E
T. S. Maskrey et al.
Letter
Synlett
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Pathol.: Mech. Dis. 2011, 6, 49.
(4) Bogdanowicz, B. S.; Hoch, M. A.; Hartranft, M. E. J. Oncol. Pharm.
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(8) Chandrasekhar, M.; Srinivasulu, D.; Seshaiah, K.; Kumar, N.
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(10) Gibson, K. H. US 5770599, 1998.
(11) Bretherick, L. 3rd ed. Hazards in the Chemical Laboratory; Royal
Society of Chemistry: London, 1981, 503.
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showed that the aniline was consumed, some quinazoline
starting material remained, and the product had formed [5%
MeOH–CH2Cl2; quinazoline: Rf = 0.85, aniline: Rf = 0.7; product
2: Rf = 0.2; byproduct (<5%; aniline dimer addition product):
Rf = 0.1]. The solid pink mixture was cooled to 40 °C then dis-
solved in warm EtOAc (0.50 L, 40 °C) and 2 M aq NaOH (275 mL)
with vigorous agitation. The solution was transferred to a sepa-
ratory funnel and vigorously shaken. The layers were separated
and the aqueous layer (~pH 10) was back-extracted with EtOAc
(2 × 100 mL). The combined organic layers were extracted with
0.5 M aq NaOH (2 × 100 mL), dried (Na2SO4, ~40 g), filtered, and
concentrated (75 mL). The precipitate was collected by filtration
and washed with EtOAc (40 mL) to yield a white powder that
was dried in vacuo (0.5 Torr, 20 °C) to yield a first batch of
product (yield: 3.99 g). The original organic filtrate was then
further concentrated to 37.5 mL, and the precipitate was col-
lected by filtration and washed with additional EtOAc (~20 mL)
to afford a second batch of product (0.60 g). After 1H and 19F
NMR analysis, the two batches were combined to give a color-
less solid; yield: 4.59 g (12.5 mmol, 65%); mp 273.0–275.8 °C;
TLC: Rf = 0.2 (5% MeOH–CH2Cl2); IR (ATR, neat): 3387, 2980,
1980, 1623, 1573, 1500, 1457, 1342, 1217, 1147, 997, 963, 846,
(13) Kang, S. K.; Lee, S. W.; Woo, D.; Sim, J.; Suh, Y.-G. Synth.
Commun. 2017, 47, 1990.
(14) Anon, Dangerous Prop. Ind. Mater. Rep. 1995, 15, 354.
(15) Wipf, P.; George, K. M. Synlett 2010, 644.
(16) Hao, C.; Zhao, F.; Song, H.; Guo, J.; Li, X.; Jiang, X.; Huan, R.;
Song, S.; Zhang, Q.; Wang, R.; Wang, K.; Pang, Y.; Liu, T.; Lu, T.;
Huang, W.; Wang, J.; Lin, B.; He, Z.; Li, H.; Li, F.; Zhao, D.; Cheng,
M. J. Med. Chem. 2018, 61, 265.
795 cm–1
(dd, J = 6.8, 2.8 Hz, 1 H), 7.84 (s, 1 H), 7.76–7.72 (m, 1 H), 7.50
(app t, J = 9.2 Hz, 1 H), 7.20 (s, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H). 13
.
1H NMR (400 MHz, DMSO-d6): = 9.92 (s, 1 H), 8.00
C
(17) Iwaki, T.; Nakamura, Y.; Tanaka, T.; Ogawa, Y.; Iwamoto, O.;
Okamura, Y.; Kawase, Y.; Furuya, M.; Oyama, Y.; Nagayama, T.
Bioorg. Med. Chem. Lett. 2017, 27, 4904.
(18) Park, H.; Jung, H.-Y.; Mah, S.; Hong, S. Angew. Chem. Int. Ed.
2017, 56, 7634.
NMR (100 MHz, DMSO-d6): = 158.2, 155.6, 154.4, 153.1, 149.6,
148.7, 136.3, 124.7, 123.5, 119.6, 117.4, 107.6, 107.2, 102.5,
56.8, 56.5. 19F NMR (376 MHz, DMSO-d6): = –121.9; HRMS
(LC/MS, ESI+): m/z [M + H]+ calcd for C16H13Cl2FN3O2: 368.0363;
found: 368.0361.
(19) Kemperman, G. J.; Roeters, T. A.; Hilberink, P. W. Eur. J. Org.
Chem. 2003, 1681.
