Organic Process Research & Development
Communication
Table 7. Optimization of epichlorohydrin addition time for the synthesis of 4
purity by HPLC (%)
entry
addition time of 3 equiv epichlorohydrin
conversion of 2 (%)
4
11
12
13
NaOH (equiv)
temperature (°C)
1
2
3
15−20 min
45−60 min
2−3 h
95.7
96.5
94.9
93.6
98.2
97.7
3.7
0.2
0.4
1.5
0.3
0.3
0.3
0.3
0.1
1.5
1.5
1.5
25−30
25−30
25−30
removing the aqueous layer before proceeding to the second
reaction.
0.5% and (5) unreacted epichlorohydrin 3 that was recovered
and reused.
After completion of the cyclization reaction, the upper layer
containing compound 4 was separated and washed with 10% aq
sodium hydroxide solution to further improve the quality of 4.
Optimization of Reaction Maintenance Temperature
during the Synthesis of 4. Temperature always plays
significant role in the reaction progress; therefore, as a part of
our optimization strategy the synthesis of 4 was performed at
different temperatures. Experimental results revealed that
compound 4 was obtained with best yield and purity at 25−
EXPERIMENTAL SECTION
Solvents and reagents were obtained from commercial sources
and used without further purification. The H and C spectra
■
1
13
were measured in DMSO-d using 200 or 400 MHz on a Varian
6
Gemini and Varian Mercury plus 2000 FT NMR spectrometer;
the chemical shifts were reported in δ (ppm). IR spectra were
recorded in the solid state as a KBr dispersion using a Perkin-
Elmer 1650 FT IR spectrometer. The mass spectrum (70 eV)
was recorded on an HP 5989 A LC/MS spectrometer. The
melting points were determined by using the capillary method
on Polmon (model MP-96) melting point apparatus. The
solvents and reagents were used without further purification.
Preparation of 1-(2-Methoxyphenoxy)-2,3-epoxypro-
pane 4. To a stirring solution of 2-methoxy phenol 2 (10 kg,
3
0 °C, compared with lower and higher temperatures such as
0−15 °C and 50−55 °C, respectively, as shown in Table 6.
Synthesis of 4 involves addition of epichlorohydrin to the
1
reaction mixture containing 2-methoxy phenol 2 and sodium
hydroxide in water. Addition and stirring impact of
epichlorohydrin 3 in the synthesis of 4 were studied. No
major changes were observed by adding epichlorohydrin to the
reaction mixture for longer time (45−60 min or 2−3 h) and
less purity was obtained by adding epichlorohydrin 3 in 15−20
min as shown in Table 7. Quality of epichlorohydrin was
8
0.55 mol) and water (40 L) at about 30 °C was added sodium
hydroxide (1.61 kg, 40.25 mol) and water (10 L). After stirring
for 30−45 min, epichlorohydrin 3 (22.35 kg, 241.62 mol) was
added and stirred for 10−12 h at 25−35 °C. Layers were
separated, and water (40 L) was added to the organic layer
11
assessed by using GC. The purities were measured against
peak area ratios.
(
(
bottom layer) containing product. Sodium hydroxide solution
Excess epichlorohydrin (as per reaction mechanism 1 equiv is
sufficient, but 3 equiv were used in the process) used in the
process was recovered (93−95%) from the reaction mass by
distillation at below 90 °C under reduced pressure (650−700
mmHg). Since epichlorohydrin along with the product was
separated from the aqueous layer, it was thus observed that the
trace amount of 3 (instead of a significant amount) was found
3.22 kg, 80.5 mol) and water (10 L) were added at 27 °C and
stirred for 5−6 h at 27 °C. The bottom product layer was
separated and washed with sodium hydroxide solution (3.0 kg
7
5 mol) and water (30 L). Excess epichlorohydrin (3) was
recovered by distillation of the product layer at below 90 °C
under vacuum (650−700 mmHg) to give 13.65 kg (94%) of
title compound with 98.3% purity by HPLC, 0.2% of 2-
methoxy phenol 2, 0.1% of epichlorohydrin 3, 0.1% of
11
to be present in aqueous waste (LoD: 0.5%). The quality of
the recovered epichlorohydrin was found to be unchanged and
chlorohydrin 11, 0.3% of dimer 12 and 0.3% of dihydroxy
1
1
1
was reused for the synthesis of 4. Experiments were
conducted by including all of the optimized parameters, and
consistent yield and quality were obtained as shown in Table 8.
1
=
3
(
3. H NMR (400 MHz, CDCl , δ) 6.8−7.0 (m, 4H), 4.3 (dd, J
3
5.6 Hz, 5.4 Hz, 1H), 3.8 (dd, J = 5.6 Hz, 5.3 Hz, 1H), 3.7 (s,
H), 3.2−3.4 (m, 1H), 2.8 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 2.7
−
1
dd, J = 5.6 Hz, 5.3 Hz, 1H); IR (KBr, cm ) 2935 (C−H,
Table 8. Experimental results by incorporating all optimal
conditions for the synthesis of 4
aliphatic), 1594 and 1509 (CC, aromatic), 1258 and 1231
(C−O−C, aralkyl ether), 1125 and 1025 (C−O−C, epoxide);
+
MS (m/z) 181 (M + H).
purity by HPLC (%)
Preparation of 1-Chloro-3-(2-methoxyphenoxy)-
propan-2-ol (11). Mixture of epoxypropane 4 (100 g, 0.555
mol) and conc HCl (400 mL, 3.835 mol) was stirred at 25−35
quantity
entry of 2 (g)
conversion
of 2 (%)
4
2
3
11
12
13
1
2
3
100
100
100
95
94
94
97.2
98.3
98.2
0.2
0.2
0.2
0.2
0.3
0.1
0.1
0.1
0.1
0.4
0.3
0.3
0.3
0.4
0.3
°
C for 8−10 h. Toluene (200 mL) and water (200 mL) were
added to the reaction mixture and stirred for 10−15 min.
Layers were separated, and aqueous layer was extracted with
toluene (100 mL). Total organic layer was distilled completely
at below 70 °C under vacuum (650−700 mmHg). The
obtained crude was distilled further under vacuum (650−700
mmHg) at vapor temperature 145−150 °C (bath temperature
CONCLUSION
■
We have developed a high-yielding and efficient synthesis of the
key starting material 4 of ranolazine, 1, that has the following
advantages over the reported processes; (1) avoids the usage of
expensive organic solvent, e.g., dioxane and ethers by
incorporating water, (2) avoids energy-intensive high-vacuum
distillation, (3) includes a simple workup procedure, (4) is
amenable to the control of all the possible impurities at below
215−235 °C) to afford the 98.4 g (89%) of titled compound.
1
H NMR (400 MHz, CDCl , δ) 6.8−7.2 (m, 4H), 5.5 (s, 1H),
3
4.1−4.2 (m, 1H), 4.05 (dd, J = 4.8, 4.8 Hz, 2H), 3.76 (s, 3H),
−1
3.7 (dd, J = 4.8, 4.8 Hz, 2H); IR (KBr, cm ) 3459 (O−H),
2938 (C−H, aliphatic), 1594 and 1508 (CC, aromatic), 1250
+
and 1225 (C−O−C, epoxide); MS (m/z) 217.2 (M + H).
D
dx.doi.org/10.1021/op300056k | Org. Process Res. Dev. XXXX, XXX, XXX−XXX