An alternate synthesis of bosentan monohydrate, an endothelin receptor antagonist 1

Article abstract of DOI:10.1055/s-0033-1340281

An alternate synthesis of an endothelin receptor antagonist bosentan monohydrate is reported. This new synthetic route involves the coupling of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)(2,2′-bipyrimidin)-4-yl] benzene sulfonamide with commercially available raw material (2,2-dimethyl-1,3-dioxolan-4-yl)methanol as the key step. Attractive features of this approach are its versatileness, commercial availability of raw materials, usage of eco-friendly reagents, and it efficiently provides the desired bosentan monohydrate free from reported impurities such as dimer, N-alkylated, and pyrimidinone impurities. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1340281

LETTER
▌265
lAettner Alternate Synthesis of Bosentan Monohydrate, an Endothelin Receptor
Antagonist1
Synthesis of Bosentan Monohydrate
Rebelli Pradeep,a,b,c Yerrabelly Jayaprakash Rao,*a Yalamanchili Bharathi Kumari,b Porala Subbanarsimulu,c
Ghojala Venkat Reddy,c Bairy Kondal Reddyc
a
Department of Chemistry, University College of Science, Saifabad, Osmania University, Hyderabad 500004, India
E-mail: yjpr_19@yahoo.com
b
Department of Chemistry, Jawaharlal Nehru Technological University College of Engineering, Hyderabad 500085, India
c
Department of Research and Development, MSN R&D Center, Pashamylaram, Medak, Andhra Pradesh 502307, India
Received: 16.08.2013; Accepted after revision: 14.10.2013
large-scale commercial synthesis of bosentan monohy-
Abstract: An alternate synthesis of an endothelin receptor antago-
drate. By use of excess ethylene glycol a huge amount of
nist bosentan monohydrate is reported. This new synthetic route in-
toxic aqueous ethylene glycol effluent is generated and
also predominant dimer impurity is formed. The crude
volves the coupling of p-tert-butyl-N-[6-chloro-5-(2-methoxy-
phenoxy)(2,2′-bipyrimidin)-4-yl]benzene sulfonamide with com-
mercially available raw material (2,2-dimethyl-1,3-dioxolan- bosentan formed requires more than three purifications to
4-yl)methanol as the key step. Attractive features of this approach
are its versatileness, commercial availability of raw materials, usage
of eco-friendly reagents, and it efficiently provides the desired
tional Conference on Harmonization (ICH) grade quality
bosentan monohydrate free from reported impurities such as dimer,
N-alkylated, and pyrimidinone impurities.
wash out dimer 2 and pyrimidinone 3 impurities (which
are formed during the synthesis) and to provide Interna-
of bosentan. Finally, the process provides bosentan mono-
hydrate (1) in very poor yields.
P. J. Harrington et al.3 developed a new (second-genera-
Key words: alternate synthesis, bosentan monohydrate, eco-friend-
ly reagents, dimer impurity, N-alkylated, pyrimidinone
tion) process for the synthesis of bosentan monohydrate
(1). In this process ethylene glycol was replaced with
mono-tert-butyl-protected ethylene glycol to eliminate di-
mer impurity 2 (Figure 2). During the deprotection of
bosentan tert-butyl ether using formic acid gave bosentan
Pulmonary hypertension is an increase in blood pressure
in the pulmonary artery, pulmonary vein, or pulmonary
capillaries. There are many pathways to control the pul-
formate, which on hydrolysis with sodium hydroxide pro-
monary hypertension, of which three are important be-
vides bosentan along with thermally degraded N-alkylat-
cause they have been targeted with drugs like endothelin
ed impurity 4 and pyrimidinone impurity 3, which are
receptor antagonists, phosphodiesterase type 5 inhibitors,
and prostacyclin derivatives. Bosentan monohydrate (1,
difficult to wash out during a single purification step. To
get high-purity bosentan a greater number of recrystalliza-
Figure 1) is the first approved endothelin receptor antago-
tions is required, which decreases the yield of bosentan
nist for endothelin receptor type A and type B in 2001 and
monohydrate (1).
marketed as Tracleer.
