Efficient synthesis and practical resolution of 1-(naphthalen-1-yl) ethanamine, a key intermediate for cinacalcet

Article abstract of DOI:10.1080/00397910903538651

An efficient synthesis of 1-(naphthalen-1-yl)ethanamine (RS-2) and its practical resolution to optically pure (1R)-(naphthalen-1-yl)ethanamine (R-(+)-2), a key intermediate in the synthesis of cinacalcet hydrochloride (1), is described. The resolution of RS-2 using R-(-)-mandelic acid as a resolving agent in ethanol was established on an industrial scale to give pure R-(+)-2 with >99.8% ee after liberation of the amine from its mandelate salt. An efficient process for the racemization of undesired isomer S-(-)-2 is also provided to maximize the yield of desired enantiomer.

Full text of DOI:10.1080/00397910903538651

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Efficient Synthesis and Practical
Resolution of 1-(Naphthalen-1-
yl)ethanamine, a Key Intermediate for
Cinacalcet
Vijayavitthal T. Mathad a , Gorakshanath B. Shinde a , Sharad S.
Ippar a , Navnath C. Niphade a , Raghavendra K. Panchangam a &
Pravinchandra J. Vankawala a
a Department of Process Research and Development, Megafine
Pharma (P) Ltd., Nashik, Maharashtra, India
Version of record first published: 13 Jan 2011.
To cite this article: Vijayavitthal T. Mathad , Gorakshanath B. Shinde , Sharad S. Ippar , Navnath C.
Niphade , Raghavendra K. Panchangam & Pravinchandra J. Vankawala (2011): Efficient Synthesis and
Practical Resolution of 1-(Naphthalen-1-yl)ethanamine, a Key Intermediate for Cinacalcet, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:3, 341-346
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Synthetic Communications1, 41: 341–346, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903538651
EFFICIENT SYNTHESIS AND PRACTICAL RESOLUTION
OF 1-(NAPHTHALEN-1-YL)ETHANAMINE, A KEY
INTERMEDIATE FOR CINACALCET
Vijayavitthal T. Mathad, Gorakshanath B. Shinde,
Sharad S. Ippar, Navnath C. Niphade, Raghavendra K.
Panchangam, and Pravinchandra J. Vankawala
Department of Process Research and Development, Megafine Pharma (P)
Ltd., Nashik, Maharashtra, India
An efficient synthesis of 1-(naphthalen-1-yl)ethanamine (RS-2) and its practical resolution
to optically pure (1R)-(naphthalen-1-yl)ethanamine (R-(þ)-2), a key intermediate in the
synthesis of cinacalcet hydrochloride (1), is described. The resolution of RS-2 using
R-(ꢀ)-mandelic acid as a resolving agent in ethanol was established on an industrial scale
to give pure R-(þ)-2 with >99.8% ee after liberation of the amine from its mandelate salt.
An efficient process for the racemization of undesired isomer S-(ꢀ)-2 is also provided to
maximize the yield of desired enantiomer.
Keywords: Cinacalcet; industrially feasible; 1-(naphthalen-1-yl)ethanamine; R-(ꢀ)-mandelic acid; resolution
INTRODUCTION
More than half of the chiral drugs in the pharmaceutical market are produced
by the diastereomeric salt-formation method using enantiopure resolving agents.[1]
Resolution via diastereomeric salt formation is widely practiced because of the ease
of operation and relative simplicity of producing laboratory-scale data efficiently on
an industrial scale. Selection of resolving agents, through both rational concepts and
practical experience, is an ongoing subject of research and development.[2] Herein,
we report a practical synthesis of (1R)-1-(naphthlen-1-yl)ethanamine (R-(þ)-2), a
crucial and cost-contributing intermediate for the preparation of cinacalcet via an
efficient resolution process.
Cinacalcet hydrochloride (1), an optically active calcimimetic drug, has been
approved by the U.S. Food and Drug Administration as Sensiper for the treatment
of secondary hyperparathyroidism, a condition characterized by the oversecretion of
parathyroid hormone in patients with chronic kidney disease on dialysis (Fig. 1).[3]
Different synthetic approaches reported for 1 by various research groups involve
R-(þ)-2 as common chiral intermediate.[4,5]
Received September 6, 2009.
Address correspondence to Vijayavitthal T. Mathad, Department of Process Research and
Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik 422 202, Maharashtra,
India. E-mail: drvtmathad@yahoo.co.in; vt.mathad@megafine.in
341

342
V. T. MATHAD ET AL.
Figure 1. Cinacalcet hydrochloride (1).
Martin and Campbell reported[6] the synthesis of R-(þ)-2 by reacting 1-acetyl-
naphthylene (6) with hydroxylamine hydrochloride to furnish oxime (7), which was
further treated with chlorodiphenylphosphine to provide imine derivative (8). This
was subjected to asymmetric transfer hydrogenation catalyzed by Rh complex, fol-
lowed by treatment of the obtained protected amine (9) with hydrogen chloride
gas in ethanol (Scheme 1, path A). This process appears to have limitations: use
of expensive ruthenium, iridium, or rhodium complexes. An additional obstacle of
this process is to show that the content of these metals in the final active pharmaceu-
tical ingredient (API) is within the acceptable limits.[7]
Blacker and Martin[8] adopted a different strategy for the synthesis of R-(þ)-2;
stereoselective reduction of 6 using [Rh(C5Me5)Cl2]2 complex and (S,S,S)-Cs-DPEN
as a chiral ligand followed by conversion of the obtained (1R)-1-naphthalen-1-
ylethanol (10) to its mesylate derivative (11), which was then converted to R-(þ)-2
Scheme 1. Reported synthetic approach of (1R)-1-(naphthalene-1-yl) ethanamine.

RESOLUTION OF 1-(NAPHTHALEN-1-YL)ETHANAMINE
343
with 90–94% ee using aqueous ammonia under reduced pressure (Scheme 1, path B).
Enantiopurity of the resulting amine was improved to >99% through diastereomeric
salt resolution using optically pure (L)-chloropropionic acid. Notable drawbacks of
this synthesis is usage of expensive rhodium complexes and the additional diastereo-
meric salt resolution step to achieve the desired chiral purity of R-(þ)-2.
Synthetic procedures reported for racemic amine (RS-2) from ketone 6 use car-
cinogenic pyridine, longer reaction period (5 days), high temperatures (190–200 ꢀC),
and high pressure (1000 lbs per inch), which make them not suitable for industrial
use (Scheme 1, path C).[6,8,9] With these limitations, development of a practical
synthetic method for R-(þ)-2 that can be carried out on a large scale with low cost
is desirable.
In this communication, we report a simple, efficient, economic, and single-pot
synthesis for large-scale preparation of RS-2 and its resolution through diastereomeric
salt formation using a commercially available resolving agent, R-(ꢁ)-mandelic acid, to
obtain R-(þ)-2 with an efficient turnaround time. The process is of significance
because it does not require any enatioselective catalysts, expensive toxic reagents, or
harsh reaction condition and is simpler than the other reported approaches.
RESULTS AND DISCUSSION
In our approach, commercially available 1-acetylnaphthalene (6) is treated with
hydroxylamine hydrochloride in methanol for 4–5 h in the presence of sodium hydrox-
ide to afford an oxime (7) in 95% yield. Oxime (7) is then reduced to racemic amine RS-
2 by catalytic hydrogenation using Raney-Ni at 55–60 ꢀC for 3–4 h under the hydrogen
pressure of 4–5 Kg=cm2 in a mixture of methanol and aqueous ammonia in the ratio of
3:1 to obtain RS-2 with 97% yield and 97% purity by high performance liquid chroma-
tography (HPLC). The resulting RS-2 obtained after usual workup (as thick syrup) is
then subjected to diastereomeric salt resolution in the same pot by adding R-(ꢁ)-man-
delic acid as a resolving agent and ethanol as solvent to furnish mandelate salt of
R-(þ)-2 in 62–64% yield and >99.5% chiral purity by HPLC and >99.8% chemical
purity. The mandelate salt of R-(þ)-2 is hydrolyzed with aqueous ammonia in toluene
to get R-(þ)-2, which can be converted to HCl salt in ethyl acetate using hydrochloric
acid in isopropyl alcohol (IPA-HCl). The mandelate salt of S-(ꢁ)-2 present in the
mother liquor is hydrolyzed, racemized, and resolved (Scheme 2) to obtain the
additional quantity of R-(þ)-2, and the details are furnished here.
Resolution of RS-2
To find a suitable resolving agent, commercially available optically pure chiral
acids such as mandelic acid, tartaric acid, dibenzoyl tartaric acid, and di-p-toluoyl
tartaric acid were screened in various solvents such as methanol, ethanol, acetoni-
trile, ethyl acetate, and acetone for their ability to resolve RS-2. Among those tested,
both the antipodes of mandelic acid are excellent choices for diastereomeric salt
formation in ethanol. It is common to apply the opposite enantiomer[10] of the target
substrate and hence we opted R-(ꢁ)-mandelic acid as a resolving agent. The
optimized experimental procedure involves heating a mixture of RS-2 and
R-(ꢁ)-mandelic acid in ethanol (six times) to 55–60 ꢀC until a clear solution is

