Process for producing 13-cis retinoic acid

Abstract

The process of the present invention relates to a process for producing 1 3-cis retinoic acid. The process of the present invention involves reacting a Wittig salt in a solvent with a butenolide in the presence of a weak base and optionally, a Lewis acid.

What is claimed is:  
     
         1 . A process for producing a compound of formula IV:  
                   
       comprising the steps of: 
 a). reacting in a solvent in the presence of a weak base, a butenolide of the formula II:  
                 
 
 with a salt of the formula:  
                 
 
 where R 1 , R 2  and R 3  are independently selected from aryl or dialkylamino, R 4  and R 5  are independently selected from hydrogen, loweralkyl, alkoxy, cycloalkyl, aryl, or heterocyclic, and X is selected from halogen or hydrogen sulfate, to form a reaction mixture; and  
 b). recovering the compound from the reaction mixture.  
 
     
     
         2 . The process of    claim 1    wherein said solvent is a polar aprotic solvent.  
     
     
         3 . The process of    claim 2    wherein the polar aprotic solvent is selected from the group consisting of: methylene chloride, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N′-dimethylformamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, N,N′-dimethylacetamide, and mixtures thereof.  
     
     
         4 . The process of    claim 2    wherein solvent is a mixture of a polar aprotic solvent and a non-polar solvent.  
     
     
         5 . The process of    claim 4    wherein the non-polar solvent is toluene, chlorobenzene or alkanes.  
     
     
         6 . The process of    claim 1    wherein the weak base is a tertiary amine, carbonate, bicarbonate or an acetate.  
     
     
         7 . The process of    claim 6    wherein the weak base is selected from tertiary amines, sodium acetate, potassium acetate, cesium acetate, and sodium bicarbonate.  
     
     
         8 . The process of    claim 1    wherein said compound is 13-cis retinoic acid.  
     
     
         9 . The process of    claim 1    wherein the ratio of weak base to butenolide is from about 2:1 to about 10:1.  
     
     
         10 . The process of    claim 1    wherein the ratio of butenolide to the Wittig salt is from about 1:1 to about 10:1.  
     
     
         11 . A process for producing a compound of formula IV:  
                   
       the process comprising the steps of reacting in a solvent in the presence of a weak base and a Lewis acid, a butenolide of the formula II:  
                 
 
       wherein R 1 , R 2  and R 3  are independently selected from aryl or dialkylamino, and R 4  and R 5  are independently selected from hydrogen, loweralkyl, alkoxy, cycloalkyl, aryl, or heterocyclic, with a salt of the formula I:  
                 
 
     
     
         12 . The process of    claim 11    wherein the solvent is a polar aprotic solvent or a mixture of a polar aprotic solvent and non-polar solvent.  
     
     
         13 . The process of    claim 11    wherein the Lewis acid is magnesium triflate, magnesium bromide, magnesium trifluoracetate, magnesium chloride, magnesium iodide or magnesium fluoride  
     
     
         14 . The process of    claim 11    wherein the molar ratio of Lewis acid to the Wittig salt is from about 1:1 to about 3:1.  
     
     
         15 . The process of    claim 11    wherein the ratio of weak base to butenolide is from about 2:1 to about 10:1.  
     
     
         16 . The process of    claim 11    wherein the ratio of butenolide to the Wittig salt is from about 1:1 to about 10:1.  
     
     
         17 . The process of    claim 11    wherein said compound is 13-cis retinoic acid.  
     
     
         18 . The process of    claim 11    wherein the weak based is a tertiary amine.  
     
     
         19 . The process of    claim 18    wherein said tertiary amine is selected from triethylamine, diisopropylethylamine, and N-ethylpiperidine.