PROCEDE DE PRODUCTION DE 2,2'-CYCLOCITIDINE ET DE LEURS ANALOGUES

PROCESS FOR PRODUCING 2,2'-CYCLOCYTIDINE AND ANALOGUES THEREOF

Abrégé anglais

A novel process for the production of 2,2'-
cyclocytidine compounds and pharmaceutically acceptable
salts thereof comprises reacting a 2',3'-O-
dialkylstannylene cytidine compound with an amine in the
presence of a sulfonyl compound. 2,2'-Cyclocytidine is
a percursor to cytarabine, a known antineoplastic and
antiviral agent.

Revendications

WE CLAIM:
1. A process for producing a compound of Formula
I, or pharmaceutically acceptable salt thereof:
<IMG> (I)
which comprises the step of reacting (i) a compound of
Formula II:
<IMG> (II)
wherein R1 is a C1-C6 alkyl group and R2 is selected
from the group comprising hydrogen, trityl,
methoxytrityl, dimethoxytrityl, acetyl, a C2-C6
alkylacyl group, a C6-C9 arylacyl group, allyl, 2,2,2-
trichloroethyl, phosphates and salts thereof, tosyl and
mesyl, with (ii) an amine selected from pyridine and
amines having the general formula
- 8 -

R3R4R5N
wherein R3, R4 and R5 can be the same or different and
each of R3, R4 and R5 is selected from the group
comprising a C1-C6 alkyl group and C6-C9 aryl group, in
the presence of (iii) a sulfonyl compound having the
general formula
R6 SO2 X
wherein R6 is selected from the group comprising -CF3, a
C1-C6 alkyl group and C6-C9 aryl group, and X is
selected from SO3CF3 and a halogen, to produce a
compound of Formula I.
2. The process defined in claim 1, wherein R2 is
hydrogen.
3. The process defined in claim 1, wherein X is
chloride.
4. The process defined in claim 2, wherein said
sulfonyl compound is selected from p-toluenesulfonyl
chloride and methanesulfonyl chloride.
5. The process defined in claim 2, wherein said
sulfonyl compound is p-toluenesulfonyl chloride.
6. The process defined in claims 1, 2, 3 or 4,
wherein said amine is selected from the group comprising
trimethylamine, triethylamine, pyridine, tripropylamine
and tributylamine.
7. The process defined in claim 5, wherein said
amine is triethylamine.
- 9 -

8. The process defined in claims 1, 2, 3 or 4,
wherein said step is conducted in the presence of an
organic solvent.
9. The process defined in claims 1, 2, 3 or 4,
wherein said step is conducted in the presence of an
organic solvent selected from the group comprising
alcohols, toluene, benzene, chloroform and
dichloromethane
10. The process defined in claim 7, wherein said
step is conducted in the presence of methanol.
- 10 -

Description

2 ~ 3
FIELD OF THE INVENTION
The present invention relates to a novel
process for producing cyclonucleosides and
pharmaceutically acceptable salts thereof. More
specifically, the present invention relates to a process
for the production of 2,2'-cyclocytidine, 2,2'-
cyclocytidine analogues and pharmaceutically acceptable
salts thereof.
BACKGROUND OF THE INYENTION
The production of cyclonucleosides is known.
For example, Walwick et al (Proc. Chem. Soc., 84 (1959))
teach the production of 2,2'-cyclocytidine hydrochloride
from cytidine. The process involved heating cytidine
with polyphosphoric acid followed by dephosphorylation
of one of the reaction products, 2,2'-cyclocytidine-
3',5'-diphosphate.
Doerr et al (J. Org. Chen., 32, 1462 (1967))
teach the production of 2,2'-cyclocytidine chloride from
uridine using a process comprising six steps. It is
interesting to note that in the final step, 2,2'-
cyclocytidine hydrochloride was obtained only in a 57%
yield. Taking into account the fact that each step is
not quantitative, the overall yield of 2,2'-
cyclocytidine hydrochloride from uridine can be expected
to be on the order of from 10% to 20%.
Kikugawa et al (Tet. Lett., 869 (1970)) teach
the production of the hydrochloride or the formate salt
of 2,2'-cyclocytidine. Specifically, the process
comprises reacting cytidine with thionyl chloride and
N,N'-dimethylformamide. It is interesting to note that
the crude 2,2'-cyclocytidine salt was obtained in a
-1- ~

2~ 3
yield of only 30.4%. Kikugawa et al (J. Org. Chem., 37,
284 (1972)) also provide an improved process for
preparing 2,2'-cyclocytidine. The improvement appears
to relate to an improved yield (55%) of the product
using ion exchange and chromatography techniques.
Sowa et al (Bull. Chem. Soc. Jap., 48, 505
(1975)) teach a process for the production of
cyclonucleosides which comprises reacting the starting
ribonucleoside with thionyl chloride and water and
subsequently reflecting the reaction mixture at an
acidic pH. It is interesting to note that a yield of
about 73% of 2,2'-cyclocytidine hydrochloride was
allegedly obtained whereas a yield of about 47% of 2,2'-
cyclouridine hydrochloride was alledgedly obtained.
Yamaguchi et al (J. Med. Chem., 19, 654
(1979)) teach the production of 2,2'-cyclocytidine
hydrochloride via reaction of cytidine with an organic
acid chloride.
The aforementioned prior art techniques for
the preparation of 2,2'-cyclonucleosides are deficient
in that they require multiple steps with inherent loss
of yield and/or they require silica/resin columns for
isolation and purification. It would be desirable to
have a relatively simple process for producing 2,2'-
cyclonucleosides in acceptable and/or comparable yields.
SUMMARY OF THE INVENTION
It is an object of the present invention to
provide a novel process for the production of 2,2'-
cyclocytidine compounds and pharmaceutically acceptable
salts thereof.

