Synthetic methods and intermediates for steroisomeric compounds useful for the treatment of gastrointestinal and central nervous system disorders

1. A method for preparing (R)-quinuclidine-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)hexanoate or a salt thereof, comprising:

1) optionally converting a compound of formula (I′)

 to a salt, wherein R is (C 1 -C 8 )alkyl;

2) converting the compound of formula (I′) or its salt to a compound of formula (II′)

 or its salt, respectively, wherein X 1 is a nitrogen protecting group and X 2 is selected from the group consisting of hydrogen and a nitrogen protecting group (wherein commonly known and used N protecting groups can be used, e.g., N-benzyl; N-nitrobenzyl; N-BoC; N-oxide; N-paramethoxybenzyl; N-benzylsulfonyl);

3) treating the compound of formula (II′) with an alkali metal hydroxide or hydride to yield a compound of formula (III′)

4) producing a chiral salt of III′ by treating the compound of formula (III′) with about 0.5 equivalents of a chiral resolving agent and isolating the chiral salt of III′;

5) optionally recrystallizing the product of 4;

6) basifying the product of 4 or 5 to yield the free base form of the product of 4 or 5;

7) contacting the product of 6 with a (C 1 -C 8 )alkyl 6-halohexanoate to yield a compound of formula (IV′)

 wherein R′ is (C 1 -C 8 )alkyl;

8) treating the product of 7 with (R)-quinuclidine-3-ol and a Lewis acid in an organic solvent to yield a compound of formula (V′)

9) deprotecting the 4-amino group of the product of 8 to yield (R)-quinuclidine-3-yl 6-[(3S,4R)-4-amino-3-methoxypiperidin-1-yl]hexanoate;

10) acylating the product of 9 with 4-amino-5-chloro-2-methoxybenzoic acid;

11) optionally converting the product of 10 to a salt.

2. The process according to claim 1 wherein R is (C 1 -C 6 )alkyl.

3. The process according to claim 1 wherein R is (C 1 -C 4 )alkyl.

4. The process according to claim 1 wherein R is ethyl.

5. The process according to claim 4 wherein X 1 is benzyl and X 2 is benzyl.

6. The process according to claim 5 wherein R′ is ethyl.

7. The process according to claim 1 wherein the chiral salt is (+)-2,3-dibenzoyl-D-tartaric acid.

8. The process according to claim 1 wherein the deprotection is with H 2 /Pd/C or ammonium formate/Pd/C.

9. The process according to claim 1 wherein the Lewis acid is a titanium tetraalkoxide.

10. The process according to claim 9 wherein the titanium tetraalkoxide is Ti(OiP) 4 (titanium (IV) isopropoxide).

11. A method of making a compound of formula III″

comprising

a) contacting a compound of formula III′

 with about 0.5 equivalents of a chiral resolving agent to yield a chiral salt of III″ and separating the chiral salt of III″;

b) optionally recrystallizing the product of a); and

c) contacting the product of a) or b) with a base to yield the compound for formula III″;

wherein X 1 is a nitrogen protecting group and X 2 is selected from the group consisting of hydrogen and a nitrogen protecting group.

12. The method of claim 11 wherein the chiral resolving agent is (+)-2,3-dibenzoyl-D-tartaric acid and the salt of III′ is a (3S,4R)-enantiomer (+)-2,3-dibenzoyl-D-tartrate salt.

13. The method of claim 12 wherein one equivalent of (+)-2,3-dibenzoyl-D-tartaric acid is used for two equivalents of III′.

14. A method of making (R)-quinuclidine-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl)hexanoate (VII′) comprising contacting a compound of formula VI′

with 4-amino-5-chloro-2-methoxybenzoic acid in the presence of a pivaloyl halide.

15. The method of claim 14 wherein the pivaloyl halide is pivaloyl chloride.