223438-61-7Relevant articles and documents
An efficient and scalable synthesis of the endothelin antagonists UK-350,926 and UK-349,862 using a dynamic resolution process
Ashcroft, Christopher P.,Challenger, Stephen,Clifford, David,Derrick, Andrew M.,Hajikarimian, Yousef,Slucock, Keith,Silk, Terry V.,Thomson, Nicholas M.,Williams, John R.
, p. 663 - 669 (2012/12/25)
The development and scale-up of a potential manufacturing route to the endothelin antagonists UK-350,926 1 and UK-349,862 2 are described. A key synthetic challenge in designing an efficient route to these molecules was the optical lability of the stereogenic centre during the construction of the acylsulfonamide functionality. In the discovery synthesis of UK-350,926 the chiral centre was introduced by classical resolution and the acylsulfonamide functionality synthesized by construction of the N-sulfonyl bond. An alternative more efficient process route was developed involving the preparation of racemic UK-350,926 and final step dynamic resolution with (S)-(-)-1-phenylethylamine as the key step. The process route prepared the acylsulfonamide by construction of the N-carbonyl bond, eliminates a cryogenic reaction and a hazardous intermediate from the synthesis, improves the overall process yield, and allows access to both endothelin antagonists from common intermediates without the need for purification by chromatography. Full experimental details of the new five-step process to prepare UK-349,862 from commercially available starting materials are given for the first time.
