An Efficient Synthesis of Ivacaftor

Article abstract of DOI:10.1002/jhet.2931

New and practical synthetic route of ivacaftor is described on a grams scale. An electrophilic addition of two t-butyl groups to the aromatic ring is adopted to prepare 5-amino-2,4-di-t-butylphenol in 61% yield over three steps with 98.1% purity (high-performance liquid chromatography). An intramolecular cyclization of ethyl 3-(2-aminophenyl)-3-oxo-propanoate with dimethylformamide-dynamic mechanical analysis is used to prepare 4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 54% yield over four steps. Ivacaftor is obtained by condensation of the two parts in 71% yield with 99.1% purity (high-performance liquid chromatography).

Full text of DOI:10.1002/jhet.2931

Month 2017
An Efficient Synthesis of Ivacaftor
Rui Zhang, Guanyu Han, Luobin Jiang, Yao Shen, Rui Yang, Yongjun Mao,*
and Hang Wang
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China
*
E-mail: yongjun.mao@hotmail.com
Received August 1, 2016
DOI 10.1002/jhet.2931
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
New and practical synthetic route of ivacaftor is described on a grams scale. An electrophilic addition of
two t-butyl groups to the aromatic ring is adopted to prepare 5-amino-2,4-di-t-butylphenol in 61% yield over
three steps with 98.1% purity (high-performance liquid chromatography). An intramolecular cyclization of
ethyl 3-(2-aminophenyl)-3-oxo-propanoate with dimethylformamide-dynamic mechanical analysis is used
to prepare 4-oxo-1,4-dihydroquinoline-3-carboxylic acid in 54% yield over four steps. Ivacaftor is obtained
by condensation of the two parts in 71% yield with 99.1% purity (high-performance liquid chromatography).
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
Gould-Jacobs procedure, heating diethyl 2-((phenylamino)
methylene)malonate (9) with diphenyl ether at
230–240°C for several hours to give ethyl 4-oxo-1,4-
dihydroquinoline-3-carboxylate in moderate yield [8,9], as
shown in Scheme 2. Compound 2 is obtained through
ester hydrolysis. The high temperature required for the
cyclization step lead to a fussy and hard operation.
Furthermore, diphenyl ether is a high boiling solvent
difficult to recover, harmful to environment and may also
cause allergies to people handling it.
Ivacaftor (VX-770, Kalydeco™) 1, as shown in Figure 1,
is a drug used to treat cystic fibrosis in people with
certain mutations in the cystic fibrosis transmembrane
conductance regulator gene [1,2]. It was developed by
Vertex Pharmaceuticals and approved by the FDA in
January 2012 [3]. The combination drug lumacaftor/
ivacaftor (Orkambi™) is also used to treat cystic fibrosis,
was approved by the FDA in 2015 [4].
With regarded to the synthesis of ivacaftor, it can be
envisioned as a combination of two structural fragments,
4
5
-oxo-1,4-dihydroquinoline-3-carboxylic acid (2) and
-amino-2,4-di-t-butylphenol (3), as shown in Figure 1.
A couple of methods have been reported for the
RESULTS AND DISCUSSION
In order to develop practical method for preparation of
ivacaftor, 4-oxo-1,4-dihydroquinoline-3-carboxylic acid
(2) and 5-amino-2,4-di-t-butylphenol (3) are prepared in
new route, as shown in Schemes 3 and 4.
synthesis of compound 3 and the methyl carbonate
derivative 8, as depicted in Scheme 1 [5–7]. 2,4-Di-t-
butylphenol (4) is adopted as the starting material, via
protection, nitration, ester hydrolysis, and reduction to
give the final product 3. Compound 8 is obtained from
intermediate 6 through catalytic hydrogenation. The main
drawback of the nitration of 5 to 6 methodology is poor
selectivity and low yield (29%). Compound 6 is isolated
by column chromatography, which is not suitable for
scale-up preparation.
As depicted in Scheme 3, the electrophilic addition of
t-butyl group to benzene ring was adopted to prepare
compound 3 after optimization [10,11], as shown in
Table 1. N-(3-hydroxyphenyl)acetamide (11) was
prepared from 3-aminophenol (10), which was treated
with t-butanol and concentrated H SO4 in CH Cl2 at
2
2
room temperature for 48 h to give compound 12 in 74%
yield after purified by recrystallization [12,13]. 5-Amino-
2,4-di-t-butylphenol (3) was obtained by acid hydrolysis
The reported approach to the synthesis of 4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (2) are mainly via
©
2017 Wiley Periodicals, Inc.

R. Zhang, G. Han, L. Jiang, Y. Shen, R. Yang, Y. Mao, and H. Wang
Vol 000
Figure 1. Chemical structures of Ivacaftor (1), (2) and (3).
