Process for the preparation of a deoxyuridine derivative

Details Process for the preparation of a deoxyuridine derivative Process for the preparation of a deoxyuridine derivative

2002-04-19

2003-07-15

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S028100, C536S028550

Reexamination Certificate

active

06593467

ABSTRACT:

The present invention relates to a process for the preparation of a deoxyuridine derivative. More particularly, the invention concerns a process for the preparation of 5′-deoxy-5-fluorouridine as well as novel intermediates useful in this process.
The compound 5′-deoxy-5-fluorouridine is a well known cytostatic agent which will be hereinafter designated by its International Non-proprietary Name doxifluridine.
Doxifluridine, having the formula I.
is described in U.S. Pat. No. 4,071,680, wherein a multi-step synthesis, starting from 5-fluorouridine and involving the removal of the 5′-hydroxy group through the corresponding 5′-iododerivative, is also disclosed. According to this document, the replacement of the 5′-hydroxy group by a iodine atom is accomplished by using triphenylphosphite methoiodide as a chemical iodinating agent which requires a particular caution because of the toxicity of the reagent owing to the presence of reaction by-products.
EP 21,231 discloses the preparation of doxifluridine by removal of the acyl groups from the corresponding 2′,3′-diesters with carboxylic acids, particularly from the corresponding 2′,3′-diacetate. However, the synthesis of the starting material involves the replacement of an hydroxy group by a bromine atom and the conversion of the bromo derivative into the corresponding deoxy compound by catalytic hydrogenation. In this case too, the bromination is carried out by using a phosphor compound, namely with bromine in the presence of a great amount of triphenylphosphine.
According to a paper by S. Aymera and P. V. Danenberg (J. Med. Chem. 1982, 25, 999) 5′-deoxy-5′-iodo-2′, 3′-O-isopropylidene-5-fluoro uridine is prepared according to the method of Cook et al. (J. Med. Chem. 1979, 22, 1330) which corresponds to U.S. Pat. No. 4,071,680. The same paper discloses the conversion of 5′-deoxy-5′-O-mesyloxy-2′,3′-O-isopropylidene-5-fluorouridine into 5′-bromo-5′-deoxy-2′,3′-O-isopropy lidene-5-fluorouridine by lithium bromide, but it does not describe any further conversion.
On the other hand, in the above cited patent EP 21,231, the replacement of a bromine atom by a hydrogen atom is conducted by catalytic hydrogenation under strong conditions, i.e. in the presence of potassium hydroxide, on a substrate which does not contain the uracil moiety, this one being introduced after the preparation of the deoxy-sugar in the presence of a strong inorganic base.
It has now been found that it is possible to replace the hydroxyl group of 2′,3′-isopropylidene-5-fluorouridine by a iodine atom by simply using sodium iodide, in the absence of any phosphor compound, if said hydroxy group is previously activated as a sulfonic ester.
It has also been found that the iodine atom of 5′-deoxy-5′-iodo-2′,3′-O-isopropylidene-5-fluorouridine can be replaced by a hydrogen atom by catalytic hydrogenation without using strong bases, thus obtaining the corresponding 5′-deoxy compound in very good yields. The same replacement can take place with other hydrogen donors such as cyclohexene, cyclohexadiene or an hydride, for example tributyltin hydride.
Thus, it is an object of the present invention to provide a process for the preparation of 5′-deoxy-5-fluorouridine, which comprises:
(a) reacting 2′,3′-O-isopropylidene-5-fluorouridine to formula II
with a functional derivative of a sulfonic acid of formula III
R—SO
3
H  (III)
wherein R is a (C
1
-C
4
)alkyl, a trifluoromethyl, an unsubstituted, mono-di- or trisubstituted phenyl group;
(b) reacting the 5′-sulfonyloxy derivative thus obtained of formula IV
wherein R is as defined above, with an alkaline or earth-alkaline iodide;
(c) hydrolysing the 5′-deoxy-5′-iodo-2′,3′-O-isopropylidene-5-fluorouridine of formula V