In all the above previously reported commercial processes
for the preparation of bosentan monohydrate (1), forma-
tion of impurities like dimer 2, pyrimidinone 3, and N-al-
O
O
S
NH
OMe
kylated impurity 4 are playing a crucial role on quality and
yield of the bosentan. Several other methods4–9 have been
reported, which have their own disadvantages like forma-
tion of prior reported impurities and provides bosentan in
less yields. To overcome these disadvantages we recently
reported two new approaches for the preparation of bosen-
tan.10 The process involved the conversion of chloro com-
pound 5 into the corresponding hydroxy compound and
condensing it with either chloro acetonitrile or α-halo es-
ters, converting the intermediates formed into bosentan
monohydrate (1) with an overall yield of 62–65%.
O
O
N
N
N
N
(H2O)
OH
1
Figure 1 Structure of bosentan monohydrate (1)
The preparation of bosentan monohydrate (1) has been re-
ported by many authors using different methodologies.
The first-generation process reported by K. Burri et al.2
using genotoxic ethylene glycol and the highly pyrophoric
base sodium metal which are not very conducive for a
As a part of our ongoing studies on the development of
new and efficient syntheses of active pharmaceutical in-
gredients, we have explored an alternate synthesis of
bosentan monohydrate (1) as shown in Scheme 1. The key
features of this approach include the use of (2,2-dimethyl-
1,3-dioxolan-4-yl)methanol11 (6) in place of ethylene gly-
col; on coupling with chloro compound 5, 6 provides pro-
SYNLETT 2014, 25, 0265–0269
Advanced online publication: 02.12.2013
DOI: 10.1055/s-0033-1340281; Art ID: ST-2013-B0747-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

266
R. Pradeep et al.
LETTER
dium hydroxide in toluene under heating for ten hours
which yielded the required compound 7 in 65% yield (Ta-
ble 1, entry 1). Further optimization results are presented
in Table 1.
O
O
S
N
NH
OMe
O
O
N
N
N
Table 1 Effect of Reaction Conditions on the Coupling of 5 with
(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (6)
N
O
N
N
Entry
Base
Solvent
Temp (°C)aTime
(h)
Yield
(%)b
N
S
O
MeO
HN
1
2
3
4
5
6
7
8
NaOH
NaOH
NaOH
Na2CO3
K2CO3
NaOMe
NaOH
NaOH
toluene
THF
110
65
80
80
80
80
80
80
10
10
10
10
10
10
9
65
75
90
45
55
58
88
90
O
O
O
O
S
2
NH
OMe
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
O
O
O
O
N
S
N
NH
OMe
N
N
H
O
N
N
3
N
O
N
8
OH
4
a Reaction temperature.
b Isolated yield of 7.
Figure 2 Structures of dimer impurity 2, pyrimidinone impurity 3,
and N-alkylated impurity 4
Replacement of toluene with acetonitrile caused a sharp
increase in the yield (to 90%) of this reaction (Table 1, en-
try 3). On the other hand, replacement of sodium hydrox-
ide with other bases such as sodium carbonate (Table 1,
entry 4), potassium carbonate (Table 1, entry 5), and sodi-
um methoxide (Table 1, entry 6) substantially reduced the
yield of the reaction. The solvent and base used were
found to have a dramatic impact on the efficiency of this
reaction. Thus among the combination of solvents and
bases screened, only the sodium hydroxide in acetonitrile
provided the required product 7 in high yield within a
short reaction time (Table 1, entry 8).
tected diol compound 7, which on deprotection followed
by oxidation gives aldehyde compound 9. The subsequent
reduction of the aldehyde compound and purification of
crude bosentan provides high pure bosentan monohydrate
(1) with an average step yield of 87% and free of impuri-
ties such as dimer impurity 2, pyrimidinone impurity 3,
and N-alkylated impurity 4.
