Improvements in the Manufacture or Preparation of Heteroxanthine, Paraxanthine, and Methylated Hypoxanthines.
Year: 1897

page_text: Improvements in the Manufacture or Preparation of Heteroxanthine,
Paraxanthine, and Methylated Hypoxanthines.
I, JAMES YATE JOHNSON, of 47, Lincoln's Inn Fields, in the County of London,
Gentleman, do hereby declare the nature of this invention (which has been com-
municated to me from abroad by C. F. Boehringer & Soehne, of Waldhof, near
Mannheim, in the Empire of Germany) to be as follows:-
"
Hitherto, heteroxanthine, paraxanthine, and hypoxanthine have been known only
as products, of animal metabolism.
Heteroxanthine, through the researches of Krüger and Salomon (Zeitschrift für
physiologische Chemie, 21, 169) was recognised as mono-inethylxanthine; and,
Paraxanthine was regarded as the last dimethylxanthine, without a direct proof
being adduced.
The structure of hypoxanthine was even less clearly explained.
My foreign correspondents have now succeeded in preparing from theobromine not
only heteroxanthine and paraxanthine but also the dimethyhypoxanthine described
by Krüger, and the still unknown mono-methylhypoxanthine.
In order to explain the process,
adopt the nomenclature, advocated by E. Fischer
(Ber. der d. chem. Ges. 1897-549) and also the structural formulae which have been
established by the latest researches.
The following formulae and names refer to the four compounds mentioned.

page_text: Both chlorine atoms in 7-methyl-2: 6-dichloropurine are highly reactive. They
can be eliminated either separately or simultaneously, and be replaced by hydroxyl.
In this way arise the following, closely related changes, which, lead to the production J
of the four above mentioned compounds.
1) Methyldichloropurine, when heated with hydrochloric acid, loses two atoms of
ablaring and passes into heteroxanthine.

page_text: 10 parts of theobromine are heated with 100 parts of posphorus oxychloride for 3
hours at 140° in autoclaves the mass being continuously agitated during the operation
The phosphorus oxychloride is completely removed from the clear, pale brown liquid
by distillation in a vacuum and the amorphous residue covered with 150 parts of cold.
water.
Under this treatment, the mass gradually changes into crystals which are mostly
colourless, the conversion being accelerated by agitation. Rise of temperature is
checked by cooling the mass with ice.
The product, which should be kept cool till the operation is completed, is then
filtered, and washed with ice water.
The crude substance is mixed with a compound which dissolves in alkali, and must
be therefore extracted with cold, very dilute, caustic soda, filtered and washed, and the
residues crystallised from hot water.
The slender, colourless needles obtained in this manner have the composition
CHIN.CI, and melt at 196-197°.
Methyldichloropurine dissolves with difficulty in cold water, and requires about 70
parts of hot water for dissolution; about 30 parts by weight of boiling alcohol
dissolve the substance
PREPARATION OF HETEROXANTHINE.
On heating one part of 7-methyl-2: 6-dichloro-purine with 10 parts of
hydrochloric acid (sp. gr. 1. 19) in a closed tube for 3 hours at 120-125° a clear, slightly
coloured solution is obtained, which, when evaporated on the water-bath, deposits the
hydrochloride of methylxanthine in prisms.
In order to isolate the base, the crystals are covered with dilute ammonia, and
after evaporating the excess of ammonia, the sparingly soluble base is filtered off, and
recrystallised from hot water.

page_text: The base as obtained in this way is a colourless powder of indefinite crystalline.
structure.
It is possible to prepare a pure specimen by purifying the base through the
beautifully crystalline sodium derivative.
Methylxanthine prepared artificially by this method agrees in properties with the
heteroxanthine closely investigated by Krüger and Salomon (Zeitschrift für
physiologische Chemie, 21,169) and also by Bondzynski and Gottlieb (Ber. d. d. Chem.
Gesell., 1895, 1113, and Archiv für exper. Pathologie and Pharmacologie, 37, 385); a
discrepancy occurred only in the melting point of the base, and its solubility in
water.
The numbers referring to these constants, which previous investigators have
obtained, are due to impurities in the products dealt with.
Purified heteroxanthine has no constant melting point, but when rapidly heated
begins to sinter above 360°, and melts at about 380°, when it becomes dark, and
evolves gas; 142 parts of boiling water are required to dissolve the substance.

