Improvements in the Preparation of Hydroxycaffeine by the Direct Methylation of Uric Acid or of 1: 3-di-methyl Uric Acid."
Year: 1897

page_text: Date of Application, 29th Jan., 1897
Complete Specification Left, 27th Oct., 1897-Accepted, 4th Dec., 1897
66
PROVISIONAL. SPECIFICATION.
Improvements in the Preparation of Hydroxycaffeine by the Direct
Methylation of Uric Acid or of 1: 3-di-methyl Uric Acid."
I, JAMES YATE JOHNSON of 47 Lincolns Inn Fields in the County of London
Gentleman, do hereby declare the nature of this Invention (which has been
communicated to me from Abroad by the firm of C. F. Boehringer & Soehne of
Waldhof near Mannheim in the Empire of Germany) to be as follows:-
This Invention is based upon the discovery by my foreign correspondents that
hydroxy-caffeine (E. Fischer, Lieb. Ann. vol 215 p. 268.) is identical with a
certain hitherto unknown tri-methyl derivative of uric acid, which my foreign
correspondents have found to result from the direct methylation of uric acid or of a
certain di-methyl derivative thereof according to the process hereafter described.
In order clearly to understand the nature of the isomeric methyl derivatives of uric
acid I refer to the constitutional formula of the latter, as first proposed by E.' Fischer
(Ber. d. deutsch. chem. Ges. vol. 17 p. 1786) wherein the four Imido groups of uric
acid are numbered from one to four respectively in the following manner, viz :-
The last named Trimethyluric acid 1: 2: 3, which my foreign correspondents have
discovered to be identical with Hydroxycaffeine, has hitherto not been obtained from
Puric acid by the employment of the known methods of methylation. Thus Hydroxy-
caffeine has up to the present not been publicly recognized as a tri-methyl
derivative of uric acid. So far it could only be prepared from Chlorocaffeine,
which resulted either from the chlorination of Caffeine or from a circuitous
treatment of the so-called y-Dimethyl and Tetramethyluric acids.
Now the nature of the present Invention consists in the preparation of
Hydroxycaffeine from uric acid or from 1-3 dimethyluric acid by the application of
a direct and novel method of methylation hereinafter described.

page_text: 10 parts of uric acid are dissolved in 200 parts of water through the agency of
20 parts (i.e. five molecular proportions) of caustic potash (80%), the liquid cooled by
means of melting ice, and agitated with methylic iodide until the iodide has
disappeared it is advantageous to cool the liquid with ice during the first 12 hours
of the operation.
When the action is at an end, the clear, alkaline liquid is rendered feebly acid,
and then the liquid is reduced to half its bulk by evaporation. After remaining for
many hours, the cooled liquid deposits unaltered dimethyluric acid, which is removed
by filtration. The filtrate is then evaporated until crystals separate, and on cooling
a considerable portion of the hydroxycaffeine crystallises out in slender needles,
whilst the remainder can be extracted by a solvent such for example as chloroform
from the residue left on evaporating the filtrate to dryness. On removing the solvent
by evaporation, hydroxycaffeine remains in the form of a slightly coloured crystalline
mass, which may be obtained in the pure state after one recrystallisation from
water.
1 2 3. Trimethyluric acid, prepared in this manner, has all the characteristic
properties ascribed to it by Fischer, on preparing hydroxycaffeine from caffeine
(Liebeg's Annalen, 215, 268), the substances being identical.
II. PREPARATION OF HYDROXYCAFFEINE FROM 1: 3 DIMETHYLURIC ACID.
5.8 parts of 1 3-dimethyluric acid are dissolved in 50 parts of water containing
4.5 parts (2 molecular proportions) of 80% caustic potash, cooled with melting ice,
and after addition of 55 parts (1 molecular proportions) of methylic iodide,
agitated until the latter has disappeared. The clear liquid is rendered feebly.acid,
and reduced to one half its bulk by evaporation. On cooling, hydroxycaffeine is
obtained in colourless crystals, and after one re-crystallisation from water is
completely pure, and is identical with the product obtained from caffeine..
Dated this 29th day of January 1897.
1
JOHNSONS & WILLCOX,
47. Lincoln's Inn Fields, London, W.C., Agents.

page_text: Date of Application, 29th Jan., 1897
· Complete Specification Left, 27th Oct., 1897-Accepted, 4th Dec., 1897
66
PROVISIONAL. SPECIFICATION.
Improvements in the Preparation of Hydroxycaffeine by the Direct
Methylation of Uric Acid or of 1: 3-di-methyl Uric Acid."
I, JAMES YATE JOHNSON of 47 Lincolns Inn Fields in the County of London
Gentleman, do hereby declare the nature of this Invention (which has been
communicated to me from Abroad by the firm of C. F. Boehringer & Soehne of
Waldhof near Mannheim in the Empire of Germany) to be as follows:-
This Invention is based upon the discovery by my foreign correspondents that
hydroxy-caffeine (E. Fischer, Lieb. Ann. vol 215 p. 268) is identical with a
certain hitherto unknown tri-methyl derivative of uric acid, which my foreign
correspondents have found to result from the direct methylation of uric acid or of a
certain di-methyl derivative thereof according to the process hereafter described.
In order clearly to understand the nature of the isomeric methyl derivatives of uric
acid I refer to the constitutional formula of the latter, as first proposed by E.' Fischer
(Ber. d. deutsch. chem. Ges. vol. 17 p. 1786) wherein the four Imido groups of uric
acid are numbered from one to four respectively in the following manner, viz :-
.
The last named Trimethyluric acid 1: 2: 3, which my foreign correspondents have
discovered to be identical with Hydroxycaffeine, has hitherto not been obtained from
Furic acid by the employment of the known methods of methylation. Thus Hydroxy-
caffeine has up to the present not been publicly recognized as a tri-methyl
derivative of uric acid. So far it could only be prepared from Chlorocaffeine,
which resulted either from the chlorination of Caffeine or from a circuitous
treatment of the so-called y-Dimethyl and Tetramethyluric acids.
.
"
Now the nature of the present Invention consists in the preparation of
Hydroxycaffeine from uric acid or from 1-3 dimethyluric acid by the application of
a direct and novel method of methylation hereinafter described.

page_text: 10 parts of uric acid are dissolved in 200 parts of water through the agency of
20 parts (i.e. five molecular proportions) of caustic potash (80%), the liquid cooled by
means of melting ice, and agitated with methylic iodide until the iodide has
disappeared it is advantageous to cool the liquid with ice during the first 12 hours
of the operation.
When the action is at an end, the clear, alkaline liquid is rendered feebly acid,
and then the liquid is reduced to half its bulk by evaporation. After remaining for
many hours, the cooled liquid deposits unaltered dimethyluric acid, which is removed
by filtration. The filtrate is then evaporated until crystals separate, and on cooling
a considerable portion of the hydroxycaffeine crystallises out in slender needles,
whilst the remainder can be extracted by a solvent such for example as chloroform
from the residue left on evaporating the filtrate to dryness. On removing the solvent
by evaporation, hydroxycaffeine remains in the form of a slightly coloured crystalline
mass, which may be obtained in the pure state after one recrystallisation from
water.
..
1 2 3. Trimethyluric acid, prepared in this manner, has all the characteristic
properties ascribed to it by Fischer, on preparing hydroxycaffeine from caffeine
(Liebeg's Annalen, 215, 268), the substances being identical.
II. PREPARATION OF HYDROXYCAFFEINE FROM 1: 3 DIMETHYLURIC ACID.
5.8 parts of 1: 3-dimethyluric acid are dissolved in 50 parts of water containing
4.5 parts (2 molecular proportions) of 80% caustic potash, cooled with melting ice,
and after addition of 5.5 parts (1 molecular proportions) of methylc iodide,
agitated until the latter has disappeared. The clear liquid is rendered feebly.acid,
and reduced to one half its bulk by evaporation. On cooling, hydroxycaffeine is
obtained in colourless crystals, and after one re-crystallisation from water is
completely pure, and is identical with the product obtained from caffeine..
Dated this 29th day of January 1897.
:
JOHNSONS & WILLCOX,
47. Lincoln's Inn Fields, London, W.C., Agents.

