Organic Process Research & Development
Article
a
Table 14. Experimental Results of 1 Prepared by New Process Conditions
residual solvents (ppm)
b
entry
1 (%)
6 (%)
9 (%)
10 (%)
11 (%)
12 (%)
13 (%)
14 (%)
methanol
acetone
yield (%)
1
2
3
99.91
99.90
99.92
0.01
ND
0.01
0.01
0.01
0.01
ND
ND
ND
0.02
0.02
0.01
ND
ND
ND
0.01
0.02
0.01
0.02
0.02
0.01
522
281
519
1164
918
46.8
47.0
47.1
1570
a
b
ND: Not detected. Overall.
2.23 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 168.5, 135.0,
133.7, 128.3, 127.2, 62.4, 55.0, 46.3, 18.6; IR (KBr, cm−1):
3337, 3298, 2949, 1677, 1595, 1500, 1479; MS (m/z): 248.1
(M+ + H); Mp: 114−116 °C; Anal. Calcd for C14H21N3O
(247.34): C 67.98, H 8.56, N 16.99. Found: C 67.88, H 8.62,
N 16.87.
1,4-Bis[(2,6-dimethylphenyl)aminocarbonylmethyl]-
piperazine (11). To a solution of 4 (10 g, 0.0506 mol) in
methanol (30 mL) was charged piperazine (5, 4.4 g, 0.0511),
and the reaction mixture was heated to reflux and stirred for
3 h. The reaction mixture was cooled to 25−35 °C and stirred
for 60 min. The precipitated solid was filtered and washed with
methanol (10 mL). Wet solid was dried at 55 °C under reduced
pressure (400 mmHg) to afford 10 g (48%) of the title com-
pound 11 with 99.0% purity by HPLC.14 1H NMR (400 MHz,
CDCl3): δ 8.56 (s, 2H), 7.14−7.07 (m, 6H), 3.25 (s, 4H), 2.82
(s, 8H), 2.24 (s, 12 H); 13C NMR (100 MHz, CDCl3): δ 168.1,
134.9, 133.5, 128.4, 127.3, 61.7, 54.0, 18.7; IR (KBr, cm−1):
3303, 3007, 2962, 2943, 1682, 1500, 1465, 1438; MS (m/z):
409 (M+ + H); Mp: 98−102 °C; Anal. Calcd for C24H32N4O2
(408.54): C 70.56, H 7.90, N 13.71. Found: C 70.66, H 7.76,
N 13.84.
1-[3-(2-Methoxyphenoxy)-2-hydroxypropyl]piperazine
(12). To a solution of piperazine (19.2 g, 0.2229 mol) in
methanol (50 mL) was slowly added epoxy derivative 9 (10 g,
0.0555) at 0−5 °C. The resulting reaction mixture was stirred
for 3 h at 0−5 °C and then poured into water (40 mL), and the
product was extracted with dichloromethane (5 × 10 mL).
Acetic acid (6.5 mL) and water (40 mL) were charged into the
dichloromethane layer and stirred for 10 min. Aqueous
ammonia (10 mL) was charged into the aqueous layer, and
product was extracted with dichloromethane (5 × 10 mL). The
dichloromethane was distilled off completely under reduced
pressure (400 mmHg) below 50 °C to obtain 8.8 g (59%) of
the title compound 12 with 98.4% purity by HPLC.14 1H NMR
(400 MHz, CDCl3): δ 6.96−6.85 (m, 4H), 4.14−4.10 (m, 1H),
4.02−3.94 (m, 2H), 3.83 (s, 3H), 3.09−3.03 (m, 2H), 2.93−
2.51 (m, 8H); 13C NMR (100 MHz, CDCl3): δ 149.7, 148.4,
121.7, 120.9, 114.4, 111.9, 72.4, 65.7, 60.6, 55.8, 54.7, 46.0; IR
(KBr, cm−1): 3408, 3009, 2942, 1593, 1505, 1470, 1253, 1223;
MS (m/z): 267 (M+ + H); Anal. Calcd for C14H22N2O3
(266.34): C 63.13, H 8.33, N 10.52. Found: C 63.25, H 8.21,
N 10.76.
1-{4-[2-Hydroxy-3-(2-methoxyphenoxy)propyl]-
piperazin-1-yl}-3-(2-methoxyphenoxy)propan-2-ol (13).
To a solution of epoxy derivative 9 (10 g, 0.0555 mol) in
methanol (30 mL) was charged piperazine (4.8 g, 0.0557 mol),
and the reaction mixture was heated to reflux for 3 h.
