Processes and intermediates

1. A process for preparing a compound of Formula 3

comprising the steps of:

a) providing a compound of formula 6 wherein R′ is C 1-5 alkyl;

b) forming a 2-anion of the compound of formula 6 in the presence of a complexing agent;

c) carboxylating the 2-anion of formula 6 of step b) to give a racemic mixture of cis- and trans-octahydrocyclopenta[c]pyrrole-1-carboxylic acids of formula 7;

d) equilibrating a trans-/cis-mixture of the compounds of formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of formula 8

 wherein the trans-/cis- ratio is greater than 80 to 20;

e) forming a salt of the compound of formula 8 with an optically active base;

f) crystallizing the salt of step e) to provide an optically active salt of formula 9;

g) esterifying the carboxylic acid of formula 9 with a compound containing the R 3 group, wherein R 3 is an optionally substituted alkyl or aralkyl;

h) removing the —COOR′ protecting group from the compound of step g) to produce a compound of Formula 1:

i) reacting the amino-ester of Formula 1 with R 1 COOH in the presence of a coupling reagent to produce a compound of Formula 1a;

j) hydrolyzing the ester of the compound of Formula 1a; and

k) reacting the carboxylic acid of step j) with a compound containing the R 2 group in the presence of a coupling reagent, to produce the compound of Formula 3;

wherein

R 1 is RW—, P 2 —, P 3 -L 2 -P 2 —, or P 4 -L 3 -P 3 -L 2 -P 2 —;

W is a bond;

T is —C(O)—;

R is H, an optionally substituted aliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;

R 5 is an aliphatic;

R 6 is H;

Each of R 7 and R 7 ′ is independently H or an optionally substituted cycloaliphatic;

R 8 is H or a protecting group;

R 2 is —(NH—CR 4 ′R 5 ′—C(O)—C(O))—NHR 4 or —(NH—CR 4 ′R 5 ′—CH(OH)—C(O))—NHR 4 ;

R 4 is H, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic; and

Each of R′ 4 and R′ 5 is independently H or an optionally substituted aliphatic.

2. The process of claim 1 , wherein R 5 is C 1-6 alkyl.

3. The process of claim 2 , wherein R 5 is

4. The process of claim 1 , wherein R 7 ′ is H; and R 7 is C 3-10 cycloalkyl.

5. The process of claim 4 , wherein R 7 is

.

6. The process of claim 1 , wherein R is C 5-10 heteroaryl.

7. The process of claim 6 , wherein R is

8. The process of claim 1 , wherein the 2-anion of step b) is prepared by treating the compound of formula 6 with a strong lithium base in the presence of a complexing agent and an aprotic solvent.

9. The process of claim 8 , wherein the base in step b) is sec-butyl lithium.

10. The process of claim 9 , wherein the complexing agent in step b) is tetramethylethylenediamine, tetraethylethylenediamine, tetramethyl-1,2-cyclohexyldiamine, sparteine, or 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane.

11. The process of claim 1 , wherein the trans-/cis- ratio in step c) is 1 to 1.

12. The process of claim 1 , wherein the trans-/cis- ratio in step c) is 60 to 40.

13. The process of claim 1 , wherein the trans-/cis- ratio in step c) is 80 to 20.

14. The process of claim 1 , wherein the trans-/cis- ratio in step c) is 90 to 10.

15. The process of claim 1 , wherein the trans-/cis- ratio in step c) is greater than 98 to 2.

16. The process of claim 1 , wherein the complexing agent in step b) is D-sparteine.

17. The process of claim 1 , further comprising equilibrating trans-/cis-mixture of the compounds of formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of formula 8 wherein the trans-/cis- ratio in step d) is greater than 90 to 10.

18. The process of claim 1 , further comprising equilibrating trans-/cis-mixture of formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of formula 8 wherein the trans/cis- ratio in step d) is greater than 98 to 2.

