223734-58-5Relevant articles and documents
PROCESS FOR PREPARATION OF PROSTACYCLIN DERIVATIVES
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, (2017/08/21)
Disclosed is an improved method of synthesis for Treprostinil comprising condensation reaction of compound (4) with a hydroxyl-protected alkynol (5) to give the condensation product, compound (6). Subjecting compound (6) to oxidation, reduction, hydroxyl protection and carbonylation, cyclization reactions gives the tricyclic derivative (10). Further reactions comprising reduction, hydrogenation and deprotection of the phenolic and side-chain hydroxyl groups, wherein the sequence and choice of reagents is governed by protecting groups, give the triol intermediate, compound (14). Cyanoalkylation at phenolic hydroxyl functionality and further hydrolysis yields the prostacyclin compound, Treprostinil (1) and its pharmaceutically acceptable salts with desired purity.
The Intramolecular Asymmetric Pauson-Khand Cyclization As A Novel and General Stereoselective Route to Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil)
Moriarty, Robert M.,Rani, Neena,Enache, Livia A.,Rao, Munagala S.,Batra, Hitesh,Guo, Liang,Penmasta, Raju A.,Staszewski, James P.,Tuladhar, Sudersan M.,Prakash, Om,Crich, David,Hirtopeanu, Anca,Gilardi, Richard
, p. 1890 - 1902 (2007/10/03)
A general and novel solution to the synthesis of biologically important stable analogues of prostacyclin PGI2, namely benzindene prostacyclins, has been achieved via the stereoselective intramolecular Pauson-Khand cyclization (PKC). This work illustrates for the first time the synthetic utility and reliability of the asymmetric PKC route for synthesis and subsequent manufacture of a complex drug substance on a multikilogram scale. The synthetic route surmounts issues of individual step stereoselectivity and scalability. The key step in the synthesis involves efficient stereoselection effected in the PKC of a benzoenyne under the agency of the benzylic OTBDMS group, which serves as a temporary stereodirecting group that is conveniently removed via benzylic hydrogenolysis concomitantly with the catalytic hydrogenation of the enone PKC product. Thus the benzylic chiral center dictates the subsequent stereochemistry of the stereogenic centers at three carbon atoms (C3a, C9a, and C1).
