A new efficient synthetic process for an endothelin receptor antagonist, bosentan monohydrate

Article abstract of DOI:10.1021/op400100s

A new and efficient synthetic process for the synthesis of an endothelin receptor antagonist, bosentan monohydrate, involves the coupling of p-tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl) benzenesulfonamide (7) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (14) as a key step. This new process provides desired bosentan monohydrate (1) with better quality and yields. Our new methodology consists of technical innovations/improvements which totally eliminate the probability for the formation of critical impurities such as pyrimidinone 8, dimer impurity 9, and N-alkylated impurity 13 in the final drug substance.

Full text of DOI:10.1021/op400100s

Article
pubs.acs.org/OPRD
A New Efficient Synthetic Process for an Endothelin Receptor
Antagonist, Bosentan Monohydrate†
Pradeep Rebelli,‡,§,⊥ Jayaprakash Rao Yerrabelly,*,§ Bharathi Kumari Yalamanchili,⊥
Rajashekar Kommera,‡ Venkat Reddy Ghojala,‡ and Kondal Reddy Bairy‡
‡Department of Research and Development, MSN R&D Centre, Pashamylaram, Medak, Andhra Pradesh 502307, India
§Department of Chemistry, University College of Science, Saifabad, Osmania University, Hyderabad 500004, India
⊥Department of Chemistry, Jawaharlal Nehru Technological University College of Engineering, Hyderabad 500085, India
S
* Supporting Information
ABSTRACT: A new and efficient synthetic process for the synthesis of an endothelin receptor antagonist, bosentan
monohydrate, involves the coupling of p-tert-butyl-N-(6-chloro-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl)-
benzenesulfonamide (7) with (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (14) as a key step. This new process provides
desired bosentan monohydrate (1) with better quality and yields. Our new methodology consists of technical innovations/
improvements which totally eliminate the probability for the formation of critical impurities such as pyrimidinone 8, dimer
impurity 9, and N-alkylated impurity 13 in the final drug substance.
drawbacks such as (a) the formation of many impurities and
(b) the use of reagents and solvents that are toxic or hazardous
in nature, presenting environmental liabilities. Therefore, there
is a need for a process which can provide more qualified
bosentan, especially without the formation of impurities in a
commercially challenging, less costly, more eco-friendly and
easily scalable industrial process.
As a part of our unceasing interest in the synthesis of active
pharmaceutical ingredients (API), we report herein a novel
synthetic route for the preparation of bosentan monohydrate
(1). p-tert-Butyl-N-[6-chloro-5-(2-methoxyphenoxy)[2,2′-bi-
pyrimidin]-4-yl]benzenesulfonamide (7) and (2,2-dimethyl-
1,3-dioxolane-4,5-diyl)dimethanol (14) are devised as key
starting materials, and high-quality bosentan monohydrate
was efficiently obtained in 50−55% overall yield, which
corresponds to an average step yield of 85% with simple
steps and commercially available chemicals. The whole
synthetic route is depicted in Scheme 3.
INTRODUCTION
■
Bosentan monohydrate, brand name Tracleer, is an anti-
hypertensive drug approved by the FDA in 2001. It is mainly
used in the treatment of pulmonary hypertension (PAH). PAH
is an increase in blood pressure in the pulmonary artery,
pulmonary vein, or pulmonary capillaries, leading to shortness
of breath, dizziness, fainting, and other symptoms such as
cough, angina pectoris, syncope, swelling of ankles and feet.
There are many pathways to control pulmonary hypertension,
in those three are important because they have targeted with
drugs like endothelin receptor antagonists, phosphodiesterase
type-5 inhibitors, and prostacyclin derivatives.
Bosentan monohydrate having the structural formula 1
became the first approved endothelin receptor antagonist for
dual type A (ETA) and type B (ETB) receptors. Bosentan is a
widely used endothelin receptor antagonist when compared to
all other currently available endothelin receptor antagonists
because its cost is lower than theirs.
RESULTS AND DISCUSSION
■
The synthesis of bosentan monohydrate (1) has been reported
by several authors using different methodologies. Each
methodology has its own demerits. The first reported method
by K. Burri et al.1 is represented in Scheme 1 with overall yield
of 40% from 4. In this process toxic ethylene glycol and highly
pyrophoric Na metal are used which cannot be handled in a
large-scale commercial process. The need to use excess ethylene
glycol leads to generation of aqueous ethylene glycol waste and
formation of dimer impurity 9. To get ICH-grade bosentan
monohydrate from crude bosentan, more than three
purifications are required to reduce the amount of dimer
Also there are many costly drugs such as prostaglandins
(prostacyclin, Epoprostenol, Iloprost) and some peptide drugs
to control pulmonary hypertension. In this widely established
market, ‘cost’ will play a major role for commercial success. In
this competitive version a non-peptide drug, bosentan
monohydrate, was developed as an endothelin receptor
antagonist with more efficient action.
Many methods have been reported for the synthesis of
bosentan. The earlier reported schemes are imbued with many
Received: April 17, 2013
© XXXX American Chemical Society
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a
Scheme 1
a
Reagents and conditions: a) sodium methoxide, methanol; b) POCl3; c) p-tert-butylbenzenesulfonamide (6), K2CO3, TBAB, toluene; d) sodium
metal, ethylene glycol.
a
Scheme 2
a
Reagents and conditions: a) ethylene glycol mono-tert-butyl ether, NaOH; b) formic acid; c) NaOH, ethanol, water.
impurity 9 and pyrimidinone impurity 8 which are formed
during the reaction.
along with a typical N-substituted compound 12 and
pyrimidinone impurities 8 by thermal degradation. Further
hydrolysis using sodium hydroxide solution produces the
bosentan monohydrate (1) along with N-alkylated impurity
13 and pyrimidinone 8 impurities which are difficult to wash
out and requires three to four recrystallizations to reduce them.
In all the above previously reported commercial processes for
the preparation of bosentan monohydrate (1), formation of
The second-generation process for the preparation of
bosentan, reported by Peter J. Harrington et al.,2 is represented
in Scheme 2. In this process formation of the dimer impurity is
eliminated by taking mono-tert-butyl protected ethylene glycol
instead of ethylene glycol. But during the cleavage of bosentan
tert-butyl ether using formic acid produces bosentan formate 11
B
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impurities such as pyrimidinone 8, dimer 9, and N-alkylated
impurity 13 affects the quality and yield of the bosentan. To
overcome these problems, many other methods3−8 have been
reported, which have their own disadvantages. Shreerang et al.8
reported a novel synthesis of bosentan monohydrate using
glycolaldehyde diethyl acetal instead of ethylene glycol. In this
approach bosentan monohydrate is obtained by coupling of 7
with glycolaldehyde diethyl acetal using a pyrophoric base
sodium hydride followed by treatment with hydrochloric acid
(HCl) providing aldehyde intermediate 17 and finally providing
the bosentan by reduction of 17 with only 25% overall yield.
The main drawback is that the use of sodium hydride is not
suitable for commercial synthesis of bosentan. All the remaining
processes3−7 also provide bosentan with many of the reported
impurities and lead to decreased yield of the bosentan
monohydrate, 1.
To overcome the above-mentioned disadvantages, we have
devised a novel synthetic route which utilizes (2,2-dimethyl-1,3-
dioxolane-4,5-diyl)dimethanol9−11 (14) instead of ethylene
glycol or mono-protected glycol. By using this new synthetic
route we have been able to eliminate the complete formation of
the chronic pyrimidinone 8, dimer 9, and N-alkylated 13
impurities. In the novel process only the acid impurity 18 was
observed, due to over-oxidation of diol intermediate 16. This
impurity was completely washed out during the workup and
isolation process of bosentan monohydrate and was controlled
in the final product with specification of not more than (NMT)
0.15% to comply with ICH guidelines.
studies for which base to use, sodium hydroxide (NaOH),
sodium carbonate (Na2CO3), sodium methoxide (NaOMe),
and potassium carbonate (K2CO3) were investigated. By using
NaOMe, Na2CO3, and K2CO3 complete conversion of 7 was
not observed, and isolated yields were less. NaOH was found to
be the most efficient in terms of yield and handling, and hence
was recommended. The results of these studies are provided in
Table 1. Deprotection of key precursor 15 using 2 N HCl was
attempted in methanol, ethanol, and acetonitrile. We found the
deprotection using alcoholic solvents gave only 70−75%. Thus,
we examined acetonitrile as the solvent and observed that
complete deprotection could be achieved in 4−5 h at room
temperature. Facile extracting workup using dichloromethane13
provided compound 16 in quantitative yield of 91%.
