Browse Prior Art Database

METHOD FOR THE PREPARATION OF 5-[4-(TETRAHYDRO-2H-PYRAN-2-YLOXY)QUINAZOLIN-6-YL]FURAN-2-CARBALDEHYDE, AN INTERMEDIATE OF LAPATINIB

IP.com Disclosure Number: IPCOM000234161D
Publication Date: 2014-Jan-15
Document File: 3 page(s) / 163K

Publishing Venue

The IP.com Prior Art Database

This text was extracted from a PDF file.
This is the abbreviated version, containing approximately 53% of the total text.

Page 01 of 3

METHOD FOR THE PREPARATION OF

5-[4-(TETRAHYDRO-2H-PYRAN-2-YLOXY)QUINAZOLIN-6-YL]FURAN-2-CARBALDEHYDE

AN INTERMEDIATE OF LAPATINIB

Preparation of 6-bromo-4-(tetrahydro-2H-pyran-2-yloxy)quinazoline ( 2 )

O N N

A 2-neck RBF previously anhydrified, equipped with magnetic stirrer, under nitrogen atmosphere, was charged with 1.01 g di 6-bromo-4(3H)-quinazolinone (I) (4.49 x 10-3 mols) and 10 mL of anhydrous toluene. 5.5 mL of 3,4-dihydro-2H-pyrane (5.1 g, 6.1 x 10-2 mols) and 42 μL of trifluoroacetic acid (6.3*10-2 g, 5.49 x 10-4 mol) were added to the above suspension.

The reaction mixture was heated to reflux temperature and kept for 120 minutes. At the end of the reaction (checked by TLC), the mixture was cooled down and treated with 50 mL of NaOH (1 M) and extracted with ethyl acetate (3 x 75 mL). The organic phase was washed with water, then anhydrifyed with sodium sulphate and the solvent was removed by means of rotavapor at 45°C. The solid was crystallized with ethyl acetate, washed with water (20 mL) and with 20 mL of cool ethyl acetate (-20 °C). The solid was dried under vacuum at 55°C for 12 hours.
938.5 mg of product were obtained as white solid (yield 68 %), HPLC Purity 100% (A%).


m.p. 167.5-168 °C;

1H-NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.26 - 8.21 (m, 1H), 7.99 (dd, J = 8.7, 2.4 Hz, 1H),


7.65 (d, J = 8.7 Hz, 1H), 5.89 - 5.77 (m, 1H), 4.16 - 4.04 (m, 1H), 3.68 (dd, J = 12.8, 9.7 Hz, 1H),


2.05-.46 (m, 6H);

13C-NMR (75 MHz, DMSO-d6) δ 157.80 (s), 146.21 (s), 144.69 (s), 137.54 (s), 129.64 (s), 128.44


(s), 122.64 (s), 119.78 (s), 81.05 (s), 68.46 (s), 30.42 (s), 24.38 (s), 22.39 (s).; ESI-MS (m/z): [M]+ calc. for (C13H13N2O2Br) 309; found 332 [M+Na]+.

1

OH N N

O

Br Br

+

O

TFA / Toluene

( 1 )

( 2 )


Page 02 of 3

Preparation of 5-[4-(tetrahydro-2H-pyran-2-yloxy)quinazolin-6-yl]furan-2-carbaldehyde ( 3 )

O

A 25 mL flask equipped with magnetic stirrer under nitrogen atmosphere was charged with 878.6 mg of 6-bromo-4-(tetrahydro-2H-pyran-2-yloxy)quinazoline (2) (2.842 x 10-3 mols), 457.2 mg of 4- (formyl)furylboronic acid (3.268 x 10-3 mols) in 6 mL of toluene (HPLC-grade degassed with nitrogen). To this suspension 1.40 mL (1.02 g, 1.01 x 10-2 mol) of triethylamine previously degassed were added and the mixture wa heated at 70°C. Then, 12.9 mg (1.58 x 10-5 mol, 0.56 % mol) of Pd(dppf)Cl2*CH2Cl2 were added, followed by 6 mL of degassed absolute Ethanol. The mixture was heated at reflux for 110 minutes and the reaction was checked by TLC. After cooling down the mi...