Process for the preparation of 4-amino 1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one
Processes for the preparation of 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3 -hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one(13, RX-3117) and its intermediates are described.
1. A process for the preparation of (1R,4S,5S)-2-iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5) from (3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (2), comprising:
reacting (3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (2) with iodoform to form 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3).
2. The process of claim 1 , further comprising:
oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4).
3. The process of claim 2 , wherein the step of oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3 -dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) comprises Swern oxidation with diisopropylcarbodiimide, pyridine, trifluoroacetic acid (CF3COOH), and sodium hypochlorite (NaOCl ).
4. The process of claim 2 , further comprising:
reacting 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) with n-BuLi to form (1R,4S,5S)-2-iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5).
5. The process of claim 1 , further comprising:
oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4); and
reacting 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) with n-BuLi to form (1R,4S,5S)-2-Iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5).
6. A process for the preparation of 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3), comprising:
reacting (3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (2) with iodoform to form 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3).
7. A process for the preparation of 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy -3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13), comprising:
reacting (3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (2) with iodoform to form 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3); and
isolating 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one(13).
8. The process of claim 7 , further comprising:
oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4).
9. The process of claim 8 , wherein the step of oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) comprises Swern oxidation with diisopropylcarbodiimide, pyridine, trifluoroacetic acid (CF3COOH), and sodium hypochlorite (NaOCl).
10. The process of claim 8 , further comprising:
reacting 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) with n-BuLi to form (1R,4S,5S)-2-iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5).
11. The process of claim 10 , further comprising:
oxidizing (1R,4S,5S)-2-iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5) to form (3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one(6).
12. The process of claim 7 , further comprising:
oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4); and
reacting 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) with n-BuLi to form (1R,4S,5S)-2-Iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5).
13. The process of claim 7 , further comprising:
reacting 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl) pyrimidin-2(1H)-one(12) with an acid to form 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13).
14. The process of claim 13 , further comprising:
reacting (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate(11) with cytosine to form 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl) pyrimidin-2(1H)-one(12).
15. The process of claim 14 , further comprising:
reacting (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) with MsCl to form (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11).
16. The process of claim 13 , further comprising:
reacting (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol(10) with MsCl to form (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate(11); and
reacting (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11) with cytosine to form 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH -cyclopenta[d][1,3]dioxol -4-yl)pyrimidin-2(1H)-one(12).