Note: Descriptions are shown in the official language in which they were submitted.
~7~25~
C1 ~ ~ M
Cl C1
N ~ ~ catalvt1c ~ ~ N
C1 N ~ hydrogenation r' N
(2) ~ (3)
~3 1~3
NH2 NH3
catalvtic
hydrogenation C1 ~ N
b4 ~ (5)
¦,RO-alk ¦ RO-alk
NH2
N INH2 hydrogenation
(6) C (7~
~p
~2Z5~
E. C. Taylor, et al., J. Or~. Chem.. 36(21~, 3211 (1971)
describe preparation of 2-, ô-, and 9-substituted adenines (6)
accDrding to the following outline.
NH2 1 2
R ~ ~ _4 ~ R ~ I i
(1)
R'NH2 !S tep b
ll R'NH
R'NCR"
R ~ ~ Step c R
(4) (3)
[H~ ¦ Step d
¦ R ~ ~ ~ ,. ~N!
(5) (~
1~72Z5~
Reductive cleavage of compound (4) (step d) is thought to involve
initial hydrogenolysis of the furazan ring to give an intermediate
4-acylamino-5,6-diaminopyrimidine (5) which then spontaneously cvclizes
to adenine (6).
G. D. Hartman, et al., J. Org~ Chem. 43(;), 960 91978)
tescribe synthesis of a (2-chloro-6-fluorobenzyl)adenine (6) utilizing
a formylated 7-amino[1,2,5]thiadiazolo[3,4-d~pyrimidine intermediate (~I)
as set forth below.
NH2 NN2
N ~ / l
~ N ~ 7
NN2
(1) (2) Cl
RCN2NH2 ¦ R =
F
RC~. ~ CHO
NHCH2R
N HC02H 2
(4)
Raney Ni
(3)
r
CH
(5) (6)
1~7~Z5'~
Detailed Description of the Invention
Adenine derivatives prepared according to the invention
are characterized by structural Formula I numbered according
to the chemical nomenclature system employed herein.
XH2
For the purpose of this disclosure, the R substituent
represents an alkyl group of 1 to 6 carbon atoms inclusiye
including those having either straight or branched hydrocarbon
chains. Particularly preferred alkyl groups are those having
from 1 to 4 carbon atoms with the most preferred being n-propyl.
Other examples of suitable Cl-C6 alkyl groups include methyl,
ethyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl,
and the like.
The following flow chart illustrates the process of the
present invention for converting 7-amino-5-(methylthio)[1,2,5]
oxadiazoloE3,4-d]pyrimidine (IIaJ X = 0) and 7-amino-5-
(methylthio)-[1,2,5]thiadiazolo[3,4-d]pyrimidine (IIb, X = S)
to 2-alkoxy-9-cyclohexyladenines of Formula I.
--5--
~17~ZS'~
PROCESS ~LOW CHART
X- O, S
C6N13~Nz N ~ 5si
ll S~ep 1 1¦
CH3S N ~NH2 CH3S ~ ~ H _
(II) (111)
Step ~ ¦ Re~Uctive
1 frm~ latin
lH2 N~2
N ~ N Cyclization N ~ ~ ~'HCHO
~ ~Step 3
CH3S ~ ~ N ~ ~ ~ ~ CH3S N ~ H
(V) ~ (IV)
Step 4 ¦ Oxidation
NH2
N ~ ND~splacement
~ Step 5
3 2
(Vl) ~
--6--
~`
1~7225~
Diazolo starting materials of Formula II required for
the instant process are prepared as described by E.C. Taylor,
et al., supra. (IIa, X = 0) or according to the general method
of G.D Hartman, et al., supra. (IIb, X = S).
Step l of the process outlined above is carried out by
reacting the diazolo[3,4-d]pyrimidine intermediate (II, X = 0,
S) with from l to 2 mole equivalents of cyclohexylamine in an
aprotic inert solvent (i.e. a solvent non-reactive with com-
ponents of the reaction mixture under the reaction conditions
lO maintained) such as acetonitrile or N,N-dimethylformamide. The
reaction is preferably conducted at temperatures ranging from
about 20 to about 130. With the solvent acetonitrile, the
reaction is preferably carried out at reflux temperature whereas,
with N,N-dimethylformamide, room temperature is preferred.
