Industrial application of the forster reaction: Novel one-pot synthesis of cinacalcet hydrochloride, a calcimimetic agent

Article abstract of DOI:10.1021/op200016a

Described is a new, practical, and one-pot process, based on the Forster reaction, for the synthesis of cinacalcet hydrochloride (1), a calcimimetic agent and calcium-sensing receptor antagonist. The synthesis comprises the condensation of (1R)-(+)-1-naphthylethyl amine (2) with benzaldehyde (3) followed by reaction of obtained Schiff's base 4 with 1-(3-halopropyl)-3- (trifluoromethyl)benzene (5) to provide highly unstable iminium salt 6. Subsequent hydrolysis of 6 with water in the same pot yielded cinacalcet. The treatment of cinacalcet with hydrochloric acid during the workup process furnished 1 with an overall yield of around 60%. Our synthetic approach for 1, discussed in this report demonstrates industrial application of the century-old, unexplored name reaction, "Forster's Reaction" or Forster-Decker synthesis.

Full text of DOI:10.1021/op200016a

COMMUNICATION
pubs.acs.org/OPRD
Industrial Application of the Forster Reaction: Novel One-Pot
Synthesis of Cinacalcet Hydrochloride, a Calcimimetic Agent
Gorakshanath B. Shinde,† Navnath C. Niphade,† Shrikant P. Deshmukh,† Raghunath B. Toche,‡ and
Vijayavitthal T. Mathad†,*
†Department of Process Research and Development, Megafine Pharma (P) Ltd., 201, Lakhmapur, Dindori, Nashik-422 202,
Maharashtra, India, and
‡Organic Chemistry Research Center, Department of Chemistry, KRT Arts, B.H. Commerce and A.M. Science College, Gangapur Road,
Nashik-422002, India.
the failure of calcium receptors on parathyroid glands to respond
ABSTRACT: Described is a new, practical, and one-pot
process, based on the Forster reaction, for the synthesis of
cinacalcet hydrochloride (1), a calcimimetic agent and
calcium-sensing receptor antagonist. The synthesis com-
prises the condensation of (1R)-(þ)-1-naphthylethyl amine
(2) with benzaldehyde (3) followed by reaction of obtained
Schiff’s base 4 with 1-(3-halopropyl)-3-(trifluoromethyl)-
benzene (5) to provide highly unstable iminium salt 6.
Subsequent hydrolysis of 6 with water in the same pot
yielded cinacalcet. The treatment of cinacalcet with hydro-
chloric acid during the workup process furnished 1 with an
overall yield of around 60%. Our synthetic approach for 1,
discussed in this report demonstrates industrial application
of the century-old, unexplored name reaction, “Forster’s
Reaction” or ForsterꢀDecker synthesis.
properly to calcium in the bloodstream. Elevated levels of
parathyroid hormone (PTH), an indicator of secondary hyper-
parathyroidism (SHPT), are associated with altered metabolism
of calcium and phosphorus, bone pain, fractures, and increased
risk for cardiovascular death. The secretion of PTH is normally
regulated by the calcium-sensing receptor. Calcimimetic agents
increase the sensitivity of this receptor to calcium, which inhibits
the release of parathyroid hormone, and lowers PTH levels
within few hours.4
Original synthetic methods were developed on the basis of
reductive amination approaches that involve the use of reagents
such as titanium isopropoxide (which is highly hygroscopic,
expensive, and pyrophoric) and sodium cyanoborohydride, and
DIBAL (which are toxic and flammable). These reported methods
as depicted in Scheme 1 also employed chiral chromatographic
techniques, which are not feasible on industrial scale. In recent
years, extensive efforts have been made towards the development
of efficient synthetic methods for 1; few of them are superior,
improved, and scalable over the first-generation syntheses.5
Our approach for the development of 1 is based on the Forster
reaction which can be performed in one pot without the isolation
of intermediates, minimizing waste and exposure and increasing
throughput. A new process for the preparation of 1 in high
chemical and optical purity has been developed and scaled up
successfully in what is believed to be the first industrial applica-
tion of Forster’s reaction.
