficulty in cold water, cold alcohol, chloroform and
benzene.
It dissolves readily in fuming hydrochloric acid, but on account of its feebly
5 basic properties is precipitated from this solution by water.

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 or preparation of derivatives of (31)-hydroxycaffeine by
causing an alcohol to act upon (31; 8)-dichlorocaffeine, then reducing the resultant
(3)-alkoxy-(8)-chlorocaffeine or treating it with an alcoholic alkali, or treating it
with ammonia,
2. As a new series of compounds, alkoxychlorocaffeines, that is, alkoxy-derivatives
of (8)-chlorocaffeine the said compounds being ethers which have the group
CnH2n+1.0.CH2.bound to the atom N in the position (3).
Dated this 9th day of August 1899.
JOHNSONS & WILLCOX,
47, Lincoln's Inn Fields, London, W.C., Agents.