Method for the synthesis of 2',3'-dideoxy-2',3'-didehydronucleosides
The present invention is an efficient synthetic route to 2′,3′-dideoxy-2′,3′-didehydro-nucleosides from available precursors with the option of introducing functionality as needed, such as, the 2′,3′-dideoxy and 2′- or 3′-deoxyribo-nucleoside analogs as well as additional derivatives obtained by subsequent functional group manipulations. Briefly, the present invention discloses a method for the preparation of β-D and β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleosides starting from appropriately substituted ribonucleosides in two, optionally three steps: Step (1) a haloacylation, such as haloacetylation, and in particular, bromoacetylation; Step (2) a reductive elimination; and optionally, Step (3) a deprotection. The haloacylation of step (1) can form the 2′-acyl-3′-halonucleoside, the 3′-acyl-2′-halonucleoside, or a mixture thereof.
1 - 46 . (canceled)
47 . A compound of Formula (VI) or (VI*):
or a pharmaceutically acceptable salt thereof, wherein:
Q is R 1 CH 2 — or R 1 CH 2 C(═O)OC(R 2 ) 2 —;
R 1 is H or C 1 -C 6 alkyl;
R 2 is independently selected from methyl, ethyl, and propyl;
R 3 is Cl, Br, or IV; and
R 4 is R 1 CH 2 C(═O)O—.
48 . A compound of claim 47 of Formula (VI-a) or (VI*-a):
or a pharmaceutically acceptable salt thereof.
49 . A compound of Formula (VII):
or a pharmaceutically acceptable salt thereof, wherein:
Q is R 1 CH 2 — or R 1 CH 2 C(═O)OC(R 2 ) 2 —;
R 1 is H or C 1 -C 6 alkyl; and
R 2 is independently selected from methyl, ethyl, and propyl.
50 . A compound of claim 49 of Formula (VII-a):
or a pharmaceutically acceptable salt thereof.
51 . A process for the preparation of a β-D- and β-L-2′,3′-dideoxy-2′,3′-didehydronucleoside comprising:
a) activating a compound of structure (1)
wherein B is a pyrimidine or purine base; and
Y is O, S or CH 2 ;
with an acyl halide of the formula X—C(═O)R 1 , X—C(═O)C(R 1 ) 2 OC(═O)R 1 or X—C(═O)phenylC(═O)OR 1 ;
wherein X is a halogen (F, Cl, Br or I), and
each R 1 is independently hydrogen, lower alkyl, alkyl, aryl or phenyl;
to form a compound of structure (2)
wherein R is R 1 , —C(R 1 ) 2 OC(═O)R 1 or -phenylC(═O)OR 1 ; and
at least one R is halogen (F, Cl, Br or I), and at least one R is an acyl of the formula —OC(═O)R 1 ; and then
b) reducing the compound of structure (2) with a reducing agent to form a 2′,3′-dideoxy-2′,3′-didehydro-nucleoside of structure (3)
c) optionally deprotecting the nucleoside if necessary.
52 . The process of claim 51 , wherein B is 5-fluorouracil or 5-fluorocytosine.
53 . The process of claim 51 , wherein Y is 0.
54 . The process of claim 51 , wherein the β-D- and β-L-2α,3α-dideoxy-2′,3′-didehydro-nucleoside is D4FC.
55 . The process of claim 51 , wherein the β-D- and β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleoside is β-D-D4FC.
56 . The process of claim 51 , wherein the β-D- and β-L-2β,3′-dideoxy-2′,3′-didehydro-nucleoside is β-D-D4FC.
57 . The process of claim 51 , further comprising reducing the β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleoside into a β-D or β-L-2′ or 3′-deoxyribo-nucleoside.
58 . The process of claim 51 , further comprising converting the β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleoside bearing a different nucleobase.
59 . The process of claim 58 , wherein the β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-nucleoside is β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorouridine which is converted to a β-D or β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine.