Process for making Hepatitis B core protein modulators
The present disclosure provides, in part, a process for preparing compounds (I) having allosteric effector properties against Hepatitis B virus Cp.
1. A process for preparing a compound represented by Formula I:
wherein w is 0, 1, or 2;
R 1 is selected from the group consisting of C 1-6 alkyl (optionally substituted with one, two or three halogens), phenyl, and a monocyclic 5-6 membered ring system containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein phenyl and the monocyclic 5-6 membered ring containing one or more heteroatoms may optionally be substituted with one or more substituents each independently selected from R 11 ;
R 11 is selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, and —S(O) w —C 1-6 alkyl (wherein w is 0, 1 or 2);
R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, and C 1-6 alkoxy; wherein C 1-6 alkyl and C 1-6 alkoxy may be optionally substituted with one, two, three or more substituents each independently selected from the group consisting of halogen, hydroxyl, and C 1-6 alkoxy;
comprising:
amidating a compound of Formula II:
to provide a compound of Formula III:
oxidizing the compound of Formula III to provide a compound of Formula IV:
cyclizing the compound of Formula IV to provide a thiazole compound of Formula V:
hydrolyzing the compound of Formula V to provide a compound of Formula VI:
coupling the compound of Formula VI with a tricyclic compound of Formula VII:
wherein w is 0, 1 or 2;
to provide the compound of Formula I.
2. The process of claim 1 , wherein amidating the compound of Formula II comprises contacting the compound of Formula II with an amine base and an acylating agent.
3. The process of claim 1 , wherein the acylating agent is an acid anhydride or an acid chloride.
4. The process of claim 1 , wherein the acylating agent is trifluoroacetic anhydride.
5. The process of claim 1 , wherein the amine base is triethylamine.
6. The process of claim 1 , wherein oxidizing the compound of Formula III comprises contacting the compound of Formula III with a chromium-based oxidizing reagent.
7. The process of claim 6 , wherein the chromium-based oxidizing reagent is Jones reagent.
8. The process of claim 1 , wherein cyclizing the compound of Formula IV comprises contacting the compound of Formula IV with a thionating reagent.
9. The process of claim 8 , wherein the thionating reagent is phosphorus pentasulfide.
10. The process of claim 1 , wherein hydrolyzing the compound of Formula V comprises contacting the compound of Formula V with an aqueous amine base.
11. The process of claim 10 , wherein the aqueous amine base is aqueous methylamine.
12. The process of claim 1 , wherein coupling the compound of Formula VI with the compound of Formula VII is conducted in the presence of a coupling agent.
13. The process of claim 12 , wherein the coupling agent is hydroxybenzotriazole/ethyl-(N′,N′-dimethylamino)propylcarbodiimide hydrochloride.
14. The process of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, fluoride, chloride, methyl, and methoxy.
15. The process of claim 1 , wherein R 1 is trifluoromethyl.
16. The process of claim 1 , wherein the compound of Formula VI is:
17. The process of claim 1 , wherein the compound of Formula I is: