Beilstein J. Org. Chem. 2012, 8, 1366–1373.
TMS) δ 2.65 (t, J = 7.6, 2H, –CH2), 3.01 (t, J = 7.6, 2H, –CH2), mixture was stirred for 1 h and quenched with saturated sodium
3.67 (s, 3H, –OCH3), 7.39 (d, J = 8.8, 2H, ArH), 7.46 (s, 2H, thiosulfate solution (2 × 100.0 mL) and water (250.0 mL). The
ArH); 13C NMR (CDCl3/TMS) δ 172.70, 141.31, 131.62, product was extracted with n-hexane (2 × 250.0 mL) and the
130.72 (q), 128.80, 124.90, 123.99 (q), 123.09, 51.50, 35.17, organic layer was dried over anhydrous sodium sulfate and
30.53.
evaporated under vacuum to get the product as colorless oil.
Yield = 65.3 g (85%); purity (GC) = 99.45%; IR (neat): absence
Preparation of 3-(3-trifluoromethylphenyl)propan-1-ol (12): of 3100–3400 (–OH), 1450, 1330, 1164, 1126, 1074, 797, 702
Compound 11 (50.0 g, 0.215 mol) was dissolved in THF cm−1; 1H NMR (CDCl3/TMS) δ 2.14 (quintet, 2H, –CH2), 2.80
(500.0 mL) and sodium borohydride (49.0 g, 1.295 mol) was (t, J = 7.3, 2H, –CH2), 3.41 (t, J = 6.6, 2H, –CH2), 7.39–7.49
added at rt. The resulting reaction solution was heated under (m, 4H, ArH); 13C NMR (CDCl3/TMS) δ 141.34, 132.01,
reflux for 10 min. Methanol (500.0 mL) was added to this solu- 131.02 (q, CF3), 128.97, 125.53, 123.26, 36.02, 34.55, 5.72.
tion at 60–65 °C over a period of 4 h. After complete addition
of methanol, the reaction solution was stirred for another 5 h to Preparation of cinacalcet hydrochloride (1): Compound 7
complete the reduction. After completion of the reaction, the (3.0 g, 0.0065 mol) and MTBE (15.0 mL) were stirred for
solvent was distilled off and the remaining reaction mixture was 15 min to become a clear solution. Conc. HCl solution (3.2 mL,
cooled to rt, water (500.0 mL) was added and the pH was 0.0129 mol) was added drop wise and stirred for 15 min at rt.
adjusted to 5 with conc. HCl solution (50.0 mL). The product The material was filtered, washed with MTBE and recrystal-
was extracted with ethyl acetate (2 × 250.0 mL) and the organic lized from acetonitrile and water (1:2 ratio) at 65 °C for 2 h.
layer was dried over anhydrous sodium sulfate and evaporated The solid was dried at 50–55 °C to a constant weight to give
under vacuum to get the product as colorless oil. Yield = 43.5 g pure hydrochloride salt of 1. Yield = 2.1 g (91%); chiral purity
(95%); purity (GC) = 99.7%; IR (neat) 3350 (–OH), 2941, (HPLC) = 99.95%; mp 174.6–176.8 °C; IR (KBr): 3427 (broad,
2870, 1450, 1331, 1162, 1124, 1073 cm−1; 1H NMR (CDCl3/ –NH–), 2951, 2797, 2750, 2712, 1587, 1450, 1327, 1165, 1128,
TMS) δ 1.90 (m, 2H, –CH2), 2.08 (s, 1H, –OH), 2.77 (t, J = 7.8, 1072, 798, 775 cm−1; 1H NMR (DMSO-d6/TMS) δ 1.67 (d, J =
2H, –CH2), 3.67 (t, J = 6.3, 2H, –CH2), 7.38 (d, J = 5.3, 2H, 6.6, 3H, –CH3), 1.99 (quintet, 2H, –CH2), 2.70 (m, 2H, –CH2),
ArH), 7.45 (d, J = 5.3, 2H, ArH); 13C NMR (CDCl3/TMS) δ 2.93 (m, 2H, –CH2), 5.30 (q, 1H, –CH), 7.46–7.61 (m, 7H,
142.64, 131.75, 130.54 (q), 128.67, 125.50, 124.99, 124.96, ArH), 7.95–8.03 (m, 3H, ArH), 8.23 (d, J = 8.0, 1H, ArH), 9.36
122.8, 122.66, 122.63, 61.69, 33.80, 31.71.
(s, 1H, –NH) and 10.04 (s, 1H, HCl); 13C NMR (DMSO-d6/
TMS) δ 142.61, 134.48, 133.70, 132.80, 130.64, 129.74,
Preparation of 1-(3-bromopropyl)-3-trifluoromethylben- 129.58,129.28, 127.29, 126.54, 125.90, 125.08, 124.67, 123.16,
zene (5): Compound 12 (50.0 g, 0.244 mol) was added to 48% 122.98, 52.37, 45.04, 31.84, 27.44, 20.30; MS m/z: 358
aqueous HBr solution (400.0 mL) at rt. The reaction mixture [M + 1]+.
was heated to 85–90 °C and stirred for 15 h. After completion
of the reaction, the mixture was cooled to rt and water
Supporting Information
(250.0 mL) was added. The product was extracted with
n-hexane (2 × 250.0 mL) and the organic layer was dried over
Supporting Information File 1
anhydrous sodium sulfate and evaporated under vacuum to get
the crude product, which was passed through a silica gel plug in
n-hexane to afford the pure product as colorless oil. Yield =
53.6 g (82%); purity (GC) = 99.0%; IR (neat): absence of 3350
(–OH), 1451, 1330, 1164, 1125, 1094, 799, 702 cm−1; 1H NMR
(CDCl3/TMS) δ 2.19 (quintet, 2H, –CH2), 2.86 (t, J = 7.3, 2H,
–CH2), 3.41 (t, J = 6.5, 2H, –CH2) and 7.39–7.49 (m, 4H, ArH);
13C NMR (CDCl3/TMS) δ 141.36, 131.87, 130.67 (q, CF3),
128.83, 125.07, 123.03, 33.70, 33.67, 32.52.
1H NMR, 13C NMR and ESI–MS spectra of compounds 1,
4, 5, 6 and 7.
Acknowledgements
We greatly acknowledge our thanks to Mr. Venkat Jasti,
Chairman and CEO, for his excellent support, and the analyt-
ical group of SUVEN for providing spectral data.
Preparation of 1-(3-iodopropyl)-3-trifluoromethylbenzene
(6): Compound 12 (50.0 g, 0.244 mol) was dissolved in CH2Cl2
(150.0 mL) and imidazole (2.0 g, 0.029 mol) and triphenylphos-
phine (70.64 g, 0.269 mol) were added at rt. To the resulting
pale yellow clear solution was added iodine (62.0 g, 0.244 mol)
in portions at less than 35 °C over a period of 1 h. The reaction
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