Synthetic processes for the preparation of aminocyclohexyl ether compounds

1. A method of making a compound of formula (I):

or a pharmaceutically acceptable salt thereof, as a single stereoisomer or as a mixture thereof;

wherein:

R 3 , R 4 and R 5 are 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 ; and

R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, acetyl, methanesulfonyl or C 1 -C 6 alkyl;

which method comprises:

a) a nucleophilic displacement step comprising treating a compound of formula (16):

wherein —OR′ is an activated leaving group and R 3 , R 4 and R 5 are as defined above, with an azide under suitable nucleophilic displacement conditions and subsequent reduction conditions to form a compound of formula (17):

wherein R 3 , R 4 and R 5 are as defined above;

b) reacting the compound of formula (17):

wherein R 3 , R 4 and R 5 are as defined above, with a compound of formula (2a2):

wherein R is H, C 2 -C 5 acyl or an oxygen-protecting group, under suitable condensation conditions to form a compound of formula (6b):

wherein R is H, C 2 -C 5 acyl or an oxygen-protecting group and R 3 , R 4 and R 5 are as defined above; and

c) reducing the compound of formula (6b) under suitable conditions to form a compound of formula (I), as set forth above; and

d) optionally forming the pharmaceutically acceptable salt of the compound of formula (I) under suitable conditions.

2. The method of claim 1 further comprising a preparation step to form the compound of formula (16), wherein the preparation step comprises reacting a compound of formula (15):

wherein R 3 , R 4 and R 5 are as described above, with an activating agent under suitable conditions to form the compound of formula (16) as set forth above.

3. The method of claim 2 wherein the activating agent is an optionally substituted alkylsulfonyl halide or an optionally substituted arylsulfonyl halide.

4. The method of claim 2 further comprising an asymmetric reduction step to form a compound (15), wherein the asymmetric reduction step comprises treating a compound of formula (14):

wherein R 3 , R 4 and R 5 are as defined above, under asymmetric reduction/hydrogenation conditions to form the compound of formula (15) as set forth above.

5. The method of claim 4 further comprising an etherification step to form a compound of formula (14), wherein the etherification step comprises treating a compound of formula (13):

with a compound of formula (5b):

wherein R 3 , R 4 and R 5 are as defined above, under suitable conditions to form the compound of formula (14), as set forth above.

6. The method of claim 1 wherein the pharmaceutically acceptable salt is an acid addition salt.

7. The method of claim 1 wherein the compound of formula (I) is a compound of formula (I) where R 3 , R 4 and R 5 are independently hydrogen, hydroxy or C 1 -C 8 alkoxy; with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen at the same time.

8. The method of claim 7 wherein the compound of formula (I) is a compound of formula (Ia):

or a pharmaceutically acceptable salt thereof.

9. The method of claim 7 wherein the compound of formula (I) is selected from the group consisting of:

or pharmaceutically acceptable salts thereof.