thus obtained in acidic medium; and
(d) submitting the 5′-deoxy-5′-iodo-5-fluorouridine of formula VI
to a reduction with hydrogen or a hydrogen donor.
In formula III R is preferably methyl, ethyl, n-butyl, trifluoromethyl, phenyl, monosubstituted phenyl, i.e. with a methyl, methoxy, nitro group or halogen, disubstituted, i.e. with two methyl groups, or trisubstituted, i.e. with three methyl groups, particularly 2,4,6-trisubstituted.
As a functional derivative of the sulfonic acid, the chloride, the anhydride or a mixed anhydride is suitably used. Methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride and 2,4,6-trimethylphenylsulfonyl chloride are particularly preferred as esterifying agents.
Thus, in step (a), the functional derivative of the sulfonic acid of formula III, preferably selected from the group consisting of those defined hereinabove, is made to react with 2′,3′-O-isopropylidene-5-fluorouridine. Advantageously, the reaction is carried cut in an organic solvent, i.e. halogenated such as dichloromethane, 12-dichloroethane or 1,1,1-trichloroethane, or a polar aprotic solvent, such as N,N-dimethylformamide. N,N-dimethylacetamide, dimethy
l
sulfoxide or acetonitrile, or ethyl acetate or an aromatic hydrocarbon such as toluene or xylene, in the presence of a base such as trimethylamine, triethylamine, diisopropylamine, N-ethyl-diisopropy
l
amine, pyridine or dimethylaminopyridine.
Generally, after 5+6 hours at a temperature of 0÷+40
20
C., the reaction is complete and the compound of formula IV thus obtained is separated from the reaction by-products by simple filtration of said by-product, after treatment with water.
The 5′-sulfonyloxy derivative of formula IV may be recovered by extraction with an organic solvent, subsequent concentration and may be isolated and characterized according to conventional methods.
Alternatively, the concentrated solution of the compound of formula IV may be straightforwardly used for step (b).
Step (b) is carried out by simply treatment of the compound of formula IV, in pure form or as the said concentrated solution obtained at the end of step (a, with an alkaline or earth-alkaline iodide in an organic solvent such as a ketone, preferably acetone, methylethy
l
ketone or methylisobutylketone, an ether, preferably dioxane or tetrahydrofurane, or a polar aprotic solvent, preferably acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide.
After 4÷6 hours at a temperature of 40÷80° C., the reaction is complete and, as in the step (a), the by-products of the reaction are removed by filtration and by washing with water. The expected end product, namely 5′-deoxy-5′-iodo-2′,3′-O-isopropylidene-5-fluor
o
uridine of formula V may be recovered with an organic solvent, preferably ethyl acetate, subsequent concentration, and may be isolated according to conventional methods. As in step (a), the concentrated solution containing the compound of formula V may be directly used for step (c).
Step (c) consists of a hydrolysis of 5′-deoxy-5′-iodo-2′,3′-O-isopropylidene-5-fluorouridine in acidic medium according to the methods commonly used in the sugar chemistry and, more particularly, in that of the nucleosides. Preferably such an hydrolysis is carried out in aqueous formic acid or, more advantageously, in aqueous acetic acid, or in N,N-dimethylformamide or N,N-dimethylacetamide in the presence of aqueous HCl, at a temperature of 80÷100° C.
The 5′-deoxy-5′-iodo-5-fluorouridine of formula VI thus obtained is isolated by evaporation of the solvent and the compound is recovered by extraction from a suitable solvent, preferably ethyl acetate.
As set Forth hereinabove, the compounds obtained at the end of steps (a) and (b) may be isolated and characterized, or, preferably, they may be used, without isolation, in a raw state or dissolved or suspended in a solvent. The yields of the three steps are very high, namely always higher than 90% of the theoretical and com

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