’ INTRODUCTION
Synthetic route selection is the critical starting point for
Process Research and Development, especially in generic phar-
maceutical industries due to cost pressure and to overcome
possible infringement issues in order to enter the regulated
markets.1 Exploration of new and efficient chemical routes
designed empirically by retrosynthetic approaches, new inter-
mediates, reaction conditions, reagents, catalysts, and poly-
morphs with superior bioavailability and efficacy etc., are the
key success factors to get rid of entry barriers. While doing so, a
chemist, working under stringent conditions and led by instinct
and experience, identifies and unearths new ways of doing
chemistry with the competitive advantages that helps companies
to generate intellectual wealth.2 This article reports a novel, one-
pot process for making the cinacalcet hydrochloride (1), a
selective calcimimetic agent, by using Forster’s reaction. This
reaction is used for the formation of secondary amine derivatives
by condensing the primary amines with an aldehyde followed by
addition of alkyl halide to the obtained Schiff’s base and
subsequent hydrolysis of the iminium salt.3 Cinacalcet hydro-
chloride (1) is a first novel drug in the class of calcimimetics,
approved by United States Food and Drug Administrative as
Sensipar, and Mimpara. Calcimimetics belong to a class of orally
active, small molecules that decrease the secretion of parathyroid
harmone (PTH) by activating calcium receptors. This class of
compounds is used to treat hyperparathyroidism (HPT), a
condition characterized by oversecretion of PTH, the result of
’ RESULTS AND DISCUSSION
Most of the synthetic endeavors published recently for synth-
esis of cinacalcet involves the use of (1R)-(þ)-1-naphthylethyl
amine (2) as one of the key starting material; recently, an
improved process for synthesis of 2 has been reported by our
laboratory.6 Another intermediate, 1-(3-bromopropyl)-3-(tri-
fluoromethyl)benzene (5) required for the synthesis was pre-
pared according to literature process5d,g with minor modifica-
tions.7 The preparation of cinacalcet was studied using Forster
reaction by reacting the (1R)-1-naphthyl ethylamine (2) with
benzaldehyde (3) at room temperature to furnish Schiff’s base
(1R)-1-(2-naphthyl)-N-[1-phenylmethylene]ethanamine (4), which
is then reacted with 1-(3-bromopropyl)-3-(trifluoromethyl)-
benzene (5) in N-methyl-2-pyrrolidone at 130ꢀ135 °C to obtain
Received: January 17, 2011
Published: February 24, 2011
r
2011 American Chemical Society
455
dx.doi.org/10.1021/op200016a Org. Process Res. Dev. 2011, 15, 455–461
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Scheme 1
Scheme 2. One-pot synthesis of cinacalcet hydrochloride (1)
an iminium salt 6. Hydrolysis of iminium salt 6 with water and/or
an acid furnished the cinacalcet hydrochloride (1).8 Syntheses of
Schiff’s base 4 and cinacalcet hydrochloride (1) were run
separately, that is consecutively during feasibility in order to
establish the reaction parameters and understand the impurity
profile at each stage. Subsequently both the steps were tele-
scoped and conveniently performed in one pot once the critical
process parameters are established (Scheme 2). Reaction of 2
with 3 was initially conducted in ethanol at 70ꢀ80 °C for 5ꢀ6 h.
The Schiff base 4 precipitated out in the reaction mass and was
isolated as white crystalline solid by filtering the reaction mass.
The solid product 4 obtained was directly used in the next step
without further purification. 4 was found unstable upon storage
for a longer period in the presence of moisture. However, the
dried sample of 4, stored under inert atmosphere, was found to
remain stable for a longer period. The structure of 4 was
characterized by different spectroscopic methods.
The reaction of 4 with 1-(3-bromopropyl)-3-(trifluoromethyl)-
benzene (5) in N-methyl-2-pyrrolidone at 130ꢀ135 °C provided
iminium salt 6, which on treatment with water or an aqueous acid
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Scheme 3. Formation of impurities in cinacalcet hydrochloride (1)
at 25ꢀ35 °C followed by usual workup procedure furnished
cinacalcet hydrochloride (1). After completion of reaction (by
TLC) the reaction mass was quenched with water, and the pH of
the mass was adjusted to 8ꢀ9 using aqueous ammonia. The
reaction mass was extracted in toluene, the toluene layer was
washed with water followed by 10% sodium metabisulphite
solution to remove traces of aldehyde 3 from the product layer.
Water was then added to the toluene layer, and the pH of the
solution was adjusted to 0.5ꢀ1.5 using concentrated hydrochlo-
ric acid. The resulting reaction solution was stirred, and the layers
were separated. The organic layer containing cinacalcet hydro-
chloride (1) was washed with water and concentrated under
reduced pressure to obtain thick syrup. The syrup was dissolved
in heptane or diisopropylether and stirred for 2 h, and the solid
obtained was filtered. This solid was suspended in ethyl acetate,
heated at 55ꢀ60 °C for 30 min, and cooled to 15ꢀ20 °C; the
resultant solid was filtered, washed with ethyl acetate, dried, and
recrystallized with acetonitrile and water (2:10 v/v) to afford
cinacalcet hydrochloride (1) as a white crystalline solid with
99.9% purity by HPLC with an overall yield of 58ꢀ60%. Of the
several reaction conditions, including catalysts such as potassium
iodide and/or phase transfer catalyst such as tetrabutyl ammo-
nium bromide, in solvents such as acetonitrile, N-methyl-2-
pyrrolidone (NMP), N,N-dimethylacetamide, tetrahydrofuran
(THF), toluene, dimethylformamide (DMF), or dimethylsulf-
oxide (DMSO), N-methyl-2-pyrrolidone (NMP) was proved to
be the superior solvent for this reaction. The use of catalyst or
phase transfer catalyst added no advantages to the established
process. The original Forster reaction does not use any solvent
for the formation of iminium salt, but in our case, many
impurities were formed when the reaction was performed with-
out solvent.
