Background and overview of the preparation method of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine
4-(4-Amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine is an organic intermediate that can be synthesized from 4-amino-3-fluorophenol and 4-chloro-N-methyl It is prepared through a one-step reaction using pyridine-2-carboxamide as raw material. 4-(4-Amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine is often used as an anti-tumor drug intermediate.
Preparation method of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine
Preparation method report 1 of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine,
Add 4-amino 3-fluorophenol (1.27g, aluminum magnesium carbonate 10mmol, 1.0eq) into dried DMF (20mL), and stir evenly. Add potassium tert-butoxide (1.34g, 12mmol, 1.0eq), stir at room temperature for 1 hour under nitrogen protection, add 4-chloro-N-methylpyridine-2-carboxamide (1.70g, 10mmol, 1.0eq), and heat to The reaction was continued at 85°C for 10 hours. The reaction solution was quenched by adding water (100mL), and then extracted with dichloromethane (200mL*2). The organic phase was dried over anhydrous magnesium sulfate, and the organic phase was spin-dried to obtain an oily liquid, which was separated by column chromatography (petroleum ether: acetic acid). Ethyl ester = 4:1), obtaining 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine (1.3g). MS: m/z 262.1[M+1]+; 1H-NMR (MHz, CDCl3): δ8.69-8.63(dd,1H),8.07-8.01(m,2H),6.55-6.48(m,3H) ,2.86(s,3H).
Preparation method report 2 of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine,
Add 41.4g of 4-sodium carbonate-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100g of toluene as a solvent into a reaction flask with a stirrer. After adding 68.5 g of water and 19.5 g of aqueous sodium hydroxide solution (45% w/w), the reaction mixture was stirred for 30 minutes. Separate the two phases and discard the aqueous layer. The organic layer was concentrated by vacuum distillation and the toluene was replaced with 1-methyl-2-pyrrolidone (70 g) to give 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone. The solution.
Add 26.7g of 4-amino-3-fluorophenol and 100g of 4-methyl-2-pentanone into the second reaction flask with a stirrer. The water was removed by azeotropic distillation by heating to reflux and stirring for an additional hour. Excess 4-methyl-2-pentanone was then removed by vacuum distillation and replaced with 1-methyl-2-pyrrolidone (70 g) to prepare a solution containing an imine compound according to formula (III). To the resulting reaction mixture was added a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone. The reaction mixture was heated to approximately 100°C. A solution of 123.2 g of potassium tert-butoxide in tetrahydrofuran (20% w/w) was added dropwise (during 75 minutes) while the tetrahydrofuran was removed by distillation. Thereafter, the reaction mixture was stirred at 100°C for an additional 3 hours to complete the reaction. After adjusting to 80°C, 350 ml of toluene, 390 ml of water and 8 g of acetic acid were added. The mixture was stirred at 80°C for 10 minutes, cooled to 50°C and seeded with crystals of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. After cooling to 0°C, the suspension was stirred for approximately 30 minutes. The product was filtered off, washed with methanol/water (1:3 v/v, 145 ml) and dried under reduced pressure (30°C, 80 mbar). In this way, 40.5 g of the product 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamine was obtained as brown crystals. The melting point of the product is 141.2-142.7°C.
References
[1] [Chinese invention] CN201811593635.1 Substituted pyridine-2-carboxamide compounds and their uses
[2] [Invented in China] CN201910674875.2 Anti-tumor drugs and their preparation methods and uses
