simultaneously hydrolyzed to pyrimidinone 18.
a mixture of 675 mL of toluene and 525 mL of H2O over
15-30 min. External cooling was used to maintain the
quench mixture temperature at less than 80 °C. Aqueous
sodium hydroxide (400 mL of 30%) was added at 70-80
°C, and then the layers were separated. The toluene layer
was washed with 500 mL of water containing 1 mL of 30%
aqueous NaOH. [NOTE: After the caustic addition, the
temperature must be kept above 70 o C to avoid precipitation
of dichloropyrimidine 8.] The combined aqueous layers were
extracted with 500 mL of toluene. The combined organic
phases were dried by distillation of the toluene azeotrope.
The resulting solution was used directly in the next step.
N-[6-Chloro-5-(2-methoxyphenoxy)[2,2′-bipyrimidin]-
4-yl]-4-(1,1-dimethylethyl)benzenesulfonamide, potassium
salt (11). 4-tert-Butylbenzenesulfonamide (10) (102.4 g,
0.480 mol), 79.6 g (0. 576 mol) anhydrous powdered (extra
fine) potassium carbonate, 4.6 g (14 mmol, 2.9 mol %) of
tetrabutylammonium bromide, and 1950 mL of toluene were
added to the toluene solution of dichloropyrimidine (8) at
50 °C. The resulting suspension was refluxed with continuous
removal of water using a Dean-Stark trap for 5-7 h. The
suspension was cooled and then used directly in the next
step.
The final recrystallization provides specification grade
material suitable for formulation. We can eliminate a drying
operation by using the bosentan crude wet cake for the final
crystallization. Alternatively, we can eliminate both an
isolation and a drying operation by decantation of the
bosentan crude suspension.
A second-generation process incorporating all these
modifications has many significant advantages over the first-
generation process. Isolations are reduced from six to three,
and drying operations, from five to two. Process solvents
are reduced from six to two. The potent sensitizer 8 is not
isolated. Toluene is used in place of methylene chloride. The
mild sensitizer 11 is not isolated. Two aqueous waste streams
are eliminated by replacing DMF and ethylene glycol by
toluene. Two methanol-isopropyl acetate recrystallizations
of bosentan (1) are replaced by a decantation of the
suspension of bosentan formate monoethanolate (16) in
ethanol-toluene. Finally, the overall yield from dione 7 to
bosentan (1) is increased from 67 to 84%, and the bosentan
(1) purity increased from 99.3 to 99.7%.
Experimental Section
The preparation of pyrimidinedione 7 is described in ref
3. 4-tert-Butylbenzenesulfonamide 10 was purchased from
Saurefabrik Schweizerhall and used as received. Phosphorus
oxychloride, potassium carbonate, tetrabutylammonium
bromide, sodium hydroxide beads, and formic acid were
purchased from Aldrich Chemical Co. and used as received.
Toluene was purchased from Burdick and Jackson and used
as received. Ethylene glycol mono tert-butyl ether (ETB)
was purchased from TCI America and used as received.
Ethanol was purchased from Spectrum Chemical and used
as received. Elemental analyses were performed by Galbraith
Laboratories, Knoxville, TN.
N-[6-[2-(1,1-Dimethylethoxy)ethoxy]-5-(2-methoxyphe-
noxy)[2,2′-bipyrimidin]-4-yl]-4-(1,1-dimethylethyl)benze-
nesulfonamide (Bosentan tert-Butyl Ether) (14). Ethylene
glycol mono-tert-butyl ether (ETB) (189 mL, 170 g, 1.44
mol) and 38.4 g (0.960 mol) of granular sodium hydroxide
were added to the sulfonamide salt (11) suspension in
toluene. The suspension was then heated at 55 °C for 3-7
h. The mixture changed from a suspension to a near solution
to a suspension during this time. The resulting suspension
was cooled and 80 mL of 12 N HCl in 720 mL of water
was added. More acid (10-15 mL) was added to adjust the
pH to 3-4 and produce two clear layers. The layers were
separated. The organic layer was washed twice with 500 mL
of water. The toluene-water azeotrope and toluene were
distilled at atmospheric pressure (3200 mL collected). The
flask was cooled, and distillation was continued under
reduced pressure until approximately 50 mL of toluene
remained. The pot solution was cooled and diluted with 1500
mL of denatured ethanol. Toluene was removed as the
ethanol azeotrope (500-750 mL collected) and the suspen-
sion were allowed to cool to 25 °C overnight. After cooling
to 2-5 °C, the suspension was stirred for 2 h. The precipitate
was suction-filtered, washed with 500 mL cold denatured
ethanol, and then dried in a vacuum oven at 40-50 °C to
afford 268 g (91.8%) of near colorless powder.
Ethylene glycol mono sec-butyl ether (ESB) was prepared
by a literature method.10 A reference sample of bosentan sec-
butyl ether 15 was then prepared using ESB and a procedure
similar to the one described for bosentan tert-butyl ether 14.
Heating bosentan formate monoethanolate 16, toluene, and
formic acid in a sealed tube at 150 °C for 5 h produced a
mixture enriched in pyrimidinone 17. Concentration in vacuo
and preparative LC of the residue afforded 17 as an oil
1
suitable for characterization by H and 13C NMR, IR, and
mass spectrometry.
Hydrolysis of 17 using a procedure similar to the one
described for preparing bosentan 1 afforded 18 as an oil
1
suitable for characterization by H and 13C NMR, IR, and
mass spectrometry.
Recrystallization from toluene and then ethyl ether
provided material for elemental analysis: mp 156-156.5 °C;
4,6-Dichloro-5-(2-methoxyphenoxy)-2,2′-bipyridine (8).
A mixture of 150.0 g (0. 480 mol) of pyrimidinedione 7 and
176 mL (290 g, 1.89 mol) of phosphorus oxychloride was
heated to 90 °C. After the vigorous gas evolution subsided,
the pot temperature was increased to 105 °C and maintained
for 5 h. The mixture was cooled to 80-90 °C, diluted with
225 mL of toluene and then added via 12-gauge cannula to
1
300 MHz H NMR (CDCl3) δ 1.13 (s, 9H), 1.28 (s, 9H),
3.62 (t, 2H, J ) 4.9 Hz), 3.99 (s, 3H), 4.62 (t, 2H, J ) 4.9
Hz), 6.83-6.88 (m, 1H), 6.96-6.99 (d, 1H, J ) 8.1 Hz),
7.08-7.13 (m, 1H), 7.29 (d, 1H, J ) 8.1 Hz), 7.38-7.42
(m, 3H), 8.38 (d, 2H, J ) 8.6 Hz), 8.98 (d, 2H), 9.1 (br,
1H); IR (KBr pellet) 3300-3200, 2975, 2890, 2840, 1575,
1500 cm-1. Anal. Calcd for C31H37N5O6S: C, 61.27; H, 6.14;
N, 11.52. Found: C, 61.53; H, 6.37; N, 11.42.
(10) Zakharkin, L. I.; Khorlina, I. M. IzV. Akad. Nauk SSR, Otd. Khim. Nauk
1959, 2255.
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