Improvements in the Manufacture or Production of Xanthines and their Derivatives.
Year: 1898

page_text: COMPLETE SPECIFICATION.
Improvements in the Manufacture or Production of Xanthines and
their Derivatives.
I, GEORGE WILLIAM JOHNSON, of 47, Lincoln's 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:-
This invention relates to the manufacture of xanthines and their derivatives,
and, more particularly, the preparation of this class of bodies from alkylised uric
acids.
In order to define more exactly the ground which this invention covers in the
art, it may be stated that a method has heretofore been found for obtaining
the halogen-derivatives of alkylised xanthines by the action of phosphorus
chloride thereon, the xanthines themselves being then obtained by reducing the
halogen-derivatives. This method has been set forth in a publication of E. Fischer
and L. Ach. Ber. der d. chem. Ges. vol. 28 p. 3135.
Such conversion was, however, only possible for such alkyl-uric acids as
contained two alkyl-groups in the alloxan-ring and whose structure would be
represented by the general formula:-
Adopting the nomenclature and the system of numbering the carbon-and nitrogen-
atoms of the purine nucleous, which have been introduced by Emil Fischer and
described in Ber. der d. chem. Ges. vol. 30 p. 549, that is, only such alkyl-uric-acids
in which alkyl-groups were bound to the molecule both at the position (1) and
position (3) could, according to that method, be converted into xanthines.
To proceed from mono-methyl-uric acids or from other dimethyl-uric acids to
halogen-or-chloro-xanthines, has hitherto been impossible.
The investigations and experiments of my foreign correspondents in this field, have
resulted in the discovery that all uric acids, which have not been completely
alkylised, may be converted into the corresponding chloro-xanthines, provided no
alkyl group has been bound to the nitrogen-atom in the position (9). In the latter
case, only chloro-purines would result.

page_text: This discovery demonstrates that, contrary to the opinion hitherto entertained it is
immaterial, for the preparation of xanthines from uric acids, whether the nitrogen-
atoms (1) and (3) .e. those in the alloxan-ring, are alkylised or not.
material in this respect is that the nitrogen-atom (9) be not alkylised.
All that is
My foreign correspondents have, moreover, ascertained as a result of their
investigations that it is necessary to act upon the alkylised uric acid with phosphorus-
oxy-chloride alone in order to proceed to xanthines, and that this result cannot be
obtained if the phosphorus-oxy-chloride acts on the alkyl-uric acid in conjunction
with phosphorus-penta-chloride, for example. A comparison of the entirely and
essentially different results obtained by acting on the same alkyl-uric acid first with
phosphorus-oxy-chloride together with phosphorus-penta-chloride, according to the
methods heretofore known, and then with phosphorus-oxy-chloride alone, will serve
admirably to emphasize the essential features of the present invention.
Thus if, for example, 7-monomethyluric acid is submitted to the joint action
phosphorus-oxy-chloride and phosphorus-penta-chloride, the oxygen bound to the
alloxan-ring alone is replaced by chlorine, the resultant compound being 7-methyl-
8-oxy-2-6 dichloropurine :-

page_text: If, on the other hand, the phosphorus-oxy-chloride alone is caused to act upon the
3-7-dimethyluric acid, substitution of chlorine will again take place in the position (8)
instead of in the alloxan-ring, the chloroxanthine: 3-7-dimethyl-2.6-dioxy-8 chloro-
purine or chlorotbeobromine being formed:-
My foreign correspondents have found that the same result is obtained with other
alkyl-uric acids and, in general, this invention shows that the use of phosphorus-oxy-
chloride alone results in the production of chloro-xanthines when acting upon alkyl-
uric acids which have no alkyl-group bound to the N occupying the position (9)
while the treatment of such uric-acids with both phosphorus-penta-chloride and the
oxy-chloride would result in chloropurines which are not xanthine derivatives.
According to my foreign correspondents observations, intermediate products,
apparently containing phosphorus and chlorine, are at first formed when phosphorus-
oxy-chloride reacts upon alkylised uric acids, these intermediate bodies being
subsequently changed into chloroxanthines by treatment with suitable means, such
as alcohol or water, while phosphoric acid and hydrochloric acid are split off.
The chloroxanthines, obtained under this invention, are converted into higher
alkylised products by employing the alkylising methods which are in use in connection
with the uric acid and xanthine-series. Thus, for example, chloro-theobromine may
be obtained from 3-methyl-chloroxanthine on further methylation, the chloro-
theobromine being, in turn, readily susceptible of conversion into chloro-caffeine by
the same methods.
The chloro-xanthines are converted into the corresponding xanthines by reducing
methods.
It should be noted that under this invention other alkyl-radicals than the methyl-
group may be introduced into the xanthine-molecule. Thus the 3-methyl-chloro-
xanthine is readily converted into
3-methyl-1-7-diethyl-chloro-xanthine by
introducing the ethyl-radical into the former.
For the purposes of this invention it is immaterial whether the lower chloro-
In both ways the process
xanthines are first alkylised and then reduced or vice versa.
may be carried to the higher alkylised xanthines, such as caffeine.
This invention having for its object to obtain xanthines from uric acids, broadly
considered, consists in submitting alkylised uric acids, which, however, have no
alkyl group at the position (9), to the action of phosphorus-oxy-chloride and in
subsequently reducing and alkylising, or alkylising and reducing the resultant
compounds.
The following are examples according to this invention showing the best manner
of carrying the said invention into effect, but the invention is not limited to the
details herein set forth.