Scheme 1. Reagents and conditions: (a) CH
3 2 3 2 2 3 2 4
CO Cl, Et N, DMAP, CH Cl ; (b) HNO , H SO , 29% via column chromatography; (c) KOH, MeOH; (d)
HCO NH , Pd/C, EtOH; (e) H , Pd-C, MeOH, rt.
2
4
2
Scheme 2. Reagents and conditions: (a) (i) PhOPh, 230–240°C, 40–60%; (ii) NaOH, EtOH, reflux; (b) (i) 1,3,5,2,4,6-trioxatriphosphorinane (T3P),
pyridine, 2-MeTHF, 50°C, 8 h, 70%; (ii) NaOMe, rt; (c) HBTU, Et N, DMF, 71%.
3
2 2 4 2 2 2
Scheme 3. Reagents and conditions: (a) Ac O, HOAc, 50°C, 2 h, 92%; (b) H SO , CH Cl , rt, 48 h, 74%; (c) HCl, EtOH-H O, 89%.
of 12 in good yield and 98.1% purity [high-performance
liquid chromatography (HPLC)].
(16) [14,15]. 2-Nitrobenzoic acid (13) was reacted with
N,N’-Carbonyldiimidazole (CDI) and ethyl potassium
malonate to give the intermediate 14 in good yield [16].
Compound 15 was obtained by catalytic hydrogenation
of 14 in high yield, which was treated with DMF-DMA
in toluene at 100°C to give 16 in 73% yield after
purification by recrystallization. Compound 2 was then
As shown in Scheme 4, the intramolecular cyclization of
ethyl 3-(2-aminophenyl)-3-oxo-propanoate (15) and N,N-
dimethylformamide dimethyl acetal dimethylformamide-
dynamic mechanical analysis (DMF-DMA) was used to
prepare ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
An Efficient Synthesis of Ivacaftor
Scheme 4. Reagents and conditions: (a) (i) CDI, MeCN; (ii) ethyl potassium malonate, MgCl
2
, Et
3
N, rt À 35°C; (iii) 3 N HCl, 82%; (b) H
N, DMF, rt, 71%.
2
, Raney-Ni,
THF, rt; (c) DMF-DMA, toluene, 100°C, 6 h, 73%; (d) NaOH, EtOH-H O, reflux, 2 h, 91%; (e) EDCI, HOBt, Et
2
3
Table 1
The Optimization Methods of Preparation Compd. 12 from 11.
Item
Alkylating agent
Catalyst acid
AlCl
Solvent
Time
4 h
Temp.
Result
1
2
3
4
5
6
7
2-chloro-2-methylpropane
2-chloro-2-methylpropane
t-butanol
t-butanol
t-butanol
3
dichloromethane
toluene
dichloromethane
toluene
dichloromethane
dichloromethane
dichloromethane
rt
No product
No product
No product
Insoluble
<50% yield
74% yield
73% yield
H
2
SO
4
4 h
rt À 60°C
0°C À rt
0°C À rt
rt À 40°C
rt
AlCl
3
12 h
12 h
24 h
48 h
4 days
H
2
H
2
H
2
H
2
SO
SO
SO
SO
4
4
4
4
t-butanol
t-butanol
rt
obtained after ester hydrolysis, which reacted with 5-
amino-2,4-di-t-butylphenol (3) directly using EDC/HOBt
as the condensing agent to give the final product
ivacaftor (1) in 71% yield and 99.1% purity (HPLC) after
purified by recrystallization [17,18].
In summary, we have developed a new and practical
synthetic route of ivacaftor (1). On the one hand, an
electrophilic addition of t-butyl group to benzene ring is
adopted to prepare 5-amino-2,4-di-t-butylphenol (3) in
UltraShield 400 Plus spectrometer using tetramethylslane
or trimethylsilyl as an internal standard. Mass spectra were
obtained from a Finnigan MAT-95/711 spectrometer.
Melting points were measured on a Shenguang WRS-1B
melting point apparatus and are uncorrected. The HPLC
results were generated using a Waters 2487 UV/Visible
Detector and Waters 515 Binary HPLC Pump.
N-(3-Hydroxyphenyl)acetamide (11).
A mixture of 3-
aminophenol (109.1 g, 1.0 mol) and HOAc (700 mL)
6
1% yield over three steps from 3-aminophenol and
was stirred and heated to 50°C. Ac O (112.3 g, 1.1 mol)
2
9
8.1% purity (HPLC). On the other hand, an
was added to the reaction solution over 1 h and stirred at
the temperature for another 1 h. It was cooled to room
temperature, and poured slowly into ice-water (3 L) while
stirring constantly. The solid formed was filtered off and
washed with cold water (300 mL × 2), dried at 45°C for
intramolecular cyclization of ethyl 3-(2-aminophenyl)-3-
oxo-propanoate (15) with DMF-DMA is used to prepare
4
yield over four steps. Lastly, compound 2 was condensed
with 3 to give ivacaftor (1) in 71% yield and 99.1%
purity (HPLC), and the overall yield of 1 from compound
-oxo-1,4-dihydroquinoline-3-carboxylic acid (2) in 54%
6
h to afford 11 (139.0 g, 92%) as a white solid, mp
1
146–148°C. H NMR [dimethyl sulfoxide (DMSO)-d ,
6
1
3 is 39%. Purification methods of the intermediates
δ]: 2.01 (s, 3H), 6.42 (m, 1H), 6.92 (m, 1H), 7.04 (m,
involved in the route were also given.
1
H), 7.18 (m, 1H), 9.33 (s, 1H), 9.78 (s, 1H);
electrospray ionization-mass spectrometry (ESI-MS) (m/z)
+
1
52.2 (M + H) .
EXPERIMENTAL
N-(2,4-di-tert-butyl-5-hydroxyphenyl)acetamide (12).
Concentrated H SO4 (176.4 g, 1.8 mol) was added
2
All commercially available chemicals and solvents were
slowly to the stirred solution of 11 (120.0 g, 0.79 mol),
t-butanol (205.0 g, 2.77 mol) and CH Cl (1.5 L) below
20°C. White sticky solid was formed immediately, and
1
used as received without any further purification. H NMR
2
2
13
and C NMR spectra were recorded on a Bruker
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Zhang, G. Han, L. Jiang, Y. Shen, R. Yang, Y. Mao, and H. Wang
Vol 000
the suspension was stirred quickly at room temperature for
8 h to give a white homogeneous suspension. The
resulting white solid was filtered, washed with H O
portion-wise, gas evolution was observed. This solution
was stirred for 4 h at the ambient temperature.
4
Flask B: To a solution of ethyl potassium malonate
2
(
400 mL × 2) and then mixed with 300 mL H O and
(510.0 g, 3.0 mol) in CH CN (4 L) was added MgCl2
2
3
stirred quickly. Saturated aqueous NaHCO was added
slowly to the mixture to adjust the pH ~ 6. The resulting
(103.0 g, 1.08 mol) in portions over 15 min. The mixture
was stirred at 35°C for 30 min and then cooled to 25°C
and triethylamine (253.0 g, 2.5 mol) was added. The
reaction mixture became very thick, and the slurry was
stirred for 30 min.
3
white solid was filtered, washed with H O (400 mL × 2)
2
and dried at 50°C for 5 h to give the crude product 12
(187 g), which was stirred and heated with 1:1 (v/v)
hexane/EtOAc (500 mL) at reflux for 2 h then cooled to
room temperature overnight, the resulting solid was
filtered off and washed with 1:1 (v/v) hexane/EtOAc
The solution in flask A was then transferred to the slurry
in flask B over 15 min. The reaction temperature rose to
35°C, and gas evolution was observed. The reaction
mixture was stirred for 1.5 h, cooled to 5°C, and
quenched with 3 N HCl (3 L), while maintaining the
reaction temperature < 20°C. The resulting solution was
(
200 mL × 2), dried at 40°C for 3 h to afford 12
1
(154.0 g, 74%) as a white solid, mp 91–94°C. H NMR
(
6
DMSO-d , δ): 1.25 (s, 9H), 1.33 (s, 9H), 1.99 (s, 3H),
6
13
.45 (s, 1H), 7.11 (s, 1H), 9.00 (s, 1H), 9.16 (s, 1H).
C
distilled to remove CH CN and the resulting concentrate
3
NMR (100 MHz, DMSO-d ): δ = 24.0, 30.9, 31.2, 35.4,
extracted with EtOAc (4 L). The organic phase was
6
3
6.8, 110.3, 126.0, 131.5, 132.2, 132.6, 149.0, 169.3.
washed with water (2 L), saturated NaHCO (2 L), and
3
+
+
ESI-MS (m/z) 264.3 (M + H) , 527.4 (2 M + H) , 549.4
brine (2 L). The organic solution was concentrated under
reduced pressure to give light yellow oil, which was
solidified at room temperature to afford 14 (194.5 g,
+
(2 M + Na) .
