Processes and intermediates for the preparations of prostaglandins

A process for preparing a compound of Formula Ia-2, having an enantiomeric purity higher than 95% enantiomeric excess and being substantially free of 15β-isomer:

• wherein R2 is a single bond or a C1-4-alkylene or —CH2O—;
• and
• R3 is a C1-7-alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a C1-4-alkyl, a halogen or a trihalomethyl;
• the process comprising the steps of:
• (1) reacting a compound of Formula IVa having an optical purity higher then 90% enantiomeric excess:
• wherein R1 is an alkyl, an alkenyl, an alkynyl, an aryl, or an aralkyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl, pyridinyl, thiophenyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl;
• P1 is a protecting group for the hydroxyl groups selected from the group consisting of methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, and SiRaRbRc wherein Ra, Rb and Rc are each independently a C1-4 alkyl, phenyl, benzyl, a substituted phenyl, or a substituted benzyl, with a cuprate derived from the compound of Formula Va-1, Formula V-2 or Formula V-3, each of which having an optical purity higher then 90% enantiomeric excess:
• wherein Y is a halogen, R6 is a lower alkyl, R2 and R3 are as defined above, and P2 is a protecting group for the hydroxyl groups selected from the group consisting of methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyL, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, and SiRaRbRc wherein Ra, Rb and Rc are each independently a C1-4 alkyl, phenyl, benzyl, a substituted phenyl, or a substituted benzyl;
• to form a high optical purity compound of Formula IIa-1;
• (2) deprotecting the compound of Formula IIa-1 to remove P1 and P2 in the presence of acids to form a high optical purity compound of Formula IIa-2;
• (3) reducing/lactonizing the compound of Formula IIa-2, with an effective amount a reducing agent to form the high optical purity compound of Formula Ia-2;
• and
• (4) isolating the compound of Formula Ia-2 and/or Formula IIa-2 by crystallization.