Improvements in the Manufacture or Preparation of Derivatives of Xanthine from Alkylated Uric Acids.
Year: 1896

page_text: Date of Application, 11th May, 1896
Complete Specification Left, 11th Feb., 1897-Accepted, 1st May, 1897
Improvements in the Manufacture or Preparation of Derivatives of
Xanthine from 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 my invention to be as
follows:-
The tetra-alkyl derivatives of uric acid may be converted into alkylated halogen-
xanthine derivatives by means of the chlorides of phosphorus, one alkyl grouph
being eliminated.
Thus chlorocaffeine is produced when tetra methyluric acid is heated with
phosphorus oxychloride.
Assuming that the methyl groups are converted into methylic phosphate, the
reaction may be expressed by the following equation :-
3 C.NO,(CH) + POCIĄ = 3 C,N,О,(CH₁), Cl + PO(OCH,),
(tetramethyluric acid)
(chlorocaffeine)
The conversion of uric acid into its tetra-methyl derivative being already
understood, it is now possible to obtain chlorocaffeine and caffeine itself from uric
acid.
The same method may also be employed for the preparation of other tri-alkylated
derivatives of xanthine.
I give the preparation of the methyl compound as an instance to further make
clear the process.
Dry tetramethyluric acid is heated with five times its weight of phosphorus
oxychloride for 10 hours at 160°-165° in closed vessels, a clear, pale brown liquid
being formed, which deposits crystals on cooling.
Evaporation leaves a slightly coloured residue, which is converted into a
crystalline powder on treatment with water.
Unchanged tetramethyluric acid can be recovered from the aqueous mother-liquor
by evaporation, neutralization with bases, and extraction with chloroform.
The portion insoluble in cold water is a mixture of chlorocaffeine with a
substance rich in chlorine. The latter compound remains in the mother liquor if
the product be repeatedly crystallised from hot alcohol.
The chlorocaffeine, however, may be purified more simply in the following
manner :-
The crude product is heated with five times its weight of fuming hydrochloric
acid for 3 hours at 130° after which the bydrochloric acid solution is evaporated
to dryness the residue being extracted with cold, dilute caustic soda.
Chlorocaffeine remains behind, whilst the impurities, being converted into acids
by the foregoing treatment are dissolved by the alkali.
A single recrystallization from hot alcohol is then sufficient to purify the
chlorocaffeine completely.
The temperature already indicated is not unconditionally essential to the
production of chlorocaffeine from tetramethyluric acid.
The reaction also proceeds at 145°-150°, but is then completed less rapidly.

page_text: Phosphorus trichloride may be employed as a substitute for phosphorus
oxychloride, but under these conditions the reaction proceeds less smoothly.
The yield of chlorocaffeine is smaller, and the product more difficult to purify.
Dated this 11th day of May 1896.
JOHNSONS & WILLCOX,
47 Lincoln's Inn Fields, London, W.C., Agents.
Improvements in the Manufacture or Preparation of Derivatives of
Xanthine from Alkylated Uric Acids.
1, 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
inanner the same is to be performed to be particularly described and ascertained in
and by the following statement :-
The tetra-alkyl derivatives of uric acid may be converted into alkylated halogen-
xanthine derivatives by means of the chlorides of phosphorus, one alkyl group
being eliminated.
Thus chlorocaffeine is produced when tetra-methyluric acid is heated with
phosphorus oxychloride.
Assuming that the methyl groups are converted into methylic phosphate, the
reaction may be expressed by the following equation:-
3 C.NO,(CH3). + POCI, = 3 C.N.O,(CH₂),CI + PO(OCH₂),
(tetramethyluric acid)
(chlorocaffeine)
The conversion of uric acid into its tetra-methyl derivative being already
understood, it is now possible to obtain chlorocaffeine and caffeine itself from uric
acid.
The same method may also be employed for the preparation of other tri-alkylated
derivatives of xanthine.
I give the preparation of the methyl compound as an instance to further make
clear the process.
Dry tetramethyluric acid is heated with five times its weight of phosphorus
oxychloride for 10 hours at 160°-165° Centigrade in closed vessels, a clear, pale
brown liquid being formed, which deposits crystals on cooling.
Evaporation leaves a slightly coloured residue, which is converted into a
crystalline powder on treatment with water.
Unchanged tetramethyluric acid can be recovered from the aqueous mother liquor
by evaporation, neutralisation with bases, and extraction with chloroform.
The portion insoluble in cold water is a mixture of chlorocaffeine with a substance
rich in chlorine. The latter compound remains in the mother-liquor if the product
be repeatedly crystallised from hot alcohol.
The chlorocaffeine, however, may be purified more simply in the following
manner :-
The crude product is heated with five times its weight of fuming hydrochloric
acid for 3 hours at 130° Centigrade after which the hydrochloric acid solution
is evaporated to dryness, the residue being extracted with cold, dilute caustic
soda.
Chlorocaffeine remaius behind, whilst the impurities, being converted into acids
by the foregoing treatment, are dissolved by the alkali.

page_text: A single recrystallisation from hot alcohol is then sufficient to purify the
chlorocaffeine completely.
The temperature already indicated is not unconditionally essential to the
production of chlorocaffeine from tetra-methyluric acid.
The reaction also proceeds at 145°-150° Centigrade, but is then completed less
rapidly.
Phosphorus trichloride may be employed as a substitute for phosphorus
oxychloride, but under these conditions the reaction proceeds less smoothly.
The yield of chlorocaffeine is smaller, and the product more difficult to purify.
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 the halogen derivatives of alkylated
xanthines by treating tetraalkyluric acids with the halogen compounds of
phosphorus.
2. The process claimed by the first claim as applied to the production of
tri-alkylated xanthines by reducing in the known manner the halogen derivatives of
tri-alkylated xanthines formed in accordance with the said claim.
1907
JOHNSONS & WILLCOX,
47 Lincoln's Inn Fields, London, W.C., Agents.