Methods of preparing 1′-cyano nucleosides
The present disclosure generally describes methods of preparing 1′-cyano nucleosides, such as a compound of Formula (I). For example, the compound of Formula (I) can be prepared from a compound of Formula (II-a) in a flow reactor.
1. A method of preparing a compound of Formula (II-a):
comprising adding a fifth input mixture to a fifth reactor, wherein the fifth input mixture comprises a compound of Formula (V):
an oxidant, and a fifth base,
wherein the fifth reactor provides a fifth output mixture comprising the compound of Formula (II-a).
2. The method of claim 1 , wherein
the oxidant is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, iodobenzene dichloride, iodobenzene diacetate, sodium hypochlorite, 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxo1-3-(1H)-one, dimethyl sulfoxide/pyridine sulfur trioxide, manganese oxide, 2,3-dichloro-5,6-dicyanobenzoquinone, or N-methylmorpholine-N-oxide/tetrapropylammonium perruthenate, or a combination thereof.
3. The method of claim 1 , wherein the fifth base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium phosphate, potassium phosphate, or ammonium acetate, or a combination thereof.
4. The method of claim 1 , wherein the fifth input mixture further comprises a fifth solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, toluene, trifluorotoluene, water, sulfolane, dimethylformamide, N-methylpyrrolidine, dimethyl sulfoxide, methyl acetate, isopropyl acetate, ethyl acetate, and acetonitrile, or a combination thereof.
5. The method of claim 4 , wherein
the oxidant is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl and iodobenzene diacetate;
the fifth base is potassium hydrogen phosphate; and
the fifth solvent is acetonitrile.
6. The method of claim 1 , wherein the fifth reactor is maintained at a temperature of from about −10° C. to about 60° C.
7. The method of claim 6 , wherein the fifth reactor is maintained at a temperature of from about 10° C. to about 30° C.
8. The method of claim 1 , further comprising preparing the compound of Formula (V), the method comprising:
(a) adding a sixth input mixture to a sixth reactor, wherein the sixth input mixture comprises an amine-protecting agent, a sixth base, and a compound of Formula (IV):
wherein the sixth reactor provides a sixth output mixture;
(b) adding a seventh input mixture to a seventh reactor, wherein the seventh input mixture comprises the sixth output mixture, a seventh transmetallating agent, and a compound of Formula (VI):
wherein the seventh reactor provides a seventh output mixture comprising a compound of Formula (V).
9. The method of claim 8 , wherein
the amine-protecting agent is chlorotrimethylsilane, chlorotriethylsilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, 1,2-bis(chlorodimethylsilyl) ethane, trifluoroacetic anhydride, or di-(tert-butyl) dicarbonate.
10. The method of claim 8 , wherein
the sixth base is phenylmagnesium chloride, phenylmagnesium bromide, phenylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, tert-butylmagnesium chloride, phenyllithium, methyllithium, isopropyllithium, tert-butyllithium, sodium hydride, potassium hydride, or calcium hydride, or a combination thereof.
11. The method of claim 8 , wherein the sixth input mixture further comprises a sixth solvent selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, and toluene, or a combination thereof.
12. The method of claim 11 , wherein
the amine-protecting agent is chlorotrimethylsilane;
the sixth base is phenylmagnesium chloride; and
the sixth solvent is tetrahydrofuran (THF).
13. The method of claims 8 , wherein the sixth reactor is maintained at a temperature of from about −70° C. to about 40° C.
14. The method of claim 13 , wherein the sixth reactor is maintained at a temperature of from about −20° C. to about 10° C.
15. The method of claim 8 , wherein
the seventh transmetallating agent is phenylmagnesium chloride, phenylmagnesium bromide, phenylmagnesium iodide, isopropylmagnesium chloride, isopropylmagnesium bromide, tert-butylmagnesium chloride, tert-butylmagnesium bromide, phenyllithium, methyllithium, isopropyllithium, or tert-butyllithium, or a combination thereof.
16. The method of claim 8 , wherein the seventh input mixture further comprises a seventh solvent selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, and toluene, or a combination thereof.
17. The method of claim 16 , wherein
the seventh transmetallating agent is isopropylmagnesium chloride; and
the seventh solvent is tetrahydrofuran (THF).
18. The method of claim 8 , wherein the seventh reactor is maintained at a temperature of from about −70° C. to about 40° C.
19. The method of claim 18 , wherein the seventh reactor is maintained at a temperature of from about −30° C. to about −10° C.
20. A method of preparing a compound of Formula (II-a):
comprising adding a fifth input mixture to a fifth reactor, wherein the fifth input mixture comprises a compound of Formula (V):
an oxidant wherein the oxidant is (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, 9-azabicyclo[3.3.1]nonane N-oxyl, iodobenzene dichloride, iodobenzene diacetate, sodium hypochlorite, 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2 -benziodoxo1-3-(1H)-one, dimethyl sulfoxide/pyridine sulfur trioxide, manganese oxide, 2,3-dichloro-5,6-dicyanobenzoquinone, or N-methylmorpholine-N-oxide/tetrapropylammonium perruthenate, or a combination thereof;
a fifth base wherein the fifth base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium phosphate, potassium phosphate, or ammonium acetate, or a combination thereof; and
a fifth solvent wherein the fifth solvent is dichloromethane, dichloroethane, chloroform, toluene, trifluorotoluene, water, sulfolane, dimethylformamide, N-methylpyrrolidine, dimethyl sulfoxide, methyl acetate,
isopropyl acetate, ethyl acetate, or acetonitrile, or a combination thereof wherein the fifth reactor provides a fifth output mixture comprising the compound of Formula (II-a).