page_text: sodium derivative, and gives numbers on analysis agreeing with the formulă
CHNO₂.
The synthetical product is identical with the preparation obtained from urine; it
inelts at 295-296°, requires about 24 parts of hot water for dissolution, crystallises,
on rapidly cooling this solution, in slender, flexible needles, and with excess of cold
caustic soda yields a sodium derivative which is sparingly soluble in the agent.
1 Part of 7-methyl-6-oxy-2-chloropurine is covered with 8 parts of colourless
hydriodic acid of 1.96 specific gravity and after addition of phosphonium iodide,
heated with frequent agitation at 60-70°, until a clear colourless solution is
obtained.
On evaporating the liquid, methyloxypurine hydriodide, remains as a colourless,
crystalline mass, which dissolves readily in water.
In order to isolate the base, the boiling solution of the salt is treated with lead
carbonate, the filtrate treated with hydrogen sulphide to remove a small quantity of
lead, and then evaporated to dryness.
Methylhypoxanthine remains as a colourless, crystalline mass, which for purification
is recrystallized from boiling alcohol. In this way slender, colourless needles are
obtained, which, on analysis, give numbers agreeing with the formula C.H.NO.
Methylhypoxanthine becomes brown at about 340° when quickly heated, and melts
somewhat indefinitely at 353°. It is very readily soluble in water.
The aqueous solution gives a white precipitate with silver nitrate, which separates
from a solution in warm, dilute nitric acid as a white, crystalline powder.
PREPARATION 1:7 DIMETHYLHYPOXANTHINE.
2 parts of 7-methylhypoxanthine are heated with 20 parts of water, 20 parts of
methylic alcohol, 2 parts of methylic iodide, and the quantity of sodium inethylate,
corresponding to one atomic proportion, in closed vessels for 3 hours at 75-80°.
From the highly concentrated solution on cooling there crystallizes out in needles
the sodium iodide compound of 1 : 7-dimethylhypoxanthine, described by Krüger
(Ber. d. d. Chem. Gesell., 26, 1921).
The base liberated from the sodium iodide compound sinters at about 243°, melts
without decomposing at 247°, and distils for the most part undecomposed when
heated in small quantities.
It separates from hot alcohol in slender needles, usually collected in aggregates.
The base possesses the characteristic properties of the substance described by
Krüger (compare loc. cit.).

page_text: COMPLETE SPECIFICATION.
Improvements in the Manufacture or Preparation of Heteroxanthine,
Paraxanthine, and Methylated Hypoxanthines.
I, JAMES YATE. JOHNSON, of 47, Lincoln's 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:-
Hitherto heteroxanthine, paraxanthine, and hypoxanthine have been known only
as products of animal metabolism.
Heteroxanthine, through the researches of Krüger and Salomon (Zeitschrift für
physiologische Chemie, 21, 169), was recognised as mono-inethylxanthine; and
paraxanthine was regarded as the last dimethylxanthine, without a direct proof
being adduced.
The structure of hypoxanthine was even less clearly explained.
My foreign correspondents have now succeeded in preparing from theobromine
not only heteroxanthine and paraxanthine but also the dimethylhypoxanthine described
by Krüger, and the still unknown monomethylhypoxanthine.
In order to explain the process, I adopt the nomenclature advocated by E. Fischer
(Ber. der d. chem. Ges. 1897-549), and also the structural formulae which have been
established by the latest researches.
The following formulae and names refer to the four compounds mentioned.

page_text: On heating one part of 7-methyl-2 6-dichloropurine with 10 parts of hydrochloric
acid (sp. gr. 1-19) in a closed tube for 3 hours at 120-125°, a clear, slightly coloured
solution is obtained, which, when evaporated on the water-bath, deposits the
hydrochloride of methylxanthine in prisms.
In order to isolate the base, the crystals are covered with dilute ammonia, and
after evaporating the excess of ammonia, the sparingly soluble base is filtered off,
and recrystallised from hot water.
The base as obtained in this way is a colourless powder of indefinite crystalline
structure.
It is possible to prepare a pure specimen by purifying the base through the
beautifully crystalline sodium derivative.
Methylxanthine prepared artificially by this method agrees in properties with the
heteroxanthine closely investigated by Krüger and Salomon (Zeitschrift für
physiologische Chemie, 21,169) and also by Bondzynski and Gottlieb (Ber.
d. d. chem. Gesell., 1895, 1113, and Archiv für exper. Pathologie und Pharmacologie,
37, 385); a discrepancy occurred only in the melting point of the base, and its
solubility in water.

