The reaction of the 2'-deoxy uracil derivative (XIII) with Ms-Cl and pyridine gives the dimesylate (XIV), which is treated with NaOH in ethanol to yield the unstable intermediate (XV), which rearranges to the epoxide (XVI). The reaction of (XVI) with 1,2,4-triazole (XVII) by means of chlorophenyl dichlorophosphate (CPCP) and pyridine affords the triazolyl derivative (XVIII), which is hydrolyzed with NaOH in dioxane to provide the cytosine intermediate (XIX). Finally, the epoxide ring of (XIX) is cleaved by means of tBu-OK in DMSO to furnish the target cytosine derivative.
Reaction of L-arabinose (XIII) with cyanamide (XIV) in aqueous methanolic ammonia gives the oxazolidine derivative (XV), which is cyclized with methyl propynoate (XVI) in refluxing ethanol to yield the anhydro uridine (XVII). Acylation of both OH groups of (XVII) by means of benzoyl cyanide (XVIII) in DMF affords the dibenzoate (XIX), which is treated with anhydrous HCl in DMF to provide the chloro uridine derivative (XX) or with HI in DMF or LiI and BH3/Et2O in DMF to provide the iodo uridine (XXI). Dehalogenation of (XX) or (XXI) by means of tri-butyltin hydride in refluxing benzene furnishes 3',5'-di-O-benzoyl-2'-deoxy-b-L-uridine (XXII). The trans-glycosylation of (XXII) with bis(trimethylsilyl)-5-fluorouracil (XXIII) by means of TMS-OTf in acetonitrile gives the corresponding 5-fluoro-L-uridine derivative (XXIV) as a mixture of the a- and b-anomers that is separated by chromatography. Debenzoylation of (XXIV) with ammonia in methanol yields 2'-deoxy-b-L-uridine (XXV), which is treated with MsCl and pyridine to afford the dimesylate (XXVI). Reaction of compound (XXVI) with NaOH in methanol/water provides the unstable intermediate (XXVII) that rearranges to the cyclic ether (XXVIII). Treatment of (XXVIII) with 1,2,4-triazole (XXIX) and p-chlorophenyl dichlorophosphate in pyridine provides the adduct (XXX), which by cleavage of the triazole ring by means of NH4OH in dioxane gives the corresponding cytidine derivative (XXXI). Finally, this compound is treated with potassium tert-butoxide in DMSO.
Condensation of the chiral lactone (IV) with 2,4,6-tris-isopropylphenylsulfanyl chloride (XXXII) by means of LiHMDS and TMS-OTf in THF gives the adduct (XXXIII), which is reduced with DIBAL in toluene to yield the lactol (XXXIV). Reaction of compound (XXXIV) with Ac2O and pyridine in THF affords the acetoxy derivative (XXXV), which is condensed with the silylated 5-fluorouracil (XXIII) by means of SnCl4 in dichloromethane to provide the nucleoside (XXXVI). Oxidation of the sulfanyl group of (XXXVI) with magnesium monoperoxyphthalate (MMPP) in THF, followed by desulfurization by heating with DBU in refluxing toluene, gives 5'-O-TBDPS-2',3'-dideoxy-2',3'-didehydro-5-fluoro-b-L-uridine (XXXVII), which by treatment with Bu4NF in THF yields 2',3'-dideoxy-2',3'-didehydro-b-L-uridine (XXXIX). Finally, this compound is converted into 2',3'-dideoxy-2',3'-didehydro-b-L-cytidine by conventional methods.
The reaction of D-glutamic acid (I) with NaNO2 and HCl gives the lactone carboxylic acid (II), which is esterified with EtOH and Ts-OH to yield the ester (III), reduced with NaBH4 in ethanol and silylated with Tbdps-Cl and imidazole to afford the protected chiral lactone (IV). The selenation of lactone (IV) with N-(phenylseleno)phthalimide (V) by means of LiHMDS and Tms-Cl in THF gives a mixture of diastereomers with a higher ratio (3:1) of the desired isomer (VI). (The unwanted isomer (VII) can be isomerized by reaction with DBU in THF.) The reduction of the lactone (VI) with DIBAL in toluene affords the lactol (VIII), which is treated with Ac2O and TEA to provide the acetoxy compound (IX). The condensation of (IX) with 5-fluoro-N,O-bis(trimethylsilyl)cytosine (X) by means of Tms-OTf in dichloromethane gives the selenated cytosine derivative (XI), which is treated with H2O2 in THF/pyridine to yield the unsaturated silylated precursor (XII). Finally, this compound is desilylated with HF and TEA in THF to afford the target cytosine derivative.
Cyclization of L-arabinose (VI) with cyanamide and NH3 in methanol gives the bicyclic oxazoline (XV), which is submitted to a cycloaddition with methyl propynoate (XVI) in refluxing ethanol/water to yield the tricyclic pyrimidinone system (XVII). Benzoylation of the two OH groups of compound (XVII) with either benzoyl cyanide and triethylamine in DMF or benzoyl chloride in anhydrous pyridine affords the dibenzoate (XVIII), which is treated with HCl in hot DMF to provide the chlorouridine derivative (XIX). Dechlorination of compound (XIX) by means of Bu3SnH and AIBN in refluxing benzene gives 3,5-di-O-benzoyl-2'deoxy-b-L-uridine (XX), which is debenzoylated by means of NaOMe in methanol to yield 2'-deoxy-b-L- uridine (XXI). Finally, this compound is methylated by reaction with formaldehyde and KOH in hot water followed by hydrogenation with H2 over Pd/C in EtOH/HCl. Optionally, telbivudine can be purified by benzoylation with benzoyl cyanide and TEA, crystallization in EtOH/ether and final hydrolysis with refluxing MeOH/ NaOMe.