New Synthetic Route to Tucatinib

Article abstract of DOI:10.1055/s-0037-1610706

A new and improved synthetic route to tucatinib is described that involves three key intermediates. The first of these, 4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g scale in 33percent yield over five steps and 99percent purity. Next, N ⁴ -(4-([1,2,4]triazolo[1,5- a ]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine was isolated in 67percent yield over three steps and >99percent purity. Then, 4,4-dimethyl-2-(methylthio)-4,5-dihydrooxazole trifluoromethanesulfonate was prepared under mild conditions in 67percent yield over two steps. Finally, tucatinib was obtained in 17percent yield over nine steps and in >99percent purity (HPLC). Purification methods used to isolate the product and the intermediates involved in the route are also reported.

Full text of DOI:10.1055/s-0037-1610706

SYNTHESIS
0
0
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7
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1
1
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1
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X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–E
psp
A
en
L. Yin et al.
PSP
Synthesis
New Synthetic Route to Tucatinib
OH
Lingfeng Yin
S
N
H2N
CF3SO3H
Yongjun Mao*
O
Yaowei Liu
Lehao Bu
O
N
67.2% over 2 steps
N
N
Long Zhang
HN
N
H
Wenxin Chen
N
O
O
N
N
N
N
N
College of Chemistry and Chemical Engineering,
Shanghai University of Engineering Science, 333
Longteng Road, Shanghai 201620, P. R. of China
yjmao@sues.edu.cn
H2N
O
N
N
32.8% over 5 steps
99.1% (HPLC)
up to 110 g
Tucatinib
N
HN
N
16.7% over 9 steps
>99.5% (HPLC)
H2N
N
67.0% over 3 steps
>99.5% (HPLC)
Received: 13.01.2019
Accepted after revision: 01.04.2019
Published online: 16.04.2019
compound 7 in 60% yield. Finally, 7 was treated with NaOH
and p-TsCl at room temperature to give tucatinib on a milli-
gram scale (no yield data reported) after purification by col-
umn chromatography. This route is suitable for medicinal
DOI: 10.1055/s-0037-1610706; Art ID: ss-2019-h0022-psp
Abstract A new and improved synthetic route to tucatinib is described
that involves three key intermediates. The first of these, 4-([1,2,4]tri-
azolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, was prepared on a 100 g
scale in 33% yield over five steps and 99% purity. Next, N4-(4-([1,2,4]tri-
azolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine
was isolated in 67% yield over three steps and >99% purity. Then, 4,4-
dimethyl-2-(methylthio)-4,5-dihydrooxazoletrifluoromethanesulfonate
was prepared under mild conditions in 67% yield over two steps. Finally,
tucatinib was obtained in 17% yield over nine steps and in >99% purity
(HPLC). Purification methods used to isolate the product and the inter-
mediates involved in the route are also reported.
N
N
NH2
N
N
HO
CN
NH2
a
CN
CN
b
c
NO2
NO2
NH2
2
3
4
O
Key Words tucatinib, irbinitinib, new route, synthetic process
N
N
N
N
N
H2N
S
Tucatinib (1; Scheme 1), which is also named irbinitinib,
ARRY-380 or ONT-380, is an orally administered inhibitor of
human epidermal growth factor receptor tyrosine kinase
ErbB-2 (also called HER2) with potential antineoplastic ac-
tivity.1 It was developed by Array BioPharma Inc. and is now
in Phase II clinical study for the treatment of HER2+ breast
cancers.2
The reported synthetic routes to 1 were developed by
Array BioPharma Inc.3 on a milligram scale, as shown in
Scheme 1. 2-Amino-5-nitrobenzonitrile (2) and N,N-di-
methylformamide dimethyl acetal (DMF-DMA) reacted to
6
HO
N
N
CN
H
H
d
5
O
N
N
N
HN
N
S
e
H
N
HO
N
N
H
7
O
N
N
give
N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformami-
N
dine (3) in 87% isolated yield. The aniline compound 4 was
obtained in good yield through catalytic hydrogenation of 3.
