Note: Descriptions are shown in the official language in which they were submitted.
FIELD OF THE INVENTION
The present invention relates to a novel
process for the production of cytarabine, cytarabine
analogues and pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
Cytarabine is a known antineoplastic and
antiviral agent. Cytarabine, which is also known as 4-
amino-l-~-D-arabinofuranosyl-2f lN J -pyrimidinone, 1-~-D-
arabinofuranosylcytosine and ~-cytosinearabinoside, has
the following chemical structure:
NH2
~ N
HO-C ~ O
~ HO~
HO
Ogilvie (Carbohyd. Res., 24, 210 (1972))
teaches the production of cytarabine from cytidine.
Specifically, the process comprised reacting cytidine
with diphenyl carbonate and sodium hydrogen carbonate at
150C in DMF. The product cytarabine was purified using
thin layer chromatography and obt~ineA in a yield of
40%.
Beranek et al (Nucleic Acid Chemistry, Vol. 1,
249, Edited by Townsend and Tipson, Wiley, New York)
- 1 -
~12~
teach the production of cytarabine from cytidine.
Specifically, cytidine is reacted with incremental
amounts of diphenyl carbonate in the presence of DMF and
water at 120C. The overall yield of pure cytarabine
was limited to 31.9%.
Roberts et al (J. Org. Chem., 32, 816 (1967))
teach the production of cytarabine from cytidine (or
from 2'(3')-cytidylic acid). Specifically, cytidine is
reacted with phosphoric acid at 80C for a period of 30
hours to produce a 2,2'-cyclocytidine analogue
intermediate. This intermediate is then hydrolyzed at a
pH of 9 utilizing lithium hydroxide to produce the
3',5'-diphosphate of cytarabine. The diphosphate is
then treated with magnesium chloride, ammonium chloride
and concentrated ammonium hydroxide, and thereafter
purified by column chromatography to yield pure
cytarabine. The overall yield of pure cytarabine is
limited to 53% based on the unrecovered portion of the
starting cytidine.
Kikugawa et al (J. Org. Chem., 37, 284-288
(1972)) teach the conversion of 2,2'-cyclocytidine
hydrochloride to cytarabine. Specifically, ammonia is
added to an aqueous solution of 2,2'-cyclocytidine
thereby raising the pH to 9. The solution is thereafter
acidified with hydrochloric acid and run through an ion
exchange column. Thereafter, cytarabine is crystallized
from ethanol in a yield of 90%.
Sowa et al (Bull. Chem. Soc. Jap., 48, 505-507
(1975) teach the production of cytarabine from 2,2'-
cyclocytidine. Specifically, sodium hydroxide is added
to an aqueous solution of 2,2'-cyclocytidine
hydrochloride thereby raising the pH of the solution to
10. Thereafter, the solution is run through a H~ ionic
exchange resin followed by recrystallization of pure
cytarabine from ethanol.
Unfortunately, the prior art processes for the
production of cytarabine and its analogues are deficient
in that the purified product is obt~ne~ in a relatively
low yield and/or the process is complicated requiring a
series of steps including the use of ion exchange
resins. Thus, it would be desirable to have a process
for the production of cytarabine, cytarabine analogues
and pharmaceutically acceptable salts thereof in
relatively high yields and by a relatively simply
process.
SUMMARY OF THE INVENTION
It is an object of the present invention to
provide a novel process for the production of
cytarabine, cytarabine analogues and pharmaceutically
acceptable salts thereof.
Accordingly, the present invention provides a
process for directly preparing a compound of Formula I,
or a pharmaceutically acceptable salt thereof:
¦ (I)
O ~ N /
Rl O-C~O~
\ HO~
HO
-- 3 --
2 ~
which comprises the step of reacting (i) a compound of
Formula II or a pharmaceutically acceptable salt
thereof:
N~
I
\ N (II)
10R1O-C ~ ~
Y
HO H
wherein Rl is selected for 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 the group comprising C5 -Cl 2 heterocyclic amines and
amines having the general formula
R2R3R4N
wherein RZ, R3 and R4 can be the same or different and
are is selected from the group comprising hydrogen, a
C1-C6 alkyl group and a C6-Cg aryl group, with the
proviso that the each of R2, R3 and R4 are not hydrogen.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compound of Formula II:
2~ 1 2094
NH
N
R'0-C ~ ~ (II)
H0 H
is known and may be prepared in a number of dlfferent
manners.
Preferably, this compound $s prepared by
reacting a cytldine compound-tin oxide con~ugate of
Formula III:
NH2
0 ~ N /
R10-C ~ 0 ~ (III)
Sn
Rs `R~
wherein Rl is as defined hereinbefore and Rs is a C1-C6
alkyl group with an amine in the pr~ce~ce of a sulfonyl
compound. Thl~ process of producing the starting
compound for the present process (i.e. the compound of
Formula III) is the subject of our copending Canadian
patent application number 2,012,093, filed March 13, 1990.
It will of course be understood that the manner in which
starting compound of
B- 5
2 ~
Formula III is made is not particularly restricted as
regards the present process.
The most preferred starting material for the
present process is 2,2'-cyclocytidine. In this
embodiment R1 of Formula II is hydrogen.
An example of a suitable "C2-C6 alkylacyl
group" for use as R1 is acetyl. Further, an example of
a suitable "C6-Cg arylacyl group" for use as R1 is
benzoyl.
The amine suitable for use in the present
process is selected from the group comprising Cs-C1 2
heterocyclic amines and amines having the general
formula
R2R3R~N
wherein R2, R3 and R4 can be the same or different and
are selected from the group comprising hydrogen, a C1-C6
alkyl groups and a C6-Cg aryl group, with the proviso
that each of R2, R3 and R4 are not hydrogen. Thus, it
will be appreciated that the use of ammonia (i.e.
R2=R3=R4=H) is outside the scope of the present
invention. Non-limiting examples of suitable
heterocyclic amines include pyridine and piperidine.
Non-limiting examples of other amines suitable for use
include t-butylamine, trimethylamine, triethylamine,
tripropylamine, tributylamine, methylamine, ethylamine,
diethylamine and aniline. The most preferred amine
suitable for use in the present process is t-butylamine.
Preferably, the present process is conducted
in the presence of an aqueous solvent. Examples of
-- 6 --
2 ~
suitable aqueous solvents include water and a mixture of
water and at least one other solvent miscible therewith.
The most preferred aqueous solvent for use in the
present comprises solely water.
Typically, the reaction can be conducted at
room temperature, preferably with agitation (such as
stirring) of the reaction mixture. The reaction may be
conducted in any polar solvent for the starting compound
of Formula I. Preferably, the solvent is water.
The crude cytarabine, cytarabine analogue or
pharmaceutically acceptable salt thereof 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 agitated in a
suitable medium to produce a purified product. Examples
of such media include alcohol and mixtures containing
alcohol and water. The preferred alcohol for use is
ethanol.
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
2,2'-Cyclocytidine hydrochloride (6.5 g) was
dissolved in 35 mL water at 80C. The solution was
cooled to room temperature and t-butylamine (2.8 g) was
added and the mixture stirred for 2 hours. Thereafter,
the solvent was evaporated under vacuum and ethanol (16
2 ~
g) was added. The mixture was stirred at room
temperature for 12 hours. Filtration of the resulting
precipitate yielded 5 g of pure cytarabine after drying,
which corresponds to a yield of 83~. The product was
characterized by comparison of its melting point, and
MMR and IR spectra with those previously reported for
cytarabine.
