PREPARATION OF 2'-FLUORO-2'-ALKYL-SUBSTITUTED OR OTHER OPTIONALLY SUBSTITUTED RIBOFURANOSYL PYRIMIDINES AND PURINES AND THEIR DERIVATIVES
The present invention provides (i) processes for preparing a 2′-deoxy-2′-fluoro-2′-methyl-D-ribonolactone derivatives, (ii) conversion of intermediate lactones to nucleosides with potent anti-HCV activity, and their analogues, and (iii) methods to prepare the anti-HCV nucleosides containing the 2′-deoxy-2′-fluoro-2′-C-methyl-β-D-ribofuranosyl nucleosides from a preformed, preferably naturally-occurring, nucleoside.
1 . A compound of formula
wherein
R′ and R″ are independently H, lower alkyl (C 1 -C 6 ), aryl (C 6 -C 20 ), optionally substituted benzyl, trialkylsilyl, t-butyl-dialkylsilyl, t-butyldiphenylsilyl, TIPDS, THP, MOM, MEM, acetyl, benzoyl, or optionally substituted acyl; or R′ and R″ form a cyclopentyl or cyclohexanyl group;
R 1 and R 2 are independently H, lower alkyl (C 1 -C 6 ), aryl (C 6 -C 20 ), hydroxymethyl, methoxymethyl, halomethyl, optionally substituted ethenyl, halovinyl, optionally substituted ethynyl, or optionally substituted allyl; and
R 3 is H, aryl, arylalkyl, or lower alkyl (C 1 -C 6 ).
2 . The compound of claim 1 ,
wherein
R′ and R″ are independently H or lower alkyl (C 1 -C 6 );
R 1 and R 2 are independently H, or lower alkyl (C 1 -C 6 ); and
R 3 is H or lower alkyl (C 1 -C 6 ).
3 . A compound of formula
wherein
each R 1 is independently lower alkyl (C 1 -C 6 ), optionally substituted phenyl, or optionally substituted benzyl; or R 1 forms a cyclopentyl or cyclohexanyl group;
R 2 and R 3 are independently hydrogen, lower alkyl (C 1 -C 6 ), hydroxymethyl, methoxymethyl, halomethyl, optionally substituted ethenyl, halovinyl, optionally substituted ethynyl, or optionally substituted allyl; and
R 4 is independently arylalkyl, or lower alkyl (C 1 -C 10 ).
4 . The compound of claim 3 ,
wherein
each R 1 is independently lower alkyl (C 1 -C 6 );
R 2 and R 3 are independently hydrogen, or lower alkyl (C 1 -C 6 ); and
R 4 is independently lower alkyl (C 1 -C 10 ).
5 . The compound of claim 3 , having the formula
6 . A compound of formula
wherein
R 2 and R 3 are independently H, alkyl (C 1 -C 10 ), hydroxymethyl, methoxymethyl, halomethyl, optionally substituted ethenyl, halovinyl, optionally substituted ethynyl, or optionally substituted allyl;
R 5 and R 6 are methoxymethyl, methoxyethyl, benzyloxymethyl, ethoxymethyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, acetyl, pivaloyl, benzoyl, toluoyl, 4-phenyl benzoyl, 2-nitrobenzoyl, 3-nitrobenzoyl, 4-nitrobenzoyl, 2-chlorobenzoyl, 3-chlorobenzoyl, 4-chlorobenzoyl, or substituted benzoyl;
Nu is F, Cl, Br, N 3 , CN, NO 3 , SCN, OR or NR 2 wherein R is acyl or lower alkyl (C 1 -C 10 ); and
L is a leaving group.
7 . The compound of claim 6 ,
wherein
R 2 and R 3 are independently H, alkyl (C 1 -C 10 ), or halomethyl;
R 5 and R 6 are benzoyl;
Nu is F; and
L is OAc.
8 . The compound of claim 7 , wherein R 2 is H and R 3 is methyl.
9 . A compound of formula
10 . A compound of formula IIIa, IIIb or IIIc
wherein
each R 1 is independently lower alkyl (C 1 -C 6 ), optionally substituted phenyl, or optionally substituted benzyl;
R 2 and R 3 are independently hydrogen, lower alkyl (C 1 -C 6 ), hydroxymethyl, methoxymethyl, halomethyl, optionally substituted ethenyl, optionally substituted ethynyl, or optionally substituted allyl; and
R 4 is independently hydrogen, aryl, arylalkyl, or lower alkyl (C 1 -C 10 ).
11 . The compound of claim 10 ,
wherein
each R 1 is lower alkyl (C 1 -C 6 );
R 2 and R 3 are independently hydrogen, or lower alkyl (C 1 -C 6 ); and
R 4 is lower alkyl (C 1 -C 10 ).
12 . The compound of claim 10 , having the formula