After establishing both reactions independently, a one-pot
process was established by telescoping both the reactions. While
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telescoping and establishing the one-pot process, the formation
of 4 was achieved without using the solvent at 25ꢀ30 °C within
1ꢀ2 h. N-Methyl-2-pyrrolidone was added to the reaction mass
containing 4, followed by 1-(3-bromopropyl)-3-(trifluoro-
methyl)benzene (5), and rest of the operations were performed
in the same manner as described above to obtain the cinacalcet
hydrochloride (1) in one pot.
spectra were CDCl3 and DMSO-d6 unless otherwise stated.
Infrared spectra were taken on Perkin-Elmer Spectrum 100 in
potassium bromide pellets unless otherwise stated. A mass
spectrum was recorded on Shimadzu GCꢀMS QP mass spectro-
meter with an ionization potential of 70 eV. Elemental analyses
were performed on a Hosli CH-Analyzer and were within the
theoretical percentage of (0.3. Progress of all reactions was
monitored by thin layer chromatography (TLC) and carried out
on 0.2 nm silica gel 60 F254 (Merck) plates, using UV light (254
and 366 nm) for detection. Common reagent-grade chemicals
were either commercially available and were used without further
purification or were prepared by standard literature procedures
One-Pot Process for the Preparation of Cinacalcet Hydro-
chloride (1). To a stirred solution of (1R)-1-naphthyl ethylamine
(2, 1.0 kg, 5.85 mol) was added benzaldehyde (3, 0.62 kg, 5.85
mol), and the contents were stirred at 25ꢀ30 °C for 1ꢀ2 h. After
completion of the reaction (by HPLC), N-methyl-2-pyrrolidi-
none (3.0 L) was added to the above mixture and stirred for
15ꢀ20 min, before the addition of 1-(3-bromopropyl)-3-(tri-
fluoromethyl)benzene (5, 1.72 kg, 6.44 mol). The temperature
of the reaction mass was slowly raised to 125ꢀ130 °C and
maintained for 10ꢀ12 h. Reaction mass was cooled to 25ꢀ30 °C
and quenched with water (10.0 L). The pH of the mass was
adjusted to 8ꢀ9 using aqueous ammonia and extracted with
toluene (10.0 L). The toluene layer was separated, washed with
water (10.0 L) followed by 10% sodium metabisulphite (10.0 L
ꢁ 2). Water (10.0 L) was added into the toluene layer, the pH of
the solution was adjusted to 0.5ꢀ1.5 using concentrated hydro-
chloric acid, the resulting solution was stirred, and the layers were
separated. The organic layer was washed with water (10.0 L ꢁ 2)
and concentrated under reduced pressure to provide thick syrup.
The syrup was dissolved in diisopropylether (6.0 L) and stirred
for 2 h; the solid obtained was filtered. The obtained solid was
suspended in ethyl acetate (5.0 L), heated at 55ꢀ60 °C for 30
min, cooled to 15ꢀ20 °C, filtered, washed with ethyl acetate
(0.10 L), and dried. The dried solid was recrystallized with
acetonitrile and water (3.0 L:15.0 L) to afford 1 as white crys-
talline solid. Yield: 1.334 kg (58.0%); HPLC purity: 99.95%;
Chiral Purity: 99.98%; mp: 178ꢀ182 °C; IR (KBr) cmꢀ1: 3436,
2962, 2797, 1587, 1450, 1379, 1327, 1166, 1129, 797, 774, 746;
MS: m/z = 358.79 [M þ H] þ; 1H NMR (400 MHz, DMSO-d6):
δ = 1.67ꢀ1.69 (d, 3H), 1.97ꢀ2.02 (m, 2H), 2.67ꢀ2.69 (t, 4H),
5.27 (q, 1H), 7.44ꢀ7.46 (m, 4H), 7.54ꢀ7.61 (m, 3H), 7.93ꢀ
7.99 (m, 2H), 8.026ꢀ8.08 (d, J = 7.2 Hz, 1H), 8.20ꢀ8.23 (d, J =
7.2 Hz, 1H), 9.46 (s, 1H), 10.17 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ = 20.49 (CH3), 27.50 (CH2), 32.02 (CH2), 45.18
(CH2), 52.60 (CH), 123.06, 123..23, 123.26, 124.94, 125.17,
125.21 (CF3), 126.0, 126.60, 127.39, 129.35, 129.39, 129.82,
130.79, 132.88, 133.83, 134.58, 142.75; Anal. Calcd for C22H23-
NF3Cl: C, 67.09; H, 5.84; N, 3.55; Found: C, 66.92; H, 5.68;
N, 3.58.
’ EVALUATION OF IMPURITIES
Evaluation (identification, characterization, and synthesis) of
impurities (by products, starting materials, intermediates, carry-
over impurities from starting materials, etc.) formed in the
reaction mass and their control in the product at the end to
meet the regulatory norms (ICH quality) is another critical
objective during the process development.9 Analysis of the
reaction mass and crude cinacalcet hydrochloride (1) by HPLC
helped to identify the impurity peaks, which are subsequently
identified by LCꢀMS. The proposed impurities were synthe-
sized, characterized, and confirmed by spiking studies using
HPLC. By understanding the structures, their control and
removal strategy have been designed for preparing chemically
and enantiomerically pure 1. Five potential impurities viz., 7, 8, 9,
10, and 11 were identified, synthesized, and characterized by
LCꢀMS (Scheme 3).
Alkylation of Schiff’s base 4 with 5 is a very slow reaction and
does not go to completion even after prolonged heating.
Unreacted 4 was converted into 2 during the workup and was
selectively removed by washing the organic layer with dilute
hydrochloric acid. Benzaldehyde (3) was removed by metabi-
sulfite wash. Dimer impurity 11, formed by the alkylation of 1,
was eliminated by purification using ethylacetate. However, 7
that was present in at 1ꢀ2% level in the crude product was not
removed. Crystallization from acetonitrileꢀwater was estab-
lished specifically to remove 7. While a set of three impurities
8, 9, and 10 that are formed due to the presence of carryover
impurities in 5(5a, 5b, and 5c) were eliminated in 5. Removal of
8, 9, and 10 by recrystallization was difficult without significant
yield loss. However, their formation during the preparation of 1
was eliminated by the purification of 5 by fractional distillation.7
Though the reaction condition for alkylation was harsh (130ꢀ
135 °C), racemization of the products was not observed as chiral
purity of the crude product was 99.98% by chiral HPLC.
The contents of all six of these potential impurities (2, 7, 8, 9,
10, and 11) and other unknown impurities were well below the
ICH limits (NMT 0.15%). However, the absence of impurity 5 in
1 has been confirmed by gas chromatography (GC) studies.
’ CONCLUSION
In conclusion, an efficient, and environmentally friendly
process to make cinacalcet hydrochloride in high chemical and
chiral purity has been developed by employing the Forster
reaction.
Preparation of (1R)-1-(2-Naphthyl)-N-(phenylmethylene)-
ethanamine (4). To a stirred solution of (1R)-1-naphthyl
ethylamine (2, 5 g, 0.029 mol) in ethanol (25 mL), was added
benzaldehyde (3, 3.71 g, 0.035 mol) at 25ꢀ30 °C, and the
resultant mass was stirred at 55ꢀ60 °C for 5ꢀ6 h. Upon com-
pletion of reaction (by TLC), the reaction mass was gradually
cooled to 5ꢀ10 °C and maintained for 30 min. The precipitated
solid was filtered, washed with ethanol (10 mL), and dried under
vacuum to yield4 asa white crystalline solid. Yield: 7.1 g (94.67%);
HPLC purity: 99.20%; mp: 90ꢀ92 °C; IR (KBr) cmꢀ1: 3446,
2975, 2926, 1641, 1445, 1392, 803, 781, 762; MS: m/z = 260.0
’ EXPERIMENTAL SECTION
General. Melting points were determined on Analab melting
point apparatus, in open capillary tubes, and were uncorrected.
1
The H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded on a Varian XL-300 spectrometer. Chemical shifts
were reported in parts per million using tetramethylsilane as the
internal standard and are given in δ units. The solvents for NMR
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Scheme 4. Synthetic route for the preparation of compound 10
[M þ H] þ; 1H NMR (400 MHz, CDCl3): δ = 1.74ꢀ1.76 (d,
3H), 5.34ꢀ5.39 (q, 1H), 7.41ꢀ7.42 (t, J = 6.0 Hz, 3H),
7.48ꢀ7.51 (m, 3H), 7.80ꢀ7.87 (m, 5H), 8.25ꢀ8.27 (d, J = 8.0
Hz, 1H), 8.44 (s, 1H).
