Improvements in the Manufacture or Preparation of Amino-Derivatives of Purine.
Year: 1897

page_text: Date of Application, 9th Aug., 1897.
Complete Specification Left, 26th Apr., 1898--Accepted, 9th July, 1898
PROVISIONAL SPECIFICATION.
Improvements in the Manufacture or Preparation of
Amino-Derivatives of Purine.
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 :-
:-
Aminocaffeïne is the only purine derivative known in which the amino group occurs
as substituent (Liebig's Annalen, 215, 265).
This derivative contains the substituent group in the paraban-ring of the purine
molecule (E. Fischer; Ber., d.d. Chem. Ges. XXX. 553).
The amino derivative has not yet been prepared containing the substituent group
in the alloxan-ring.
It has now been found, by my foreign correspondents, that the halogen atoms in
the alloxan-ring of purine are capable of being replaced by ammonia when heated
with that agent.
In this way a series of new amino derivatives of purine has been prepared, which
is represented in accordance with the system of nomenclature put forward by E.
Fischer (Ber d.d. Chem Ges XXX 557)
In the case of the purine derivatives hereinafter described, the substituent amino-
group is attached to carbon atom (2) or (6) of the purine molecule.
The amino purines are crystalline products, which generally yield well crystallized
salts in consequence of their basic properties; just, as in the case of guanine, their
amino-groups are replaceable by hydroxyl under the influence of nitrous acid.
The following examples explain the process further. The parts are by weight.
EXAMPLE 1.
PREPARATION OF 3:7-DIMETHYL-6-AMINO 2: 8-DIOXYPURINE FROM 3:7-DIMETHYL
6-CHLORO-28-DIOXYPURINE.
7 parts of dimethyldioxychloropurine (Ber. d.d. Chem. Gesell. 28, 2486), which,
according to the recent researches of E. Fischer, has the structural formula herein-
after ascribed to it, is heated for 3 hours at 130° Centigrade in an autoclave with
50 parts. of ammonia (saturated at 0° Centigrade). A considerable quantity of
Price R71

page_text: the ammonium salt of the amino-derivative separates out on cooling. Without
filtration, however, the liquid is evaporated to drive off ammonia, and the residue
is extracted with cold water. Under this treatment, the new base remains behind
as a greyish-green mass, which, for further purification, is dissolved in hot, dilute
hydrochloric acid, and precipitated from the hot solution by sodium acetate.
The yield amounts to 70 per cent. of the chloro-compound employed.
The new base, which constitutes an almost colourless, crystalline powder, has
the formula C,H,N, O., and is produced according to the equation.
The base decomposes at high temperatures with production of carbon. It is
practically insoluble in hot water, dissolves with great difficulty in boiling alcohol,
and is insoluble in chloroform.
Mineral acids give rise to stable salts; the aurochloride is obtained in slender
yellow needles from hot dilute hydrochloric acid, or in red plates when separation
is slow.
The base dissolves very readily in dilute alkalies, the concentrated agents
precipitating the corresponding alkali derivative in small, slender needles.
The amino-derivative is readily soluble in warm, aqueous ammonia, but is
precipitated again on boiling off the ammonia.
Warm dilute nitric acid quickly decomposes the base, with liberation of gas.
EXAMPLE 2.
PREPARATION OF 6-AMINO-8-OXY-2-CHLOROPURINE FROM 2: 6-DICHLORO-8-OXYPURINE.
1 part of oxy-dichloropurine is heated for six hours at 150° Centigrade in an
autoclave with 25 parts of alcoholic ammonia-consisting of equal volumes of
alcoholic ammonia, saturated at 0° Centigrade, and absolute alcohol.
On cooling, a reddish yellow, crystalline mass separates out, consisting of
spherical aggregates, and comprising the greater part of the amino-derivative. This
is converted into the hydrochloride, by treatment with 60 parts of a boiling,
13 per cent. solution of hydrochloric acid.
On cooling the hydrochloride separates in pale yellow needles.
The free base is obtained by saturating the aqueous suspension of the salt with
ammonia.
For complete purification, it is best to convert the base into the barium derivative
by treating one part of the base with 2 parts of crystallised barium hydrate and
70 parts of boiling water. As the liquid cools the barium derivative separates in
long, slender, colourless needles.
Acetic acid liberates the base from the hot aqueous solution of the barium
derivatives, in small, fibrous needles. It has the formula C,H,N,C10, and is
produced in accordance with the equation

page_text: If the oxydichloropurine used in Example 2 be heated at 150° Centigrade with
aqueous, instead of alcoholic, ammonia both halogen atours are replaced by amino-
groups.
9 parts of dichloroxypurine are heated for 4 hours at 150° Centigrade in an
autoclave with 90 parts of 14 per cent. aqueous ammonia. When the liquid cools,
the base separates out in pale yellow, crystalline leaflets, and may be purified by
conversion into the bydrochloride. The base is liberated from the latter by
ammonia, and is thus obtained in long, colourless needles; it has the formula
CHNO, and is produced according to the equation

page_text: The yield amounts to more than 95 per cent. of that required by theory.
For complete purification, the base is dissolved in about 200 parts of boiling
alcohol; on cooling the concentrated liquid, stellar aggregates of microscopic
needles are deposited, giving numbers which agree with the formula C,H,NC₁₂.
The base is produced according to the equation :——
5
The compound has no melting point, but gradually decomposes above 300°
Centigrade. It requires more than 2000 parts of hot water to completely dissolve
it, and crystallises in microscopic needles when the solution cools.
About 200 parts of hot alcohol are required to dissolve it.
The compound is only a feeble base and consequently is taken up with difficulty
by dilute mineral acids.
It dissolves freely in 15 per cent. hot hydrochloric acid and in 25 per cent. nitric, or
sulphuric acids. The corresponding salts crystallisc out as the liquids cool.
Decomposition occurs when the substance is boiled for some time with dilute acids.
It dissolves readily in dilute alkalies the concentrated agents precipitating the
corresponding alkali derivatives in slender needles.
The ammonium salt decomposes when boiled, and yields, with silver nitrate a
colourless amorphous precipitate, which is stable when heated and dissolves
sparingly in excess of ammonia.
.
The constitution of the base is indicated by its conversion into adenin.
EXAMPLE 5.
PREPARATION OF 7 METHYL-2-AMINO-6-CHLOROPURINE FROM 7 METHYL-2: 6-
DICHLOROPURINE.
5 parts of methyldichloropurine are heated for 3 hours at 85-90° Centigrade in
closed vessels with 200 volumes of alcoholic ammonia half saturated at ordinary
atmospheric temperatures. At the commencement it is advantageous to agitate
the mass. When the operation is complete, the liquid is evaporated without
filtration, and the residue is dissolved in boiling water. On cooling the base
separates out in small, slender white needles and forms a paste with the solvent.
The compound is produced according to the equation.

page_text: The new base is to be regarded as 7-methyl-2-amino-6-chloropurine, the proof
of the position of the amino-group being afforded by the production of guanidine
when 7-methyl-2-amino-6-oxypurine, obtained from the base is decomposed.
The base melts and evolves gas at about 276° Centigrade, and dissolves in
about 70 parts of boiling water; cold water and hot alcohol dissolve it with
great difficulty.
It dissolves readily in mineral acids, forming well crystallised salts.
Methyldiaminopurine melts and completely decomposes at about 385°
Centigrade. It dissolves in about 90 parts of boiling water, and is very sparingly
soluble in alcohol; it forms well crystallised salts, from solutions of which
alkalies and ammonia precipitate the base.
A solution of the substance in nitric acid gives immediately, with silver nitrate,
a colourless precipitate which crystallises from warm nitric acid in small blunt
needles.
PREPARATION OF
EXAMPLE 7.
7-METHYL-2-AMINO-6-OXYPURINE
OXYPURINE.
FROM
7-METHYL-2-CHLORO-6-
7-methyl-2-chloro-6-oxypurine is heated for 6 hours at 150° Centigrade with 12
parts of ammonia saturated at 50 Centigrade. Without previous filtration the solu-
tion, when cold, is evaporated to dryness, and the residue is extracted with cold
water, dissolved in dilute caustic soda, and precipitated with acetic acid. The
amorphous precipitate which is thus thrown down, changes, when heated for some
time on the water-bath, into a voluminous crystalline mass, which is recrystallised
from hot water. The slender needles obtained in this way give numbers agreeing
with the formula C₂H,N₂O.

page_text: The base decomposes above 400° Centigrade, and requires protracted treatment
with 900 parts of boiling water to dissolve it; it dissolves with great difficulty in
alcohol.
It forms well crystallised salts with mineral acids, and dissolves readily in cold
dilute alkalis: In warm, dilute ammonia it dissolves with difficulty.
Silver nitrate gives rise to a colourless, gelatinous precipitate in an ammoniacal
solution; with the solution in nitric acid, the same agent yields an amorphous
precipitate, which crystallises from hot, dilute nitric acid in slender needles.
When oxodised with chlorate of potassium and hydrochoric acid the base yields
guanidine.
atto
day of August 1897.
JOHNSONS & WILLCOX,
47, Lincoln's Inn Fields, London, W.C., Agents.
Improvements in the Manufacture or Preparation of
Amino-Derivatives of Purine.
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) and in what manner the same is to be
performed to be particularly described and ascertained in and by the following
statement :-
Aminocaffeine is the only purine derivative known in which the amino-group
occurs as substituent (Liebig's Annalen, 215, 265).
This derivative contains the substituent group in the paraban-ring of the purine
molecule (E. Fischer; Ber. d. d. Chem. Ges. XXX. 553).
The amino-derivative has not yet been prepared containing the substituent group
in the alloxan-ring.
It has now been found, by my foreign correspondents, that the halogen atoms in the
alloxan-ring of purine are capable of being replaced by ammonia when heated with
that agent.

page_text: In this way a series of new amino-derivatives of purine has been prepared, which is
represented in accordance with the system of nomenclature put forward by E. Fischer
(Ber. d.d. Chem. Ges. XXX. 557).
In the case of the purine derivatives hereinafter described, the substituent
amino-group is attached to carbon atom (2) or (6) of the purine molecule.
The amino-purines are crystalline products, which generally yield well crystallised.
salts in consequence of their basic properties; just, as in the case of guanine, their
amino-groups are replaceable by hydroxyl under the influence of nitrous acid.
The following examples explain the process further. The parts are by weight.
EXAMPLE 1.
PREPARATION OF 3:7-DIMETHYL-6-AMINO-2: 8-DIOXYPURINE FROM 3: 7-DIMETHYL-
6-CHLORO-2: 8-DIOXYPURINE.
7 parts of dimethyldioxychloropurine (Ber. d.d. Chem. Gesell., 28, 2486), which,
according to the recent researches of E. Fischer, has the structural formula
hereinafter ascribed to it, is heated for 3 hours at 130° Centigrade in an autoclave
with 50 parts of ammonia (saturated at 0° Centigrade). A considerable quantity
of the ammonium salt of the amino-derivative separates out on cooling. Without
filtration, however, the liquid is evaporated to drive off ammonia, and the residue
is extracted with cold water. Under this treatment the new base remains behind
as a greyish-green mass, which, for further purification, is dissolved in hot, dilute
hydrochloric acid, and precipitated from the hot solution by sodium acetate.
The yield amounts to 70 per cent. of the chloro-compound employed.
The new base, which constitutes an almost colourless, crystalline powder, has the
formula C,H,NO2, and is produced according to the equation.
The base decomposes at high temperatures with production of carbon. It is
practically insoluble in hot water, dissolves with great difficulty in boiling alcohol,
and is insoluble in chloroform.

page_text: Mineral acids give rise to stable salts; the aurochloride is obtained in slender
yellow needles from hot dilute hydrochloric acid, or in red plates when separation
is slow.
The base dissolves very readily in dilute alkalies, the concentrated agents
precipitating the corresponding alkali derivative in small, slender needles.
The amino-derivative is readily soluble in warm, aqueous ammonia, but is
precipitated again on boiling off the ammonia.
Warm dilute nitric acid quickly decomposes the base, with liberation of gas.
EXAMPLE 2.
PREPARATION OF 6-AMINO-8-OXY-2-CHLOROPURINE FROM 2: 6-DICHLORO-8-OXYPURINE.
1 part of oxydichloropurine is heated for 6 hours at 153° Centigrade in an
autoclave with 25 parts of alcoholic ammonia-consisting of equal volumes of
alcoholic ammonia, saturated at 0° Centigrade, and absolute alcohol.
On cooling, a reddish yellow, crystalline mass separates out, consisting of
spherical aggregates, and comprising the greater part of the amino-derivative. This
is converted into the hydrochloride, by treatment with 60 parts of a boiling,
13 per cent. solution of hydrochloric acid.
On cooling the hydrochloride separates in pale yellow needles.
The free base is obtained by saturating the aqueous suspenion of the salt with
ammonia.
For complete purification, it is best to convert the base into the barium derivative
by treating one part of the base with parts of crystallised barium hydrate
and 70 parts of boiling water. As the liquid cools the barium derivative separates
in long, slender, colourless needles.
Acetic acid liberates the base from the hot aqueous solution of the barium
derivative, in small, fibrous needles. It has the formula C,H,N, CIO, and is
produced in accordance with the equation.

page_text: Dry trichloropurine is heated with 10 parts of aqueous ammonia saturated at
ordinary atmospheric temperatures for 6 hours at 100° Centigrade in an autoclave;
in this way one chlorine atom is replaced by the amino-group.
When cold, the ammoniacal liquid is evaporated to dryness, the residue extracted
with warm water, and the amino-compound remaining undissolved is filtered
off.
The yield amounts to more than 95 per cent. of that required by theory.
For complete purification, the base is dissolved in about 200 parts of boiling
alcohol, on cooling the concentrated liquid, stellar aggregates of microscopic
needles are deposited, giving numbers which agree with the formula C, H, N, Cl.
The base is produced according to the equation :-
NC CI
NH
-
N = C – NH,
NH
KEB
CI.C
N – C – NH
C.Cl
+2NH,=C1.C
5
+ NH.Cl.
C.CI
The compound has no melting point, but gradually decomposes above 300°
Centigrade. It requires more than 2000 parts of hot water to completely dissolve
it, and crystallizes in microscopic needles when the solution cools.
About 200 parts of hot alcohol are required to dissolve it.
The compound is only a feeble base and consequently is taken up with difficulty
by dilute mineral acids.
It dissolves freely in 15 per cent. hot hydrochloric acid, and in 25 per cent. nitric,
or sulphuric acids. The corresponding salts crystallize out as the liquids cool.
Decomposition occurs when the substance is boiled for some time with dilute
acids. It dissolves readily in dilute alkalies, the concentrated agents precipitating
the corresponding alkali derivatives in slender needles.

page_text: The ammonium salt decomposes when boiled, and yields, with silver nitrate, a
colourless, amorphous precipitate, which is stable when heated, and dissolves
sparingly in excess of ammonia.
The constitution of the base is indicated by its conversion into adenin.
PREPARATION OF 7-METHYL-2-AMINO-6-CHLOROPURINE FROM 7-METHYL-2: 6-DICHLORO-
PURINE.
5 parts of methyldichloropurine are heated for 3 hours at 85-90° Centigrade in
closed vessels with 200 volumes of alcoholic ammonia half saturated at ordinary
atmospheric temperatures. At the commencement it is advantageous to agitate the
mass. When the operation is complete, the liquid is evaporated without filtration, and
the residue is dissolved in boiling water. On cooling the base separates out in
small, slender white needles and forms a paste with the solvent.
The compound is produced according to the equation
The new base is to be regarded as 7-methyl-2-amino-6-chloropurine, the proof of
the position of the amino- group being afforded by the production of guanidine
when 7-methyl-2-amino-6-oxypurine, obtained from the base, is decomposed.
The base melts and evolves gas at about 276° Centigrade, and dissolves in about 20
70 parts of boiling water; cold water and hot alcohol dissolve it with great
difficulty.
It dissolves readily in mineral acids, forming well crystallized salts
PREPARATION OF 7-METHYL-2: 6-DIAMINO-PURINE FROM 7-METHYL-2: 6-DICHLORO-
PURINE.
If 2 parts of methyldichloropurine be heated with 40 parts of 14 per cent. aqueous
ammonia for 4 hours at 160° Centigrade the diamino-compound separates out in
slender needles on cooling. After remaining for several hours the crude product is
filtered off, and re-crystallized from 90 parts of boiling water.
When the liquid cools slowly, the diamino-base separates in small, compact
crystals, which give numbers agreeing with the formula C, H₂ No.
8

page_text: Methyldiaminopurine melts and completely decomposes at about 385° Centigrade.
It dissolves in about 90 parts of boiling water, and is very sparingly soluble in
alcohol; it forms well crystallized salts, from solutions of which alkalies and
ammonia precipitate the base.
A solution of the substance in nitric acid gives immediately, with silver nitrate, a
colourless precipitate, which crystallizes from warm nitric acid in small, blunt
needles.
EXAMPLE 7.
PREPARATION OF 7-METHYL-2-AMINO-6-OXYPURINE FROM 7-METHYL-2-CHLORO-6-
OXYPURINE.
7-methyl-2-chloro-6-oxy-purine is heated for 6 hours at 150° Centigrade with 12
parts of ammonia saturated at 5° Centigrade. Without previous filtration the
solution, when cold, is evaporated to dryness, and the residue is extracted with cold
water, dissolved in dilute caustic soda, and precipitated with acetic acid. The
amorphous precipitate which is thus thrown down, changes, when heated for some
time on the water bath, into a voluminous, crystalline mass, which is recrystallized
from hot water. The slender needles obtained in this way give numbers agreeing
with the formula C, H, N, O.
The base is produced according to the equation

page_text: with 900 parts of boiling water to dissolve it; it dissolves with great difficulty in
alcohol.
It forms well crystallized salts with mineral acids, and dissolves readily in cold
dilute alkalis. In warm, dilute ammonia it dissolves with difficulty.
Silver nitrate gives rise to a colourless, gelatinous precipitate in an ammoniacal
solution. With the solution in nitric acid, the same agent yields an amorphous
precipitate, which crystallizes from hot, dilute nitric acid in slender needles.
When oxidised with chlorate of potassium and hydrochloric acid the base yields
guanidine.
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 amino-purine derivatives by causing
ammonia to act upon a chlorine derivative of purine having chlorine bound to the
alloxan-nucleus.
2. As new chemical compounds amino-purine derivatives which are distinguished
by having the amino-radical bound to the alloxan-nucleus of the purine residue.
Apri
JOHNSONS & WILLCOX,
47 Lincoln's Inn Fields, London, W.C., Agents.