Journal of Medicinal Chemistry is published by theAmerican Chemical Society. 1155 Sixteenth StreetN.W., Washington, DC 20036
The Synthesis of 6-Fluoro-9-methylpurine
Alden G. Beaman, and Roland K. Robins
J. Med. Chem.
,
1962
, 5 (6), 1067-1074• DOI:10.1021/jm01241a001 • Publication Date (Web): 01 May 2002
Downloaded from http://pubs.acs.org on April 8, 2009
More About This Article
The permalinkhttp://dx.doi.org/10.1021/jm01241a001provides accessto:•Links to articles and content related to this article•Copyright permission to reproduce figures and/or text from thisarticle
Journal
of
MEDICINAL AND PHARMACEUTICALCHEMISTRY
@
Copyright
2080
b
:he
Volume
5,
Number 6
American
Chmical
k!ociety
November 27, 1962
The Synthesis
of
6-Fluoro-9-methylpurine*
XLDEK
G.
BEAMAX
nd
ROLAND
<.
ROBINS
Departitlent
of
Chemistry, Arizona
State
University, Tempe,
Arizona
Received May
8,
1961
4,li-L)ichloro-5-nitropyrimidide
I),
pon treatment with silver fluoride, gave
4,6-difluoro-5-nitropyrimidine
(11)
which was monoaminated and reduced
to
yield
4.5-dianiino-6-fluoropyrimidine
IV).
This substance failed
to
cyclize to
6-
fluoropurine
by
standard cyclization procedures. Reduction
of
4,6-difluoro-5-nitropyrimidine
(11)
yielded
5-amino-4,6-difluoropyrimidine
(VII),
and
VI1
withmethylamine gave
5-amino-6-fluoro-4-methylaminopyrimidine
VIII)
which wasreadily cyclized
to
6-fluoro-9-methylpurine
(X).
The chemistry
of
X
is
dib-cussed.
The clinical success
of
the use of 6-chloropurine in the treatmentofchronic granulocytic leukemia'" has stimulated the preparation
of
other 6-halogenated purines.
6-Chlor0-9-methylpurine~~
nd other9-alkyl-6-chloropurines have exhibited significant antitumor activityin experimental mice.lc The antitumor actionofB-chl~ropurine,'~-~6-hromopurine,1h and 6-iodopurinelh strongly suggests that 6-fluoro-purine and derivatives thereof would be excellent candidates forstudy in various tumor systems. There has been great interestin the synthesis of 6-fluoropurine1 and it is noteworthy that the
(*)
Supported by research grant
CY-4008
(CZ)
and
(C3)
from the National Cancer Institute
ut
the National Institutes of Health, Public Health Service. Presented in part before theUirision of Medicinal Chemistry, 141st Meeting of the American Chemical Society, Washing-ton,
D.
C.,
March,1962.(1)
(a)
R.
K.
Ellison
and
.T.
H.
Burolienal,
Clin.
Plaarmacol. and Therapewtics,
1,
Gal
(1960):
(b)
R.
K.
Robins and
H. H.
Lin,
J.
Am.
Chem.
Soc.,
79,
490
(1957);
c)
H.
E.
Skipper,
.J.
A.
Montyoniery,
J.
R.
Thornson, and
P'.
M.
Schabel,
Jr.,
Cancer Research,
19, 425
(1959);
(11)
A.
C.
Sartorelli and
B.
A.
Bootti,
Cancer
Research,
20,
198 (1900);
(e)
A.
C.
Sartorelliand
B.
A.
Booth,
Biochem.
I'ImrmacoZ.,
6,
245
(1WGO);
(f)
A.
C.
Sartorelli,
.J.
R.
Akers, and
B.
A.
Booth, Biochem.
I'harmacol.,
5,
238
(1900):
(g)
A.
C.
Sartorelii and
B.
A. Booth. Arch. Biochcm.
&'OP/~YS.,
89,
118
(19GO);
(h)
A.
C.
Sartorelii,
in
press;
(i)
A.
Bendich.
P.
,J.
Russell,
Jr.,
and
J.
J.
Fox.
J.
Am.
Chem.
Soc.,
76,
0078
(1954).
