Process for the synthesis of nabumetone

Abstract

New process for the synthesis of the antiinflammatory drug known as nabumetone that consists in reacting 2-acetyl-5-bromo-6-methoxynaphthalene with an alkyl acetate in presence of an alkaline alcoholate to get 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one that by catalytic hydrogenation in a polar solvent and in presence of a base gives 4-(6-methoxy-2-naphthyl)butan-2-one known as nabumetone.

We claim:  
     
       1. A process for the synthesis of 4-(6-methoxy-2-naphthyl)butan-2-one of formula I                    
       which comprises the steps of: a) reacting a molar equivalent of 2-acetyl-5-bromo-6-methoxynaphthalene of formula II                    
       with an alkyl acetate of formula III                    
       wherein R is an alkyl group containing from 1 to 6 carbon atoms, in a solvent, said solvent being a member selected from the group consisting of said alkyl acetate of formula III and mixtures of said alkyl acetate of formula III with toluene, acetonitrile or N,N-demethylformamide in presence of 1-3 molar equivalents of an alkaline alcoholate for a period of time from 0.5 to 6 hours at a temperature of 10° C.-90° C. whereby 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one of formula IV is obtained                    
       after acidifying the reaction mixture at a pH value of 3-5 by means of an aqueous solution of an organic or inorganic acid; b) submitting to catalytic hydrogenation a molar equivalent of said compound of formula IV with hydrogen at a pressure of 1-10 atmospheres, for a period of time of 2-24 hours, at a temperature from room temperature to 90° C., in presence of from 0.005 to 0.05 molar equivalents of a hydrogenation catalyst and 0.30 to 0.99 molar equivalents of a base; c) filtering the mixture from step b) and concentrating it under vacuum whereby an oily product is formed; d) purifying said oily product from step c) to obtain the pure compound of formula I. 
     
     
       2. The process according to  claim 1  wherein step d) is carried out by crystallization from an alcohol containing from 1 to 6 carbon atoms. 
     
     
       3. The process according to  claim 1  wherein step d) is carried out through formation of the crystalline bisulfite complex by reaction with sodium bisulfite in a polar solvent or a mixture of said polar solvent with water and treatment of said resulting bisulfite complex with an aqueous solution of hydroxide, carbonate or bicarbonate of an alkali metal in order to recover the 4-(6-methoxy-2-naphthyl)butan-2-one of formula I. 
     
     
       4. The process according to  claim 1  wherein in step a) said alkaline alcoholate is a sodium or potassium alcoholate of an alcohol containing from 1 to 4 carbon atoms. 
     
     
       5. The process according to  claim 1  wherein said hydrogenation catalyst in step b) is 5% or 10% palladium on carbon. 
     
     
       6. The process according to  claim 1  wherein in step b) the amount of said base is from 0.66 to 0.98 molar equivalents, and said base is an acetate or a carbonate of sodium or potassium. 
     
     
       7. The process according to  claim 1  wherein step b) is carried out in a solvent which is an alcohol containing from 1 to 6 carbon atoms or mixtures thereof with water or non-polar solvents. 
     
     
       8. A process for the synthesis of  4 -(   6   - methoxy -   2   - naphthyl ) butan -   2   - one of formula I                      
       
         which comprises:  
       
         a )  reacting  2   - acetyl -   5   - bromo -   6   - methoxynaphthalene of formula II                      
       
         with an alkyl acetate of formula III  
         
           
           
               
               
           
         
       
         wherein R represents an alkyl group containing from  1  to  6  carbon atoms, in the presence of an alkaline alcoholate to form  4   -(   5   - bromo -   6   - methoxy -   2   - naphthyl )-   4   - hydroxybut -   3   - en -   2   - one of formula IV                      
         b )  reacting the compound of formula IV with hydrogen, in the presence of a hydrogenation catalyst and a base; and    
         c )  optionally recovering the product.   
     
     
       9. The process of  claim 8  wherein the compound of formula IV is acidified prior to catalytic hydrogenation. 
     
     
       10. The process of  claim 8  wherein the compound of formula IV is acidified at a pH of from  3  to  5  prior to catalytic hydrogenation. 
     
