合成路线1

The reaction of 1,4-dithiane-2,5-diol (XII) with 2-(benzoyloxy)acetaldehyde (XIII) in hot pyridine gives 5-acetoxy-2-(benzoyloxymethyl)-1,3-oxathiolane (XIV), which is condensed with fully silylated cytosine (XV) (obtained by silylation of cytosine (XVI) with HMDS) by means of TBDMS-OTf, yielding, after acetylation with Ac2O, a mixture of the desired racemic-cis substituted fluorocytosine (XVII) along with its racemic trans isomer, which are separated by flash chromatography. The deacylation of (XVII) with ammonia in methanol gives the racemic cis-2-(hydroxymethyl)-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (XVIII), which is phosphorylated with POCl3 and water in trimethyl phosphate yielding the racemic phosphate (XIX). The enantioselective dephosphorylation of (XIX) with 5'-nucleotidase (Sigma), affords a mixture of the (+)-(cis)-dephosphorylated compound (XXI) and unreacted (-)-(cis)-compound (XX) that are separated by column chromatography. Finally, (XX) is dephosphorylated by means of alkaline phosphatase (Sigma) to afford the target compound.

合成路线2

The acylation of 2-butene-1,4-diol (XXII) with butyryl chloride and DMAP in pyridine gives the dibutyrate (XXIII), which is ozonolyzed with O3 in dichloromethane yielding the aldehyde (XXIV). The cyclization of (XXIV) with mercaptoacetic acid (XXV) in refluxing toluene affords 2-(butyryloxymethyl)-1,3-oxathiolane-5-one (XXVI), which is reduced with lithium tri-tert-butoxyaluminum hydride and acetylated with acetic anhydride in THF to give 5-acetoxy-2-(butyryloxymethyl)-1,3-oxathiolane (XXVII). The condensation of (XXVII) with disilylated 5-fluorocytosine (XV) (obtained from cytosine (XVI) as described) by means of SnCl4 in dichloromethane yields the racemic butyryl nucleoside rac-(cis)-(XXVIII). The biological resolution of this racemic mixture has been performed by digestion with the enzyme pig liver esterase (PLE-A) providing a mixture of unreacted (-)-(cis)-(2R,5S)-(XXVIII) butyrate and hydrolyzed (+)-(cis)-(2S,5R)-(XXIX) that are separated by fractional extraction. The desired (-)-(cis)-(2R,5S)-enantiomer is finally hydrolyzed to the target compound with NaOMe in methanol. The biological resolution of rac-(cis)-(XXVIII) can also be performed with the enzyme Amano PS-800 yielding a mixture of unreacted (+)-(cis)-(2S,5R)-(XXVIII) butyrate and the desired (-)-(cis)-(2R,5S) target nuceloside that are separated by fractional extraction.

合成路线3

A new process for the preparation of emtricitabine has been described: The esterification of 2-butene-1,4-diol (I) with butyryl chloride and DMAP in pyridine gives the diester (II), which by ozonolysis with O3 in methanol provides the hemiacetal (III). Cyclization of (III) with 2-mercaptoacetic acid in refluxing toluene affords racemic 2-(butyryloxymethyl)-1,3-oxathiolan-5-one (V), which is submitted to optical resolution to afford the (R)-enantiomer (VI). The reduction of (VI) with Li(t-BuO)3AlH, followed by acetylation with acetic anhydride gives 5-(acetoxy)-2(R)-(butyryloxy)-1,3-oxathiolane (VII), which by treatment with HCl in dichloroethane is converted into 2(R)-(butyryloxy)-5-chloro-1,3-oxathiolane (VIII). Condensation of (VIII) with 5-fluoro-bis(trimethylsilyl)cytosine (IX) ­ obtained by silylation of cytosine (X) with HMDS ­ by means of NaHCO3 in dichloroethane gives a diastereomeric mixture of the butyrate nucleosides (XI), which is hydrolyzed with butylamine in methanol yielding the corresponding diastereomeric mixture of the (2R,5S)-isomer, emtricitabine, and the (2R,5R)-isomer (XII). This mixture is separated by crystallization of the corresponding hydrochlorides obtained by treatment with HCl in methanol/dioxane.

合成路线4

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.

合成路线5

The acylation of 2,3-O-isopropylidene-alpha-D-xylofuranose (I) with benzoyl chloride and pyridine gives the dibenzoyl ester (II), which is deprotected by means of H2SO4/HOAc in hot THF to yield 3,5-di-O-benzoyl-alpha-D-xylofuranose (III). The reaction of (III) with PPh3, I2 and imidazole in dichloromethane affords the glycal (IV), which is used in the glycosylation of the N,O-disilylated 5-fluorocytosine (V) by means of NIS in dichloromethane to provide the 2'-alpha-iodonucleoside (VI). The treatment of (VI) with Zn in EtOH/ethyl acetate (HOAc is used as catalyst) gives the unsaturated nucleoside (VII), which is finally debenzoylated by means of butylamine in THF.

合成路线6

The condensation of the known acetate (I) with N,O-disylilated cytosine (II) by means of Tms-OTf or SnCl4 gives the selenium containing nucleoside (III), which is submitted to an oxidative elimination reaction by means of H2O2 and pyridine in dichloromethane to yield the unsaturated nucleoside (IV). Finally, this compound is desilylated by means of TBAF in THF.

合成路线7

The silylated 5-fluorocytosine (I) is coupled with D-ribofuranose tetraacetate (II) in the presence of SnCl4 in acetonitrile to afford the triacetyl 5-fluorocytidine (III). Acylation of (III) with allyl chloroformate (IV) yields carbamate (V). Then, methanolysis of the acetate ester groups of (V) provides 5-fluoro-N-(allyloxycarbonyl)cytidine (VI). Finally, selective oxidation of the primary alcohol group of (VI) with oxygen and PtO2 gives the target carboxylic acid

合成路线8

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合成路线11