Upon treatment with 2-amino-2-methyl-1-propanol and
1,1′-(thiocarbonyl)-diimidazole (TCDI) at –10 °C for 16
hours, the thiourea compound 5 was obtained in 34% yield,
which was purified by column chromatography, and then
cyclized with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-
methylaniline (6) to give the 4-phenylaminequinazolin
HN
H
N
O
N
N
N
1
Scheme 1 Reagents and conditions: (a) DMF-DMA, 100 °C, 2 h, 87%; (b)
H2, 10% Pd/C, cyclohexene, MeOH, 10 h, 90%; (c) TCDI, THF, –10 °C, 16
h, 34%; (d) AcOH, iPrOAc, r.t., 16 h, 62%; (e) NaOH, p-TsCl, THF, r.t., 3 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E

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Synthesis
chemistry research but is not fit for scale-up preparation of
tucatinib.
of tucatinib, we have not yet optimized the conditions to
increase the isolated yield of this step. Compound 10 was
reacted with DMF-DMA and hydroxylamine hydrochloride
in EtOH to obtain the N-hydroxyformimidamide compound
12 in 81% yield. The latter was treated with trifluoroacetic
acid anhydride (TFAA) to give triazolo[1,5-a]pyridine 13 in
around 70% yield. Compound 6 was obtained in 93% yield
and 99.1% purity, through a catalytic hydrogenation reac-
tion of 13.
2-Amino-5-nitrobenzonitrile (2) was reacted with
DMF-DMA to give compound 3 in 88% isolated yield based
on the reported method.3 The subsequent ring-forming re-
action was carried out by treating 6 and 3 in acetic acid
solution to give 14 in 83% yield and 99% purity (Scheme 2).
Compound 15 was obtained in 92% yield and 99.5% purity,
through catalytic hydrogenation of 14 under H2, Pd/C, THF
at room temperature. During the catalytic hydrogenation
reaction of compound 13 to 6 and 14 to 15, a hydrogen gas
balloon was used to conduct the reaction. No over-reduced
impurities have yet been found, presumably because the
hydrogen pressure was relatively low.
The methylthio-4,5-dihydrooxazole compound 17 was
prepared based one the reported method after optimiza-
tion.5,6 2-Amino-2-methyl-1-propanol and 1,1′-(thiocar-
bonyl)-diimidazole (TCDI) was cyclized in CH2Cl2 to give
4,4-dimethyloxazolidine-2-thione (16) in 83% isolated
yield, which was then reacted with methyl trifluorometh-
anesulfonate to give compound 17 in 81% isolated yield
(Scheme 3). Compound 16 is relatively stable and it can be
stored at 4 °C for a couple of weeks, whereas compound 17
was used immediately in the next step after it was pro-
duced. We found that compound 17 decomposed after one
week at room temperature, but it can be stored at –18 °C for
two weeks under argon without deterioration.
To develop a practical process for preparing tucatinib, a
new, convergent synthetic route was designed, as shown in
Scheme 2 and Scheme 3. Three key intermediates were pre-
pared: compound 6, the quinazoline-4,6-diamine com-
pound 15, and the methylthio-4,5-dihydrooxazole com-
pound 17.
With regard to compound 6, to date there is no reported
synthetic method available. This intermediate was prepared
on a 100 gram scale in high purity, based on the reported
synthesis of the nitrobenzene compound 13 after optimiza-
tion.3,4 2-Methyl-4-nitrophenol (8) and 4-chloropyridin-2-
amine (9) were used as starting materials to give 4-(2-
methyl-4-nitrophenoxy)pyridine-2-amine (10) in 64% iso-
lated yield, which was relatively low for a process route
(Scheme 2). We think the yield was reduced during the
work-up preparation when using active charcoal and when
THF was used for recrystallization. We did not identify any
clear impurities by TLC or HPLC analysis. Certainly, this step
should be optimized in the future; however, since the syn-
thesis of compound 10 is not the key step in the synthesis
OH
Cl
NH2
a
O
NH2
b
N
N
O2N
O2N
9
8
10
H
O
N
N
c
O
N
N
OH
N
N
O2N
O2N
12
11
S
S
OH
a
N
O
N
N
H2N
O
NH
N
N
3
e
N
d
6
N
f
O2N
16
13
S
O
N
15
N
N
b
1
CF3SO3H
O
c
N
HN
g
O2N
17
N
O
N
Scheme 3 Reagents and conditions: (a) CH2Cl2, r.t., 17 h, 83%; (b) CF3-
SO2OCH3, r.t., 15 h, 81%; (c) DMF, Cs2CO3, 125 °C, 20 h, 76%.
