Improved Large-Scale Synthesis of Bosentan Monohydrate

Full text of DOI:10.1080/00304948.2016.1234826

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Improved Large-Scale Synthesis of Bosentan
Monohydrate
K. Rajasekhara Raju, B. Shankar Reddy, Y. S. Somannavar, B. K. Sinha, P. N.
Kishore Babu & K. Mohana Raju
To cite this article: K. Rajasekhara Raju, B. Shankar Reddy, Y. S. Somannavar, B. K. Sinha,
P. N. Kishore Babu & K. Mohana Raju (2016) Improved Large-Scale Synthesis of Bosentan
Monohydrate, Organic Preparations and Procedures International, 48:6, 481-491, DOI:
10.1080/00304948.2016.1234826
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Date: 27 October 2016, At: 22:50

Organic Preparations and Procedures International, 48:481–491, 2016
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2016.1234826
Improved Large-Scale Synthesis of
Bosentan Monohydrate
K. Rajasekhara Raju,1,2 B. Shankar Reddy,1 Y. S. Somannavar,1
B. K. Sinha,1 P. N. Kishore Babu,1 and K. Mohana Raju2
1Chemical Research and Development, Aurobindo Pharma Ltd, Survey No.71
and 72, Indrakaran (V), Sangareddy (M), Medal District 502329, Telangana,
India
2Synthetic Polymer Laboratory, Department of Polymer Science and
Technology, Sri Krishnadevaraya University, Anantapur 515055, Andhra
Pradesh, India
Bosentan is a non-peptidic endothelin receptor antagonist used for the treatment of pulmonary
artery hypertension (PAH), congestive heart failure and cardiovascular pathology.1,2 Bosentan
monohydrate [4-t-butyl-N-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2,20-bipyrimidin-4-
yl) benzenesulfonamide monohydrate (7, Scheme 2) is marketed by Actelion Pharmaceuticals
under the trade name TracleerÒ in the form of tablets of 62.5 mg and 125 mg.
Several method of synthesis have been reported using different methodologies, each with
its own merits and disadvantages. In the first generation route,3 bosentan was prepared from
dimethyl-2-(2-methoxyphenoxy)malonate (1) in a 53% overall yield (Scheme 1). The major
problems associated in the first generation process were i) the formation of undesired by-prod-
ucts such as 4-(t-butyl)-N-(6-hydroxy-5-(2-methoxyphenoxy)[2,20-bipyrimidin]-4-yl)benzene-
sulfonamide (8) and N,N0-(6,600-(ethane-1,2-diylbis(oxy))bis(5-(2-methoxyphenoxy)-[2,20-
bipyrimidine]-6,4-diyl) bis(4-(t-butyl)benzenesulfonamide) (9) as shown in Figure 1 and ii)
less efficiency because of the need for six isolation steps.
Harrington et al. reported,4, 5 avoiding the use of excess ethylene glycol by using eth-
ylene glycol mono tert-butyl ether. However, the disadvantages in their process are the
multiple steps relating to protection and deprotection, leading to a low throughput and
use of expensive ethylene glycol mono tert-butyl ether. Moreover, large volumes of sol-
vents had to be used for extraction and isolation (Scheme 2).
Navnath et al.6 has described a one-pot process by the reaction of 4 with 5 and ethyl-
ene glycol in acetonitrile in the presence of potassium carbonate yielding 7 in 69% overall
yield- (Scheme 3). However, this process uses i) higher volumes of the solvent mixture
during condensation of compound 6 with ethylene glycol, ii) higher volume of solvent to
purify crude bosentan and iii) a mixture of solvents used during preparation of 7.
In another process (Scheme 4), Manne et al.7 reported the reaction of 6 with sodium
hydroxide to give the hydroxy intermediate 8 which was subsequently treated with
Received February 9, 2016; in final form August 23, 2016.
Address correspondence to K. Rajasekhara Raju, Chemical Research and Development, Auro-
bindo Pharma Ltd, Survey No.71 and 72, Indrakaran (V), Sangareddy (M), Medal District 502329,
Telangana, India. E-mail: krsrajuk@gmail.com
481

