131818-18-3

Upstream product

• 141-82-2 malonic acid 
• 144072-30-0 4-((tert-butoxycarbonyl)amino)benzaldehyde 
• 149506-05-8 3-(4-((tert-butoxycarbonyl)amino)phenyl)propanoic acid 
• 162936-33-6 4-aminocinnamic acid tert-butyl ester 
• 555-16-8 4-nitrobenzaldehdye 
• 209344-13-8 4-nitrophenylacrylic acid tert-butyl ester 

Downstream Products

• 216371-66-3 8-O-(4-aminocinnamoyl)-8-O-debutanoylthapsigargin 

Relevant academic research and scientific papers

Ligand-controlled divergent dehydrogenative reactions of carboxylic acids via C–H activation

Dehydrogenative transformations of alkyl chains to alkenes through methylene carbon-hydrogen (C–H) activation remain a substantial challenge. We report two classes of pyridine-pyridone ligands that enable divergent dehydrogenation reactions through palladium-catalyzed b-methylene C–H activation of carboxylic acids, leading to the direct syntheses of a,b-unsaturated carboxylic acids or g-alkylidene butenolides. The directed nature of this pair of reactions allows chemoselective dehydrogenation of carboxylic acids in the presence of other enolizable functionalities such as ketones, providing chemoselectivity that is not possible by means of existing carbonyl desaturation protocols. Product inhibition is overcome through ligand-promoted preferential activation of C(sp3)–H bonds rather than C(sp2)–H bonds or a sequence of dehydrogenation and vinyl C–H alkynylation. The dehydrogenation reaction is compatible with molecular oxygen as the terminal oxidant.

Toward a Scalable Synthesis and Process for EMA401, Part II: Development and Scale-Up of a Pyridine- A nd Piperidine-Free Knoevenagel-Doebner Condensation

During route scouting for EMA401 (1), an angiotensin II type 2 antagonist, we identified the synthesis of key amino acid intermediate 2 via its cinnamic acid derivative 3 as a streamlined option. In general, cinnamic acids can be synthesized from the corresponding aldehydes by a Knoevenagel-Doebner condensation in pyridine with piperidine as an organocatalyst. We aimed to replace both of these reagents and found novel conditions involving toluene as the solvent and morpholine as the organocatalyst. Scale-up of the process allowed the production of 25 kg of cinnamic acid 3 that was of the quality required for process development of the subsequent phenylalanine ammonia lyase-catalyzed step. The modified conditions were found to be widely applicable to alternative aldehydes and thus are of relevance to practitioners of chemical scale-up.

CINNAMOYL INHIBITORS OF TRANSGLUTAMINASE

A compound of Formula, (I) or Formula: (II)