Industrial Application of the Forster Reaction: Novel One-Pot Synthesis of Cinacalcet Hydrochloride, a Calcimimetic Agent

• Published in: Organic process research & development Vol. 15; no. 2; pp. 455 - 461
• Main Authors: Shinde, Gorakshanath B, Niphade, Navnath C, Deshmukh, Shrikant P, Toche, Raghunath B, Mathad, Vijayavitthal T
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 18.03.2011; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Organic; Physical Sciences; Science & Technology
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op200016a

Described is a new, practical, and one-pot process, based on the Forster reaction, for the synthesis of cinacalcet hydrochloride (1), a calcimimetic agent and calcium-sensing receptor antagonist. The synthesis comprises the condensation of (1R)-(+)-1-naphthylethyl amine (2) with benzaldehyde (3) followed by reaction of obtained Schiff’s base 4 with 1-(3-halopropyl)-3-(trifluoromethyl)benzene (5) to provide highly unstable iminium salt 6. Subsequent hydrolysis of 6 with water in the same pot yielded cinacalcet. The treatment of cinacalcet with hydrochloric acid during the workup process furnished 1 with an overall yield of around 60%. Our synthetic approach for 1, discussed in this report demonstrates industrial application of the century-old, unexplored name reaction, “Forster’s Reaction” or Forster−Decker synthesis.