Synthetic processes for the preparation of aminocyclohexyl ether compounds
This invention is directed to stereoselective synthesis of compounds of formula (I) or formula (II): or a pharmaceutically acceptable salt, ester, amide, complex, chelate, clathrate, solvate, polymorph, stereoisomer, metabolite or prodrug thereof; wherein R 3 , R 4 and R 5 are defined herein. Compounds of formula (I) and formula (II) are known to be useful in treating arrhythmias.
1. A compound selected from the group consisting of the following:
or a pharmaceutically acceptable salt, solvate in solution phase or clathrate with cyclodextrin thereof, as a single stereoisomer or a mixture thereof;
wherein:
each R 3 , R 4 and R 5 is independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, cyano, sulfamyl, trifluoromethyl, —CHF 2 , —SO 2 N(R 8 )R 9 , —OCF 3 , C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 7 -C 12 aralkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, aryl or —N(R 6 )R 7 , with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen at the same time;
each R 6 , R 7 , R 8 , and R 9 is independently selected from hydrogen, acetyl, methanesulfonyl or C 1 -C 6 alkyl;
each R 2a is O or H 2 where at least one R 2a in each compound is O;
each R is independently a H, C 2 -C 5 acyl or an oxygen-protecting group; and
each R 1 is an oxygen-protecting group,
provided that the compound is not one of the following compounds:
2. The compound of claim 1 wherein each R 3 , R 4 and R 5 is independently hydrogen, hydroxy or C 1 -C 6 alkoxy; with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen at the same time.
3. A compound which is (3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol.
4. A compound selected from the group consisting of the following:
or a pharmaceutically acceptable salt, solvate in solution phase or clathrate with cyclodextrin thereof, as a single stereoisomer or a mixture thereof;
wherein:
each R 2a is O or H 2 where at least one R 2a in each compound is O;
each R 3 , R 4 and R 5 is independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, cyano, sulfamyl, trifluoromethyl, —CHF 2 , —SO 2 N(R 8 )R 9 , —OCF 3 , C 2 -C 7 alkanoyloxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 7 -C 12 aralkoxy, C 2 -C 7 alkoxycarbonyl, C 1 -C 6 thioalkyl, aryl or —N(R 6 )R 7 , with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen at the same time;
each R 6 , R 7 , R 8 , and R 9 is independently selected from hydrogen, acetyl, methanesulfonyl or C 1 -C 6 alkyl;
each R 2a is O or H 2 where at least one R 2a in each compound is O;
each R is independently a H, C 2 -C 5 acyl or an oxygen-protecting group; and
each R 1 is an oxygen-protecting group.
5. The compound of claim 4 wherein each R 3 , R 4 and R 5 is independently hydrogen, hydroxy or C 1 -C 6 alkoxy; with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen at the same time.