Process for preparation of 4,5-Epoxymorphinan-6-oxyglucuronides

Abstract

Conjugation of 4,5-Epoxymorphinan-6-ols with Bromoglucuronides in the presence of Zinc containing compounds as activator under conditions capable of forming 4,5-Epoxymorphinan-6-oxyglucuronides is disclosed. This novel approach provides an efficient method for preparation of both anomers of 4,5-Epoxymorphinan-6-oxyglucuronides. The deprotected end products are useful as analgesic agents.

1 . A process for the synthesis of a protected 4,5-Epoxymorphinan-6-oxyglucuronide of formula [1] or a salt or complex thereof  
       
         
           
           
               
               
           
         
       
       wherein: 
 position 7 and 8 are olefin as shown or dihydro adduct;  
 R 1  is alkyl, hialoalkyl, arylmnethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, lialoalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl,  
 R 2  is alkyl, haloalkyl or aralkyl;  
 R 3  is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, halo alko xycarbonyl , vinyl oxycarbonyl or all yl oxycarbonyl ;  
 R 4  is alkyl, haloalkyl, arylmethyl, 2(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl.  
 comprising reaction of a Bromoglucuronide of the formula [2] 
                     
 wherein  
 R 1  and R 2  are as previously defined;  
 with a 4,5-Epoxymoiphinan-6-ols of the formula [3] or a salt or complex thereof  
                     
 wherein  
 R 3  and R 4  are as previously defined;  
 in the presence of a Zinc containing compound under conditions capable of forming said protected 4,5-Epoxymoiphinan-6-oxyglucuronide [1] or a salt or complex thereof.  
 
     
     
         2 . A process according to  claim 1  wherein said 4,5-Epoxymorphinan-6-ol is selected from the compounds of the formula [3a] 
       
         
           
           
               
               
           
         
       
       wherein 
 R 4  is as previously defined.  
 
     
     
         3 . A process according to  claim 1  wherein said 4,5-Epoxymorphinan-6-ol is selected from 3-O-Acylmorphine, 3-O-Acylnormorphine, 3-O-Acylnalbuphine, 3-O-Acylnalorphine, 3-O-Acyldihydromorphine, 3-O-Benzylmorphine, 3-O-Benzyldihydromorphine, N,O 3 -Dibenzylnormorphine, Codeine, Ethylmorphine, Dihydrocodeine, Pholcodine, 3-O-Alkoxycarbonylmorphine, 3-O-Benzyloxycarbonylmorphine, N,O 3 -Bis(benzyl oxycarbonyl)normorphine.  
     
     
         4 . A process according to  claim 1  wherein said Bromoglucuronide is selected from compounds of formula [2a] 
       
         
           
           
               
               
           
         
       
       wherein 
 R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl; R 2  is as previously defined.  
 
     
     
         5 . A process according to  claim 1  wherein said Bromoglucuronide is selected from compounds of formula [2b] 
       
         
           
           
               
               
           
         
       
       wherein 
 R is as previously defined.  
 
     
     
         6 . A process as recited in  claim 1  wherein said protected 4,5-Epoxymorphinan-6-oxyglucuronide is an N-Methyl-4,5-epoxymorphinan-6-oxyglucuronide of formula [1a] or derivative.  
       
         
           
           
               
               
           
         
       
       wherein: 
 position 7 and 8 can be olefin as shown or dihydro adduct;  
 R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, benzyoxylcarbonyl, nitrobenzyloxycarbonyl, methoxybenzylcarbonyl or aroxycarbonyl R2 is alkyl, haloalkyl or aralkyl;  
 R 4  is alkil, haloalkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl.  
 
     
     
         7 . A process as recited in  claim 1  wherein R 2  and R 3  are methyl.  
     
     
         8 . A process according to  claim 1  wherein said protected 4,5-epoxymorphinan-6-oxyglucuronide is of formula [1b].  
       
         
           
           
               
               
           
         
       
       wherein 
 R and R 4  are as previously defined.  
 
     
     
         9 . A process as recited in  claim 1  wherein the said reaction occurs in the presence of molecular sieves.  
     
     
         10 . A process as recited in  claim 1  wherein the reaction occurs in a non-protic reaction inert solvent.  
     
     
         11 . A process as recited in  claim 10  wherein the inert solvent is selected from Chloroform, Dichloromethane or Dichloroethane.  
     
     
         12 . A process as recited in  claim 1  wherein the Zinc containing compound is Zinc Bromide.  
     
     
         13 . Use of a Zinc complex of a general formula [3b] 
       
         
           
           
               
               
           
         
       
       wherein 
 R 3  and R 4  are as previously defined;  
 X is a halogen or a cyano-group;  
 n 0.5÷2  
 for preparation of a protected 4,5-Epoxymorphinan-6-oxyglucuronide of a general formula [1] or a salt or complex thereof  
                     
 wherein  
 R 1 , R 2 , R 3  and R 4  are as previously defined.  
 
     
     
         14 . A process for the synthesis of a protected 4,5-Epoxymorphinan-6-oxyglucuronide of formula [1] or a salt or complex thereof  
       
         
           
           
               
               
           
         
       
       wherein: 
 position 7 and 8 are olefin as shown or dihydro adduct; R 1  is alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl;  
 R 2  is alkyl, haloalkyl or aralkyl;  
 R 3  is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl;  
 R 4  is alkyl, haloalkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl  
 comprising reaction of Bromoglucuronide of the formula [2] 
                     
 wherein  
 R 1  and R 2  are as previously defined;  
 with complex of the formula [3b] under conditions capable of forming said protected 4,5-Epoxymorphinan-6-oxyglucuronide [1] or a salt or complex thereof.  
 
     
     
         15 . A compound having the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 position 7 and 8 is olefin as shown or dihydro adduct;  
 R 2  and R 3  are as previously defined;  
 R 6  is selected from alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl and R 5  is selected from alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl or R 6  is selected from alkyl, haloalkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl when one of R 5  is selected from alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl.  
 
     
     
         16 . A compound having the following formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 position 7 and 8 is olefin as shown or dihydro adduct;  
 R 7  is hydrogen, alkyl, haloalkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl;  
 R 8  is hydrogen, alkyl, haloalkyl or aralkyl;  
 R 9  is hydrogen, alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl;  
 R 10  is hydrogen, alkyl, haloalkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl or allyloxycarbonyl.  
 
     
     
         17 . A compound of formula [1c] according to  claim 15  wherein R 2  and R 3  are both Me.  
     
     
         18 . A protected 4,5-Epoxymorphinan-6-oxyglucuronide synthesised according to any of  claims 1  to  12  or  14 .  
     
     
         19 . A process for synthesising M6G comprising: synthesising a protected 4,5-Epoxymorphinan-6-oxyglucuronide according to any of  claims 1  to  12  or  14 ; and hydrolysing the protected 4,5-Epoxymorphinan-6-oxyglucuronide to form M6G.  
     
     
         20 . M6G synthesised according to  claim 19 .  
     
     
         21 . M6G synthesised using a zinc complex according to  claim 13.