Cinacalcet hydrochloride

The potential application of this catalytic system in industry lies in the synthesis of (R) a (1 naphthyl)ethylamine (50), a key precursor to Cinacalcet hydrochloride (51) for the treatment of hyperparathyroidism and hypercalcemia, via the hydrogenation of a (1 naphthyl)enamide at a decreased catalyst loading (0.1 mol%) in TFE under 80 bar of H2 within 24h (Scheme 9.12) [53]. 

Scheme 9.12 Asymmetric hydrogenation route to Cinacalcet hydrochloride.

PTH levels observed but also a decrease in serum calcium and phosphorous levels. This represents a significant therapeutic advantage over vitamin D-based treatments for secondary hyperparathyroidism (19). Cinacalcet hydrochloride is a second-generation calcimimetic approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid cancer. It can be used alone, with vitamin D, and/or with a phosphate binder (51). 

Iqbal J, Zaidi M, Schneider AE. Cinacalcet hydrochloride. IDrugs 2003 6 587-592. 

Teva has patented two routes towards Cinacalcet hydrochloride 23, a calcium mimetic that helps regulate calcium levels in the treatment of bone disease, based on the Heck reactirMi (Scheme 7). In both routes /n-bromo-trifluorotoluene 20 was... 

Scheme 7 Heck approaches towards Cinacalcet hydrochloride...

Ranbaxy has a patent application on the production of Cinacalcet hydrochloride 23 in which the Kumada-Corriu reaction is used. They use 5 mol% of Fe(acac)3 as catalyst in the reaction between vinyl chloride 136 and Grignard reagent 137, and the coupling product was isolated in 70% yield (Scheme 31) [88]. 

To circumvent this steric problem, the Boc group was replaced by a formyl group, which was installed on amine 80 by the in situ generated mixed anhydride 86 (Scheme 22). The newly formed formamide 87 was successfully used for the Heck-Matsuda reaction. This was followed by a reduction of the styrenic double bond by simply adding a balloon of hydrogen to the reaction flask (98% yield over two steps). Next, the A-formyl moiety of 88 was hydrolyzed in concentrated HCl to furnish cinacalcet hydrochloride in quantitative yield. 

Our first applications of this new method have allowed the successful regio- and stereoselective arylation of acyclic allylic esters and A -protected allylamine derivatives. As a consequence of the high synthetic value of the arylated products, they were applied in the total synthesis of several bioactive compounds. Starting from allyUc esters, the synthesis of kavalactones such as the yagonine (27), methysticin (28), and dehydromethysticine (29) was accomplished in a straightforward way. Additionally, the y-arylated allylamine derivatives were applied to the total synthesis of the bioactive compounds naftifine (68), abamine (75), abamine SG (77), cinacalcet hydrochloride (85), and alverine (91). 

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