Application of 3-fluoro-4-(4-methylpiperazinyl)aniline_Kain Industrial Additive

Background and overview^[1]

3-Fluoro-4-(4-methylpiperazinyl)aniline can be used as a pharmaceutical synthesis intermediate. If 3-fluoro-4-(4-methylpiperazinyl)aniline is inhaled, move the patient to fresh air; if skin contact occurs, remove contaminated clothing and wash skin thoroughly with soap and water, if any If you feel discomfort, seek medical attention; if eye contact occurs, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Preparation^[1]

The preparation of 3-fluoro-4-(4-methylpiperazinyl)aniline is as follows:

The specific steps are as follows: Heat the mixture of compound 1 (5.0g, 31.4mmol) and compound 2 (70mL, 628.0mmol) in a sealed tube to 100°C for 12 hours. After TLC showed complete consumption of starting material, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5 × 100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford compound 3 (3.0 g, 62% yield) as a yellow solid, which was used without further purification. 1HNMR (400MHz, CDCl3): δ8.09-7.71 (m, 2H), 6.90 (t, J=8.8Hz, 1H), 3.31 (dd, J=5.9, 3.9Hz, 4H), 2.73-2.52 (m, 4H), 2.35(s, 3H). MS[ESI,MH+]=240.15.

Pd/C (10%, 200 mg) was added to a solution of compound 3 (1.0 g, 4.18 mmol) in ethanol (10 mL), and the resulting mixture was stirred under H2 atmosphere (balloon pressure) for 12 h. After TLC showed complete consumption of starting material, the reaction mixture was passed through a pad of Celite and the solids were washed with EtOAc (30 mL). The filtrate was dried over Na2SO4, filtered and concentrated to give 3-fluoro-4-(4-methylpiperazinyl)aniline (600 mg, 69% yield) as a brown semi-solid. 1HNMR (400MHz, DMSO-d6): δ6.75 (dd, J=10.0, 8.3Hz, 1H), 6.50-6.21 (m, 2H), 4.97 (s, 2H), 2.81 (t, J=4.9Hz) , 4H), 2.41 (s, 4H), 2.19 (s, 3H). MS[ESI,MH+]=210.13.

Main reference materials

[1] WO2014151871 JAK2 AND ALK2 INHIBITORS AND METHODS FOR THEIR USE