Biphenyl tetrazole, synthesis

Scheme 2.9 Example of the synthesis process for the production of the biphenyl tetrazole group...

The synthesis of valsartan (2) by Novartis/Ciba-Geigy chemists is highlighted in Scheme 9.5. Biphenylbenzyl bromide 18 is converted to biphenyl acetate 19 in the presence of sodium acetate in acetic acid. Hydrolysis of 19 followed by Swern oxidation delivered the biphenyl aldehyde 20, which underwent reductive amination with (L)-valine methyl ester (21) to give biphenyl amino acid 22. Acylation of 22 with penta-noyl chloride (23) afforded biphenyl nitrile 24, which is reacted with tributyltin azide to form the tetrazole followed by ester hydrolysis and acidihcation to provide valsartan (2). [See Biihlmayer et al. (1994, 1995).]... 

Synthesis of 2-n-butyl-4-spirocyclopentane-l-[(2 -(tetrazol-5-yl)biphenyl-4-yl)-methyl]-2-imidazolin-5-one... 

The key repeating component of these antihypertensives is the tetrazolylbiphenyl methyl moiety, which has been derived from the corresponding nitrile. During the course of development, groups have oftentimes benchmarked against how well their method faired when applied to the synthesis of the corresponding biphenyl nitrile. Two recent reports reviewing methods to prepare tetrazoles have appeared. ... 

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