5
-amino-2,4-di-tert-butylphenol (3).
Concentrted HCl
1
(
(
167.0 mL, 2.0 mol) was added to a suspension of 12
135.0 g, 0.51 mol), EtOH (1.4 L) and H O (200 mL).
82%) as a light yellow solid, mp 34–36°C. H NMR
(CDCl , δ): 1.33 (t, J = 7.2 Hz, 3H), 3.48 (s, 2H), 4.27
2
3
13
The reaction mixture was stirred and heated to reflux for
h to give a clear solution. It was cooled to room
(q, J = 7.2 Hz, 2H), 7.71 (m, 2H), 7.90 (m, 1H).
C
6
NMR (100 MHz, DMSO-d ): δ = 13.9, 49.0, 61.8, 124.1,
6
temperature, and around 1 L solvent was recovered under
reduced pressure. The residue was stirred at room
temperature for 2 h. The resulting white solid was
filtered, washed with cold water (200 mL × 2) and then
mixed with 200 mL water and stirred quickly. Saturated
128.0, 130.9, 132.8, 134.7, 144.6, 166.5, 194.5. HRMS
(ESI): Calcd for C H NO : 237.2110, Found 237.2105.
11
11
5
Ethyl 3-(2-aminophenyl)-3-oxopropanoate (15). Compound
14 (130.0 g, 0.55 mol) and Raney Ni (wet, 30 g) were added
to THF (2 L), and stirred for 6 h at room temperature under
hydrogen bag at atmospheric pressure to form a clear brown
solution. The reaction mixture was then filtered through a
celite pad, the filter cake was washed by THF (200 g × 2).
The combined filtrate was concentrated to give the product
aqueous NaHCO was added slowly to the mixture to
3
adjust the pH ~ 6 and the mixture was stirred for another
2
h. The resulting white solid was filtered, washed with
cold water (200 mL × 2) and dried at 45°C for 5 h to
afford the crude product (110 g), which was stirred and
heated with 1:1 (v/v) hexane/EtOAc (350 mL) at reflux
for 2 h then cooled to room temperature overnight, the
resulting solid was filtered off and washed with 1:1 (v/v)
hexane/EtOAc (100 mL × 2), dried at 40°C for 3 h to
15 (114.0 g) as a light brown oil, which was used directly
1
at the next step. H NMR (CDCl , δ): 1.31 (t, J = 7.2 Hz,
3
3H), 3.44 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 6.68 (m, 2H),
7.30 (m, 1H), 7.86 (m, 1H), 8.77 (brs, 2H). ESI-MS (m/z)
À
207.0 (M – H) .
1
afford 3 (100.5 g, 89%) as a gray solid, mp 86–89°C. H
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (16). To
a stirred solution of 15 (50.0 g, 0.24 mol) in toluene
(600 mL) was added DMF-DMA (57.2 g, 0.43 mol). The
mixture was stirred and heated to 100°C for 6 h and then
cooled to room temperature. A gray suspension was
formed and the resulting solid was collected by suction
NMR (DMSO-d , δ): 1.32 (s, 9H), 1.34 (s, 9H), 6.79
6
(
2
s, 1H), 7.19 (s, 1H), 9.78 (brs, 2H). ESI-MS (m/z)
22.3 (M + H) .
+
HPLC Conditions: Column: InertSustain C18
(
250 mm × 4.6 mm × 5 μm); Detection: 220 nm; Flow
rate: 0.8 mL/min; Temperature: 30°C; Injection load:
μL; Solvent: MeOH; Concentration: 0.2 mg/mL; Run
filtration, washed with 50% EtOH/H O (80 mL × 2), and
2
1
dried at 60°C to give a gray solid. The crude product was
stirred and heated with 1:1 (v/v) EtOH/EtOAc (160 mL)
at reflux for 2 h then cooled to room temperature
overnight, the resulting solid was filtered off and washed
with 1:1 (v/v) EtOH/EtOAc (50 mL × 2), dried at
time: 15 min; Mobile phase A: water; Mobile phase B:
MeOH/AcOH = 100:0.1; Gradient program: Mobile
phase A/Mobile phase B = 10/90: tR = 5.404 min,
purity: 98.1%.
Ethyl 3-(2-nitrophenyl)-3-oxopropanoate (14). Flask A:
To a suspension of 2-nitrobenzoic acid (167.1 g, 1.0 mol)
60°C for 4 h to afford 16 (38.0 g, 73%) as an light
1
yellow solid, mp >250°C. H NMR (DMSO-d , δ): 1.29
6
in CH CN (2 L) was added CDI (178.4 g, 1.1 mol)
(t, J = 7.2 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 7.42 (m,
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
An Efficient Synthesis of Ivacaftor
1
3
1
1
H), 7.62 (m, 1H), 7.71 (m, 1H), 8.16 (m, 1H), 8.55 (s,
H), 12.31 (s, 1H). C NMR (100 MHz, DMSO-d6):
(brs, 1H). C NMR (100 MHz, DMSO-d ): δ = 29.9,
6
1
3
31.1, 34.4, 34.8, 111.3, 116.4, 119.5, 124.2, 125.6, 126.0,
126.5, 132.0, 132.8, 133.3, 134.0, 139.6, 144.5, 153.7,
163.3, 176.9. HRMS (m/z): Calcd for C H N O :
δ = 14.5, 59.5, 110.0, 118.8, 124.6, 125.6, 127.4, 132.4,
39.1, 144.9, 164.9, 173.5. MS (ESI): m/z = 218.2
1
24 28 2 3
+
(M + H) .
392.4990, Found 392.4944.
HPLC Conditions: Column: InertSustain C18
250 mm × 4.6 mm × 5 μm); Detection: 220 nm; Flow
rate: 0.8 mL/min; Temperature: 30°C; Injection load:
HPLC Conditions: Column: InertSustain C18
(250 mm × 4.6 mm × 5 μm); Detection: 220 nm; Flow
rate: 0.8 mL/min; Temperature: 30°C; Injection load:
1 μL; Solvent: MeOH; Concentration: 0.2 mg/mL; Run
time: 15 min; Mobile phase A: water; Mobile phase B:
(
1
μL; Solvent: MeOH; Concentration: 0.2 mg/mL; Run
time: 15 min; Mobile phase A: water; Mobile phase B:
MeOH; Gradient program: Mobile phase A/Mobile phase
MeOH/HCO H = 100:0.1; Gradient program: Mobile
2
B = 10/90: t = 3.436 min, purity: 98.6%.
phase A/Mobile phase B = 10/90: tR = 4.942 min,
R
4
-Oxo-1,4-dihydroquinoline-3-carboxylic acid (2).
purity: 99.1%.
NaOH (13.8 g, 0.34 mol) was disolved in water
150 mL) and ethanol (250 mL) solution, and compound
6 (30.0 g, 0.13 mol) was added, and the resulting
(
1
Acknowledgments. This work was supported by the
Undergraduate Innovative Training Project of Shanghai (No.
cs1504001 and cs1604004).
suspention was stirred and heated to reflux for 2 h to give
a clear solution. Most of ethanol was removed under
vacuum and the residue was adjusted with 6 N HCl to
pH ~ 3, the resulting solid was filtered, washed with
water (50 g × 2), and dried at 60°C for 5 h to give
REFERENCES AND NOTES
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6
13
(
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1
1
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2
[
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purity: 97.8%.
Ivacaftor (1). To a suspension of compound 2 (9.8 g,
.052 mol) and 3 (11.5 g, 0.052 mol) in DMF (100 mL)
was added triethylamine (22.0 mL, 0.16 mol). The
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[
[
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diluted with water (500 mL) to give a light yellow solid,
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at 50°C for 4 h to afford the crude product 1 (19.0 g).
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MeOH/EtOAc (120 mL) at reflux for 1 h then cooled to
room temperature overnight, the resulting solid was
filtered off and washed with 1:2 (v/v) MeOH/EtOAc
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[
(
7
20 mL × 2), dried at 50°C for 3 h to afford 1 (14.5 g,
1%) as an off-white solid, mp 124–128°C. H NMR
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Mudunuri, P.; Numa, M.; Sheth, U. J.; Silina, A.; Sullivan, M. J.; Verwijs,
M. J.; Yang, X.; Young, C. R.; Zaman, N. T.; Zhang, B.; Zhang, Y.;
Zlokarnik, G. WO 2011133953, 2011.
1
(
DMSO-d , δ): 1.36 (s, 9H), 1.38 (s, 9H), 7.11 (s, 1H),
6
7
8
.17 (s, 1H), 7.51 (m, 1H), 7.80 (m, 2H), 8.33 (m, 1H),
.85 (m, 1H), 9.23 (s, 1H), 11.81 (s, 1H), 13.12
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet