Chemical Properties
Off-White Solid
Uses
Methyl 6-aminonicotinate can be used in ointments for treatment of psoriasis.
Reactions
Methyl 6-aminonicotinate is stable under normal conditions, it reacts with strong oxidizing agents and strong bases.
Hazard
Methyl 6-aminonicotinate has an acute oral toxicity, acute dermal toxicity and acute inhalation toxicity.
Synthesis
GENERAL STEPS: A mixture of 6-aminonicotinic acid (4.0 g, 28.9 mmol), methanol (75 mL) and concentrated hydrochloric acid (4 mL) was placed in a reflux apparatus and heated to reflux the reaction for 16 hours. Upon completion of the reaction, the mixture was cooled to 25 °C and subsequently concentrated under reduced pressure by rotary evaporator to remove methanol. Water (20 mL) was added to the residual solid and the pH was adjusted with sodium bicarbonate to 8. Subsequently, extraction was performed with ethyl acetate (3 x 25 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give methyl 6-aminonicotinate (3.12 g, 71% yield) as a white foamy solid: EI-HRMS m/e Calculated value of C7H8N2O2 (M+) 152.0586, measured value 152.0586.
[0199] 2-(4-Methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (prepared according to the method of Example 12, 300 mg, 0.79 mmol) was dissolved in dichloromethane (6 mL), N,N-dimethylformamide (7 drops) was added, and then cooled to 0°C. To this solution was added 2.0 M dichloromethane solution of oxalyl chloride (0.48 mL, 0.95 mmol) dropwise. The reaction mixture was stirred at 0 °C for 30 min and then slowly warmed to 25 °C, followed by concentration under reduced pressure to remove the solvent and excess oxalyl chloride. The resulting residue was redissolved in anhydrous tetrahydrofuran (6 mL) and a tetrahydrofuran (5 mL) solution of methyl 6-aminonicotinate (252 mg, 1.67 mmol) and 2,6-dimethylpyridine (0.48 mL, 3.95 mmol) were added dropwise. The reaction mixture was stirred at 25 °C for 16 h before being diluted with water (100 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by Biotage Fast Chromatography System (FLASH 40S, silica gel column, elution gradient 7/3 hexane/ethyl acetate to 1/1 hexane/ethyl acetate) afforded methyl 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propanoylamino]-nicotinate (227 mg, 55% yield) as a white Frothy solid: E23-HRMS m/e Calculated value C23H25F3N2O6S(M+H)+ 537.1277, measured value 537.1284.
References
[1] Organic Letters, 2018, vol. 20, # 15, p. 4393 - 4396
[2] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 42 - 51
[3] Patent: WO2015/105779, 2015, A1. Location in patent: Page/Page column 11
[4] Patent: US2016/333005, 2016, A1. Location in patent: Paragraph 0041
[5] Patent: US2015/166535, 2015, A1. Location in patent: Paragraph 0039; 0040
