Synthesis 2016; 48(06): 783-803
DOI: 10.1055/s-0035-1561506
review
© Georg Thieme Verlag Stuttgart · New York

Syntheses of Cinacalcet: An Enantiopure Active Pharmaceutical Ingredient (API)

Marta Barniol-Xicota
a   Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona, 08028, Spain   Email: svazquez@ub.edu
,
Rosana Leiva
a   Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona, 08028, Spain   Email: svazquez@ub.edu
,
Carmen Escolano
b   Laboratori de Química Orgànica, Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona, 08028, Spain
,
Santiago Vázquez*
a   Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona, 08028, Spain   Email: svazquez@ub.edu
› Author Affiliations
Further Information

Publication History

Received: 10 October 2015

Accepted after revision: 30 November 2015

Publication Date:
20 January 2016 (online)


Abstract

Cinacalcet hydrochloride is the only approved drug acting as calcimimetic, a new class of compounds 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 molecule, 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 molecule: amide formation followed by reduction, reaction with an aldehyde and reduction 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 Reduction

2.1 Approaches Involving Saturated Amide 2 from Acid 3

2.2 Approaches Involving Acrylamide 5

2.3 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 18

3.3 Processes Involving 20

4 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 Miscellaneous Synthetic Approaches

6 Conclusions

 
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