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 maribavir polymorph Form VI, wherein the method comprises crystallizing maribavir Form VI from a crystallization mixture comprising maribavir, or a pharmaceutically acceptable salt thereof, and isopropyl acetate.
2. The method of claim 1 , wherein the crystallization mixture comprises less than 0.2% w/w of water.
3. The method of claim 1 , wherein the crystallization mixture comprises less than 0.09% w/w of water.
4. The method of claim 1 , wherein the crystallization mixture comprises between about 17-20% w/w of maribavir, or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 , wherein the crystallization mixture comprises between about 17-19% w/w of maribavir, or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein a seed crystal is added to the crystallization mixture.
7. The method of claim 6 , wherein the seed crystal is maribavir, or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , comprising a step of reacting compound
or a salt thereof, to provide maribavir, or a pharmaceutically acceptable salt thereof, wherein maribavir seed crystal is added in an amount of between about 0.05% and 0.30% w/w relative to compound 3, or a salt thereof.
9. The method of claim 8 , wherein the seed crystal is added in an amount of about 0.15% w/w relative to compound 3, or a salt thereof.
10. The method of claim 8 , wherein the size of the seed crystal (d(50)) is between about 2.25-7.00 μm.
11. The method of claim 10 , wherein the size of the seed crystal (d(50)) is between about 2.75-6.25 μm.
12. The method of claim 1 , wherein crystallization further comprises heating the crystallization mixture to a temperature T 3 , wherein temperature T 3 is between about 77 and about 88° C.
13. The method of claim 1 , wherein a secondary solvent is added to the crystallization mixture, wherein the secondary solvent is toluene.
14. The method of claim 8 , wherein after the seed crystal is added, the crystallization mixture is aged for about 30 minutes.
15. The method of claim 14 , wherein, after aging the crystallization mixture, additional secondary solvent is added to the crystallization mixture in a relative amount of about 11/7 of total primary solvent (kg/kg).
16. The method of claim 15 , wherein, after the additional secondary solvent is added, the crystallization mixture is agitated for about 1 hour at temperature T 3 , wherein temperature T 3 is between about 77 and about 88° C.
17. The method of claim 16 , wherein, after agitating the crystallization mixture at temperature T 3 , the crystallization mixture is cooled to temperature T 4 , wherein temperature T 4 is between about 3° C. and about 7° C., wherein the crystallization mixture is cooled to temperature T 4 over about 3 hours, and wherein the crystallization mixture is agitated at temperature T 4 for about 3 to about 18 hours.
18. The method of claim 8 , further comprising filtering or washing the crystallization mixture to provide a filtered mixture.
19. The method of claim 18 , wherein the crystallization mixture is washed with toluene.
20. The method of claim 18 , further comprising drying the filtered mixture.