Organic Process Research & Development
Article
analyses were determined using Heraeus CHN-O-Rapid
analyzer. High performance liquid chromatography (HPLC)
analysis was carried out on Agilent Technologies 1200 series.
The gas chromatography analysis was carried out on Agilent
Technologies 7683B for analyzing the residual solvents.
p-tert-Butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2′-
bipyrimidin]-4-yl]benzenesulfonamide (7). A mixture of
4-tert-butylbenzenesulfonamide (6) (0.85 kg, 4.0 mol), toluene
(2.8 L), and potassium carbonate (1.1 kg, 8.0 mol) was heated
to 50 °C for 30 min. To the reaction mixture was added 5 (1.4
kg, 4.0 mol) followed by heating to 110 °C for 10 h. The
reaction mixture was cooled to 25 °C, water (28 L) was added,
and the pH was adjusted to below 3 by using 5 N hydrochloric
acid and stirred for 30 min. The precipitated solid was filtered,
washed with water (4.8 L), and dried in the oven at 60 °C for 6
h to afford 7 (2.05 kg, 97%). Mp: 214−216 °C. 1H NMR (300
MHz, CDCl3): δ 1.21 (9H, s), 3.72 (3H, s), 6.54−6.55 (1H,
d), 6.72−6.76 (1H, t), 6.86−6.98 (2H, m), 7.23−7.25 (2H, d),
7.43−7.49 (3H, m), 8.97−8.98 (2H, d); MS: m/z 526.3 (M +
H); IR (KBr) (υmax, cm−1): 3466.7 (−NH stretching), 1592.9
(CO stretching).
34.11, 54.93, 62.96, 69.74, 111.5, 117.95, 120.21, 123.56,
123.57, 124.4, 128.35, 135.23, 144.5, 148.52, 150.8, 151.05,
153.81, 156.16, 156.75, 160.19; MS: m/z 1102.3 (M + H);
Elem. Anal: Found: C 58.77, H 5.20, N 12.87; Calcd for
C54H56N10O12S2: C 58.90, H 5.13, N 12.72.
4-tert-Butyl-N-(5-(2-methoxyphenoxy)-6-(2-oxo-
ethoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide (17).
To a solution of N,N′-(6,6′-(2,3-dihydroxybutane-1,4-diyl)bis-
(oxy)bis(5-(2-methoxy phenoxy)-2,2′-bipyrimidine-6,4-diyl))-
bis(4-tert-butylbenzenesulfonamide) was slowly added 16
(100 g, 0.09 mol) in acetone (500 mL) and sodium periodate
(44 g, 0.2 mol) in water (200 mL) for 30 min. The reaction
mixture was stirred for 2−3 h at 25−35 °C. The remaining
solid was removed by filtration, and the solvent was evaporated
under reduced pressure. The residue was extracted with
methylene chloride (600 mL) and washed with water (250
mL), and the solvent was evaporated under reduced pressure.
Cyclohexane (250 mL) was added to the obtained residue and
stirred for 30−45 min at 25−30 °C. The precipitated solid was
filtered and washed with cyclohexane (50 mL) and dried in the
oven at 60 °C for 6 h to afford 17 (85 g, 87%). Mp: 208−210
°C. 1H NMR (300 MHz, CDCl3): δ 1.26 (9H, s), 3.98 (3H, s),
5.15 (2H, s), 6.85−7.6 (7H, m), 8.42−8.45 (2H, d), 9.0 (2H,
N,N′-(6,6′-(2,2-Dimethyl-1,3-dioxolane-4,5-diyl)bis-
(methylene)bis(oxy)bis(5-(2-methoxy phenoxy)-2,2′-bi-
pyrimidine-6,4-diyl))bis(4-tert-butylbenzenesulfona-
mide) (15). To a solution of (2,2-dimethyl-1,3-dioxolane-4,5-
diyl)dimethanol (14) (60.8 g, 0.37 mol) in acetonitrile (2.5 L)
was added sodium hydroxide (95.05 g, 2.38 mol) and heated to
80−85 °C for 4 h. To this p-tert-butyl-N-[6-chloro-5-(2-
methoxyphenoxy)[2,2′bipyrimidin]-4-yl]benzene sulphona-
mide (7) (250 g, 0.48 mol) was added followed by heating
to 80−85 °C for 14 h. Then water (2.0 L) was added, and the
pH was adjusted to 5.0−6.0 by using 5 N hydrochloric acid and
stirred for 30 min. The resulting precipitate was collected,
washed with water (1.25 L), and dried in the oven at 60 °C for
6 h to afford 15 (490 g, 90%). Mp: 72−74 °C. 1H NMR (400
MHz, CDCl3): δ 1.25 (6H, s), 1.29 (18H, s), 3.84−3.90 (4H,
m), 4.27−4.31 (2H, m), 6.84−6.87 (3H, t), 6.97−7.00 (2H,
dd), 7.09−7.13 (3H, t), 7.43−7.45 (10H, m), 9.0−9.01 (4H,
d), 8.43 (2H, br s); 13C NMR (100 MHz, CDCl3): δ 25.88,
30.02, 34.10, 55.01, 61.53, 77.36, 108.43, 111.4, 118.73, 120.4,
124.09, 124.34, 126.67, 127.38, 128.35, 135.30, 138.25, 144.74,
148.62, 150.99, 156.07, 156.71, 160.56; MS: m/z 1142.2 (M +
H); Elem. Anal: Found: C 59.87, H 5.20, N 12.38; Calcd for
C57H60N10O12S2: C 59.99, H 5.30, N 12.27.
