VEGF Receptor Tyrosine Kinase Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 26 5383
ration, water was added to the residue, the solid was collected
by filtration, washed with water, and dried. Recrystallization
from acetic acid gave 8.7 g of 40 (84%). Mp 266 °C. H NMR:
δ 3.85 (s, 3H, CH3O), 5.25 (s, 2H, CH2O), 7.25 (s, 1H, H8), 7.4
(m, 6H, Ph and H5), 7.95 (s, 1H, H2), 12.0 (br s, 1H, NH). 13C
NMR: δ 55.7 (CH2O), 70.0 (OCH3), 105.1 (C5), 109.3 (C8),
115.7 (C10), 127.9 (2 C12), 128.0 (C14), 128.5 (2 C13), 136.3
(C11), 143.8 (C2), 144.7 (C6), 148.7 (C7), 153.3 (C9), 160.0 (C4).
MS-ESI m/z 305 [MNa]+. Anal. (C16H14N2O3‚0.24 H2O) C, H,
N.
washed with water and brine, and dried (MgSO4). Most of the
solvent was removed by evaporation, the mixture was cooled,
and hexane added to obtain a solid product that was collected
by filtration, washed with hexane/ethyl acetate, and dried to
give 170 mg of 50 (45%). 1H NMR: δ 2.37 (s, 3H, CH3CO),
3.95 (s, 3H, CH3O), 7.08 (s, 1H, H3′), 7.59 (s, 1H, H8), 7.68 (d,
1H, H6′), 7.78 (s, 1H, H5), 8.34 (s, 1H, H2), 9.48 (s,1H, NH or
OH). 13C NMR δ 15.1 (Ar CH3), 55.6 (COOCH3), 56.0 (OCH3),
102.2 (C5), 108.0 (C10), 110.0 (C8), 117.5 (d, C3′, J C-F )
22.0 Hz), 121.1 (d, C6′, J C-F ) 2.3 Hz), 125.0 (d, C3′, J C-F
) 14.7 Hz), 128.4 (d, C6′, J C-F ) 7.4 Hz), 144.6 (C6 or C7),
144.7 (C7 or C6), 148.6 (C9), 152.8 (C2), 153.3 (O-CdO), 154.3
(d, C2′, J C-F ) 244.6 Hz), 157.0 (C4). MS-ESI m/z 394
[MH]+.
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N-7-Ben zyloxy-(4-ch lor o-2-flu or op h en yl)-6-m eth oxy-4-
qu in a zolin yla m in e h yd r och lor id e 42. (P r oced u r e J ). A
solution of 7-Benzyloxy-4-chloro-6-methoxyquinazoline hydro-
chloride 41 (1.2 g, 3.5 mmol) and 4-chloro-2-fluoroaniline (444
µL, 4 mmol) in 2-propanol (40 mL) was refluxed for 1.5 h. After
the solution was cooled, the precipitate was collected by
filtration, washed with 2-propanol then ether and dried under
7-Ben zyloxy-6-m eth oxy-3-(p iva loyloxym eth yl)-3,4-d i-
h yd r oqu in a zolin -4-on e 51. Sodium hydride (1.44 g of a 60%
suspension in mineral oil, 36 mmol) was added in portions over
20 min to a solution of 7-benzyloxy-6-methoxy-3,4-dihydro-
quinazolin-4-one 40 (8.46 g, 30 mmol) in DMF (70 mL) and
the mixture was stirred for 1.5 h. Chloromethyl pivalate (5.65
g, 37.5 mmol) was added dropwise and the mixture stirred for
2 h at ambient temperature. The mixture was diluted with
ethyl acetate (100 mL) and poured onto ice-water (400 mL)
and 2 N hydrochloric acid (4 mL). The organic layer was
separated and the aqueous layer extracted with ethyl acetate,
the combined extracts were washed with brine, dried (MgSO4),
and the solvent removed by evaporation. The residue was
triturated with a mixture of ether and petroleum ether, the
solid was collected by filtration, and dried under vacuum to
1
vacuum to give 1.13 g of 42 (71%). Mp 239-242 °C. H NMR:
δ 4.0 (s, 3H, CH3O), 5.36 (s, 2H, CH2O), 7.39-7.52 (m, 9H, Ph
and H3′, H5′, H6′and H8), 8.1 (s, 1H, H5), 8.75 (s, 1H, H2).
13C NMR: δ 57.0 (O-CH3), 70.7 (O-CH2), 100.8 (C8), 104.3
(C5), 107.1 (C10), 116.9 (d, C3′, J C-F ) 23.8 Hz), 123.8 (d,
C1′, J C-F ) 13.4 Hz), 125.0 (d, C5′, J C-F ) 3.0 Hz), 128.3
(C13), 128.4 (C14), 128.6 (C12), 129.9 (C6′), 132.4 (d, C4′, J
C-F ) 9.1 Hz), 135.2 (C11), 135.5 (C4), 148.8 (C2), 150.5 (C9),
155.4 (C7), 156.8 (d, C2′, J C-F ) 252.2 Hz), 159.0 (C6). MS-
ESI m/z 410 [MH]+. Anal. (C22H17N3O2ClF‚1.0 HCl) C, H, N.
A similar procedure was used to prepare 43-45. In the case
of 44 and 45, the mixture was heated for 4 h and 2 h,
respectively.
1
give 10 g of 51 (84%). H NMR: δ 1.11 (s, 9H, C(CH3)3), 3.89
(s, 3H, CH3O), 5.3 (s, 2H, OCH2N), 5.9 (s, 2H, CH2OPh), 7.27
(s, 1H, H8), 7.35 (m, 1H, H14), 7.47 (t, 2H, H13), 7.49 (d, 2H,
H12), 7.51 (s, 1H, H5), 8.34 (s, 1H, H2). 13C NMR: δ 26.5 (C-
(CH3)3), 38.3 (C-Me3), 55.8 (OCH3), 69.0 (NCH2O), 70.1
(OCH3), 105.6 (C5), 109.5 (C8), 114.4 (C10), 127.9 (2 C13),
128.1 (C14), 128.5 (2 C12), 136.1 (C11), 143.6 (C6), 146.3 (C2),
149.1 (C7), 153.8 (C9), 159.0 (C4), 177.0 (O-CdO). MS-ESI
m/z 397 [MH]+. Anal. (C22H24N2O5‚0.5 H2O) C, H, N.
7-Hyd r oxy-6-m eth oxy-3-(p iva loyloxym eth yl)-3,4-d ih y-
d r oqu in a zolin -4-on e 52. A mixture of 7-benzyloxy-6-meth-
oxy-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one 51 (7 g,
17.7 mmol) and 10% palladium-on-charcoal catalyst (700 mg)
in ethyl acetate (250 mL), DMF (50 mL), methanol (50 mL),
and acetic acid (0.7 mL) was stirred under hydrogen at
atmospheric pressure for 40 min. The catalyst was removed
by filtration and the solvent removed from the filtrate by
evaporation. The residue was triturated with ether, collected
by filtration, and dried under vacuum to give 4.36 g of 52
(80%). 1H NMR: δ 1.1 (s, 9H, C(CH3)3), 3.89 (s, 3H, CH3O),
5.89 (s, 2H, OCH2N), 7.0 (s, 1H, H8), 7.48 (s, 1H, H5), 8.5 (s,
1H, H2). 13C NMR: δ 26.5 (C-(CH3)3), 38.3 (C-Me3), 55.8
(OCH3), 69.0 (NCH2O), 106.0 (C5), 111.4 (C8), 113.3 (C10),
143.8 (C7 or C6), 146.1 (C2), 148.5 (C6 or C7), 153.6 (C9), 159.0
(C4), 177.0 (O-CdO). MS-ESI m/z 329 [MNa]+. Anal.
(C15H18N2O5‚0.3 H2O, 0.02 DMF) C, H, N.
N-(5-Acetoxy-4-ch lor o-2-flu or op h en yl)-7-ben zyloxy-6-
m eth oxy-4-qu in a zolin yla m in e 46. Triethylamine (216 mL,
1.5 mmol) and acetic anhydride (133 mL, 1.4 mmol) were
added to a stirred suspension of N-7-benzyloxy-(4-chloro-2-
fluoro-5-hydroxyphenyl)-6-methoxy-4-quinazolinylamine hy-
drochloride 45 (600 mg, 1.4 mmol) in methylene chloride (7
mL). The mixture was stirred at ambient temperature for 3 h
and insoluble material removed by filtration. Volatiles were
removed from the filtrate by evaporation, and the residue
purified by flash chromatography, eluting with methylene
chloride/methanol (100:0, increasing in polarity to 97:3) to give
1
340 mg of 46 (52%). H NMR: δ 2.34 (s, 3H, CH3CO), 3.94 (s,
3H, CH3O), 5.28 (s, 2H, CH2O), 7.28 (s, 1H, H8), 7.35-7.44
(m, 2H, H3′ and H14), 7.50 (d, 2H, H12), 7.58 (d, 1H, H6′),
7.70 (d, 1H, H13), 7.80 (s, 1H, H5), 8.37 (s, 1H, H5′), 9.30 (s,-
1H, H2). MS-ESI m/z 468 [MH]+.
N-(4-Ch lor o-2-flu or op h en yl)-7-h yd r oxy-6-m et h oxy-4-
qu in a zolin yla m in e 47. (P r oced u r e K). A solution of N-(4-
chloro-2-fluorophenyl)-7-benzyloxy-6-methoxy-4-quinazoliny-
lamine hydrochloride 42 (892 mg, 2 mmol) in TFA (10 mL)
was refluxed for 50 min. After the solution was cooled, the
mixture was poured onto ice. The precipitate was collected by
filtration, dissolved in methanol (10 mL) and basified to pH )
11 with aqueous ammonia. After concentration by evaporation,
the solid product was collected by filtration, washed with water
then ether and dried under vacuum to give 460 mg of 47 (72%).
7-(2-Meth oxyeth oxy)-6-m eth oxy-3-(pivaloyloxym eth yl)-
3,4-d ih yd r oqu in a zolin -4-on e 53. (P r oced u r e L). Diethy-
lazodicarboxylate (1.16 mL, 7.35 mmol) was added dropwise
to a solution of 7-hydroxy-6-methoxy-3-(pivaloyloxymethyl)-
3,4-dihydroquinazolin-4-one 52 (1.5 g, 4.9 mmol) in dichlo-
romethane (15 mL) containing triphenylphosphine (1.93 g, 7.35
mmol) and 2-methoxyethanol (0.46 mL, 5.88 mmol). After the
solution was stirred for 1 h at ambient temperature, the
volatiles were removed under vacuum. The solid was purified
by column chromatography eluting with ethyl acetate/petro-
leum ether (1:1) followed by 3:2. After evaporation of the
solvent, the solid was triturated with ether, filtered and dried
1
Mp 141-143 °C. H NMR: δ 3.95 (s, 3H, CH3O), 7.05 (s, 1H,
H8), 7.35 (d, 1H, H3′), 7.54-7.59 (m, 2H, H5′ and H6′), 7.78
(s, 1H, H5), 8.29 (s, 1H, H2). 13C NMR: δ 56.1 (CH2O), 101.2
(C5), 108.6 (C8), 108.8 (C10), 111.9 (d, C3′, J C-F ) 23.9 Hz),
116.6 (d, C1′, J C-F ) 18.4 Hz), 119.9 (d, C5′, J C-F ) 3.7
Hz), 130.9 (C6′), 147.6 (C7), 150.2 (C6), 151.5 (C2), 151.9 (d,
C4′, J C-F ) 11.0 Hz), 155.2 (C9), 157.3 (d, C2′, J C-F )
246.3 Hz), 164.6 (C4). MS-ESI m/z 320-322 [MH]+.
A similar procedure was used to prepare 48 and 49.
N-(5-Acet oxy-4-ch lor o-2-flu or op h en yl)-7-h yd r oxy-6-
m eth oxy-4-qu in a zolin yla m in e 50. A solution of N-(5-ac-
et oxy-4-chloro-2-flu oroph enyl)-7-ben zyloxy-6-m et h oxy-4-
quinazolinylamine 46 (250 mg, 0.54 mmol) in methanol (5 mL),
chloroform (5 mL), and DMF (1 mL) was stirred under
hydrogen at 1 atm with 5% palladium-on-charcoal catalyst
(100 mg) for 4 h. The catalyst was removed by filtration
through diatomaceous earth and the solvent removed by
evaporation. The residue was dissolved in ethyl acetate,
1
under vacuum to give 1.5 g of 53 (84%). H NMR: δ 1.13 (s,
9H, tBu), 3.35 (s, 3H, CH3O), 3.72 (m, 2H, CH2O), 3.9 (s, 3H,
CH3O), 4.3 (m, 2H, CH2O), 5.92 (s, 2H, NCH2O), 7.2 (s, 1H,
H8), 7.51 (s, 1H, H5), 8.37 (s, 1H, H2). 13C NMR: δ 26.5
(C(CH3)3), 38.1 (C(CH3)3, 55.7 (PhOCH3), 58.2 (CH2-O-CH3),
68.0 (N-CH2-O), 69.0 (Ph-CH2-O), 70.0 (CH2-O-CH3),
105.4 (C5 or C8), 108.9 (C8 or C5), 114.3 (C10), 143.6 (C6 or