合成路线1

Compound can be prepared in three different ways: 1) The reduction of cytidine (I) with H2 over Rh/Al2O3 in water in a Parr apparatus at 2.8 bar gives 3,4,5,6-tetrahydrocytidine (II), which is then hydrolyzed with water at pH 5.5. 2) The reduction of uridine (III) with H2 over Rh/Al2O3 as before gives 5,6-dihydrouridine (IV), which is then reduced again with NaBH4 in water or with H2 over Rh/Al2O3 in water containing ammonia. 3) The reduction of (III) can also be performed in a single step with H2 over Rh/Al2O3 in water containing NH3, in a Parr apparatus at 2.94 bar.

合成路线2

A new synthesis of 2',3'-dideoxyadenosine has been described: The reaction of uridine (I) with methyl orthoformate and p-toluenesulfonic acid gives the cyclic orthoester (II), which is acetylated with acetic anhydride at 100 C to the acetate (III). The reaction of (III) with acetic anhydride at temperatures over 120 C yields 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydrouridine (IV), which is hydrogenated to 5'-O-acetyl-2',3'-dideoxyuridine (V).

合成路线3

2) The reaction of uridine (I) with methyl orthoformate and p-toluenesulfonic acid gives the cyclic orthoester (II), which is acetylated with acetic anhydride at 100 C, yielding the 5'-acetoxy derivative (III). The reaction of (III) with acetic anhydride at temperatures over 120 C affords 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydrouridine (IV), which is hydrogenated to 5'-O-acetyl-2',3'-dideoxyuridine (V). Hydrolysis of (V) affords 2',3'-dideoxyuridine (VI), which is finally submitted to a transdideoxyribosylation with hypoxanthine (VII) by incubation in an appropriate medium with Escherichia coli AJ 2595 resting cells.

合成路线4

The acetylation of uridine (I) with acetic anhydride gives the 2',3',5'-triacetyl derivative (II), which is treated with SOCl2 and sodium ethoxide yielding the 4-ethoxypyrimidinone (III). The partial protection of (III) with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (IV) yields the silylated compound (V), which is oxidized with oxalyl chloride to the silylated furanone (VI). The reaction of (VI) with fluoromethyl phenyl sulfone (A) by means of diethyl chlorophosphate (B) and lithium hexamethyldisylazide in THF affords the fluorovinyl sulfone (VII) as a mixture of (E) and (Z) isomers that is separated by flash chromatography. The (Z)-isomer (VII) is treated with tributyl tin hydride and AIBN in refluxing benzene to give the fluorovinyl stannane (VIII), which is finally treated with CsF and NH3 in refluxing methanol to afford the target compound.

合成路线5

INS-365 can also been obtained by the following ways: 4) Dimerization of uridine-5'-monophosphate tributyl-ammonium salt (I) with bis(tributylammonium) pyrophosphate (II) by means of CDI, followed by purification by semipreparative ion­exchange chromatography. 5) Dimerization of uridine-5'-monophosphate tributyl-ammonium salt (I) with pyrophosphoryl chloride (III) in pyridine, followed by chromatographic purification as before. 6) Condensation of uridine (IV) with POCl3 and bis(tributylammonium) pyrophosphate (II) by means of tributylamine in trimethyl phosphate, followed by chromatographic purification as before. 7) Dimerization of uridine-5'-diphosphate tributylammonium salt (V) by means of CDI in DMF, followed by purification over Dowex 50Wx4 Na+. 8) Condensation of uridine-5'-triphosphate tributylammonium salt (VI) with uridine-5'-monophosphate tributyl-ammonium salt (I) by means of DCC in DMF, followed by chromatographic purification as before. 9) Reaction of uridine-5'-monophosphate tributylammonium salt (I) with CDI in DMF, followed by condensation with uridine-5'-triphosphate (VI) and chromatographic purification as before.

合成路线6