Efficient synthesis of substances related to cinacalcet hydrochloride via heck coupling

Article abstract of DOI:10.1080/00397911.2014.895383

Efficient synthetic methods to process substances related to cinacalcet hydrochloride 1, generated during the preparation, were described. The compounds were identified as [1-(7,8-dihydro-naphthalen-1-yl)-ethyl]-[3-(3- trifluoromethyl-phenyl)-propyl]-amine hydrochloride 2,[1-(5,6,7,8-tetrahydro- naphthalen-1-yl)-ethyl]-[3-(3-trifluoromethyl-phenyl)-propyl]-amine hydrochloride 3 and [1-(naphthalen-2-yl)-ethyl]-[3-(3-trifluoromethyl-phenyl)- propyl]-amine hydrochloride 4. All were prepared from commercially available materials in several linear steps and characterized by their respective spectral data.

Full text of DOI:10.1080/00397911.2014.895383

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Efficient Synthesis of Substances Related
to Cinacalcet Hydrochloride via Heck
Coupling
Fan Lei a , Boyi Qu a , Xiaolong Li a , Li Guo a , Mei Guan b , Li Hai a ,
Hui Jin a & Yong Wu a
a Key Laboratory of Drug Targeting and Drug Delivery Systems, West
China School of Pharmacy , Sichuan University , Chengdu , China
b West China Hospital , Sichuan University , Chengdu , Sichuan ,
China
Accepted author version posted online: 15 Apr 2014.Published
online: 08 Aug 2014.
To cite this article: Fan Lei , Boyi Qu , Xiaolong Li , Li Guo , Mei Guan , Li Hai , Hui Jin & Yong Wu
(2014) Efficient Synthesis of Substances Related to Cinacalcet Hydrochloride via Heck Coupling,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:19, 2879-2885, DOI: 10.1080/00397911.2014.895383
To link to this article: http://dx.doi.org/10.1080/00397911.2014.895383
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Synthetic Communications1, 44: 2879–2885, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.895383
EFFICIENT SYNTHESIS OF SUBSTANCES RELATED TO
CINACALCET HYDROCHLORIDE VIA HECK COUPLING
Fan Lei,1 Boyi Qu,1 Xiaolong Li,1 Li Guo,1 Mei Guan,2
Li Hai,1 Hui Jin,1 and Yong Wu1
1Key Laboratory of Drug Targeting and Drug Delivery Systems,
West China School of Pharmacy, Sichuan University, Chengdu, China
2West China Hospital, Sichuan University, Chengdu, Sichuan, China
GRAPHICAL ABSTRACT
Abstract Efficient synthetic methods to process substances related to cinacalcet hydro-
chloride 1, generated during the preparation, were described. The compounds were identified
as [1-(7,8-dihydro-naphthalen-1-yl)-ethyl]-[3-(3-trifluoromethyl-phenyl)-propyl]-amine
hydrochloride 2,[1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-ethyl]-[3-(3-trifluoromethyl-phenyl)-
propyl]-amine hydrochloride 3 and [1-(naphthalen-2-yl)-ethyl]-[3-(3-trifluoromethyl-
phenyl)-propyl]-amine hydrochloride 4. All were prepared from commercially available
materials in several linear steps and characterized by their respective spectral data.
Keywords Cinacalcet hydrochloride; HPLC; process-related substances; synthesis
INTRODUCTION
(R)-N-(1-(Naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine
hydrochloride, known as cinacalcet hydrochloride 1 (AMG 073, Sensipar, Mimpara),
is a selective calcimimetic agent[1] 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.
Several methods have been reported in the literature for the preparation of
cinacalcet hydrochloride 1 that rely on various reductive amination approaches[2]
Received January 2, 2014.
Address correspondence to H. Jin or Y. Wu, Key Laboratory of Drug Targeting and
Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041,
China. E-mail: jinhui_1974@126.com; wyong@scu.edu.cn
2879