482
Raju et al.
Scheme 1 First Generation Route for the Synthesis of Bosentan Sodium (7a)
chloroethanol to afford 7 in relatively low overall yield (67%). The disadvantage of this
method is the use of sodium hydroxide and large quantities of chloroethanol and the formation
of degradation products (impurities).
To overcome these limitations discussed above, we developed a method8 that affords
Bosentan monohydrate (7) in 60% overall yield from 2-cyanopyrimidine (14). As a fur-
ther elaboration of our ongoing research on the patent route,8 we now report an improved
overall yield of compound 7 (66% from 14).
In this improved process, the synthesis of 7 starts from two key starting materials,
namely 2-cyanopyrimidine (14) and guaiacol (Schemes 5 and 6). O-alkylation of guaiacol
(13) with dimethyl 2-chloromalonate (12) in the presence of sodium hydroxide in toluene
Figure 1 Process Impurities of Bosentan Monohydrate (7)

Large-Scale Synthesis of Bosentan Monohydrate
483
Scheme 2 Harringtons’s Route for the Preparation of Bosentan Monohydrate (7)
Scheme 3 Navnaths’s Route for the Preparation of Bosentan Monohydrate (7)
as solvent affords 1 with a purity of (78–82%) with 95% yield as an oily product. In this
reaction, the formation of major impurities such as tetra-carbomethoxyethylene (16),
dimethyl 2-chloro-2-(2-methoxyphenoxy)malonate (17), and methyl- 2-(2-methoxy phe-
noxy)acetate (18) were observed in 2–5% a/a by HPLC (Figure 2).
Using this as such for the synthesis of 3 gave less purity of 96.61% and yield of 87%.
Further, this compound was converted to 6 with less yield (85.70%) and 1.20% of 19 as
shown in Figure 3.

484
Raju et al.
Scheme 4 Manne et al Route for the Preparation of Bosentan Monohydrate (7)
Scheme 5 Synthetic Route for Dimethyl- 2-(2-methoxyphenoxy)malonate (1) and Pyrimidine-2-
carboximidamide Hydrochloride (2)
To overcome this we developed a crystallization method, where compound 1 was
crystallized from methyl tert-butyl ether and heptanes which resulted in a solid with a
purity of > 95% a/a and »65% overall yield.
Addition of 2-cyanopyrimidine (14) with methanol in the presence of NaOEt and metha-
nol as solvent yielded intermediate 15 with purity of 92% a/a. In this step, based on the experi-
mental data resulted in the formation of compound 20 as an impurity (7–12%) as shown in
Figure 4. This problem was overcome by carrying out the reaction at lower the temperature
(0–5ꢀC) and the use of a catalytic amount of NaOEt (0.1 m.eq), which led to a maximum con-
version to the intermediate 15. Subsequently, intermediate 15 was treated in situ with ammo-
nium chloride at 20–30ꢀC, resulting in compound 2 in 4 h. Cyclization of 2 (without isolation)
with 1 was carried out in the presence of base (NaOEt) to an 83% yield of 3 with 100% a/a of
HPLC pure compound.
Chlorination of 3 was performed using phosphorus oxychloride at reflux temperature to
afford 4 in 6 h. The reaction mixture was then quenched by addition to a mixture of water
and toluene followed by addition of aqueous sodium hydroxide (30% w/w). Separation of
the organic layer was performed at 80ꢀC (to avoid the precipitation of 4) and washed with

Large-Scale Synthesis of Bosentan Monohydrate
485
Scheme 6 Improved Synthetic Route for Bosentan monohydrate (7)
de-mineralized water at the same temperature. During the preparation of 4, we had observed
(by HPLC analysis) an intermediate 21 containing impurity 22 as shown in Figure 4. In this
improved process, impurity 22 and its subsequent impurity 23 were well controlled in the syn-
thesis of 4 by using highly pure 3 which was prepared by using crystalline compound 1.
Figure 2 Process Impurities of 1
Figure 3 Critical Process Impurities of 3

