Viral inhibitors, the synthesis thereof, and intermediates thereto
The present disclosure discloses compositions comprising maribavir, methods of providing the same, and compositions providing intermediates useful in providing maribavir. Maribavir (((2S,3S,4R,5S)-2-(5,6-dichloro-2-(isopropylamino)-1H-benzo[d]imidazol-1-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol) is a benzimidazole riboside and is an orally available antiviral medication against cytomegalovirus (CMV).
1. A method of preparing compound 2
or a salt thereof, comprising
reacting compound 5:
or a salt thereof,
with compounds 6 and 7:
to provide compound 2,
wherein the reaction takes place in the presence of 1,4-dioxane.
2. The method of claim 1 , wherein the method further produces one or more of the following compounds:
or a salt thereof.
3. The method of claim 2 , wherein compound 9 is produced in an amount less than 0.1% w/w, relative to compound 2.
4. The method of claim 2 , wherein compound 10 is produced in an amount less than 0.1% w/w, relative to compound 2.
5. The method of claim 2 , wherein compound 11 is produced in an amount less than 0.1% w/w, relative to compound 2.
6. The method of claim 2 , wherein compound 12 is produced in an amount less than 0.1% w/w, relative to compound 2.
7. The method of claim 1 , wherein compound 6, or a salt thereof, is present at an amount of about 0.90 to about 1.09 equivalents relative to compound 5, or a salt thereof.
8. The method of claim 7 , wherein compound 6, or a salt thereof, is present at an amount of about 1.00 equivalents relative to compound 5, or a salt thereof.
9. The method of claim 7 , wherein compound 6, or a salt thereof, is present at an amount of about 1.04 equivalents relative to compound 5, or a salt thereof.
10. The method of claim 7 , wherein compound 7, or a salt thereof, is present at an amount of about 1.03 to about 1.13 equivalents relative to compound 5, or a salt thereof.
11. The method of claim 10 , wherein compound 7, or a salt thereof, is present at an amount of about 1.08 equivalents relative to compound 5, or a salt thereof.
12. The method of claim 1 , wherein the reaction of compound 5 or a salt thereof, with compounds 6 and 7 comprises heating the reaction mixture to a temperature T 7 wherein the temperature T 7 is about 100° C.; and maintaining the reaction at temperature T 7 for between about 14 and about 15 hours.
13. The method of claim 12 , wherein, after heating to a temperature T 7 , the method further comprises cooling the reaction mixture to a temperature T& wherein the temperature T 8 is between about 60° C. and about 90° C. and wherein the reaction mixture is cooled to temperature T 8 at a rate of between about 5° C./hr and about 10° C./hr.
14. A method of preparing maribavir or a salt thereof comprising preparing compound 2 according to the method of claim 1 and further comprising:
reacting compound 2 or a salt thereof with compound 8 to provide compound 3 or a salt thereof
and
reacting compound 3 or a salt thereof to provide maribavir.
15. The method of claim 14 , wherein the reaction of compound 3 or a salt thereof to provide maribavir or a salt thereof comprises phase separation and/or extraction.
16. The method of claim 15 , wherein the phase separation and/or extraction comprises adding a first phase separation solvent and a second phase separation solvent.
17. The method of claim 15 , wherein the phase separation and/or extraction comprises adjusting the pH of the reaction mixture to between about 6 and about 8.
18. The method of claim 14 , wherein the reaction of compound 3 or a salt thereof to provide maribavir or a salt thereof further comprises distillation and/or solvent exchange of the reaction mixture.
19. The method of claim 14 , wherein the reaction of compound 3 or a salt thereof to provide maribavir or a salt thereof further comprises crystallization of maribavir.
20. The method of claim 14 , wherein the reaction of compound 2 or a salt thereof with compound 8 to provide compound 3 or a salt thereof comprises heating to a temperature T b wherein T b is between about 65° C. and about 80° C. and aging and/or stirring the reaction mixture at temperature T b for from about 1 to about 48 hours.
21. The method of claim 20 , further comprising, following the aging and/or stirring, cooling the reaction mixture to a temperature T c wherein T c is between about 16° C. and about 30° C.
22. The method of claim 14 , wherein the reaction of compound 2 or a salt thereof with compound 8 to provide compound 3 or a salt thereof further comprises washing the reaction mixture with an aqueous base.
23. The method of claim 14 , wherein the reaction of compound 2 or a salt thereof with compound 8 to provide compound 3 or a salt thereof further comprises distillation and/or solvent exchange.
24. The method of claim 14 , further comprising crystallization of compound 3 and formation of a hydrochloride salt of compound 3.
25. The method of claim 14 , wherein the reaction of compound 3 or a salt thereof to provide maribavir or a salt thereof comprises a base.
26. The method of claim 25 , wherein the base is NaOH.