Practical synthesis of the calcimimetic agent, cinacalcet

Article abstract of DOI:10.1016/j.tetlet.2007.11.030

A practical synthesis of cinacalcet (Sensipar, Mimpara) is described. The synthesis starts from readily available starting materials and relies on safe and practical reaction conditions. The sequence comprises three synthetic steps and only one isolation point. The overall yield for the sequence is 85%.

Full text of DOI:10.1016/j.tetlet.2007.11.030

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Tetrahedron Letters 49 (2008) 13–15
Practical synthesis of the calcimimetic agent, cinacalcet
Oliver R. Thiel,* Charles Bernard, Wanda Tormos, Alan Brewin, Shuji Hirotani,
Kazuo Murakami, Kenji Saito, Robert D. Larsen, Michael J. Martinelli and Paul J. Reider
Chemistry, Research and Discovery, Amgen Inc., Thousand Oaks, CA 91320-1799, United States
Received 5 October 2007; accepted 5 November 2007
Available online 26 November 2007
Abstract—A practical synthesis of cinacalcet (SensiparÒ, MimparaÒ) is described. The synthesis starts from readily available starting
materials and relies on safe and practical reaction conditions. The sequence comprises three synthetic steps and only one isolation
point. The overall yield for the sequence is 85%.
Ó 2007 Elsevier Ltd. All rights reserved.
Cinacalcet HCl (AMG 073, SensiparÒ, MimparaÒ) 1, a
selective calcimimetic agent, acts on the calcium-sensing
receptor of the parathyroid, the principal negative regu-
lator of parathyroid hormone release, to increase its
sensitivity to activation by extracellular calcium, thus
decreasing parathyroid hormone.1 Cinacalcet is effective
in the clinical setting, and is approved for the treatment
of secondary hyperthyroidism in patients with chronic
kidney disease on dialysis, and for the treatment of
elevated calcium levels in patients with parathyroid
carcinoma.
by reduction with sodium cyanoborohydride requires
resolution of the racemic product, generally achieved
by chiral HPLC separation. Alternatively a chiral
arylethylamine can be condensed with a 3-arylpropional-
dehyde followed by reduction to afford the enantiomeri-
cally pure compounds (Scheme 1). Several alternative
approaches to R-568 2 have also been described over
recent years. VanWagenen and co-workers used a one-
pot reduction–transimination–reduction protocol to
obtain 2 directly from 3-(2-chlorophenyl)propionitrile
and (R)-1-(3-methoxyphenyl)ethylamine.3 Buchwald
and Hansen reported a titanium-catalyzed asymmetric
hydrosilylation of an imine for the synthesis of 2.4 Kibay-
ashi and co-workers used an auxiliary based approach
for the synthesis of (R)-1-(3-methoxyphenyl)ethylamine,
further functionalization by DCC-mediated peptide cou-
pling with 3-(2-chlorophenyl)propionic acid, followed by
reduction with DIBAL afforded 2 in acceptable yield
(68%).5 Herein, we disclose an alternative and practical,
atom-economical synthesis of 1, which relies exclusively
on readily available starting materials.
Cinacalcet 1 and R-568 2 (Fig. 1) are structurally related
type II calcimimetics.2 The original synthetic approaches
for these types of compounds rely on various reductive
amination approaches. Condensation of an aromatic
ketone with the suitable 3-aryl propylamine followed
H
N
· HCl
F3C
Cinacalcet 1
Retrosynthetically, the target compound 1 is divided
into the building blocks (R)-1-(1-naphthyl)ethylamine
(3) and 3-(trifluoromethyl)cinnamic acid (4) (Scheme
2). The chiral amine 3 is readily accessed through classi-
cal or enzymatic resolution of the racemic precursor.6
Cl
H
N
OMe
R-568 2
3-(Trifluoromethyl)cinnamic acid (4) is also commer-
cially available.7 It is derived from 3-trifluoromethyl-
benzaldehyde by Perkin condensation with acetic
anhydride/sodium acetate8 or Knoevenagel–Doebner
condensation with malonate/acetic acid/piperidine.9
Figure 1. Type II calcimimetics.
*
Corresponding author. Tel.: +1 805 447 9520; fax: +1 805 375
4532; e-mail: othiel@amgen.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.030

14
O. R. Thiel et al. / Tetrahedron Letters 49 (2008) 13–15
O
N
NH2
Ti(OiPr)4
F3C
F3C
F3C
F3C
H
N
F3C
H2N
NaBH3CN
N
O
Cinacalcet 1
Ti(OiPr)4
H
Scheme 1. Discovery route to cinacalcet 1.
Pd(OH)2/C, H2 (3-4 bar)
40 - 60 °C
O
O
F3C
F3C
quantitative
OH
OH
4
5
H
N
toluene, aq. NaOH
H2N
quantitative
5, 140 - 150 °C
H2N
·HCl
F3C
95 %
O
3·HCl
toluene solution
6
1) NaBH4, BF3·THF
THF.diglyme, 45 - 60 °C
2) toluene, HCl
H
N
H
MeOH/water
·HCl
N
·HCl
F3C
F3C
95 %
95 %
Crude HCl salt
Cinacalcet HCl 1
Scheme 2. Practical synthesis of cinacalcet 1.
Alternatively, this cinnamic acid may be accessed by
Heck reaction of a 3-trifluoromethylarylhalide with
acrylic acid.10
with peptide coupling reagents are typical methods,
the most atom-economical process for the preparation
of an amide is the direct condensation of a carboxylic
acid with an amine.11 The coupling was successfully
performed by heating an equimolar mixture of (R)-1-
(1-naphthyl)ethylamine (3) and 3-(3-trifluoromethyl-
phenyl)-propionic acid (5) in the absence of solvent to
140–150 °C. The water formed is removed by continu-
ous distillation. The key to this reaction is the amide
remains liquid throughout the condensation. A clean
reaction profile is observed despite the rather forcing
conditions employed. The addition of a solvent (DMF,
diglyme, xylenes) and the use of acidic (Amberlite IR-
120, methane sulfonic acid) or basic promoters (sodium
methoxide) offered no significant improvement. After
extractive removal of low residual staring materials by
aqueous basic and acidic washes, the crude amide
(95% solution yield, >99% HPLC purity) was used
directly in the subsequent reaction.
The synthetic sequence to cinacalcet 1 starts with hydro-
genation of 3-(trifluoromethyl)cinnamic acid (4) in the
presence of palladium hydroxide (20 wt% on carbon)
under moderate hydrogen pressure (40–60 psi). A sol-
vent survey concludes that rapid conversions (2 h at
ambient temperature) are observed with primary alco-
hols (methanol or ethanol) as solvent, but the formation
of alkyl ester byproducts is problematic. This side reac-
tion can be suppressed using isopropanol as solvent, but
slower reaction rates are observed (>12 h for full conver-
sion). Diglyme or xylenes are suitable alternatives for
this hydrogenation, but these solvents lead to lower
reaction rates in the second synthetic step. Ultimately
toluene was chosen as an ideal solvent for this hydro-
genation, where a declination in the reaction rate was
compensated for by an increase in the reaction temper-
ature. Complete conversion is accomplished at 50 °C
within 1–3 h. After catalyst filtration the crude product
can be used directly in the next reaction.
During the scale-up of the amide coupling reaction it
was noted that the free amine (R)-1-(1-naphthyl)ethyl-
amine (3) is sensitive to oxidation and carbonate forma-
tion when exposed to air. To address this potential
stability issue, (R)-1-(1-naphthyl)ethylamine hydrochlo-
ride can be used as alternative form of the starting mate-
rial. It is a stable, crystalline non-hygroscopic salt, and
can be conveniently converted in quantitative yield to
A variety of conditions could be suitable for the cou-
pling of 3-(3-trifluoromethylphenyl)-propionic acid (5)
with (R)-1-(1-naphthyl)ethylamine (3) to the amide.
Although activation of the acid via an acid chloride or

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.