The reaction mixture was cooled to 25−35 °C and stirred for
60 min. The precipitated solid was filtered and washed with
methanol (5 mL). The wet solid was charged into methanol
(25 mL), heated to reflux, and stirred for 30 min. The resultant
reaction mixture was cooled to 25−35 °C and stirred for
60 min. The solid precipitate was filtered, washed with
methanol (5 mL), and dried at 65 °C under reduced pressure
(400 mmHg) to afford 13.6 g (55%) of the title compound 13
with 98.5% purity by HPLC.14 1H NMR (400 MHz, CDCl3): δ
6.97−6.87 (m, 8H), 4.15−4.10 (m, 2H), 4.0 (d, J = 4.8 Hz,
4H), 3.85 (s, 6H), 2.69−2.52 (m, 8H), 2.57 (d, J = 5.2 Hz,
4H); 13C NMR (100 MHz, CDCl3): δ 149.9, 148.3, 121.9,
(
)-N-(2,6-Dimethylphenyl)-4-[2-hydroxy-3-(2-
methoxyphenoxy)propyl]-1-piperazine Acetamide (Ra-
nolazine). Acetone (25 L), epoxy derivative 9 (4.75 kg,
26.3596 mol), and piperazine derivative 6 (5 kg, 20.2151 mol)
were charged into a reactor and then heated to 54−58 °C for
16−18 h. The reaction mixture was cooled to 0−5 °C and
stirred for 3−4 h. The precipitated solid was filtered and
washed with chilled acetone (5 L). The resultant wet solid was
charged into a mixture of acetone (28 L) and methanol (7 L),
and heated to 52−56 °C for 45 min. The reaction mixture was
cooled slowly to 0−5 °C and stirred for 4 h. The precipitated
solid was filtered, washed with chilled acetone (5 L), and dried
at 70−75 °C under reduced pressure (400 mmHg) to afford
5.9 kg (68%) of the title compound 1 with 99.92% purity by
HPLC.14 Residual solvents: methanol, 519 ppm; acetone, 1570;
1H NMR (500 MHz, DMSO-d6): δ 9.13 (s, 1H), 7.06 (s, 3H),
6.98−6.85 (m, 4H), 4.77 (s, 1H), 3.95 (d, J = 7.2 Hz, 2H),
3.93−3.83 (m, 1H), 3.75 (s, 3H), 3.10 (s, 2H), 2.51−2.37 (m,
10H), 2.08 (s, 6H); 13C NMR (125 MHz, DMSO-d6): δ 167.9,
149.2, 148.3, 135.0, 134.9, 127.6, 126.3, 120.9, 120.7, 113.6,
112.3, 71.9, 66.6, 61.4, 61.1, 55.5, 53.3, 53.1, 18.2; IR (KBr,
cm−1): 3330, 3002, 2955, 2936, 1686, 1592, 1506, 1495, 1253,
1224; MS (m/z): 428 (M+ + H); Mp: 120−121.5 °C; Anal.
Calcd for C24H33N3O4 (427.54): C 67.42, H 7.78, N 9.83.
Found: C 67.62, H 7.47, N 9.68.
2,2-Dichloro-N-(2,6-dimethylphenyl)acetamide (10).
Dichloroacetyl chloride (14.6 g, 0.0990 mol) was slowly ad-
ded to a suspension of 2,6-dimethylaniline (10 g, 0.0825 mol)
and sodium carbonate (8.8 g, 0.0830 mol) in dichloromethane
(50 mL) at 10−15 °C. The resulted reaction mixture was
stirred for 1.5 h at 10−15 °C. Water (100 mL) was charged
into the reaction mixture at 25−35 °C, and the dichloro-
methane was distilled off completely below 45 °C under
reduced pressure. Then the reaction mixture was cooled to 25−
35 °C for 60 min, and the solid was removed by filtration and
washed with water (20 mL). The wet solid was charged into n-
hexane (50 mL) and stirred for 30 min at 25−35 °C. The solid
was filtered, washed with n-hexane (10 mL), and dried under
reduced pressure at 70 °C under reduced pressure (400 mmHg)
to provide 15 g (78%) of the title compound 10 with 99.7%
purity by HPLC.14 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H),
7.18−7.09 (m, 3H), 6.07 (s, 1H), 2.26 (s, 6H); 13C NMR
(100 MHz, CDCl3): δ 162.6, 135.6, 131.7, 128.5, 128.2, 66.8,
18.0; IR (KBr, cm−1): 3245, 3039, 2925, 1676, 1593, 1541, 1470;
MS (m/z): 232 (M− − H); Mp: 169−171 °C; Anal. Calcd for
C10H11Cl2NO (232.11): C 51.75, H 4.78, N 6.03. Found: C
51.92, H 4.90, N 6.15.
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dx.doi.org/10.1021/op300026r | Org. Process Res. Dev. 2012, 16, 748−754