Synthesis of a Precursor to Sacubitril Using Enabling Technologies.
An efficient preparation of a precursor to the neprilysin inhibitor sacubitril is described. The convergent synthesis features a diastereoselective Reformatsky-type carbethoxyallylation and a rhodium-catalyzed stereoselective hydrogenation for installation of the two key stereocenters. Moreover, by integrating machine-assisted methods with batch processes, this procedure allows a safe and rapid production of the key intermediates which are promptly transformed to the target molecule (3·HCl) over 7 steps in 54% overall yield.
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
Shing-Hing
SH
Lau
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
Samuel L
SL
Bourne
Novartis Pharma AG, Postfach, 4002 Basel, Switzerland.
Benjamin
B
Martin
Novartis Pharma AG, Postfach, 4002 Basel, Switzerland.
Berthold
B
Schenkel
Novartis Pharma AG, Postfach, 4002 Basel, Switzerland.
Gerhard
G
Penn
Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
Steven V
SV
Ley
D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds; D002384:Catalysis; D004338:Drug Combinations; D006865:Hydrogenation; D015394:Molecular Structure; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012238:Rhodium / Q000737:chemistry; D013237:Stereoisomerism; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000068756:Valsartan
D000613:Aminobutyrates; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D012238:Rhodium; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination