A synthetic route amenable to large-scale synthesis of the glycine antagonist (2R,4E)-7-chloro-4-(2-oxo-1-phenyl-pyyrrolidin-3-ylidene)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-penta-ol 12 is presented. The route consists of four stages of chemistry. Stage 1 starts from 5-chloro-2-iodoaniline hydrochloride and is a three-step telescoped stage consisting of an imine formation with ethyl glyoxalate, Mannich reaction using vinyloxytrimethylsilane, and subsequent Wittig reaction with (2-oxo-1-phenyl-3-pyrrolidinyl)triphenylphosphonium bromide. The stage 1 product (4E)-2[(5-chloro-2-iodophenyl)amino]-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)butanoic acid ethyl ester 17 is subjected to an enzyme-catalysed kinetic resolution to prepare the single (2R)-enantiomer 19 as the ethyl ester. Stage 3 is the intramolecular Heck reaction to yield (2R,4E)-7-chloro-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid ethyl ester 31. The final stage is ester saponification and meglumine salt formation to afford the drug candidate molecule 12. In total, more than 300 kg of target 12 was produced with a purity >99.9%. Aspects of route selection as well as elements of process understanding and control are discussed.
Aliskiren is the first‐in‐class orally active direct renin inhibitor. It was approved in 2007 for the treatment of hypertension. We have designed a new strategy for the convergent synthesis of aliskiren that involves a catalytic stereoselective nitroaldol reaction as the key step. A new enantiopure nitroalkane (synthon A1), prepared in only three steps from a commercially available enantiopure 2‐(arylmethyl)‐3‐methyl butanol derivative, was successfully used in a copper‐catalysed Henry reaction to give a nitrolactone intermediate in which the correct configuration for the final product was established at all four stereocentres. Nitro‐group reduction, Boc‐protection of the resulting amine, aminolysis of the lactone with 3‐amino‐2,2‐dimethylpropionamide, and finally Boc‐deprotection led to the enantiopure renin inhibitor aliskiren.
GV143253A is a broad-spectrum injectable β-lactam belonging
to the class of trinem antibiotics. A key intermediate (3S,4R)-3-[(1R)-1-(tert-butyldimethyl- silyloxy)ethyl]-4-[-(6‘R)-2‘-[(E)-(pyrid-4yl)methylene]-1‘-oxocyclohex-6‘-yl]azetidin-2-one (10)
was identified and synthesized via different enolate coupling
approaches, using enol ether, lithium, sodium, magnesium, tin,
zinc, zirconium, and titanium enolates. Among these approaches, the synthesis of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[-(6‘R)-2‘-[(E)-(pyrid-4yl)-methylene]-1‘-oxocyclohex-6‘-yl]azetidin-2-one (10) via a titanium enolate offered
advantages in terms of greater diastereoselectivity, higher yield,
robustness, and isolation of intermediates and was superior to
the method previously used for preparing large quantities of
drug substance for early development studies.
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