Succinct synthesis of bosentan utilizing glycol Mono-THP ether

Article abstract of DOI:10.1080/00397911.2014.904881

GRAPHICAL ABSTRACT A concise synthetic method for bosentan, a nonpeptide orally active dual endothelin (ET-1A/B) receptor antagonist used for the treatment of pulmonary artery hypertension (PAH), was developed. We developed a new succinct synthetic route for bosentan by employing an acid-labile tetrahydropyran (THP)-protected glycol. THP group is advantageous over the previously known protection groups used in bosentan synthesis in that it provides a clean and quantitative deprotection. Bosentan was constructed via two parallel reaction pathways, yet the better product yield was obtained from a pathway via 6. Deprotection of THP ether was achieved under a mild acidic condition to afford bosentan.

Full text of DOI:10.1080/00397911.2014.904881

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Succinct Synthesis of Bosentan Utilizing
Glycol Mono-THP Ether
a b
a
a
Chung Ryul Lee
, Sang Yeul Lee & Tae-gyu Nam
a
Department of Pharmacy and Institute of Pharmaceutical Science
and Technology , Hanyang University , Ansan , Gyeonggi-do , South
Korea
b
Medichem Korea , Gunpo , Gyeonggi-do , South Korea
Accepted author version posted online: 08 May 2014.Published
online: 01 Jul 2014.
To cite this article: Chung Ryul Lee , Sang Yeul Lee & Tae-gyu Nam (2014) Succinct Synthesis
of Bosentan Utilizing Glycol Mono-THP Ether, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:17, 2488-2493, DOI:
10.1080/00397911.2014.904881
To link to this article: http://dx.doi.org/10.1080/00397911.2014.904881
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1
Synthetic Communications , 44: 2488–2493, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.904881
SUCCINCT SYNTHESIS OF BOSENTAN UTILIZING
GLYCOL MONO-THP ETHER
1
,2
1
Chung Ryul Lee, Sang Yeul Lee, and Tae-gyu Nam
1
1
Department of Pharmacy and Institute of Pharmaceutical Science and
Technology, Hanyang University, Ansan, Gyeonggi-do, South Korea
2
Medichem Korea, Gunpo, Gyeonggi-do, South Korea
GRAPHICAL ABSTRACT
Abstract A concise synthetic method for bosentan, a nonpeptide orally active dual endothelin
ET-1A/B) receptor antagonist used for the treatment of pulmonary artery hypertension
PAH), was developed. We developed a new succinct synthetic route for bosentan by
(
(
employing an acid-labile tetrahydropyran (THP)–protected glycol. THP group is advan-
tageous over the previously known protection groups used in bosentan synthesis in that it
provides a clean and quantitative deprotection. Bosentan was constructed via two parallel
reaction pathways, yet the better product yield was obtained from a pathway via 6. Depro-
tection of THP ether was achieved under a mild acidic condition to afford bosentan.
Keywords Bosentan; endothelin receptor antagonist; pulmonary arterial hypertension;
tetrahydropyran ether
INTRODUCTION
Pulmonary arterial hypertension (PAH) is a devastating chronic disease
characterized by vasoconstriction, remodeling of pulmonary arteries, progressive
[
1]
increase in pulmonary vascular resistance, and thrombosis. Over the past decade,
significant progress in the understanding of the pathogenesis has been achieved, and
[
2]
targeted therapies in the management of PAH have been developed. One of the sig-
nificant abnormalities in PAH is an overexpression of endothelin-1 (ET-1). The
endothelins (ET-1, ET-2, and ET-3) are a family of 21 amino acid peptides and they
play an important role in vascular homeostasis. ET-1 is the most important mediator
of PAH. The action of ET-1 is complex and mediated via two cell-surface,
Received February 18, 2014.
Address correspondence to Tae-gyu Nam, Department of Pharmacy and Institute of
Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 426-791, South
Korea. E-mail: tnam@hanyang.ac.kr
2
488

