Improved and single-pot process for the synthesis of macitentan, an endothelin receptor…
obtained solid was filtered and washed with 1 dm3
methanol to provide crude 1. Then, the wet solid was
dissolved in 25 dm3 methanol at 60–65 °C, maintained for
30 min, and the reaction mass cooled slowly to 0–5 °C and
maintained for 60 min. The obtained solid was filtered,
washed with 1 dm3 methanol, suck dried, and dried at
50–55 °C for 2–4 h to offer pure 1. Yield: 1.20 kg (88.0%,
calculated starting from 6); purity by HPLC 99.90%. The
spectral data of compound 1 were found to agree with the
reported data [8].
(0.157 mol) was added at 25–30 °C. The reaction mass was
heated to 40–45 °C and a solution of 12.20 g 5-bromo-2-
chloropyrimidine (7, 0.063 mol) in a mixture of 25 cm3
THF and 25 cm3 DMF was added. The reaction mass was
maintained at 40–45 °C until completion of the reaction
(around 1–2 h, monitored by HPLC). After ensuring the
completion of the reaction, the reaction mass was cooled to
25–30 °C and quenched with 250 cm3 5% citric acid
solution. The resulting reaction mass was extracted with
ethyl acetate (250 cm3 9 2) and the ethyl acetate layer was
washed with 5% brine solution (250 cm3 9 2) and con-
centrated under reduced pressure to obtain the residue. The
residue was dissolved in 250 cm3 diisopropyl ether and the
resulting solution was heated at 55–60 °C for 30 min. The
reaction mass was cooled to 10–15 °C and maintained for
60 min. The solid obtained was filtered and washed with
25 cm3 diisopropyl ether. The wet solid crystallized in a
mixture of ethyl acetate and diisopropyl ether to give the
title compound 16. Yield: 25.0 g (86%); purity by HPLC
N-[5-(4-Bromophenyl)-6-[2-(2-hydroxy-
ethoxy)ethoxy]pyrimidin-4-yl]-N0-propylsulfamide
(15, C17H23BrN4O5S)
To a stirred solution of 50.0 g 5-(4-bromophenyl)-4,6-
dichloropyrimidine (2, 0.164 mol) in 500 cm3 DMSO,
7.6 g lithium amide (0.32 mol) and 25.0 g N-propylsul-
famide (3, 0.18 mol) were added at 20–25 °C. The reaction
mass was stirred at 20–25 °C for 2–6 h (completion of the
reaction was monitored by HPLC). To this reaction mass,
446.5 g diethylene glycol (13, 4.20 mol) and 7.6 g lithium
amide (0.32 mol) were added and the reaction mass heated
to 100–105 °C. The reaction mass was maintained at the
same temperature until completion of the reaction (around
18–20 h, monitored by HPLC). After ensuring the com-
pletion of the reaction, the reaction mass was cooled to 25–
30 °C and quenched with 500 cm3 5% citric acid solution.
The resulting reaction mass was extracted with ethyl
acetate (500 cm3 9 2). The ethyl acetate layer was washed
with 5% brine solution (500 cm3 9 2) and concentrated
under reduced pressure to obtain the residue. The residue
was dissolved in 250 cm3 diisopropyl ether and the
resulting solution was heated at 55–60 °C for 30 min.
The reaction mass was slowly cooled to 0–5 °C and
maintained for 60 min. The solid obtained was filtered,
washed with 12 cm3 diisopropyl ether, and dried at 40–
45 °C for 2 h to offer compound 15. Yield: 48.5 g (62.0%);
purity by HPLC: 90.0%; m.p.: 83–85 °C; 1H NMR
(300 MHz, DMSO-d6): d = 9.83 (s, 1H), 8.49 (s, 1H),
7.64–7.61 (d, J = 8.1 Hz, 2H), 7.27–7.24 (d, J = 8.1 Hz,
2H), 4.58 (bs, 1H), 4.42–4.39 (t, J = 9.6 Hz, 2H), 3.36–
3.60 (t, J = 8.1 Hz, 2H), 3.42–3.35 (m, 4H), 2.78 (t, 2H),
1.48–1.36 (m, 2H), 0.82–0.77 (t, 3H) ppm; 13C NMR
(DMSO-d6): d = 165.96 (C), 156.28, 155.87 (C), 132.73,
131.43, 129.72, 121.32, 104.88, 72.41, 68.30, 66.03, 60.26,
1
98.91%; m.p.: 113–115 °C; H NMR (400 MHz, CDCl3):
d = 8.53 (s, 2H), 8.46 (s, 1H), 7.63–7.60 (d, J = 8.4 Hz,
2H), 7.24–7.21 (d, J = 8.1 Hz, 2H), 6.96 (s, NH), 5.67–
5.63 (t, J = 12.3 Hz, NH), 4.52–4.39 (m, 4H), 3.78–3.74
(m, 4H), 2.99–2.92 (q, J = 6.6 Hz, 2H), 1.64–1.52 (h,
J = 7.2 Hz, 2H), 0.96–0.91 (t, J = 7.5 Hz, 3H) ppm; 13C
NMR (CDCl3): d = 166.46 (C), 163.69 (C), 159.69,
156.51, 155.63, 132.81, 131.76, 128.26, 123.40, 112.12,
104.63, 96.19, 96.16, 67.48, 66.47, 45.79, 22.41,
ꢀ
11.32 ppm; IR (KBr): m = 3292, 3060, 2972, 2873, 1569,
1556, 1431, 1312, 1172, 1087, 934 cm-1; MS (70 eV): m/
z = 634.0 [M?].
2,20-[Ethane-1,2-diylbis(oxy)]bis(5-bromopyrimidine)
(17, C10H8Br2N4O2)
To a stirred solution of 50.0 g 5-bromo-2-chloropyrimidine
(7, 0.258 mol) in 359.7 g ethylene glycol (5, 5.79 mol),
18.0 g lithium amide (0.781 mol) was added at 5–10 °C.
The temperature of the reaction mass was raised to 25–
30 °C and maintained for 3–6 h (completion of the reaction
was monitored by HPLC). The reaction mass was
quenched with 500 cm3 10% citric acid solution and the
resulting reaction mass was extracted with ethyl acetate
(500 cm3 9 2); the ethyl acetate layer was washed with
250 cm3 10% brine solution and concentrated under
reduced pressure to obtain the residue. The residue was
dissolved in 200 cm3 THF and 200 cm3 DMF, and 55.0 g
lithium tert butoxide (0.69 mol) and 53.0 g 5-bromo-2-
chloropyrimidine (7, 0.274 mol) were added. The reaction
mass was heated to 45–50 °C and maintained as such for
1 h (completion of the reaction was monitored by HPLC).
After completion of the reaction, the reaction mass was
cooled to 25–30 °C and quenched with 500 cm3 10% citric
acid solution. The resulting reaction mass was extracted
ꢀ
44.63, 21.99 (CH2), 11.26 (CH3) ppm; IR (KBr): m = 3310,
1570, 1430, 1340, 1170, 1080, 836 cm-1; MS (70 eV): m/
z = 477.0 [M?].
N-[5-(4-Bromophenyl)-6-[2-[2-(5-bromo-2-pyrimidiny-
loxy)ethoxy]ethoxy]pyrimidin-4-yl]-N0-propylsulfamide
(16, C21H24Br2N6O5S)
To a stirred solution of 25.0 g 15 (0.052 mol) in 100 cm3
THF and 100 cm3 DMF, 12.63 g lithium tert butoxide
123