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F. LEI ET AL.
Scheme 1. Reported synthetic route for cinacalcet hydrochloride 1 via reductive amination.
Scheme 2. Reported synthetic route for cinacalcet hydrochloride 1.
(Scheme 1). Thiel et al.[3] reported a practically synthetic route via hydrogenation,
amide coupling, reduction, and salification (Scheme 2). A similar route was also
reported by Bijukumar et al.[4]
During our development of cinacalcet hydrochloride 1, high-performance liquid
chromatographic (HPLC) analysis of crude product revealed other three impurities
ranging from 0.05 to 0.20%, besides the starting materials and unreacted intermediates.
The International Conference of Harmonization (ICH) has published guidelines
on impurities in new drug substances, products, and residual solvents that state that
the acceptable levels for known and unknown compounds in a final drug candidate must
be less than 0.15% and 0.10%, respectively, and the impurities need to be extensively
controlled and prepared for the quality controls of the main product.[5] Hence, crude
cinacalcet hydrochloride 1 was initially analyzed by liquid chromatography–mass
spectrometry (LC-MS) to provide these three impurities. To confirm their proposed
structures and complete their characterization, all three substances were individually
synthesized and characterized by their respective spectral data, and retention time was
checked in HPLC. We confirmed their structural assignment as shown in Fig. 1.
Figure 1. Structures of the three substances related to cinacalcet hydrochloride 1.

SUBSTANCES RELATED TO CINACALCET HYDROCHLORIDE
2881
Herein, to meet the strict requirement of the ICH, we report the efficient
synthesis of all the three substances related to cinacalcet hydrochloride 1.
RESULTS AND DISCUSSION
Thiel and coworkers reported that the dihydronaphthalene related substance 2,
recognized as congeners by Wang et al.[6] before, was formed when the amide was
reduced by NaBH4 in the presence of Lewis acid.[3] Initially, we planned to synthe-
size the substance 2 shown in Scheme 3, but during our preparation the substance 2
was obtained with the purity of 87.49% by HPLC. It showed an impurity of 9.21%
in the product, which could not be purified by normal recrystallization or column
chromatography. Afterward, the impurity was identified as the tetrahydronaphtha-
lene related substance 3 by LC-MS and HPLC. We speculated that it formed in the
process of reductive amination. On one hand, because of the inductive effects in the
formation of the imine, it decreased the dihydronaphthalene ring electron density
and the offset of the p electron cloud, so as to result the polarization in the molecule
and the reduction of the double bond by NaBH4. On the other hand, to catalyze
the formation of the imine, Lewis acid Ti(O-i-Pr)4 was added as solvent and the
reactivity of NaBH4 could be greatly enhanced in the presence of Lewis acid[7] (Fig. 2).
For obtaining the substance 2 with satisfactory purity (>95%), it is necessary to
avoid the reductive amination process. Through retrosynthetic analysis the substance 2
was decided to be synthesized by nucleophilic substitution in strategy 2 (Scheme 4).
Our approach utilized 5-hydroxytetralone 6 as starting material, which was
first reduced by NaBH4 to get the alcohol 7 in 93% yield (Scheme 5). Formation
of the bis-triflate and the elimination step were carried out in one pot using 2.4 equiv
of triflic anhydride and Et3N in anhydrous dichloromethane to give the triflate 8 in
overall 46% yield. The reaction conversions were nearly quantitative, but the poor
isolated yield was attributed to partial decomposition of the triflate 8 during
silica-gel chromatographic purification. The triflate 8 was converted to enol vinyl
Scheme 3. Original route of the related substance 2.
Figure 2. Formation and polarization of the imine intermediate.

