aqueous medium gave compound 7 in 95% yield. We treated
compound 7 with DMF–DMA in toluene to obtain formamidine
derivative 8, which was reacted with 3-ethynylaniline, involving
the same procedure discussed under gefitinib (through Dimroth
rearrangement) to give compound 2. Compound 2 on further
recrystallization gave pure compound in 70% yield with purity
>99% by HPLC. The free base obtained was converted to
erlotinib hydrochloride (9) by passing HCl gas.
All of the intermediates employed in the synthesis of
erlotinib have been made for the first time and are not
reported in the literature. Intermediates obtained from each
step were used for further reaction without purification,
and yields obtained were good to excellent, thus making
the process commercially viable.
4-(3′-Chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholi-
nopropoxy)quinazoline (1). To a reaction flask fitted with a
condenser and a Dean–Stark apparatus were added compound
4 (283 g, 0.97 mol), toluene (2.5 L), acetic acid (3 mL), and
DMF–DMA (280 mL, 2.10 mol). The reaction mixture was
heated to 105 °C and stirred for 3 h. While stirring, methanol
was collected using the Dean–Stark apparatus. Toluene was
completely stripped off under vacuum to obtain N′-[2-cyano-
5-methoxy-4-{3-(4-morpholinyl) propoxy}phenyl]-N,N-dimeth-
yl formamidine (5) as a brown liquid. IR (thin film): 864, 1010,
1118, 1384, 2214, 2812, 2950 cm-1. 1H NMR (CDCl3): δ 2.0
(m, 2H), 2.47 (m, 6H), 3.06 (s, 6H), 3.72 (t, J ) 4.5 Hz, 4H),
3.87 (s, 3H), 4.03 (t, J ) 6.5 Hz, 2H), 6.45 (s, 1H), 6.98 (s,
1H), 7.57 (s, 1H). HRMS: calcd for C18H26N4O3 (M + H)
347.2083, found 347.2081.
Conclusion
To the residue (5) were added acetic acid (2.5 L) and
3-chloro-4-fluoroaniline (175 g, 1.20 mol). The reaction mixture
was heated to 125–130 °C and stirred for 3 h. The reaction
mixture was then cooled to 25 °C, quenched in ice–water (4
L), and adjusted pH ∼9 with ammonia solution. To this reaction
mass was added ethyl acetate (1 L), and the mixture was stirred
for 1 h. The solid precipitate was filtered to obtain crude product
1. Crude material was suspended in MeOH (4 L, and cooled to
20 °C. To this reaction mass was added concentrated HCl (190
mL) slowly with efficient stirring. The precipitate was filtered
and washed with chilled methanol (200 mL) to give gefitinib
hydrochloride. The solid was suspended in H2O (5 L), stirred
for 1 h at room temperature, cooled to 5 °C, filtered, and washed
with chilled water (100 mL) to obtain an off-white solid of
gefitinib hydrochloride. The solid was then suspended in water
(2 L), and the suspension was adjusted to pH ∼8 using ammonia
solution, filtered, and dried at 50 °C to give 1 as off-white solid
(304 g, 70% yield). Mp 193–195 °C. HPLC purity >99%. 1H
NMR (CDCl3, 200 MHz): δ 2.11 (m, 2H), 2.46–2.59 (m, 6H),
3.74 (dd, J ) 4.5 and 4.4Hz, 4H), 3.98 (s, 3H), 4.17 (t, J )
6.5Hz, 2H), 7.09 (s, 1H), 7.16 (t, J ) 8.8Hz, 1H), 7.26 (s, 1H),
7.34 (brs, 1H, exchangeable with D2O), 7.50–7.58 (m, 1H),
7.84–7.88 (m, 1H), 8.66 (s, 1H). MS (m/z): 446(M+),128, 100.
Elemental Anal. Calcd for C22H24ClFN4O3: C, 59.19; H, 5.38;
N, 12.55. Found: C, 59.17; H, 5.21; N, 12.33.
Efficient, commercially viable, and multigram-scale prepara-
tions of gefitinib and erlotinib with a convergent approach have
been described. The convergent processes lead to a reduction
of the number of steps, which provides many advantages over
the original processes reported in the literature.
Experimental Section
General. Starting materials 3 and 6 were prepared using
the procedure described in ref 10. All solvents, sodium
hydroxide, hydrochloric acid, and sodium dithionite were
procured from Loba chemicals, Bhiwandi, India. DM-
F–DMA was obtained from spectrochem, Mumbai, India.
3-Chloro-4-fluoro-aniline and 3-ethynyl aniline were
available commercially and obtained from D. Maniar and
Bros, M/S Madhukar Pharma, Mumbai, India, respectively,
and were used without further purification. IR spectra were
recorded using a Nicolet Avatar 320 FT-IR spectrometer.
1H NMR spectra were recorded in CDCl3/DMSO-d6 at 200
MHz on a Bruker A G Spectrometer. All chemical shift
values are reported in δ units downfield from TMS as
internal standard. Mass spectra were recorded using GC
MS-QP2010S (Direct probe) and on Q-TOF micro AMPS
MAX 10/6A system. HPLC analysis was done using a
Shimadzu CLASS VP using the following column condi-
tions: ODS-3V 4.6 mm × 250 mm, particle size 5µ, λ )
254 nm, flow rate 1 mL/min, mobile phase (40:60) buffer/
acetonitrile (buffer 1% aqueous ammonium acetate).
Melting points were recorded using the melting point
apparatus Acro Steel Pvt. Ltd.
2-Amino-4-methoxy-5-(3-morpholinopropoxy)benzo-
nitrile (4). To a suspension of 3 (329 g, 1.02 mol) in water (5
L) was added sodium dithionite (585 g, 3.35 mol). The reaction
mixture was heated to 50 °C and stirred for 2.5 h, and then the
temperature of the reaction mixture was raised to 70 °C and
25% HCl (1.5 L) was added slowly in 3 h. The reaction mixture
was cooled to 20 °C and adjusted to pH ∼10 with 50% aqueous
sodium hydroxide solution (1.5 L). The product was extracted
into dichloromethane (1.5 L), the organic phase washed with
water (2 × 200 mL) and brine (1 × 200 mL), and the organic
solvent was evaporated to give 4 as brown solid (283g, 95%
yield). 1H NMR (CDCl3): δ 2.01 (m, 2H), 2.51 (m, 6H), 3.72
(t, J ) 4.6 Hz, 4H), 3.84 (s, 3H), 3.97 (t, J ) 6.5 Hz, 2H), 4.14
(br s, 2H), 6.23 (s, 1H), 6.85 (s, 1H).
2-Amino-4,5-bis(2-methoxyethoxy)benzonitrile (7). To a
suspension of 6 (420 g, 1.41 mol) in water (7 L) was added
sodium dithionite (736 g, 4.24 mol). The reaction mixture was
heated to 50 °C and stirred for 2.5 h. Temperature was raised
to 70 °C, and concentrated HCl (1.8 L) was added slowly in
3 h. The reaction mass was cooled to 20 °C and adjusted to pH
∼10 with 50% aqueous sodium hydroxide solution (1.8 L). The
product was extracted into dichloromethane (3 × 250 mL), the
organic phase was washed with water (2 × 200 mL) and brine
(1 × 200 mL), and the organic solvent was evaporated to give
10 as brown solid (358 g, 95% yield). Mp 73–77 °C. IR (KBr):
1
866, 1048, 1132, 2202, 2889, 3359, 3455 cm-1. H NMR
(CDCl3): δ 3.43 (s, 6H), 3.73 (m, 4H), 4.08 (m, 4H), 4.20 (br
s, 2H), 6.25 (s, 1H), 6.90 (s, 1H). HRMS: calcd for C13H18N2O4
(M + Na) 289.1164, found 289.1165.
[6,7-Bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphen-
yl) Amine (2). To a reaction flask fitted with a condenser
and a Dean–Stark apparatus were added compound 7 (358
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