Synthetic process for aminocyclohexyl ether compounds

1. A method for stereoselectively making an aminocyclohexyl ether of the following formula (79), formula (80) or formula (81):

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 , C 2 -C 7 alkanoyloxy, 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 where R 6 , R 7 , R 8 , and R 9 , are each independently hydrogen, acetyl, methanesulfonyl or C 1 -C 6 alkyl;

or R 3 , R 4 and R 5 are 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,

which method comprises:

(a) reacting a compound of formula (75):

where R 3 , R 4 and R 5 are as defined above, with a compound of formula (82), a compound of formula (83) or a compound of formula (84):

wherein each Lg is independently a leaving group and each R 11 is C 1 -C 6 alkyl, under suitable conditions to form a compound of formula (85), a compound of formula (86) or a compound of formula (87), respectively:

or reacting a compound of formula (75) with a compound of formula (88), a compound of formula (89) or a compound of formula (90):

wherein each Lg is independently a leaving group and each R 12 is C 2 -C 4 acyl or C 7 -C 12 aralkyl, under suitable conditions to form a compound of formula (91), a compound of formula (92) or a compound of formula (93), respectively:

or reacting a compound of formula (75) with a compound of formula (94), a compound of formula (95) or a compound of formula (96):

wherein each R 13 is C 2 -C 4 acyl or C 7 -C 12 aralkyl, under suitable conditions to form a compound of formula (97), a compound of formula (98) or a compound of formula (99), respectively;

and

(b) reducing the compound of formula (85), the compound of formula (91) or the compound of formula (97) formed in step (a) under suitable conditions to form a compound of formula (79) as set forth above; or

reducing the compound of formula (86), the compound of formula (92) or the compound of formula (98) formed in step (a) under suitable conditions to form a compound of formula (80) as set forth above; or

reducing the compound of formula (87), the compound of formula (93) or the compound of formula (99) formed in step (a) under suitable conditions to form a compound of formula (81) as set forth above.

2. The method of claim 1 wherein R 3 , R 4 and R 5 are 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. The method of claim 2 wherein R 3 is hydrogen, and R 4 and R 5 are each C 1 -C 4 alkoxy.

4. The method of claim 3 wherein R 4 and R 5 are each C 1 alkoxy at the S- and 4-carbon position of the phenyl group, respectively.

5. The method of claim 1 wherein each Lg is independently chloro or bromo; R 11 is C 1 -C 3 alkyl; R 12 is C 2 -C 3 acyl; and R 13 is C 2 -C 3 acyl.

6. The method of claim 1 wherein the reducing reagent for step (b) is Red-Al.

7. A method for stereoselectively making an aminocyclohexyl ether of the following formula (100), formula (101) or formula (102):

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 , C 2 -C 2 alkanoyloxy, C 1 -C 6 alkoxy, C 7 -C 12 aralkoxy, C 2 -C 2 alkoxycarbonyl, C 1 -C 6 thioalkyl, aryl or N(R 6 )R 7 where R 6 , R 7 , R 8 , and R 9 , are each independently hydrogen, acetyl, methanesulfonyl or C 1 -C 6 alkyl;

or R 3 , R 4 and R 5 are 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,

which method comprises:

(a) reacting a compound of formula (76):

where R 3 , R 4 and R 5 are as defined above, with a compound of formula (82), a compound of formula (83) or a compound of formula (84):

wherein each Lg is independently a leaving group and each R 11 is C 1 -C 6 alkyl, under suitable conditions to form a compound of formula (103), a compound of formula (104) or a compound of formula (105), respectively:

or reacting a compound of formula (76) with a compound of formula (88), a compound of formula (89) or a compound of formula (90):

wherein each Lg is independently a leaving group and each R 12 is C 2 -C 4 acyl or C 7 -C 12 aralkyl, under suitable conditions to form a compound of formula (106), a compound of formula (107), or a compound of formula (108), respectively:

or reacting a compound of formula (76) with a compound of formula (94), a compound of formula (95) or a compound of formula (96):

wherein each R 13 is C 2 -C 4 acyl or C 7 -C 12 aralkyl, under suitable conditions to form a compound of formula (109), a compound of formula (110) or a compound of formula (111), respectively:

and

(b) reducing the compound of formula (103), the compound of formula (106) or the compound of formula (109) formed in step (a) under suitable conditions to form a compound of formula (100) as set forth above; or

reducing the compound of formula (104), the compound of formula (107) or the compound of formula (110) formed in step (a) under suitable conditions to form a compound of formula (101) as set forth above; or

reducing the compound of formula (105), the compound of formula (108) or the compound of formula (111) formed in step (a) under suitable conditions to form a compound of formula (102) as set forth above.

8. The method of claim 7 wherein R 3 , R 4 and R 5 are 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.

9. The method of claim 8 wherein R 3 is hydrogen, and R 4 and R 5 are each C 1 -C 4 alkoxy.

10. The method of claim 9 wherein R 4 and R 5 are each C 1 alkoxy at the S- and 4-carbon position of the phenyl group, respectively.

11. The method of claim 7 wherein each Lg is independently chloro or bromo; R 11 is C 1 -C 3 alkyl; R 12 is C 2 -C 3 acyl; and R 13 is C 2 -C 3 acyl.

