Synthesis of 4-((9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-benzo[c]pyrimido[5,4-d]azepine[5,4-d]-2-yl)amino)-2-methoxybenzoic acid from the compound (CAS:1028486-08-9) and 8-chloro-4-[(dimethylamino)methylene]-1-(2-fluoro-6-methoxyphenyl)-3,4-dihydro-5H-2-benzazepin-5-one -2-yl)amino)-2-methoxybenzoic acid in the following general steps:
1. compound 6 (3.81 kg, 15.5 mol), potassium carbonate (4.3 kg, 31.1 mol), compound 9 (5.27 kg, 14.1 mol) and methanol (63 L) were added to the reactor.
2. the suspension was heated to 50 to 55 °C and stirred continuously for at least 24 hours until a conversion of >96.0% was confirmed by HPLC analysis.
3. Methanol (10 L) and water (37 L) were added while keeping the temperature between 50 and 55 °C.
4. The pH of the mixture was adjusted to 3.0 to 4.0 using a 7% w/w HCl solution (prepared from 7.0 kg of concentrated HCl and 24 L of water) while maintaining the temperature between 50 and 55°C.
5. the suspension was cooled to 20 to 25 °C over a period of at least 1 hour and stirring was continued for at least 60 minutes.
6. The resulting suspension was filtered and the filter cake was washed sequentially with water (2 x 26.3 L) at 50 to 55°C and methanol (2 x 10 L) at 20 to 25°C.
7. the wet filter cake was vacuum dried at 45 to 50 °C to give 5.85 kg (80% yield) of the target product formula (II).
Product characterization data:
3/4 NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.22 (s, 1H), 8.72 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J = 2.4, 8.9 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H) , 7.39 (m, 3H), 7.21 (s, 1H), 6.89 (s, 2H), 3.82 (s, 6H); MS (ESI) m/z 517.2 (M-H+, 45%).
![(1E,4E)-8-chloro-4-((diMethylaMino)Methylene)-1-(2-fluoro-6-Methoxyphenyl)-3,4-dihydrobenzo[c]azepin-5-one](/CAS/GIF/869367-33-9.gif)