page_text: Improvements in the Preparation of Hydroxycaffeine by the Direct
Methylation of Uric Acid or of 1-3-dimethyl Uric Acid."
I, JAMES YATE JOHNSON of 47 Lincolns Inn Fields, in the County of London,
Gentleman, 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 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 :-.
This Invention is based upon the discovery by my foreign correspondents that
hydroxycaffeine (E. Fischer, Lieb. Ann. vol. 215 p. 268) is identical with a certain
hitherto unknown trimethyl derivative of uric acid, which my foreign correspondents
have found to result from the direct methylation of uric acid or of a certain dimethyl
derivative thereof according to the process hereafter described.
In order clearly to understand the nature of the isomeric methyl derivatives of
uric acid, I refer to the constitutional formula of the latter, as first proposed by
E. Fischer (Berichte der deutschen chemischen Gesellschaft, vol. 17 page 1786)
wherein the four imido groups of uric acid are numbered from one to four respectively
1254
2.
"
3.
"
4.
"
1:24 (Ber. D. chem. Ges. 28, 2478)
2:3:4 (yet unknown)
1 : 2 : 3 (identical with hydroxycaffeine)
The last named trimethyluric acid 1:2:3, which my foreign correspondents have
discovered to be identical with hydroxycaffeine, has hitherto not been obtained from
uric acid by the employment of the known methods of methylation. This hydroxy-
caffeine has up to the present not been publicly recognised as a trimethyl derivative
of uric acid. So far it could only be prepared from chlorocaffeine, which resulted
either from the chlorination of caffeine or from a circuitous treatment of the so called
y-dimethyl and tetramethyluric acids.
Now the nature of the present invention consists in the preparation of hydroxy-
caffeine from uric acid or from 1-3 dimethyluric acid by the application of a direct
and novel method of methylation hereinafter described.
The method of direct methylation, which my foreign correspondents have found
suitable for the production of the above named new results, consists in the action of

page_text: :
I. PREPARATION OF HYDROXYCAFFEINE FROM URIC ACID.
10 parts of uric acid are dissolved in 200 parts of water through the agency of
20 parts (i.e. five molecular proportions) of caustic potash (80%) the liquid cooled
by means of melting ice and agitated with methylic iodide, until the iodide has
disappeared it is advantageous to cool the liquid with ice during the first 12 hours
of the operation.
f
When the action. is at an end, the clear alkaline liquid is rendered feebly acid, and
then the liquid is reduced to half its bulk by evaporation. After remaining for in any
hours the cooled liquid deposits unaltered dimethyl uric acid, which is removed by
filtration. The filtrate is then evaporated until crystals separate, and on cooling a
considerable portion of the hydroxycaffeine crystallises out in slender needles, whilst
the remainder can be extracted by a solvent, such for example, as chloroform from
the residue left on evaporating the filtrate to dryness. On removing the solvent by
evaporation hydroxycaffeine remains in the form of a slightly coloured crystalline
mass which may be obtained in the pure state after one recrystallisation from water.
1.2.3 Trimethyluric acid prepared in this manner, has all the characteristic
properties ascribed to it by Fischer, on preparing hydroxycaffeine from caffeine
(Liebig's Annalen, 215, 268) the substances being identical.
-་ ྃ་
II. PREPARATION OF HYDROXYCAFFEINE FROM 1:3 DIMETHYLURIC ACID.
5-8 parts of 1:3 dimethyluric acid are dissolved. in 50 parts of water containing
4.5 parts (2 molecular proportions) of 80 per cent. caustic potash, cooled with melting
ice, and after addition of 5.5 parts (1 molecular proportions) of methylic iodide,
agitated until the latter has disappeared. The clear liquid is rendered feebly acid,
and reduced to one half its bulk by evaporation. On cooling, hydroxycaffeine is
obtained in colourless crystals, and after one recrystallisation from water is completely
pure, and is identical with the product obtained from caffeine.
Instead of the haloid esters other alkylizing esters may be used, such for example,
as alkyl nitrate or alkyl sulphuric acid.
Having now particularly described and ascertained the nature of this
invention and in what manner the same is to be performed, I declare that what I
claim is:-
1. The preparation of hydroxycaffeine (1.2.3 trimethyluric acid): by treating
an alkaline solution of uric acid with a methylating agent at a low temperature, the
-minimum-proportion of alkali being as 4 molecules to 1 molecule of the uric acid.
=