O. R. Thiel et al. / Tetrahedron Letters 49 (2008) 13–15
15
HO
OH
In summary a short, atom-economical and highly effi-
cient approach to cinacalcet was developed. The starting
materials are readily available and the sequence involves
only three synthetic steps with an overall yield of 85%.
Only a single isolation and one recrystallization are
necessary to obtain the material in high purity. This
synthesis allows convenient access to kilogram quanti-
ties of cinacalcet.
OH
B
H
N
H
N
F3C
F3C
7
8
H
N
H
N
F3C
F3C
Acknowledgements
9a
9b
Dr. Shawn Eisenberg, Dr. Xin Wang, Ying Chen,
Dr. Ben Zhi, Richard Crockett and Dr. John Ng are
acknowledged for helpful discussions.
Scheme 3. Impurities in the amide reduction.
the free base by treatment of a toluene solution with aq
sodium hydroxide (20%). A solution of the amine is then
mixed with a solution of the dihydrocinnamate. Distilla-
tive removal of the toluene is followed by direct conden-
sation to the amide.
References and notes
1. (a) Hebert, S. C. Annu. Rev. Med. 2006, 57, 349; (b)
Nagano, N. Pharmacol. Ther. 2006, 109, 339.
2. Sorbrera, L. A.; Castaner, R. M.; Bayes, M. Drugs Future
2002, 27, 831.
3. Barmore, R. M.; Logan, S. R.; VanWagenen, B. C.
Tetrahedron Lett. 1998, 39, 3451.
The key step of this synthetic sequence to 1 is the reduc-
tion of amide 6 to the corresponding amine. This reac-
tion was investigated with lithium aluminum hydride
or borane as reducing agents. The former led to the
formation of significant amounts (up to 30%) of uniden-
tified impurities. Cleaner reactions (<1% starting
material, no impurity >0.5%) were usually observed
with borane. Initially the borane was generated in situ
from sodium borohydride in the presence of sulfuric
acid, but this protocol led to the formation of the two
impurities 7 and 8 in low quantities (Scheme 3).12 Fortu-
itously, these side products were not observed when
boron trifluoride was used as the acid source under
anhydrous conditions. In the optimized process the reac-
tion is carried out by the addition of boron trifluoride–
THF to sodium borohydride in a mixture of diglyme/
THF at 45–60 °C. After complete conversion the result-
ing amine–borane complex is hydrolyzed by the addition
of water. The organic solvents are removed by vacuum
distillation. The crude product is extracted into toluene,
followed by washes of the organic phase with aq sodium
hydroxide and water. The product is isolated by the
formation of the HCl salt from a mixture of toluene
and heptane. Two impurities 9a and 9b arising from
reduction of the naphthalene substituent were observed
in low levels (<0.1%). The structures of these impurities
were established by independent synthesis.13 The crude
HCl salt of cinacalcet can be recrystallized from aqueous
methanol to obtain material of very high purity
(>99.5%).
4. Hansen, M. C.; Buchwald, S. L. Tetrahedron Lett. 1999,
40, 2033.
5. (a) Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetrahedron
Lett. 2001, 42, 5029; (b) Atobe, M.; Yamazaki, N.;
Kibayashi, C. J. Org. Chem. 2004, 69, 5595.
6. Catalog suppliers like Aldrich and Acros sell small-scale
quantities; larger quantities are, for example, available
from BASF, Chiron and Finorga.
7. Catalog suppliers like Aldrich and Acros sell small-scale
quantities; larger quantities are, for example, available
from Central Glass, Indofine and TCI.
8. Brown, T. H.; Blakemore, R. C.; Durant, G. J.; Emmett,
J. C.; Ganellin, C. R.; Parsons, M. E.; Rawlings, D. A.;
Walker, T. F. Eur. J. Med. Chem. 1988, 23, 53.
9. (a) Knoevenagel, E. Chem. Ber. 1898, 31, 2585; (b)
Doebner, O. Chem. Ber. 1900, 33, 2140.
10. (a) Bumagin, N. A.; More, P. G.; Beletskaya, I. P. J.
Organomet. Chem. 1989, 371, 397; (b) Beller, M.; Kueh-
lein, K. Synlett 1995, 441.
11. Beckwith, A. L. J. In The Chemistry of Amides; Zabicky,
J., Ed.; Synthesis of Amides; Interscience: London, 1970;
pp 105–109.
12. The mechanism of the formation of these impurities is not
fully understood at the present time.
13. Wang, X.; Chen, Y.; Crockett, R.; Briones, J.; Yan, T.;
Orihuela, C.; Zhi, B.; Ng, J. Tetrahedron Lett. 2004, 45,
8355.