Prostaglandin synthesis and intermediates for use therein

Abstract

Fused cyclopentane-4-substituted 3,5-dioxalane lactone compounds useful as an intermediate in the synthesis of prostaglandin analogs are provided. The compounds have the formula A: wherein R represents an aryl group such as p-methoxyphenyl. This compound can be reacted with a lower alkyl aluminum compound to open the dioxalane ring and reduce the lactone to lactol, without over-reducing to diol. The resulting compound can be functionalized to insert chemical side groups of target prostaglandins, adding the required α-side chain and then the required ω-side chain sequentially and independently of each other. The compounds and process are particularly suitable for preparing lubiprostone.

1 . A fused cyclopentane-4-substituted 3,5-dioxalane lactone compound useful as an intermediate in the synthesis of prostaglandin analogs, the compound having the formula A: 
       
         
           
           
               
               
           
         
       
       wherein R represents an aryl group. 
     
     
         2 . Compound A according to  claim 1  wherein R represents a substituted phenyl group. 
     
     
         3 . Compound A according to  claim 1  wherein R represents p-methoxyphenyl. 
     
     
         4 . A substituted cyclopentane lactone compound useful as an intermediate in the synthesis of prostaglandin analogs, the compound having the formula B: 
       
         
           
           
               
               
           
         
       
       wherein R′ represents a lower alkoxy substituted benzyl group. 
     
     
         5 . Compound B according to  claim 4  wherein R′ represents p-methoxybenzyl. 
     
     
         6 . Compound 28 ((Z)-benzyl 7-((1R,2R,3R)-2-((E)-4,4-difluoro-3-oxooct-1-enyl)-3-(4-methoxybenzyloxy)-5-oxocyclopentyl)hept-5-enoate) of formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A process of preparing lubiprostone, of formula: 
       
         
           
           
               
               
           
         
       
       which comprises hydrogenating (Z)-benzyl 7-((1R,2R,3R)-2-((E)-4,4-difluoro-3-oxooct-1-enyl)-3-(4-methoxybenzyloxy)-5-oxocyclopentyl)hept-5-enoate with hydrogen over a palladium catalyst in solution, wherein said reaction is conducted at room temperature in solution in ethanol/isopropanol, solid product so obtained is dissolved in isopropyl acetate, crystallized by addition of heptane to the solution, and solid, crystalline lubiprostone recovered.