A Novel Synthesis of Macitentan, an Endothelin Receptor Antagonist

Full text of DOI:10.1080/00304948.2017.1320921

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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A Novel Synthesis of Macitentan, an Endothelin
Receptor Antagonist
Majid Nami, Sara Nasiri Sovari, Yaghoub Haghighatnia, Minoo Dabiri &
Peyman Salehi
To cite this article: Majid Nami, Sara Nasiri Sovari, Yaghoub Haghighatnia, Minoo
Dabiri & Peyman Salehi (2017) A Novel Synthesis of Macitentan, an Endothelin Receptor
Antagonist, Organic Preparations and Procedures International, 49:3, 258-264, DOI:
10.1080/00304948.2017.1320921
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Date: 01 June 2017, At: 21:09

Organic Preparations and Procedures International, 49:258–264, 2017
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2017.1320921
A Novel Synthesis of Macitentan, an Endothelin
Receptor Antagonist
Majid Nami,1 Sara Nasiri Sovari,2 Yaghoub Haghighatnia,2 Minoo
Dabiri,1 and Peyman Salehi3
1Faculty of Chemistry, Shahid Beheshti University, G. C., Evin, Tehran
1983963113, Iran
2Department of Research and Development, Hasti Aria Shimi Co., Tehran
1463745481, Iran
3Department of Phytochemistry, Medicinal Plants and Drugs Research Institute,
Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran
Macitentan (systematic name N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]
ethoxy]-4-pyrimidinyl]-N’-propylsulfamide, 5, Scheme 1) is an endothelin receptor antago-
nist (ERA) approved by the FDA in 2013. It is a pharmaceutically active agent utilized in the
treatment of pulmonary arterial hypertension (PAH), by delaying progression of the dis-
ease.1–7 Moreover, it exhibits higher efficacy, has less adverse effects and drug interactions
than currently available treatments (e. g., bosentan, ambrisentan and sitaxsentan) for
PAH.8–16 Macitentan is stable in the solid state and is neither hygroscopic nor light sensi-
tive.17–19
In recent years, some alkylsulfamide-substituted pyrimidines such as 5 have been
synthesized.20,21 The procedure for the preparation of 5 by Bolli is illustrated in
Scheme 1.22 In that method, DMSO was used as solvent and NaH was utilized as base,
both of which are unsuitable for large scale synthesis; the use of forty equivalents of eth-
ylene glycol is another disadvantage of this method.
In 2015, another synthetic route to macitentan was published by Abele. The first step
of this method also used DMSO as the solvent, and tetrabutylammonium fluoride
(TBAF:3H2O) and potassium carbonate. Also, two routes were mentioned to synthesize
compound 6, a key precursor to 5.23
In order to sustain the manufacture of useful products, the overall cost of production
processes has a great impact on commercial success. As well, finding optimized chemical
processes reduces pollutants and replaces toxic chemical reactions with more eco-friendly
alternatives. In this article, we introduce a new and very efficient method for the prepara-
tion of 5, using lower temperatures and milder base in less toxic solvents. To obviate the
drawbacks of the previously reported methods, we have proposed a novel and efficient
approach which involves using a very mild and inexpensive base (K2CO3) for all steps,
solvents such as acetonitrile and THF which can be recycled during the process, and
Received September 23, 2016; in final form February 16, 2017.
Address correspondence to Peyman Salehi, Department of Phytochemistry, Medicinal Plants
and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, Tehran 1983963113, Iran.
E-mail: p-salehi@sbu.ac.ir
258

A Novel Synthesis of Macitentan
259
Scheme 1
reducing the amount of some reagents, such as ethylene glycol (using only 1.5 equiv). A
good yield of the final product was obtained using our method.
In this procedure, the reaction between 5-(4-bromo-phenyl)-4,6-dichloro-pyrimidine
(1) and N-propylsulfamide (2) resulted in the formation of 3 (Scheme 2). During develop-
ment studies, acetonitrile, THF and toluene were tested as the solvents for this step. By
utilizing THF and toluene, completion of the reaction was not attained. But using acetoni-
trile as a solvent resulted in a high yield (85%). Therefore, acetonitrile was selected as the
solvent of choice. KOtBu and potassium carbonate (K2CO3) were examined as bases. In
terms of commercial consideration, K2CO3 at 50ꢀC was found to be suitable. The results
are summarized in Table 1.
Table 1
Optimization of the Reaction Conditions for Synthesis of 3
Entry
Base
Solvent
Temp. (ꢀC)
Yield (%)
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOtBu
KOtBu
KOtBu
THF
THF
r.t.
50
r.t.
50
r.t.
50
50
50
50
20
60
30
85
10
30
70
80
40
acetonitrile
acetonitrile
Toluene
Toluene
THF
acetonitrile
toluene