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F. LEI ET AL.
Scheme 4. Retrosynthetic analysis of the related substance 2.
ethers via Heck coupling[8] and hydrolyzed in 3 N hydrochloride to obtain the pure
key intermediate 9 by silica-gel chromatography. The ketone 9 was reduced to the
alcohol 10 by NaBH4 in 94% yield. The alcohol 10 was chlorinated using 5 equiv
of thionyl chloride in anhydrous dichloromethane to give the compound 11 in
72% yield, which was further reacted with 3-(3-(trifluoromethyl)phenyl) propan-
1-amine 5[6] in the presence of potassium carbonate and a catalytic amount of
potassium iodide. The crude product was salified and purified by recrystallization
in acetonitrile to get 2 with satisfactory purity of 95.26% by HPLC.
Tetrahydronaphthalene-related substance 3 was reported to be formed in the
reduction process.[9] In the preparation procedure of cinacalcet hydrochloride 1,
the amide was reduced by NaBH4=BF3–tetrahydrofuran (THF) and the HPLC
analysis showed that there was 0.20% of the tetrahydronaphthalene substance 3
in the crude product. The substance 3 was designed and synthesized (Scheme 6).
We also took advantage of 5-hydroxytetralone 6 as starting material. The key
intermediate 12 was obtained by Kishner–Wolff–Huang reduction in quantitative
yield and treated with triflic anhydride and Et3N in anhydrous dichloromethane
Scheme 5. Synthesis of the related substance 2. Reagents and conditions: (i) NaBH4, MeOH, 0 ꢀC–rt,
overnight, 93%; (ii) Tf2O, TEA, DCM, ꢁ10 ꢀC, 2 h, 46%; (iii) (a) n-butyl vinyl ether, Pd(OAc)2, 1,3-dppp,
TEA, DMF, 65 ꢀC, 8 h; (b) 3 N HCl, acetone, rt, 1 h, 61% over two steps; (iv) NaBH4, MeOH, 0 ꢀC–rt,
2 h, 94%; (v) SOCl2, DCM, 0 ꢀC–rt, 10 h, 72%; (vi) (a) 5, K2CO3, KI, MeCN, reflux, overnight; (b) conc.
HCl, i-PrOH reflux, 15 min, 78% over two steps.

SUBSTANCES RELATED TO CINACALCET HYDROCHLORIDE
2883
Scheme 6. Synthesis of the related substance 3. Reagents and conditions: (i) (a) (NH2)2-H2O, diglycol,
80 ꢀC, 1.5 h; (b) KOH, 180 ꢀC, 7 h, 97% over two steps; (ii) Tf2O, TEA, DCM, ꢁ10 ꢀC, 2 h, 67%;
(iii) (a) n-butyl vinyl ether, Pd(OAc)2, 1,3-dppp, TEA, DMF, 65 ꢀC, 8 h; (b) 3 N HCl, acetone, rt, 1 h,
56% over two steps; (iv) (a) 5, Ti(O-i-Pr)4, rt, overnight; (b) NaBH4, MeOH, 0 ꢀC–rt, 1 h; (c) conc.
HCl, i-PrOH, reflux, 15 min, 81% over three steps.
to give the triflate 13 in overall 67% yield. The ketone 14 was also obtained via
Heck coupling and hydrolization, directly reacted with the amine 5 in Ti(O-i-Pr)4,
and reduced by NaBH4 in methanol to get the crude 3, which was further salified
and recrystallized in acetonitrile to get 3 with the purity of 97.88% by HPLC.
The naphthalen-2-yl related substance 4 is a structural isomer of cinacalcet
hydrochloride 1 and generated due to presence of 1-(2-naphthyl)ethylamine as
an impurity in the key raw material 1-(1-naphthyl)ethylamine. In the HPLC analytic
result it showed 0.08% in the crude cinacalcet hydrochloride 1. Thus, we reported the
synthesis of the naphthalen-2-yl substance 4 here (Scheme 7). 2-acetylnaphthalene 15
was treated with 5 in the presence of Ti(O-i-Pr)4, and then reduced by NaBH4 in
methanol. The crude product was salified and recrystallized in acetonitrile to get 4
with the purity of 99.79% by HPLC.
In conclusion, we have synthesized and characterized the potential process-
related substance 2, 3, and 4 of cinacalcet hydrochloride 1 with satisfactory purity,
which made us better understand the synthetic pathway of an active pharmaceutical
ingredient (API). Meanwhile, this study provided us an access to the reference
standard of this impurity for regulatory authorities and established the related
substances profile.
EXPERIMENTAL
All reactions were carried out under an argon atmosphere. Most chemicals and
solvents were analytical grade and used without further purification. Thin-layer
Scheme 7. Synthesis of the related substance 4. Reagents and conditions: (i) (a) 5, Ti(O-i-Pr)4, rt,
overnight; (b) NaBH4, MeOH, 0 ꢀC–rt, 1 h; (c) conc. HCl, i-PrOH, reflux, 15 min, 84% over three steps.

