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.
A synthesis of methyl 3-(2-methoxy-4-pyridy1)propionate ( Z ) , a key intermediate in the synthesis of the potent long-acting histamine H,-receptor antagonist SK&F 93574 ( I ) , is described. The key step in the synthesis of compound (1 ) involves alkylation of 2-methoxy-4-methylpyridine (5) with sodium chloroacetate in the presence of sodamide. The scope and limitations of the alkylation is investigated using a variety of electrophiles. The application of this reaction to other 2-substituted 4-methylpyridines is also discussed.
N
‐acetyl‐
N
‐phenylhydroxylamine via catalytic transfer hydrogenation of nitrobenzene using hydrazine and rhodium on carbon
solvent: 100 mL of petroleum ether
product: N‐acetyl‐N‐phenylhydroxylamine
The development of an efficient manufacturing route to 2,3,4,5tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester SB-235349, a key intermediate in the synthesis of lotrafiban is described. The synthesis starts with 2-nitrobenzyl alcohol which is mesylated, reacted with methylamine and then dimethylacetylene dicarboxylate followed by reduction of the nitro group. Treatment of the resultant aniline with acid gives an intermediate quinazoline which rearranges on treatment with base to give a 1,4-benzodiazapine. Reduction of the exocyclic double bond affords SB-235349. The process can be run without isolation of any of the intermediates and has been used to prepare several tons of SB-235349.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.