Formation of tetra-substituted enamides and stereoselective reduction thereof

Abstract

The present invention is directed to a practical process for the preparation of an enamide (II) by palladium catalyzed coupling of a primary amide (IV) with a compound of structural formula (III), as shown below: As well as to crystalline forms of a compound produced by this process, in particular, an anhydrous crystal form, Form B, and crystalline solvates falling into three patterns, Type 1, Type 2, and Type 3, and crystalline intermediate compounds produced in the process. Still further, the present invention relates to the stereoselective reduction of the tetrasubstituted enamide (II) to the corresponding amide (I).

1 - 10 . (canceled) 
     
     
         11 . A process for the synthesis of enamide (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from: hydrogen, halogen, —C(O)OR e , —C(O)NR f   2 , —NR f   2 , and cyano; 
 R 2  is selected from: hydrogen, halogen and hydroxyl; 
 R 3  is selected from: hydrogen, straight or branched chain C 1-10  alkyl, wherein the alkyl moiety is unsubstituted or substituted with substituents selected from halogen, CF 3 , OCF 3 , and OR a ; 
 wherein R a  is selected from cycloalkyl, aryl, aryl-C 1-3  alkyl- and heteroalkyl unsubstituted or substituted with one or two R b  substituents independently selected from halogen, C 1-3  alkyl, cyano, methoxy and trifluoromethyl; 
 each R c  is independently selected from halogen, hydroxy, C 1-3  alkyl, cyano, methoxy and trifluoromethyl; 
 each R d  is independently selected from: halogen, hydroxy, cyano, methoxy and trifluoromethyl; 
 R e  is selected from: hydrogen, straight or branched chain C 1-10  alkyl, aryl-C 1-6  alkyl-, aryl, heteroaryl, wherein aryl and heteroaryl moieties are optionally substituted with one to three R c  substituents, and the alkyl moiety is unsubstituted or substituted with one, two or three R d  moieties; 
 each R f  is independently selected from hydrogen, straight or branched chain C 1-6  alkyl, phenyl-C 1-6  alkyl-, wherein alkyl moieties are unsubstituted or substituted with one or two R d  substituents and wherein the phenyl moiety is unsubstituted or substituted with one, two or three R c  substituents; 
 comprising: 
 treating a compound of formula (III): 
 
       
         
           
           
               
               
           
         
       
       wherein R 4  is selected from: aryl and heteroaryl, wherein the aryl and heteroaryl moieties are unsubstituted or substituted with one to three R c  substituents; 
       with amide (IV): 
       
         
           
           
               
               
           
         
       
       in the presence of a base and a palladium catalyst. 
     
     
         12 . Anhydrous crystalline N-[1S,2S]-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethylpyridin-2-yl)oxy]propanamide Form B, characterized by the solid-state carbon-13 CPMAS NMR characteristic signals with chemical shift values of 164.6, 137.1, 111.3, 23.6, and 16.9 ppm, according to  FIG. 19 . 
     
     
         13 . A compound selected from:
 crystalline N-[1S,2S]-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethylpyridin-2-yl)oxy]propanamide solvate type 1, characterized by solid-state carbon-13 CPMAS NMR characteristic signals with chemical shift values of 164.1, 142.3, 112.5, 26.6, and 18.6 ppm according to  FIG. 26 ;   crystalline N-[1S,2S]-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethylpyridin-2-yl)oxy]propanamide solvate type 2, characterized by solid-state carbon-13 CPMAS NMR characteristic signals with chemical shift values of 164.1, 142.3, 112.5, 48.7, 26.6, and 18.6 ppm, according to  FIG. 27 ;   crystalline N-[1S,2S]-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethylpyridin-2-yl)oxy]propanamide solvate type 3, characterized by solid-state carbon-13 CPMAS NMR characteristic signals with chemical shift values of 143.6, 140.3, 25.6, 29.7, 24.1, and 20.9 ppm, according to  FIG. 28 ;   crystalline 3-[1-(4-chlorobenzyl)-2-oxopropyl]benzonitrile characterized by the X-ray powder diffraction pattern exhibiting characteristic diffraction peaks corresponding to d-spacings of 7.4, 4.6, 4.0, 3.8, 3.5, 3.4 angstroms generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console using a PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation as the source according to  FIG. 1 ;   crystalline 3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylprop-1-en-1-yl 4-methylbenzenesulfonate characterized by the X-ray powder diffraction pattern exhibiting characteristic diffraction peaks corresponding to d-spacings of 9.3, 8.1, 6.6, 5.7, 4.1, 3.4 angstroms generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console using a PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation as the source according to  FIG. 4 ;   crystalline N-[(1Z)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylprop-1-en-1-yl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide, characterized by the X-ray powder diffraction pattern exhibiting characteristic diffraction peaks corresponding to d-spacings of 7.6, 5.7, 5.3, 5.1, 4.6, 4.1 angstroms generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console using a PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation as the source according to  FIG. 7 ;   crystalline 3-{(1Z)-1-(4-chlorobenzyl)-2-[(2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoyl)amino]-prop-1-en-1-yl}benzamide, characterized by the X-ray powder diffraction pattern exhibiting characteristic diffraction peaks corresponding to d-spacings of 6.2, 5.9, 5.2, 4.6, 4.2, 3.9 angstroms generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console using a PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation as the source according to  FIG. 10 ; and   crystalline 3-{(1S,2S)-1-(4-chlorobenzyl)-2-[(2-methyl-2-{[5-(trifluoromethyl)pyridine-2-yl]oxy}propanoyl)amino]-propyl}benzamide, characterized by the X-ray powder diffraction pattern exhibiting characteristic diffraction peaks corresponding to d-spacings of 9.0, 6.0, 5.3, 5.1, 4.5, 3.9 angstroms generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console using a PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation as the source according to  FIG. 13 .   
     
     
         14 . A compound selected from:
 3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylprop-1-en-1-yl 4-methylbenzenesulfonate;   N-[(1Z)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylprop-1-en-1-yl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide; and   3-{(1Z)-1-(4-chlorobenzyl)-2-[(2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoyl)amino]-prop-1-en-1-yl}benzamide.