Organic Process Research & Development
Technical Note
Scheme 2
65:35 (45−55 min) with flow rate 0.8 mL/min]. The chiral
HPLC analysis was performed using a CHIRALPAK IA, 5 μm
(
250 mm × 4.6 mm) column and mobile phase n-hexane,
isopropyl alcohol and diethylamine in the ratio 980:20:04 (v/v/
v) with flow rate 0.3 mL/min (UV detector at 223 nm).
Preparation of Unsaturated Cinacalcet Hydrochloride
(
2
9). Part A: 3-Chloro-N-[(1R)-1-(naphthalen-1-yl)ethyl ]prop-
-en-1-amine (6). To a mixture of 3 (5.0 kg, 0.029 kmol),
toluene (25 L), water (2.5 L) and TBAB (1.0 kg, 0.031 kmol)
was added potassium carbonate (4.2 kg, 0.03 kmol) at room
temperature. The mixture was heated to 60−70 °C. At this
temperature 1,3-dichloropropene (4.2 kg, 0.038 kmol) was
added and the resulting mixture was refluxed for 1−2 h and
monitored by HPLC. After completion of the reaction, it was
cooled to room temperature, water (15 L) was added, the
mixture was stirred for 10−15 min and the layers were
separated. The toluene layer was washed with water (15 L) and
recovered under vacuum. The residue was dissolved in acetone
(
25 L) and water (5 L), and the pH was adjusted to 0.5−1.0
with 6 N hydrochloric acid (∼ 5.0 L) .The resulting slurry was
stirred at 25−30 °C for 60 min, and the solid was filtered and
washed with acetone (10 L) followed by water (15 L). The wet
solid was suspended in a mixture of toluene (25 L), methanol
(
12.5 L) and water (12.5 L). The pH of the resulting mixture
was adjusted to 11−12 with aqueous sodium hydroxide
solution (20%, ∼5.0 L) and stirred for 10−15 min. The
mixture was allowed to settle, the layers were separated and the
organic layer was washed with water (10 L) .Concentration of
the toluene layer under vacuum yielded 6 as an oil, which was
used in the subsequent step of C−C coupling.
Part B: Preparation of Grignard Reagent (8). To a
suspension of magnesium turnings (1.92 kg, 0.079 kmol) in
THF (15 L) was added iodine (10 g), and the mixture was
heated to reflux. To this, a solution of 3-bromobenzotrifluoride
(
7.5 kg, 0.033 kmol) in THF (10 L) was added in portions
under reflux conditions and stirred for 60 min. The resulting
suspension was cooled to −50 to −55 °C.
scaled up at pilot plant using inexpensive and commercially
available raw materials.
Part C: Preparation of Unsaturated Cinacalcet Hydro-
chloride (9). Intermediate 6 (from part A) was dissolved in
THF (18 L) and cooled to −5 to 0 °C. NMP (50 g, 0.5 mol)
and iron acetyl acetonate (180 g, 0.5 mol) were added at −5 to
CONCLUSION
■
An efficient, scalable and inexpensive novel method for the
preparation of cinacalcet hydrochloride in good yield and high
purity is reported.
0
°C and stirred for 5−10 min. This solution was added to the
above Grignard reagent (part B) maintained at −50 to −55 °C
over a period of 20−30 min keeping the temperature below 0
°C (reaction is exothermic). The reaction mixture was stirred
for an additional 20−30 min, and after completion of the
reaction, it was quenched with water (7.5 L) followed by
addition of 6 N hydrochloric acid solution (25 L) at 25−35 °C
and stirred for 60 min. Toluene (25 L) was added, the mixture
was stirred for 10−15 min and the layers were separated. The
toluene layer was washed with dilute HCl (2 × 2.5 L) and
concentrated under reduced pressure. The residue obtained was
dissolved in isopropyl acetate (25 L) and stirred for 6−8 h at
EXPERIMENTAL SECTION
General. Reagents were used as such without purification.
,3-Dichloropropene is toxic and harmful by inhalation.
■
1
Suitable personal protective equipment should be used while
handling. Melting point points were determined on a Buchi
1
B545 capillary melting point apparatus and are uncorrected. H
1
3
NMR (400 MHz) and C NMR (100 MHz) spectra were
recorded using a Bruker spectrometer. The chemical shift data
are reported as δ (ppm) using tetramethylsilane as internal
standard. Mass spectra were recorded using an API 2000 (MPS
SCIEX) instrument. Infrared spectra were recorded using
Perkin-Elmer FTIR (Spectrum One) instrument. HPLC
analysis was performed on a Waters instrument with a UV
detector (223 nm) using a Inertsil ODS-4 (150 × 4.6 mm, 5
μm) column and mobile phase [buffer (prepared by dissolving
1
5−25 °C. The resultant solid was filtered, washed with
isopropyl acetate (10 L) and dried at 45−50 °C under vacuum
for 8 h to give unsaturated cinacalcet hydrochloride (9) (6.92
kg, 61% yield). HPLC purity: 98.85%. MS (m/z): 356.2 [M +
+
1
H] . Mp: 176−178 °C. H NMR (CDCl ): δ 1.97 (d, J = 6.76
3
Hz, 3H), 3.37−3.39 (m, 1H), 3.68 −3.71 (m, 1H), 5.23−5.27
(m, 1H), 6.12−6.16 (d, J = 15.88 Hz, 1H), 6.44−6.50 (m, 1H),
7.26−7.95 (m, 10H), 8.28 (d, 1H), 10.34 (br, H), 10.83 (br,
1H).
2
.72 g of potassium dihydrogen phosphate in water (1 L) and
adjusted pH to 6.0 ± 0.05 with dilute KOH solution):acetoni-
trile, gradient 65:35 (0−25 min), 25:75 (25−45 min) and
1
567
dx.doi.org/10.1021/op300164y | Org. Process Res. Dev. 2012, 16, 1566−1568