1067
hitherto published attempted syntheses
of
this caompound have allstarted with
a
purine having some group in
the
6-position which it
was
hoped could
be
conlwted
to
fliiorinrThus,
the
iollon irig meth-ods have been tried
u
thout hu(*(~ss.ypoxanthine and phosphorusoxyfluoride,? adenine, qodium nitrite and fluorotioriv acid,? 6-hydra-zinopurine arid ferrir fluoiide,
?
arid (i-cahloropurinf.
(or
0-iodopurine)and
a
variety offluoride,
I11
addition,
u
c
huvr
found1 that thoSchiemann reachon
R
ith adenine-S-oxide failed
to
gi\
c>
6-fluoro-purine-S-oxide, and that heating
of
purine-fi-sulfonyl
fluoride5
failrd
to
give 6-fluoropiirine
It
has
ken iiiggrsted? that the inabiiity
CJ
prepare ti-fluoropurine may
tie
diie
to it5 instabiliti~ Hendic*h6
ha.
predieted that 6-fluoropiirinrx
IT
ould
he
iinstahle
to avid.
in
addition.thermal instahility might
be
mentioned The latter may cvplain thefailure to obtain 0-fluoropurint.
11
heii piiririr-fj-bulf on~lluoride
was
heated at ahoiit
200'
in tetralin. under which conditions
sulfur
dioxide
aas
evolved caopiouslj
.
Thus,
a
c*ornplrtely different
approticah
\\ah
sought
iza
fluoropy-rimidines. which it
was
hoped would avoid the difficulties inherent inthe previous synthetic. methods aimed
at
6-fluoropurine. In addition.appropriate I-substituted aminopyrimidii1r.j caould
serve
as
inter-mediates
for
various
S-sut)stitiited-~-fliioropurinee
of interest. I'i-nally, t)ecause
of
thc
antitumor activity
of
.S-fl~iorouracil.~t
was
feltthat certain fluoropjrrimidine, might
tw
of intereht in themsehrs.Schroeder8 found that heating
L'.1,0-trichloropyrimidine
ith silverfluoride gave
2,1,&trifluoropyrimidine.
We fouiid that 1,G-dichloro-z-nitropyrimidine
(I)9
nd silver fluoride gave the corresponding
dl-
fluoronitropyrimidine
(11)
\
hich
tipon
monoaminatiori and reductiongave the important iiitermediatc
l.j-diamino-(j-fluoropyrimidinc
(IT').
The standard reagents
for
cyclizing
&c*hloro-I,.',-diaminopyrimidirlc
to
6-chloropurine.
I
iz.,
ethyl orthoformate-acetic anhydride,"'
I'
diethoxymethyl acetate
[(C,H50),CHOCOCH,11~
nd ethyl ortho-formate plus an acidic ratalyst
all
gave hypoxanthine nhen applied
(2)
4
Bendl(1i
i
(
in~*~-~uioIla
nd
1
I
I.o\
in
1
hi
CliLiiiibti)
and
Biolod\
of
l'uiinc.
(3)
4
Ginei-horolla
and
A
Benddi
J
4m
Chrm
\ai
80,
57-14
(lqj8)
(4)
(5)
.4
L
Beaiiisn and
1%
I<
Robin5
J
Im
C'hrln
>uc
83,
038
11Jiil)
(IJ)
Ref
2
11
lii
(7)
%e
Canccr Chemot/~e,ap~
liplu
\(I
ii
i,
W
ilUCi0)
fcii
,
wmpilatiun
of
tiit
rtftlt
II
t
-
(8)
H
f3chrodr.i
.I
Ani
Chum
Sa,
illi
1WLJ)
(4)
\I
R
Boon
\\
C
31
Jiinrr
itndC:
It
Raiiiari
I
Chrfri
bur
O~i~l~l~Il
(10)
1
1
hlontyon~ri~
lin
Chrni
hor
78,
192R
illtil~)
(1
1) L
C~oldman,
1%
Alarsiw
dnd
I,
(ra/dula
I
Oru
('hrm
21,
jl!(J
i
'1
)Ol
Wolstoniioline
and
0
Cunnw
(eds
)
Littk
BI
OUII
nnd
C
ij
Bmton
l9i7
/)I)
7-8
Unpublished
obseri
ations
of
the
autlioib
on
5-fluo1ouiaril
anrlC'
TLiiilrlL
11
I
tm
Ctirni
Su(
79,
i238Il~l57)
and
Tciuplc
11
I
Orv
Cirm
26,
JOB
(lWi(l~
Search History:
Result 00 of 00
00 results for result for
p.
Notes
Load more