Cleavage of Diol to Aldehyde 17. Generally cleavage of
diol is well reported using sodium periodate and lead
tetraacetate (LTA). The convenient strategy was to use sodium
periodate for oxidative cleavage of diol as it is very cheap and
easy to handle when compare to LTA and, hence, is useful for a
scale-up process. Thus, we have chosen sodium periodate14 for
the cleavage of 16 to afford 17. The progress of the reaction is
dependent on the solvent used in the reaction and the
temperature of the reaction. When toluene or acetonitrile was
used, it was found that, even after 7−9 h, complete conversion
of starting material to the product was not observed, whereas
by using acetone the reaction was completed in 2−3 h, and the
aldehyde 17 was obtained in good quality and yield (Table 2).
Reduction of Aldehyde 17 and Isolation of Bosentan
Monohydrate (1). Conversion of aldehyde 17 to bosentan
monohydrate can be easily done using sodium borohydride
(NaBH4). This reaction was conducted in toluene, THF, and
alcoholic solvents such as ethanol and methanol. Rate of
reaction in toluene and THF was found to be slow, whereas in
alcoholic solvents the reaction was complete in 2−3 h, and the
crude bosentan was obtained by quenching in chilled water, and
adjusting the pH to 2−3 using 6 N HCl, followed by extraction
and isolation using methanol and water.
Purification of this crude bosentan to obtain pure bosentan
monohydrate is the challenging task. Our primary aim was to
decrease the production cost by minimizing the loss of the
product during the purification process. Therefore, we have
attempted several purifications using various solvents such as
methanol, isopropyl alcohol, ethanol, ethylacetate, isopropyl
acetate, tert-butylacetate, and combinations of these solvents.
Finally, a combination of ethylacetate and methanol in 1:1 ratio
with 1% water provided good (∼75%) yields of pure bosentan
monohydrate (1) having ICH-grade quality. The residual
solvents present in the finished bosentan were analyzed using a
GC method, and it was found that all the solvents were well
within the specified ICH limits (Table 3).
Polymorphic Stability of Bosentan Monohydrate, 1.
The polymorphism was investigated as a step in the
development of a new synthetic design for APIs. The
polymorphic stability of bosentan monohydrate was examined
under different temperatures and humidities by powder X-ray
diffraction studies and thermogravimetric analysis. The PXRD
pattern of bosentan monohydrate shows a prior art form. We
have also studied the polymorphic stability at 25 °C/60% RH
and 40 °C/75% RH for 6 months and obtained a polymorph
found to be stable under both conditions.
Novel Synthesis of Bosentan Monohydrate (1). We
designed a novel synthesis of bosentan monohydrate by using
the key starting materials p-tert-butyl-N-[6-chloro-5-(2-
methoxyphenoxy)[2,2′-bipyrimidin]-4-yl]benzenesulfonamide
(7) and (2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol12
(14), as depicted in Scheme 3.
Synthesis and Deprotection of Protected Diol 15. The
coupling of 7 and 14 in the presence of a base at elevated
temperatures affords the key precursor 15. After optimization
studies of this stage it was observed that the most suitable
method to carry out the reaction was by performing the
coupling of 7 and 14 in acetonitrile solvent in the presence of
NaOH at 80 °C. The coupling reaction involves the formation
of dialkoxide ion of 14 on reaction with a strong base, sodium
hydroxide, which is further reacting with compound 7 to
provide 15. Since a strong base is being used, protic solvents are
not favorable when compared to aprotic solvents. During
development studies we have attempted this condensation
reaction using acetonitrile, tetrahydrofuron (THF), and
toluene. When toluene or THF was used, a highly viscous
reaction mass was obtained, leading to a difficulty in stirring the
reaction mass and hampering the reaction. Hence, the starting
material is not completely converted into the product. The
stirring state of the reactants was improved when acetonitrile
was used as a solvent, and the yield also increased. Thus,
acetonitrile is preferred for this reaction. During optimization
C
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a
Scheme 3
a
Reagents and conditions: a) p-tert-butylbenzenesulfonamide 6, K2CO3, TBAB, toluene; b) NaOH, acetonitrile; c) 2 N HCl, acetonitrile; d) NaIO4,
acetone; e) NaBH4, methanol.