page_text: The numbers referring to these constants which previous investigators have
obtained, are due to impurities in the products dealt with.
Purified heteroxanthine has no constant melting point, but when rapidly heated
begins to sinter above 360°, and melts at about 380°, when it becomes dark, and
5 evolves gas; 142 parts of boiling water are required to dissolve the substance.
10 parts of finely powdered 7-methyl- 2 6-dichloropurine are suspended in 100
parts of boiling water, and treated with the quantity of caustic soda calculated for 2
molecular proportions. On agitation, a clear solution is quickly obtained, indicating
the termination of the action.
On saturating the cooled liquid with acetic acid, methyloxychloropurine separates
out in crystalline form.
On extracting the product with 150 parts of boiling water, and allowing the filtrate
to cool, pale yellow columns are obtained.
A highly purified product may be prepared through the barium derivative,
crystallizing in slender prisms. The base gives numbers on analysis which agree
with the formula CH NO Cl.
Pure methyloxychloropurine becomes yellow at about 310°, becoming darker at
higher temperatures owing to further decomposition. In order to dissolve it com-
pletely, about 150 parts of boiling water and 250 parts of boiling alcohol are required.

page_text: heated with frequent agitation, at 60-70°, until a clear, colourless solution is
obtained.
'
On evaporating the liquid, methyloxypurine hydriodide remains as a colourless
crystalline mass, which dissolves readily in water.
In order to isolate the base, the boiling solution of the salt is treated with lead
carbonate, the filtrate treated with hydrogen sulphide to remove a small quantity of
lead, and then evaporated to dryness.
Methylhypoxanthine remains as a colourless, crystalline mass, which for purification
is recrystallised from boiling alcohol. In this way slender, colourless needles are
obtained, which, on analysis, give numbers agreeing with the formula CH NO.
Methylhypoxanthine becomes brown at about 340° when quickly heated, and melts
somewhat indefinitely at 353°. It is very readily soluble in water.
.
The aqueous solution gives a white precipitate with silver nitrate, which separates
from a solution in warm, dilute nitric acid as a white, crystalline powder.
2 parts of 7-methylhypoxanthine are heated with 20 parts of water, 20 parts of
methylic alcohol, 2 parts of methylic iodide, and the quantity of sodium met bylate
corresponding to one atomic proportion, in closed vessels for 3 hours at 75-80°.
From the highly concentrated solution on cooling there crystallizes out in needles
the sodium iodide compound of 1: 7-dimethylhypoxanthine, described by Krüger
(Ber. d. d. chem. Gesell., 26, 1921).
The base liberated from the sodium iodide compound sinters at about 243°, melts
without decomposing at 247°, and distils for the most part undecomposed when
heated in small quantities.
It separates from hot alcohol in slender needles, usually collected in aggregates.
The base possesses the characteristic properties of the substance described by
Krüger (compare loc. cit.)
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 manufacture or preparation of heteroxanthine by heating theobromine with
phosphorus-oxychloride, and then treating the 7-methyl-2-6-dichloropurine so
obtained with a mineral acid, substantially as described.
2. The manufacture or preparation of paraxanthine by heating theobromine with
phosphorus-oxychloride, treating the 7-methyl-2-6-dichloropurine so obtained, with
dilute alkali, whereby methyloxychloropurine results, then methylating the latter
and finally heating the resulting dimethyloxychloropurine with a mineral acid,
substantially as described.
3. The manufacture or preparation of 7-methyl-hypoxanthine by reducing the
7-methyl-6-oxy-2-chloropurine obtained according to the preceding second claiming
clause, the product being further methylated for its conversion (when required) into
1-7-dimethyl-hypo-xanthine substantially as described.
4. The preparation and production of alkylated oxypurines according to the
methods described in the several examples.
JOHNSONS & WILLCOX,
47, Lincoln's Inn Fields, London, W.C., Agents.