Reaction Steps
A stirred mixture of (E)-methyl 5-(4-chlorophenyl)-3-((dimethylamino)methylene-amino)thiophene-2-carboxylate (33.9 g, 105 mmol) prepared in Example 1 Part E and 1-((4-amino-2-methoxy-phenoxy)methyl)-3,3-difluorocyclobutanol (27.2 g, 105 mmol) prepared in Part C and phenol (200 g) was heated at 135-140° C. for 45 min while the reaction being monitored by LC. The mixture was diluted with methanol (700 mL), stirred at RT for 15 min and allowed to stand at RT overnight. The precipitated product was isolated by filtration, washed with chilled methanol and dried under vacuum to yield 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (37 g, 73.3 mmol, 69.8% yield) as a white solid. Dilution of the mother liquor with Et2O and hexane precipitated more solid which was triturated with MeOH to yield 1.8 g of a second crop of the desired product. MP 198-199° C. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1 H, s), 7.66 (2 H, d, J=8.56 Hz), 7.54 (1 H, s), 7.45 (2 H, d, J=8.56 Hz), 7.08 (1 H, d, J=8.56 Hz), 6.99 (1 H, d, J=2.27 Hz), 6.95 (1 H, dd, J=8.31, 2.27 Hz), 4.14 (2 H, s), 3.89 (3 H, s), 2.72-2.93 (4 H, m). 13C NMR (126 MHz, CDCl3) δ ppm 157.3, 156.7, 151.8, 150.4, 148.60 (1C, s), 148.0, 135.7, 131.4, 131.4, 129.4, 127.6, 123.1, 120.8, 119.4, 115.7, 117.6 (dd, J=282, 269. Hz), 111.4, 75.5, 64.6 (dd, J=18, 8 Hz), 56.0, 46.0 (t, J=22.89 Hz).
