A new synthesis of the orally active renin inhibitor aliskiren
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Synthesis of intermediate 5
The synthesis of 5 was efficiently carried out starting from the readily available chloride8 2 using the malonic ester synthesis (Scheme 2). The reaction of 2 with diethyl malonate in NaOEt/EtOH was sluggish and required the addition of sodium iodide to proceed to completion. The diester 3 was obtained as oil. Conversion to the acid was carried out in two steps. First, the diester was decarboxylated to the mono ester 4 using KOAc/DMSO/water.13 Following an aqueous work up, 4 was saponified with
Synthesis of intermediate 8
The synthesis of 8 is shown in Scheme 3. Compound 6 was prepared in greater than 95% yield from the corresponding oxazolidinone and isovaleryl chloride according to the procedure of Evans.14 The alkylation proceeded smoothly to afford 7 with >99% diastereomeric purity.15 For the oxidation step,16 the reaction was carried out initially at 0 °C for 3 h, followed by warming to 20 °C overnight. The yield of 8 was 57% over two steps.
Synthesis of intermediate 15 and the construction of aliskiren
We envisioned joining 5 and 8 via an asymmetric anti-aldol reaction using the norephedrine-derived chiral auxiliary 10 introduced by Masamune.17 This reagent had been successfully employed in the enantioselective anti-aldol processes.18 Formation of the ester 11 was very slow under Masamune’s conditions (Scheme 4). However, treatment with an additional 5 equiv of pyridine and heating at 40 °C for 12 h afforded ester 11 in 47% yield (purity 99.5%) after column chromatography. Ester 11 was treated
Acknowledgments
We thank Drs. Oljan Repic and Gerhard Penn for various suggestions and helpful discussions during this work.
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