Synthesis of deuterated morpholine derivatives

Abstract

The present invention is directed to a process for preparing a 2,26,6-d 4 -morpholine derivative represented by Structural Formula (I): or a salt thereof.

1 .- 10 . (canceled) 
     
     
         11 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 R 1  is —H, —OH, —NH 2 , —NHR a , —N(R a ) 2 , —C(═O)NR c R d , —C(═O)OR g , -phthalimido, —SO 2 —R b , or a group selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, wherein the alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl are each independently optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR e , —C(═O)OR e , —C(═O)R e , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R e , —C(═O)NR c R d , —S(O)R e , —S(O) 2 R e , —SR e , and —SO 2 NR c R d , wherein each C 1-6  alkyl is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
 each R a  is independently an alkyl optionally substituted with halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl or C 1-6  haloalkoxy; 
 R b  is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, —OR e , —C(═O)OR e , —C(═O)R e , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R e , —C(═O)NR c R d , —S(O)R e , —S(O) 2 R e , —SR e , and —SO 2 NR c R d , wherein each C 1-6  alkyl is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
 R c  and R d  are each independently —H or alkyl optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR e , —C(═O)OR e , —C(═O)R e , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R e , —C(═O)NR c R d , —S(O)R e , —S(O) 2 R e , —SR e , and —SO 2 NR c R d , wherein each C 1-6  alkyl is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
 R e  is —H or alkyl optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR f , —C(═O)OR f , —C(═O)R f , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R f , —C(═O)NR c R d , —S(O)R f , —S(O) 2 R f , —SR f , and —SO 2 NR c R d , wherein each C 1-6  alkyl substituent is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
 R f  is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
 R g  is alkyl optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR f , —C(═O)OR f , —C(═O)R f , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R f , —C(═O)NR c R d , —S(O)R f , —S(O) 2 R f , —SR f , and —SO 2 NR c R d , wherein each C 1-6  alkyl substituent is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; and 
 R 4 , R 4′ , R 5  and R 5′  are each independently —H or C 1-4  alkyl optionally substituted with one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl, or C 1-6  haloalkoxy. 
 
     
     
         12 . The compound of  claim 11 , wherein the deuterium enrichment at each position designated as deuterium is at least about 85%. 
     
     
         13 . The compound of  claim 12 , wherein R 4 , R 4′ , R 5  and R 5′  are each —H; R 1  is benzyl; and the deuterium enrichment at each position designated as deuterium is 95%. 
     
     
         14 . A compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 R 1  is —H, —OH, —NO, —NH 2 , —NHR a , —N(R a ) 2 , —C(═O)NR c R d , —C(═O)OR g , -phthalimido, —SO 2 —R b , or a group selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, wherein the alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl are each independently optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR e , —C(═O)OR e , —C(═O)R e , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R e , —C(═O)NR c R d , —S(O)R e , —S(O) 2 R e , —SR e , and —SO 2 NR c R d , wherein each C 1-6  alkyl is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
 each R a  is independently an alkyl optionally substituted with halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl or C 1-6  haloalkoxy; 
 R b  is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR e , —C(═O)OR e , —C(═O)R e , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R e , —C(═O)NR c R d , —S(O)R e , —S(O) 2 R e , —SR e , and —SO 2 NR c R d , wherein each C 1-6  alkyl is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
 R c  and R d  are each independently —H or alkyl optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR e , —C(═O)OR e , —C(═O)R e , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R e , —C(═O)NR c R d , —S(O)R e , —S(O) 2 R e , —SR e , and —SO 2 NR c R d , wherein each C 1-6  alkyl is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
 R e  is —H or alkyl optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR f , —C(═O)OR f , —C(═O)R f , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R f , —C(═O)NR c R d , —S(O)R f , —S(O) 2 R f , —SR f , and —SO 2 NR c R d , wherein each C 1-6  alkyl substituent is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
 R f  is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
 R g  is alkyl optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —OR f , —C(═O)OR f , —C(═O)R f , —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —NR c C(═O)R f , —C(═O)NR c R d , —S(O)R f , —S(O) 2 R f , —SR f , and —SO 2 NR c R d , wherein each C 1-6  alkyl substituent is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy; and 
 
       R 4 , R 4′ , R 5  and R 5′  are each independently —H or C 1-4  alkyl optionally substituted with one or more halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl, or C 1-6  haloalkoxy;
 and wherein the deuterium enrichment at each position designated as deuterium is at least about 85%. 
 
