Refernces
10.1055/s-2008-1078259
The research investigates an asymmetric 1,4-addition reaction of arylboronic acids to α,β-unsaturated esters catalyzed by a dicationic palladium(II)–chiraphos complex, aiming to provide a short-step synthesis of an endothelin receptor antagonist reported by SmithKline Beecham. The study found that in the presence of the Pd(chiraphos)(PhCN)22 catalyst, aryl esters selectively afforded 1,4-addition products with high enantioselectivity (up to 98% ee), while alkyl esters resulted in Heck coupling. The protocol was effective for various arylboronic acids and ester derivatives, with phenyl and 4-acetylphenyl esters yielding particularly high selectivity for 1,4-addition. The findings highlight the potential of palladium catalysts for constructing chiral centers in bioactive compounds, offering a simple and efficient route to synthesize optically active endothelin receptor antagonists.
10.1021/op400100s
The study presents a novel and efficient synthetic process for bosentan monohydrate, an endothelin receptor antagonist used to treat pulmonary hypertension. The key innovation involves coupling p-tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2'-bipyrimidin-4-yl)benzenesulfonamide (7) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (14). This method eliminates the formation of critical impurities such as pyrimidinone 8, dimer impurity 9, and N-alkylated impurity 13, which are common in previous synthesis methods. The new process achieves an overall yield of 50-55%, corresponding to an average step yield of 85%, using simple steps and commercially available chemicals. The study also details the optimization of reaction conditions, such as the use of acetonitrile as a solvent and NaOH as a base, and the final purification of bosentan monohydrate using a combination of ethylacetate and methanol. The resulting bosentan monohydrate meets ICH-grade quality standards and exhibits polymorphic stability under various conditions.
10.1016/S0960-894X(97)00132-7
The study investigates the structure-activity relationships of endothelin receptor antagonists, specifically focusing on replacing the ester or amide bond in a series of ETA selective endothelin antagonists with an aryloxymethylene group. Endothelins (ETs) are potent vasoconstrictors, and their receptors (ETA and ETB) are therapeutic targets for various diseases. The researchers synthesized and tested a series of 3-aryloxymethylthiophene-2-sulfonamides and 2-aryloxymethylthiophene-3-sulfonamides. They found that substituting the phenyl ring with methyl groups improved binding affinity for both ETA and ETB receptors. Notably, compound 27c showed the highest ETB receptor binding affinity. However, replacing the carbonyl group with a methylene group resulted in a significant loss of ETA binding affinity, indicating the importance of the carbonyl group for ETA receptor interactions.
10.1016/j.tetlet.2010.06.037
The study presents a simplified and scalable procedure for the TiCl4-promoted aldol reaction, a method for forming carbon-carbon bonds widely used in natural product and pharmaceutical synthesis. The researchers compared the conventional method of adding TiCl4, DIPEA, and aldehydes sequentially to a new method where TiCl4 is added last to a solution of the substrates and DIPEA in CH2Cl2. The new procedure yielded cleaner reactions at higher temperatures and was reproducible on a large scale, though it lacked stereoselectivity. Key chemicals used were TiCl4 as the promoter, (i-Pr)2NEt (DIPEA) as the base, and various aldehydes and carbonyl compounds as substrates for the aldol reaction. The purpose of these chemicals was to facilitate the formation of the desired aldol products, which are intermediates in the synthesis of endothelin receptor antagonists.
