1,2-Dichloroethane → 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester

Participants

Reaction Steps

The next steps in this process comprise reacting (FIG. 5, compound 3) with Me2NCH(OMe)2 in DMF to form (FIG. 5, compound 4), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine, which is the amino-protected form of (FIG. 5, compound 3); reacting (FIG. 5, compound 4) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (FIG. 5, compound 4) as N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (FIG. 5, compound 5), where the use of DCM provides the advantage of having greater control over disilyl by-product formation; reacting (FIG. 5, compound 5) with N-Boc-L-valine, EDC and DMAP in DCM at room temperature to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (FIG. 5, compound 6); removing the silyl and amino-protecting groups by reacting (FIG. 5, compound 6) with NH4F in MeOH in the presence of approximately 10 mole equivalents of ethyl acetate to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia, and refluxing the mixture to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester to provide (FIG. 5, compound 2); and finally, reacting (FIG. 5, compound 2) with HCl in EtOH to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (FIG. 5, compound 8) as a final product.

Provenance & Evidence