(20) Kemperman, G. J.; Ter Horst, B.; Van de Goor, D.; Roeters, T.;
Bergwerff, J.; Van der Eem, R.; Basten, J. Eur. J. Org. Chem. 2006,
3169.
(21) Anon; Q3C — Tables and List Guidance for Industry: Revision 4;
U.S. Department of Health and Human Services Food and Drug
Administration, Center for Drug Evaluation and Research
(CDER), Center for Biologics Evaluation and Research (CBER):
[TMAH][Al2Cl7]
A suspension of AlCl3 (9.00 g, 67.5 mmol) in CH2Cl2 (67.5 mL)
was cooled in an ice bath and treated by portionwise addition of
Me3NH+ Cl– (3.23 g, 33.7 mmol). After addition was complete,
the reaction mixture was warmed to r.t. and stirred for 2 h. This
mixture (12.2 g in 67.5 mL CH2Cl2) was used in the subsequent
reaction without further purification or concentration.
2-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-
quinazolin-6-ol (3)
Silver
Springs,
2018;
A suspension of quinazolinamine 2 (4.11 g, 11.2 mmol) in
CH2Cl2 (11 mL) was added in two portions to a freshly prepared
solution of [TMAH][Al2Cl7] (12.2 g, 33.5 mmol) in CH2Cl2 (67.5
mL). The first batch (7.0 mL) was added at a rate of 1 mL/min,
and the second batch, along with a rinse of CH2Cl2 (4.0 mL), was
added at a rate of 2 mL/min. The reaction mixture was then
magnetically stirred and heated for 2 h at reflux, while the
external temperature was maintained at ~50 °C. After 1 h, a
light-brown suspension formed. TLC analysis (5% MeOH–
CH2Cl2) after 2 h showed that the starting material had been
consumed and a product spot corresponding to the mixture of
phenol regioisomers had formed (Rf = 0.4). The suspension was
cooled to 0 °C, and 2 M aq HCl (~200 mL) was added dropwise
from an addition funnel at a rate of 4.0 mL/min over 50 min
while the rapidly forming suspension was stirred vigorously.
The internal temperature of the solution was maintained below
20 °C to avoid solvent evaporation. After complete addition of
the 2 M aq HCl, the resulting mixture (pH = 0) was filtered
through a fritted glass funnel (~200 mL of filtrate was collected).
The collected filter cake was washed with H2O (2 × 40 mL) and
briefly dried by vacuum filtration to give ~50 g of a viscous
residue that was transferred into a round-bottomed flask and
concentrated by rotary evaporation under vacuum until a slurry
(about 15–16 g) was obtained. This residue was suspended in
drugs/guidances/ucm073395.pdf
(22) Chelucci, G.; Figus, S. J. Mol. Catal. A: Chem. 2014, 393, 191.
(23) Röver, S.; Andjelkovic, M.; Bénardeau, A.; Chaput, E.; Guba, W.;
Hebeisen, P.; Mohr, S.; Nettekoven, M.; Obst, U.; Richter, W. F.;
Ullmer, C.; Waldmeier, P.; Wright, M. B. J. Med. Chem. 2013, 56,
9874.
(24) Yee, N. K.; Farina, V.; Houpis, I. N.; Haddad, N.; Frutos, R. P.;
Gallou, F.; Wang, X.-J.; Wei, X.; Simpson, R. D.; Feng, X.; Fuchs,
V.; Xu, Y.; Tan, J.; Zhang, L.; Xu, J.; Smith-Keenan, L. L.; Vitous, J.;
Ridges, M. D.; Spinelli, E. M.; Johnson, M.; Donsbach, K.; Nicola,
T.; Brenner, M.; Winter, E.; Kreye, P.; Samstag, W. J. Org. Chem.
2006, 71, 7133.
(25) 2-Chloro-N-(3-chloro-4-fluorophenyl)-6,7-dimethoxy-
quinazolin-4-amine (2)
A vigorously stirred, pale-pink, homogeneous solution of 3-
chloro-4-fluoroaniline (3.37 g, 23.2 mmol) in AcOH (22.5 mL,
394 mmol) was treated at 45 °C with neat 2,4-dichloro-6,7-
dimethoxyquinazoline (1; 5.00 g, 19.3 mmol) in a single batch.
The temperature was monitored with an internal thermometer.
After the addition was complete (1 min), the resulting mixture
was warmed to 55 °C for a total of 2 h. The pink solution turned
viscous and then solidified after about 30 min, after which
the magnetic stirring was stopped. TLC analysis after 2 h
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F