Asymmetric synthetic processes for the preparation of aminosulfone compounds
Processes for synthesizing aminosulfone compounds are provided. The processes provided herein utilize asymmetric reduction reactions, e.g., asymmetric hydrogenation, of protected or unprotected enamine or ketone substrates. Aminosulfone compounds obtained using methods provided herein are useful in production or synthesis of sulfone group containing isoindoline based compounds.
1. A process for preparing an enantiomerically enriched compound of Formula (I):
or a salt, solvate, isotopologue, or polymorph thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy, (C 3 -C 18 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, cyano, —CF 3 , or (C 3 -C 18 )cycloalkyl-(C 1 -C 6 )alkoxy, or an isotopologue thereof; and R 3 is (C 1 -C 6 )alkyl, or an isotopologue thereof; comprising the step of reducing an enamine of Formula (II):
or a salt or isotopologue thereof, via hydrogenation in the presence of (1) a metal catalyst and a chiral ligand, or (2) a chiral metal catalyst/ligand complex to form the compound of Formula (I) with an enantiomeric excess of at least 10%.
2. The process of claim 1 , wherein R 1 and R 2 are substituted or unsubstituted (C 1 -C 6 )alkoxy, or an isotopologue thereof.
3. The process of claim 2 , wherein R 1 is OMe, or an isotopologue thereof, R 2 is OEt, or an isotopologue thereof, and R 3 is Me, or an isotopologue thereof.
4. The process of claim 1 , wherein the metal catalyst contains rhodium.
5. The process of claim 4 , wherein the metal catalyst is Rh(cod) 2 OTf.
6. The process of claim 1 , wherein the chiral ligand or chiral metal catalyst/ligand complex is (S, R)-t-Bu Josiphos, Josiphos SL-J011-2, (S,S)-Me-Duphos, (S,S)-Chiraphos, (R)-Phanephos, (R)—Ru(OAc) 2 (DM-segphos), [(R,R)-Me-BPE]Rh(cod)BF 4 , (R)—C 3 -TunePhos, (R)-[Rh(cod)TCFP]BF 4 , or a stereoisomer thereof.
7. The process of claim 6 , wherein the chiral ligand is (S, R)-t-Bu Josiphos.
8. The process of claim 1 , wherein the load of catalyst is between about 0.05 mol % and about 5 mol %.
9. The process of claim 1 , wherein the molar ratio of the chiral ligand to the metal catalyst is from about 3:1 to about 1:1.
10. The process of claim 1 , wherein the hydrogen pressure is between about 15 psig and about 250 psig.
11. The process of claim 1 , wherein the solvent is ethyl acetate, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide, formic acid, acetic acid, methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, or mixtures thereof.
12. The process of claim 11 , wherein the solvent is 2,2,2-trifluoroethanol.
13. The process of claim 1 , wherein the reaction temperature is about 50° C.
14. The process of claim 1 , wherein the compound of Formula (I) is formed with an enantiomeric excess of at least 25%.
15. The process of claim 1 , wherein the compound of Formula (I) is formed with an enantiomeric excess of at least 85%.
16. The process of claim 1 , wherein the compound of Formula (I) is formed with an enantiomeric excess of at least 95%.
17. The process of claim 1 , wherein the compound of Formula (I) is formed with at least 75% by weight of one enantiomer.
18. The process of claim 1 , wherein the compound of Formula (I) is formed with at least 85% by weight of one enantiomer.
19. The process of claim 1 , wherein the compound of Formula (I) is formed with at least 95% by weight of one enantiomer.
20. A process for preparing a compound of Formula (I):
or a salt, solvate, isotopologue, or polymorph thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy, (C 3 -C 18 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, cyano, —CF 3 , or (C 3 -C 18 )cycloalkyl-(C 1 -C 6 )alkoxy, or an isotopologue thereof; and R 3 is (C 1 -C 6 )alkyl, or an isotopologue thereof;
comprising the steps of
(a) reacting a ketone of Formula (V):
or an isotopologue thereof, with ammonia or an ammonium salt to form an enamine of Formula (II):
or a salt or isotopologue thereof;
(b) optionally isolating the enamine of Formula (II), or a salt or isotopologue thereof; and
(c) reducing the enamine of Formula (II), or a salt or isotopologue thereof, via hydrogenation in the presence of (1) a metal catalyst and a chiral ligand, or (2) a chiral metal catalyst/ligand complex.