page_text: phosphorus-oxy-chloride and heated in a digester to from 130 to 140 degrees
Centigrade and maintained at this temperature for from 3 to 4 hours, the mass being
steadily agitated. The resulting clear reddish brown solution is then evaporated in
vacuo for the purpose of completely removing the phosphorus-oxychloride. The
brownish residue which has a tough varnish-like consistency, is, thereupon, brought
into solution by boiling the same with about 5 times its quantity of alcohol or
water.
The alcoholic solution, which at first is clear, but soon becomes turbid on account
of the precipitation of granular crystalline methyl-chloro-xanthine, is boiled for from
2 to 3 hours with reflux and then allowed to cool. Upon filtering, the methyl-chloro-
xanthine remains on the filter as a yellow granular crystalline mass. The filtrate is
then evaporated whereby a second crystallization ensues resulting in a further yield
of the above product, methyl-chloro-xanthine.
The crude product, so obtained, is brought into solution with dilute alkali, such
as 2% potash-lye, treated with animal charcoal or other decolorizing agent, and
finally precipitated with dilute sulphuric acid. On cooling, the new compound is
obtained in the form of yellow-hued coarse crystals, from whose analysis are obtained
figures, which show the formula of this compound to be C, H, N₁ O₂ Cl + H₂ O.
Its structural formula is found to be :
such formula being established by the fact of the ready conversion of this compound
into chloro-caffeine (see II, 1).
The tenaciously adhering yellow tint, which is very difficult of removal, has no
influence on the percentage composition of the product. Absolute decolouration of
the 3-methyl-8-chloroxanthine may be attained by thoroughly boiling it with a large
quantity (30 parts to one part) of acetone. The xanthine is thereby gradually
brought into solution, while the adhering colouring matter remains undissolved.
Upon cooling after such solution is effected, the methyl-chloro-xanthine crystallizes in
anhydrous, fine, colourless, shining, foliated crystals or scales.
3-methyl-chloro-xanthine is soluble in about 250 parts boiling water and, on cooling
the solution slowly, the same crystallizes therefrom in coarse needles, which under the
microscope are found to be elongated flat prisms and which contain one molecule of
water of crystallization. This water of crystallization escapes on protracted heating
at 1200 Centigrade.
It is difficult of solution in boiling alcohol, in acetone, acetic ether, benzol or
chloroforın but readily soluble in dilute alkalies, in ammonia and soda or potash
solutions. It is equally soluble in concentrated sulphuric acid and fuming hydro-
chloric acid. From a solution in the latter the original product is precipitated by
water on standing for some time.
Heated with chlorine-water or with dilute nitric acid it gives a strong murexide
reaction.
An ammoniacal solution of the same added to an ammoniacal silver-solution
yields a gelatinous silver-salt which remains unchanged on boiling.
3-methyl-chloro-xanthine has no melting point, but on being rapidly heated it
begins to turn yellow at 320° Centigrade, and at about 345° Centigrade it decomposes
with effervescence.

page_text: 2. PREPARATION OF 7 METHYL-2-6 DIOXY-8-CHLOROPURINE OR CHLORO-HETERO-
XANTHINE FROM 7 MONO-METHYL URIC. ACID.
One part by weight of dried and finely powdered 7 monomethyl-uric acid is added
to ten parts by volume of phosphorus-oxy-chloride and boiled for from 24 to 30 hours
with reflux. This treatment results in the solution of methyl uric acid, a clear,
slightly coloured liquor being formed.
This liquor is evaporated in vacuo and the tough, varnish-like residue is taken up
with warm alcohol. After boiling such solution a short time the chloro-hetero-
xanthine is thrown out in the form of a colourless crystalline mass, which is
separated by filtration. This product is not quite pure but is contamined with
some unchanged methyl-uric acid, which may be removed by boiling with much
acetone, which dissolves the chloro-heteroxanthine but not the methyl-uric acid.
The acetone solution is then evaporated and the resulting crystalline residue is taken
up with dilute ammonia, treated with decolourizing carbon and precipitated with
dilute sulphuric acid.
The 7-methyl-chloro-xanthine or chloro-heteroxanthine is thereby obtained in the
form of colourless short prismatic crystals, which give figures corresponding to the
formula C H N O₂ Cl. Its structural formula is :—
4
as is shown by its conversion into chloro-caffeine (see II., 1b).
That this new product is a xanthine-derivative is also corroborated by the fact that
it gives the murexide test with chlorine water or dilute nitric acid.
From boiling water, in which it is moderately soluble it crystallises in short needles
which are frequently aggregated in bunches. It is soluble with difficulty in alcohol
and acetone and with very great difficulty in benzol or chloroform. It is readily
taken up by dilute alkalies, ammonia and soda or potash (carbonates) solutions. An
ammoniacal solution of the same added to an ammoniacal silver solution gives
rise to a colourless silver-salt consisting of fine needles, which salt remains unchanged
on boiling.
Chloroheteroxanthine has no melting point, but on being heated rapidly it becomes
yellow at about 300° Centigrade, and is decomposed at about 340° Centigrade the
decomposition being attended by dark brown colouration and effervescence.
3. PREPARATION OF 3-7-DIMETHYL-2-6-DIOXY-8-CHLORO-PURINE OR CHLORO-
THEOBROMINE FROM 3-7-DIMETHYL-URIC ACID.
One part, by weight, of 3-7-dimethyl-urie-acid which has been reduced to the
finest possible powder is added to five parts, by volume, of phosphorus oxychloride
and the whole boiled with reflux until a clear solution is formed. This requires about
20 hours.
From the resulting liquid, which is slightly coloured, the unchanged phosphorus-
oxy-chloride is distilled off in vacuo and the residue is dissolved with alcohol. The

page_text: solution is then boiled. After a short time the chlorotheobromine, which has been
formed, begins to crystallize out of the solution.
The crystals are then separated by filtration and dissolved in dilute alkali and
treated with carbon for decolouration, whereupon the chlorotheobromine is thrown out
by dilute sulphuric acid.
The colourless product, so obtained, has the composition indicated by the formula
C. H. NO. Cl and the structure:—
The above structure is established by the ready and smooth conversion of this new
compound into chloro-caffeine, as described under Example II. 1c.
8. Chlorotheobromine heated with chlorine water or with dilute nitric acid gives
the murexide test.
On heating the same rapidly it melts at about 292°-293° Centigrade, to a slightly
coloured liquid which on cooling soon congeals to a crystalline mass.
about 250 parts of water on boiling.
It dissolves in
From such aqueous solution it is thrown out in the form of colourless vitreous,
shining, short prisms on cooling slowly and in the form of fine needles aggregated in
bunches, on cooling rapidly. It is only difficultly soluble in boiling alcohol. On the
other hand it is readily soluble in dilute alkalies and dilute warm ammonia.
solution of the same in soda lye its sodium salt is rapidly thrown out in the form of
fine acicular crystals by concentrated soda lye.
From a
If an ammoniacal solution of the same be added to an ammoniacal silver-solution
and the ammonia be removed by boiling, a gelatinous colourless silver-salt of the
chloro-theobromine is thrown out.
a. FROM 3-METHYL-CHLORO-XANTHINE.
One part, by weight, of 3-methyl-chloro-xanthine which has been already described,
is brought into solution with five and four tenths parts, by volume, of double-normal
potash lye (potassium hydrate) and equal parts of water and, after one and one half
parts, by weight, of methyl-iodide have been added thereto, the whole is heated to 90°
Centigrade in the pressure tube, and maintained at this temperature for from two to
three hours, the mass being constantly agitated.
The mass is then allowed to cool, when the greater portion of the chloro-caffeine,
which has been formed, is thrown out in the form of fine needles. The balance of the
chloro caffeine is obtained by extraction from the lyes, which have previously been
rendered slightly alkaline, by a suitable solvent, such as chloroform, for example.