N
14
N
N
HN
N
H2N
N
15
Finally, compounds 17 and 15 were coupled in Cs2-
CO3/DMF solution at 125 °C for 20 hours to give the final
compound 1, in 76% yield and >99% purity after recrystalli-
zation (Scheme 3). Methyl mercaptan can be generated
during the preparation of compound 1 from 15 and 17. To
Scheme 2 Reagents and conditions: (a) NMP, DIPEA, 150 °C, 48 h, 64%;
(b) (i) EtOH, DMF-DMA, 75 °C, 3 h; (ii) NH2OH.HCl, 50 °C, 3 h, 81%; (d)
THF, TFAA, 20–25 °C, 68%; (e) H2, Pd/C, THF, 40 °C, 15 h, 93%; (f) AcOH,
85 °C, 2 h, 83%; (g) H2, Pd/C, r.t., 5 h, 92%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E

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L. Yin et al.
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date, we have carried out the reaction in a simple fuming
hood and have not developed exhaust gas absorption meth-
ods. The final product was purified by recrystallization and
no strong odor was retained in the final product.
ed to 75 °C for 3 h. The resulting solution was cooled to 40 °C, then
hydroxylamine hydrochloride (130 g, 1.9 mol) was added to the reac-
tant and the resulting solution was stirred and heated to 50 °C for an-
other 3 h. A yellow solid formed during this time. The reaction sus-
pension was cooled to r.t. and the resulting yellow solid was collected
by suction filtration, washed with EtOH (2 × 80 g), and dried at 45 °C
for 6 h to give 12 (370 g, 81%) as a light-tan solid.
1H NMR (400 MHz, DMSO-d6):  = 10.08 (s, 1 H), 9.37 (d, J = 9.9 Hz,
1 H), 8.33 (d, J = 2.3 Hz, 1 H), 8.16 (dd, J = 8.9, 2.6 Hz, 1 H), 8.10 (d, J =
5.8 Hz, 1 H), 7.82 (d, J = 9.9 Hz, 1 H), 7.32 (d, J = 10.6 Hz, 1 H), 6.61 (d,
J = 2.1 Hz, 1 H), 6.55 (dd, J = 5.8, 2.2 Hz, 1 H), 2.28 (s, 3 H).
In summary, a new and practical synthetic route to tu-
catinib (1) has been developed. Firstly, the 4-([1,2,4]triazo-
lo[1,5-a]pyridin-7-yloxy)-3-methylaniline (6) was prepared
on a 100 gram scale in 33% yield over five steps, and with
99% purity. Secondly, the triazolo[1,5-a]pyridine compound
15 was prepared from 6 in 67% yield over three steps, and
with >99% purity. Thirdly, the methylthio-4,5-dihydrooxaz-
ole trifluoromethanesulfonate compound 17 was prepared
under mild conditions in 67% yield over two steps. Finally, 1
was obtained by reaction of 15 and 17 in 76% yield and
>99% purity. Purification methods for the product and the
intermediates involved in the route were also described.
13C NMR (100 MHz, DMSO-d6):  = 16.1, 97.8, 106.5, 121.6, 123.9,
127.3, 132.2, 135.9, 144.7, 150.2, 155.2, 157.9, 164.6.
MS (ESI): m/z = 289.1 [M + H]+.
Anal. Calcd for C13H12N4O4: C, 54.17; H, 4.20; N, 19.44. Found: C,
54.29; H, 4.18; N, 19.52.
7-(2-Methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (13)
A suspension of compound 12 (220 g, 0.77 mol) in anhydrous THF
(1.3 kg) was stirred and cooled to 5 °C, TFAA (170 g, 0.80 mol) was
slowly added to the reactant while maintaining the reaction tempera-
ture below 15 °C. The reaction suspension was stirred at 20–25 °C for
another 5 h to give a clear solution. The solvents were removed under
reduced pressure to give a yellow oil, then EtOAc (1.2 kg) was added to
the residue to give a solution. The organic layer was washed with H2O
(2 × 1 kg) and saturated NaHCO3 (1 × 1 kg). The solvents were re-
moved under reduced pressure to obtain a light-yellow oil. MeOH
(650 g) and active charcoal (20 g) were added to the oil and the mix-
ture was stirred and heated to reflux for 1 h. The solids were removed
by hot filtration and the filtrate was stirred at r.t. for 12 h. The result-
ing solid was collected by suction filtration, washed with MeOH
(2 × 80 g), and dried at 45 °C for 12 h to give the product 13 (142 g,
68%) as a yellow solid.4
1H NMR (400 MHz, DMSO-d6):  = 9.02 (d, J = 7.4 Hz, 1 H), 8.46 (s,
1 H), 8.33 (d, J = 2.4 Hz, 1 H), 8.13 (dd, J = 8.9, 2.7 Hz, 1 H), 7.30 (d, J =
9.0 Hz, 1 H), 7.27 (d, J = 2.4 Hz, 1 H), 7.10 (dd, J = 7.4, 2.5 Hz, 1 H), 2.36
(s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 16.1, 101.9, 108.9, 120.2, 123.9,
127.4, 131.4, 131.5, 144.4, 151.2, 154.9, 157.9, 158.6.
