Synthesis of pyrrolidine compounds

Abstract

Provided are methods for the preparation of certain substituted pyrrolidine compounds, forms of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride, and methods for preparing and using these forms.

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 including 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 including 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 including 5-10 atoms; 
 optionally substituted C 1 -C 20  alkyl; 
 optionally substituted C 3 -C 10  cycloalkyl; and 
 optionally substituted heterocycloalkyl including 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 . (canceled) 
   
   
       6 . 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. 
   
   
       7 . (canceled) 
   
   
       8 . The method of  claim 2 , wherein the carboxylic acid of formula (IV) is converted to a mixed anhydride. 
   
   
       9 . (canceled) 
   
   
       10 . The method of  claim 1 , wherein the metal hydroxide is a Group IA metal hydroxide. 
   
   
       11 - 12 . (canceled) 
   
   
       13 . 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. 
   
   
       14 - 16 . (canceled) 
   
   
       17 . 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. 
   
   
       18 - 20 . (canceled) 
   
   
       21 . The method of  claim 1 , wherein the reaction of the compound of formula (III) with a metal hydroxide or other suitable base provides a compound of formula (I-A) or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein R 3  is chosen from hydrogen and optionally substituted C 1 -C 6  alkyl. 
   
   
       22 - 26 . (canceled) 
   
   
       27 . 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). 
 
   
   
       28 - 48 . (canceled) 
   
   
       49 . The method o  claim 1 , wherein W is —CH 2 —. 
   
   
       50 . The method of  claim 1 , wherein R 5  is optionally substituted C 6 -C 10  aryl or optionally substituted heteroaryl including 5-10 atoms. 
   
   
       51 - 52 . (canceled) 
   
   
       53 . The method of  claim 1 , wherein each of R 3  and R 4  is hydrogen. 
   
   
       54 . The method of  claim 1 , wherein R 7  is CH 3 . 
   
   
       55 . The method of  claim 1 , wherein the —NR 1 R 2  group and the —COOH group in formula (I) are trans with respect to one another. 
   
   
       56 . (canceled) 
   
   
       57 . The method of  claim 1 , wherein the —NR 1 R 2  group and the —COOR 7  group in formula (II) are trans with respect to one another. 
   
   
       58 . (canceled) 
   
   
       59 . 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: 
     
       
         
         
             
             
         
       
     
   
   
       60 - 63 . (canceled) 
   
   
       64 . A composition comprising
 (1) a compound of formula (I) or a salt thereof   
     
       
         
         
             
             
         
       
     
     and/or
 a compound of formula (III) 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 including 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 including 6-12 atoms; 
 optionally substituted C 3 -C 10  cycloalkyl; and 
 optionally substituted C 3 -C 10  cycloalkenyl; 
 
 
 W is C 1-6  alkylene; 
 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 including 5-10 atoms; 
 optionally substituted C 1 -C 20  alkyl; 
 optionally substituted C 3 -C 10  cycloalkyl; and 
 optionally substituted heterocycloalkyl including 5-10 atoms; and 
 
 
 R 7  is chosen from hydrogen and optionally substituted C 1 -C 6  alkyl; and 
 (2) a detectable amount of one or more compounds selected from: 
 N-((7R,8aS)-1,4-dioxooctahydropyrrolo[1,2-a]pyrazin-7-yl)benzamide or a salt thereof, i.e., a compound of formula 
 
     
       
         
         
             
             
         
       
       or a salt thereof; 
       triphenylphosphine; 
       triphenylphosphine oxide; 
       a hydrazine dicarboxylate; 
       triethylamine; 
       benzotriazole; 
       (2S,4R)-4-benzamido-1-(2-(tert-butylamino)acetyl)pyrrolidine-2-carboxylic acid or a salt thereof, i.e., a compound of formula: 
     
     
       
         
         
             
             
         
       
       or a salt thereof; 
       and a compound of formula (II) or a salt thereof: 
     
     
       
         
         
             
             
         
       
     
   
   
       65 . The composition of  claim 64  comprising greater than about 99% of a compound of formula (I). 
   
   
       66 . (canceled) 
   
   
       67 . The composition of  claim 64 , wherein the compound of formula (I) is (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid or a salt thereof. 
   
   
       68 . (canceled) 
   
   
       69 . The composition of  claim 64 , wherein the compound of formula (I) is (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate. 
   
   
       70 . (canceled) 
   
   
       71 . A pharmaceutical formulation comprising a composition of  claim 64  and one or more pharmaceutically acceptable carriers. 
   
   
       72 . A method for treating a condition selected from 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; CNS related conditions; seizures; ischemia; dental tissue disorders; kidney diseases; anaemia; leukopenia; thrombocytopenia; pancytopenia; superficial wounds; deep wounds resulting from trauma; bone fractures; erectile dysfunction; urinary bladder incontinence; neuropathic pain; subchronic and chronic inflammation; cancer; failure of bone marrow; stem cell transplantation; conditions arising during transplantation of cells and tissues; conditions arising during medical procedures; conditions caused by an excess of reactive oxygen species, free radicals or nitric oxide; diseases or disorders of pregnancy; female infertility; and stroke, comprising administering to a patient a therapeutically effective amount of the composition of  claim 64 . 
   
   
       73 . A compound that is (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride. 
   
   
       74 . A compound that is (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate. 
   
   
       75 - 80 . (canceled) 
   
   
       81 . 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. 
   
   
       82 . The method of  claim 81 , 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. 
   
   
       83 - 93 . (canceled) 
   
   
       94 . The method of  claim 81 , 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 
   
   
       95 . The method of  claim 81 , 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. 
   
   
       96 . The method of  claim 81 , wherein the crystallization medium comprises up to 5% by volume of water. 
   
   
       97 . The method of  claim 81 , further comprising drying the (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride monohydrate at elevated temperature and under vacuum. 
   
   
       98 . A pharmaceutical formulation comprising one or more pharmaceutically acceptable carriers and a compound of  claim 73 . 
   
   
       99 . A method for treating a condition selected from 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; CNS related conditions; seizures; ischemia; dental tissue disorders; kidney diseases; anaemia; leukopenia; thrombocytopenia; pancytopenia; superficial wounds; deep wounds resulting from trauma; bone fractures; erectile dysfunction; urinary bladder incontinence; neuropathic pain; subchronic and chronic inflammation; cancer; failure of bone marrow; stem cell transplantation; conditions arising during transplantation of cells and tissues; conditions arising during medical procedures; conditions caused by an excess of reactive oxygen species, free radicals or nitric oxide; diseases or disorders of pregnancy; female infertility; and stroke, comprising administering to a patient a therapeutically effective amount of the compound of any  claim 73 . 
   
   
       100 .- 101 . (canceled)