Application of dimethylnitrophenol_Kain Industrial Additive

Background

Dimethylnitrophenol is an intermediate in organic synthesis and pharmaceutical research and development, and can be used in laboratory organic synthesis and chemical and pharmaceutical research and development processes.

Application ^[1]

2,3-Dimethyl-4-nitro-phenol is used to prepare the following compound N⁴-[2,3-dimethyl-4-([1,2, 4]Triazolo[4,3-c]pyrimidin-7-yloxy)phenyl)-N⁶-(4,4-dimethyl-4,5-dihydroxane Azol-2-yl)quinazoline-4,6-diamine has high inhibitory activity against ErbB2 tyrosine kinase and is effective against human breast cancer cells BT-474 and human gastric cancer cells NCI-N87 with high ErbB2 expression. It has good inhibitory activity and relatively weak inhibitory activity against EGFR kinase, which means it is a small molecule inhibitor with good selectivity for the ErbB2 target.

The synthesis method refers to the following compound N⁴-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)-3 -Fluorophenyl)-N⁶-(4,4-dimethyl-4, 5-dihydroxazol-2-yl)-quinazoline-4,6-diamine The difference in synthesis conditions is that 2,3-dimethyl-4-nitro-phenol is used instead of 2-fluoro-4-nitro-phenol, sodium carbonate is used instead of sodium bicarbonate, and the mixture is stirred at 80 degrees for 16 hours.

Step A: Preparation of 7-(2-fluoro-4-nitro-phenoxy)-[1,2,4]triazolo[4,3-c]pyrimidine: 2-Fluoro-4 – Nitro-phenol (1000mg, 6.36mmol), 7-chloro-[1,2,4]triazolo[4,3-c]pyrimidine (984mg, 6.36mmol) and sodium bicarbonate (700mg, 8.33mmol) Suspended in N,N-dimethylformamide (6 mL), stirred at 95 degrees for 16 hours. Cool to room temperature, add ethyl acetate (100 mL) and water (100 mL) to the reaction solution, separate the organic layer, and wash with saturated sodium bicarbonate solution (50 mL × 3), saturated sodium chloride aqueous solution (50 mL), and no Dry over hydrated magnesium sulfate for 2 hours. Filter and evaporate to dryness under reduced pressure to obtain crude product, which is separated by silica gel chromatography column to obtain 300 mg of light yellow solid with a yield of 17.1%.

Step B: Preparation of 3-fluoro-4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)aniline: 7-(2-fluoro- 4-Nitro-phenoxy)-[1,2,4]triazolo[4,3-c]pyrimidine (250 mg, 0.91 mmol) was dissolved in a mixed solvent of methanol (50 mL) and ethyl acetate (50 mL) , add Raney nickel (50 mg), replace with argon three times, and stir for 3 hours at room temperature under a hydrogen balloon. It was filtered through diatomaceous earth and concentrated under reduced pressure to obtain 240 mg of viscous solid with a yield of 100%, which was directly used in the next reaction.

Step C: N4-(4-([1,2,4]triazolo[4,3-c]pyrimidin-7-yloxy)-3-fluorophenyl)-N6-(4, Preparation of 4-dimethyl-4,5-dihydroxazol-2-yl)-quinazoline-4,6-diamine: 3-fluoro-4-([1,2,4]triazole And[4,3-c]pyrimidin-7-yloxy)aniline (260 mg, 1.06 mmol) and N’-[2-cyano-4-[(4,4-dimethyl-4,5-di Hydroxazol-2-yl)amino]phenyl]-N,N-dimethylformamidine (302 mg, 1.06 mmol) was added to the reaction flask, and then acetic acid (0.9 mL) and isopropyl acetate (2.7 mL), and the reaction was stirred at room temperature for 48 hours. The crude product was evaporated to dryness under reduced pressure, and the crude product was separated and purified by thin layer chromatography to obtain 900 mg of oil, which was then separated and purified by acidic preparative HPLC to obtain 120 mg of light yellow solid, with a yield of 23.2%.

Main reference materials

[1] CN201710118352.0 A nitrogen-containing heterocyclic compound���Preparation methods, intermediates, compositions and applications