Synthesis of Cinacalcet congeners

Article abstract of DOI:10.1016/j.tetlet.2004.09.063

Two related substances 1 and 2 of Cinacalet were prepared. Two racemic isomeric dihydronaphthalenes 1 and 2 were prepared from commercially available 5-hydroxytetralone in five linear steps. A key palladium-catalyzed double bond migration led to the synthesis of both isomers from the same starting material. Preparative chiral HPLC separation provided the enantiomerically pure materials. An asymmetric synthesis employing CBS reduction to furnish 1 was also developed.

Full text of DOI:10.1016/j.tetlet.2004.09.063

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8355–8358
Synthesis of Cinacalcet congeners
Xin Wang,* Ying Chen, Richard Crockett, Jorge Briones, Tony Yan, Carlos Orihuela,
Benxin Zhi and John Ng
Chemical Process Research & Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA
Received 18 August 2004; revised 2 September 2004; accepted 8 September 2004
Available online 25 September 2004
Abstract—Two racemic isomeric dihydronaphthalenes 1 and 2 were prepared from commercially available 5-hydroxytetralone in
five linear steps. A key palladium-catalyzed double bond migration led to the synthesis of both isomers from the same starting mate-
rial. Preparative chiral HPLC separation provided the enantiomerically pure materials. An asymmetric synthesis employing CBS
reduction to furnish 1 was also developed.
ꢀ 2004 Elsevier Ltd. All rights reserved.
During the late phase manufacturing studies of Cinacal-
cet,1 low levels (<0.1%) of two new isomeric dihydro-
desired product 5 under the reported Buchwald reaction
conditions or slight variations. Through subsequent
communication with Professor Buchwald, it was con-
firmed that similar observations were reported in their
laboratories.
naphthalene related substances
1
and
2
were
discovered (Scheme 1). Their structures have been
assigned based on NMR spectroscopic studies of a small
sample isolated by preparative HPLC from the original
drug substance. To further establish the structural
assignment, we prepared these two impurities via an
unambiguous total synthesis approach.
Our second approach also utilized 5-hydroxytetralone
(3), which was first reduced with NaBH4 to the alcohol
6 in 93% yield (Scheme 3). Formation of the bis-triflate
and the elimination step were carried out in one pot
using 2equiv of triflic anhydride and Et3N in CH2Cl2
to give the triflate 7 in overall 46% yield. The reaction
conversions were nearly quantitative, but the low iso-
lated yield is attributed to partial decomposition of the
triflate 74 during silica gel chromatography purification.
The triflate 7 was converted to a mixture of two isomeric
enol vinyl ethers 8a/b via a Heck coupling protocol.5
The partial double bond shift is not entirely surprising
and similar examples have been precedented.6 The Heck
Based on retro-synthetic analysis, we decided to take
advantage of the commercially available 5-hydroxytetra-
lone2 (3). Our first approach relies on a key carbon–
carbon bond formation as reported by Vogl and
Buchwald,3 in which monoarylation of nitroalkane
was catalyzed by palladium (Scheme 2). Although this
reference reported alkylation with aryl bromide sub-
strates, our aryl triflate was unfortunately not a suitable
partner for this type of coupling. We observed no
H
N
H
N
H
N
CF3
CF3
CF3
2
1
Cinacalcet
Scheme 1.
Keywords: Dihydronaphthalene; Double bond migration; Cinacalcet.
*
Corresponding author. Tel.: +1 805 447 6522; fax: +1 805 375 8753; e-mail: xinw@amgen.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.063

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X. Wang et al. / Tetrahedron Letters 45 (2004) 8355–8358
NO2
OTf
OH
NO2
Tf2O/CH2Cl2
94%
1
Pd(dba)3, Cs2CO3
O
O
O
3
5
4
Scheme 2.
OH
OH
OTf
NaBH4/MeOH
Tf2O/Et3N
CH2Cl2
O
Pd(OAc)2/dppp
O
6
OH
3
7
O
O
+
O
CH2
O
CH2
Bu
Bu
3N HCl
+
8a
8b
9a
9b
Scheme 3.
reaction required 16h to complete, at which time the
ratio of two isomers (8a:8b) was 6:1. This mixture was
treated with HCl to afford the ketones 9a and 9b. The
isolated yield for the ketone 9a was 67% after prepara-
tive HPLC isolation. However, when the Heck reaction
time was increased to 48h, we believe the thermody-
namic equilibrium ratio of two isomers (8a:8b) was
terminal at 1.7:1. After the hydrolysis with HCl and
the preparative HPLC separation, the ketone 9b was
obtained in 30% yield over two steps.7
9b, respectively, in 56% isolated yield. Finally, prepara-
tive chiral HPLC separation of 1 and 2 furnished the
desired enantiomerically pure (R)-isomers, of the same
configuration as Cinacalcet. Their spectroscopic data8
was identical with the compounds isolated from drug
substance in every aspect.
An alternative asymmetric synthesis of 1 was also devel-
oped to avoid the chiral HPLC purification (Scheme 5).
The triflate 4 was subjected to the Heck conditions to
afford 14. HCl hydrolysis of the vinyl ether and ketone
reduction followed by elimination produced the ketone
8a. After much experimental effort with different chiral
reducing agents, we found that methyl oxazaborol-
idine-catalyzed borane reduction9 (Me-CBS/BH3 or
Me-CBS/catecholborane) was effective for the chiral
reduction. Under optimal conditions [(R)-Me-CBS
(1equiv), BH3/THF (1equiv), toluene], the alcohol 17
was obtained in 92% yield and 91.5% ee.11 The alcohol
The amino component was accessed via commercially
available trans-3-(trifluoromethyl)-cinnamoyl chloride
(10), which was treated with NH4OH/dioxane to give
the desired amide 11 in 92% yield (Scheme 4). The
double bond was hydrogenated in 89% yield, and
LAH reduced the amide 12 to afford the amine 13 in
65% yield. The direct reductive amination of 9 with 13
was sluggish due to the low reactivity of aryl methyl
ketone 9. Therefore, a stepwise reductive amination
was employed. The amine 13 and the ketone 9 were
mixed in neat Ti(OiPr)4 overnight and the resulting
imine was reduced by NaBH4 in MeOH to give the
desired products racemic 1 and racemic 2 from 9a and
10
17 was converted to the azide 18 using (PhO)2PON3
in 88% yield, which was then reduced to amine 19 using
the conventional Ph3P conditions in 92% yield and 92%
ee. Reductive amination with the aldehyde 2012 afforded
1 in 90% yield and 92% ee.11
NH4OH
Cl
H2/Pd-C/RT
NH2
Dioxane/0 oC
F3C
MeOH/16h
F3C
O
O
10
92%
11
89%
1. 9/Ti(OiPr)4
2. NaBH4/MeOH
NH2
LAH/THF
1 or 2
F3C
NH2
Reflux/4h F3C
65%
3. Chiral HPLC
28%
O
12
13
Scheme 4.

X. Wang et al. / Tetrahedron Letters 45 (2004) 8355–8358
8357
O
O
OTf
n-Bu
n-Bu
NaBH4/MeOH
3N HCl
O
Pd(OAc)2/dppp
79%
O
15
O
OH
14
4
O
O
OH
N3
Tf2O/CH2Cl2
TEA
(PhO)2PON3
88%
BH3-THF
(R)-CBS
40%, 3 steps
18
17
OH
16
8a
92%, 91.5%ee
NH2
F3C
CHO
Ph3P/THF-H2O
92%, 92% ee
20
1
NaBH(OAc)3/HOAc
90%
19
Scheme 5.
7. The two isomers were separated by preparative HPLC.
Column = X-terra C-18 RP, 10l; column size =
5cm · 30cm; particle size = 10l; wavelength = 220nm;
cycle time/per cycle = 20min; total separation time for
each injection = 80min; sample loading/per injection:
0.55g; mobile phase = 45/55/MeCN/H2O; tempera-
ture = 25ꢁC; sample concentration = 22mg/mL; injection
volume = 25mL; flow rate = 120mL/min. Compound 9a:
1H NMR (300MHz, CDCl3): 2.25 (2H, dt), 2.57 (3H, s),
3.01 (2H, t), 6.05 (1H, dt), 6.45 (1H, d), 7.12 (1H, d), 7.19
(1H, dd), 7.45 (1H, d). 13C NMR (75MHz, CDCl3): 23.2,
24.6, 30.4, 125.6, 127.1, 127.3, 127.9, 129.5, 135.3, 135.7,
138.2, 202.8. Compound 9b: 1H NMR (300MHz, CDCl3):
2.21 (2H, m), 2.59 (3H, s), 2.79 (1H, t), 6.15 (1H, dt), 7.02
(1H, d), 7.12 (1H, d), 7.19 (1H, dd), 7.45 (1H, d). 13C
NMR (75MHz, CDCl3): 22.3, 28.1, 29.9, 125.6, 127.1,
127.3, 127.9, 129.5, 135.3, 135.7, 138.2, 202.1.
In summary, we discovered a novel palladium catalyzed
double bond migration to afford a mixture of dihydro-
naphthalene isomers that was conducted in tandem with
the key Heck coupling reaction in a single operation.
Subsequent reductive amination was developed to afford
the target isomers. In parallel, we established an asym-
metric synthesis of the desired (R)-isomer, to unambigu-
ously correlate the stereochemical assignment.
Acknowledgements
We thank Dr. Paul J. Reider for his useful discussion
and consistent encouragement. We sincerely thank Dr.
Mike Martinelli for extensive proofreading and useful
suggestions. We are also grateful to Bo Shen, Mike
Ronk and Duncan Smith for technical assistance with
HPLC, MS and NMR.
8. Chiral HPLC separation was achieved: Chirobiotic
V column 150 · 4.6mm; wavelength = 260nm; mobile
phase = MeOH/HOAc/TEA 1000/0.2/0.2 (v:v:v); flow
rate = 1mL/min; column temperature = ambient. Com-
1
pound 1: H NMR (400MHz, CDCl3): 7.40 (1H, s); 7.26
References and notes
(3H, m); 7.21 (2H, m); 7.0 (1H, d); 6.45 (1H, d); 6.05
(1H, q); 4.59 (1H, m); 2.95 (1H, m); 2.68 (5H, m);
2.25 (2H, m); 1.91 (1H, m); 1.52 (3H, d); 13C NMR
(100MHz, CDCl3): 140.9, 134.8, 133.1, 132.9, 131.7,
130.7, 129.0, 128.8, 127.9, 127.0, 125.1, 125.0, 124.0,
123.2, 53.7, 45.2, 32.6, 27.2, 23.1, 22.9, 20.6. Compound 2:
1H NMR (400MHz, CDCl3): 7.44 (1H, d); 7.43 (1H, s);
7.38 (1H, t); 7.34 (1H, d); 7.32 (1H, d); 7.15 (1H, t); 7.02
(1H, d); 6.84 (1, d); 6.14 (1H, m); 4.16 (1H, q); 2.81 (2H, t);
2.71 (2H, m); 2.55 (2H, m); 2.29 (2H, m); 1.83 (2H, m);
1.35 (3H, d); 13C NMR (100MHz, CDCl3): 143.5, 140.9,
140.6, 136.5, 132.2, 131.7, 129.7, 129.0, 127.3, 126.5, 124.0,
125.5, 123.9, 123.0, 53.6, 47.5, 33.8, 32.2, 28.9, 23.8, 23.0.
9. For a recent example utilizing a CBS reduction of a ketone
on a kilogram scale, see: Duquette, J.; Zhang, M.; Zhu, L.;
Reeves, R. S. Org. Process Res. Dev. 2003, 7,
285.
1. Cinacalcet HCl is an oral calcimimetic drug, first in class
agent for the treatment of hyperparathyroidism and the
preservation of bone density in patients with kidney failure
or hypercalcemia due to cancer. Cinacalcet received the
FDA approval on March 8, 2004. Franceschini, N.; Joy,
M. S.; Kshirsagar, A. Expert Opin. Invest. Drugs 2003, 12,
1413.
2. 5-Hydroxy-1-tetralone was purchased from Aldrich at 5g/
$124.40.
3. Vogl, E. M.; Buchwald, S. L. J. Org. Chem. 2002, 67,
106.
4. The crude triflate 7 is not suitable for the next step and
needs purification before use.
5. Pendrak, I.; Chambers, P. A. J. Org. Chem. 1995, 60,
3249.
10. Thompson, A. S.; Humphrey, G. R.; Demarco, A. M.;
Mathre, D. J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58,
5886.
6. Cruikshank, B. I.; Davies, N. R. Aust. J. Chem. 1973, 26,
1935, Olefin isomerization can also be catalyzed by other
transition metals.

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X. Wang et al. / Tetrahedron Letters 45 (2004) 8355–8358
11. Enantiomeric excess of all the relevant compounds
was determined by chiral HPLC. Two types of chiral
columns were used: OD-H 250 · 4.6mm or OJ-H 250 ·
4.6mm; mobile phase = hexane/IPA 90/10 or 95/5 (v:v);
flow rate = 0.5mL/min; wavelength = 260nm; column
temperature = ambient.
12. The aldehyde 20 is prepared by the following scheme in
good yield:
1. Pd/C/H (91%)
2
F3C
CHO
2. LAH (85%)
F3C
COOH
20
3. Swern oxidation (65%)