ChemicalBook CAS DataBase List Azilsartan

Azilsartan synthesis

9synthesis methods

Product Name:Azilsartan
CAS Number:147403-03-0
Molecular formula:C25H20N4O5
Molecular Weight:456.45

The most likely process-scale synthetic route likely mimics that which is disclosed in Takeda’s patents, and this is described in the scheme below. Commercial available benzoic acid 21 was activated as the correspndong acyl azide and underwent a Curtius rearrangement to give carbamate 22 in 57% yield (three steps from compound 21). The resulting aniline 22 was then alkylated with commercial 4- (bromomethyl)-2'-cyanobiphenyl 23 to give benzylamine 24 in 85% yield. Nitroamine 24 was then exposed to mildly acidic conditions to affect Boc-removal prior to reduction via ferric chloride hydrate in the presence of hydrazine hydrate. The resulting diamine 25 arose in 64% yield across the two-step sequence. Interestingly, tt was found that metal catalysts under conventional hydrogenation conditions caused partial debenzylation, which led the authors to arrive at the hydrazine/ferric chloride conditions. Next, benzimidazole formation was achieved upon treatment of diamine 25 with ethyl orthocarbonate in acetic acid. The resulting ethoxylbenzimidazole 26 was procured in 86% yield, and this benzonitrile was further reacted with hydroxylamine hydrochloride and sodium methoxide to provide amidoxime 27 in 90% as white powder. Next, activation with ethyl chlorocarbonate gave 28 followed by heating in refluxing xylene to give oxadiazolone 29 in 23% yield from hydroxyamidine 27. Finally ester 29 was saponified with 2N LiOH in methanol to give azilsartan (V) in 84% yield.

An improved scalable route (Scheme below) to azilsartan was reported and features reproducibly better yields.43 Hydroxyamidine 30 was treated with dimethyl carbonate and sodium methoxide, which triggered they key cyclization along with concomitant transesterification to deliver 29. Milder aqueous sodium hydroxide hydrolysis converted this methyl ester 29 to azilsartan (V) in 88-90% yield.

1H-BenziMidazole-7-carboxylic acid, 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]Methyl] -2-ethoxy-, ethyl ester

1403474-70-3
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147403-03-0
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Yield:147403-03-0 98.5%

Reaction Conditions:

with water;sodium hydroxide at 50; for 4 h;

Steps:

9 Example 9: Preparation of 2-ethoxy-l-((2'-(5-oxo-4₅5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-lH-benzo[ ]-imidazole-7-carboxylic acid (III).

The starting ethyl ester of azilsartan (V, 250 g) was suspended in a solution of sodium hydroxide in water (56 g/800ml). The suspension was heated at 50°C for 4 h, after pH adjustment to 4-5, the product crystallized providing 232 g (98.5 %).

References:

WO2014/48404,2014,A1 Location in patent:Page/Page column 11

147404-82-8 Synthesis