Table 1. Condensation of 7 with 14 using various conditions
Table 3. Trend data for residual solvents in bosentan
monohydrate
a
b
s. no.
base
solvent
T
[°C]
yield [%]
c
trend data for residual solvents
(ppm)
1
2
3
4
5
6
NaOH
NaOH
NaOH
Na2CO3
K2CO3
NaOMe
THF
65
80
75
90
65
45
55
58
acetonitrile
toluene
ICH limit
(ppm)
110
a
a
a
s. no.
solvent
batch 1 batch 2 batch 3
acetonitrile
acetonitrile
acetonitrile
80
80
80
1
2
3
4
5
6
acetonitrile
dichloromethane
methanol
410
600
ND
ND
560
ND
ND
510
15
ND
40
3000
5000
3880
5000
416
ND
43
a
b
c
Reaction temperature. Isolated yield of 15. THF = tetrahydrofuran.
acetone
ND
115
cyclohexane
ethylacetate
142
970
Table 2. Reaction conditions and yield from 16 to 17
1185
825
a
b
a
s. no.
solvent
T
[°C]
maintenance time (h)
yield (%)
Not detected.
1
2
3
4
toluene
25−30
25−30
25−30
0−5
9
50
58
87
70
acetonitrile
acetone
7.5
2.5
8
thus minimizes the generation of hazardous waste, which makes
the process more environmentally friendly.
acetone
a
b
Reaction temperature. Isolated yield of 17.
EXPERIMENTAL SECTION
■
The preparation of (2,2-dimethyl-1,3-dioxolane-4,5-diyl)-
dimethanol (14) is described in refs 9−11. 4-tert-Butylbenze-
nesulfonamide (6) was purchased from Spectrochem and used
as received. Common reagent-grade chemicals used were
commercially available and were used without further
purification. FT-IR spectra were determined on a Perkin-
Elmer 100 FT-IR spectrophotometert. Melting points were
determined on polmon instrument. The mass spectrum was
recorded on Agilent 6150 quadrapole LC/MS spectrometer, 1H
NMR spectra were acquired in CDCl3 as solvent on a Bruker
300 MHz or 400 MHz spectrometer using TMS as internal
standard, and 13C NMR spectra were recorded on a Bruker 100
MHz spectrometer using TMS as internal standard. Elemental
CONCLUSION
■
In conclusion, we have designed and developed a novel, cost-
effective, industrially scalable synthetic route to the endothelin
receptor antagonist, bosentan monohydrate (1). The synthetic
route developed uses cheaper raw material (2,2-dimethyl-1,3-
dioxolane-4,5-diyl)dimethanol (14) and provided bosentan
monohydrate with an overall yield of 53%, which corresponds
to an average step yield of more than 85%. The synthetic
process involves the formation of novel intermediates 15 and
16. The new process does not use any hazardous reagents and
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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
(CO 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 (CO 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
■
S
* 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
charge via the Internet at http://pubs.acs.org.
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
*Telephone: +91-9849814236. E-mail: yjpr_19@yahoo.com.
■
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Notes
†MSNRD Communication No.007.
*The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.R. thanks the HOD’s Osmania University and JNTU
Hyderabad for the opportunity to pursue his Ph.D. Our sincere
thanks to Dr. M. S. N. Reddy, Dr. Ch. Nagaraju for providing
infrastructural facilities to carry out the research work, and we
are also indebted to S. Eswaraiah, S. T. Rajan, and Dr. M.
Srinivas for their continuous guidance and support.
REFERENCES
■
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(12) The advantage of synthon 14 is that the two moles of the
starting material 7 condenses with a single mole of synthon 14 to
provide a dimeric product 15 which is deprotected and cleaved to
provide two moles of 17. This is finally converted to bosentan
monohydrate 1 free of impurities.
(13) The motivation to use dichloromethane for extraction of
intermediates 16 and 17 is it provided better yields and could be
distilled off and reused, thereby conserving and decreasing the use of
solvent, avoiding pollution.
(14) As sodium periodate is used as an oxidizing agent, there is a
possibility of the formation of N-oxide impurities, but on the contrary
it was observed that they were not formed. The experiments to
specifically prepare N-oxides using hydrogen peroxide also reiterated
the fact.
F
dx.doi.org/10.1021/op400100s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX