Chemical Papers
22.67, 24.66, 25.57, 27.32 and 28.16 0.2 [°theta] and DSC
endotherms at 164.8 and 167.5 °C. A sharp melting point
was not observed, but solid discoloration with decompo-
sition of the compound was observed within the range of
196–223 °C. Sodium content by the titration method was
6.70% (theoretical 6.73%, with respect to compound 11).
mass was stirred at 80–85 °C and progress of the reaction
was monitored by HPLC. The reaction was completed in
2–3 h, isopropanol was distilled, water (110.0 ml) was added
to the resulting residue, stirred for 30 min, the solid fltered,
washed with water (50.0 ml) and dried under vacuum for
30 min. The wet solid was dissolved in dilute aq. HCl solu-
tion (1 N, 215 ml) at 80–85 °C, to get a clear solution which
was treated with activated charcoal and fltered through a
celite bed. The bed was washed with dilute aq HCl solu-
tion (1 N, 50 ml) and the pH of the clear fltrate adjusted
to 8–9 using 2 N sodium hydroxide solution (145–160 ml)
at 80–85 °C. The resulting heterogenous mass was cooled
to 25–30 °C and stirred for 30 min. The solid was fltered,
washed with water (50 ml) and dried under vacuum at
60–65 °C. The obtained crude N-(3-chloro-4-fuorophenyl)-
7-methoxy-6-(3-morpholin-4-ylpropoxy) quinazolin-
4-amine (geftinib 1) was crystallized from isopropanol by
the following procedure: the crude compound was dissolved
in 800 ml isopropanol, the suspension was heated to refux
to get a clear solution, the clear solution was fltered through
a micron flter, the clear fltrate was cooled to 0–10 °C and
stirred for 3 h, and the crystallized solid was fltered and
washed with chilled isopropanol, 25 ml, and dried under a
vacuum not less than 660 mmHg at 70–75 °C for 6 h to get
23.4 g pure N-(3-chloro-4-fuorophenyl)-7-methoxy-6-(3-
morpholin-4-ylpropoxy) quinazolin-4-amine (geftinib 1) as
pale yellow-coloured crystals. The compound was anhydrous
and crystalline in nature. HPLC purity was 99.90%. Melt-
ing point: 193.3–194.0 °C. DSC endotherm: at 195.4 °C.
Moisture content, 0.10%. 1H NMR (300 MHz, DMSO-d6)
δ 1.966-2.007 (t, 2H), 2.289–2.498 (m, 6H), 3.579 (s, 4H),
3.931 (s, 3H), 4.143 (s, 2H), 7.178 (s, 1H), 7.394–7.455
(t, 1H), 7.773 (s, 2H), 8.099–8.129 (m, 1H), 8.489 (s, 1H),
9.531 (s, 1H) ppm. 13C NMR (300 MHz, DMSO-d6): δ
26.06, 53.62, 55.16, 56.04, 66.37, 67.33, 102.69, 107.44,
108.98, 116.51, 116.79, 118.84, 119.04, 122.44, 123.65,
137.00, 147.14, 148.53, 151.72, 152.77, 154.69 and
156.19 ppm. The principal IR peaks were at 3398, 2958,
2808, 1624, 1577, 1531, 1500, 1469, 1427, 1388, 1265,
1246, 1219, 1107, 1026, 1010, 952, 929, 910, 844, 775 and
682 cm−1. X-Ray powder difractogram peaks were at 7.149,
9.384, 11.317, 12.283, 13.914, 14.276, 14.518, 15.363,
15.967, 16.390, 17.659, 18.746, 19.350, 20.739, 21.403,
22.370, 22.672, 23.336, 24.001, 24.363, 25.148, 26.417,
26.779, 27.383, 28.651, 29.255, 29.739, 30.705, 32.094,
33.000, 33.906, 34.269, 34.933, 35.960, 37.711, 38.074,
38.738 and 39.523 [°theta]. Elemental analysis: C, 59.13%;
H, 5.41%; N, 12.54% (calculated), C, 59.44%; H, 5.09%; N,
12.21% (found).
Preparation of potassium‑4‑(3‑chloro‑4‑fuorophen
ylamino)‑7‑methoxyquinazolin‑6‑olate (12)
4-(3′-Chloro-4′-f luoroanilino)-6-hydroxy-7-
methoxyquinazolin, 10 (10.0 g, 0.0312 mol), was added
to 2 N aqueous potassium hydroxide solution (250 ml) at
25–30 °C and stirred at the same temperature for 60 min.
The obtained solid was filtered and washed with water
(12.5 ml), followed by toluene wash (20 ml). The wet solid
was dried under vacuum, not less than 660 mmHg for 4 h
at 60–65 °C, to get the title compound 12 (13.5 g, 135%
with respect to compound 10). X-Ray powder difractogram
peaks were at 11.13, 12.34, 12.88, 16.08, 17.23, 20.86,
21.70, 22.67, 23.27, 24.30, 24.54, 25.51, 27.14, 28.34,
29.61, 31.36, 32.39, 34.32, 35.83 and 36.92 0.2 [°theta].
A sharp melting point was not observed, but solid discolora-
tion with decomposition of compound was observed within
the range of 147.7–171.1 °C.
Preparation of lithium‑4‑(3‑chloro‑4‑fuorophenyla
mino)‑7‑methoxyquinazolin‑6‑olate (13)
4-(3′-Chloro-4′-f luoroanilino)-6-hydroxy-7-
methoxyquinazolin 10 (10.0 g, 0.0312 mol) was added to 3 N
aqueous lithium hydroxide solution (250 ml) at 25–30 °C
and stirred at the same temperature for 60 min. The obtained
solid was fltered and washed with water (12.5 ml), followed
by toluene wash (20 ml). The wet solid was dried under
vacuum, not less than 660 mmHg at 60–65 °C for 4 h, to
get the title compound 13 (10.25 g, 102.5% with respect
to compound 10). X-Ray powder difractogram peaks were
at 10.71, 11.80, 14.88, 17.41, 18.38, 18.74, 23.57, 24.36,
25.02, 25.45, 26.41, 27.32, 28.41, 29.55, 30.22, 32.39, 35.96
and 36.98 0.2 [°theta] and DSC endotherms at 224.2 °C. A
sharp melting point was not observed, but solid discoloration
with decomposition of the compound was observed within
the range of 222.4–239.8 °C.
Preparation of N‑(3‑chloro‑4‑fuorophenyl)‑7‑
methoxy‑6‑(3‑morpholin‑4‑ylpropoxy) quinazo‑
lin‑4‑amine (geftinib, 1)
4-(3-Chloropropyl) morpholine (15.44 g, 0.0943 mol)
was added to a suspension of sodium-4-(3-chloro-4-
fluorophenylamino)-7-methoxyquinazolin-6-olate 11
(21.5 g, 0.0629 mol) in isopropanol (430 ml), the resulting
The above process was repeated at the scale of 100.0 g
(input quantity) and the details obtained are given below.
4-(3′-Chloro-4′-f luoroanilino)-6-hydroxy-7-
methoxyquinazolin 10 (100.0 g, 0.312 mol) was added
1 3