page_text: The actual amount of chloro caffeine obtained corresponds to the theoretical yield.
It is fully purined on once recrystallising from water and has all the characteristic
properties found for chloro-caffeine by Emil Fischer (Annalen vol. 215 p. 263).
It is fully purined on once recrystan
ани
properties found for chloro-caffeine by Emil Fischer (Annalen vol. 215 p. 263).
b. FROM 7-METHYL CHLOROXANTHINE.
Three parts, by weight, of 7-methyl chloroxanthine or chloro-heteroxanthine, which
has been hereinbefore described, are dissolved in 18 parts, by volume, of double
normal caustic potash lye and 36 parts, by volume, of water and after adding thereto
five parts, by weight, of methyl iodide, the same is heated to 90° Centigrade in the
pressure tube, this temperature being maintained for two and a half hours, the mass
being constantly agitated.
After allowing the same to cool the resultant chloro-caffeine will be found to exist in
the tube in the form of a paste or pulp. It is isolated as set forth under (a).
In this case also the practical yield is equivalent to the theoretical, and the chloro
caffeine is obtained pure.
c. FROM CHLORO-THEOBROMINE.
The same treatment applied to dimethyl-chloro-xanthines, such as chloro-theobro-
mine, which is 3-7-dimethyl-2-6-dioxy-8-chloro-purine or 3-7-dimethyl-8-chloro-
xanthine will again result in the trimethyl-chloro-xanthine or chloro-caffeine.
If two parts, by weight, of the chloro-theobromine, which has been described under
head I, be dissolved in seven volumes of double normal potash lye (potassium
hydrate) and seven volumes of water and heated to 90° Centigrade under pressure
together with one and a half parts of methyl-iodide, this temperature being main-
tained for 3 hours and the liquid constantly agitated, the formation of chloro caffeine
will take place. The greater portion of the same is thrown out in the form of fine
acicular crystals after cooling, while the remainder is obtained by extraction with a
suitable vehicle, such as chloroform. Here again the theoretical and practical yield
are identical.
2: PREPARATION OF CHLOROTHEOBROMINE FROM 3-METHYL-CHLORO-XANTHINE.
.;
6 parts, by weight, of 3-methyl-chloroxanthine are dissolved in 18 parts, by volume,
of double normal caustic potash lye and 30 parts by volume of water. Seven and

page_text: two tenths parts of methyl sulphate of potassium are then added to the solution and
the whole is then heated to from 140° to 150° Centigrade under pressure, this
temperature being maintained for from 4 to 5 hours and the mass constantly
agitated.
Upon cooling the chlorotheobromine is separated out of the solution in the
form of coarse yellowish brown granular crystals. It is purified by redissolving and
crystallising out of alkalies, such as potash lye, and possesses all of the characteristic
properties as
well as the melting point of the chlorotheobromine described
under I³.
The reaction proceeds according to the equation :
3. PREPARATION OF 3-METHYL-1-7-DIETHYL-2-6-DIOXY-8-CHLOROPURINE FROM
3-METHYL-CHLOROXANTHINE.
Four parts, by weight, of 3-methyl-chloroxanthine are dissolved in 23 parts, by
volume of double-normal potash-lye and diluted with 20 parts, by volume of alcohol.
Six and one-half parts, by weight, of ethyliodide are then added and the whole is
boiled for from 3 to 4 hours with reflux. The mass is then allowed to cool when it
solidifies in the form of a pulp or fine felted needles. These are separated by filtra-
tion, re-dissolved in boiling water and re-crystallized therefrom. The fine acicular
crystals, so obtained, have the composition indicated by the formula CËHËN O̟₂ Cl or,
structurally expressed:
This new compound, with chlorine water, gives a strong murexide-reaction. Its
melting-point is 136° Centigrade it is moderately soluble in boiling and difficultly 25
soluble in hot water. It dissolves readily in hot alcohol, and in cold acetone or chloro-

page_text: REDUCTION OF THE HALOGEN-DERIVATIVES TO THE CORRESPONDING XANTHINES.
1. PREPARATION OF 3-METHYL-XANTHINE FROM 3-METHYL-CHLORO-XANTHINE.
If one part, by weight, of 3-methyl-chloro-xanthine, described under Example I',
is heated with ten times its weight of fuming hydriodic acid, a gradual solution and
reduction of the chloro-compound takes place which is attended by a liberation of
iodine. The heating at a temperature of 90° to 100° Centigrade is continued and
phosphonium-iodide added from time to time until a clear colourless solution is
formed.
The solution is then evaporated, whereby the iodohydrate of this new base is
thrown out in the form of coarse colourless prismatic crystals. After the evaporation
has been continued to complete dryness, the residue is taken up with water, which
causes the iodohydrate to be decomposed and the methyl-xanthine to be isolated in
the form of fine colourless needles. The practical yield corresponds to the
theoretical.
The base is re-crystallized from boiling water and so obtained in the form of fine
shining needles. Its formula is CH NO₂ or, structurally:
This new base, as a xanthine, gives a strong murexide-reaction only with chlorine
water, while if it is evaporated together with moderately concentrated nitric acid it
yields a slightly coloured residue, which is dissolved in strong potash-lye and thus
forms a clear deep-yellow solution.
It requires from 300 to 330 parts of boiling water to form a solution, but is readily
soluble in dilute alkalies and ammonia and also in concentrated sulphuric or
hydrochloric acid.
An ammoniacal solution of the same, when added to a solution of nitrate of silver,
gives rise to a colourless silver salt consisting of fine needles. This silver salt
dissolves in a large excess of ammonia on heating and remains unchanged on
boiling.

page_text: 4. PREPARATION OF 3-METHYL-1-7-DIETHYL 2-8-DIOXYPURINE.
This new body is obtained by reduction of 3-methyl-1-7-diethyl-2-6-dioxy-8-chloro-
purine or 3-methyl-1-7-diethyl-8-chloroxanthine, which has been described under
Example II³.
If one part, by weight, of this chloroxanthine be heated with ten parts, by weight,
of fuming hydriodic acid to 90° Centigrade a solution is speedily effected. The heat-
ing is then continued on a boiling water-bath until, with the addition of phosphonium-
iodide in sufficient quantity to take up the liberated iodine, a clear solution is formed.
This solution is then evaporated to dryness and the crystalline residue is taken up with
water and supersaturated with alkali. Through this treatment the new base separates
as a colourless oil which very soon congeals forming fine acicular crystals. The base
is then extracted with a suitable vehicle such as chloroform or ether, whereupon the
extract is evaporated and the colourless residue recrystallized from benzol.

page_text: From the benzol-solution, to which ligroine is preferably added, the 3-methyl-1-7-
diethyl-2-8-dioxypurine crystallises in the form of splendidly developed, vitreous
colourless prisms, whose analysis gives figures which correspond well to the formula
C10 H₁4 N O₂
As a xanthine, this new body with chlorine-water gives a strong murexide-reaction.
It melts at from 127° to 128° Centigrade. It is readily soluble in water, alcohol,
chloroform, benzol, ether and concentrated hydrochloric or sulphuric acid.
From an aqueous solution this mass is precipitated by concentrated alkaline lyes as
a colourless oil which soon solidifies to a crystalline mass.
ALAILATION
ATHINE
In preparing the higher alkylized xanthines from the chloro-xanthines, described
under I, it is not always necessary to first further alkylize the chloroxanthines and
then to reduce such higher alkylized products, as the order of these steps may be
equally well reversed by first reducing the chloro-xanthines and then alkylizing the
reduced products.

page_text: 3. As a new chemical compound: 3 methylchloroxanthine, having the formula
Cô Hà Nɩ O̟₂ Cl + N2O, which is difficult of solution in boiling alcohol, in acetone,
acetic ether, benzol or chloroform but readily soluble in dilute alkalies, in ammonia,
soda or potash solutions, soluble in concentrated sulphuric or fuming hydrochloric
acid, has no melting point, begins to turn yellow at about 320° Centigrade with
effervescence and crystallizes from boiling water or cooling in coarse needles, containing
one molecule of water of crystallisation which escapes on heating at 120° Centigrade.
4. The manufacture or production of xanthines and their derivatives, substantially
as hereinbefore described.
1000
JOHNSONS & WILLCOX,
47, Lincoln's Inn Fields, London, W.C., Agents.