Improved procedure for the preparation of Bosentan, an endothelin receptor antagonist

Full text of DOI:10.1080/00304948.2013.835222

This article was downloaded by: [University of Haifa Library]
On: 25 October 2013, At: 02:02
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
Improved Procedure for the Preparation
of Bosentan, an Endothelin Receptor
Antagonist
Satyanarayana Reddy Manne a , Thirumalai Rajan Srinivasan a ,
Eswaraiah Sajja a , Pradeep Rebelli a , Hareesh Kumar Nadendla
a , Kondal Reddy Bairy a b , Venkat Reddy Ghojala a & Kista Reddy
Chepyala b
a Department of Research and Development , MSN Laboratories
Limited , Rudraram Village, Patancheru Mandal, Medak Dist, Andhra
Pradesh , 502329 , India
b Department of Chemistry , P.G College of Science , Saifabad ,
Hyderabad , 500004 , India
Published online: 24 Oct 2013.
To cite this article: Satyanarayana Reddy Manne , Thirumalai Rajan Srinivasan , Eswaraiah Sajja ,
Pradeep Rebelli , Hareesh Kumar Nadendla , Kondal Reddy Bairy , Venkat Reddy Ghojala & Kista
Reddy Chepyala (2013) Improved Procedure for the Preparation of Bosentan, an Endothelin Receptor
Antagonist, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 45:6, 510-514, DOI: 10.1080/00304948.2013.835222
To link to this article: http://dx.doi.org/10.1080/00304948.2013.835222
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Organic Preparations and Procedures International, 45:510–514, 2013
Copyright © MSN Laboratories Ltd.
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.835222
OPPI BRIEF
Improved Procedure for the Preparation
of Bosentan, an Endothelin Receptor
Antagonist
Satyanarayana Reddy Manne,1 Thirumalai Rajan Srinivasan,1
Eswaraiah Sajja,1 Pradeep Rebelli,1 Hareesh Kumar Nadendla,1
Kondal Reddy Bairy,1,2 Venkat Reddy Ghojala,1 and Kista Reddy
Chepyala2
1Department of Research and Development, MSN Laboratories Limited,
Rudraram Village, Patancheru Mandal, Medak Dist Andhra Pradesh 502329,
India
2Department of Chemistry, P.G College of Science, Saifabad, Hyderabad,
500004, India
Endothelins are a family of structurally related 21-amino acid peptides with two cysteine-
cysteine disulfide bridges. Endothelin itself has recently been shown to play a pivotal
role in the development of pulmonary hypertension and elevated endothelin concen-
trations have been found to be strongly correlated with the severity of the disease.1–3
Endothelin antagonists, especially 4-(1,1-dimethyl ethyl)-N-[6-(2-hydroxyethoxy)-5-(2-
methoxyphenoxy)[2,2ꢀ-pyrimidin]-4-yl] benzenesulfonamide monohydrate (bosentan),
represent a new approach for the treatment of pulmonary hypertension. Bosentan
ꢁR
(Tracleer ) became the first endothelin antagonist to reach the market for the treatment of
pulmonary hypertension and to date, only a few drugs such as sitaxentan and ambrisen-
tan have been specifically approved for this indication. Bosentan can also be used for the
treatment of circulatory disorders such as ischemia, vasospasms and angina pectoris and
offers a new strategy for the treatment of patients with cardiovascular pathology and in
particular, congestive heart failure.4,5 We sought to establish a new manufacturing process
for bosentan, free of impurities.
In the first process6 disclosed earlier, bosentan 4 is obtained in 40% yield from 1
(Scheme 1). One of the chlorine atoms of 2 is replaced by 4-t-butyl-benzenesulfonamido
Submitted by January 30, 2013.
Address correspondence to Reddy Ghojala, Department of Research and Development, MSN
Laboratories Limited, Rudraram Village, Patancheru Mandal, Medak Dist, Andhra Pradesh, India
502329. E-mail: drvenkatreddy@msnlabs.com
510

