Preparation of 2′-fluoro-2′-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives
View Patent ↗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 the following general formula, 49B:
wherein
R 2 is independently hydrogen, a (C 1 -C 6 ) alkyl, hydroxymethyl, methoxymethyl, halomethyl, vinyl, halovinyl, ethynyl, haloethynyl, allyl, or haloallyl;
R 3 is independently a (C 1 -C 6 ) alkyl, hydroxymethyl, methoxymethyl, halomethyl, vinyl, halovinyl, ethynyl, haloethynyl, allyl, or haloallyl;
R 5 , R 6 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl; and
Nu is F, Cl, N 3 , CN, NO 2 , CF 3 , SCN, OR or NR 2,
wherein R is independently selected from the group consisting of arylalkyl, a (C 1 -C 6 ) alkyl, and CH 2 R′,
wherein R′ is hydrogen or a (C 1 -C 6 ) alkyl.
2. A process for the preparation of a compound of formula 49B:
wherein
R 2 is independently hydrogen, a (C 1 -C 6 ) alkyl, hydroxymethyl, methoxymethyl, halomethyl, vinyl, halovinyl, ethynyl, haloethynyl, allyl, or haloallyl;
R 3 is independently a (C 1 -C 6 ) alkyl, hydroxymethyl, methoxymethyl, halomethyl, vinyl, halovinyl, ethynyl, haloethynyl, allyl, or haloallyl;
R 5 , R 6 are independently H, methyl, benzyl, trityl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, ethoxymethyl, methoxymethyl (MOM), methoxyethyl (MEM), benzyloxymethyl (BOM), acetyl, benzoyl, pivaloyl, 2-, 3-, or 4-nitrobenzoyl, 2-, 3-, or 4-chlorobenzoyl, or toluoyl; and
Nu is F, Cl, N 3 , CN, NO 2 CF 3 , SCN, OR or NR 2,
wherein R is independently selected from the group consisting of arylalkyl, a (C 1 -C 6 ) alkyl, and CH 2 R′,
wherein R′ is hydrogen or a (C 1 -C 6 ) alkyl, the process comprising the steps of:
(a) treating a compound of formula 51B or 52B:
with an acid in at least one solvent,
wherein
R 1 is independently a (C 1 -C 6 ) alkyl, phenyl, or benzyl; alternatively, R 1 is an ethylene (—CH 2 CH 2 —), or a trimethylene (—CH 2 CH 2 CH 2 —) which forms a cyclopentyl or a cyclohexyl;
R 4 is independently hydrogen, aryl, arylalkyl, or a (C 1 -C 6 ) alkyl; and
M + is tetrabutylammonium, tetraethylammonium, tetramethylammonium, sodium, potassium, cesium, rubidium, or silver;
(b) optionally, followed by azeotropic distillation in benzene or toluene in presence of acid to provide a compound of formula 53B; and
(c) protection of a compound of formula 53B with a protecting agent and a base in a solvent.
3. The process of claim 2 , wherein the acid from either step (a) or step (b) is selected from one or more of the group consisting of HCl, H 2 PO 3 , H 2 SO 4 , TsOH, CH 3 CO 2 H, CF 3 CO 2 H and HCO 2 H.
4. The process of claim 2 , wherein the solvent from step (a) is selected from one or more of the group consisting of MeOH, EtOH, i-PrOH, CH 3 CN, THF and water.
5. The process of claim 2 , wherein compound 53B from step (c) is protected with:
a protecting agent selected from one or more of the group consisting of methoxymethyl chloride, methoxyethyl chloride, benzyloxymethyl chloride, ethoxymethyl chloride, trityl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, acetyl chloride, acetic anhydride, benzoic anhydride, benzoyl chloride, toluoyl chloride, 4-phenylbenzoyl chloride, 2-, 3-, or 4-nitrobenzoyl chloride, and 2-, 3-, or 4-chlorobenzoyl chloride; and a base in a solvent.
6. The process of claim 5 , wherein the base is selected from one or more of the group consisting of imidazole, pyridine, 4-(dimethylamino)pyridine, triethyllamine, diisopropylethylamine, and 1,4-diazabicyclo[2,2,2]octane.
7. The process of claim 5 , wherein the solvent is selected from one or more of the group consisting of pyridine, dichloromethane, chloroform, and 1,2-dichloroethane, and tetrahydrofuran.