21. The process of claim 20 , wherein R 1 and R 2 are substituted or unsubstituted (C 1 -C 6 )alkoxy, or an isotopologue thereof.
22. The process of claim 21 , wherein R 1 is OMe, or an isotopologue thereof, R 2 is OEt, or an isotopologue thereof, and R 3 is Me, or an isotopologue thereof.
23. The process of claim 20 , wherein the ammonium salt in step (a) is ammonium acetate.
24. The process of claim 20 , wherein the metal catalyst in step (c) contains rhodium.
25. The process of claim 24 , wherein the metal catalyst in step (c) is Rh(cod) 2 OTf.
26. The process of claim 20 , wherein the chiral ligand or chiral metal catalyst/ligand complex in step (c) is (S, R)-t-Bu Josiphos, Josiphos SL-J011-2, (S,S)-Me-Duphos, (S,S)-Chiraphos, (R)-Phanephos, (R)—Ru(OAc) 2 (DM-segphos), [(R,R)-Me-BPE]Rh(cod)BF 4 , (R)—C 3 -TunePhos, (R)-[Rh(cod)TCFP]BF 4 , or a stereoisomer thereof.
27. The process of claim 26 , wherein the chiral ligand in step (c) is (S,S)-Me-Duphos.
28. The process of claim 20 , wherein the load of catalyst in step (c) is between about 0.05 mol % and about 5 mol %.
29. The process of claim 20 , wherein the molar ratio of the chiral ligand to the metal catalyst in step (c) is from about 3:1 to about 1:1.
30. The process of claim 20 , wherein the hydrogen pressure in step (c) is between about 15 psig and about 250 psig.
31. The process of claim 20 , wherein the solvent in step (c) is ethyl acetate, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide, formic acid, acetic acid, methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, or mixtures thereof.
32. The process of claim 31 , wherein the solvent in step (c) is 2,2,2-trifluoroethanol.
33. The process of claim 20 , wherein the reaction temperature in step (c) is about 50° C.
34. A process for preparing an enantiomerically enriched compound of Formula (I):
or a salt, solvate, isotopologue, or polymorph thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy, (C 3 -C 18 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, cyano, —CF 3 , or (C 3 -C 18 )cycloalkyl-(C 1 -C 6 )alkoxy, or an isotopologue thereof; and R 3 is (C 1 -C 6 )alkyl, or an isotopologue thereof;
comprising the step of reducing an enamine of Formula (II):
or a salt or isotopologue thereof, via borane reduction in the presence of a borane reagent and a chiral ligand.
35. The process of claim 34 , wherein R 1 and R 2 are substituted or unsubstituted (C 1 -C 6 )alkoxy, or an isotopologue thereof.
36. The process of claim 35 , wherein R 1 is OMe, or an isotopologue thereof, R 2 is OEt, or an isotopologue thereof, and R 3 is Me, or an isotopologue thereof.
37. The process of claim 34 , wherein the borane reagent is borane N,N-diethylaniline.
38. The process of claim 34 , wherein the molar ratio of the compound of Formula (II) to the borane reagent is from about 3:1 to about 1:3.
39. The process of claim 34 , wherein the chiral ligand is (1R,2S)-aminoindanol, or a stereoisomer thereof.
40. The process of claim 34 , wherein the molar ratio of the compound of Formula (II) to the chiral ligand is from about 3:1 to about 1:3.
41. The process of claim 34 , wherein the solvent is ethyl acetate, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide, formic acid, acetic acid, methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, or mixtures thereof.
42. The process of claim 41 , wherein the solvent is tetrahydrofuran.
43. A process for preparing an enantiomerically enriched compound of Formula (I):
or a salt, solvate, isotopologue, or polymorph thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )alkoxy, (C 3 -C 18 )cycloalkyl, (C 3 -C 6 )cycloalkoxy, cyano, —CF 3 , or (C 3 -C 18 )cycloalkyl-(C 1 -C 6 )alkoxy, or an isotopologue thereof; and R 3 is (C 1 -C 6 )alkyl, or an isotopologue thereof;
comprising the step of reducing an enamine of Formula (II):
or a salt or isotopologue thereof, via hydrogenation in the presence of (1) a metal catalyst and a chiral ligand, or (2) a chiral metal catalyst/ligand complex, wherein the metal catalyst is Rh(cod) 2 OTf.