     
     
         15 . The compound of  claim 14 , wherein each of R 4 , R 4′ , R 5  and R 5′  is hydrogen, or a salt thereof; and wherein the deuterium enrichment at each position designated as deuterium is at least about 95%. 
     
     
         16 . The compound of  claim 14 , wherein R 1  is —H, benzyl, —SO 2 -aryl, or —SO 2 -heteroaryl. 
     
     
         17 . The compound of  claim 15 , wherein R 1  is benzyl. 
     
     
         18 . The compound of  claim 14 , wherein R e  is alkyl optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, —NO 2 , —CN, —NH 2 , —NHR a , —N(R a ) 2 , —C(═O)NR c R d , and —SO 2 NR c R d , wherein each C 1-6  alkyl substituent is optionally substituted with one or more groups selected from halogen, C 1-6  alkyl, C 1-6  alkoxy, —OH, C 1-6  haloalkyl and C 1-6  haloalkoxy. 
     
     
         19 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof,
 wherein the deuterium enrichment at each position designated as deuterium is at least about 95%. 
 
     
     
         20 . A pyrogen-free pharmaceutical composition comprising the compound of  claim 19 ; and a pharmaceutically acceptable carrier. 
     
     
         21 . A composition comprising the compound of  claim 19 ; and a pharmaceutically acceptable carrier for use in treating a bacterial infection or a fungal disorder in a subject in need thereof. 
     
     
         22 . The composition of  claim 21 , wherein the bacterial infection is caused by a bacteria selected from  Enterococcus faecium, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyrogenes, Enterococcus faecalis, Staphylococcus epidermidis, Staphyloccocus haemolyticus , and  Pasteurella multocida.    
     
     
         23 . The composition of  claim 21 , wherein the bacterial infection or fungal disorder is selected from a Gram-positive bacterial infection; Vancomycin-resistant  Enterococcus faecium  infection; nosocomial pneumonia due to  Staphylococcus aureus  and  Streptococcus pneumoniae ; complicated skin and skin structure infections caused by  Staphylococcus aureus, Streptococcus pyogenes , or  Streptococcus agalactiae ; uncomplicated skin and skin structure infections caused by  Staphylococcus aureus  or  Streptococcus pyogenes ; and community-acquired pneumonia caused by  Streptococcus pneumoniae  or  Staphylococcus aureus.    
     
     
         24 . A method of treating a bacterial infection or a fungal disorder in a subject in need thereof comprising the step of administering to the subject in need thereof the composition of  claim 20 . 
     
     
         25 . The method of  claim 24 , wherein the bacterial infection is caused by a bacteria selected from  Enterococcus faecium, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyrogenes, Enterococcus faecalis, Staphylococcus epidermidis, Staphyloccocus haemolyticus , and  Pasteurella multocida.    
     
     
         26 . The method of  claim 25 , wherein the bacterial infection or fungal disorder is selected from a Gram-positive bacterial infection; Vancomycin-resistant  Enterococcus faecium  infection; nosocomial pneumonia due to  Staphylococcus aureus  and  Streptococcus pneumoniae ; complicated skin and skin structure infections caused by  Staphylococcus aureus, Streptococcus pyogenes , or  Streptococcus agalactiae ; uncomplicated skin and skin structure infections caused by  Staphylococcus aureus  or  Streptococcus pyogenes ; and community-acquired pneumonia caused by  Streptococcus pneumoniae  or  Staphylococcus aureus.    
     
     
         27 . The method of any one of  claim 24 , further comprising the step of administering to the subject in need thereof a second therapeutic agent selected from gentamicin, tobramycin, aztreonam, cefazolin, ceftazidime, piperacillin, ciprofloxacin, ofloxacin, levofloxacin, celecoxib, and rofecoxib. 
     
     
         28 . The method of  claim 24 , wherein the infection is an infection of the eye or tuberculosis. 
     
     
         29 . The method of  claim 24 , wherein the infection is an infection selected from the group consisting of diabetic foot infections, nocardiosis, endophthalmitis, keratitis, conjunctivitis, and impetigo. 
     
     
         30 . A compound represented by a structural formula selected from: 
       
         
           
           
               
               
           
         
       
       or a salt thereof,
 wherein the deuterium enrichment at each position designated as deuterium is at least about 95%.