Preparation background and overview of 4-amino-3-pyridinemethylamine
4-Amino-3-pyridinemethylamine can be used as a pharmaceutical synthesis intermediate. If 4-amino-3-pyridinemethylamine 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 unwell; if the eye contact If exposed to sunlight, 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 structure of 4-amino-3-pyridinemethylamine
Preparation of 4-amino-3-pyridinemethylamine
The preparation of 4-amino-3-pyridinemethylamine is as follows:
Step 1: To a stirred solution of KOH (5.82g, 0.104mol) in EtOH (80mL) was added 1H-pyrimidin-6-one (10g, 0.104mol) at room temperature, followed by MeI (7.20mL, 0.114 mol). The reaction mixture was refluxed for 2 hours (TLC showed 10-15% unreacted starting material). An additional amount of MeI (1.5 g, 0.01 mol) was added, refluxed for 1 hour (TLC showed complete consumption of starting material) and slowly warmed to room temperature. The reaction mixture was filtered, washed with DCM (100 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (100-200 silica gel, 200 g, 2-5% MeOH-DCM) to obtain 3-methylpyrimidine -4-one (4.5g, 39%), as an off-white solid.
Step 2: Add 3-methylpyrimidin-4-one (5.5g, 50.00mol) to sulfuric acid (50mL) cooled to 10°C, and then add fuming nitric acid (6.6mL, 157.15mol). The reaction mixture was slowly raised to room temperature, heated at 100°C for 4 hours (TLC showed that the raw materials were completely consumed), then brought to room temperature again and poured into crushed ice (500g); then 50% sodium hydroxide aqueous solution was slowly added until pH=5. The reaction mixture was extracted with di-tert-butyl dicarbonate with CHCl3 (3 Methyl-5-nitro-pyrimidin-4-one (2 g, 26%) was a yellow solid.
Step 3: In a CEM microwave vial, 3-methyl-5-nitro-pyrimidin-4-one (300mg, 1.94mmol), methyl acetoacetate (2.7g, 23.27mmol), ammonium acetate (1.79 g, 23.22 mmol) and MeOH (8.0 mL) were added and irradiated at 80 °C for 2 h (TLC showed complete consumption of starting materials). The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (100-200 silica gel, 40g, 5-10% MeOH-DCM) to obtain 4-aminopyridine-3-carboxylic acid methyl ester; the reaction mixture was divided into 6 The batches (300 mg per group) were post-processed, and the crude products were combined and purified to obtain 4-aminopyridine-3-carboxylic acid methyl ester (9 benzylpyridine 00 mg, 51%) as a yellow solid.
Step 4: Add a stirring solution of 4-aminopyridine-3-carboxylic acid methyl ester (2g, 13.15mmol) in EtOH-water (120mL, 1:1), LiOHH2O (1.21g, 28.80mmol) at room temperature. And heat to 80°C for 2 hours (TLC shows complete consumption of raw materials). The volatiles were removed under reduced pressure to obtain the crude compound, which was dissolved in water (30 mL) and washed with EtOAc (2 × 25 mL) to remove non-polar impurities. The aqueous layer was acidified with 1NHCl to pH=1 and extracted with EtOAc (2×10 mL). The combined organic extracts were concentrated under reduced pressure to give a crude residue, which was crystallized from MeOH (20 mL) to give 4-aminopyridine-3-carboxylic acid (1 g, 55%) as an off-white solid.
Step 5: Add SOCl2 (3.6 mL, 0.045 mol) and catalytic DMF (30 μL) to a stirred solution of 4-aminopyridine-3-carboxylic acid (3 g, 0.013 mol) in THF (50 mL) at room temperature. and stir for 3 hours. h under argon atmosphere (TLC showed complete consumption of starting material). The volatiles were removed under reduced pressure to obtain the crude product, which was dissolved in THF (30 mL), cooled to 0°C, and 7NNH3-methanol (22 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours, the precipitate was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound, which was purified by column chromatography (100-200 silica gel, 60g, 10% MeOH). -10% NH4OH-DCM) to give 4-amino-3-pyridinemethylamine (475 mg, 27%).