344
V. T. MATHAD ET AL.
Scheme 2. Synthesis and resolution of RS-2 and racemization of S-(ꢀ)2.
obtained. The mixture is gradually cooled to 25–30 ꢁC, and the solid obtained is
stirred at 15–20 ꢁC for 50–60 min and then filtered to get crude mandelate salt of
R-(þ)-2 in 72% yield with enantiomeric purity of >95% by chiral HPLC. The ee
of the obtained solid has been improved to >99.5% by HPLC by recrystallizing
the crude at 55–60 ꢁC in ethanol. In this process, maintaining the reaction mass
below 15 ꢁC for a longer period resulted in coprecipitation of the undesired S-isomer
S-(ꢀ)-2 as evidenced by the drop in an enantiomeric purity.
Racemization of S-(ꢀ)-2
The undesired isomer S-(ꢀ)-2 recovered from the mother liquor after liberating
it from its mandelate salt is heated in dimethylsulfoxide in the presence of potassium
hydroxide for 20 h to obtain RS-2 in quantitative yield. The racemate so obtained is
then subjected to resolution using aforementioned process to maximize the yield of
desired enantiomer R-(þ)-2 via another cycle of resolution.
EXPERIMENTAL
1-(1-Naphthyl)ethanone Oxime (7)
A mixture of 1-acetylnaphthalene (6, 100 g) and hydroxylamine hydrochloride
(123 g) was stirred in methanol (500 mL) at 25–35 ꢁC. The pH of the reaction mass
was adjusted 6.0 to 6.5 using 40% solution of sodium hydroxide. The resulting

RESOLUTION OF 1-(NAPHTHALEN-1-YL)ETHANAMINE
345
mixture was then stirred at ambient temperature for 2–3 h. After completion of the
reaction as monitored by thin-layer chromatography (TLC), the reaction mass was
quenched slowly over water (800 mL), and the obtained suspension was stirred at
25–35 ꢁC for 3–4 h. The slurry was filtered, and the wet cake was washed with cold
water (2 ꢂ 100 mL) and dried under vacuum to afford compound 7 as a white solid.
Yield: 100 g (92%). IR (cmꢀ1): 3280, 3105, 3055, 2358, 2329, 1504, 1307, 1272. MS:
1
m=z 186.5 (Mþ þ 1). H NMR (CD3OD, d ppm): 8.04 (s, 1H), 7.87–7.90 (dd, 2H),
7.84–7.78 (m, 2H), 7.48–7.49 (m, 2H), 2.34 (s, 3H).
(1R)-1-(Naphthalen-1-yl)ethanamine Mandelate [Mandelate
Salt of R-(þ)-2]
A mixture of oxime 7 (100 g), Raney nickel (25 g, 25% loading with respect to
oxime 7), methanol (1 L), and aqueous ammonia (300 mL) was stirred under hydro-
gen pressure at 3.5–4.0 Kg=cm2 at 58–62 ꢁC for 3–4 h. The catalyst was removed by
filtration and washed with methanol (400 mL), and the filtrate was concentrated in
vacuo to obtain the thick residue. The residue was dissolved in dichloromethane
(400 mL), water (1200 mL) was added, the pH was adjusted between 1 and 2 using
conc. hydrochloric acid, the mixture was stirred for 15–20 min, and the organic layer
was separated and discarded. The aqueous layer was further washed with
dichloromethane (2 ꢂ 300 mL) and separated. The pH of the aqueous layer was
adjusted to 10–11 using aqueous ammonia, and the desired compound was extracted
in toluene (2 ꢂ 500 mL). The organic layer was washed with water and brine and dis-
tilled to get the residue. The residue containing RS-2 was dissolved in ethanol
(425 mL), and a solution of R-(ꢀ)-mandelic acid (76 g) in ethanol (255 mL) was added
over 10 min. The mixture was maintained at 60–65 ꢁC for 45 min. The resulting clear
solution was slowly cooled to 25–35 ꢁC and stirred for 2–3 h. The separated solid was
filtered, washed with ethanol (40 mL), and dried under vacuum to afford the crude
product, which was recrystallized from ethanol (396 mL) to furnish mandelate salt
of R-(þ)-2 as a white crystalline solid. Yield: 56 g (64%). IR (cmꢀ1): 3415, 3190,
1
1712, 1180. MS: m=z 172 (Mþ þ 1). H NMR (DMSO-d6, d ppm): 7.47 (ddd, 1H),
7.49 (ddd, 1H), 7.80 (dd, 1H), 7.82 (dd, 1H), 7.87 (dd, 1H), 7.90 (dd, 1H), 8.04 (d, 1H).
(1R)-1-(Naphthalen-1-yl)ethanamine Hydrochloride [HCl
Salt of R-(þ)-2]
A mixture of (1R)-1-(napthyalene-1-yl) ethanamine mandelate (75 g) and
aqueous ammonia (ꢃ40 mL) in toluene (750 mL) were stirred, and the organic layer
containing the free base was separated and concentrated under vacuum to get a thick
residue. The residue was dissolved in ethyl acetate (200 mL), and the pH of the solution
was adjusted to 3–4 using IPA-HCl. The resulting solution was cooled to 10–15 ꢁC and
stirred for 40–50 min. The solid separated was filtered, washed with ethyl acetate
(20 mL), and dried under vacuum to furnish HCl salt of R-(þ)-2 as a white solid. Yield:
40 g (84%). IR (cmꢀ1): 3415, 3190, 2983, 2839, 1610, 11.80. MS: m=z 172.6 (Mþ þ 1).
1H NMR (DMSO-d6, d ppm): 1.60 (dd, 3H), 5.22–5.30 (m, 1H), 7.52–7.62 (m, 3H),
7.80 (dd, 1H), 7.93–8.10 (dd, 2H), 8.13–8.18 (d, 1H), 8.80 (s, 2H).

346
V. T. MATHAD ET AL.
Racemization of (1S)-1-(Naphthalen-1-yl)ethanamine
A mixture of (1S)-1-(naphthalen-1-yl)ethanamine (S-(ꢀ)-2), free base liberated
from the mother liquors containing ꢃ15% of R-enantiomer, 10.0 g), dimethylsulfox-
ide (100 mL), and potassium hydroxide (13.1 g) was heated at 150–160 ꢁC for 20 h.
The reaction mixture was cooled to ambient temperature; water (100 mL) was added
and stirred for 15 min. The product was extracted into toluene (50 mL ꢂ 2), washed
with water, and concentrated under vacuum gave the RS-2 as a thick residue. Yield:
9.5 g (95%); chiral HPLC: R-isomer, 44%, and S-isomer, 56%.
ACKNOWLEDGMENTS
The authors thank the management of Megafine Pharma (P) Ltd. for the per-
mission to publish this work. The authors also thank the colleagues of the Analytical
Research and Development team for their valuable contribution to this work.
REFERENCES
1. Rouhi, A. M. Chiral business. Chem. Eng. News 2003, 81 (18), 45.
2. (a) Hoeveten, W.; Wynberg, H. Design of resolving agents; Chiral cyclic phosphoric acids.
J. Org. Chem. 1985, 50, 4508; (b) Pallavicini, M.; Valoti, E.; Villa, L.; Piccolo, O. Isopro-
pylidene glycerol hydrogen phthalate: A new resolving agent: Application to the resol-
ution of 1-arylethylamines. Tetrahedron: Asymmetry 1996, 7, 1117.
3. Franceschini, N.; Joy, M. S.; Kshirsagar, A. A calcimimetic agent for the management of
primary and secondary hyperparathyroidism. Expert Opin. Invest. Drugs 2003, 12, 1413.
4. (a) Sorbera, L. A.; Castaner, R. M.; Bayes, M. Cinacalcet hydrochloride. Drugs Future
2002, 27, 831–836; (b) Van Wagene, B. C.; Balandrin, M. F.; DelMar, E. G.; Nemeth,
E. F. Calcium receptor active compounds. US Patent 6,211,244, April 3, 2001.
5. (a) Revital, L. L. Process for the preparation of cincacalcet base. US Patent 7,449,603,
November 11, 2008; (b) Revital, L. L.; Eisenstadt, A.; Wizel, S.; Avhar-Maydan, S.; Raizi,
Y.; Revital, R. Process for preparing cincalcet hydrochloride. US Patent 7,250,533, July
31, 2007; (c) Bijukumar, G.; Biswas, M.; Bhirud S. B.; Agarwal, R. Efficient synthesis
of cinacalcet hydrochloride. Synth. Commun. 2008, 38, 1512; (d) Thiel, O.; Bernard, C.;
Larsen, R.; Martinelli, M.; Raza, M. Methods of synthesizing cinacalcet and salts thereof.
WO Patent 2009=002427, December 31, 2008; (e) Srinivasan, C. V.; Johar, P. S.; Wadhwa,
L. Process for the preparation of amine derivatives as calcimimetics. WO Patent
2008=035381, March 27, 2008.
6. Martin, J.; Campbell, L. A. Transfer hydrogenation process. WO Patent 2001=012574 A1,
February 22, 2001.
7. International Conference on Harmonization of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). Section Q3B: Guidelines on Impurities in New
Drug Products via Food and Drug Administration (FDA). Available at http://www.fda.
gov/cder/guidance/1317fnl.pdf.
8. Blacker, A. J.; Martin, J. Process for the preparation of aromatic amines. WO 2004=
110976, December 23, 2004.
9. Bottoms, R. R. Optical resolution of alpha-(a-a00-naphthyl)ethylamine. US Patent 2,
996,545, August 15, 1961.
10. (a) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolution; Wiley:
New York, 1981; p. 251; (b) Kozma, D. Handbook of Optical Resolution via Diastereo-
meric Salt Formation; CRC Press: Boca Raton, FL, 2002.