The key step in this approach is the coupling of chloro
compound 5 with (2,2-dimethyl-1,3-dioxolan-4-yl)meth-
anol (6) in the presence of a base. In the initial phase of
this study we investigated this condensation step using so-
O
O
O
O
S
S
NH
OMe
NH
N
OMe
O
O
O
a
O
N
N
+
HO
O
N
N
N
Cl
6
N
N
O
5
O
O
7
O
O
O
O
O
S
N
S
N
S
NH
OMe
NH
OMe
NH
OMe
O
O
O
O
O
O
N
b
c
d
N
N
N
N
N
N
N
N
N
OH
OH
O
(H O)
2
OH
H
1
9
8
Scheme 1 Alternate synthesis of bosentan monohydrate (1). Reagents and conditions: (a) NaOH, MeCN, 80–85 °C, 12 h; (b) 2 M HCl, MeCN,
r.t., 5 h; (c) NaIO4, acetone, H2O, 0 °C to r.t., 3 h; (d) NaBH4, MeOH, 0 °C to r.t., 4 h.
Synlett 2014, 25, 265–269
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Bosentan Monohydrate
267
The condensed product 7 on deprotection using 2 M HCl
in acetonitrile afforded the desired diol intermediate 8 in
almost quantitative yield (92%). The diol intermediate 8
was converted into the corresponding aldehyde 9 by oxi-
dizing with sodium periodate. The effect of temperature
and nature of solvent on the yields of the reaction were in-
vestigated, and the results are tabulated in Table 2. The
preliminary study was conducted using toluene (Table 2,
entry 1) as a solvent at 0–5 °C for nine hours, but the yield
of the desired product 9 was only 45%. Replacement of
toluene with acetone at 0–5 °C (Table 2, entry 3) provided
the required aldehyde 9 in 75% yields.
O
O
S
N
NH
N
OMe
O
O
N
N
O
OH
10
Figure 3 Structure of acid impurity
this purification using a mixture of solvents. When we
used a mixture of methanol and ethyl acetate (Table 3, en-
try 6), the purity of compound 1 increased gradually to
99.82%, but the obtained yield decreased. On the other
hand, replacement of ethyl acetate with cyclohexane (Ta-
ble 3, entry 7) increases the yield, but the quality of the
product decreased. Finally, we concluded that the high-
purity bosentan could be obtained using the combination
of methanol and ethyl acetate as solvent. Surprisingly, a
mixture of methanol and ethyl acetate (1:1) in combina-
tion with 1% water (Table 3, entry 9) provided pure
bosentan monohydrate (1) having HPLC13 purity of
99.8% in 85% yield. The results of the optimization stud-
ies are tabulated in Table 3.
Table 2 Effect of Solvent and Reaction Conditions on the Cleavage
of Diol Intermediate 8 Using Sodium Periodate
Entry
Solvent
Temp (°C)a Time (h) Yield (%)b
1
2
3
4
5
6
7
toluene
toluene
acetone
acetone
CH2Cl2
MeCN
THF
0–5
30
0–5
30
13
9
45
50
75
89
45
58
65
8
2.5
30
30
30
8
8
8
Table 3 Effect of Solvent on the Quality and Yield of Bosentan
Monohydrate (1)
a Reaction temperature.
b Isolated yield of 9.
Entry Solvent
Solvent Yield Purity by
volumea (%)b
HPLC (%)c
Increasing the reaction temperature to room temperature
resulted in the highest yield (89%) within a short time (Ta-
ble 2, entry 4). Next the reaction was carried out using var-
ious solvents, and the results are shown in Table 2 (entries
5–7). Finally, we have concluded that using acetone at
room temperature was the most suitable method for the
conversion of diol intermediate 8 into aldehyde inter-
mediate 9.
The aldehyde compound 9,12 on reduction using sodium
borohydride, provided the crude bosentan monohydrate
(1) using methanol as solvent. This conversion does not
give any scope for the formation of prior known impuri-
ties. There is only a scope for the formation of acid impu-
rity 10 (Figure 3), which may be due to overoxidation of
compound 9. This impurity was completely washed out
(<0.15% impurity in the final product) during the isolation
process of bosentan monohydrate. For commercial syn-
thesis the isolation of pure bosentan from crude bosentan
at low production cost by minimizing the yield loss during
the purification is a very challenging task.
