Improvements in the Preparation of Alkylated Uric Acids.
Year: 1896

page_text: Date of Application, 11th May, 1895
Complete Specification Loft イイトム Ech 1907 Accepted
10th Ane 4907
PROVISIONAL SPECIFICATION.
Improvements in the Preparation of Alkylated Uric Acids.
I, EMIL FISCHER, of Dorotheenstrasse No. 10, Berlin, in the Empire of Germany,
Professor of Chemistry, do hereby declare the nature of this invention to be as
follows:-
The methylation and ethylation of uric acid has been hitherto exclusively effected
by treating dry lead urate with the corresponding alkyl iodide.
Drygin states (Jahresbericht für Chemie 1864, 629) that his diethyluric and
triethyluric acids were obtained in this way.
Hill and Mabery, however, who studied the reaction much more closely (American
Chemical Journal, 2, 305, and Berichte der Deutsch. Chem. Ges. 9, 370) observed that
only the monomethyl- and dimethyl-compounds are formed on methylation, according
as the acid- or neutral-lead salt of uric acid is employed.
Further methylation by this method has not been hitherto effected (Berichte der
Deutsch. Chem. Ges. 17, 1782) and I was obliged to institute the indirect method for
the production of trimethyluric and tetramethyluric acids by means of the chlorinated
purines (Berichte der Deutsch. Chem. Ges. 17, 33 and 1782).
I have found that direct methylation may be extended to the formation of the
tetramethyl derivative, if the appropriate salt of dimethyluric acid-for example, the
cuprous salt-be treated in the dry state with methyl haloid, and further that the dry
method is not essential to the alkylation of uric acid, which may be also carried out
in aqueous solution by the action of halogen alkyl on the alkali salts of uric acid.
When repeatedly applied, the latter method likewise leads to the direct conversion
of uric acid into its tetra-alkyl derivatives.
It has the advantage over the older method of rendering superfluous the
troublesome preparation of the lead salt. It is capable, moreover, of so much
variation as to allow of the production of numerous mixed alkyl derivatives of
uric acid.
Finally, it may be used in combination with the former method, since the alkyl
compounds produced in the dry way may be further alkylated in aqueous alkaline
solution.
As a further illustration of this invention I give the following examples, the parts
being by weight.
1. CONVERSION OF URIC ACID INTO ALPHA-MONOMETHYLURIC ACID.
20 parts of uric acid are dissolved in 1300 parts of water and 240 parts of normal
caustic potash, and heated with 38 parts of methyl iodide for 2 hours in an autoclave
at 100° Centigrade, the liquid being continually agitated.
On adding a small quantity of hydrochloric acid and allowing it to cool, the solution
deposits monomethyluric acid as a crystalline powder.
The yield amounts to 80 per cent. of the uric acid employed.
In so far as the quantities of alkali and methyl iodide used correspond to two

page_text: 6.-CONVERSION OF BETA-TRIMETHYLUBIC ACID INTO BENZYL-TRIMETHYLURIC ACID.
1 part of beta-trimethyluric acid is dissolved in 4-7 parts of normal caustic pota <h
and the same quantity of water and digested with 0-7 part of benzylic chloride for
one hour at 100°.
During the operation the new product already separates out in the crystalline state.
After extracting it with dilute ammonia, the residue is recrystallised from hot alcohol.
The yield amounts to 90 per cent. of the trimethyluric acid employed.
Trimethyluric acid forms large compact crystals, which melt at 171-173°, and do.
not dissolve in alkalies.
7.-CONVERSION OF ALPHA-DIMETHYLURIC ACID INTO TETRA-METHYLURIC ACID BY
THE DRY METHOD.
For this purpose the cuprous salt is the most suitable.
It is obtained as an almost colourless powder when an alkaline solution of alpha-
dimethyluric acid is warmed with excess of Fehling's solution.
1 part of the salt dried in a vacuum at 100° is mixed with powdered glass and
heated with one part of methylic iodide and 2 parts of ether for 8 hours in a closed
vessel at 120-130°.
In order to isolate the tetramethyluric acid the product of the reaction is boiled
out with water, the solution evaporated to dryness and the residue extracted with
chloroform.
The preparation of tetramethyluric acid by this last method, however, does not
proceed so smoothly as in the wet way.
The alkyluric acids so produced may be used for the preparation of alkylated
xanthines.
1000
JOHNSONS & WILLCOX.
47 Lincoln's Inn Fields, London, W.C., Agents.
Improvements in the Preparation of Alkylated Uric Acias.
I, EMIL FISCHER, of Dorotheenstrasse No. 10 Berlin, in the Empire of Germany,
Professor of Chemistry, 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:-
The methylation and ethylation of uric acid has been hitherto exclusively effected
by treating dry lead urate with the corresponding alkyl iodide.
Drygin states (Jahresbericht für Chemie 1864, 629) that his diethyluric and
triethyluric acids were obtained in this way.
Hill and Mabery, however, who studied the reaction much more closely (American
Chemical Journal, 2, 305; and Berichte der Deutsch. Chem. Ges. 9, 370) observed
that only the monomethyl- and dimethyl-compounds are formed on methylation,
according to whether the acid- or neutral-lead salt of uric acid is employed.,
Further methylation by this method has not been hitherto effected (Berichte der
Deutsch. Chem. Ges. 17, 1782) and I was obliged to institute the indirect method
for the production of trimethyluric and tetramethyluric acids by means of the
chlorinated purines (Berichte der Deutsch. Chem. Ges. 17, 33 and 1782).
I have found that direct methylation may be extended to the formation of the

page_text: tetramethyl derivative, if the appropriate salt of amethyfuric acid-for example, the
cuprous salt-be treated in the dry state with methyl haloid, and further that the dry
method is not essential to the alkylation of uric acid, which may be also carried out
in aqueous solution by the action of halogen alkyl on the alkali salts of uric acid.
When repeatedly applied, the latter method likewise leads to the direct conversion
of uric acid into its tetra-alkyl derivatives.
It has the advantage over the older method of rendering superfluous the trouble-
some preparation of the lead salt. It is capable, moreover of so much variation as
to allow of the production of numerous mixed alkyl derivatives of uric acid.
Finally, it may be used in combination with the former method, since the alkyl
compounds produced in the dry way may be further alkylated in aqueous alkaline
solution.
As a further illustration of this invention and the manner in which it is to be
practically carried into effect I give the following examples, the parts being by
weight.
EXAMPLE 1.-CONVERSION OF URIC ACID INTO ALPHA-MONO METHYLURIC ACID.
20 parts of uric acid are dissolved in 1300 parts of water and 240 parts of normal
caustic potash, and heated with 38 parts of methyl iodide for 2 hours in an autoclave
at 100° Centigrade, the liquid being continually agitated.
On adding a small quantity of hydrochloric acid and allowing it to cool, the
solution deposits monomethyluric acid as a crystalline powder.
The yield amounts to 80 per cent. of the uric acid employed.
In so far as the quantities of alkali and methyl iodide used correspond to two
molecular proportions, and would consequently suffice for the production of the
dimethyl compound, the course of the reaction is not quite in accordance with theory;
experience, however, has shewn that on using less alkali and methyl iodide, a portion
of the uric acid remains unchanged and is mixed with the monomethyl compound.
EXAMPLE 2.-CONVERSION OF ALPHA-METHYLURIC ACID INTO TETRA-METHYLURIC
ACID.
This is effected by repeated action of methyl iodide on an alkaline solution of the
acid in the following manner :-
3 parts of alpha monomethyluric acid, prepared either according to the foregoing
example or by the process of Hill and Mabery, are dissolved in 30 parts of
normal caustic potash, and after the addition of 45 parts of methyl iodide, the
solution is heated in a closed vessel for one hour at 100° Centigrade, the liquid being
meanwhile continuously agitated.
When cold, 15 parts of normal caustic potash and 2 parts of methyl iodide are
added, and the liquid is once more heated for an hour at the same temperature.
The clear liquid, which is feebly acid, is evaporated to dryness, and the residue
is extracted with chloroform.
On evaporating the chloroform, tetramethyluric acid remains behind as a
crystalline mass, and may be obtained pure by a single recrystallisation from alcohol.
EXAMPLE 3. CONVERSION OF ALPHA-DIMETHYLURIC ACID INTO TETRAMETHYLURIC
ACID.
3 parts of alpha-dimethyluric acid (one molecular proportion) containing water of
crystallisation, either obtained from the neutral lead salt according to the directions
of Hill and Mabery by means of methylic iodide, or prepared, as I have found is
quite easily done, through the agency of methylic bromide and methylic chloride,
are dissolved in 28-2 parts of normal caustic potash, and after the addition of
5 parts of methylic iodide (two molecular proportions) heated in a closed vessel for
one hour at 100° Centigrade.

page_text: The yield of tetramethyluric acid amounts to 85 per cent. of the dimethyl
compound employed.
If the corresponding amount of methylic bromide be used in place of methylic
iodide, the reaction proceeds in the same manner, but the yield only amounts to
70 per cent.
Further, methylic chloride may be used for the same purpose.
EXAMPLE 4.-CONVERSION OF BETA-TRIMETHYLURIC ACID (BERICHTE DER DEUTSCH.
CHEM. GES. 28, 2478) INTO TETRAMETHYLURIC ACID.
By employing molecular proportions of acid, alkali, and methylic iodide, the
reaction proceeds so smoothly that the yield amounts to 80 per cent. of the quantity
required by theory.
EXAMPLE 5.-CONVERSION OF ALPHA-DIMETHYLURIC
DIMETHYLURIC ACID.
ACID INTO BENZYL-
2 parts of alpha-dimethyluric acid are dissolved in 14 parts of normal caustic potash
and 42 parts of water, and heated in a reflux apparatus with 1-6 parts of benzylic
chloride for one hour.
During the operation already a separation of precipitate occurs.
When cold, the product is filtered, and recrystallised from hot alcohol.
Benzyldimethyluric acid, which has hitherto been unknown, melts at 282°-283°
Centigrade (uncorrected).
It dissolves in about 300 parts of boiling alcohol, and crystallises on cooling in
slender, lustrous leaflets.
It forms a crystalline silver salt.
On dissolving the substance in a molecular proportion of normal caustic potash,
and treating it in the same way with methylic iodide, it is converted into benzyl
trimethyluric acid, which is hereinafter described.
EXAMPLE 6.-CONVERSION OF BETA-TRIMETHYLURIC ACID INTO BENZYL
TRIMETHYLURIC ACID.
1 part of beta-trimethyluric acid is dissolved in 4-7 parts of normal caustic potash
and the same quantity of water and digested with 0-7 part of benzylic chloride for
one hour at 100° Centigrade.
During the operation the new product already separates out in the crystalline state.
After extracting it with dilute ammonia, the residue is recrystallized from hot alcohol.
The yield amounts to 90 per cent. of the trimethyluric acid employed.
Benzyl-trimethyluric acid forms large compact crystals, which melt at 171°-173°,
Centigrade, and do not dissolve in alkalies.
EXAMPLE 7.-CONVERSION OF ALPHA-DIMETHYLURIC ACID INTO TETRAMETHYLURIO
ACID BY THE DRY METHOD.
For this purpose the cuprous salt is the most suitable.
It is obtained as an almost colourless powder when an alkaline solution of alpha-
dimethyluric acid is warmed with excess of Fehling's solution.
1 part of the salt, dried in a vacuum at 100° Centigrade is mixed with powdered
glass and heated with one part of methylic iodide and 2 parts of ether for 8 hours in
a closed vessel at 120°-130° Centigrade.
In order to isolate the tetramethyluric acid the product of the reaction is boile
out with water, the solution evaporated to dryness, and the residue extracted with
chloroform.
The preparation of tetramethyluric acid by this last method, however, does not
proceed so smoothly as in the wet way.

page_text: The alkyluric acids so produced may be used for the preparation of alkylated
xanthines.
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 preparation of alkylated uric acids by causing halogen alkyls to act upon
. the alkaline salts of uric acid or of the alkyl derivatives of uric acid.
2. The preparation of alkylated uric acids according to the hereinbefore given
several examples.
Dated this 11th day of February 1897.
JOHNSONS & WILLCOX,
47 Lincoln's Inn Fields, London, W.C., Agents.