合成路线1

合成路线2

合成路线3

合成路线4

合成路线5

合成路线6

The selective tosylation of L-gulose with tosyl chloride in pyridine, followed by complete acetylation with acetic anhydride gives tetraacetyl-6-O-tosyl-L-gulose (II), which is treated with HBr in AcOH to yield the bromo derivative (III). The reaction of (III) with potassium O-ethylxanthate in refluxing acetone, followed by deacetylation with NH4OH in methanol affords 1,6-thioanhydro-L-gulopyranose (IV). The selective oxidative cleavage of (IV) by means of NaIO4, followed by reduction with NaBH4 and protection of the resulting diol with acetone and TsOH provides the acetonide (V), which is silylated at the primary OH group with TBDMS-Cl giving the silyl ether (VI). Elimination of the acetonide group with TsOH in methanol yields the diol (VII), which is cleaved with Pb(OAc)4 and oxidized with PDC in DMF to afford the carboxylic acid (VIII). The treatment of (VII) with Pb(OAc)4/pyridine in THF furnishes the diacetate (IX), which is condensed with N4-acetyl-5-fluoro-O-(trimethylsilyl)cytosine (X) by means of TBDMS-OTf in dichloromethane yielding a mixture of the desired (-)(2R,5S)-isomer (XI) along with its (+)-(2R,5R)-isomer that is separated by column chromatography. Finally, deacetylation of (XI) with ammonia in methanol, followed by desilylation with TBAF in THF afforded the target compound.

合成路线7

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8

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9

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.