2884
F. LEI ET AL.
chromatography (TLC) was performed using precoated silica gel GF254 (0.2 mm),
while column chromatography was performed using silica gel (100–200 mesh). The
melting point was measured on a YRT-3 melting-point apparatus (Shantou Keyi
1
Instrument & Equipment Co. Ltd, Shantou, China). H NMR spectra was taken
on a Varian Inova 400 (Varian, Palo Alto, CA, USA) using CDCl3, dimethyl-
sulfoxide (DMSO-d6), and D2O as solvent. Chemical shifts were expressed in d (ppm),
with tetramethylsilane (TMS) functioning as the internal reference, and coupling
constants (J) were expressed in Hz. The high-resolution mass (HRMS) spectra were
recorded on a Bruker Maxis Impact Q-TOF instrument (Bruker, Billerica, MA,
USA) coupled with a Dionex Ultimate 3000 spectrometer (Dionex, Sunnyvale,
CA, USA). The purity was determined by HPLC-UV obtained on an Agilent
1946B electrospray ionization–mass spectrometry (ESI-MS) instrument (Agilent,
Palo Alto, CA, USA). The HPLC parameters were as follows: column, Topsil
C18 4.6 ꢂ 150 mm, 5 mm; wavelength, 210 nm for substance 2, 223 nm for substance
3 and 4; mobile phase, MeCN = 0.02 M NaH2PO4(aq)(0.20% TEA, pH was adjusted
to 6.0 by H3PO4) 50=50; column temperature, 35 ꢀC; flow rate, 1.0 ml=min.
General Procedure for the Preparation of the Dihydro- and
Tetrahydro-naphthalen-1-ethanone (9) or (14) via Heck Coupling
TEA (2 eq) and n-butyl vinyl ether (4 eq) were added to a solution of
trifluoro-methanesulfonic acid ester 8 or 13 (1 eq) in DMF at room temperature.
The solution was bubbled with argon for 10 min and added to the mixture of pal-
ladium acetate (0.1eq) and 1,3-dppp (0.1 eq) in a flask purged by argon. The reaction
was heated to 65 ꢀC and stirred for 8 h. The reaction was cooled to room tempera-
ture. Ethyl ether was added, and the solution was washed with saturated Na2CO3
solution and brine and then dried over Na2SO4. After the solvent was evaporated
in vacuum brown oil was obtained, which was hydrolyzed directly in acetone and
3 N HCl (1=1 v=v) for 1 h at room temperature. When most acetone was evaporated
in vacuum, DCM was added, followed by saturated Na2CO3 solution. The organic
layer was separated, washed by brine, and dried over Na2SO4. After the solvent was
evaporated in vacuum, a light-brown oil was obtained, which was purified by flash
chromatography on silica gel to get colorless oil.
1-(7,8-Dihydronaphthalen-1-yl)ethanone (9)
1
Yield 61%. H NMR (400 MHz, CDCl3): d 2.21–2.31 (m, 2H), 2.57 (s, 3H),
3.02 (t, J ¼ 8.0 Hz, 2H), 6.08–6.12 (m, 1H), 6.47 (dt, J ¼ 1.6 Hz, 9.6 Hz, 1H), 7.12
(d, J ¼ 7.6 Hz, 1H), 7.20 (t, J ¼ 7.6 Hz, 1H), 7.45 (dd, J ¼ 1.2 Hz, 7.6 Hz, 1H);
ESI-HRMS calcd. for C12H13Oþ [M þ H]þ 173.0966; found: 173.0968.
1-(5,6,7,8-Tetrahydronaphthalen-1-yl)ethanone (14)
1
Yield 56%. H NMR (400 MHz, CDCl3): d 1.78–1.83 (m, 4H), 2.55 (s, 3H),
2.80 (t, J ¼ 5.6 Hz, 2H), 2.95 (t, J ¼ 5.6 Hz, 2H), 7.14 (d, J ¼ 7.2 Hz, 1H), 7.20
(t, J ¼ 7.2 Hz, 1H), 7.43 (d, J ¼ 7.2 Hz, 1H); ESI-HRMS calcd. for C12H15Oþ
[M þ H]þ 175.1123; found: 175.1131.

SUBSTANCES RELATED TO CINACALCET HYDROCHLORIDE
2885
FUNDING
We sincerely thank the Sichuan Provincial Science and Technology Support
Program (Grant No. 2011SZ0014). Also, we express our gratitude for the support
from Sichuan Bali Pharmaceutical Co., Ltd.
SUPPORTING INFORMATION
Full experimental details and 1H and 13C NMR spectra are available.
Supplemental data for this article can be accessed on the publisher’s website.
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