5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (19-Aug-2009)

5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2- carbaldehyde

5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde, having the following formula:

is an important intermediate in the preparation of N-[3-chloro-4-[(3- fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2- furyl]quinazolin-4-amine, which is an anti-cancer drug.

Provided are processes for the preparation of 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}- 6-quinazolinyl)-furan-2-carbaldehyde.

Example 1:

50g of 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde monotosylate and 300 ml of acetonitrile were added to a 1L reactor. To the resulted suspension a solution of 12.3g sodium carbonate in 350 ml water was added. The resulted yellow suspension was stirred at RT for an hour. The product was filtered in vacuum, washed with 50 ml of cold acetonitrile and dried overnight in vacuum oven at 40°C. Yield - 30g (82%); purity - 99.14%.

The product was analyzed by X-ray powder diffraction and its XRD peaks are represented by the characteristic XRPD pattern:

3000

2000

1000

6.0 10.0 14.0 18.0 22.0 26.0 30.0 34.0 38.0

Main XRD peaks are: 4.6, 11.3, 12.0, 13.1, 14.4, 16.0, 18.5, 19.6, 21.6, 22.3, 22.7, 24.8, 25.2 and 26.5.± 0.2 degrees 2-theta.

The analysis was performed on ARL (Scintag) X-Ray powder diffractometer model X'TRA with CuKα source.

Example 2:

100 liter reactor was charged at ambient temperature with N-[3-chloro-4-(3- fluorobenzyloxy)-phenyl]-6-iodoquinazolin-4-amine (3.0 kg), 5-formyl-2-furanboronic acid
(0.913 kg), Palladium(II) Acetate (6.66gr), ethanol 95% (33L), N,N-diisopropylethylamine
(2.58L), and THF (21L). The solution was then heated to 65ºC and stirred for 5 hours.

The solution was filtered, and more THF was charged (3L). The solution cooled to 30ºC and part of the THF (14L) of the reaction mixture was evaporated under vacuum (100-300 mm Hg), yellow precipitation was obtained, the mixture was stirred for half an hour and then the evaporation of THF was completed.

Ethanol 95% (15L) was added the mixture was stirred for half an...