Synthesis of pyrrolidine compounds

1. A method for preparing a compound of formula (I) or a salt thereof:

wherein:

one of R 1 and R 2 is hydrogen or C 1 -C 6 alkyl, and the other is —C(O)R 5 ;

wherein R 5 is chosen from:

optionally substituted C 6 -C 10 aryl;

optionally substituted heteroaryl, wherein the heteroaryl includes 5-10 atoms;

optionally substituted C 1 -C 20 alkyl;

optionally substituted C 1 -C 20 haloalkyl;

optionally substituted C 7 -C 12 aralkyl;

optionally substituted heteroaralkyl, wherein the heteroaralkyl includes 6-12 atoms;

optionally substituted C 3 -C 10 cycloalkyl; and

optionally substituted C 3 -C 10 cycloalkenyl;

W is C 1-6 alkylene; and

R 3 and R 4 may be the same or different and are each independently chosen from hydrogen, optionally substituted C 1 -C 6 alkyl, —C(O)OR 6 , and —C(O)R 9 ;

wherein R 6 is optionally substituted C 1 -C 20 alkyl; and

wherein R 9 is chosen from

hydrogen;

optionally substituted C 6 -C 10 aryl;

optionally substituted heteroaryl, wherein the heteroaryl includes 5-10 atoms;

optionally substituted C 1 -C 20 alkyl;

optionally substituted C 3 -C 10 cycloalkyl; and

optionally substituted heterocycloalkyl, wherein the heterocycloalkyl includes 5-10 atoms;

the method comprising:

converting a compound of formula (II) or a salt thereof:

wherein:

R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl;

to a compound of formula (III) or a salt thereof:

and, where R 7 in formula (III) is optionally substituted C 1 -C 6 alkyl,

reacting the compound of formula (III) with a metal hydroxide or other suitable base to provide a compound of formula (I) or a salt thereof.

2. The method of claim 1 , wherein converting the compound of formula (II) to a compound of formula (III) comprises contacting the compound of formula (II) with a compound of formula (IV):

3. The method of claim 2 , wherein the compound of formula (II) is contacted with the carboxylic acid of formula (IV) in the presence of a coupling agent.

4. The method of claim 3 , wherein the coupling agent is a carbodiimide.

5. The method of claim 2 , wherein the compound of formula (II) is contacted with the carboxylic acid of formula (IV) in the presence of a coupling agent and a hydroxylated moiety.

6. The method of claim 2 , wherein the carboxylic acid of formula (IV) is converted to a mixed anhydride.

7. The method of claim 1 , wherein the metal hydroxide is a Group IA metal hydroxide, and the Group IA metal hydroxide is NaOH.

8. The method of claim 1 , wherein the reaction of the compound of formula (III) with a metal hydroxide or other suitable base is conducted in the presence of at least one solvent.

9. The method of claim 8 , wherein the at least one solvent includes a C 1 -C 3 alcohol, and the C 1 -C 3 alcohol is CH 3 OH.

10. The method of claim 1 , wherein the reaction of the compound of formula (III) with a metal hydroxide or other suitable base is conducted at a temperature of at most about 5° C.

11. The method of claim 1 , wherein the compound of formula (II) is prepared by a method comprising:

contacting a compound of formula (V):

wherein:

R 2 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl;

R 7 is chosen from hydrogen and optionally substituted C 1 -C 6 alkyl; and

R 8 is a nitrogen protecting group;

with an activated carboxylic acid to provide a compound of formula (VII) or a salt thereof:

and

removing the protecting group from the compound of formula (VII).

12. The method of claim 11 , wherein the activated carboxylic acid is a compound of formula (VI):

R 5 C(O)CI  (VI).

13. The method of claim 12 , wherein removing the protecting group from the compound of formula (VII) provides the compound of formula (II) as an HCl salt.

14. The method of claim 1 , wherein W is —CH 2 —.

15. The method of claim 1 , wherein the compound of formula (I) or a salt thereof is:

the compound of formula (II) or a salt thereof is:

and

the compound of formula (III) or a salt thereof is:

16. The method of claim 2 , wherein the compound of formula (I) or a salt thereof is:

the compound of formula (II) or a salt thereof is:

the compound of formula (III) or a salt thereof is:

and

the compound of formula (IV) or a salt thereof is Boc-Gly-OH.

17. A method for preparing (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate, comprising providing a solution of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride in a crystallization medium, wherein the crystallization medium comprises at least one water-miscible organic solvent and water, and maintaining the solution for a time and under conditions suitable for forming the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.

18. The method of claim 17 , wherein the at least one water-miscible organic solvent comprises at least one solvent selected from water-miscible alcohols, water-miscible ketones, and water-miscible ethers.

19. The method of claim 18 , wherein the at least one water-miscible organic solvent is a water-miscible C 1 -C 4 alcohol, and the C 1 -C 4 alcohol is isopropanol.

20. The method of claim 18 , wherein the at least one water-miscible organic solvent is a water-miscible C 1 -C 6 ketone, and the C 1 -C 6 ketone is acetone.

21. The method of claim 18 , wherein the at least one water-miscible organic solvent is a water miscible C 1 -C 6 ether, and the C 1 -C 6 ether is t-butyl methyl ether.

22. The method of claim 17 , wherein the conditions suitable for forming the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate comprise maintaining the solution at room temperature.

23. The method of claim 17 , wherein the conditions suitable for forming the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate comprise evaporation of at least some of the crystallization medium.

24. The method of claim 17 , wherein the crystallization medium comprises up to 5% by volume of water.

25. The method of claim 17 , further comprising drying the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate at elevated temperature and under vacuum.

26. A method for treating a condition selected from the group consisting of cardiovascular disease; osteoporosis; inflammation of airway epithelium; disorders of alveolar tissue; bladder incontinence; impaired hearing; endothelial lesions; Type I or Type II diabetes; diabetic retinopathy; diabetic neuropathy; atherosclerosis; conditions; seizures; ischemia; dental tissue disorders; kidney diseases; anaemia; leukopenia; thrombocytopenia; pancytopenia; superficial wounds; deep wounds resulting from trauma; bone fractures; erectile dysfunction; neuropathic pain; subchronic and chronic inflammation; cancer; failure of bone marrow; stem cell transplantation; female infertility; and stroke, comprising administering to a patient a therapeutically effective amount of the compound (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate.