Improvements in the Manufacture or Preparation of Theobromine.
Year: 1897

page_text: Date of Application, 16th June, 1897-Accepted, 24th July, 1897
COMPLETE SPECIFICATION.
Improvements in the Manufacture or Preparation of Theobromine.
I, BENJAMIN WILLCOX, of 47 Lincolns 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 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:—
Theobromine was recognised by E. Fischer (Liebig's Annalen, 215, 319) as
dimethylxanthine, and was prepared artificially by methylating the lead derivative of
xanthine with methylic iodide (loc. cit. 311).
It has not hitherto been possible to obtain theobromine from the corresponding
dimethyluric acid.
Unlike 13-dimethyluric
acid (German Patent 86562) treatment of
3: 7-dimethyluric acid (for nomenclature vide E. Fischer, Ber. d. d. Chem.
Gesell. 30, 557) with phosphorus pentachloride does not give rise to the corresponding
dimethylchloroxanthine, substitution by halogen occurring in the alloxan-ring; the
product is 3:7-dimethyl-6-chloro-2: 8-dioxypurine (Ber. d. d. Chem. Gesell. 28.
page 2486, and 30, page 554).
At higher temperatures and under the influence of phosphorus pentachloride this
product loses one methylic group, and passes into 7-methyl-2: 6: 8-trichloropurine
(loc. cit. 28, 2489). The former attempts to convert 3: 7-dimethyluric acid into the
closely related theobromine failed at this stage, but the difficulty may be overcom.e
as hereinafter described.
It is possible to eliminate halogen from 3: 7-dimethyl-6-chloro-2: 8-dioxypurine
by heating it with ammonia, producing the base 3:7 dimethyl-6-amino-2 :
8-dioxypurine. On further treating the latter with phosphorus oxychloride, the oxygen
in position (8) is removed, and there arises 3:7-dimethyl-6-amino-2-oxy-8-chloropurine,
in accordance with the equation

page_text: The influence of reducing agents such for example as hydriodic acid, converts the
. chloro-compound into 3: 7-dimethyl-6-amino-2-oxypurine, and when this is treated
with nitrous acid, theobromine is produced.
These changes are represented by the following equations
PREPARATION OF 3: 7-DIMETHYL-6-AMINO-2-OXY-8-CHLOROPURINE FROM 3:7-DIMETHYL-
6-AMINO-28-DIOXYPURINE.
When dimethylaminodioxypurine (obtained by heating dimethylchlorodioxypurine
with ammonia) having been previously dried at 120° Centigrade and finely powdered,
is heated with 10 times its weight of phosphorus oxychloride in an autoclave for
4 hours at 170° Centigrade and frequently agitated a clear solution is obtained.
When this cools, a portion of the new chloro-base separates out in the form of
hydrochloride and the mother-liquor is freed from oxychloride by evaporation in a
vacuum. The sticky residue gradually passes into solution on treatinent with water,
and on neutralising the greater part of the acid with caustic soda, the hydrochloride
of the new base separates from the dark brown acid liquid as a yellow crystalline
mass. This is filtered when cold, and washed with a small quantity of water.
On saturating the solution of the hydrochloride with ammonia the base is
precipitated, and may be purified by crystallising it from about 90 parts by weight
of boiling water with the addition of animal charcoal.
In this way dimethylamino-oxychloropurine is obtained in beautiful long needles,
which contain three molecular proportions of water when dried in air; this is removed
at 105° Centigrade. The base has the composition C,H.N,OCI.
When heated, it decomposes without melting; it dissolves with great difficulty in
cold water, cold alkalis and ammonia. It is readily crystallised from hot water, and
is dissolved in considerable quantity by boiling alcohol. Chloroform dissolves it with
great difficulty.

page_text: to the separation of dimethylamino-oxypurine hydriodide, the mass becomes a thick
crystalline paste, of a dark colour because of the free iodine. More phosphonium
iodide is added, and the heating is continued until the reddish-brown colour of the
crystals and liquid changes to a pale yellow.
.
The reduction is now complete; water is added in sufficient quantity to give a
clear solution when the liquid is heated, and it is then evaporated to dryness on the
water-bath. The residue is taken up with a small quantity of water, and saturated
with cold caustic soda.
The free base separates slowly from the cold solution in stellar aggregates of small
prismatic needles, which, after standing for a considerable time, are filtered off at
0° Centigrade.
After being dried in air, the base which separates from water contains three
molecular proportions of water of crystallisation, which is completely removed at
105° Centigrade.
The anhydrous substance has the formula C,H,NO.
3:7 dimethyl-6-amino-2-oxypurine dissolves in about twice its weight of boiling
water, and is moderately soluble in cold water. It is comparatively sparingly soluble
in hot alcohol, and dissolves with difficulty in chloroform.
The base forms stable salts, which are usually beautifully crystalline.
-
Dated May Jun 13
JOHNSONS & WILLCOX,
47 Lincoln's Inn Fields, London, W.C., Agents.