reduced pressure to provide a thick syrup. The syrup was then
dissolved in n-heptane (60 mL) and stirred for 2ꢀ3 h; the
obtained solid was filtered. This solid was suspended in ethyl
acetate (50 mL); the suspension was heated at 55ꢀ60 °C for 30
min and cooled to 15ꢀ20 °C; the obtained solid was filtered,
washed with ethyl acetate, and dried to afford compound 8 as a
white crystalline solid. Yield: 13.80 g (60%); HPLC purity:
90.20%; Chiral Purity: 99.9%; IR (KBr) cmꢀ1: 2961, 2925,
2853, 1734, 1595, 1448, 1331, 1164, 1124, 1072, 799, 778, 696
; MS: m/z = 356.1 [M þ H] þ; 1H NMR (400 MHz, DMSO-d6):
δ = 1.46ꢀ1.48 (d, 3H), 3.32ꢀ3.35 (d, J = 7.6 Hz, 2H), 4.82 (q,
1H), 6.47ꢀ6.52 (dt, J = 18.0 and 7.6 Hz, 1H), 6.57ꢀ6.61 (d, J =
16.0 Hz, 1H), 7.49ꢀ7.54 (m, 6H), 7.68ꢀ7.70 (d, J = 8.0 Hz, 1H),
7.77ꢀ7.79 (d, J = 8.0 Hz, 1H), 7.83ꢀ7.85 (d, J = 8 Hz, 1H),
7.93ꢀ7.95 (dd, J = 8.0 Hz, 1H) 8.23ꢀ8.25 (dd, J = 8.0 and 7.2
Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 20.19 (CH3),
46.61 (CH2), 51.44 (CH), 122.62 (CH), 122.72 (CH), 122.93,
124.69, 125.48 (CF3), 125.63, 126.15, 126.87, 128.97, 129.37,
129.69, 129.90, 130.25, 130.36, 133.41, 134.03, 134.61.
Preparation of (1R)-N-Benzyl-1-(1-naphthyl)ethanamine
(7). To a stirred solution of (1R)-1-(2-naphthyl)-N-(phenyl-
methylene)ethanamine (4, 10 g, 0.038 mol) in ethanol (200 mL)
was added sodium cyanoborohydride (3.63 g, 0.057 mol) at
25ꢀ30 °C. The reaction mass was further stirred at 45ꢀ50 °C for
5ꢀ6 h. Upon completion of the reaction (by TLC), the reaction
mass was cooled, quenched with water (100 mL), and extracted
with n-heptane (100 mL). The organic layer was separated,
washed with water (100 mL), and concentrated under reduced
pressure to provide thick oil. The oil was dissolved in n-heptane
(90 mL) and stirred, and the pH of the solution was adjusted to
1ꢀ2 using concentrated hydrochloric acid. The precipitated
solid was filtered, washed with n-heptane (10 mL), and dried
under vacuum to yield 7 as a white crystalline solid. Yield: 8.2 g,
(81.42%); HPLC purity: 99.10%; IR (KBr) cmꢀ1: 3445, 2965,
2759, 2728, 2682, 1596, 1457, 1378, 801, 781, 779; MS: m/z =
262.07 [M þ H] þ; 1H NMR (400 MHz, CDCl3): δ = 1.73ꢀ
1.75 (d, J = 8.8 Hz, 3H), 3.95ꢀ3.99 (br dd, 1H), 4.16ꢀ4.19 (br
dd, 1H), 5.24ꢀ5.26 (q, J = 8.8 Hz, 1H), 7.38ꢀ7.39 (m, 3H),
7.48ꢀ7.50 (t, 2H), 7.57ꢀ7.59 (m, 2H), 7.64ꢀ7.66 (d,
1H),7.98ꢀ8.03 (m, 3H), 8.08ꢀ8.11 (d, J = 9.2 Hz, 1H), 9.72
(bs, 1H), 10.48 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ =
21.15 (CH3), 48.34 (CH2), 51.48 (CH), 121.35, 125.04, 125.9,
126.69, 128.52, 129.0, 129.11, 129.61, 130.21, 130.76, 132.11,
133.60.
Preparation of (2E)-N-[(1R)-1-(1-Naphthyl) ethyl]-3-[3-(tri-
fluoromethyl)phenyl]prop-2-en-1-amine (8). To a stirred
solution of (1R)-1-naphthyl ethylamine (2, 10 g, 0.058 mol),
was added benzaldehyde (3, 17.04 g, 0.064 mol) and maintained
at 25ꢀ30 °C for 1ꢀ2 h. After the completion of reaction (by
HPLC), N-methyl-2-pyrrolidinone(30 mL) was added followed
by 1-[(1E)-3-bromopropyl-1en-1-yl]-3-(trifluoromethyl)benzene10
(5a, 17.04 g, 0.064 mol), and the temperature of the reaction
mass was raised to 125ꢀ130 °C and maintained for 12 h. After
completion of the reaction (by HPLC), the reaction mass was
quenched with water (100 mL); the pH was adjusted to 8ꢀ9
using aqueous ammonia, and the solution was extracted with
toluene (100 mL). The toluene layer was separated, washed with
water (100 mL) followed by an aqueous solution of 10% sodium
metabisulphite (100 mL ꢁ 2). Water (100 mL) was added to the
toluene layer, and the pH of the solution was adjusted to 0.5ꢀ1.5
using concentrated hydrochloric acid, and the resulting reaction
solution was stirred for 10ꢀ15 min. Organic layer was separated,
washed with water (100 mL ꢁ 2), and concentrated under
Preparation of 3-(3-Methylphenyl)-N-[(1R)-1-(1-naph-
thyl)ethyl]propan-1-amine (9). To a stirred solution of (1R)-
1-naphthyl ethylamine (2, 10 g, 0.058 mol) was added the
benzaldehyde (3, 17.04 g, 0.058 mol) and stirred at 25ꢀ30 °C
for 1ꢀ2 h. After completion of the reaction (by HPLC) N-
methyl-2-pyrrolidinone (30 mL) was added to the mixture and
stirred for 15ꢀ20 min followed by addition of 1-(3-bromo-
propyl)-3-methylbenzene (18.68 g, 0.087 mol). The temperature
of reaction mass was raised to 125ꢀ130 °C and maintained until
completion of the reaction (by HPLC). The reaction mass was
quenched with water (100 mL), pH of the resulting solution was
adjusted to 8ꢀ9 using aqueous ammonia, and the solution was
extracted with toluene (100 mL). The toluene layer was sepa-
rated, washed with water (100 mL) followed by 10% sodium
metabisulphite (100 mL ꢁ 2). Water (100 mL) was added into
toluene layer, and the pH of the solution was adjusted to 0.5ꢀ1.5
using concentrated hydrochloric acid. The resulting solution was
stirred, and the layers were separated. The organic layer was
washed with water (100 mL ꢁ 2) and concentrated under
reduced pressure to provide thick syrup. Syrup was dissolved
in n-heptane (60 mL) and stirred for 2 h, and the solid obtained
was filtered. The wet solid was suspended in ethyl acetate
(50 mL); the solution was heated at 55ꢀ60 °C for 30 min,
cooled to 15ꢀ20 °C, filtered, washed with ethyl acetate, and
dried to afford des(trifluorocinacalcet) (9) as a white crystalline
solid. Yield: 11.0 g (55.92%); HPLC purity: 99.60%; Chiral
Purity: 99.90%; IR (KBr) cmꢀ1: 3435, 3006, 2962, 2945, 2798,
1
1588, 1455, 799, 771, 702; MS: m/z = 304.2 [M þ H] þ; H
NMR (400 MHz, DMSO-d6): δ = 1.66ꢀ1.68 (d, 3H),
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1.93ꢀ1.96 (m, 2H), 2.22 (s, 3H), 2.52ꢀ2.54 (m, 2H),
2.71ꢀ2.74 (dt, 1H), 2.90ꢀ2.94 (dt, 1H), 5.29ꢀ5.31 (q, 1H),
6.89ꢀ6.97 (dd, J = 8.0 Hz and 3.0 Hz, 3H), 7.11ꢀ7.13 (t, J = 8.0
Hz, 1H), 7.59ꢀ7.63 (dd, J = 8.0 Hz and 3.0 Hz, 3H), 7.97ꢀ8.02
(m, 3H), 8.23ꢀ8.25 (d, J = 8.0 Hz, 1H), 9.24 (bs, 1H), 9.84 (s,
1H); 13C NMR (100 MHz, DMSO-d6): δ = 20.13 (CH3), 21.02
(CH3), 27.16 (CH2), 31.92 (CH2), 44.88 (CH2), 52.07 (CH),
122.68, 124.51, 125.25, 125.62, 126.19, 126.64, 126.98, 128.64,
128.89, 130.36, 133.39, 134.22, 137.36, 140.59.
under reduced pressure to obtain thick oil. The crude oil was then
purified by column chromatography on silica gel (70 mm ꢁ
60 cm column) by eluting with chloroform to afford compound
11 as a thick transparent oil. Yield: 10.50 g (69.03%); HPLC
purity: 91.22%; IR (NaCl) cmꢀ1: 3441, 3049, 2940, 2861, 1596,
1492, 1449, 1331, 900, 702, 661; MS: m/z = 544.0 [M þ H] þ;
1H NMR (400 MHz, CDCl3): δ = 1.35ꢀ1.37 (d, 3H), 1.57ꢀ
1.63 (m, 4H), 2.42ꢀ2.46 (t, 4H), 2.52ꢀ2.55 (t, 4H), 4.60ꢀ4.62
(m, 1H), 7.23ꢀ7.25 (d, J = 8.0 Hz, 1H), 7.32(s, 2H), 7.37ꢀ7.41
(t, 3H), 7.47ꢀ7.51 (m, 6H), 7.76ꢀ7.78 (d, J = 8.0 Hz, 1H),
7.87ꢀ7.89 (dd, 1H), 8.42ꢀ8.44 (d, J = 8.0 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6): δ = 15.46 (CH3), 29.38 (CH2), 32.99
(CH2), 50.03 (CH2), 56.90 (CH), 122.68, 122.72, 122.76,
123.37, 124.78, 124.83, 124.86, 124.91, 125.58, 125.68, 125.72
(CF3), 128.88, 129.28, 129.33, 129.40, 129.49, 129.58, 129.60,
129.91, 132.06, 132.63, 134.04, 140.62, 144.01.
Preparation of 3-(3-(Trifluoromethyl)cyclohexyl)-N-((R)-
1-(naphthalen-1-yl)ethyl)propan-1-amine (10). (2E)-3-[3-
(Trifluoromethyl)phenyl]acrylic acid (100 g, 0.462 mol), metha-
nol (1000 mL), and 10% Pd/C (25.0 g, 50% wet) were added
into an autoclave, and hydrogen pressure of 5 kg/cm2 was
applied; the reaction was maintained at 50ꢀ55 °C for 8 days.
The catalyst was filtered, and solvent was removed under reduced
pressure to obtain 3-[3-(trifluoromethyl)cyclohexyl]propanoic
acid (98.0 g) as an oil. The oil was then treated with 2 (67.68 g,
0.395 mol) in toluene (670 mL) at 110 °C for 16ꢀ18 h in the
presence of boric acid (1.4 g, 0.022 mol) under azeotropic con-
ditions. After completion of the reaction (by TLC), the reaction
mass was cooled to 25ꢀ30 °C, and washed with 2 N hydrochloric
acid solution (670 mL) followed by 10% aqueous solution of
sodium bicarbonate (670 mL) and water (500 mL). The organic
layer was separated and concentrated under reduced pressure to
yield 114.0 g of amide compound 12 (Scheme 4). To a cooled
solution of amide 12 in tetrahydrofuran (1700 mL) was added
NaBH4 (89.62 g, 3.258 mol) lotwise at ꢀ5 to 0 °C, followed by
slow addition of BF3-etherate (349.55 g, 5.14 mol). Reaction
mass was heated to 50ꢀ55 °C, maintained for 5ꢀ6 h, and
quenched over 2 N hydrochloric acid solution (456 mL). The
resulting reaction mass was distilled out atmospherically below
70 °C to remove THF and cooled to 25ꢀ30 °C; the pH of the
reaction mass was adjusted to 8ꢀ9 using aqueous ammonia. The
reaction mass was extracted with toluene (1140 mL), the toluene
layer was washed with water (500 mL) and concentrated to get
crude 10 as oil. The obtained crude oil was purified by column
chromatography on silica gel (70 mm ꢁ60 cm column) using
neat chloroform as the elution solvent to afford compound 10 as
a white solid.
’ AUTHOR INFORMATION
Corresponding Author
drvtmathad@yahoo.co.in, vt.mathad@megafine.in.
’ ACKNOWLEDGMENT
We are grateful to the management of Megafine Pharmaceu-
tical (P) Ltd., Lakhmapur, Dindori, Nashik-02, for supporting
this work. We also thank colleagues of Analytical Research and
Development department, Megafine Pharmaceutical (P) Ltd.,
for valuable cooperation in developing the chromatographic
methods (chiral and related substances) for establishing the
process and identifying the impurities.
’ REFERENCES
(1) Walter, C.; Romano, D, F. From Bench to Market: The Evolution of
Chemical Synthesis; Oxford University Press, 2000.
(2) Tony, Y. Z. Chem. Rev. 2006, 106, 2583–2595.
(3) (a) Forster, M. O. J. J. Chem. Soc. 1899, 75, 934. (b) Decker, H.;
Becker, P. Ann. 1913, 395, 362.
(4) (a) Herbert, S. C. Annu. Rev. Med. 2006, 57, 349. (b) Sorbera,
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(c) Franceschini, N.; Joy, M. S.; Kshirsagar, A. Expert Opin. Invest. Drugs
2003, 12, 1413.
Yield: 13.0 g ; HPLC purity: 86.3%; Chiral Purity: 99.9%; IR
(KBr): cmꢀ1 3434, 2938, 2859, 2736, 1587, 1453, 1256, 1170,
1096, 800, 778; MS: m/z = 364.10 [M þ H] þ; 1H NMR (400
MHz, DMSO-d6): δ = 0.82ꢀ0.88 (m, 2H), 1.14ꢀ1.22 (m, 4H),
1.48ꢀ1.52 (t, 4H), 1.49 ꢀ1.52 (d, 3H), 1.72ꢀ1.86 (m, 4H),
2.50ꢀ2.56 (t, 2H), 4.63ꢀ4.64 (q, 1H), 7.45ꢀ7.48 (m, J = 8.0
and 3.0 Hz, 3H), 7.62ꢀ7.64 (d, J = 8.0 Hz, 1H), 7.73ꢀ7.75 (d,
J = 8.0 Hz, 1H), 7.86ꢀ7.88 (d, J = 8.0 Hz, 1H), 8.16ꢀ8.18 (d, J =
8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ = 20.03
(CH3), 22.70, 23.59, 24.46, 28.79, 30.94, 31.32, 33.22, 34.91,
45.42, 52.01, 122.65, 124.41, 125.60, 126.18, 126.96, 128.92
(CF3), 130.31, 133.38, 134.27.
Preparation of (1-Naphthalen-1-yl-ethyl)-N,N-bis-[3-(3-
trifluoromethylphenyl)-propyl]amine (11). To a stirred solu-
tion of cinacalcet hydrochloride (1, 10 g, 0.028 mol) in toluene
(150 mL) was added potassium carbonate (7.74 g, 0.056 mol)
followed by 1-(3-bromopropyl)-3-(trifluoromethyl)benzene (5,
14.95 g, 0.056 mol) under stirring at 25ꢀ30 °C. The reaction
mass was heated and stirred at 110ꢀ111 °C for 48 h. Upon
completion of the reaction (by TLC), the reaction mass was
cooled and quenched with water (100 mL). The organic layer
was separated, washed with water (100 mL), and concentrated
(5) (a) Nemeth, E. F.; Van Wagenen, B. C.; Balandrin, M. F.;
delMar, E. G.; Moe, S. T. U.S. Patent 6,011,068, 2000. (b) Van Wagene,
B. C.; Balandrin, M. F.; DelMar, E. G.; Nemeth, E. F. U.S. Patent
6,211,244, 2001, (c) Oliver, R. T.; Charles, B.; Wanda, T.; Alan, B.;
Shuji, H.; Kazuo, M.; Kenji, S.; Robert, D. L.; Michael, J. M.; Paul, J. R.
Tetrahedron Lett. 2008, 49, 13.(d) Padi, P. R.; Akrundi, S. P.; Suthrpu,
S. K.; Kolla, N. K. WO/2008/058235, 2008. (e) Oliver, T.; Charles, B.;
Robert, L.; John, M. M.; Tamim, R. M. WO/2009/002427 A2 2009.
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(7) Preparation of 1-(3-bromopropyl)-3-(trifluoromethyl)benzene
(5): To a stirred solution of 3-[3-(trifluoromethyl)phenyl]propan-1-ol
(10 g, 49 mmol) was added concentrated sulphuric acid (14.4 g, 114
mmol) under stirring at 25ꢀ30 °C followed by aqueous hydrobromic
acid (86.3 g, 107.8). The reaction mass was heated and stirred at
50ꢀ55 °C for 3ꢀ4 h. Upon completion of the reaction by thin layer
chromatography (TLC), the reaction mass was cooled, quenched with
water (100 mL), and extracted with methylene dichloride (100 mL).
The organic layer was separated, washed with 10% sodium bicarbonate
(100 mL) followed by 5% brine solution, and concentrated under
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Organic Process Research & Development
COMMUNICATION
reduced pressure to yield the crude 5 as an oil. Obtained crude oil was
purified by fractional distillation to afford highly pure compound 5.
Yield: 11.0 g (76.45%); GC purity: 99.85%; IR (NaCl): 3017 w, 2940 s,
292863 w, 1597 w, 1492 w, 1451 s, 1165 s, 1125 s, 799 s, 702 s; MS:
m/z = 272.80 [M þ H] þ; 1H NMR (400 MHz, CDCl3): δ = 2.14ꢀ2.23
(m, 2H), 2.82ꢀ2.87 (t, 2H), 3.38ꢀ3.42 (t, 2H), 7.40ꢀ7.48 (dd, 4H).
(8) Vijayavitthal, T. M.; Navnath, C. N.; Gorakshanath, B. S.; Sharad,
S. I.; Shrikant, P. D.; Panchangan, R. WO/2010/103531 A2, 2010.
(9) http://www.ich.org/products/guidelines/quality/article/qual-
ity-guidelines.html
(10) 1-[(1E)-3-Bromopropyl-1en-1-yl]-3-(trifluoromethyl)benzene
(5a) was recovered by repeated distillation of residue obtained after
fractional distillation of crude 5, and its structure was identified by
GCꢀMS.
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dx.doi.org/10.1021/op200016a |Org. Process Res. Dev. 2011, 15, 455–461