486
Raju et al.
Figure 4 Process Impurities of Compound 4 and 6
The organic layer containing 4 was treated with sulfonamide 5 in the presence of
potassium carbonate and tetra(n-butyl)ammonium bromide (TBAB) as phase-transfer
catalyst at reflux. The reaction mixture was then cooled to room temperature and the solid
formed was collected. It was suspended in de-mineralised water and heated at 60ꢀC under
reduced pressure to remove toluene. The resulting slurry was acidified with conc. hydro-
chloric acid to pH 0.5–0.7 at room temperature and the solid formed was collected to
afford 6 in 96% yield and purity > 99% a/a.
The literature preparation of bosentan has its own negative aspects such as the use of
higher mole ratio of ethylene glycol for the reaction and requirement of longer reaction
times for completion.9–12 Moreover, the reported yields were low (70–75%) compared to
the improved process due to the formation of impurities 8 and 9.
Hence, there is a need to control the formation of these impurities and to also have an effi-
cient purification method to obtain higher yields. Thereafter, the reaction was conducted with
in the presence of NaOH, Na2CO3, K2CO3 in ethylene glycol without additional solvent. How-
ever, the results revealed that the reaction was very slow due to the formation of water as a by-
product and the increase in the formation of undesired impurities. The etherification of 6 was
performed with 5.7% w/v concentration of monosodium ethylene glycolate13 in ethylene gly-
col to improve the yield of the product and results are shown in Table 1.
The experimental results revealed that higher temperatures lead to a higher level of impu-
rity 8 and the use of higher milliequiv. of base leads to increased formation of dimer 9. In par-
ticular, the removal of dimer impurity 9 in bosentan requires column chromatographic
separation. To achieve the optimum level of dimer 9 formation during reaction and to avoid
longer reaction times, the conditions were optimized in the etherification of 6 with 2.50 mole
ratio of 5.7% w/v of monosodium ethylene glycolate in ethylene glycol which resulted in
bosentan of 94.5% a/a HPLC purity with impurities of 8, dimer 9 and 24 (shown in Figure 5)
in the level of 3.85% a/a, 0.23% a/a and 0.18% a/a respectively (Table 1, Entry 3). In this pro-
cess, to increase the yield and reduce the cost of the product as well as to minimize the amount
of aqueous waste generated, the volume of ethylene glycol was decreased by using 2.50 mole
ratio of »5.7% w/v monosodium ethylene glycolate in ethylene glycol. The reaction time was
also reduced to 5 h when compared to the literature processes.6
After completion of etherification of 6, bosentan was extracted into dichloromethane
and the solution was acidified with conc. hydrochloric acid. The separated organic layer
was washed with water, dried and then concentrated to yield the crude bosentan. Surpris-
ingly, we found that the amount of dimer 9 was drastically reduced to a minimum of
0.07% in the conversion to bosentan potassium from the above crude using potassium
hydroxide in 8% w/w aqueous isopropanol. The resulting wet bosentan potassium was
acidified with sodium bisulfate to afford crude bosentan which is converted to 7b by addi-
tion of potassium hydroxide in de-mineralized water. By this process, the impurity 8

Large-Scale Synthesis of Bosentan Monohydrate
487

488
Raju et al.
Figure 5 Process Related Impurity of 7
remained in the mother liquor without loss of 7b because of 7b is only very slightly solu-
ble in water while the potassium salt of 8 is soluble in water. In the improved procedure,
the crude bosantan was purified by using inexpensive de-mineralized water and 8–10%
w/w aqueous isopropanol in the presence of potassium hydroxide instead of a mixture of
organic solvents used in the earlier reported process6 which advantageous from the stand-
point of the solvent recovery. Moreover, the 7b purification to control 8 was performed
with inexpensive potassium hydroxide and lesser volumes of de-mineralized water,
instead of large volumes of mixture of solvents as reported in literature.4,6
Wet bosentan potassium was extracted with dichloromethane after acidification with
aqueous sodium bisulfate monohydrate (NaHSO4.H2O). The organic layer was concen-
trated and the resulted mass was dissolved in ethanol and treated with activated carbon.
Then the solution was filtered to remove activated carbon, heated to 75–80ꢀC and de-min-
eralized water was added. Upon cooling to 20–25ꢀC, the product formed was collected
and dried at 30–35ꢀC under vacuum to yield the title compound 7 in 81% yield with a
purity of 99.90% a/a.
In conclusion, the work described in this investigation discloses a large scale
and safe method for the production of highly pure bosentan monohydrate (7) in
excellent overall yield (66%) from 2-cyanopyrimidine (14). This newly developed
process involves a lesser number of isolation steps and the use of lesser volume of
solvents.
Experimental Section
1H NMR and 13C NMR spectral data were obtained in dimethyl sulfoxide (DMSO-d6) and
CDCl3 at 300 MHz and 75 MHz spectrometers respectively. The chemical shift values are
reported on the d scale in parts per million (ppm), downfield from tetramethylsilane (TMS) as an
internal standard. IR spectra were recorded as KBr dispersions using a Perkin-Elmer Fourier
Transform (FT)-IR spectrophotometer. The mass spectrum was recorded using a Perkin-Elmer
PE SCIEX-API 2000, equipped with an ESI source used online with a HPLC system after the
ultraviolet (UV) detector. HPLC chromatographic purity was determined by using the area nor-
malization method. The thermal analysis was carried out on a DSC Q 1000 TA. The thermogram
was recorded from 30 to 200ꢀC. The solvents and reagents were used without purification.
Preparation of Dimethyl 2-(2-Methoxyphenoxy)malonate (1)
Sodium hydroxide (28.27 kg, 706.86 mol) was added in one portion to a mixture of 2-
methoxyphenol (13, 75 kg, 604.16 mol) and toluene (525 L) at 20–30ꢀC under stirring.
The reaction mixture was heated to reflux temperature and the water was separated

Large-Scale Synthesis of Bosentan Monohydrate
489
azeotropically using a Dean-Stark trap for 2 h. Then dimethyl chloromalonate (12,
110.69 kg, 664.57 mol) was added to the reaction mixture at 60–65ꢀC over a period of
30 min and heated to reflux and stirred for 3 h. After completion of the reaction, the mix-
ture was cooled to 20–30ꢀC and diluted with de-mineralized water (150 L). The two
layers were separated, and the organic layer was washed with 1% w/v aqueous sodium
hydroxide (2 £ 150 L). The organic layer was separated and concentrated to give oily
mass which was dissolved in methyl tert-butyl ether (225 L) at 20–30ꢀC; then n-heptane
(60 L) was cautiously added over 45 min at 20–30ꢀC. The resulting solution was seeded
with crystals of compound 1 (0.075 kg) to induce crystallization, then stirred for 1 h,
cooled to ¡10ꢀC and stirred for 2 h at the same temperature. Then the solid formed was
collected and dried at 30ꢀC under reduced pressure to afford 99.10 kg (65% yield) of 1 as
1
colorless crystals, mp: 38–40ꢀC, (purity of 95.13% a/a). H NMR (CDCl3, 300 MHz): d
7.02–7.06 (m, 2H), 6.84–6.93 (m, 2H) 5.26 (s, 1H), 3.85 (s, 9H). MS M/z (ESI): 253.0
[(MCH) ¡].
Anal. Calcd for C12H14O6: C, 56.69; H, 5.55. Found: C, 56.58; H. 5.49.
Preparation of 5-(2-Methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidine-4,6(1H, 5H)-
dione (3)
2-Cyanopyrimidine (14, 25 kg, 237.87 mol) was added to a solution of sodium ethoxide
(1.62 kg, 23.78 mol) in methanol (400 L) at 0–5ꢀC. The reaction mixture was stirred for 6 h at
0–5ꢀC, and the reaction temperature was raised to 25–30ꢀC. Ammonium chloride (13.36 kg,
249.76 mol) was added and the mixture was stirred for 4 h at 25–30ꢀC to yield 2 followed by
the addition of dimethyl 2-(2-methoxyphenoxy)malonate (1, 79.22 kg, 311.6 mol) at 0–5ꢀC.
Sodium ethoxide (55 kg, 808.75 mol) was added in portion wise for 1 h at 0–5ꢀC, the reaction
mixture was heated and stirred for 5 h at 35–40ꢀC. After completion of the reaction, de-miner-
alized water (1100 L) was added at 20–30ꢀC, and the pH was adjusted to 0.5–0.7 with 1 N
aqueous hydrochloric acid at 20–30ꢀC for 1 h and stirred for 1 h. The precipitated product was
collected, washed with de-mineralized water (50 L) and dried at 75–80ꢀC to give compound 3
as a light brown solid (61.36 kg, 83% yield¡and purity of 99.98%) mp. 262–264ꢀC. DSC:
279.11ꢀC and MS M/z (ESI): 311.2 [(MCH) ]; 1H NMR (DMSO, 300 MHz): d 3.83 (s, 3H),
6.66–6.69 (dd, 1H), 6.77–6.82 (dd, 1H), 6.94–6.96 (dd, 1H), 7.03–7.06 (dd, 1H), 7.73 (dd, 1H),
9.03–9.05 (d, 2H), 12.39 (brs, 2H).
Anal. Calcd for C15H12N4O4: C, 57.67; H, 3.87; N, 17.94. Found: C, 57.62; H, 3.81;
N, 17.88.
Preparation of 4-tert-Butyl-N-(6-chloro-5-(2-methoxyphenoxy)-2,20-bipyrimidin-4-yl)
benz-zenesulfonamide (6)
Bipyrimidinedione (3, 30 kg, 96.07 mol) was added to phosphorous oxychloride
(58.8 kg, 384.50 mol) and the reaction mixture was heated to 103–105ꢀC and stirred for
4 h. It was diluted with toluene (45 L), added to a mixture of toluene (315 L) and water
(105 L) at 20–50ꢀC and then treated with 30% w/w aqueous sodium hydroxide solution
(82.5 L) at 70–80ꢀC. The two layers were separated, and the organic layer was washed
with 0.4% w/v aqueous sodium hydroxide solution (120 L) at 70–80ꢀC. 4-(1,1-Dimethy-
lethyl)benzene sulfonamide (5, 20.49 kg, 96.06 mol) was added to the organic layer at
50ꢀC followed by potassium carbonate (15.9 kg, 115.21 mol) and tetra(n-butyl)ammo-
nium bromide (0.96 kg, 2.98 mol). Then it was heated to reflux and the water generated
was separated azeotropically using a Dean-Stark trap for 5 h. The reaction mixture was

490
Raju et al.
cooled to 20–25ꢀC and the wet product was collected, added to de-mineralized water
(360 L) and heated to 50–60ꢀC. Then, the toluene was distilled off under reduced pres-
sure at 60ꢀC and the residue was acidified with conc. hydrochloric acid (18 kg, 35% w/w)
over 40 min at 25ꢀC and stirred for 2 h at 20–30ꢀC. Then the precipitated solid was col-
lected, washed with de-mineralized water (60 L) and dried at 60ꢀC to provide compound
6 as colorless crystals (49.51 kg, 98%, and purity of 99.05% a/a), mp. 229–230ꢀC, MS
(ESI): m/z 524.2.0 [(MCH) ¡]; 1H NMR (DMSO, 300 MHz): d 1.27 (s, 9H), 3.72 (s, 3H),
6.77 (d, 1H), 6.85 (dd, 1H), 7.11 (m, 2H), 7.57 (d, 2H), 7.73 (dd, 1H), 8.28 (brs, 2H), 9.13
(d, 2H), 12.09 (brs, 1H).
Anal. Calcd for C25H24ClN5O4S: C, 57.08; H, 4.60; N, 13.31; S, 6.10. Found: C,
57.16; H, 4.54; N, 13.29, S, 6.04.
Preparation of Bosentan Monohydrate (7)
Compound (6, 38 kg, 72.24 mol) was added to 5.7% w/v monosodium ethylene glycolate
solution (266.41 L, 180.67 mol), and then the reaction mixture was heated to 110–115ꢀC
and maintained at that temperature for 5 h. The reaction mixture was then cooled to 20–
30ꢀC and dichloromethane (228 L) was added at 20–30ꢀC. Then the pH of mixture pH
was adjusted to 0.5–1.0 with conc. hydrochloric acid (12.16 kg, 36% w/w). The two
layers were separated and the aqueous ethylene glycol layer was extracted with dichloro-
methane (2 £114 L) at 20–25ꢀC. The combined organic layer was washed with de-miner-
alized water (2 £ 228 L) and concentrated to yield crude bosentan as a pale yellow solid.
Aqueous isopropyl alcohol (380 L, 8% w/w) was added to the crude bosentan at room
temperature and the slurried mass was heated to 55–60ꢀC. Potassium hydroxide (5.70 kg,
85% w/w, assay) was added and the mixture was heated to 75–85ꢀC and maintained at
that temperature for 1 h. Thereafter the reaction mixture was cooled to 10–12ꢀC and
stirred for 30 min. The wet bosentan potassium was collected, washed with isopropyl
alcohol (76 L, 10–12ꢀC) and added to a mixture of de-mineralized water (152 L) and
dichloromethane (228 L). After acidification to pH 1.0–2.0 with a solution of sodium
bisulfate monohydrate (13.68 kg) in de-mineralized water (38 L) at 20–30ꢀC, the two
layers were separated, and the aqueous layer was extracted with dichloromethane
(114 L). The combined organic layers were washed with de-mineralized water (152 L)
and concentrated to afford crude bosentan which was dissolved in a solution of potassium
hydroxide (5.93 kg, 85% w/w) in de-mineralized water (152 L) at 55–60ꢀC. The reaction
mixture was heated to 90–100ꢀC and maintained at that temperature for 1 h. Upon cool-
ing to 0–5ꢀC, the precipitated wet bosentan potassium was collected [chromatographic
purity of (by HPLC): 99.86% a/a, dimer 9: 0.06% and compound 15: 0.03%]. The wet
bosentan potassium was added to a mixture of de-mineralized water (152 L) and
dichloromethane (228 L) and acidified to pH 1.0–2.0 with a solution of sodium bisulfate
monohydrate (11.80, 85.46 mol) in water (38 L) at 20–30ꢀC. The organic layer was sepa-
rated and washed with de-mineralized water (2 £ 114 L) and concentrated to afford crude
bosentan. It was dissolved in ethanol (95 L) at 60–65ꢀC, treated with carbon enoantichro-
mos (2.6 kg), filtered through a hyflo bed and the residue was washed with hot ethanol
(19 L, 60–65ꢀC). The combined filtrate was heated to reflux temperature and added de-
mineralized water (114 L) at 75–78ꢀC. The resulting reaction mixture was allowed stand
to 20–25ꢀC over a period of 6 h for the product to crystallize completely. It was collected
and dried at 30–35ꢀC to yield bosentan monohydrate as colorless crystals (33.43 kg,
81%), mp. 114–116ꢀC (lit.6 mp.114–118ꢀC); MC (KF): 3.30%; Chromatographic purity
(by HPLC): 99.90% a/a, Impurity 8: 0.04% a/a, and dimer 9: 0.04% a/a; DSC: 123.71ꢀC;