In Step 2, reductive formylation of the diazole[3,4-d]-
pyrmidine intermediate III affords the formylaminopyrimidine
intermediate IV in yields ranging from 88 to 98%. In the case
of the oxadiazolo intermediate (III, X = 0) formylation is
preferably carried out by catalytic hydrogenation employing 10
20 palladium-on-carbon with formic acid as the solvent. In the
case of the thiadiazolo intermediate (III, X = S), formylation
is preferably carried out with Raney nickel employing formic
acid as solvent.
In Step 3, cyclization of the formylaminopyrimidine IV
25 is readily effected by heating it with an alkali metal base
such as sodium hydroxide or potassium hydroxide in aqueous
solution or a mixture of ethanol-water.
In Step 4, oxidation of the methylthio intermediate V to
the corresponding methyl sulfone VI is carried out with the suitable
-- 7 --
.
~, .~` .l
117Z25~
oxidizing agent such as meta-chloroperbenzoic acid and the
like. Conversion of V to the sulfone VI takes place vla the
methylsulfoxide intermediate, 6-amino-9-cyclohexyl-2-(methyl-
sulfinyl)purine which also provides similar yields of Formula
I adenine products when reacted with RO-alk according to
Step S.
The final Step (5) of the process wherein the
methylsulfonyl radical is displaced, is accomplished by heating
the methylsulfone intermediate VI with an alkoxide of the
formula RO-alk in alkanol solvent ~i.e., ROH) wherein alk is
sodium or potassium and R is as defined above.
As depicted above, the process of the present invention
for preparing an adenine derivative of Formula I comprises
consecutive steps of:
1) reacting a diazolo[3,4-d]pyrimidine of Formula II
wherein X is oxygen or sulfur
N _ X
N ~ (~I)
CH S ~ N ~ NH
with 1 to 2 equivalents of cyclohexylamine in
an inert reaction solvent at a temperature
ranging from 20-130 to produce the diazolo
[3,4-d]pyrimidine of Formula III wherein X is
oxygen or sulfur;
--8--
1172ZS;~
N X
CH35 ~N 1~H C~
2) reductively formylating III in 50-100% formic acid
employing, when X is oxygen, catalytic hydrogenation
with palladium-on-carbon catalyst or when ~ is sulfur,
Raney nlckel, to produce the formylated co~pound of
Formula IV;
NH2
J~, NHCHO
CH3S N ~
3) cyclizing IV with alkali metal hvdroxide to produce
the adenine derivative of Formula V;
NH2
CH35 ~
_ 9 _
~1~2ZS'~
4) oxidizing V in an inert solvant to produce sulfone
VI;
C~352 ~ ~ (Vl)
5) displacing the methylsulfone radical of VI with an
alkali metal alkoxide of the formula RO-alk wherein
alk represents sodium or potassium and R is 1 to 6
carbon atoms inclusive in an inert reaction solvant
to produce a 2-alkoxy-9-cyclohexyladenine of Formula I.
Representative examples of Formula I adenines provided by
the above process employing appropriate RO-alk reactants in
Step 5 are:
Ia. 9-cyclohexyl-2-n-propoxy-9H-adenine,
Ib. 9-cyclohexyl-2-ethoxy-9H-adenine, and
Ic. 9-cyclohexyl-2-n-butoxy-9H-adenine.
A preferred embodiment of the invention is directed to a
process for preparing 6-amino-9-cyclohexyl-2-(n-propoxy)purine
comprising consecutive steps of
reductively formylating 2-(cyclohexylamino)-5-
(methylthio)-[1l2,5]oxadiazolo[3,4-d]pyrimidine
in formic acid with palladium-on-carbon catalyst
to produce 4-amino-6-(cyclohexylamino)-5-
(formylamino)-2-(methylthio)pyrimidine;
--10--
'
~17~2S~
cyclizing 4-amino-h-(cyclohexylamino)-5-(formylamino)-
2-(methylthio~pyrimidine with an alkali metal base in
aqueous of alkanol solvent to produce 6-amino-9-
cyclohexyl-2-(methylthio)purine;
oxidizing 6-amino-9-cyclohexyl-2-(methylthio)purine
with m-chloroperbenzoic acid in an inert solvent (e.g.
acetic acid) to produce 6-amino-9-cyclohexyl-2-(methyl
sulfonyl)-purine; and
reacting 6-amino-9-cyclohexyl-2-(methylsulfonyl)purine
with sodium n-propoxide or potassium n-propoxide in n-
propanol to displace the methylsulfonyl radical and
produce 6-amino-9-cyclohexyl-2-(n-propoxy)purine.
