Improvements in the Manufacture or Preparation of Derivatives of Purine containing Sulphur.
Year: 1898

page_text: Date of Application, 25th Feb., 1898-Accepted, 28th May, 1898
COMPLETE SPECIFICATION.
Improvements in the Manufacture or Preparation of Derivatives
of Purine containing Sulphur.
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:-
It has been shewn by E. Fischer that single halogen atoms in halogen substitu-
tion compounds of purine may be replaced by hydroxyl under the influence of
alkalies.
For example, 7-methyltrichloropurine (Berichte d. d. chem. Gesell. 28, 2488),
7-methyl-2 6-dichloropurine (Ber. d. d. c. G. 30, 2406), trichloropurine
(Ber. d. d. c. G. 30 2227), chloro-caffeine, and bromo-theobromine, readily lose
halogen by the action of caustic alkali, and pass into the corresponding oxypurine.
My foreign correspondents have found that the halogen substitution compounds
of purine also react easily with alkali hydrosulphides, with formation of
compounds of purine containing sulphur, so-called thio-purines, corresponding to
the oxypurines.
The exchange of halogen for the H S-group is effected without difficulty by the
action for instance of potassium hydrogen sulphide, and takes place with appreciably
greater readiness than does the replacement of halogen by hydroxyl. It is, for
example, a simple matter to produce thio-xanthine from bromoxanthine, whereas
the corresponding oxypurine, i.e., uric acid, has not been yet obtained from
bromoxanthine (Berichte d. d. chem. Ges. 28, 2486).
As in the case of the oxypurines (Liebig's Annalen, 228, 166, Berichte, d. d.. c. G.
30, 550) so also as regards the constitution of the thiopurines, there is offered the
choice between the tautomeric formulæ
The first of these formulæ has the advantage, because it has been shewn that
many sulphur derivatives of similar ring systems contain the mercaptan group,
and because in this case also, on methylating in solution, the alkylic group does
not become attached to nitrogen, as generally happens in the case of oxypurines,
but combines with sulphur. The other thiopurines will be formulated in the same
way.
According to the conditions of experiment, one, two, or three halogen atoms in
the di- or tri-halogen derivatives of purine, may be substituted by the mercapto-

page_text: group; the thio-chloropurines first produced exhibit, in their behaviour towards
various re-agents, close similarity to the chloroxypurines.
:
For instance, the chlorine atom in 7-methyl-6-thio-2-chloropurine, obtained
from 7-methyl 2 6-dichloropurine, may be easily replaced by hydrogen,
hydroxyl, ethoxyl etc. just as in the case of 7-methyl-6-oxy-2-chloropurine
(Berichte d. d. c. G. 30, 2400).
The following examples serve to further explain the invention. The parts are
by volume.
I. PREPARATION OF 7-METHYL-6-THIO-2-CHLOROPURINE FROM 7-METHYL-2: 6-
DICHLOROPURINE.
On agitating 5 parts of finely powdered methyldichloropurine with 60 parts of a
normal solution of potassium hydrogen sulphide (prepared from normal, caustic
potash by saturation with hydrogen sulphide) a vigorous evolution of sulphuretted
hydrogen occurs, a clear solution being produced in from 10 to 15 minutes and
indicating the end of the reaction. On saturating the clear yellow solution with
Colourless precipitate,
hydrochloric acid, methylthioctioropurine separates
which is filtered on cooling and washed with water.
23
In order to purify the substance, it is dissolved in about 800 parts of boiling
alcohol, the solution being evaporated at about 30° Centigrade in vacuum to one
quarter its bulk, and then rapidly cooled.
Slender, pale yellow needles crystallise out, generally aggregated in cubes. When
dried at 100° Centigrade, they give figures corresponding to the formula
hydrochloric acid, methyπumocnioropurine separates
which is filtered on cooling and washed with water.
2
PAPAN)
In order to purify the substance, it is dissolved in about 800 parts of boiling
alcohol, the solution being evaporated at about 30° Centigrade in vacuum to one
quarter its bulk, and then rapidly cooled.
Slender, pale yellow needles crystallise out, generally aggregated in cubes. When
dried at 100° Centigrade, they give figures corresponding to the formula
C*H*N*SCI,
being produced in accordance with the equation.
N = C.CI
N = C.SH
<B:<E:
CH
+ KSH CL.C
+ KCl.
CH
N-C-N'
7 methyl-6-thio-2-chloropurine has no definite melting point; it begins to turn
brown towards 250° Centigrade, and decomposes as the temperature rises. It is
considerably less soluble in water than in alcohol, and dissolves with great
It dissolves readily in
difficulty in ether, acetone, benzene and chloroform.
dilute alkalies, the salts being precipitated from these solutions by concentrated
alkalies.
The ammonium salt also dissolves readily in water, and yields a gelatinous
precipitate with silver nitrate which becomes black when boiled. The compound is
rapidly decomposed by potassium chlorate and hydrochloric acid, but does not give
murexide reaction on evaporation.
The behaviour of methylthiochloropurine towards nitric acid is characteristic.
It dissolves readily at the ordinary temperature in acid of specific gravity: 1.4, a
dark brown colouration being temporarily produced, and small lustrous crystals
being precipitated on dilution with a little water.
Methylthiochloropurine dissolves freely in warm concentrated hydrochloric acid;
at higher temperatures the hydrochloric acid acts as in the case of chloropurines
which do not contain sulphur replacing oxygen by chlorine. Simultaneously
however, the sulphur is in part eliminated by the halogen.
Methylthiochloropurine is reduced by the action of fuming hydriodic acid

page_text: (specific gravity = 1.96) to 7-methyl-6-thiopurine, C,H,N,S, which forms
colourless prisms melting at 306-307° Centigrade; this is readily alkylated in
solution in aqueous alkali, yielding 7-methyl-6-methylthiopurine, CH₂NS
forming tough, colourless needles inelting at 207-208° Centigrade, whilst
oxidation with dilute nitric acid converts it into 7 methyl-6-hydroxypurine, which
has been previously described (Ber. d. d. c. G. 30, 2409).
The production of this substance establishes the constitution of 7-methyl-6-thio-
2-chloropurine.
On heating 1 part of the chloro-compound with 24 parts of a normal solution
of potassium hydrogen sulphide in sealed tubes at 100° Centigrade, both chlorine
atoms become replaced by the thio-group. After being heated for 3 hours the
reaction is finished.
On acidifying the clear yellow solution, methyl-dithiopurine separates as a
thick, pale yellow crystalline precipitate.
It is purified by conversion into the barium salt. This is obtained in colourless,
slender needles from the solution in water, from which also dimethylthiopurine is
obtained as an almost colourless powder on acidification with hydrochloric acid,
consisting of whetstone like forms.
When dried at 110° Centigrade it gives figures agreeing with the formula
CHNS and has the constitution

page_text: :
4. 2 6-dioxy-8-thiopurine from bromo-xanthine, a pale yellow, crystalline
powder, containing one molecular proportion of water of crystallisation; it chars
at high temperatures without melting.
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 :-
The manufacture or preparation of derivatives of purine containing sulphur
(so-called thio-purines) by treating the halogen substitution compounds of purine
with alkali hydrosulphide.
ebruary 1898.
JOHNSONS & WILLCOX,
47, Lincoln's Inn Fields, London, W.C., Agents.