All commercially available materials and solvents were used as re-
ceived without further purification. The equipment was used directly
after drying in an air-dry oven. 1H and 13C NMR spectra were recorded
with a Bruker UltraShield 400 Plus spectrometer using TMS as an in-
ternal standard. Mass spectra were obtained with a Finnigan MAT-
95/711 spectrometer. Melting points were measured with a Shen-
guang WRS-1B melting point apparatus and are uncorrected. Gener-
ally, TLC was used to monitor the progress of the reactions in the ex-
periments. HPLC data were acquired with a Waters 2487 UV/Vis De-
tector and Waters 515 Binary HPLC Pump. The purities of the
compounds were based on the peak areas in the HPLC UV traces.
4-(2-Methyl-4-nitrophenoxy)pyridin-2-amine (10)
To a 10 L reactor was added N-methyl pyrrolidone (NMP) (2 kg), diiso-
propylethylamine (DIPEA) (670 g, 5.2 mol), 2-methyl-4-nitrophenol
(8) (400 g, 2.6 mol) and 4-chloro-2-aminopyridine (9) (340 g, 2.6
mol), and the resulting solution was stirred at 150 °C for 48 h. The re-
action solution was cooled to r.t., poured into H2O (8 kg) and stirred
for 2 h. The resulting solid was collected by suction filtration, washed
with H2O (2 × 600 g), and dried at 45 °C for 6 h to give a brown solid
(680 g). The crude product and active charcoal (70 g) were suspended
in THF (3 kg) and heated to reflux for 2 h. The solids were removed by
hot filtration and the filtrate was concentrated to around 1 kg, and
stirred at r.t. for 12 h. The resulting solid was collected by suction fil-
tration, washed with THF (2 × 180 g), and dried at 45 °C for 12 h to
give the product 10 (405 g, 64%) as an off-white solid.3
MS (ESI): m/z = 271.1 [M + H]+.
Anal. Calcd for C13H10N4O3: C, 57.78; H, 3.73; N, 20.73. Found: C,
57.90; H, 3.70; N, 20.81.
4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline (6)
1H NMR (400 MHz, DMSO-d6):  = 8.29 (d, J = 2.6 Hz, 1 H), 8.14 (dd, J =
8.9, 2.8 Hz, 1 H), 7.88 (d, J = 5.8 Hz, 1 H), 7.23 (d, J = 8.9 Hz, 1 H), 6.21
(dd, J = 5.8, 2.2 Hz, 1 H), 6.10 (s, 2 H), 5.90 (d, J = 2.1 Hz, 1 H), 2.28 (s,
3 H).
13C NMR (100 MHz, DMSO-d6):  = 16.1, 95.1, 102.8, 120.9, 123.8,
127.2, 131.8, 144.2, 150.5, 158.5, 162.3, 164.0.
A suspension of 13 (135 g, 0.5 mol) and Pd/C (5% wet, 7 g) in THF (1.2
kg) was stirred under hydrogen atmosphere at 40 °C for 15 h to give a
clear brown solution. The reaction mixture was then filtered through
a Celite pad, the filter cake was washed with THF (1 × 80 g). The com-
bined filtrate was concentrated to give a yellow oil. MeOH (160 g) was
added to the crude product and the mixture was stirred at 50 °C to
give a clear solution, then H2O (200 g) was added slowly to the solu-
tion and the mixture was stirred at r.t. for 12 h. The resulting solid
was collected by suction filtration, washed with MeOH (2 × 80 g), and
dried at 45 °C for 12 h to give 6 (112 g, 93%) as an off-white solid; mp
155.5−160.0 °C.
MS (ESI): m/z = 246.1 [M + H]+.
Anal. Calcd for C12H11N3O3: C, 58.77; H, 4.52; N, 17.13. Found: C,
58.90; H, 4.50; N, 17.06.
1H NMR (400 MHz, DMSO-d6):  = 8.87 (d, J = 7.4 Hz, 1 H), 8.34 (s,
1 H), 6.95 (dd, J = 7.4, 2.1 Hz, 1 H), 6.82 (d, J = 8.5 Hz, 1 H), 6.63 (d, J =
2.1 Hz, 1 H), 6.54 (s, 1 H), 6.50 (d, J = 8.4 Hz, 1 H), 5.11 (s, 2 H), 1.99 (s,
3 H).
N-Hydroxy-N′-(4-(2-methyl-4-nitrophenoxy)pyridin-2-
yl)formimidamide (12)
To a solution of 10 (390 g, 1.59 mol) in EtOH (2 kg) was added DMF-
DMA (210 g, 1.75 mol) and the reaction solution was stirred and heat-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E

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13C NMR (100 MHz, DMSO-d6):  = 16.1, 96.9, 107.6, 113.2, 116.7,
122.3, 130.5, 130.6, 142.1, 147.3, 151.7, 154.9, 161.1.
MS (ESI): m/z = 241.0 [M + H]+.
1H NMR (400 MHz, DMSO-d6):  = 9.38 (d, J = 13.8 Hz, 1 H), 8.93 (d, J =
7.4 Hz, 1 H), 8.38 (s, 1 H), 8.36 (s, 1 H), 7.90 (d, J = 2.1 Hz, 1 H), 7.85
(dd, J = 8.7, 2.3 Hz, 1 H), 7.54 (t, J = 8.1 Hz, 1 H), 7.38 (d, J = 2.2 Hz,
1 H), 7.26 (dd, J = 8.9, 2.2 Hz, 1 H), 7.18 (d, J = 8.7 Hz, 1 H), 7.03 (dd, J =
7.5, 2.6 Hz, 1 H), 6.79 (d, J = 2.4 Hz, 1 H), 5.59 (s, 2 H), 2.19 (d, J =
5.5 Hz, 3 H).
Anal. Calcd for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found: C, 64.78;
H, 5.06; N, 23.27.
HPLC Conditions: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5
m); Detection: 254 nm; Flow rate: 1.0 mL/min; Temperature: 35 °C;
Injection load: 1 L; Solvent: MeOH; Concentration: 0.5 mg/mL; Run
time: 20 min; Mobile phase: MeOH/H2O = 80:20; tR: 4.088 min, puri-
ty: 99.13%.
13C NMR (100 MHz, DMSO-d6):  = 16.3, 98.3, 107.8, 107.9, 121.3,
121.6, 122.7, 126.3, 127.1, 129.9, 130.5, 130.9, 136.5, 145.0, 148.7,
151.7, 153.5, 155.5, 158.1, 159.2, 159.9.
MS (ESI): m/z = 384.1 [M + H]+.
Anal. Calcd for C21H17N7O: C, 65.79; H, 4.47; N, 25.57. Found: C, 65.60;
H, 4.49; N, 25.49.
N-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-
nitroquinazolin-4-amine (14)
HPLC Conditions: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5
m); Detection: 254 nm; Flow rate: 1.0 mL/min; Temperature: 35 °C;
Injection load: 1 L; Solvent: MeOH; Concentration: 0.5 mg/mL; Run
time: 40 min; Mobile phase: MeOH/H2O = 70:30; tR: 6.475 min, puri-
ty: 99.90%.
N′-(2-Cyano-4-nitrophenyl)-N,N-dimethylformimidamide (3) was
prepared based on the reported method as a red solid in 88% isolated
yield.3
1H NMR (400 MHz, DMSO-d6):  = 8.48 (d, J = 2.4 Hz, 1 H), 8.29–8.26
(m, 2 H), 7.38 (d, J = 9.2 Hz, 1 H), 3.17 (s, 3 H), 3.09 (s, 3 H).
4,4-Dimethyloxazolidine-2-thione (16)
MS (ESI): m/z = 219.1 [M + H]+.
To a stirred solution of 2-amino-2-methyl-1-propanol (13.4 g, 0.15
mol) in CH2Cl2 (200 g) was slowly added a solution of 1,1′-(thiocar-
bonyl)diimidazole (26.7 g, 0.15 mol) in CH2Cl2 (260 g), maintaining
the reaction temperature below 25 °C. The resulting solution was
stirred at r.t. for 17 h. The reaction solution was washed with H2O
(2 × 150 g) and the solvent was removed under reduced pressure to
give 16 (16.3 g, 83%) as a white solid,5 which was used directly in the
next step without purification, or should be stored below 4 °C for no
more than two weeks under argon atmosphere.