SYNTHESIS OF BOSENTAN VIA THP-ETHER INTERMEDIATE
2489
Figure 1. Structure of bosentan (1).
G-protein-coupled receptors, ET and ET . Both receptors have been implicated in
A
B
[
3]
the pathological processes associated with PAH. Orally active nonpeptide endothe-
lin receptor antagonists might offer an opportunity to treat patients with PAH and
[4]
congestive heart failure.
Bosentan is an orally active dual endothelin (ET-1A=B) receptor antagonist
(
(
ERA) that competitively blocks the binding of endothelins to both ET and ETB
A
[
Fig. 1). Clinical trial data indicated an improvement of exercise capacity, PAH
5]
[
6]
symptoms, and pulmonary hemodynamics. Bosentan is the first nonpeptide
ERA that was approved for the treatment of PAH and currently used in the clinical
practice. The development of bosentan including the initial process chemistry was
conducted by Hoffmann–La Roche, but the clinical study was carried out by
Actelion, which ultimately licensed the drug on the market.
[
7]
We developed a new succinct synthetic route for bosentan by employing an acid-
labile tetrahydropyran (THP)–protected glycol 15. Bosentan was constructed via two
parallel reaction pathways, yet the better product yield was obtained from a pathway
via 6. THP ether could be removed under a mild condition to afford bosentan.
RESULTS AND DISCUSSION
The initial bosentan synthesis began with a condensation reaction between an
[
7]
amidine 2 and a malonate 3 to provide a pyrimidinedione 4 (Scheme 1). Treating
with POCl afforded a dichloropyrimidine 5, where one of two chloro substituents
4
3
was displaced by potassium tert-butylbenzenesulfonamide to afford a sulfonamide 6.
Remaining chloride in 6 was replaced with ethylene glycol to afford the desired
bosentan 1. Disadvantages associated with the original route include the formation of
undesired dimeric compound 7, which was hard to remove, and the use of excess amount
(100 equiv) of ethylene glycol in the last step, which resulted in poor throughput.
Since successful establishment of the pharmaceutical market, several cost-
effective synthetic routes for bosentan have been developed in pursue of more
competitive market position. The second synthetic route was designed to eliminate
[
8]
problems in the original route (Scheme 2). The main idea was the displacement
of a chloride in sulfonamide 6 with stoichiometric amount of glycol mono-tert-butyl
ether, avoiding the use of excess amount of ethylene glycol, to afford bosentan

2490
C. R. LEE, S. Y. LEE, AND T.-G. NAM
Scheme 1. Original synthetic route for bosentan.
tert-butyl ether 8. In this modified scheme, the formation of dimeric 7 could be
circumvented, but deprotection of 8 resulted in bosentan formate ester 9. Although
hydrolysis of 9 afforded bosentan, this route required an additional deprotecting
step.
Several synthetic procedures for bosentan were reported subsequently, and one
[
9]
of the elegant works is depicted in Scheme 3. In this process, the chloro substituent
on compound 10, a potassium salt of 6, was displaced by glycolaldehyde diethylace-
tal to form an acetal 11, where diethylacetal protecting group was in situ removed in
an acidic environment to afford an aldehyde 12. Reduction of the aldehyde function-
ality to an alcohol produced bosentan.
From thorough analysis of reported processes, we could envisage a succinct
synthetic pathway to bosentan by introducing a monoprotected glycol where its
hydroxyl protecting group should be stable in basic condition yet labile in mild acidic
environment. Herein, we report our effort to synthesize bosentan by utilizing glycol
mono-THP ether 15 (Scheme 4). Although THP ether has an advantage as a protec-
tion group in that it provides a clean and quantitative deprotection, difficulty in the
preparation of glycol mono-THP ether on a mass production scale hampered its use
[8]
in bosentan synthesis. THP was selected as a protection group in our synthesis for
the following reasons. First of all, the use of THP ether as the protecting group can
reduce one step in synthesis (Scheme 2) and its mild acidic removal condition is likely
to improve the impurity profile. Second, the structure of bosentan does not tolerate
basic deprotection conditions because of the possible deprotonation of the sulfona-
mide group or a possible attack on pyrimidine core if fluoride ion is involved in
Scheme 2. Second synthetic route for bosentan.

SYNTHESIS OF BOSENTAN VIA THP-ETHER INTERMEDIATE
2491
Scheme 3. Preparation of bosentan from glycolaldehyde.
deprotection step. Thus, an acid-labile protecting group should be used in the syn-
thesis. Of acids, Lewis acids are not recommendable because the removal of metal
from the final bosentan active pharmaceutical ingredient (API) can be a challenging
task. Strong acids such as sulfuric acid or formic acid are not suitable because of the
possible formation of corresponding sulfate or formate esters (Scheme 2). At an elev-
ated temperature, even a mild acidic condition can convert the pyrimidine core to the
isomeric pyrimidinone form. Thus, the ideal protecting group should be acid labile
and robust under basic conditions.
Therefore, the synthesis began with the preparation of ethylene glycol mono-
[
10]
THP ether 15 following a literature procedure.
With 15 in hand, two possible
synthetic pathways toward the bosentan–THP ether 14 from commercially available
compounds 5 and 6 were pursued in a parallel manner. In one method, the chloro
[
7–9]
substituent in 6 (the conversion from 5 to 6 was well established in literature
)
was displaced with 15 to produce bosentan–THP ether 14 (68%). In another
pathway, one of two chlorines on 5 was displaced with 15 to provide 13 (62%), which
was converted to 14 by treating with tert-butylbenzenesulfonamide in basic
conditions (63%). Successful construction of 14 from both pathways might be
evidence for the robustness of our approach. Deprotection of THP ether with
[
10]
pyridinium p-toluenesulfonate (PPTS) afforded bosentan 1 in good yield (84%).
Scheme 4. Synthesis of bosentan from glycol mono-THP ether.

2492
C. R. LEE, S. Y. LEE, AND T.-G. NAM
EXPERIMENTAL
-(2-Methoxyphenoxy)-6-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)-4-
amino-2,2’-bipyrimidine (13)
5
A solution of compound 15 (604 mg, 4.12 mmol) in anhydrous dimethylforma-
ꢀ
mide (DMF; 20 mL) at 0 C was treated with NaH (60% in mineral oil, 198 mg,
ꢀ
4
3
.95 mmol, washed with hexanes). The resulting mixture was stirred at 0 C for
0 min under Ar and treated with a solution of commercially available 5 (purchased
from TCI, 1872 mg, 5.36 mmol) in DMF (20 mL). The reaction mixture was stirred
ꢀ
at 0 C for 1 h and then at ambient temperature for 3 h under Ar. The reaction mix-
ture was diluted with EtOAc (500 mL); washed with aqueous 1 N HCl (3 ꢁ 30 mL),
water (3 ꢁ 50 mL), and saturated aqueous NaCl; dried over anhydrous MgSO ;
4
and concentrated under reduced pressure to provide the crude product. Flash chro-
matography (SiO , 5% MeOH–CH Cl ) afforded 13 as a white semi solid (1170 mg,
2
2
2
1
2%) along with a trace amount of undesired bis-alkylated product: H NMR
6
(
(
1
400 MHz, CDCl ) d 8.95 (d, J ¼ 5.0 Hz, 2H), 7.38 (t, J ¼ 5.0 Hz, 1H), 7.02–6.97
3
m, 1H), 6.91 (dd, J ¼ 8.0, 1.2 Hz, 1H), 6.78–6.747 (m, 1H), 6.64 (dd, J ¼ 8.0,
.2 Hz, 1H), 4.72–4.62 (m, 2H), 4.42 (t, J ¼ 3.2 Hz, 1H), 3.86–3.80 (m, 1H), 3.84
(s, 3H), 3.65–3.58 (m, 1H), 3.56–3.49 (m, 1H), 3.35–3.28 (m, 1H), 1.64–1.30 (m,
1
3
6
1
2
4
H); C NMR (100 MHz, CDCl ) d 163.3, 161.3, 158.0 (2C), 156.1, 153.1, 149.3,
3
45.6, 134.8, 124.0, 121.4, 120.7, 115.7, 112.8, 98.3, 67.5, 64.7, 61.5, 56.3, 30.3,
55 9. 4. 1, 41 48 4. 9. . HRMS (ESI) m=z [M þ H]þ calcd. for C H O N Cl 459.1430; found
2
2
24
5
4
4
-tert-Butyl-N-(5-(2-methoxyphenoxy)-6-(2-(tetrahydro-2H-
pyran-2-yloxy)ethoxy)-2,2’-bipyrimidin-4-yl)benzenesulfonamide
14)
(
A solution of compound 13 (2.0 g, 4.36 mmol) and commercially available
-tert-butylbenzenesulfoamide (1.0 g, 4.79 mmol) in toluene (30 mL) was treated with
K CO (723 mg, 5.23 mmol) and tetra-n-butylammonium bromide (142 mg,
4
2
3
ꢀ
0
.44 mmol). The reaction mixture was warmed at 100 C for 18 h and cooled down
to ambient temperature. The resulting mixture was filtered through a pad of Celite,
and the filtrate was diluted with EtOAc (100 mL); washed with aqueous 1 N HCl,
water, and brine; dried over anhydrous MgSO ; and concentrated under reduced
4
pressure to provide the crude product. Flash chromatography (SiO , 3% MeOH–
2
ꢀ
1
CH Cl ) to provide 14 as a green foam (1.75 g, 63%): mp ¼ 75–77 C; H NMR
2
2
(
400 MHz, CDCl ) d 9.04 (d, J ¼ 4.0 Hz, 2H), 8.99 (m, 1H), 8.44–8.31 (m, 2H),
3
7
6
.45 (m, 1H), 7.42 (d, J ¼ 8.4 Hz, 2H), 7.22 (m, 1H), 7.09 (t, J ¼ 7.4 Hz, 1H),
.97 (d, J ¼ 8.0 Hz, 1H), 6.86–6.80 (m, 1H), 4.78–4.66 (m, 2H), 4.60–4.55
(
(
m, 1H), 4.06–3.90 (m, 4H), 3.79–3.60 (m, 2H), 3.48–3.43 (m, 1H), 1.78–1.38
1
3
m, 6H), 1.28 (s, 9H); C NMR (125 MHz, CDCl ): d 162.0, 161.4, 157.8 (2C),
3
1
1
2
6
57.1, 156.1, 151.6, 149.8, 146.0, 136.3, 129. 6, 129.5 (2C), 125.5, 125.4 (2C),
21.4, 121.2, 120.1, 112.4, 98.5, 66.9, 65.1, 61.8, 56.1, 35.2, 31.1 (3C), 30.5,
35 6. 5. 2, 41 99 0. 1. . HRMS (ESI) m=z [M þ H]þ calcd. for C H O N S 636.2486; found
3
2
38
7
5

SYNTHESIS OF BOSENTAN VIA THP-ETHER INTERMEDIATE
2493
CONCLUSION
We developed new succinct synthetic routes for bosentan by employing
[
11]
acid labile THP-protected ethylene glycol 15.
parallel reaction pathways, yet pathway through 6 afforded the better product yield.
Bosentan was constructed via two
THP ether could be removed in a mild acidic condition to afford bosentan.
FUNDING
This work was supported by the Research Fund of Hanyang University
(HY-2012-N).
SUPPORTING INFORMATION
1
13
Full experimental details, H and C NMR spectra, and HPLC tracers for this
article can be accessed on the publisher’s website.
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