d), 9.72 (1H, s); MS: m/z 550.5 (M + H); IR (KBr) (υmax
,
cm−1): 1720 (CO stretching).
4-tert-Butyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxy-
phenoxy)-2,2′-bipyrimidin-4-yl)benzenesulfonamide,
Bosentan Monohydrate (1). A solution of 17 (100 g, 0.18
mol) in methanol (500 mL) was cooled to 0−5 °C, and sodium
borohydride (6.91 g, 0.18 mol) was slowly added in portions.
The reaction mass was stirred for 2−3 h; methanol was distilled
off and quenched with ice-cold water; pH adjusted to 2−3
using 6 N HCl, and the reaction mixture was extracted with
ethyl acetate. The ethyl acetate layer was washed with 5% brine
solution (2 × 500 mL) and concentrated under reduced
pressure to obtain the residue. The obtained residue was
dissolved in methanol (120 mL) and reprecipitated with water
(240 mL); precipitated solid was filtered and washed with water
(100 mL). The resultant solid was dissolved in ethylacetate
(100 mL), methanol (100 mL), and water (1 mL), was heated
to 65−70 °C for 1 h, cooled to 30 °C, and maintained for 4−5
h. The solid was filtered and washed with cyclohexane (25 mL),
dried under vacuum at 30−35 °C for 3−4 h to get highly pure
bosentan monohydrate 1 (77.6 g, 75%) as a white to pale-
yellow solid. Mp: 138−140 °C. 1H NMR (300 MHz, CHCl3):
δ 1.29 (9H, s), 3.86 (2H, s), 4.0 (3H, s), 4.57 (2H, m), 4.88
(1H, s), 6.85 (1H, m), 7.10 (2H, m), 7.15 (1H, m), 7.41 (3H,
m), 8.42 (2H, d), 8.8 (1H, br), 9.0 (2H, d); MS: m/z 552 (M +
H); IR (KBr) (υmax, cm−1): 3437.4 (−NH); 1342 (−SO2);
HPLC purity: 99.70%; water content: 3.2% (w/w).
N,N′-(6,6′-(2,3-Dihydroxybutane-1,4-diyl)bis(oxy)bis-
(5-(2-methoxyphenoxy)-2,2′-bipyrimidine-6,4-diyl))bis-
(4-tert-butylbenzenesulfonamide) 16. The solution of
N,N′-(6,6′-(2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis-
(methylene)bis(oxy)bis(5-(2-methoxyphenoxy)-2,2′-bipyrimi-
dine-6,4-diyl))bis(4-tert-butylbenzenesulfonamide) 15 (150 g,
0.14 mol) in acetonitrile (750 mL), 2 N HCl (750 mL) was
added slowly for 20−30 min, and stirring continued for 5 h.
Then the reaction mass was extracted twice with dichloro-
methane (2 × 750 mL). The organic solvent was evaporated,
and the residue dissolved in methanol (150 mL) was added
slowly to water (750 mL) for 45 min. The resulting precipitate
was filtered, washed with water (150 mL), and dried in the
oven at 60 °C for 6 h to provide 16 (132 g, 91%). Mp: 108−
ASSOCIATED CONTENT
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* Supporting Information
Structure elucidation for compounds 15 and 16 (1H NMR, 13
C
NMR); HPLC methods for related substances of bosentan and
GC method for residual solvents; additional information related
to physical characteristics of bosentan monohydrate, such as
DSC, TGA, and XRD data. This material is available free of
1
111 °C. H NMR (400 MHz, CDCl3): δ 1.31 (18H, s), 3.58
(2H, broad s), 3.84−3.87 (2H, m), 3.95 (6H, s), 4.11−4.16
(2H, m), 4.32−4.36 (2H, dd), 6.88−6.92 (2H, m), 6.98−7.04
(6H, t), 7.11−7.15 (2H, t), 7.44−7.47 (8H, d), 8.45 (2H, s),
8.96−9.02 (4H, m); 13C NMR (100 MHz, CDCl3): δ 30.02,
AUTHOR INFORMATION
Corresponding Author
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dx.doi.org/10.1021/op400100s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX