Synthesis of Ramipril

Ramipril (5, HOE-498), discovered at Hoechst (now Sanofi-Aventis), was launched in the United States as Altace in 1991 and is currently marketed by King Pharmaceuticals. Upon administration, rapid hepatic cleavage of the ethyl ester results in ramiprilat (42), the 

Hoechst has reported an enantioselective approach toward the key azabicyclo[3.3.0] octane-3-carboxylic acid 46 that preserves the stereochemistry of the L-serine-derived starting material (Urbach and Henning, 1991). L-Serine methyl ester (48) was alkylated 

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An ester of 136 is now used as resolving agent in coupling to the rest of the ramipril molecule. Conjugate addition of alanine to the ketoester 145 gives a 2 1 mixture of 146 and its diastereoisomer. Coupling with 136 allows separation of the right compound and hence completes the synthesis of ramipril. 

Feng and coworkers reported a highly enantioselective Michael reaction of p-ketoesters and nitro-olefins. Ethyl acetate, the recommended solvent, (Table 23.1), is rarely employed in guanidine catalysed asymmetric reactions. It was found to be optimal for this reaction and 2 to 5 mol% of catalyst gives excellent enantioselectivity and diastereoselectivity. The yields are generally high and a practical application of the reaction was demonstrated with a 2-g-scale synthesis of an intermediate for the synthesis of Ramipril analogues (Scheme 23.8). 

Scheme 23.8 Gram-scale synthesis of Ramipril analogues developed by Feng and coworkers. ...

The usefulness of the asymmetric conjugate addition of P-ketoesters to nitrooleflns has been demonstrated through to the synthesis of analogues of the antihypertensive ramipril [249], naturally occurring y-butyrolactone autoregulators IM-2 and VB-D [257], and the marine alkaloid (-)-nakadomarin A (Scheme 2.91) [258]. 

Synthesis of Chiral Indazoles. The desymmetrization of mcyo-epoxides using scandium triflate using benzopyrazole as nucleophile in the presence of ramipril-derived chiral ligands affords a quick entry to synthesize chiral benzopyrazoles. The reaction delivers excellent yield and stereoselectivity for the transformation (eq 31). 

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