Synthesis of cinacalcet: an enantiopure active pharmaceutical ingredient (API)

Abstract

Cinacalcet hydrochloride is the only approved drug acting as calcimimetic, a new class of compds. used in the therapy of secondary hyperparathyroidism and parathyroid carcinoma. Several generic drug manufacturers and research groups from academia have reported alternative approaches to this mol., mainly from (R)​-​(+)​-​1-​(1-​naphthyl)​ethylamine. There are mainly three strategies that have been used to couple this readily accessible enantiopure amine to the other part of the mol.: amide formation followed by redn., reaction with an aldehyde and redn. of the resulting imine, and nucleophilic substitution with a suitable partner that carries a leaving group. More exotic approaches have also been disclosed. In the present review all of them are discussed. 1 Introduction 2 Synthetic Approaches Involving the Synthesis of an Amide Followed by Its Redn. 2.1 Approaches Involving Satd. Amide 2 from Acid 32.2 Approaches Involving Acrylamide 52.3 Alternatives Approaches Involving Amides 3 Synthetic Approaches Involving a Reductive Amination 3.1 Processes for the Synthesis of 3-​(Trifluoromethyl)​cinnamaldehyde (18) and 3-​[3-​(Trifluoromethyl)​phenyl]​propanal (20) 3.2 Processes Involving 183.3 Processes Involving 204 Synthetic Approaches Involving a Substitution Reaction 4.1 Substitutions Involving Alkyl Halides or Pseudohalides 4.2 Substitutions Involving Allyl Halides or Pseudohalides 4.3 Substitution Involving a Propynyl Mesylate 4.4 Direct Substitution without Activating the Hydroxyl Group 5 Misc. Synthetic Approaches 6 Conclusions.