Large-Scale Synthesis of Bosentan Monohydrate
491
MS m/z (ESI): 550.0 [(MCH) ¡]; IR: 3626, 3439, 3093, 3064, 3045, 3013, 2962, 2906,
1
2870, 1580, 1557, 1454, 1171, 1083; H NMR (DMSO, 300 MHz): d 1.27 (s, 9H), 3.49
(m, 2H), 3.80 (s, 3H), 4.35 (m, 2H), 4.69 (brs, 1H), 6.70 (d, 1H), 6.82 (dd, 1H), 7.08 (m,
2H), 7.56 (d, 2H), 7.68 (dd, 1H), 8.31 (d, 2H), 9.10 (d, 2H), 11.36 (brs, 1H); 13C NMR
(DMSO, 300 MHz):d 30.8, 34.8, 55.9, 59.2, 68.6, 113.1, 116.1, 120.6, 121.8, 123.5,
123.6, 125.3, 129.0, 137.04, 145.8, 149.1, 151.3, 155.5, 156.1, 157.9, 161.4.
Acknowledgements
The authors are grateful to colleagues in the Analytical Research Department of APL
Research center, a division of Aurobindo Pharma Ltd, Hyderabad for their valuable con-
tribution to this work. The authors also thank the management for permission to publish
this work and gratefully acknowledge the Executive Editor, Professor J.-P. Anselme, for
his patience, corrections and continuous suggestions in writing this manuscript.
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