PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]-PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND SOLID STATE FORMS THEREOF

Abstract

The present disclosure relates to processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, solid state forms thereof, and corresponding pharmaceutical compositions, methods of treatment (including treatment of rheumatoid arthritis), kits, methods of synthesis, and products-by-process.

1 - 116 . (canceled) 
     
     
         117 . A solid state form of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the solid state form is selected from the group consisting of:
 a) a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   b) a crystalline hemihydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   c) a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   d) a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide wherein the crystalline hydrate has at least one characteristic selected from the group consisting of:
 i) an X-ray powder diffraction pattern substantially as shown in  FIG. 3C ; 
 ii) a thermogravimetric analysis profile substantially as shown in  FIG. 4E ; 
 iii) a differential scanning calorimetry profile substantially as shown in  FIG. 5C ; 
 iv) a moisture sorption isotherm profile substantially as shown in  FIG. 6B ; 
 v) an orthorhombic lattice type that has a P212121 space group, a unit cell a value of about 12.7 Å, a unit cell b value of about 13.1 Å, and a unit cell c value of about 22.6 Å; and 
 vi) any combination of i) to v); 
   e) a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   f) a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the crystalline hydrate has at least one characteristic selected from the group consisting of:
 vii) an X-ray powder diffraction pattern substantially as shown in  FIG. 3B ; 
 viii) a thermogravimetric analysis profile substantially as shown in  FIG. 4D ; 
 ix) a differential scanning calorimetry profile substantially as shown in  FIG. 5B ; and 
 x) any combination of vii) to ix); 
   g) amorphous freebase (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   h) a crystalline anhydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   i) a crystalline anhydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   j) a crystalline anhydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the crystalline anhydrate has at least one characteristic selected from the group consisting of:
 xi) an X-ray powder diffraction pattern substantially as shown in  FIG. 3J ; 
 xii) a thermogravimetric analysis profile substantially as shown in  FIG. 4I ; 
 xiii) a differential scanning calorimetry profile substantially as shown in  FIG. 5E ; 
 xiv) a moisture sorption isotherm profile substantially as shown in  FIG. 6D ; 
 xv) an orthorhombic lattice type that has a P21212 space group, a unit cell a value of about 43.8 Å, a unit cell b value of about 8.6 Å, and a unit cell c value of about 9.2 Å; and 
 xvi) any combination of xi) to xv); 
   k) a crystalline tartrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   l) a crystalline tartrate tetrahydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide;   m) a crystalline tartrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 3.9±0.2, 6.8±0.2, and 14.1±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation; and   n) a crystalline tartrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the crystalline tartrate has at least one characteristic selected from the group consisting of xvii) an X-ray powder diffraction pattern substantially as shown in  FIG. 3D ;
 xviii) a thermogravimetric analysis profile substantially as shown in  FIG. 4F ; 
 xix) a differential scanning calorimetry profile substantially as shown in  FIG. 5D ; 
 xx) a moisture sorption isotherm profile substantially as shown in  FIG. 6C ; and 
 xxi) any combination of xvii) to xx). 
   
     
     
         118 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a solid state form of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, wherein the solid state form is a solid state form of  claim 117 . 
     
     
         119 . The pharmaceutical composition of  claim 118 , wherein greater than about 90% by weight of the (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in the composition is selected from the group consisting of:
 a) a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   b) a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 3.1±0.2, 9.3±0.2, and 12.0±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation;   c) amorphous freebase (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide; and   d) a crystalline anhydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)-pyrrolidine-1-carboxamide having an X-ray powder diffraction pattern characterized by peaks at 8.0±0.2, 9.7±0.2, 14.2±0.2, 14.5±0.2, and 20.3±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.   
     
     
         120 . A process for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, the process comprising:
 a) reacting a compound of formula (Ib)   
       
         
           
           
               
               
           
         
         with trimethylsulfoxonium chloride in the presence of carbonyldiimidazole and a strong base to form a compound of formula (IIa) 
       
       
         
           
           
               
               
           
         
         wherein Cbz is carboxybenzyl; 
         b) contacting the compound of formula (IIa) with lithium bromide and a sulfonic acid to form a compound of formula (IIIa) 
       
       
         
           
           
               
               
           
         
         c) reacting the compound of formula (IIIa) with a compound of formula (IVa) 
       
       
         
           
           
               
               
           
         
         in the presence of lithium tert-butoxide to produce a compound of formula (Va) 
       
       
         
           
           
               
               
           
         
         wherein R2 is methyl or ethyl, and Ts is tosyl; 
         d) contacting the compound of formula (Va) with a perfluoro acid anhydride and an organic base to form a compound of formula (VIa) 
       
       
         
           
           
               
               
           
         
         e) deprotecting the compound of formula (VIa) to form a compound of formula (VII) 
       
       
         
           
           
               
               
           
         
         f) contacting the compound of formula (VII) with hydrochloric acid to form a compound of formula (VIIa) 
       
       
         
           
           
               
               
           
         
       
       and
 g) reacting the compound of formula (VIIa) with 2,2,2-trifluoroethylamine in the presence of carbonyldiimidazole to produce (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide. 
 
     
     
         121 . The process of  claim 120 , wherein:
 the strong base of step a) is potassium tert-butoxide;   the sulfonic acid of step b) is selected from the group consisting of methanesulfonic acid and p-toulenesulfonic acid;   the perfluoro acid anhydride of step d) is trifluoroacetic anhydride;   the organic base of step d) is pyridine;   the compound of formula (VIa) is deprotected using hydrogen gas and Pd(OH 2 )/C; and   the reaction of step g) is conducted in the presence of dipotassium phosphate and potassium hydroxide.   
     
     
         122 . An extended release formulation comprising a therapeutically effective amount of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or a crystalline anhydrate of Compound 1, a release control polymer, and a pH modifier. 
     
     
         123 . The extended release formulation of  claim 122 , wherein the pH modifier comprises about 20 w/w % of tartaric acid. 
     
     
         124 . The extended release formulation of  claim 122 , wherein the release control polymer comprises hydroxypropylmethyl cellulose. 
     
     
         125 . The extended release formulation of  claim 122 , wherein the therapeutically effective amount of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof, or a crystalline hydrate or a crystalline anhydrate of Compound 1 is in an amount sufficient to deliver about 7.5 mg, 15 mg, 30 mg, or 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide freebase equivalent. 
     
     
         126 . The extended release formulation of  claim 122 , wherein the extended release formulation is administered once daily. 
     
     
         127 . The extended release formulation of  claim 125 , wherein the extended release formulation comprises a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in an amount sufficient to deliver about 15 mg of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide freebase equivalent, wherein the release control polymer comprises hydroxypropylmethyl cellulose, wherein the pH modifier comprises about 20 w/w % of tartaric acid, and wherein the crystalline hydrate is Freebase Hydrate Form C. 
     
     
         128 . The extended release formulation of  claim 125 , wherein the extended release formulation comprises a crystalline hydrate of (3 S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in an amount sufficient to deliver about 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide freebase equivalent, wherein the release control polymer comprises hydroxypropylmethyl cellulose, wherein the pH modifier comprises about 20 w/w % of tartaric acid, and wherein the crystalline hydrate is Freebase Hydrate Form C.