Process for the preparation of prostaglandin precursors

Abstract

A propargylic alcohol, enriched in the (R)-enantiomer, has the formula wherein R is C 1-4 alkoxy, halogen, or C 1-4 alkyl optionally substituted by OH or halogen. This is prepared by the steps of: (a) enantioselective (R)-esterification of the racemic alcohol using any acyl donor and a first enzyme; (b) removal of the untreated (S)-alcohol; and (c) enantioselective hydrolysis of the (R)-ester, using a second enzyme.

1 . A process for the preparation of a propargylic alcohol, enriched in the (R)-enantiomer, of the formula  
                   
       wherein R is C 1 , 4  alkoxy, halogen, or Cl  4  alkyl optionally substituted by OH or halogen, which comprises the steps of 
 (a) enantioselective (R)-esterification of the racemic alcohol using any acyl donor and a first enzyme;  
 (b) removal of the untreated (S)-alcohol; and  
 (c) enantioselective hydrolysis of the (R)-ester, using a second enzyme.  
 
     
     
         2 . The process according to    claim 1   , wherein the product is in at least 97% enantiomeric excess.  
     
     
         3 . The process according to    claim 2   , wherein the product is in at least 99% enantiomeric excess.  
     
     
         4 . The process according to    claim 1   , wherein the first enzyme is  Mucor miehei  lipase.  
     
     
         5 . The process according to    claim 1   , wherein the removal comprises conversion of the unreacted (S)-alcohol to a derivative more readily separable from the (R)-ester, and separation of the derivative.  
     
     
         6 . The process according to    claim 5   , wherein the derivative is the hemisulfate ester.  
     
     
         7 . The process according to    claim 1   , wherein the removal comprises conversion of the unreacted (S)-alcohol to the (R)-ester, by conversion of the OH group to a leaving group displaceable by the acyloxy group, and displacement with inversion using an acyloxy donor.  
     
     
         8 . The process according to    claim 7   , wherein the leaving group is an alkenesulfonate or arenesulfonate group, and the displacement comprises using a carboxylic acid or a salt thereof.  
     
     
         9 . The process according to    claim 8   , wherein the leaving group is methanesulfonate or p-toluenesulfonate.  
     
     
         10 . The process according to    claim 1   , wherein the ester is the butyrate or propionate.  
     
     
         11 . The process according to    claim 1   , wherein the second enzyme is  Candida antarcitica  lipase.  
     
     
         12 . The process according to    claim 1   , wherein R is CF 3 .  
     
     
         13 . The process according to    claim 1   , wherein R is Cl.  
     
     
         14 . An (R)-propargylic alcohol having the following structure:  
                   
       wherein R is C 1-4  alkoxy, halogen, or C 1-4  alkyl optionally substituted by OH or halogen, wherein said alcohol is present in at least 97% enantiomeric excess.  
     
     
         15 . The propargylic alcohol according to    claim 14   , which is (R)-4-[3-(trifluoromethyl)-phenoxy]-1-butyn-3-ol.  
     
     
         16 . The propargylic alcohol according to    claim 14   , which is (R)-1-(3-chlorophenoxy)-3-butyn-2-ol.  
     
     
         17 . A process for the preparation of a protected allylic alcohol, enriched in the (R)-enantiomer, of the formula  
                   
       wherein R is C 1-4  alkoxy, halogen, or C 1-4  alkyl optionally substituted by OH or halogen, and wherein R 1  is a blocking group, and X is a metal or a metal-containing group such that the compound is an organometallic reagent or X is a group convertible thereto, wherein said process comprises the steps of 
 (a) enantioselective (R)-esterification of the racemic alcohol using any acyl donor and a first enzyme;  
 (b) removal of the untreated (S)-alcohol;  
 (c) enantioselective hydrolysis of the (R)-ester, using a second enzyme to obtain a compound of the formula  
                 
 
 wherein R is as defined above;  
 (d) introducing the blocking group; and  
 (e) converting the C≡C group to the (E)—CH═CH—X group.  
 
     
     
         18 . The process according to    claim 17   , wherein the metal is copper.  
     
     
         19 . The process according to    claim 17   , wherein X is halide.  
     
     
         20 . The process according to    claim 17   , wherein X is iodide.  
     
     
         21 . The process according to    claim 17   , wherein the blocking group is tert-butyldimethylsilyl.  
     
     
         22 . A process for the preparation of a prostaglandin having an (-side chain including the group  
                   
       wherein R is C 1-4  alkoxy, halogen, or C 1-4  alkyl optionally substituted by OH or halogen, and ═ represents a single or double bond, which comprises the steps of 
 (a) enantioselective (R)-esterification of the racemic alcohol using any acyl donor and a first enzyme;  
 (b) removal of the untreated (S)-alcohol;  
 (c) enantioselective hydrolysis of the (R)-ester, using a second enzyme to obtain a compound of the formula  
                 
 
 wherein R is as defined above;  
 (d) introducing the blocking group; and  
 (e) converting the C≡C group to the (E)—CH═CH—X group, wherein if X is the convertible group, converting it to a metal or metal-containing group; and converting the protected organometallic allylic alcohol to the prostaglandin.  
 
     
     
         23 . The process according to    claim 22   , wherein the prostaglandin is an 11-oxaprostaglandin.  
     
     
         24 . The process according to    claim 22   , wherein the prostaglandin is (+)-16-[-3-(trifluoromethyl)phenoxy]17,18,19,20-tetranor PGF 2α , isopropyl ester.