Efficient synthesis of cinacalcet hydrochloride

Article abstract of DOI:10.1080/00397910801928541

A new route to synthesize cinacalcet hydrochloride ((R)-α-methyl-N- [3-[3-(trifluoromethyl) phenyl] propyl]-1-naphthalene methane amine hydrochloride) has been described. The key steps include the Knoevenagel-Doebner condensation and the amide reduction under milder conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801928541

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Efficient Synthesis of Cinacalcet
Hydrochloride
Gopinathenpillai Bijukumar a , Biswas Maloyesh a , Bhirud Shekhar Bhaskar a
& Agarwal Rajendra a
a Chemical Process Research and Development, Research and Development
Centre, Macleods Pharmaceuticals Ltd., Mumbai, India
Version of record first published: 24 Apr 2008.
To cite this article: Gopinathenpillai Bijukumar , Biswas Maloyesh , Bhirud Shekhar Bhaskar & Agarwal
Rajendra (2008): Efficient Synthesis of Cinacalcet Hydrochloride, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:10, 1512-1517
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Synthetic Communicationsw, 38: 1512–1517, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801928541
Efficient Synthesis of Cinacalcet
Hydrochloride
Gopinathenpillai Bijukumar, Biswas Maloyesh,
Bhirud Shekhar Bhaskar, and Agarwal Rajendra
Chemical Process Research and Development, Research and Development
Centre, Macleods Pharmaceuticals Ltd., Mumbai, India
Abstract: A new route to synthesize cinacalcet hydrochloride ((R)-a-methyl-N-[3-[3-
(trifluoromethyl) phenyl] propyl]-1-naphthalene methane amine hydrochloride) has
been described. The key steps include the Knoevenagel–Doebner condensation and
the amide reduction under milder conditions.
Keywords: Calcimimetics, cinacalcet, Knoevenagel-Doebner condensation
Cinacalcet hydrochloride[1] (Fig. 1) is the first of the calcimimetics class. Cal-
cimimetics are orally active molecules that decrease the secretion of parathyr-
oid hormone by activating calcium receptors. This class of compounds is used
to treat hyperparathyroidism, a condition characterized by the oversecretion of
parathyroid hormone. Cinacalcet hydrochloride is approved for the treatment
of secondary hyperparathyroidism in patients with chronic kidney disease on
dialysis.
Cinacalcet 5 can be synthesized by reacting (R)-1-(1-naphthyl) ethyl
2 with 3-[3-(trifluoromethyl)phenyl]propionaldehyde 3 in the
amine
presence of titanium isopropoxide to get an imine 4. The imine 4 was
reduced with methanolic sodium cyanoborohydride to get cinacalcet[2]
(Scheme 1).
Received November 6, 2007
Address correspondence to G. Bijukumar, Chemical Process Research and Develop-
ment, Research and Development Centre, Macleods Pharmaceuticals Ltd., G-2,
Mahakali Caves Road, Shanti Nagar, Andheri (E), Mumbai 400 093, India. E-mail:
dbijuin@yahoo.co.in
1512

Synthesis of Cinacalcet Hydrochloride
1513
Figure 1. Cinacalcet hydrochloride.
The reaction of 3-trifluromethyl cinnamonitrile 6 with diisobutyl
aluminium hydride, followed by treating the resultant intermediate
aluminium-imine complex 7 with (R)-1-(1-naphthyl) ethyl amine 2, gives
the resultant 4. The imine 4, on reduction with ethanolic sodium cyanoboro-
hydride, gave 5 (Scheme 2).[3]
Another reported synthesis[4] of cinacalcet involves the Heck coupling of
1-bromo-3-trifluoromethyl benzene 8 with ethylacrylate 9 to get the unsatu-
rated ester 10. Compound 10, when subjected to double bond and carbonyl
moiety reduction, furnished saturated alcohol 11. Compound 11 was
converted to a moiety with a good leaving group 12 and was condensed
with (R)-1-(1-naphthyl) ethyl amine to get cinacalcet (Scheme 3).
The reported syntheses of cinacalcet involved the use of reagents such as
titanium isopropoxide and diisobutyl aluminium hydride (DIBAL-H). Both
the reagents have to be handled in large volumes because the product has to
be produced commercially. The handling of these moisture-sensitive and pyr-
ophoric reagents on a large scale makes the synthesis more strenuous. Another
reported synthesis used ethyl acrylate, which is a known carcinogen. Keeping
these points in mind, we designed an alternate synthesis of cinacalcet hydro-
chloride. Our synthesis is depicted in Scheme 4.
We identified 3-trifluoromethyl benzaldehyde 13 and malonic acid 14 as
key starting materials. Knoevenagel–Doebner condensation was employed
for the reaction of aldehyde 13 with acid 14. The reaction was carried out
in refluxing pyridine, where piperidine is used as an organocatalyst. The con-
densation proceeded smoothly to yield 3-[3-(trifluoromethyl) phenyl]-2-
Scheme 1.

1514
G. Bijukumar et al.
Scheme 2.
propenoic acid 15 in good purity.The propenoic acid 15 has been reduced to
3-(3-trifluoromethylphenyl) propionic acid 16. The catalytic hydrogenation
was carried out in methanol in the presence of 10% Pd-C under a hydrogen
pressure of 4 kg/cm2. The removal of catalyst by filtration and evaporation
of the filtrate furnished 16 in good yield and purity. The 3-(3-trifluoromethyl-
phenyl) propionic acid 16 was converted to the corresponding acid chloride
and condensed with (R)-1-(1-naphthyl) ethyl amine to get N-[1-(R)-(1-
naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propanamide 17.
The reduction of amide 17 to amine (cinacalcet) was carried out under
mild conditions. The amide reductions are generally carried out by hydride
reagents such as lithium aluminium hydride[5–7] because sodium borohydride
does not reduce the amide functionality. We decided to use a sodium borohy-
dride–iodine[8] system to reduce amide. Other reducing agents such as lithium
aluminium hydride and lithium aluminium hydride–aluminium chloride were
also used for the conversion of amide to amine, but the sodium borohydride–
iodine system was the most appropriate for a large-scale synthesis.
N-[1-(R)-(1-Naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propanamide
17 was treated with sodiumborohydride–iodine in tetrahydrofuran under
reflux conditions. The in situ generated diborane cleanly converted the
Scheme 3.

Synthesis of Cinacalcet Hydrochloride
1515
Scheme 4.
amide to amine, which was isolated as the hydrochloride salt to complete the
synthesis of cinacalcet hydrochloride 1. In short, we have developed an
efficient synthesis of cinacalcet hydrochloride using environmentally
friendly and easy to handle reagents.
EXPERIMENTAL
All reagents were commercially obtained and used as received unless
otherwise noted. All nonaqueous reactions were performed in dry glassware
under an atmosphere of dry nitrogen. Organic solutions were concentrated
by rotary evaporation under reduced pressure. Thin-layer chromatography
(TLC) was performed on Merck precoated silica-gel 60F254 plates. Visualiza-
tion of the developed chromatogram was performed by fluorescence
quenching, phosphomolybdic acid stain, or 20% sulfuric acid char. 1H
NMR spectra were measured on a Varian-Gemini 300-MHz spectrometer.
IR spectra were recorded on KBr discs/neat on a Shimadzu FT-IR. Melting
points were obtained by the open capillary method and are uncorrected.
3-[3-(Trifluoromethyl)phenyl]-2-propenoic Acid (15)
3-Trifluoromethylbenzaldehyde (50.0 g, 0.287 mol), malonic acid (32.90 g,
0.315 mol), and piperidine (3.66 g, 0.043 mol) in dry pyridine (80 ml) were
heated at 110–115 8C for 4–5 h. On completion of the reaction (measured
by thin-layer chromatography, TLC), the mixture was cooled to room temp-
erature, and cold water (400 ml, 0–5 8C) was added to the reaction mass. It
was stirred for 1 h. pH of the reaction mass was adjusted to 2–3 with 2 N
HCl at 5–10 8C, and it was stirred for 1 h. The resulting solid was filtered,
washed with cold water (400 ml, 0–5 8C), and dried at 50–55 8C to get the

1516
G. Bijukumar et al.
title compound (45 g, 72%). HPLC purity ¼ 99.73%; melting point: 136–
137 8C. IR (vmax; cm21): 2923, 2854, 1681, 1627, 1442, 1218, 1164, 1072,
690, 543; H NMR (CDCl3) (d ppm): 7.53–7.84 (5H, m), 6.53 (1H, d); MS
1
(m/z): 215 [M 2 1].
3-[3-(Trifluoromethyl)phenyl]-2-propanoic Acid (16)
3-[3-(Trifluoromethyl)phenyl]-2-propenoic acid (50 g, 0.231 mol), methanol
(250 mL), and 10% palladium on carbon (2.5 g, 5%) were autoclaved
for 2.5–3.0 h under hydrogen pressure of the 4 kg/cm2 at 20–25 8C.
Upon completion of the reaction (TLC), the reaction mass was filtered
through Celitew, and the filtrate was distilled under reduced pressure at
40–45 8C to get a residue. Hexane was added to the residue, filtered, and
dried to get the title compound (48 g, 95.20%). HPLC purity ¼ 99.21%;
melting point: 30–35 8C; IR (vmax; cm21): 2966, 2947, 2889, 1712,
1454, 1330, 1168, 1134, 1076, 802, 702; 1H NMR (CDCl3) (d ppm):
11.4 (1H, bs), 7.51–7.41 (4H, m), 3.03 (1H, t), 2.72 (1H, m); MS (m/z):
217 [M 2 1].
N-[1-(R)-(1-Naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-
propanamide (17)
Thionyl chloride (25.1 ml, 0.343 mol) was added dropwise to a solution of
3-[3-(trifluoromethyl)phenyl]-2-propanoic acid (50 g, 0.229 mol) in toluene
(250 ml) at 25–30 8C under nitrogen. The reaction mixture was heated to
70–75 8C for 2.0 h. After 2.0 h, the toluene was distilled under reduced
pressure at 50–55 8C to get a residue. Methylene chloride (100 mL) was
added to the residue to get a clear solution. This solution was added
dropwise to a solution of (1R)-1(1-naphthyl) ethyl amine (29.43 g,
0.171 mol) and triethylamine (69.51 g, 0.687 mol) in methylene chloride
(250 ml) maintained at 0–5 8C under a nitrogen atmosphere. After completion
of the reaction (TLC), water (250 ml) was added to the reaction mixture. The
layers were separated, and the organic layer was washed again with water
(250 ml). The organic layer was evaporated under reduced pressure to get a
crude solid, which was recrystallized from a mixture of hexane (100 ml)
and ethyl acetate (150 ml) to get the title compound (60.38 g, 70.87%);
HPLC purity ¼ 99.64%; melting point: 108–111 8C; IR (KBr) (vmax
1
702; H NMR (CDCl3-DMSO-d6) (d ppm): 7.26–8.03 (11H, m), 5.91 (1H,
;
cm21): 3294, 3051, 2974, 1631, 1539, 1450, 1334, 1114, 1076, 798, 775,
m), 5.58 (1H, d), 3.03 (2H, m), 2.46 (2H, m), 1.60 (3H, d); MS (m/z): 372
[M þ 1].

Synthesis of Cinacalcet Hydrochloride
Cinacalcet Hydrochloride (1)
1517
A solution of iodine (167.5 g, 0.66 mol) in dry THF (500 mL) was added to a
suspension of N-[1-(R)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-
propanamide (50 g, 0.134 mol) and sodium borohydride (50 g, 1.313 mol)
in dry THF (100 ml) under nitrogen at 0–5 8C. The reaction mixture was
then brought to room temperature and refluxed for 4.0 h. After completion
of the reaction (TLC), the reaction mass was cooled to 0–5 8C, and 3 N
HCl (100 ml) was added. The pH of the reaction mixture was adjusted to
8–9 with sodium hydroxide (3 N; 150 ml). The organic layer was
separated, and the aqueous layer was extracted with methylene chloride
(2 ꢀ 100 ml). The combined organic layer was evaporated to dryness under
vacuum at 40–45 8C to get a residue, which was dissolved in hexane
(250 ml), and 10% HCl solution (200 mL) was added at room temperature
and stirred for 1 h. The solids were filtered and washed with hexane
(5 ꢀ 25 mL) and dried to get the crude product. The crude product was recrys-
tallized from acetonitrile (250 mL) to get cinacalcet HCl (47.84 g, 90.22%);
HPLC purity ¼ 99.93%; melting point: 180–184 8C; IR (KBr) (vmax; cm21
)
3437, 3363, 2962, 2796, 2750, 2712, 2511, 1585, 1450, 1327, 1168, 1130,
1
1072, 798, 775, 702; H NMR (DMSO-d6) (d ppm): 10.1 (1H, br.s), 9.41
(1H, br.s), 7.45–8.25 (11H, m), 5.29 (1H, q), 2.93 (1H, t), 2.71 (3H, m), 2.0
(2H, m), 1.68 (3H, d); MS (m/z): 358 [M þ 1].
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