Preparation method of 4-(isobutylcarboxamide)phenylboronic acid_Kain Industrial Additive

Background and overview^[1]

4-(Isobutylcarboxamide)phenylboronic acid can be used as a pharmaceutical synthesis intermediate. If 4-(isobutylcarboxamido)phenylboronic acid is inhaled, move the patient to fresh air; if skin contact occurs, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical attention if you feel uncomfortable; 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]

4-(Isobutylcarboxamide)phenylboronic acid can be used as a pharmaceutical synthesis intermediate. For example, prepare (2R)-2-({[3-fluoro-6-(2,3,4-trifluorophenyl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol , the reaction steps are as follows:

1) (2R)-2-{[(6-bromo-3-fluoropyridin-2-yl)methyl]amino}-3-methylbutan-1-ol.

Dissolve 6-bromo-3-fluoropyridinecarboxaldehyde (4.0g, 19.61mmol) and (R)-2-amino-3-methylbutan-1-ol (2.281mL, 20.59mmol) in methanol (100mL ) and stir at ambient temperature for 1 hour and 15 minutes. Sodium borohydride (0.742g, 19.61mmol) was added and the mixture was stirred for a further 1 hour and 30 minutes. Reduce the volume of the reaction mixture, quench the mixture with 200 mL of 1.0 N NaOH, and extract with 200 mL of dichloromethane (2x). The organic phase was extracted with 1.0 N HCl and partitioned. The aqueous phase was separated, neutralized with 3.0 N NaOH, extracted with EtOAc, the organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated to give the title compound. Orange solid. MS (ESI+) m/z291.0 (M+H); 11HNMR (300MHz, DMSO-d6 (δ7.69 (t, J=8.8, 1H), 7.60 (dd, J=8.6, 3.7, 1H), 4.42 (t, J=5.2, 1H), 3.92-3.75 (m, 2H), 3.43 (dt, J=10.7, 4.8, 1H), 2.34-2.24 (m, 1H), 2.08 (s, 1H), 1.87- 1.71 (m, 1H), 0.83 (dd, J=8.5, 6.9, 6H).

2) (2R)-2-({[3-fluoro-6-(2,3,4-trifluorophenyl)pyridin-2-yl]methyl}amino)-3-methylbutan- 1-alcohol

Charge a 4 mL vial with SiliaCatDPP-Pd (0.1 equiv, 26 mg). Add step 1) a solution of the compound (20 mg, 0.07 mmol) in ethanol (1.0 mL) and a solution of 4-(isobutylformamide)phenylboronic acid (14 mg, 0.08 mmol) in ethanol (0.3 mL), then add 1 MCS2CO3 aqueous solution (0.21 mL)). The mixture was heated (Synthos 3000 Anton Paar Microwave Reaction System) at 120 °C for 30 min, then filtered and concentrated. The residue was purified by reverse phase HPLC to give the title compound. 4-[5-Fluoro-6-({[(2R)-1-hydroxy-3-methylbut-2-yl]amino}methyl)pyridin-2-yl]-N-(2-methylpropane base) benzamide. MS(ESI+)m/z388(M+H)+.

Main reference materials

[1] (WO2012129491) TRPV3 MODULATORS