5) The benzoylation of 2'-deoxyinosine (I) with benzoyl chloride in pyridine gives the 5'-O-benzoyl derivative (II), which is treated with 1,1'-thiocarbonyldiimidazole (DTI) in DMF to afford the 2'-O-thiocarbonyl derivative (III). The reaction of (III) with bis(tributyltin)oxide, polymethylhydroxysilane and AIBN in refluxing dioxane yields 5'-O-benzoyl-2',3'-dideoxyinosine (IV), which is finally deprotected with anhydrous NH3 in methanol. Another microbial conversion of 2',3'-dideoxyuridine to 2',3'-dideoxyinosine by transdideoxyribosylation with hypoxanthine in a culture medium of Escherichia coli ATCC 10798 is described, and industrially applicable methods for the purification of enzymatically or microbially obtained dideoxyinosines are reported.
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).
The hydrolysis of (V) affords 2',3'-dideoxyuridine (VI), which is finally submitted to transdeoxyribosilation with adenine (VII) by means of Escherichia coli AJ-2595 microorganisms.
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.
This compound is prepared by two related ways: 1) The partial silylation of adenosine (I) with tert-butyldimethylsilyl chloride and imidazole gives 5'-O-(tert-butyldimethylsilyl)adenosine (II), which by reaction with 1,1'-thiocarbonyldiimidazole (III) in hot DMF is converted into 5'-O-(tert-butyldimethylsilyl)-2',3'-O-thionocarbonyladenosine (IV). The desulfurization of (IV) with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine (V) or triethyl phosphite in THF yields 5'-O-(tert-butyldimethylsilyl)-2',3'-didehydro-2',3'-dideoxyadenosine (VI), which is deprotected with tetrabutylammonium fluoride in THF affording 2',3'-didehydro-2',3'-dideoxyadenosine (VII). Finally, this compound is hydrogenated with H2 over Pd/C in methanol. 2) The reaction of silylated adenosine (II) with CS2 and NaOH in DMSO, followed by methylation with methyl iodide gives 5'-O-(tert-butyldimethylsilyl)-2',3'-bis-O-[(methylthio)thiocarbonyl]ad enosine (VIII), which is desulfurized with tributyltin hydride and AIBN in refluxing toluene to yield the dideoxy-didehydroadenosine (VI), already obtained.
3) The reaction of inosine (I) with tert-butyldimethylsilyl chloride by means of imidazole in DMF gives the 5'-O-silyl derivative (II), which by reaction with CS2 and 3-bromopropionitrile by means of NaOH in DMSO is converted into 5'-O-(tert-butyldimethylsilyl)-2',3'-bis-O-(2-cyanoethyldithiocarbonyl)inosine (III). The reaction of (III) with tri-n-butyltin hydride and AIBN in refluxing toluene affords 5'-O-(tert-butyldimethylsilyl-2',3'-dideoxy-2',3'-didehydroinosine (IV), which is deprotected with tetrabutylammonium fluoride in THF to 2',3'-dideoxy-2',3'-didehydroinosine (V). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol - water. 4) The reaction of (II) with 1,1'-thiocarbonyldiimidazole (DTI) in DMF gives 5'-O-(tert-butyldimethylsilyl)-2',3'-O-(thionocarbonyl)inosine (VI), which by reaction with refluxing triethyl phosphite is converted into the didehydro derivative (IV), already obtained (5).
A new synthesis of 2',3'-dideoxyadenosine has been described: The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol - p-toluenesulfonic acid to the ester (III). The selective reduction of (III) with NaBH4 in ethanol yields (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride as usual, affording the benzoate (V). The selective reduction of (V) with disiamyl borane in THF gives the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane yields the tetrahydrofuryl bromide (VIII), which is condensed with the silylated adenine (IX) to afford 5'-O-benzoyl-2',3'-dideoxyadenosine (X). Finally, this compound is deprotected with NH3 in methanol.
1) The stereospecific deamination - lactonization of L-glutamic acid (I) with NaNO2 - HCl in water gives (S)-(+)-gamma-carboxy-gamma-butyrolactone (II), which is esterified with ethanol and p-toluenesulfonic acid in the usual way, yielding the ethyl ester (III). The selective reduction of (III) with NaBH4 in ethanol affords (S)-(+)-gamma-(hydroxymethyl)-gamma-butyrolactone (IV), which is benzoylated with benzoyl chloride to the benzoate (V). The selective reduction of (V) with disiamyl borane in THF yields the alcohol (VI), which is acetylated with acetic anhydride in pyridine to the acetate (VII). The reaction of (VII) with trimethylsilyl bromide in dichloromethane affords the tetrahydrofuryl bromide (VIII), which is then condensed with the adenine (IX), giving 5'-O-benzoyl-2',3'-dideoxyadenosine (X). The deprotection of (X) with NH3 in methanol yields 2',3'-dideoxyadenosine, which is finally deaminated enzymatically with the enzyme adenosine deaminase.
A new synthesis of ddI has been described: The reaction of inosine (I) with 2-acetoxyisobutyryl bromide (II) gives a mixture of two bromodiacyloxy derivatives (IIIa) and (IIIb) that, without separation, are hydrolyzed either with ammonia in methanol or with the pair Zn-Cu in the same solvent, yielding a mixture of the 2- and 3-bromo derivatives (IVa) and (IVb). The acylation of this mixture with chlorothionoformic acid O-phenyl ester and dimethylaminopyridine (DMAP) in acetonitrile gives a new mixture of the thiono esters (Va) and (Vb), which is treated with tributyltin hydride and azoisobutyronitrile (AIBN) in refluxing benzene to yield 5'-O-(2-acetoxyisobutyryl)-2',3'-didehydro-2',3'-dideoxyinosine (VI). The hydrolysis of (VI) with ammonia in methanol affords 2',3'-didehydro-2',3'-dideoxyinosine (VII), which is finally hydrogenated with H2 over Pd/C.
A new synthesis of didanosine has been described: Treatment of 2'-deoxyadenosine (I) with adenosine deaminase (ADA) in water gives 2'-deoxyinosine (II), which is treated with vinyl acetate (III) and Candida antarctica lipase (CAL) in hot pyridine yielding 5'-O-acetyl-2'-deoxyinosine (IV). The reaction of (IV) with phenyl chlorothionoformate (V) and DMAP in acetonitrile affords the corresponding thiocarbonate (VI), which is treated with tributylstannane and AIBN in hot toluene to provide 5'-O-acetyl-2',3'-dideoxyinosine (VII). Finally, this compound is deacetylated with NH3 in methanol.