19. The process of claim 1 , wherein the base in step d) is lithium hexamethyldisilazide, lithium di-isopropylamide, or lithium 2,2,6,6-tetramethylpiperidide.

20. The process of claim 1 , wherein the base in step d) is lithium hexamethyldisilazide.

21. The process of claim 1 , where in steps b) and c) the lithium base is sec-butyl lithium and the complexing agent is 3,7-dipropyl-3,7-diazabicyclo[3.3.1]nonane to give a mixture of racemic trans-/cis-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acids of formula 7, in which the trans-/cis- ratio is greater than 90 to 10.

22. The process of claim 21 , wherein the trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid of step c) is trans-N-t-butoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid.

23. The process of claim 1 , further comprising resolving the racemic trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid of step c) to produce an (1S,2S,3R) trans-N-alkoxycarbonyl-octahydrocyclopenta[c]pyrrole-1-carboxylic acid.

24. The process of claim 1 , wherein the optically active base in step e) is (R) α-aminoethylbenzene.

25. The process of claim 1 , wherein the optically active base in step e) is (S) 1,2,3,4-tetrahydro-1-naphthylamine.

26. The process of claim 1 , wherein R 3 is t-butyl.

27. The process of claim 1 , wherein the reaction between the amino ester of Formula 1 with R 1 COOH in step i) is carried out further in the presence of histamine, glycine, or lysine.

28. The process of claim 1 , wherein R 1 is P 2 —.

29. The process of claim 1 , wherein R 1 is P 3 -L 2 -P 2 —.

30. The process of claim 1 , wherein R 1 is P 4 -L 3 -P 3 -L 2 -P 2 —.

31. The process of claim 1 , wherein R 1 is RW—.

32. The process of claim 1 , wherein R 2 is

33. A process for preparing a compound of Formula 1a

comprising the steps of:

a) providing a compound of formula 6 wherein R′ is C 1-5 alkyl;

b) forming a 2-anion of the compound of formula 6 in the presence of a complexing agent;

c) carboxylating the 2-anion of formula 6 of step b) to give a racemic mixture of cis- and trans-octahydrocyclopenta[c]pyrrole-1-carboxylic acids of formula 7;

d) equilibrating a trans-/cis-mixture of the compounds of formula 7 in the presence of a suitable base to produce a predominantly trans-cis racemic acid of formula 8

 wherein the trans-/cis- ratio is greater than 80 to 20;

e) forming a salt of the compound of formula 8 with an optically active base;

f) crystallizing the salt of step e) to provide an optically active salt of formula 9;

g) esterifying the carboxylic acid of formula 9 with a compound containing the R 3 group, wherein R 3 is an optionally substituted alkyl or aralkyl;

h) removing the —COOR′ protecting group from the compound of step g) to produce a compound of Formula 1; and

i) reacting the amino-ester of Formula 1 with R 1 COOH in the presence of a coupling reagent to produce a compound of Formula 1a;

wherein

R 1 is RW—, P 2 —, P 3 -L 2 -P 2 —, or P 4 -L 3 -P 3 -L 2 -P 2 —;

W is a bond;

T is —C(O)—;

R is H, an optionally substituted aliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl;

R 5 is an aliphatic;

R 6 is H;

Each of R 7 and R 7 ′ is independently H or an optionally substituted cycloaliphatic; and

R 8 is H or a protecting group.

34. The process of claim 33 , further comprising:

j) hydrolyzing the ester of the compound of Formula 1a; and

k) reacting the carboxylic acid of step j) with a compound containing the R 2 group in the presence of a coupling reagent, to produce the compound of Formula 3

wherein

R 2 is —(NH—CR 4 ′R 5 ′—C(O)—C(O))—NHR 4 or —(NH—CR 4 ′R 5 ′—CH(OH)—C(O))—NHR 4 ;

R 4 is H, an optionally substituted aliphatic, or an optionally substituted cycloaliphatic; and

Each of R′ 4 and R′ 5 is independently H or an optionally substituted aliphatic.