     
       11. The process of  claim 8  wherein one molar equivalent of the  2 - acetyl -   5   - bromo -   6   - methoxynaphthalene is reacted with the alkyl acetate.   
     
     
       12. The process of  claim 8  wherein the  2 - acetyl -   5   - bromo -   6   - methoxynaphthalene is reacted with the alkyl acetate in a solvent.   
     
     
       13. The process of  claim 8  wherein the  2 - acetyl -   5   - bromo -   6   - methoxynaphthalene is reacted with the alkyl acetate in a solvent selected from the group consisting of the alkyl acetate of formula III, and mixtures of the alkyl acetate of formula III with toluene, acetonitrile or N,N - dimethylformamide.   
     
     
       14. The process of  claim 8  wherein the  2 - acetyl -   5   - bromo -   6   - methoxynaphthalene is reacted with the alkyl acetate in the presence of  1 - 3  molar equivalents of the alkaline alcoholate.   
     
     
       15. The process of  claim 8  wherein the  2 - acetyl -   5   - bromo -   6   - methoxynaphthalene is reacted with the alkyl acetate for from about  0 . 5  to about  6  hours.   
     
     
       16. The process of  claim 8  wherein the  2 - acetyl -   5   - bromo -   6   - methoxynaphthalene is reacted with the alkyl acetate at a temperature of from about  10 ° C. to about  90 ° C.   
     
     
       17. The process of  claim 8  wherein the  2 - acetyl -   5   - bromo -   6   - methoxynaphthalene is reacted with the alkyl acetate and then the result acidified with an aqueous solution of an organic or inorganic acid.   
     
     
       18. The process of  claim 8  wherein in step a)  said alkaline alcoholate is a sodium or potassium alcoholate of an alcohol containing from  1  to  4  carbon atoms.   
     
     
       19. The process of  claim 8  wherein step a)  is conducted in a solvent selected from the group consisting of the alkyl acetate of formula III, and mixtures of the alkyl acetate of formula III with toluene, acetonitrile or N,N - dimethylformamide; in the presence of  1 - 3  molar equivalents of an alkaline alcoholate which is a sodium or potassium alcoholate of an alcohol containing from  1  to  4  carbon atoms; for from about  0 . 5  to about  6  hours and at a temperature of from about  10 ° C. to about  90 ° C., then acidifying the compound of formula IV with an aqueous solution of an organic or inorganic acid at a pH of from  3  to  5 .   
     
     
       20. The process of  claim 8  wherein one molar equivalent of the compound of formula IV is reacted with hydrogen in the presence of  0 . 005  to  0 . 05  molar equivalent of a hydrogenation catalyst and  0 . 30  to  0 . 99  molar equivalent of a base. 
     
     
       21. The process of  claim 8  wherein the hydrogenation is conducted at a pressure of from  1 - 10  atmospheres. 
     
     
       22. The process of  claim 8  wherein the hydrogenation is conducted at a temperature of from room temperature to  90 ° C. 
     
     
       23. The process of  claim 8  wherein the hydrogenation is conducted for a period of time of  2 - 24  hours. 
     
     
       24. The process of  claim 8  wherein said hydrogenation catalyst in step b)  comprises 5   %  or  10   %  palladium on carbon.   
     
     
       25. The process of  claim 8  wherein step b)  the base is selected from the group consisting of an acetate or a carbonate of sodium or potassium and is present in an amount of from  0 . 30  to  0 . 99  molar equivalents.   
     
     
       26. The process of  claim 8  wherein step b)  is conducted in a solvent comprising an alcohol having from  1  to  6  carbon atoms, mixtures of an alcohol having from  1  to  6  carbon atoms with water, or non - polar solvents.   
     
     
       27. The process according to  claim 8  wherein the alkaline alcoholate is selected from the group consisting of sodium and potassium alcoholates of alcohols containing from  1  to  4  carbon atoms, the catalyst of hydrogenation comprises  5 %  or  10   %  palladium on carbon, the amount of base is from  0 . 90  to  0 . 98  molar equivalents, the base is selected from acetates and carbonates of sodium or potassium and the hydrogenation is conducted in the presence of a solvent selected from the group consisting of alcohols containing from  1  to  6  carbon atoms and mixtures thereof with water or non - polar solvents.   
     
