Organic Process Research & Development
COMMUNICATION
Table 2. Trend data of residual solvent
After ensuring the completion of reaction, the reaction mass was
cooled at 25ꢀ30 °C and quenched with water (200.0 mL). The
resulting reaction mass was extracted with dichloromethane
(200 mL ꢁ 2). The combined dichloromethane layer was
washed with water (200 mL) and concentrated under reduced
pressure to obtain crude residue. The obtained residue was dissolved
in ethanol (120 mL) and reprecipitated with di-isopropyl ether
(240 mL), and cooled to 10ꢀ15 °C; the solid was filtered, washed
with di-isopropyl ether (20.0 mL), and dried under vacuum
(650ꢀ700 mm/Hg) to afford compound 8 as a light-yellow solid.
Yield: 25.00 g, (64.71%); HPLC purity: 99.34%; IR (KBr): 3447,
trend data for residual solvents (ppm)
ICH limit
sr. no. solvent name (ppm)
batch 1a
batch 2a
batch 3a
1
2
3
4
5
6
methanol
3000
5000
410
123
1383
ND
ND
ND
3
85
257
ND
ND
ND
ND
71
304
ND
ND
ND
ND
ethanol
acetonitrile
dichloromethane
600
isopropyl acetate 5000
3214, 3039, 2962, 1663, 1565, 1345, 1248, 1170, 1081, 759 cmꢀ1
;
ethylene glycol 620
1H NMR (CDCl3): δ 1.3 (s, 9H), 4.1 (s, 3H), 6.84ꢀ6.94 (t, 1H),
6.95ꢀ7.03 (d, 1H), 7.07ꢀ7.14 (t, 1H), 7.40ꢀ7.44 (d, 3H),
7.45ꢀ7.55 (t, 1H), 8.35ꢀ8.45 (d, 2H), 8.99ꢀ9.02 (d, 2H), 9.1
(s, 1H), 11.1 (s, 1H). MS m/z (%): 508.49 [M + 1]+ (100).
a Not detected.
Preparation of Bosentan Monohydrate. The wet bosentan
(1, 2.30 kg, 4.17 mol), ethanol (5.06 L), and activated charcoal
(5% wt/wt, 115 g) were heated at 50ꢀ55 °C and filtered hot.
Water (5.06 L) was then added to the obtained filtrate under stirring
at the same temperature, and reaction mass was maintained for
20 min. The solution was cooled to 25ꢀ30 °C and maintained
for 60 min. The crystalline solid obtained was filtered, washed
with chilled ethanol, and dried under vacuum (650ꢀ700 mm/Hg)
at 35ꢀ40 °C for 2ꢀ4 h to afford bosentan monohydrate as a
white, crystalline solid. Yield 2.20 kg, (68.7%); HPLC purity:9
99.90%; IR (KBr): 3629, 3064, 2962, 2837, 1579, 1559, 1342,
’ ASSOCIATED CONTENT
S
Supporting Information. Additional information related
b
to physical characteristics of bosentan monohydrate, such as
DSC, TGA and XRD data. This material is available free of charge
’ AUTHOR INFORMATION
1252, 1171, 1083, 1052, 685 cmꢀ1 1H NMR (CDCl3):
;
Corresponding Author
*Telephone: +91 2557 250121; +91 9822 581611. Fax:+91 2557
250586. E-mail: drvtmathad@yahoo.co.in, vt.mathad@megafine.in.
δ 8.98ꢀ8.99 (d, 2H), 8.75 (s, 1H), 8.39 ꢀ8.41 (d, 2H), 7.41
(t, 1H), 7.39ꢀ7.40 (d, 2H), 6.84ꢀ7.13 (m, 4H), 4.89 (s, 1H),
4.58ꢀ4.56 (t, 2H), 3.93 (s, 3H), 3.84 (t, 2H), 1.27 (s, 9H).
13C NMR (100 MHz, CDCl3): δ 30.99, 55.97 (CH3), 62.48, 71.7
(CH2), 35.10, 62.48, 112.41, 121.32, 125.35, 129.33, 135.99,
145.47, 149.5, 151.7, 155.15, 157.2, 157.69, 161.30 (CH). MS m/z
(%): 552.10 [M + 1]+ (100). Anal. Calcd for C27H31N5O6S
(Mol wt: 569.64): C, 56.87; H, 5.44; N, 12.28; S, 5.62; Found: C,
57.23; H, 5.44; N, 12.32 ; S, 5.68 % ; water content: 3.2 % wt/wt
(theory: 3.16 %); melting point: 114ꢀ118 °C.
Notes
#Megafine Publication Number: MF/011/2011
’ ACKNOWLEDGMENT
We are grateful to the management of Megafine Pharma (P)
Ltd., for supporting this work. We also thank colleagues of
Analytical Research and Development Department, Megafine
Pharma (P) Ltd., for valuable cooperation in developing the
chromatographic methods for establishing the process and
identifying the impurities.
Preparation of 1,2-Bis[[5-(2-methoxy phenoxy)-2-(2-pyr-
imidin-2-yl-pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide]-
ethanediol (Dimer Impurity 7). Toa stirred solutionofbosentan
(1, 150.0 g 0.27 mol) in ethylene glycol (240.0 mL), were added
5 (143.19 g, 0.27 mol) and sodium metal (7.5 g, 0.32 mol) at
25ꢀ30 °C. The reaction mass was stirred at 115ꢀ120 °C for
60ꢀ90 h (monitored by TLC). The reaction mass was cooled to
25ꢀ30 °C and quenched in water (750.0 mL). The resulting
reaction mass was extracted with dichloromethane (750.0 mL ꢁ 2),
and the DCM layer was washed with water (750.0 mL) and
distilled off completely to obtain the residue. The crude residue
was then purified by column chromatography (silica gel: 60ꢀ120
mesh) using ethyl acetateꢀchloroform (9:1) as eluent to yield
compound 7 as a light-yellow solid. Yield: 15.00 g; HPLC purity:
99.15%; IR (KBr): 3063, 2963, 2869, 2837, 1574, 1558, 1335,
1257, 1163, 749 cmꢀ1; 1H NMR (CDCl3): δ 1.09ꢀ1.17 (s, 18H),
3.72 (s, 6H), 3.81 (t, 2H), 4.0 (t, 2H), 6.13ꢀ6.99 (m, 8H),
7.25ꢀ7.32 (d, 4H), 7.44 (d, 4H), 8.29 (s, 2H), 8.89 (t, 2H), 8.98
(d, 4H). MS m/z (%): 1041.20 [M + 1]+ (100).
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dx.doi.org/10.1021/op200197z |Org. Process Res. Dev. 2011, 15, 1382–1387