Process for preparation of 13,14-dihydro-PGF2 alpha derivatives

A process for the preparation of a 13,14-dihydro-PGF2α derivative of the general formula (VIII) having an R or an S optical configuration at carbon 15

• wherein:
• R represents —COOH or —COOY;
• Y is a C1-6-alkyl, an alkylphenyl or a phenyl, optionally substituted by C1-3-alkyl;
• Z represents H, a methyl or a phenyl, optionally substituted by a C1-3-alkyl, a C1-3-alkoxy or at least one halogen atom;
• R3 represents H or a hydroxyl protecting group, and
• n represents an integer from 0 to 6;
• the process comprising the steps of:
• (a) generating an anion of the sulfone of formula (V) at the α position in relation to the sulfonyl group
• wherein
• R1 and R2, independently, represent a hydroxyl protecting group;
• Ar represents a substituted or an unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group consisting of O, N, P and S atoms;
• R4 is an orthoester group represented by the general formula —C(OR6)3 or by the general formula (Va),
• R5 represents H, a substituted or an unsubstituted C1-C6-alkyl or Ar;
• and
• R6 is a substituted or an unsubstituted C1-C10-alkyl or Ar;
• (b) reacting the anion generated in step (a) with an alkylating agent of the general formula (VI),
• to yield a compound of the general formula (VII)
• wherein
• LG represents a leaving group, and R3 represents a hydroxyl protecting group;
• or LG and R3 represent a chemical bond and/or taken together with the atoms to which they are attached and with an —S(O)— or an —SO2— group form a cyclosulfite or a cyclosulfate;
• or LG and R3 represent chemical bonds and/or taken together with the atoms to which they are attached form an epoxide;
• R7 is —C(═O)—OR8, —CH2—C(CH2OH)2—R5, or an orthoester group represented by the general formula —C(OR6)3 or by the general formula (Va),
• R5 represents H, substituted or unsubstituted C1-C6-alkyl or Ar;
• and
• R6 is substituted or unsubstituted C1-C10-alkyl or aryl;
• R8 represents H, substituted or unsubstituted C1-10-alkyl or phenyl;
• Z represents H, methyl or phenyl, optionally substituted by C1-3-alkyl, C1-3-alkoxy or at least one halogen atom;
• n represents an integer from 0 to 6;
• R1 and R2, independently, represent a hydroxyl protecting group;
• and
• Ar represents a substituted or an unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group consisting of O, N, P and S atoms;
• (c) performing a reductive desulfonation of the compound of the general formula (VII) obtained in step (b) to yield the compound of the general formula (VIIa)
• wherein
• R1, R2 and R3, independently, represent a hydroxyl protecting group;
• R7 is —C(═O)—OR8, —CH2—C(CH2OH)2—R5, or an orthoester group represented by the general formula —C(OR6)3 or by the general formula (Va),
• R5 represents H, substituted or unsubstituted C1-C6-alkyl or Ar;
• and
• R6 is substituted or unsubstituted C1-C10-alkyl or aryl;
• R8 represents H, substituted or unsubstituted C1-10-alkyl or phenyl;
• Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group consisting of O, N, P and S atoms;
• n represents an integer from 0 to 6;
• and
• Z represents H, methyl or phenyl, optionally substituted by C1-3-alkyl, C1-3-alkoxy or at least one halogen atom;
• (d) removing the hydroxyl protecting groups from the compound of the general formula (VIIa) to yield the compound of formula (VIIb)
• wherein
• R7 is —C(═O)—OR8, —CH2—C(CH2OH)2—R5, or an orthoester group represented by the general formula —C(OR6)3 or by the general formula (Va),
• R5 represents H, substituted or unsubstituted C1-C6-alkyl or Ar;
• and
• R6 is substituted or unsubstituted C1-C10-alkyl or aryl;
• R8 represents H, substituted or unsubstituted C1-10-alkyl or phenyl;
• Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group consisting of O, N, P and S atoms;
• n represents an integer from 0 to 6;
• and
• Z represents H, methyl or phenyl, optionally substituted by C1-3-alkyl, C1-3-alkoxy or at least one halogen atom;
• and
• (e) converting the compound of formula (VIIb) obtained in step (d) to a compound of the general formula (VIII);
• wherein
• R represents COOH;
• R3 represents H;
• n represents an integer from 0 to 6;
• and
• Z represents H, methyl or phenyl, optionally substituted by C1-3-alkyl, C1-3-alkoxy or at least one halogen atom.