Elsevier

Tetrahedron Letters

Volume 52, Issue 33, 17 August 2011, Pages 4349-4352
Tetrahedron Letters

A new synthesis of the orally active renin inhibitor aliskiren

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Abstract

A convergent synthesis of the orally active renin inhibitor aliskiren (1) is described. The synthesis was accomplished in 12 steps starting from the known chloride 2. The key step involves the Curtius rearrangement of the advanced intermediate 15, which provides lactone/carbamate 17 containing the correct stereochemistry and all of the functionality required for the preparation of the drug substance.

Section snippets

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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