HPLC Conditions: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5
m); Detection: 254 nm; Flow rate: 0.8 mL/min; Temperature: 45 °C;
Injection load: 1 L; Solvent: MeOH; Concentration: 0.5 mg/mL; Run
time: 30 min; Mobile phase: MeOH/H2O = 80:20; tR: 5.289 min, puri-
ty: 98.82%.
A stirred suspension of compound 3 (26.2 g, 0.12 mol) and 6 (29.0 g,
0.12 mol) in acetic acid (250 g) was stirred and heated to 85 °C for 2 h
to give a light-yellow suspension. The solvent was partially distilled
under reduced pressure, and then poured into H2O (120 g) and stirred
at 0–5 °C for 1 h. The resulting solid was collected by suction filtra-
tion, washed with H2O (2 × 50 g), and dried at 45 °C for 12 h to give 14
(41.2 g, 83%) as a yellow solid.
1H NMR (400 MHz, DMSO-d6):  = 10.50 (s, 1 H), 9.69 (s, 1 H), 8.95 (d,
J = 7.5 Hz, 1 H), 8.75 (s, 1 H), 8.57 (dd, J = 9.2, 2.2 Hz, 1 H), 8.39 (s, 1 H),
7.95 (d, J = 9.2 Hz, 1 H), 7.86 (d, J = 11.5 Hz, 2 H), 7.25 (d, J = 8.5 Hz,
1 H), 7.04 (dd, J = 7.5, 2.5 Hz, 1 H), 6.84 (d, J = 2.4 Hz, 1 H), 2.22 (s,
3 H).
1H NMR (400 MHz, DMSO-d6):  = 10.05 (br. s, 1 H), 4.27 (s, 2 H), 1.26
(s, 6 H).
4,4-Dimethyl-2-(methylthio)-4,5-dihydrooxazole Trifluorometh-
anesulfonate (17)
To a stirred solution of 16 (13.1 g, 0.1 mol) in CH2Cl2 (200 g) was slow-
ly added methyl trifluoromethanesulfonate (18.0 g, 0.11 mol), main-
taining the reaction temperature below 25 °C. The resulting solution
was stirred at r.t. for 15 h. The reaction solution was diluted with tert-
butyl methyl ether (400 g) and stirred at 0–5 °C for 2 h. The resulting
solid was collected by suction filtration, washed with t-butyl methyl
ether (2 × 20 g), and dried under vacuum at r.t. for 6 h to give 17 (23.9
g, 81%) as a white solid,6 which was used directly in the next step, or
should be stored below –18 °C for no more than two weeks under ar-
gon atmosphere.
13C NMR (100 MHz, DMSO-d6):  = 16.3, 98.3, 107.9, 114.8, 121.2,
121.6, 122.6, 126.2, 127.0, 129.9, 130.4, 130.9, 136.6, 144.9, 148.7,
151.6, 153.5, 155.1, 158.1, 159.1, 159.9.
MS (ESI): m/z = 414.1 [M + H]+.
Anal. Calcd for C21H15N7O3: C, 61.01; H, 3.66; N, 23.72. Found: C,
61.22; H, 3.62; N, 23.81.
1H NMR (400 MHz, DMSO-d6):  = 4.56 (s, 2 H), 2.61 (s, 3 H), 1.39 (s,
6 H).
HPLC Conditions: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5
m); Detection: 254 nm; Flow rate: 1.0 mL/min; Temperature: 35 °C;
Injection load: 1 L; Solvent: MeOH; Concentration: 0.5 mg/mL; Run
time: 40 min; Mobile phase: MeOH/H2O = 70:30; tR: 23.30 min, puri-
ty: 99.47%.
Tucatinib (1)
Cs2CO3 (26.5 g, 0.082 mol) was added in portions to a suspension of
17 (16.2 g, 0.055 mol) in DMF (70 g) at r.t. and the solution was stirred
for 1 h. Compound 15 (16.9 g, 0.044 mol) was added to the reactant
and the resulting mixture was stirred at 125 °C for 20 h. The reaction
solution was cooled to r.t. and poured into ice H2O (300 g), then
stirred at r.t. for 1 h. The resulting solid was collected by suction fil-
tration, washed with H2O (2 × 20 g), and dried at 45 °C for 6 h to give a
light-yellow solid (21 g). The crude product and active charcoal (4 g)
were suspended in EtOAc (80 g) and heated to reflux for 1 h. The sol-
ids were removed by hot filtration and the filtrate was concentrated
to around 50 g. Heptane (40 g) was added slowly to the warm solution
and the mixture was stirred at r.t. for 12 h. The resulting solid was
N4-(4-([1,2,4]Triazolo[1,5-a]pyridin-7-yloxy)-3-methylphe-
nyl)quinazoline-4,6-diamine (15)
A suspension of 14 (32.0 g, 0.077 mol) and Pd/C (5% wet, 1.8 g) in THF
(240 g) was stirred under hydrogen atmosphere at r.t. for 5 h to give a
clear brown solution. The reaction mixture was then filtered through
a Celite pad, the filter cake was washed with THF (2 × 40 g). The com-
bined filtrate was concentrated to around 70 g, the residue was
poured into H2O (120 g) and stirred at r.t. for 2 h. The resulting solid
was collected by suction filtration, washed with H2O (2 × 30 g), and
dried at 45 °C for 12 h to give 15 (27.6 g, 92%) as a yellow solid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E

E
L. Yin et al.
PSP
Synthesis
collected by suction filtration, washed with heptane (2 × 15 g), and
dried at 45 °C for 12 h to give 1 (16.1 g, 76%) as a white solid;3 mp
251.2−254.7 °C.
1H NMR (400 MHz, DMSO-d6):  = 9.58 (s, 1 H), 8.94 (d, J = 7.5 Hz,
1 H), 8.50 (s, 1 H), 8.38 (s, 1 H), 8.03 (br. s, 1 H), 7.92 (s, 1 H), 7.87 (d,
J = 8.5 Hz, 1 H), 7.67 (d, J = 8.5 Hz, 1 H), 7.59–7.41 (m, 1 H), 7.20 (d, J =
8.7 Hz, 1 H), 7.03 (dd, J = 7.5, 2.6 Hz, 1 H), 6.80 (d, J = 2.3 Hz, 1 H), 4.08
(s, 2 H), 2.19 (s, 3 H), 1.29 (s, 6 H).
References
(1) Dinkel, V.; Anderson, D.; Winski, S.; Winkler, J.; Koch, K.; Lee, P.
A. Cancer Res. 2014, 72, 852.
(2) Lee, P.; Anderson, D.; Bouhana, K.; Garrus, J.; Napier, C.;
Avrustkaya, A.; White, A.; Pheneger, T.; Winkler, J. Cancer Res.
2014, 69, 5104.
(3) Lyssikatos, J. P.; Marmsater, F. P.; Zhao, Q.; Greschuk, J. M. PCT
Int. Appl WO 2007059257, 2007.
(4) Tsou, H. R.; Mamuya, N.; Johnson, B. D.; Reich, M. F.; Gruber, B.
C.; Ye, F.; Nilakantan, R.; Shen, R.; Discafani, C.; DeBlanc, R.
J. Med. Chem. 2001, 44, 2719.
(5) Matsushima, T.; Shirotori, S.; Takahashi, K.; Kamada, A.;
Wakasugi, K.; Sakaguchi, T. US Pat. Appl. Publ US 20080319188,
2008.
(6) Allen, J. R.; Hitchcock, S. A.; Turner, W. W. Jr.; Liu, B. PCT Int.
Appl WO 2004094382, 2004.
13C NMR (100 MHz, DMSO-d6):  = 16.3, 27.5, 78.1, 97.9, 107.8, 116.2,
121.6, 121.9, 125.4, 128.5, 130.2, 130.8, 137.9, 145.9, 147.7, 151.7,
152.6, 155.1, 157.4, 160.2.
MS (ESI): m/z = 481.2 [M + H]+.
Anal. Calcd for C26H24N8O2: C, 64.99; H, 5.03; N, 23.32. Found: C,
64.84; H, 5.06; N, 23.25.
HPLC Conditions: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5
m); Detection: 254 nm; Flow rate: 1.0 mL/min; Temperature: 35 °C;
Injection load: 1 L; Solvent: MeOH; Concentration: 0.5 mg/mL; Run
time: 40 min; Mobile phase: MeOH/H2O = 70:30; tR: 7.563 min, puri-
ty: 99.9%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E