The following examples further illustrate the present
invention and will enable those skilled in the art to under-
stand it more completely. All temperatures expressed herein
are in degrees centigrade.
EXAMPLE 1
7-Amino-5-(methylthio)[1,2,5~oxadiazolo[3,4-d]pyrimidine
(IIa)
~ - q
N ~
CH3S ~ N ~ 2
5
Methyl iodide (169.0 g., 1.19 mole) is added in one
portion to a stirred solution of 4,6-diaminopyrimidine-2(1H) thione (146
g., 1.02 mDle) in 1.0 liter IN sodium hydroxide. The thione starting
-- 11 --
, . '
~17225'~
material is obtained by reaction of thiourea and malononitrile
according to Kikugawa, et al., Chem. Pharm. sull~ 25(7?,
1811-1821(1977). In about five minutes following the addition
a precipitate forms. After stirring overnight, the reaction
mixture is filtered and air-dried affording 135.1 g. (81%)
of 4,6-diamino-2-(methylthio)-pyrimidine; m.p. 185-186
(recrystallized from acetonitrile).
Sodium nitrite (48.3g., 0.7 mole) added in one portion
to a stirred suspension of 4,6-diamino-2-(methylthio)pyrimidine
(95.0 g., 0.6 mole) in a mixture of 950 ml. water and 285 ml.
acetic acid forms a thick, blue slurry which is stirred for a
6 hr. period. The product is collected on a filter and oven
dried overnight to afford 108.5 g (97%) of 4,6-diamino-2-
(methylthio)-5-nitrosopyrimidine as a blue solid, m.p. 254-255.
Lead tetraacetate (221.0 g., 0.5 mole) is added in one
portion to a stirred suspension of 4,6-diamino-2-(methylthio)-
5-nitrosopyrimidine (89.0 g., 0.48 mole) in 2.4 liter acetic
acid. The reaction mixture is stirred for 1.5 days and the
yellow solid which forms collected by filtration with a second
crop isolated by partial concentration of the filtrate to
provide a total yield of 64.3 g. (73%) of 7-amino-5-(methyl-
thio)[1,2,5]oxadiazolo[3,4-d]pyrimidine, m.p. 240-243.
Crystallization from dimethylformamide-water followed by a
second crystallization from acetonitrile-water affords yellow
crystals of this material with melting point unchanged.
Anal. Calcd. for C5H5N50S; C, 32.78; H, 2-75; N, 38-23-
Found; C, 32.57; H, 2.73; N, 38.06.
-12-
1~72Z5~
EXAMPLE 2
7-(Cyclohexylamino)-5-(methylthio)
[1,2,5]oxadiazolo[3,4-d]pyrimidine (IIIa)
N
CH3S ~ ~ NH ~
A mixture of 7-amino-5-(methylthio)[1,2,5]oxadiazolo
[3,4-d]-pyrimidine (52.3g., 0.29 mole) and cyclohexylamine
(56.5g., 0.58 mole) in 175 ml. dry acetonitrile is heated at
reflux with stirring for a 2 hr. period during which time
ammonia evolution occurs and a solution slowly forms. After
cooling and filtering the solution, the filtrate is diluted
with acetonitrile to produce a yellow-green precipitate which
is collected on a filter and air-dried to yield 64.0 g. (86%)
of 7-(cyclohexylamino)-5-(methylthio~[1,2,5]oxadiazolo[3,4-d]
pyrimidine, m.p. 129-130. Crystallization from acetonitrile-
water affords analytically pure material of unchanged melting
point.
Anal. Cacld. for CllH15N5OS: C, 49.80; H,5.70; ~, 26.40.
Found: C, 49.80; H, 5.65; N, 26.21.
EXAMPLE 3
4,5,6-Triamino-2-(methylthio)pxrlmidine
NH2
- ~ ~ NH2
CH35 N~2
~ -13-
~7225'~
Sodium hydrosulfite (sodium dithionite, 78.3 g., 0.45
mole) is added in one portion to a stirred suspension of 4,
6-diamino-2-~methylthio)-5-nitrosopyrimidine (27.8g., 0.15
mole) in 300 ml. lN sodium hydroxide. Within a 15-20 minute
period, the temperature of the mixture increases to 60 with
concommitant foaming. The mixture is stirred for a 16 hr.
period, insolubles collected and washed well with water,
air-dried, and crystallized from acetonitrile to yield 19.73 g.
(76.8~) of 4,5,6-triamino-2-~methylthio)pyrimidine as yellow
10 crystals, m.p. 180-182.
EXAMPLE 4
7-Amino-5-(methylthio)[1,2,5]-
thiadiazolo[3,4-d]pyrimidine (IIb)
N S
~ ~N
CH3S N NH2
A mixture of 4,5,6-triamino-2-(methylthio)pyrimidine
(5.14 g., 0.03 mole) and thionyl chloride (32.12 g., 0.27 mole)
is refluxed with stirring for an 18 hr. period. Excess thionyl
chloride is removed under reduced pressure, 40 ml. of water
added to the residue and the suspension mixture adjusted to pH
8 with saturated sodium bicarbonate solution. Insolubles are
collected, washed with water and air-dried to provide 4.7 g.
25 (78.3%) of 7-amino-5-(methyl-thio)[1,2,5]thiadiazolo[3,4-d]
pyrimidine, m.p. 197-199.
Anal. Calcd. for C5H5N5S2: C, 30.15; H, 2.53; N, 35.15.
Found: C, 29.82; H, 2.40; N, 35.01
-14-
~7Z~S~
EXAMPLE 5
7-(Cyclohexylamino)-5-(methylthio)
[1,2,5]thiadiazolo[3,4-d]pyrimidine (IIIb)
---S
~,tl
CH3S ~ N ~ NH ~
A mixture of 7-amino-5-(methylthio)[1,2,5]thiadiazolo
20 [3,4-d]-pyrimidine (16.9 g., 0.085 mole) and cyclohexylamine
(34.0 g., 0.34 mole) is stirred and heated at 105-110 for a
20 hr. period. To the cooled reaction mixture is added 50 ml.
of water and 50 ml. of hexane. Insolubles are collected and
crystallized from hexane to give a material having two spots
on TLC (silica gel, CHC13-EtOH, 9:1). The material is
purified by column chromatography employing 180 g. silica gel
using chloroform as the eluent. All fractions showing a single
component on TLC (higher Rf spot) are combined and
concentrated in vacuo affording a solid which triturated with
hexane yields 9.75 g. (41%) of 7-(cyclohexylamino)-5-(methyl-
thio)[1,2,5]-thiadiazolo[3,4-d]pyrimidine, m.p. 134-136.
Anal- Calcd- for CllH15N5S2 C, 46-96; H~ 5-38; N~ 24-89-
Found: C, 46.98; H, 5.46; N, 24.90.
-15-
~k
3~7225~
EXAMPLE 6
4 Amino-6-(cyclohexylamino)-5-
(formylamino)-2-(methylthio)pyrimidine (IV)
NH2
~ NHCH0
ll
CH3S ~ N9~ NH ~
Method A.- 2-(Cyclohexylamino)-5-(methylthio)[1,2,5]oxa-
diazolo[3,4-d]pyrimidine (54.0 g., 0.20 mole) is hydrogenated
in 350 ml. 90% formic acid employing 5.0 g. of 10% palladium-
on-carbon as catalyst. After the reduction is complete (about
2.5 hr.), the catalyst is collected on a filter employing
diatomaceous earth and the filtrate concentrated in vacuo to
yield a viscous oil. Water is added to the residual oil and
the mixture made basic with concentrated ammonia or a solution
of 50~ sodium hydroxide. The resulting white solid is
filtered and air-dried yielding 50.2 g. (88%) of 4-amino-6-
(cyclohexylamino)-5-(formylamino)-2-(methylthio)pyrimidine.
Crystallization from chloroform-hexane affords analytically
pure material as white crystals, m.p. 200-201.
Anal. Calcd. for C12HlgN5OS.1/4H2O: C, 50.42; H,6.87;
N, 24.68. Found: C, 50.61; H, 6.80; N, 24.68.
NMR: 8.09 ppm, s, lH and 8.60, s, lH; NH-CHO; 5.86, m, 3H;
NH, NH6.
METHOD B.- Formic acid (90%, lOOml.) is added to a mixture of 7-
(cyclohexylamino)-5%(methylthio)[1,2,5]thiadiazolo[3,4-d]pyrimid~e
-16-
~7l
; .~1.
~7225'~
(3.82 g., 0.014 mole) and 15.28 g. Raney nickel. When the
reaction is complete as shown by disappearance of
starting material according to TLC (CHC13-EtOH, 9:1),
diatomaceous earth is added and the mixture filtered.
Concentration of the filtrate _ vacuo provides a residue
which is stirred with 50 ml. of ethanol and filtered. Concen-
tration of the filtrate in vacuo affords 4.46 g. (98%) of
4-amino-6-(cyclo-hexylamino)-5-(formylamino)-2-(methylthio)
pyrimidine formate salt as a thick oil which can be used in
Example 7 without further purification.
EXAMPLE 7
6-Amino-9-cyclohexyl-2-(methylthio)purine (V)
NH2
CH35 N N
.~
A solution of 4-amino-6-(cyclohexylamino)-5-(formylamino)
-2-(methylthio)pyrimidine (25.0 g., 0.088 mole) or a mole
equivalent to the formate salt thereof in 125 ml. ethanol and
500 ml. lN sodium hydroxide is refluxed for a 4 hr. period,
cooled in an ice-bath, and then filtered affording 14.1 g.
(61%) of yellow material. Crystallization from ethanol gives
6-amino-9-cyclohexyl-2-(methylthio)purine as off-white crystals,
m.p. 222-224.
Anal. Calcd. for C12H17N5S: C, 54.73; H, 6.51; N, 26.59.
Found: C, 54.62; H, 6.72; N, 26.63.
-17-
~72ZS~
EXAMPLE 8
6-Amino-9-cyclohexyl-2-(methylsulfonyl)purine (VI
CH3502 J~N ~N ~
A solution of approximately 80~ pure m-chloroperbenzoic
acid t430 g., 2.0 mole) in 540 ml. of ethanol is added drop-
wise over a 1 hr. period to a solution of 6-amino-9-cyclohexyl
-2-(methylthio)-purine (250 g., 0.95 mole) in 1.2 liter of
acetic acid while maintaining a reaction temperature of 35-40.
Following the addition, the reaction mixture is stirred for
0.5 hr., mixed with 6 liter of water with rapid stirring and
then filtered. The filter-cake is first washed with water
and then suspended in 5 liter of water. Concentrated
potassium hydroxide is added to this suspension with vigorous
stirring until the mixture is strongly basic. Suspended
material is then collected, washed with water and air-dried
20 to provide 248 g. (88.6%) of 6-amino-9-cyclohexyl-2-
(methylsulfonyl)purine, m.p. 272-274.
EXAMPLE 9
6-Amino-9-cyclohexyl-2-(n-propoxy)purine (Ia)
NH2
n-C3~7-0 1 ~
..L i~,
~72ZS~
6-Amino-9-cyclohexyl-2-(methylsulfonvl)purine (61 g., 0.207
mole) is added in one portion to 0.414 mole of sodium n-propoxide in
800 ml. of n-propanol. The mixture is refluxed for a 6 hr. period
and then concentrated under reduced pressure. Stirring the residual
oily material with water provides a solid which is collected and
crystallized from acetonitrile-wacer yielding ;3 g. (93~,) of 6-amino-
9-cyclohexyl-2-(n-propoxy)purine, m.p. 146-148.
- 19 -
