Synthetic methods
Methods for the preparation of the following compound are disclosed. The compound can be incorporated into pharmaceutical formulations, including tablets and such tablets can be used for treating cholestatic liver diseases.
1. A method for synthesis of the compound GSK2330672:
comprising the step of preparation of intermediate A, (R)-2-butyl-2-ethyloxirane
followed by conversion of (R)-2-butyl-2-ethyloxirane through one or more steps to GSK2330672.
2. The method of claim 1 further comprising the step of reacting (R)-2-butyl-2-ethyloxirane with 3-hydroxy-4-methoxythiophenol to produce intermediate C:
3. The method of claim 2 further comprising the step of converting intermediate C via a stereoselective Ritter reaction to intermediate E:
4. A method for synthesis of the compound GSK2330672:
comprising the step of preparation of intermediate H:
followed by conversion of intermediate H through one or more steps to GSK2330672.
5. The method of claim 1 further comprising the step of preparing intermediate H:
6. The method of claim 4 further comprising the step of converting intermediate H to intermediate I:
7. The method of claim 6 further comprising the step of converting intermediate Ito intermediate J:
8. The method of claim 1 wherein said compound A is made by the kinetic resolution of racemic 2-butyl-2-ethyloxirane with an epoxide hydrolase.
9. The method of claim 8 wherein said epoxide hydrolase is from Agromyces mediolanus ZJB1202030ID: JX467176.
10. The method of claim 9 wherein said epoxide hydrolase is a mutant N240D of the epoxide hydrolase from Agromyces mediolanus ZJB1202030ID:
JX467176.
11. The method of claim 8 wherein the concentration of said racemic 2-butyl-2-ethyloxirane is from 200-330 g/L.
12. A method for synthesizing the compound GSK2330672:
comprising the steps of:
preparing intermediate A, (R) -2 -butyl-2 -ethyloxirane
by kinetic resolution of racemic 2-butyl-2-ethyloxirane with an epoxide hydrolase;
reacting (R)-2-butyl-2-ethyloxirane with 3-hydroxy-4-methoxythiophenol to produce intermediate C:
converting intermediate C via a stereoselective Ritter reaction to intermediate E:
benzoylating intermediate E to produce intermediate F:
cyclizing intermediate F followed by diastereoselective sulfoxidation to produce intermediate H:
reducing the imine of intermediate H to produce intermediate I:
and
sulfoxidizing intermediate Ito produce intermediate J:
followed by conversion of intermediate J through one or more steps to GSK2330672.
13. The method of claim 12 wherein the epoxide hydrolase is from Agromyces mediolanus ZJB1202030ID: JX467176.
14. The method of claim 13 wherein the epoxide hydrolase is a mutant N240D of the epoxide hydrolase from Agromyces mediolanus ZJB1202030ID:
JX467176.
15. The method of claim 12 wherein the concentration of the racemic 2-butyl-2-ethyloxirane is from 200-330 g/L.
16. The method of claim 12 wherein the epoxide hydrolase is used in a form selected from the group consisting of whole cell, lyophilized unclarified lysate, lyophilized clarified lysate, and immobilized clarified lysate.
17. The method of claim 16 wherein the epoxide hydrolase used is in the lyophilized clarified lysate form.
18. The method of claim 12 wherein the step of benzoylating intermediate E to produce intermediate F includes triflic acid and benzoyl chloride.
19. The method of claim 1 wherein the epoxide hydrolase is used in a form selected from the group consisting of whole cell, lyophilized unclarified lysate, lyophilized clarified lysate, and immobilized clarified lysate.
20. The method of claim 19 wherein the epoxide hydrolase used is in the lyophilized clarified lysate form.
21. The method of claim 3 further comprising the step of benzoylating intermediate E using triflic acid and benzoyl chloride to produce intermediate F: