Synthesis of an antiviral azasugar triphosphate
Provided are methods of making the active 5′-triphosphate form of galidesivir (compound 1) and the active 5′-triphosphate form of azasugar nucleoside analogues (compound 2): a potent anti-viral compound useful for broad spectrum treatment, suppression, and prevention of viral infections. The syntheses of compound 1 and compound 2 can be achieved via selective formation of protected intermediate 1b and protected intermediate 2b, respectively:
1 . A method of preparing compound 2b1 or a salt thereof:
comprising combining compound 2b or a salt thereof and a phosphorylation reagent, thereby producing compound 2b1 or a salt thereof;
wherein:
compound 2b is represented by
B is a heterocyclic base;
R 0 , independently for each occurrence, is selected from the group consisting of H, C 1 -C 6 alkyl, and C(O)—C 1 -C 6 alkyl;
R 2 and R 3 are each independently H, halide, azide, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, CN, OR 0 , —C(O)OR 10 , or SR 0 ;
or R 2 and R 3 , taken together with the intervening atoms, form an optionally substituted fused heterocycloalkyl;
R 10 , independently for each occurrence, is selected from the group consisting of H, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
R 11 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, OR 0 , and CN;
R 12 and R 13 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, OR 0 , C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, CN, azide, and halide; and
R 14 is selected from the group consisting of H, C 1 -C 6 alkyl, OR 0 , C 1 -C 6 alkynyl, CN, azide, and halide.
2 . The method of claim 1 , wherein the phosphorylation reagent comprises phosphorus oxychloride.
3 . The method of claim 1 , further comprising subsequently combining compound 2b1 or a salt thereof with a pyrophosphate reagent, thereby producing compound 2c or a salt thereof;
wherein:
compound 2c is represented by
4 . The method of claim 3 , wherein the pyrophosphate reagent is pyrophosphoric acid or a pyrophosphate salt.
5 . The method of claim 4 , wherein the pyrophosphate reagent is a pyrophosphate salt.
6 . The method of claim 5 , wherein the pyrophosphate salt is bis(tributylammonium)pyrophosphate.
7 . The method of claim 1 , wherein the method does not comprise isolating compound 2b1 or a salt thereof.
8 . The method of claim 1 , comprising combining compound 2c or a salt thereof and a deprotection reagent, thereby producing compound 2 or a salt thereof;
wherein:
compound 2 is represented by
9 . The method of claim 8 , wherein the deprotection reagent is aqueous ammonia or an amine.
10 . The method of claim 9 , wherein the deprotection reagent is aqueous ammonia.
11 . The method of claim 1 , further comprising combining compound 2a or a salt thereof and an acylating reagent, thereby producing compound 2b or a salt thereof; wherein:
compound 2a is represented by
12 . The method of claim 11 , wherein the acylating reagent has the following structure:
and X represents a leaving group.
13 . The method of claim 12 , wherein X is O-alkyl.
14 . The method of claim 11 , wherein the acylating reagent is ethyl trifluoroacetate.
15 . The method of claim 11 , wherein the step of combining compound 2a or a salt thereof and the acylating reagent further comprises a base.
16 . The method of claim 15 , wherein the base is triethylamine.
17 . The method of claim 1 , further comprising purifying compound 2 or a salt thereof via chromatography.
18 . The method of claim 17 , wherein the chromatography is column chromatography.
19 . The method of claim 18 , wherein the column chromatography comprises anion-exchange chromatography and reverse-phase chromatography.
20 . The method of claim 19 , wherein the column chromatography comprises (step i) anion-exchange chromatography; (step ii) reverse-phase chromatography; and (step iii) anion-exchange chromatography.
21 . The method of claim 20 , wherein at least one of the column chromatography steps i-iii comprises a gradient of an aqueous buffer as a mobile phase.
22 . The method of claim 21 , wherein the aqueous buffer is aqueous triethylammonium bicarbonate.
23 . The method of claim 17 , further comprising drying compound 2 or a salt thereof prior to the purification step.
24 . The method of claim 1 , wherein compound 2b1 has the structure of compound 1b1:
and
compound 2b has the structure of compound 1b:
25 . The method of claim 3 , wherein compound 2c has the structure of compound 1c:
26 . The method of claim 8 , wherein compound 2 has the structure of compound 1:
27 . The method of claim 11 , wherein compound 2a has the structure of compound 1a:
28 . A compound having the structure:
wherein:
B is a heterocyclic base;
R 0 , independently for each occurrence, is selected from the group consisting of H, C 1 -C 6 alkyl, and C(O)—C 1 -C 6 alkyl;
R 2 and R 3 are each independently H, halide, azide, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, CN, OR 0 , —C(O)OR 10 , or SR 0 ;
or R 2 and R 3 , taken together with the intervening atoms, form an optionally substituted fused heterocycloalkyl;
R 10 , independently for each occurrence, is selected from the group consisting of H, C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;
R 11 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, OR 0 , and CN;
R 12 and R 13 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, OR 0 , C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, CN, azide, and halide; and
R 14 is selected from the group consisting of H, C 1 -C 6 alkyl, OR 0 , C 1 -C 6 alkynyl, CN, azide, and halide.
29 . The compound of claim 28 , wherein the compound has a structure selected from the group consisting of
30 . The compound of claim 28 , wherein the compound has a structure selected from the group consisting of:
31 . The compound of claim 28 , wherein the compound has a structure selected from the group consisting of:
32 . The compound of claim 28 , wherein the compound has the structure:
or a salt thereof.
33 . A compound having the structure:
wherein:
B is a heterocyclic base.