Methods of synthesizing nicotinamide riboside

Abstract

Provided herein are efficient and scalable methods for the synthesis of nicotinamide riboside from riboside triacetate. Also provided are compositions comprising nicotinamide riboside, and therapeutic methods employing nicotinamide riboside.

1 . A method of preparing compound 3, comprising the steps of: 
       
         
           
           
               
               
           
         
         (a) combining compound 1 and a chlorinating agent, thereby producing a first reaction mixture comprising compound 2, wherein:
 compound 1 is represented by 
 
       
       
         
           
           
               
               
           
         
         
           compound 2 is represented by 
         
       
       
         
           
           
               
               
           
         
       
       and
 the chlorinating agent is gaseous HCl or HCl in dioxane; and 
 (b) combining compound 2 with nicotinamide, thereby producing a second reaction mixture comprising compound 3. 
 
     
     
         2 - 27 . (canceled) 
     
     
         28 . A method of preparing compound 4, 
       comprising the steps of: 
       
         
           
           
               
               
           
         
         (c) combining compound 3 with an ammonia reagent, thereby producing a first reaction mixture comprising compound 4, wherein:
 compound 3 is represented by 
 
       
       
         
           
           
               
               
           
         
       
       and
 the ammonia reagent is methanolic ammonia or diethylamine. 
 
     
     
         29 . The method of  claim 28 , wherein the ammonia reagent is diethylamine. 
     
     
         30 . The method of  claim 28 , wherein the ammonia reagent is methanolic ammonia. 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 28 , wherein step (c) occurs in a third solvent. 
     
     
         33 . The method of  claim 32 , wherein the third solvent is methanol. 
     
     
         34 . The method of  claim 28 , wherein step (c) takes place at a temperature below room temperature. 
     
     
         35 . The method of  claim 28 , wherein the ammonia reagent is diethylamine;
 further comprising step (c′), which occurs after step (c):   (c′) adding cold aqueous HCl to the third reaction mixture, thereby producing a fourth mixture comprising compound 4.   
     
     
         36 . The method of  claim 28 , wherein the ammonia reagent is methanolic ammonia;
 further comprising step (c′), which occurs after step (c):   (c′) concentrating the third reaction mixture under reduced atmospheric pressure, thereby producing a fourth mixture comprising compound 4.   
     
     
         37 . The method of  claim 35 , further comprising step (c″), which occurs after step (c′):
 (c″) filtering the fourth mixture. 
 
     
     
         38 . The method of  claim 37 , further comprising rinsing the retentate with cold methanol or ethanol. 
     
     
         39 . The method of  claim 37 , further comprising rinsing the retentate with cold acetone. 
     
     
         40 . The method of  claim 28 , further comprising
 (a) combining compound 1 and a chlorinating agent, thereby producing a first reaction mixture comprising compound 2, wherein:
 compound 1 is represented by 
   
       
         
           
           
               
               
           
         
         
           compound 2 is represented by 
         
       
       
         
           
           
               
               
           
         
       
       and
 the chlorinating agent is gaseous HCl or HCl in dioxane; and 
 (b) combining compound 2 with nicotinamide, thereby producing a second reaction mixture comprising compound 3. 
 
     
     
         41 - 54 . (canceled) 
     
     
         55 . Compound 4, made according to method of  claim 28 . 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . A method of improving cellular health in a subject, comprising administering to the subject a compound of  claim 55 . 
     
     
         59 . A method of improving sleep quality, stimulating or increasing REM sleep, or treating or preventing insomnia, desynchronosis, or a circadian rhythm sleep disorder in a subject, comprising administering to the subject a compound of  claim 55 . 
     
     
         60 . A method of treating or preventing a motor neuron disease or ALS, or slowing or reversing the progression of motor neuron degeneration in a subject, comprising administering to the subject a compound of  claim 55 . 
     
     
         61 . A method of improving fertility, treating or preventing infertility, inducing ovulation, increasing sperm count, or increasing lactation, comprising administering to the subject a compound of  claim 55 . 
     
     
         62 . A method of treating or preventing kidney damage, acute kidney injury, or kidney disease, or increasing blood flow to the kidneys, comprising administering to the subject a compound of  claim 55 . 
     
     
         63 . A method of treating or preventing liver damage or fatty liver, or decreasing the serum level of alanine transaminase (ALT) or aspartate transaminase (AST) in a subject, comprising administering to the subject a compound of  claim 55 .