Application background and overview of 2-chloro-4-aminomethylpyridine
2-Chloro-4-aminomethylpyridine, also called 1-(2-chloropyridin-4-yl)methylamine hydrochloride, can be used in organic synthesis to prepare certain herbicides and fungicides.
Application and preparation of 2-chloro-4-aminomethylpyridine
Step 1. Add di-tert-butyl dicarbonate (300mg) and NiCl 2·6H2O (20mg), then carefully add NaBH4 (220mg) in portions. The resulting black mixture was stirred at 0-5°C (ice bath) for 20 minutes, then the ice bath was removed and stirring was continued at room temperature overnight. Diethylenetriamine was then added and the mixture was concentrated to dryness. The remaining residue was suspended in EtOAc, subsequently washed with 10% aqueous citric acid solution, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried (MgSO4), filtered, Concentrate and purify by chromatography (silica, cyclohexane/EtOAc). Yield: 74%[M+H] + = 243
Step 2,
To a solution of N-BOC-2-chloropyridine-4-methylamine (52 mg) in EtOAc (600 μL) was added 4 M HCl in 1,4-dioxane (600 μL). The reaction mixture was stirred at room temperature for 1~2 h and concentrated. Yield: > 99% [M-Cl] + = 143
Applications of 2-chloro-4-aminomethylpyridine [2]
It can be used to prepare substituted 3-heteroarylisoxazoline-5-carboxamides and 3-heteroarylisoxazoline-5-thioamides. These compounds can be used as herbicides and fungicides. Examples are as follows: 3-(2-chloro-6-methylpyrimidin-4-yl)-N-[(2-chloropyridin-4-yl)methyl]-5-methyl-4,5-dihydro- Preparation of 1,2-oxazole-5-carboxamide.
Intermediate 1: (2-chloro-6-methylpyrimidin-4-yl)methanol
Dissolve 2-chloro-6-methylpyrimidine-4-carboxylic acid propyl methocarbonate (4.0g) in ethanol (46ml) and cool with ice, and add sodium borohydride (8.0g) in batches. After 30 minutes, the ice bath was removed and stirring of the reaction mixture continued for 15 minutes. The reaction mixture was mixed with ice and water, concentrated, extracted with EtOAc, dried over MgSO4 and concentrated at 40°C. The crude product was purified by HPLC. Obtained: 1.4 g of (2-chloro-6-methylpyrimidin-4-yl)methanol.
Intermediate 2: 2-chloro-6-methylpyrimidine-4-carbaldehyde
Dissolve (2-chloro-6-methylpyrimidin-4-yl)methanol (1.6g) in dimethyl sulfoxide (150ml), slowly add triethylamine (4.2ml) dropwise and add in batches Sulfur trioxide-pyridine complex (4.9g). The reaction mixture was stirred for 5 h, adjusted to pH 3 with 2M hydrochloric acid and extracted twice with EtOAc by shaking. The organic phase was washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated at 40°C. Obtained: 2.0 g of 2-chloro-6-methylpyrimidine-4-carbaldehyde.
Intermediate 3: 2-chloro-6-methylpyrimidine-4-carboxaldehyde oxime
First put hydroxylamine hydrochloride (0.72g) and sodium acetate (0.85g) into ethanol (50ml) under nitrogen (white suspension). 2-Chloro-6-methylpyrimidine-4-carbaldehyde was dissolved in ethanol (150 ml) and added dropwise to the suspension over 45 minutes. The reaction mixture was stirred for 20 hours and concentrated at 40°C. Water (100 ml) was added and the mixture was extracted three times with EtOAc. The organic phase was dried with MgSO4 and the crude product was purified by column chromatography. Obtained: 0.31 g of 2-chloro-6-methylpyrimidine-4-carboxaldehyde oxime.
Intermediate 4: 2-chloro-N-hydroxy-6-methylpyrimidine-4-carboximidoyl chloride
First, put 2-chloro-6-methylpyrimidine-4-carboxaldehyde oxime (0.31g) into N,N-dimethylformamide (12ml) under nitrogen, and add N-chlorobutadiene Imide (0.31g). After 2 h, the reaction mixture was poured into ice water (33 ml) and extracted three times with diethyl ether. The organic phase was washed with 0.5 M HCl solution and saturated NaCl solution, dried over MgSO4 and concentrated at 40°C. Obtained: 0.37 g of 2-chloro-N-hydroxy-6-methylpyrimidine-4-imidoyl chloride.
Intermediate 5: 3-(2-chloro-6-methylpyrimidin-4-yl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid methyl ester
Dissolve 2-chloro-N-hydroxy-6-methylpyrimidine-4-imidoyl chloride (0.37g) in 2-propanol (15ml), and add methyl methacrylate (1.9g) . Sodium bicarbonate (1.6g) was added and the reaction mixture was heated to 40°C for 2 hours. The reaction mixture was filtered and concentrated at 40°C. The crude product was purified by column chromatography. Obtained: 0.37g ground 3-(2-Chloro-6-methylpyrimidin-4-yl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid methyl ester.
Intermediate 6: 3-(2-chloro-6-methylpyrimidin-4-yl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid
Methyl 3-(2-chloro-6-methylpyrimidin-4-yl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylate (0.37g ) was dissolved in THF (320ml) and water (14ml), and 2MLiOH aqueous solution (0.66ml) was added. The reaction mixture was stirred at RT for an additional 3 h and then concentrated at 40°C. The residue was taken up in water and washed twice with EtOAc in a separatory funnel. The aqueous phase was adjusted to pH 1 with 2M hydrochloric acid and extracted twice with EtOAc. The organic phase was dried with MgSO4 and concentrated by rotary evaporation at 40°C. Obtained: 0.29 g of 3-(2-chloro-6-methylpyrimidin-4-yl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid.
Final step: 3-(2-chlorodichlorotetrahydrofuran-6-methylpyrimidin-4-yl)-N-[(2-chloropyridin-4-yl)methyl]-5-methyl-4 ,5-dihydro-1,2-oxazole-5-carboxamide
Combine 3-(2-chloro-6-methylpyrimidin-4-yl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid (87 mg) and N – Hydroxysuccinimide (41 mg) was dissolved in dichloromethane (5 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71 mg) was added. After 2 h, triethylamine (0.2 ml) and 1-(2-chloropyridin-4-yl)methanamine hydrochloride (73 mg) were added and the reaction mixture was stirred at RT for a further 65 h. The reaction mixture was diluted with EtOAc and washed with 2M HCl and saturated NaHCO3 solution. The organic phase was dried with MgSO4 and concentrated by rotary evaporation at 40°C. The crude product was chromatographed on silica gel. Obtained: 34 mg of 3-(2-chloro-6-methylpyrimidin-4-yl)-N-[(2-chloropyridin-4-yl)methyl]-5-methyl-4,5-dihydro -1,2-oxazole-5-carboxamide.
