Method of synthesizing enantiopure mexiletine analogues and novel β-thiophenoxy and pyridyl ethers
View Patent ↗A practical and efficient procedure for the enantioselective synthesis of mexiletine analogues using 10% of a novel spiroborate ester as chirality transfer agent is presented. A variety of mexiletine analogues were prepared with excellent enantioselectivities (91-97% ee) in good yield from readily available starting materials. The developed methodology was also successfully applied for the synthesis of novel β-amino ethers containing thiophenyl and pyridyl fragments.
1. A method of synthesizing enantiopure Mexiletine Analogues and Novel β-Thiophenoxy and Pyridyl ethers comprising: reducing an O-benzyl oxime having the formula I:
where R is a substituted or unsubstituted, alkyl, aryl group; Y is an oxygen atom or a sulfur atom and Ar is an aryl, alkyl, Pyridyl group; wherein said reduction is done in the presence of a catalyst agent having the formula II:
where, the R and R1 groups are equal or different; a hydrogen atom or a substituted or unsubstituted, aryl, alkyl, cycloalkyl or aralkyl; R2 and R 3 groups are different; a hydrogen atom or a substituted or unsubstituted, alkyl, aryl, aralkyl group; and the R4 group is a H or a cycloalkyl or aralkyl group; and wherein the substituents R, R1, R2, R3, and R4 groups are substantially non-reactive.
2. The method of claim 1 , wherein said O-benzyl oxime is reduced to form a mexiletine analogue having the formula III:
where, R is an aryl, alkyl group; Y is an oxygen atom or sulfur atom and Ar is an aryl, alkyl, Pyridyl group.
3. The method of claim 2 , wherein said mexiletine analogue comprises:
4. The method of claim 2 , wherein said mexiletine analogue comprises:
5. The method of claim 2 , wherein said mexiletine analogue comprises:
6. The method of claim 2 , wherein said mexiletine analogue comprises:
7. The method of claim 2 , wherein said mexiletine analogue comprises:
8. The method of claim 2 , wherein said mexiletine analogue comprises:
9. The method of claim 2 , wherein said mexiletine analogue comprises:
10. The method of claim 2 , wherein said mexiletine analogue comprises:
11. The method of claim 2 , wherein said mexiletine analogue comprises:
12. The method of claim 2 , wherein said mexiletine analogue comprises:
13. The method of claim 2 , wherein said mexiletine analogue comprises:
14. The method of claim 2 , wherein said reduction produces an amine comprising:
15. The method of claim 2 , wherein said reduction produces an amine comprising:
16. The method of claim 2 , wherein said reduction produces an amine comprising:
17. The method of claim 2 , wherein said reduction produces an amine comprising:
18. The method of claim 2 , wherein said reduction produces an amine comprising:
19. The method of claim 1 , wherein said catalyst agent comprises:
20. The method of claim 1 , wherein said catalyst agent comprises:
21. The method of claim 1 , wherein said catalyst agent comprises:
22. The method of claim 1 , wherein said catalyst agent comprises:
23. The method of claim 1 , wherein said catalyst agent comprises:
24. The method of claim 1 , wherein the catalyst agent is able to reduce said oxime to obtain an enantioselectivity of at least 91%.
25. The method of claim 1 , wherein the catalyst agent is able to reduce said oxime to obtain an enantioselectivity of from about 91% to about 97%.
26. The method of claim 1 , comprising:
adding anhydrous dioxane and BH3.THF in one portion to a reaction tube with said catalyst agent under N 2 .
27. The method of claim 26 , further comprising:
stirring the mixture for a first period of time at a first predetermined temperature; and
cooling said mixture at a second predetermined temperature.
28. The method of claim 27 , further comprising:
adding benzyl oxime in dioxane to the cooled mixture dropwise for a second period of time.
29. The method of claim 28 , further comprising:
stirring the resulting mixture at said second predetermined temperature until the conversion is completed.
30. The method of claim 26 , wherein 10 mL of anhydrous dioxane and at least 4 mL of BH3.THF (1M in THF) in one portion are added to a reaction tube with 33 mg (0.1 mmol) of said catalyst agent under N 2 .
31. The method of claim 27 , wherein:
said first period of time is 1 hour;
said first predetermined temperature is about room temperature; and
said second predetermined temperature is about 0° C.
32. The method of claim 28 , wherein 1 mmol of benzyl oxime in 5 ml of dioxane is added to the cooled mixture dropwise for about 1 hour.
33. The method of claim 29 , wherein said second predetermined temperature is about 0° C. and said conversion is completed in about 48 hours.