12. The method of claim 7 wherein the reducing reagent for step (b) is Red-Al.

13. A method for stereoselectively making an aminocyclohexyl ether of the following formula (112), formula (113) or formula (114):

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 , C 2 -C 2 alkanoyloxy, C 1 -C 6 alkoxy, C 7 -C 12 aralkoxy, C 2 -C 2 alkoxycarbonyl, C 1 -C 6 thioalkyl, aryl or N(R 6 )R 7 where R 6 , R 7 , R 8 , and R 9 , are each independently hydrogen, acetyl, methanesulfonyl or C 1 -C 6 alkyl;

or R 3 , R 4 and R 5 are 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;

which method comprises:

(a) reacting a compound of formula (77):

where R 3 , R 4 and R 5 are as defined above, with a compound of formula (82), a compound of formula (83) or a compound of formula (84):

wherein each Lg is independently a leaving group and each R 11 is C 1 -C 6 alkyl, under suitable conditions to form a compound of formula (115), a compound of formula (116) or a compound of formula (117), respectively:

or reacting a compound of formula (77) with a compound of formula (88), a compound of formula (89) or a compound of formula (90):

wherein each Lg is independently a leaving group and each R 12 is C 2 -C 4 acyl or C 7 -C 12 aralkyl, under suitable conditions to form a compound of formula (118), a compound of formula (119), or a compound of formula (120), respectively:

or reacting a compound of formula (77) with a compound of formula (94), a compound of formula (95) or a compound of formula (96):

wherein each R 13 is C 2 -C 4 acyl or C 7 -C 12 aralkyl, under suitable conditions to form a compound of formula (121), a compound of formula (122) or a compound of formula (123), respectively:

and

(b) reducing the compound of formula (115), the compound of formula (118) or the compound of formula (121) formed in step (a) under suitable conditions to form a compound of formula (112) as set forth above; or

reducing the compound of formula (116), the compound of formula (119) or the compound of formula (122) formed in step (a) under suitable conditions to form a compound of formula (113) as set forth above; or

reducing the compound of formula (117), the compound of formula (120) or the compound of formula (123) formed in step (a) under suitable conditions to form a compound of formula (113) as set forth above.

14. The method of claim 13 wherein R 3 , R 4 and R 5 are 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.

15. The method of claim 14 wherein R 3 is hydrogen, and R 4 and R 5 are each C 1 -C 4 alkoxy.

16. The method of claim 15 wherein R 4 and R 5 are each C 1 alkoxy at the S- and 4-carbon position of the phenyl group, respectively.

17. The method of claim 13 wherein each Lg is independently chloro or bromo; R 11 is C 1 -C 3 alkyl; R 12 is C 2 -C 3 acyl; and R 13 is C 2 -C 3 acyl.

18. The method of claim 13 wherein the reducing reagent for step (b) is Red-Al.

19. A method for stereoselectively making an aminocyclohexyl ether of the following formula (124), formula (125) or formula (126):

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 , C 2 -C 2 alkanoyloxy, C 1 -C 6 alkoxy, C 7 -C 12 aralkoxy, C 2 -C 2 alkoxycarbonyl, C 1 -C 6 thioalkyl, aryl or N(R 6 )R 7 where R 6 , R 7 , R 8 , and R 9 , are each independently hydrogen, acetyl, methanesulfonyl or C 1 -C 6 alkyl;

or R 3 , R 4 and R 5 are 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,

which method comprises:

(a) reacting a compound of formula (78):

where R 3 , R 4 and R 5 are as defined above, with a compound of formula (82), a compound of formula (83) or a compound of formula (84):

wherein each Lg is independently a leaving group and each R 11 is C 1 -C 6 alkyl, under suitable conditions to form a compound of formula (127), a compound of formula (128) or a compound of formula (129), respectively:

or reacting a compound of formula (78) with a compound of formula (88), a compound of formula (89) or a compound of formula (90):

wherein each Lg is independently a leaving group and each R 12 is C 2 -C 4 acyl or C 7 -C 12 aralkyl, under suitable conditions to form a compound of formula (130), a compound of formula (131), or a compound of formula (132), respectively:

or reacting a compound of formula (78) with a compound of formula (94), a compound of formula (95) or a compound of formula (96):

wherein each R 13 is C 2 -C 4 acyl or C 7 -C 12 aralkyl, under suitable conditions to form a compound of formula (133), a compound of formula (134) or a compound of formula (135), respectively:

and

(b) reducing the compound of formula (127), the compound of formula (130) or the compound of formula (133) formed in step (a) under suitable conditions to form a compound of formula (124) as set forth above; or

reducing the compound of formula (128), the compound of formula (131) or the compound of formula (134) formed in step (a) under suitable conditions to form a compound of formula (125) as set forth above; or

reducing the compound of formula (129), the compound of formula (132) or the compound of formula (135) formed in step (a) under suitable conditions to form a compound of formula (126) as set forth above.

20. The method of claim 19 wherein R 3 , R 4 and R 5 are 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.

21. The method of claim 20 wherein R 3 is hydrogen, and R 4 and R 5 are each C 1 -C 4 alkoxy.

22. The method of claim 21 wherein R 4 and R 5 are each C 1 alkoxy at the S- and 4-carbon position of the phenyl group, respectively.

23. The method of claim 19 wherein each Lg is independently chloro or bromo; R 11 is C 1 -C 3 alkyl; R 12 is C 2 -C 3 acyl; and R 13 is C 2 -C 3 acyl.

24. The method of claim 19 wherein the reducing reagent for step (b) is Red-Al.