260
Salehi et al.
Figure 1 Structure of the byproduct of the first step.
The coupling reaction formed monochloropyrimidine (3). Reacting 2 with compound
1, using the molar ratio 1.05:1, and carefully adding 2 to 1 in a dropwise manner elimi-
nated the formation of byproduct 7 (Figure 1).
In the course of the preparation, compound 6 was synthesized by the reaction of 1.5
equiv of ethylene glycol with 5-bromo-2-chloropyrimidine in THF using K2CO3 at 45ꢀC
(Scheme 2). To find optimal conditions, the reaction was performed in different solvents
such as THF, toluene, and acetonitrile. Even after 12–15 h, completion of reaction was
not observed in acetonitrile and toluene, whereas by applying THF as the solvent, com-
pound 6 was obtained in excellent yield. Our results are presented in Table 2. In a previ-
ous literature procedure,24
6 was prepared using benzotriazol-1-yloxy) tris
(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs2CO3 in the first step;
Table 2
Different Conditions for the Synthesis of 6 as Intermediate
Entry
Base
Solvent
Temp. (ꢀC)
Yield (%)
1
2
3
4
5
6
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
r.t.
45
r.t.
45
r.t.
45
60
98
10
50
15
40
acetonitrile
acetonitrile
toluene
toluene
Table 3
Synthesis of Final Product 5
Entry
Base
Solvent
Temp. (ꢀC)
Yield (%)
1
2
3
4
5
6
7
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
THF
r.t.
45
60
r.t.
60
r.t.
60
35
75
83
30
60
20
50
THF
acetonitrile
acetonitrile
toluene
toluene

A Novel Synthesis of Macitentan
261
afterwards, the product was reacted with 20 molar equivalents of ethylene glycol to give
75% of product.
Compound 6 was dissolved in THF and reacted with 3 at 60ꢀC, after addition of 5
equiv of K2CO3. For this step also toluene, acetonitrile and THF were examined. Toluene
and acetonitrile did not lead to suitable reaction progress, but THF was found to be the
most efficient solvent for preparation of the final product 5 in good yield as a white solid
after crystallization from methanol (Table 3, Entry 3). The complete synthesis path is
depicted in Scheme 2.
Scheme 2
In conclusion, a new, low-cost and industrially scalable synthetic route has been
developed for the preparation of the endothalin receptor antagonist macitentan (5)
with an overall yield of 70%. This method involved the use of inexpensive reagents,
less toxic and recoverable solvents, and decreasing the formation of hazardous
waste, which makes this route attractive from both commercial and environmental
points of view.

262
Salehi et al.
Experimental Section
Commercially available materials were used without further purification. The melting
points were determined on an Electrothermal IA9300 apparatus and are not cor-
rected. All reactions and the purity of the products were monitored by thin-layer
chromatography (TLC) using aluminum plates coated with silica gel F254 (Merck).
IR Spectra were recorded on FT-IR Bruker Tensor 27 FT-IR spectrometer in cm¡1
.
The 1H- and 13C-NMR spectra were determined on Bruker spectrometer operating
at 500 and 125 MHz respectively; in DMSO-d6 and CDCl3 (d in ppm relative to
Me4Si as internal standard, with J in Hz. Elemental analyses were acquired on an
Eager 300 for EA1112.
N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N’-propylsulfamide (3)
A mixture of 1 (100 g, 0.33 mol), K2CO3 (221 g, 1.6 mol), and acetonitrile (1.3 L) was
heated to 50ꢀC and stirred for 20 min. The solution of 2 (43 g, 0.31 mol) in acetonitrile
(200 mL) was added dropwise and maintained at 50ꢀC for 10 h. The reaction solvent was
replaced with toluene (2 L) using a Dean-Stark apparatus. The precipitated solid was fil-
tered and suspended in water (2 L). The pH was adjusted to 7 by using 6 N hydrochloric
acid and stirred for 20 min. The resulting precipitate was filtered and dried in the oven at
55ꢀC for 5 h. The crude product was recrystallized from ethyl acetate to acquire 106 g
(85%) of 3 as a white solid, mp 236ꢀC–238ꢀC. IR (KBr): 3272, 2966, 1593, 1566, 1438.
1H NMR (500 MHz, DMSO-d6): d 0.73–0.76 (t, JD6.9, Me); 1.30–1.36 (m, CH2), 2.52–
2.56 (m, CH2), 5.68–5.71 (t, JD6.6, NH), 7.12–7.14 (d, 2 H, ArH), 7.50–7.51 (d, 2 H,
ArH), 8.04 (s, 1 H, ArH). 13C NMR (125 MHz, DMSO): d 12.41, 21.63, 45.75, 120.26,
120.93, 131.50, 133.38, 136.21, 155.26, 156.73, 164.76.
Anal. Calcd. for C13H14BrClN4O2S: C, 38.49; H, 3.48; N, 13.81; Found: C, 38.56; H,
3.55; N, 13.51.
2-((5-Bromopyrimidin-2-yl)oxy)ethan-1-ol (6)
A mixture of 5-bromo-2-chloro-pyrimidine (100 g, 0.51mol), THF (1.5 L), and K2CO3
(286 g, 24 mol) was heated to 45ꢀC, then ethylene glycol (43 ml, 0.7 mol) was added to the
reaction mixture and maintained at 45ꢀC for 8 h. The reaction mixture was cooled to room
temperature, filtered, and the residue was washed with THF (400 ml).The solvent of The fil-
trate was replaced with ethyl acetate using Dean-Stark apparatus, and the solution was refluxed
for 1h, then cooled to 15ꢀC, filtered and washed with ethyl acetate (200 ml) and dried in the
oven at 60ꢀC for 6 h to obtain 110 g (98%) of 6 as a white solid, mp 68ꢀC–70ꢀC (dec.). IR
1
(KBr): 3346 (-OH stretching), 1572, 1545. H NMR (500 MHz, DMSO-d6): d 3.65–3.68
(ABq, CH2), 4.24–4.26 (t, JD4.9), 4.85–4.88 (t, JD5.5, OH), 8.70 (s, 2 H, ArH). 13C NMR
(125 MHz, DMSO-d6): d 61.25, 66.21, 160.05, 163.87, 164.11.
Anal. Calcd. for C6H7BrN2O2: C, 32.90; H, 3.22; N, 12.79; Found: C, 32.79; H, 3.31;
N, 13.03.
N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-
propylsulfamide (5)
Potassium carbonate (170 g, 1.2 mol) was added to a solution of 3 (100 g, 0.24 mol) in
THF (1.5 L), heated to 50ꢀC and stirred for 30 min under a nitrogen atmosphere.

A Novel Synthesis of Macitentan
263
Compound 7 (59.2 g, 0.27mol) was added to the mixture in portions. The temperature
was increased to 65ꢀC and stirred for 8 h. The reaction mixture was cooled to 20ꢀC, and
then water (2 L) was added. The pH was adjusted to 6.5 with 6 N HCl, then the resulting
precipitate was filtered and washed with water. The crude product was recrystallized
from methanol (700 ml) to provide macitentan (5) (120 g, 83%) as a white solid, mp
134ꢀC–135ꢀC. IR (KBr): 3285 (-NH stretching), 2360 (C D N stretching), 1571, 1385.
1H NMR (500 MHz, CDCl3): d 0.89–0.91 (t, JD7.4, Me), 1.50–1.58 (m, CH2), 2.90–2.94
(m, CH2), 4.58–4.59 (m, CH2), 4.67–4.69 (m, CH2), 5.67–5.69 (t, JD6.1, NH), 7.07 (s,
NH), 7.12–7.13 (d, 2 H, ArH), 7.49–7.51(d, 2 H, ArH), 8.41(s, 1 H, ArH), 8.43 (s, 2 H,
ArH). 13C NMR (125 MHz, CDCl3): d 11.65, 22.73, 46.09, 65.37, 66.03, 104.95, 112.55,
123.69, 128.42, 131.99, 133.05, 156.11, 156.79, 159.96, 163.80, 166.57.
Anal. Calcd. for C19H20Br2N6O4S: C, 38.79, H, 3.43; N, 14.29; Found: C, 38.60; H,
3.51; N, 14.31.
Acknowledgment
The authors wish to thank the financial support provided by Shahid Beheshti University
Research Council.
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