1
2
3
4
5
6
7
8
9
EtOAc
4×
3×
3×
3×
3×
4:4
3:3
2:2
71
69
74
72
70
68
74
76
85
97.5
98.25
98.1
96.7
98.3
99.82
97.3
99.65
99.8
MeOH
t-BuOAc
2-PrOH
EtOH
MeOH–EtOAc
MeOH–cyclohexane
MeOH–EtOAc
MeOH–EtOAc (1% H2O) 1:1
a Solvent volume is with respect to input quantity.
b Isolated yield of 1 from crude bosentan.
c Purity of bosentan monohydrate.
The residual solvents present in the final purified bosentan
monohydrate (1) were analyzed using the described GC
method,14 and it was found that all the solvents were well
within the specified ICH limits as shown in Table 4.
So we have attempted several purifications using different
solvents such as methanol, isopropyl alcohol, ethanol,
ethyl acetate, isopropyl acetate, tert-butyl acetate, and
combinations of these solvents. Optimization results are
presented in Table 3. Initially, the purification was at-
tempted using a single solvent (Table 3, entries 1–5), but
the purity of compound 1 is less. So we turned to attempt
In conclusion, an alternate, improved, efficient, and in-
dustrially scalable synthetic route was developed for the
endothelin receptor antagonist bosentan monohydrate (1).
A further feature of this sequence was involving of novel
intermediates 7 and 8 and finally provided bosentan
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 265–269

268
R. Pradeep et al.
LETTER
Table 4 Trend Data for Residual Solvents Present in the Bosentan Monohydrate (1)
Entry
Solvent
ICH limit (ppm)
Residual solvents trend data for batch 1 Residual solvents trend data for batch 2
1
2
3
4
5
6
7
MeCN
410
600
n.d.a
n.d.
174
n.d.
n.d.
566
n.d.
n.d.
n.d.
260
n.d.
n.d.
510
n.d.
CH2Cl2
MeOH
3000
5000
3880
5000
890
acetone
cyclohexane
EtOAc
toluene
a n.d. = not detected.
H), 9.08–9.10 (d, J = 1.5 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ
= 31.14, 34.31, 55.73, 62.37, 69.63, 71.93, 113.9, 117.92, 120.92,
123.52, 123.59, 124.89, 128.11, 129.15, 135.84, 144.29, 149.04,
152.06, 153.62, 156.55, 156.93, 160.96, 162.35. MS: m/z = 582.3
[M + H]. IR (KBr): νmax = 3364.54 (NH), 3184.34 (OH), 1384.67
(SO2) cm–1. Anal. Calcd (%) for C28H31N5O7S: C, 57.82; H, 5.37; N,
12.04. Found: C, 57.75; H, 5.25; N, 12.17.
monohydrate (1) free of dimer 2, pyrimidinone 3, and
N-alkylated 4 impurities. The new process reduces the
number of hazardous reagents and the amount of hazard-
ous waste generated, which was making the process more
environmentally friendly. The quality of the final active
pharmaceutical ingredient (API) easily meets the specifi-
cations approved by ICH guidelines.
4-tert-Butyl-N-[5-(2-methoxyphenoxy)-6-(2-oxoethoxy)-2,2′-bi-
pyrimidin-4-yl]benzenesulfonamide (9)
To a solution of 4-tert-butyl-N-{6-[(2,2-dimethyl-1,3-dioxolan-4-
yl)methoxy]-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl}ben-
zenesulfonamide (8, 40 g, 0.07 mol) in acetone (200 mL), NaIO4
(36.8 g, 0.17 mol) in H2O (200 mL) was added slowly for 30 min at
0–5 °C. The reaction mixture was further stirred for 2–3 h at ambi-
ent conditions. The reaction mixture was extracted twice with
CH2Cl2 (2 × 200 mL), and washed with H2O (160 mL). The organic
solvent was evaporated under reduced pressure. Cyclohexane (200
mL) was added to the obtained residue and stirred for 30–45 min.
The precipitated solid was filtered and washed with cyclohexane
(40 mL) and dried in oven at 60 °C to afford 9 (33.5 g, 89%); mp
208–210 °C. 1H NMR (300 MHz, CDCl3): δ = 1.26 (s, 9 H), 3.98 (s,
3 H), 5.15 (s, 2 H), 6.85–7.6 (m, 7 H), 8.42–8.45 (s, 2 H), 9.0 (d, 2
H), 9.72 (s, 1 H). MS: m/z = 550.5 [M + H]. IR (KBr): νmax = 1720
(C=O stretching) cm–1.
4-tert-Butyl-N-{6-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-5-
(2-methoxyphenoxy)-2,2′-bipyrimidin-4-yl}benzenesulfon-
amide (7)
To a solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (6, 62.7
g, 0.47 mol) in MeCN (1000 mL), NaOH (20.9 g, 0.52 mol) was
added 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 sul-
fonamide (5, 50 g, 0.1 mol) was added, and the mixture was agitated
for 8 h. MeCN was distilled off from the reaction mixture, and
MeOH (100 mL) was added to it. To this clear solution H2O (1000
mL) was slowly added and stirring continued for 1 h. The resulting
precipitate was filtered, washed with H2O (50 mL) and dried in oven
at 65 °C to afford 7 (53.5 g, 90%); mp 185–188 °C. 1H NMR (300
MHz, CDCl3): δ = 1.20 (s, 9 H), 1.27 (s, 6 H), 3.53–3.82 (m, 2 H),
3.85 (s, 3 H), 4.52–4.57 (m, 1 H), 6.68–6.98 (m, 4 H), 7.10–7.25 (m,
5 H), 8.81 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 26.05, 30.41,
34.27, 55.52, 62.98, 73.65, 77.16, 111.82, 118.23, 120.19, 122.39,
123.87, 125.66, 125.85, 127.69, 128.19, 135.71, 144.56, 149.18,
152.79, 155.11, 156.1, 156.91, 160.86, 162.36. MS: m/z = 622.3 [M
+ H]. IR (KBr): νmax = 3467.57 (NH), 1368.4 (SO2) cm–1. Anal.
Calcd (%) for C31H35N5O7S: C, 59.89; H, 5.67; N, 11.26. Found: C,
59.77; H, 5.71; N, 11.16.
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxy phenoxy)-
2,2′-bipyrimidin-4-yl]benzenesulfonamide, Bosentan Monohy-
drate (1)
A solution of 9 (100 g, 0.18 mol) in MeOH (500 mL) was cooled to
0–5 °C and NaBH4 (6.91 g, 0.18 mol) was slowly added in portions.
The reaction mixture was stirred for 2–3 h, and MeOH was distilled
off. Then the mixture was quenched with ice-cold H2O, and the pH
value was adjusted to 2–3 using 6 M HCl. Afterwards the reaction
mixture was extracted with EtOAc. The EtOAc layer was washed
with 5% brine solution (2 × 500 mL) and concentrated under re-
duced pressure to obtain the residue. The obtained residue was dis-
solved in MeOH (120 mL) and reprecipitated with H2O (240 mL).
The precipitated solid was filtered, washed with H2O (100 mL). The
resultant solid dissolved in EtOAc (100 mL), MeOH (100 mL), and
H2O (1 mL), heated to 65–70 °C for 1 h, cooled to 30 °C, and main-
tain 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 high-pu-
rity bosentan monohydrate (1, 79.6 g, 80%) as a white to pale yel-
low solid; mp 138–140 °C. 1H NMR (300 MHz, CHCl3): δ = 1.29
(s, 9 H), 3.86 (s, 2 H), 4.0 (s, 3 H), 4.57–4.60 (m, 2 H), 4.88 (s, 1 H),
6.85–7.15 (m, 4 H), 7.41–7.45 (m, 3 H), 8.42–8.45 (d, J = 8.5 Hz, 2
H), 8.8 (br s, 1 H), 9.00–9.10 (d, J = 4.9 Hz, 2 H). MS: m/z = 552
[M + H]. IR (KBr): νmax = 3437.4 (NH), 1342 (SO2) cm–1. HPLC
purity: 99.8%; water content: 3.2% (w/w).
4-tert-Butyl-N-[6-(2,3-dihydroxypropoxy)-5-(2-methoxyphe-
noxy)-2,2′-bipyrimidin-4-yl]benzenesulfonamide (8)
The solution of 4-tert-butyl-N-{6-[(2,2-dimethyl-1,3-dioxolan-4-
yl)methoxy]-5-(2-methoxy phenoxy)-2,2′-bipyrimidin-4-yl}ben-
zenesulfonamide (7, 50 g, 0.08 mol) in MeCN (250 mL), 2 M HCl
(250 mL) was added slowly for 20–30 min and stirring continued
for 5 h at ambient conditions. Then reaction mass was extracted
twice with CH2Cl2 (2 × 250 mL). The organic solvent was evaporat-
ed, and the residue was dissolved in MeOH (50 mL). The MeOH so-
lution was added slowly to H2O (250 mL) for 45 min. The resulting
precipitate was filtered, washed with H2O (50 mL) and dried in oven
at 60 °C for 6 h to provide 8 (43 g, 92%) as a yellow color solid; mp
100–103 °C. 1H NMR (300 MHz, CDCl3): δ = 1.29 (s, 9 H), 3.51–
3.53 (d, J = 1.4 Hz, 2 H), 3.81–3.88 (m, 1 H), 3.92 (s, 3 H), 4.60–
4.71 (m, 2 H), 6.88–6.90 (d, J = 2.7 Hz, 1 H), 6.97–7.06 (m, 2 H),
7.10–7.15 (t, 1 H), 7.44–7.54 (m, 3 H), 8.40–8.43 (d, J = 2.2 Hz, 2
Synlett 2014, 25, 265–269
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Bosentan Monohydrate
269
(7) Vinayak, G.; Manojkumar, B.; Dattatraya, S.; Dattatrey, K.;
Sushanth, G.; Ramesh, D. WO 2012/56468 A1, 2012.
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G. US 2012/0136015A1, 2012.
(10) Pradeep, R.; Jayaprakash, R. Y.; Bharathi, K. Y.;
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Acknowledgement
One of the author (Pradeep Rebelli) thanks to the HOD’s Osmania
university and JNTU Hyderabad for giving opportunity to pursue
PhD studies. Our sincere thanks to Dr. M. S. N. Reddy and Dr. Ch.
Nagaraju for providing infrastructural facilities to carry out the re-
search work and also be indebted to S. Eswaraiah, S. T. Rajan, and
Dr. M. Srinivas for their continuous guidance and support.
(11) Krief, A.; Froidbise, A. Tetrahedron 2004, 60, 7637.
(12) Aldehyde intermediate 9 was found to be stable at r.t. in
airtight polythene bags. Hence special storage and packing
conditions are not required.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(13) HPLC Method
References and Notes
Column: BDS Hypersil C18, 250 × 4.6 mm, 5 μm; UV, λ =
220 nm; temp: 30 °C; load: 20 μL; elution: gradient; buffer:
dipotassium hydrogen orthophosphate; diluent: mobile
phase A + mobile phase-B; mobile phase A: 95% buffer +
5% MeOH; mobile phase B: 95% MeOH + 5% H2O.
(14) GC Method for Residual Solvents
(1) This is MSNRD communication number 008.
(2) Burry, K.; Clozel, M.; Fischli, W.; Hirth, G.; Loffler, B. M.;
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(6) Raman, J. V.; Patel, S.; Mistry, S.; Parmar, B.; Timbadiya,
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Column: DB-624; length: 30 m; film thickness: 30 μm;
injector temp: 140 °C; split: 1:5; detector temp: 260 °C
(FID); carrier gas: helium; load: 1.0 μL; diluent: DMSO;
oven temp: 40 °C; program to 130 °C at 6 °C per min; hold
for 5 min; then again raised to 240 °C at 35 °C per min.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 265–269

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