Process for the preparation of doxifluridine
A process is described for the preparation of doxifluridine of formula at high yields and with reduced formation of impurities, which comprises the reaction of coupling of a compound of formula (III) with a compound of formula (IV), as defined in the description, in the presence of a Lewis acid and in an inert organic solvent, characterized in that said Lewis acid is added at a temperature below 0° C.
1 . A process for preparing a compound of formula
in which R represents linear or branched C 1 -C 5 aliphatic acyl or benzoyl, optionally substituted with C 1 -C 5 alkyls, C 1 -C 5 alkoxyls or halogens, which comprises the reaction of coupling of a compound of formula
in which
R represents a linear or branched C 1 -C 5 aliphatic acyl or benzoyl, optionally substituted with C 1 -C 5 alkyls, C 1 -C 5 alkoxyls or halogens,
R′ represents R or a linear or branched C 1 -C 5 alkyl, with a compound of formula
in which R″, being identical or different, represents a C 1 -C 6 alkyl or a phenyl, in the presence of a Lewis acid catalyst and in an inert organic solvent, wherein said Lewis acid catalyst is added to a reaction mixture of the compounds of formula (III) and formula (IV) at an addition temperature below −10° C.
2 . The process according to claim 1 in which said addition of the Lewis acid catalyst is carried out at an addition temperature between approx. −15 and −20° C.
3 . The process according to claim 1 in which, on completion of said addition of said Lewis acid catalyst, the reaction mixture is held further at the addition temperature.
4 . The process according to claim 1 in which R and R′ represent acyl, and R″ represents methyl.
5 . The process according to claim 1 in which said Lewis acid is selected from the group consisting of trimethylsilyltrifluoromethanesulphonate, tin tetrachloride, and mixtures thereof.
6 . The process according to claim 1 in which said inert organic solvent is selected from the group consisting of a chlorinated solvent aromatic solvent, and mixtures thereof preferably.
7 . The process according to claim 1 in which said compound of formula II,
in which R represents a linear or branched C 1 -C 5 aliphatic acyl or benzoyl, optionally substituted with C 1 -C 5 alkyls, C 1 -C 5 alkoxyls or halogens, and the compound of formula (II) is further submitted to a reaction of deprotection to give doxifluridine of formula I
8 . A process for the preparation of doxifluridine of formula (I)
said process comprising coupling a compound of formula (III)
where R represents a linear or branched C 1 -C 5 aliphatic acyl or benzoyl, optionally substituted with C 1 -C 5 alkyls, C 1 -C 5 alkoxyls or halogens, with a compound of formula (IV)
where R″ being identical or different represents a C 1 -C 6 alkyl or a phenyl, said coupling reaction taking place in the presence of a Lewis acid being added at a temperature of less than −10° C. to provide a compound of formula (II)
and deprotecting the compound of formula (II) to provide the compound of formula I
9 . The process of claim 1 , wherein R and R′ are acetyl and R″ is methyl.
10 . The process of claim 1 , wherein the Lewis acid is tetrachloride.
11 . The process of claim 1 , wherein the inert organic solvent is a chlorinated solvent.