     
       28. The process of  claim 8  wherein step b)  is conducted by reacting one molar equivalent of the compound of formula IV with hydrogen, in the presence of  0 . 005  to  0 . 05  molar equivalent of a  5   %  or  10   %  palladium on carbon hydrogenation catalyst and  0 . 30  to  0 . 99  molar equivalent of a base selected from the group consisting of an acetate or a carbonate of sodium or potassium; in a solvent comprising one or more components selected from the group consisting of an alcohol having from  1  to  6  carbon atoms, mixtures of an alcohol having from  1  to  6  carbon atoms with water, or non - polar solvents; at a pressure of from  1 - 10  atmospheres, a temperature of from room temperature to  90 ° C. and for a period of time of  2 - 24  hours.   
     
     
       29. The process of  claim 8  wherein the product  4 -(   6   - methoxy -   2   - naphthyl ) butan -   2   - one of formula I is recovered.   
     
     
       30. The process of  claim 8  further comprising filtering the product of step b)  to recover the compound of formula I and concentrating the compound of formula I under vacuum.   
     
     
       31. The process of  claim 30  further comprising purifying the compound of formula I. 
     
     
       32. The process of  claim 30  further comprising purifying the compound of formula I by crystallizing the compound of formula I from an alcohol containing from  1  to  6  carbon atoms. 
     
     
       33. The process of  claim 30  further comprising purifying the compound of formula I by forming a crystalline bisulfite complex by reacting the product of step b)  with sodium bisulfite in a polar solvent or a mixture of a polar solvent with water, and treating the resulting bisulfite complex with an aqueous solution of a hydroxide, carbonate or bicarbonate of an alkali metal to thereby recover the purified  4   -(   6   - methoxy- -   2   - naphthyl ) butan -   2   - one of formula I.   
     
     
       34. The process of  claim 8  wherein step c)  is conducted by filtering the product of step b )  to recover the compound of formula I and concentrating the compound of formula I under vacuum; and purifying the compound of formula I either by crystallizing the compound of formula I from an alcohol containing from  1  to  6  carbon atoms, or forming a crystalline bisulfite complex by reacting the product of step b )  with sodium bisulfite in a polar solvent or a mixture of a polar solvent with water, and treating the resulting bisulfite complex with an aqueous solution of a hydroxide, carbonate or bicarbonate of an alkali metal to thereby recover the purified  4   -(   6   - methoxy -   2   - naphthyl ) butan -   2   - one of formula I.   
     
     
       35. The process of  claim 34  wherein the purifying is conducted by crystallizing the compound of formula I from an alcohol containing from  1  to  6  carbon atoms. 
     
     
       36. The process of  claim 34  wherein the purifying is conducted by forming a crystalline bisulfite complex by reacting the result of step b)  with sodium bisulfite in a polar solvent or a mixture of a polar solvent with water, and treating the resulting bisulfite complex with an aqueous solution of a hydroxide, carbonate or bicarbonate of an alkali metal to thereby recover the  4   -(   6   - methoxy -   2   - naphthyl ) butan -   2   - one of formula I.   
     
     
       37. A process for the synthesis of  4 -(   6   - methoxy -   2   - naphthyl ) butan -   2   - one of formula I                      
       
         which comprises:  
       
         a )  reacting a molar equivalent of  2   - acetyl -   5   - bromo -   6   - methoxyraphthalene of formula II                      
       
         with an alkyl acetate of formula III  
         
           
           
               
               
           
         
       
         wherein R represents an alkyl group containing from  1  to  6  carbon atoms, in presence of from  1  to  3  molar equivalents of an alkaline alcoholate for a period of time from  0 . 5  to  6  hours at a temperature from  10 ° C. to  90 ° C. to produce the  4   -(   5   - bromo -   6   - methoxy -   2   - naphthyl )-   4   - hydroxybut -   3   - en -   2   - one of formula IV                      
       
         then acidifying the compound of formula IV at a pH value from  3  to  5  with an aqueous solution of an organic or inorganic acid;  
       
         b )  catalytically hydrogenating one molar equivalent of the compound of formula IV with hydrogen at a pressure from  1  to  10  atmospheres, for a period of time from  2  to  24  hours, at a temperature from room temperature to  90 ° C., in presence of from  0 . 005  to  0 . 05  molar equivalents of a hydrogenation catalyst and from  0 . 30  to  0 . 99  molar equivalents of a base in a solvent selected from the group consisting of a polar solvent, a mixture of polar solvents and a mixture of polar and non - polar solvents;    
         c )  filtering the product of step b )  and concentrating the product under vacuum;    
         d )  purifying the result of step c )  either by crystallizing the compound of formula I from an alcohol containing from  1  to  6  carbon atoms; or by forming a crystalline bisulfite complex by reacting the result of step c )  with sodium bisulfite in a polar solvent or a mixture of a polar solvent with water, and treating the resulting bisulfite complex with an aqueous solution of a hydroxide, carbonate or bicarbonate of an alkali metal to thereby recover the purified  4   -(   6   - methoxy -   2   - naphthyl ) butan -   2   - one of formula I.   
     
     
       38. The process of  claim 37  wherein the alkaline alcoholate is selected from the group consisting of sodium or potassium alcoholates of alcohols having from  1  to  4  carbon atoms, the hydrogenation catalyst is  5 %  or  10   %  palladium on carbon, the base is selected from the group consisting of acetates and carbonates of sodium or potassium in an amount of from  0 . 90  to  0 . 98  molar equivalents; and hydrogeration conducted in a solvent selected from the group consisting of alcohols having from  1  to  6  carbon atoms, mixtures of alcohols having from  1  to  6  carbon atoms with water, and non - polar solvents.   
     
     
       39. The process of  claim 37  wherein step a)  in conducted in a solvent selected from the group consisting of toluene, acetonitrile, N,N - dimethylformamide and mixtures thereof.   
     
     
       40. A process for the synthesis of  4 -(   6   - methoxy -   2   - naphthyl ) butan -   2   - one of formula I                      
       
         which comprises:  
       
         a )  reacting one molar equivalent of  2   - acetyl -   5   - bromo -   6   - methoxynaphthalene of formula II                      
       
         with an alkyl acetate of formula III  
         
           
           
               
               
           
         
       
         wherein R represents an alkyl group containing from  1  to  6  carbon atoms, in a solvent selected from the group consisting of the alkyl acetate of formula III, and mixtures of the alkyl acetate of formula III with toluene, acetonitrile or N,N - dimethylformamide; and in the presence of  1 - 3  molar equivalents of an alkaline alcoholate which is a sodium or potassium alcoholate of an alcohol containing from  1  to  4  carbon atoms, to form  4   -(   5   - bromo -   6   - methoxy -   2   - naphthyl )-   4   - hydroxybut -   3   - en -   2   - one of formula IV:                      
       
         for from about  0 . 5  to about  6  hours and at a temperature of from about  10 ° C. to about  90 ° C.; then acidifying the compound of formula IV with an aqueous solution of an organic or inorganic acid at a pH of from  3  to  5 ;  
       
         b )  reacting one molar equivalent of the compound of formula IV with hydrogen, in the presence of  0 . 005  to  0 . 05  molar equivalent of a  5   %  or  10   %  palladium on carbon hydrogenation catalyst and  0 . 30  to  0 . 99  molar equivalent of a base selected from the group consisting of an acetate or a carbonate of sodium or potassium; in a solvent comprising an alcohol having from  1  to  6  carbon atoms, mixtures of an alcohol having from  1  to  6  carbon atoms with water, or non - polar solvents; at a pressure of from  1 - 10  atmospheres, a temperature of from room temperature to  90 ° C. and for a period of time of  2 - 24  hours;    
         c )  filtering the product of step b )  to recover the compound of formula I and concentrating the compound of formula I under vacuum; and purifying the compound of formula I either by crystallizing the compound of formula I from an alcohol containing from  1  to  6  carbon atoms or forming a crystalline bisulfite complex by reacting the product of step b )  with sodium bisulfite in a polar solvent or a mixture of a polar solvent with water, and treating the resulting bisulfite complex with an aqueous solution of a hydroxide, carbonate or bicarbonate of an alkali metal to thereby recover the purified  4   -(   6   - methoxy -   2   - naphthyl ) butan -   2   - one of formula I.