Preparation of Bosentan
511
Scheme 1
(i) POCl3; (ii) 4-(t-Butyl)benzenesulfonamide, K2CO3, TBAB, toluene; iii) Sodium metal, ethylene
glycol.
group and the second chlorine is substituted with ethylene glycol in presence of sodium
metal to provide bosentan. This step is not feasible on an industrial level as the handling of
sodium metal is a concern, furthermore the use of a large excess of ethylene glycol leads to
the generation of aqueous ethylene glycol waste. In addition, three recrystallizations of the
final product are required to diminish the amount of dimeric impurity 6 and of pyrimidinone
5 that are by-products of the reaction. Complete elimination of the dimeric impurity 6 is
not possible even after four to five recrystallizations.
An improved method7 for the preparation of bosentan involves the reaction of 3 with
mono-protected ethylene glycol to provide 7, which on deprotection provides bosentan
(Scheme 2). While this procedure avoids the formation of the dimeric impurity, but the
deprotection of 7 not only requires the use of large quantities of formic acid, but also in
addition leads to the formation of thermal degradation impurities.
The improved process8 for the manufacture of bosentan (4) using chloroethanol il-
lustrated above overcomes the disadvantages burdening the other prior art processes. The
Scheme 2
(i) Ethylene glycol-(t-butyl) ether; (ii) Formic acid, NaOH.

512
Ghojala et al.
Scheme 3
(i) NaOH, toluene, DMSO; (ii) Chloroethanol, DMF, Na2CO3.
disadvantages such as the use of excess ethylene glycol, the use of sodium metal etc. have
been overcome. It is easier to perform, cost effective, economically viable and can also
be carried out at a commercial scale. It has been performed on a two kilograms scale and
has provided bosentan of good quality and in good yield. The formation of the dimeric
impurity is minimized, because intermediate 5 does not contain any intermediate 3. If any
amount of 3 is present, it gets carried over into the next stage and reacts with the bosentan
formed leading to the formation of the dimeric impurity. The absence of the dimeric im-
purity eliminates the need for additional purification steps required to remove it and hence
improves the yield of 4 (Scheme 3).
In conclusion, we have devised a novel, cost-effective, industrially scalable approach
to the endothelin receptor antagonist bosentan 4.
Experimental Section
Chlorosulfonamide 3 is prepared according to procedure as described in US Patent
5,292,740 [Chem. Abstr., 120, P217711p (1994)]. 4-(t-Butyl)benzenesulfonamide was pur-
chased from Spectrochem and used as received. Toluene, DMSO and ethanol were obtained
from Spectrum Chemical and used as received. Elemental analyses were performed at the
Indian Institute of Chemical Technology, Hyderabad. The FT-IR spectrum of bosentan
was determined on a Thermo model Nicolet-380 as KBr pellet and its thermal analysis
and that of its hydrate was carried out on a Waters DSC Q-10 model differential scanning
calorimeter. The mass spectrum was recorded on positive Q1 MS mass spectrometer and
the 1H NMR data was acquired in CDCl3 on an Avance 300 MHz spectrometer using TMS
as internal standard.
Bosentan and its impurities were analyzed by HPLC. The liquid chromatographic
system is equipped with ‘Inertsil ODS 3 V, 250 × 4, 6 mm, 5 μm or equivalent’ column
which is packed with C-18 silica. The system is maintained at 25◦C and a sample 20 μl
is injected into the column. A variable wavelength UV detector monitored at 220 nm is
used to detect the elution of the compounds. The flow rate of the diluent is maintained at
1.0 ml/min. The diluents consist of 1:1 mixture of mobile phase-A and mobile phase-B;
wherein the mobile phase-A is a mixture of 95% buffer and 5% methanol and mobile phase-
B consists of 95% methanol and 5% water. The 95% buffer was prepared by dissolving
3.48 grams (0.02 M) of di-potassium hydrogen orthophosphate in 1000 ml of water. Load:
20 μl.

Preparation of Bosentan
513
4-t-Butyl-N-[6-(hydroxy)-5-(2-methoxyphenoxy)[2,2ꢀ-bipyrimidin]-4-yl]-benzenesulfon-
amide(5)
A mixture of toluene (175 ml), DMSO (75 ml), water (50 ml), sodium hydroxide (15.2 g,
0.38 mol) and 3 (50.0 g, 0.095 mol) was refluxed for 13 h and cooled to room temperature.
Then 400 ml of water was added to the reaction mixture which was then acidified with
6N HCl to pH ∼ 2.0. The resulting precipitate was collected and washed with water
(3 × 50 ml). The solid obtained was suspended in methanol (75 ml) and stirred for 1 h at
room temperature. The solid was collected, washed with methanol and dried under vacuum
to afford 5 (38.0 g, 78% yield), mp. 105–108◦C. HPLC Purity: 98.35%. MS: m/z 508.3
(M+H). 1H-NMR: δ 1.29 (s, 9H), 4.02 (s, 3H), 6.85–7.13 (m,4H), 3.69–3.74 (m, 2H), 3.94
(s, 3H), 4.67–4.70 (m, 2H), 6.81–7.11(m, 4H), 7.44–7.50 (m, 3H), 8.39 (d,2H, J = 4.8 Hz),
9.00 (d, 2H, J = 4.8 Hz). IR: 3214.8 (NH), 1663.8 cm−1 (C O).
Anal. Calcd for C25H25N5O5S: C, 59.16; H, 4.96; N, 13.80. Found: C, 59.01; H, 4.99;
N, 13.62.
Preparation of Bosentan Hydrate (4)
A mixture of 5 (38.5 g, 0.075 mol) in dimethylformamide (450 ml), sodium carbonate
(32.15 g, 0.303 mol) was heated to (∼115◦C) for 4 h. 2-Chloroethanol (30.53 g, 0.379 mol)
was then added and the mixture was stirred for 16 h. Water (∼400 ml) was added and the
reaction mixture was then acidified with 6N HCl to a pH ∼ 2.0. The reaction mixture was
stirred for 10 min and extracted with methylene chloride (700 ml). The organic layer was
separated, and the aqueous layer was extracted with toluene (∼200 ml). The organic layers
were combined, dried over sodium sulfate and evaporated under reduced pressure. The solid
residue was dissolved in methanol (150 ml) and stirred for 30 min. The reaction mixture
was then added to water (200 ml) and stirred for 4 h. The solid which precipitated out was
collected and dried to afford bosentan 4. (36.0 g, 86% yield) as a solid, mp. 138–140◦C.
1
HPLC Purity: 99.70%. Water content: 3.2% (w/w). MS: m/z: 552 (M-OH). H-NMR: δ
1.29 (s, 9H), 3.86 (s, 2H), 3.94 (s, 3H), 4.57 (m, 2H), 4.88 (s,1H), 6.85 (m, 1H), 7.10 (m,
2H), 7.15 (m, 1H), 7.41(m, 3H), 8.42 (d, 2H, J = 4.9 Hz), 9.0 (d, 2H, J = 4.9Hz). IR:
3437.4, (NH), 1342 cm−1 (SO2).
Anal. Calcd for C27H31N5O7S: C, 56.93; H, 5.49; N, 12.29. Found: C, 56.68; H, 5.25;
N, 12.48.
References
1. T. Sasaki, T. Noguchi, K. Komamura, T. Nishikimi, H. Yoshikawa and K. Miyatake, J. Card. Fail.,
5, 38 (1999).
2. R. J. Cody, G. J. Haas, P. F. Binkley, Q. Capers and R. Kelley, Circulation., 85, 504 (1992).
3. N. Galie, A. Manes and A. Branzi, Cardiovasc. Res., 61, 227 (2004).
4. W. Neidhart, V. Breu, D. Bur, K. Burri, M. Clozel, G. Hirth, M. Muller, H.P. Wessel and H. Ramuz,
Chimia, 50, 519 (1996).
5. W. Neidhart, V. Breu, D. Bur, K. Burri, M. Clozel, G. Hirth, U. Klinkhammer, T. Giller and H.
Ramuz, Bioorg. Med. Chem. Lett., 7, 2223 (1997).

514
Ghojala et al.
6. K. Burri, M. Clozel, W. Fischli, G. Hirth, B. M. Loffler, W. Neidhart and H. Ramuz, US Patent
5,292,740 (1994); Chem. Abstr., 120, P217711p (1994).
7. P. J. Harrington, H. N. Khatri, B. S. Dehoff, G. R. Martin, B. A. Mark and G. A. Karl, Org. Process
Res. Dev., 6, 120 (2002).
8. S. R. Manne, V. R. Ghojala and E. Sajja, PCT Publication WO2009095933 (2009); Chem. Abstr.,
151, P221196g (2009).