Process for preparation of 13,14-dihydro-pgf2 alpha derivatives

Abstract

The invention relates to a process for the preparation of 13,14-dihydro-PGF 2α derivatives of R or S configuration at carbon 15, represented by the general formula (I), wherein the identity of the substituents is defined in the description. Compounds of the formula (I) are valuable biologically-active substances or intermediates in the preparation thereof. The invention especially relates to the process for preparation of 13,14-dihydro-15(R)-17-substituted-18,19,20-trinor-PGF 2α , i.e., latanoprost.

1 - 29 . (canceled) 
     
     
         30 . A compound of the general formula (VI) 
       
         
           
           
               
               
           
         
       
       wherein
 LG represents a halogen, an alkylsulfonyloxy, an alkylarylsulfonyloxy, or a arylsulfonyloxy group, and R 3  represents H or a hydroxyl protecting group; or LG and R 3  represent a chemical bond and/or taken together with the atoms to which they are attached and with an —S(O)— or an —SO 2 — group form a cyclosulfite or a cyclosulfate; or LG and R 3  represent chemical bonds and/or taken together with the atoms to which they are attached form an epoxide; 
 Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; 
 n represents an integer from 0 to 6; and 
 the compound has an R or S chiral configuration at the carbon atom substituted by —OR 3 . 
 
     
     
         31 . The compound of  claim 30 , having an enantiomeric excess above 99%. 
     
     
         32 . The compound of  claim 30 , having an enantiomeric excess above 99.5%. 
     
     
         33 . The compound of  claim 30 , wherein
 LG represents a halogen, an alkylsulfonyloxy, an alkylarylsulfonyloxy, or a arylsulfonyloxy group, and R 3  represents H or —Si(R 9 )(R 10 )(R 11 ); or LG and R 3  represent a chemical bond and/or taken together with the atoms to which they are attached and with an —S(O)— or an —SO 2 — group form a cyclosulfite or a cyclosulfate; or LG and R 3  represent chemical bonds and/or taken together with the atoms to which they are attached form an epoxide;   R 9 , R 10 , and R 11  are the same or different, and represent independently a C 1-6 -alkyl or a phenyl;   Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; and   n represents an integer from 0 to 6.   
     
     
         34 . The compound of  claim 30 , wherein LG is iodine, bromine or p-toluenesulfonyloxy group, and R 3  represents a hydroxyl protecting group. 
     
     
         35 . The compound of  claim 30 , wherein LG is iodine, bromine or p-toluenesulfonyloxy group; R 3  represents —Si(R 9 )(R 10 )(R 11 ); and R 9 , R 10 , and R 11  are the same or different, and represent independently a C 1-6 -alkyl or a phenyl. 
     
     
         36 . The compound of  claim 30 , wherein LG is p-toluenesulfonyloxy; R 3  represents —Si(R 9 )(R 10 )(R 11 ); and R 9 , R 10 , and R 11  are the same or different, and represent independently a C 1-6 -alkyl or a phenyl. 
     
     
         37 . A process for the preparation of a compound of the general formula (VI) 
       
         
           
           
               
               
           
         
       
       wherein
 LG represents a halogen, an alkylsulfonyloxy, an alkylarylsulfonyloxy, or a arylsulfonyloxy group, and R 3  represents H or a hydroxyl protecting group; or LG and R 3  represent a chemical bond and/or taken together with the atoms to which they are attached and with an —S(O)— or an —SO 2 — group form a cyclosulfite or a cyclosulfate; or LG and R 3  represent chemical bonds and/or taken together with the atoms to which they are attached form an epoxide; 
 Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; 
 n represents an integer from 0 to 6; and 
 the compound has an R or S chiral configuration at the carbon atom substituted by —OR 3 . 
 
       comprising the steps of:
 (a) converting a 2(S)- or 2(R)-4-phenyl-1,2-alkyldiol of the formula HO—CH 2 —CH(OH)—(CH 2 ) n -Z, wherein Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; and n represents an integer from 0 to 6; to a compound of the general formula (VI) 
 
       
         
           
           
               
               
           
         
       
       wherein R 3  is H; LG is —OSO 2 —Ar; Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; n represents an integer from 0 to 6; and Ar represents substituted or unsubstituted aryl or heteroaryl;
 (b) converting the compound obtained in step (a) to a compound of the general formula (VI) 
 
       
         
           
           
               
               
           
         
       
       wherein R 3  is a hydroxyl protecting group; LG is —OSO 2 —Ar; Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; n represents an integer from 0 to 6; and Ar represents substituted or unsubstituted aryl or heteroaryl;
 (c) converting the compound obtained in step (b) to a compound of the general formula (VI) 
 
       
         
           
           
               
               
           
         
       
       wherein R 3  is a hydroxyl protecting group; LG is a halogen; Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; and n represents an integer from 0 to 6; and
 (d) converting the compound obtained in step (c) to a compound of the general formula (VI) 
 
       
         
           
           
               
               
           
         
       
       wherein LG and R 3  represent chemical bonds and taken together with the atoms to which they are attached form an epoxide; Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; and n represents an integer from 0 to 6. 
     
     
         38 . A process for the preparation of a compound of the general formula (VI) 
       
         
           
           
               
               
           
         
       
       wherein
 LG represents a halogen, an alkylsulfonyloxy, an alkylarylsulfonyloxy, or a arylsulfonyloxy group, and R 3  represents H or a hydroxyl protecting group; or LG and R 3  represent a chemical bond and/or taken together with the atoms to which they are attached and with an —S(O)— or an —SO 2 — group form a cyclosulfite or a cyclosulfate; or LG and R 3  represent chemical bonds and/or taken together with the atoms to which they are attached form an epoxide; 
 Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; 
 n represents an integer from 0 to 6; and 
 the compound has an R or S chiral configuration at the carbon atom substituted by —OR 3 . 
 
       comprising the steps of:
 (a) converting a 2(S)- or 2(R)-4-phenyl-1,2-alkyldiol of formula HO—CH 2 —CH(OH)—(CH 2 ) n -Z, wherein Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; and n represents an integer from 0 to 6; to a compound of the general formula (VI) 
 
       
         
           
           
               
               
           
         
       
       wherein LG and R 3  represent a chemical bond and taken together with the atoms to which they are attached and with an —S(O)— group form a cyclosulfite; and
 (b) converting the compound obtained in step (a) to a compound of the general formula (VI) 
 
       
         
           
           
               
               
           
         
       
       wherein LG and R 3  represent a chemical bond and taken together with the atoms to which they are attached and with an —SO 2 — group form a cyclosulfate. 
     
     
         39 . The process of  claim 37 , wherein the enantiomeric excess of the compound of the formula HO—CH 2 —CH(OH)—(CH 2 ) n -Z is above 99%. 
     
     
         40 . The process of  claim 37 , wherein the enantiomeric excess of the compound of the formula HO—CH 2 —CH(OH)—(CH 2 ) n -Z is above 99% and the compound of the formula HO—CH 2 —CH(OH)—(CH 2 ) n -Z is (S)-4-phenyl-1,2-butanediol. 
     
     
         41 . A process for the preparation of a compound of  claim 30  of the general formula (VI) 
       
         
           
           
               
               
           
         
       
       wherein
 LG represents a halogen, an alkylsulfonyloxy, an alkylarylsulfonyloxy, or a arylsulfonyloxy group, and R 3  represents a hydroxyl protecting group; or LG and R 3  represent a chemical bond and/or taken together with the atoms to which they are attached and with an —S(O)— or an —SO 2 — group form a cyclosulfite or a cyclosulfate; or LG and R 3  represent chemical bonds and/or taken together with the atoms to which they are attached form an epoxide; 
 Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; 
 n represents an integer from 0 to 6; and 
 
       comprising the steps of:
 (a) reacting a derivative of D- or L-glyceric aldehyde of formula R 10 —CH—CH(OR 2 )—CHO in a Wittig reaction with a tertiary phosphonium salt of the formula  (+) PPh 3 -CH 2 —(CH 2 ) n-2 -ZX (−)  to obtain an alkene intermediate; wherein R 1  and R 2  represent independently a hydroxyl protecting group, or taken together constitute a fragment of a dioxolane ring; Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; 
 n represents an integer from 0 to 6; and, and X (−)  represents a bromide anion, an iodide anion, or chloride anion; 
 (b) hydrogenating the alkene intermediate obtained in step (a) and removing hydroxyl protecting groups to obtain a 1,2-diol derivative; 
 (c) converting the primary hydroxyl group of (S)-4-phenyl-1,2-alkyl-diol or (R)-4-phenyl-1,2-alkyl-diol of the general formula OH—CH—CH(OH)—(CH 2 ) n -Z obtained in step (b) to a —OSO 2 —Ar, a —O—S(O)—Cl, or a —OS(O) 2 —Cl group; wherein Z represents H, a methyl or a phenyl, optionally substituted by a C 1-3 -alkyl, a C 1-3 -alkoxy or at least one halogen atom; n represents an integer from 0 to 6; and Ar represents substituted or unsubstituted aryl or heteroaryl; and protecting the secondary hydroxyl group; and 
 (d) optionally, substituting the —OSO 2 —Ar group by a halogen.