~ 2~3
-
Accordingly, the present invention provides a
process for producing a compound of Formula I, or a
pharmaceutically acceptable salt thereof:
NH
,,
Nl ~
\ N (I)
R~0-C ~ 0~
H0 H
which comprises the step of reacting (i) a compound of
Formula II:
NH2
N (II)
R2 o-c~o~J
Sn
Rl~ `Rl
wherein Rl is a Cl-C6 alkyl group and R2 is selected
from the group comprising hydrogen, trityl,
methoxytrityl, dimethoxytrityl, acetyl, a C2-C6
alkylacyl group, a C6-Cg arylacyl group, allyl, 2,2,2-
trichloroethyl, phosphates and salts thereof, tosyl and
mesyl, with (ii) an amine selected from pyridine and
amines having the general formula

R3R4RsN
wherein R3, R4 and R5 can be the same or different and
each of R3, R4 and Rs is selected from the group
comprising a C1-C6 alkyl group and C6-Cg aryl group, in
the presence of (iii) a sulfonyl compound having the
general formula
R6 SO2 X
wherein R6 is selected from the group comprising -CF3, a
C1-C6 alkyl group and C6-Cg aryl group, and X is
selected from a halogen and S03CF3, to produce a
compound of Formula I.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Thus, the present process can be used to
produce 2,2'-cycloribosides such as 2,2'-cyclocytidine
20or pharmaceutically acceptable salts thereof.
The compound of Formula II:
NH2
I (II)
0~\ /
N
R2 O-C~O~)
O~ ~0
~Sn~

2 ~
is known. Generally, this compound may be prepared by
reacting the appropriate nucleoside with the appropriate
dialkyl tin oxide.
In one preferred embodiment of the invention,
R1 is butyl and R2 is hydrogen. With these definitions
for R1 and R2, the compound of Formula II is 2',3'-0-
dibutylstannylene cytidine.
An example of a suitable "C2-C6 alkylacyl
group" for use as R2 is acetyl. Further, an example of
a suitable ''C6-Cg arylacyl group" for use as R2 is
benzoyl.
Provided that it does not contain a hydrogen
bonded to nitrogen, the amine suitable for use in the
present process is not particularly restricted and may
be selected from the group comprising trimethylamine,
triethylamine, pyridine, tripropylamine and
tributylamine. The most preferred amine is
triethylamine.
The reaction of the compound of Formula II
with the amine is conducted in the presence of a
sulfonyl compound, preferably a sulfonyl chloride
compound. More preferably the sulfonyl chloride
compound is one of p-toluenesulfonyl chloride and
methanesulfonyl chloride.
Typically, the reaction can be conducted at
room temperature, preferably with agitation of the
reaction mixture (such as stirring). The reaction may
be conducted in any suitable organic solvent system.
Examples of suitable organic solvents include:
alcohols, toluene, benzene, chloroform, dichloromethane

2~
and the like. The preferred organic solvents are
alcohols, more preferably methanol.
The crude 2,2'-cyclocytidine product may be
separated from the reaction mixture and purified using
conventional techniques within the purview of a person
skilled in the art. For example, after the reaction is
complete the solvents may be evaporated under vacuum and
the resulting solid suspended and refluxed in a suitable
medium (e.g. chloroform). Thereafter, the crude 2,2'-
cyclonucleoside may be purified from water (in which the
product is soluble) and alcohol (in which the product is
relatively insoluble).
Aspects of the present invention will be
described with reference to the following Example which
should not be considered to limit the scope of the
invention.
EXAMPLE
A 500 mL flask was charged with 50 mL
methanol, 1.95 g cytidine and 2 g dibutyl tin oxide.
The resulting suspension was refluxed for five hours and
then stirred at room temperature for twelve hours. To
the mixture was then added triethylamine (7.8 mL)
followed by slow addition of p-toluenesulfonyl chloride
(10.68 g). The resulting mixture was stirred for twelve
hours at room temperature. Thereafter, the solvents
were evaporated under vacuum and chloroform (100 mL) was
added to the resulting white gum. The chloroform/white
gum suspension was refluxed for fifteen minutes and then
cooled to room temperature. The resulting white
precipitate was filtered and washed with chloroform, and
dried to yield 1 g of crude 2,2'-cyclocytidine
hydrochloride. The crude cyclocytidine hydrochloride
-- 6

2~2~3
was suspended in 5 mL water and the mixture was heated
to 60C. This solution was filtered and the solvent
reduced under vacuum to obtain a turbid oil. Ethanol
(18 mL) was added and the mixture was stirred at 5C for
twelve hours. The resulting precipitate was filtered
and dried to provide 0.6 g of pure 2,2'-cyclocytidine
hydrochloride (29% yield). The product was
characterized by comparison of its melting point, and
MMR and IR spectra with those previously reported for
2,2'-cyclocytidine.

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