Process of manufacture of 1,3-oxathiolane nucleosides using titanium trichloride mono-isopropoxide
View Patent ↗Processes for the preparation of 1,3-oxathiolane nucleosides are provided that include reacting a 5-O-protected-oxymethyl-1,3-oxathiolane with a silylated nucleoside in the presence of (Cl) 3 Ti(isopropoxide). Using the processes described herein, the compounds can be provided as isolated enantiomers.
1. A process for producing a 1,3-oxathiolane nucleoside comprising reacting a 5-O-protected-oxymethyl-1,3-oxathiolane with a silylated nucleoside in the presence of (Cl) 3 Ti(isopropoxide).
2. The process of claim 1 wherein the nucleoside is a pyrimidine.
3. The process of claim 1 wherein the nucleoside is a purine.
4. The process of claim 1 , wherein the reaction produces a mixture of α and β anomers.
5. The process of claim 1 , wherein the reaction produces nucleosides with high β-selectivity.
6. The process of claim 1 , wherein the nucleoside is bis-silylated cytosine.
7. The process of claim 4 , wherein the mixture of α and β anomers are separated by crystallization.
8. The process of claim 4 , wherein the mixture of α and β anomers are separated by chromatography.
9. The process of claim 8 , wherein the chromatography is achiral.
10. The process of claim 8 , wherein the chromatography is chiral.
11. The process of claim 1 , wherein the 5-O-protected-oxymethyl-1,3-oxathiolane has a 5-O-acyl moiety selected from the group consisting of acetate, propionate, butyrate, benzoate, p-methoxybenzoate and p-(t-butyl)-benzoate.
12. The process of claim 1 , wherein the nucleoside is 6-alkylpurine, N 6 -alkylpurine, N 6 -acylpurine, N 6 -benzylpurine, 6-halopurine, N 6 -acetylenic purine, N 6 -acylpurine, N 6 -hydroxyalkylpurine, 6-thioalkyl purine, N 2 -alkylpurine, N 4 -alkyl-pyrimidine, N 4 -acylpyrimidine, 4-halopyrimidine, N 4 -acetylenic pyrimidine, 4-amino-pyrimidine, N 4 -acylpyrimidine, 4-hydroxyalkylpyrimidine, 4-thioalkylpyrimidine, thymine, cytosine, 6-azapyrimidine, 6-azacytosine, 2-mercaptopyrmidine, 4-mercapto-pyrimidine, uracil, C 5 -alkylpyrimidine, C 5 -benzylpyrimidine, C 5 -halopyrimidine, C 5 -vinylpyrimidine, C 5 -acetylenic pyrimidine, C 5 -acylpyrimidine, C 5 -hydroxyalkyl purine, C 5 -amidopyrimidine, C 5 -cyanopyrimidine, C 5 -nitropyrimidine, C 5 -amino-pyrimidine, N 2 -alkylpurine, N 2 -alkyl-6-thiopurine, 5-azacytosine, 5-azauracil, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, 5-fluorocytosine, adenine, guanine, xanthine, 2,6-diaminopurine, 6-aminopurine, 6-chloropurine or 2,6-dichloro-purine.
13. The process of claim 1 , wherein the nucleoside is cytosine, 5-fluorocytosine, uracil, thymine, adenine, guanine, xanthine, 2,6-diaminopurine, 6-aminopurine, 6-chloropurine or 2,6-dichloropurine.
14. The process of claim 1 , wherein the nucleoside is 5-fluorocytosine.