N-甲基-2-氟-4-碘苯甲酰胺

反应条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Glycine (80 mg, 1.07 mmol) and K2CO3 (207 mg, 1.5 mmol) were added to solution of 4-iodo-N-methyl-2-fluorobenzamide (279 mg, 1 mmol) in DMF (3 ml). The reaction mixture was stirred at 140° C. for 18 min. in microwave oven, cooled, diluted with AcOEt (10 ml) and water (10 ml), neutralized with HCl to pH 2-3, organic layer was separated, water layer was extracted with AcOEt (5×20 ml). The combined extracts were washed with brine, dried over Na2SO4 and evaporated in vacuo. The product was isolated by column chromatography on SiO2. It gave N-(4-methylcarbamoyl-2-fluorophenyl)glycine 4.2(1) (R1=CH3, R4=R5=H,). A solution of N-(4-methylcarbamoyl-2-fluorophenyl)glycine 4.2(1) (113 mg, 0.5 mmol) and 4-isothiocyanato-2-(trifluoromethyl)benzonirile 3.2 (174 mg, 1.0 mmol) in DMF (2 ml) was stirred at 90° C. for 12 h. The reaction mixture was evaporated in vacuo, and N-methyl-4-{4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]-imidazolidin-1-yl}-2-fluorobenzamide 1.2(1), was isolated by HPLC method, LCMS (M+H)+437. cooled was separated water layer was extracted with AcOEt (5×20 ml) The combined extracts were washed with brine dried over Na2SO4 evaporated in vacuo The product was isolated by column chromatography on SiO2

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 4-amino-2-fluoro-N-methylbenzamide (1.68 g, 10 mmol), H2SO4 (0.68 mL) and water (13 mL) was gently heated until all components were completely dissolved. The mixture was cooled under stirring to 0-5° C., and NaNO2 (0.7 g, 10 mmol) dissolved in water (2 mL) was then added dropwise. The resulting mixture was stirred at 0-5° C. for 0.5 h and then slowly poured into a solution of KI (5 g) in cold water (20 mL). The solution was then heated up to 80° C. and stirred for 0.5 h. After cooling, it was treated with 30 mL of chloroform and filtered. The organic layer was washed with a 5% Na2SO3 solution, dried over Na2SO4, and rotovapped. Column chromatography on silica gel (hexane/EtOAc=6:1) afforded 2.33 g (83%) of 2-fluoro-4-iodo-N-methylbenzamide (4.1). MS (ESI) [M+H]+ 280. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (m, 1H), 7.73 (d, J=10.0 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 2.75 (d, J=4.4 Hz, 3H). A solution of compound 4.1 (9 g, 32 mmol) in DMF (25 mL) was added to an ice-cooled suspension of NaH (1.48 g, 36.8 mmol, 60% in oil, washed with hexane) dissolved in DMF (50 mL). The resulting mixture was vigorously stirred for 0.5 h in an ice bath, then SEM-chloride (6.46 g, 39 mmol) was added and the mixture was continuously stirred overnight at the ambient temperature. After the reaction was completed, the mixture was poured into water (400 mL) and the obtained product was extracted with benzene (2×200 mL), washed with water, dried over Na2SO4, and then filtered through a 3-cm layer of silica gel washing with 5:1 hexane/EtOAc. The solvent was evaporated in vacuum providing 11 g (84%) of 2-fluoro-4-iodo-N-methyl-N-[2-(trimethylsilyl)ethoxymethyl]benzamide (6.1). MS (ESI) [M+H]+ 520. 1H NMR (400 MHz, CDCl3) δ 7.58 (m, 1H), 7.52 (m, 1H), 7.12 (m, 1H), 5.01 (s, 0.8H), 4.58 (s, 1.2H), 3.63 (t, J=8.2 Hz, 0.8H), 3.31 (t, J=8.2 Hz, 1.2H), 3.14 (s, 1.8H), 2.92 (d, J=0.8 Hz, 1.2H), 0.99 (t, J=8.2 Hz, 0.8H), 0.82 (t, J=8.2 Hz, 1.2H), 0.04 (s, 3.6H), −0.01 (s, 5.4H). A mixture of 6.69 g (51 mmol) of amino acid (R)-4.2 or 9.55 g of (R)-4.3, 17.4 g (42.5 mmol) of 6.1, 1.62 g (8.5 mmol) of CuI, 23.5 g (0.17 mol) of K2CO3, 36 mL of water, 145 mL of DMF, and 3-5 drops of Et3N was stirred for 10 min, then 6.56 g (46.8 mmol) of 2-acetylcyclohexanone was added and the stirring continued at 100° C. for 24 h. After cooling, the mixture was rotovapped, the residue was treated with 200 mL of water and acidified with hydrochloric acid to pH 2-3 (˜30 mL). Then, 200 ml, of ether was added, the mixture was stirred for 0.5 h, and the resulting precipitate was filtered off, washed with 50 mL of ether, and dried in vacuum to give 10.7 g (65% from acid (R)-4.2) of (R)-3-(3-fluoro-4-{methyl[2-(trimethylsilyl)ethoxymethyl]carbamoyl}phenylamino)-tetrahydrofuran-3-carboxylic acid ((R)-6) (55% from ester (R)-4.3). MS (ESI) [M+H]+ 413. 1H NMR (400 MHz, DMSO-d6) δ 12.97 (brs, 1H), 7.07 (m, 2H), 6.31 (brs, 1H), 6.17 (brs, 1H), 4.85 (brs, 0.67H), 4.60 (brs, 1.33H), 4.10 (brs, 1H), 3.87 (brs, 3H), 3.51 (brs, 0.67H), 3.24 (brs, 1.33H), 2.93 (s, 2H), 2.86 (brs, 1H), 2.56 (brs, 1H), 2.16 (brs, 1H), 0.89 (brs, 0.67H), 0.73 (brs, 1.33H), 0.03 (m, 9H). cooled the mixture was continuously stirred overnight at the ambient temperature the obtained product was extracted with benzene (2×200 mL) washed with water dried over Na2SO4 filtered through a 3-cm layer of silica gel washing with 5:1 hexane/EtOAc The solvent was evaporated in vacuum