3-amino-2-chloro-4-methylpyridine

Bromine (1.6 g) was added to a solution of sodium hydroxide (1.6 g) in fresh water or sea water (11.8 g) at 0-5°C. 2-Chloro-4-methyl nicotinamide (1.7 g) was added to cold sodium hypobromite solution in 1.5 h. The ice bath was removed, and the reaction mixture was allowed to warm to room temperature. The resulting yellow solution was heated to 65°C for 2 h, and warmed to 75°C for 2 h. When the solution cooled to room temperature, the product was extracted three times with chloroform (30 mL). The combined extract was dried over anhydrous sodium sulfate, filtered, and concentrated to a solid. Recrystallization with n-hexane yielded a coarse white crystal product. The product yield using zinc powder-treated sea water as raw material was 98percent, mp 70-71°C. (Literature [7]: Yield 92.3percent, mp 69-70°C). The synthesis route of 3-amino-2-chloro-4-methylpyridine is shown in Scheme 2.1. COMAD (10, 3 g) was added to a 3-neck flask fitted with a thermocouple, a dropping funnel, and a heating and cooling system.2. Water (15 g) was added to the reactor and the suspension was agitated.3. The mixture was cooled to 0-5°C.4. The NaOBr solution of vessel I was added to the COMAD suspension in vessel 2 slowly while maintaining the temperature between 0-5°C.5. Afier charging was complete, the temperature of the reaction mixture was held at0-5°C for 15-20 minutes. A clear yellow solution resulted; no solid or suspension was formed.6. The reactor contents were allowed to warm to 15°C and were held at this temperature for 15-20 minutes.7. The reaction mixture was heated to 25°C and maintained at a temperature between22-25°C for 1.5 hours, or until the evolution of heat subsided.8. 10 ml of water was added to the reaction mixture which was then heated to 80°C and held for 1 hour.9. The reaction mixture was then cooled to 50-60°C and toluene (21.62 g) was added; the mixture was agitated for 15-20 minutes.10. The top organic layer was separated.11. Toluene (10.3 g) was added to the aqueous layer and the mixture was agitated for15-20 minutes. The agitation was stopped and the top organic layer was separated.12. The organic layers were combined and washed with water (10 g) and the water layer was decanted.13. Toluene (25.0 g) was removed via distillation under reduced pressure.14. The reactor temperature was adjusted to 55-60°C and hexane (6.5 g) was added slowly with agitation over 15 minutes. The solution because cloudy and a white precipitate started to appear.15. The mixture was cooled slowly to room temperature and then to 0-5°C.16. The mixture was held at 0-5°C for 1 hour.17. The solid precipitate was retrieved by filtered and washed once with hexanes (6.6 g).18. The product was dried under vacuo at 25°C to a constant weight.In an exemplary synthesis, the isolated yield was 8.34 g (96.9percent) of off white to white crystalline product.Synthesis of 3-amino-2-chloro-4-methylpyridine (1) Example 6 EXAMPLE 6 To the above mixture, 61.5 g of calcium hypochlorite was added in portions, After the addition was complete, the heat was kept stirring for 30 minutes, 50 mL of an aqueous solution of 40 wtpercent calcium oxide was further added in portions, Control temperature does not exceed 10 , The reaction was continued for 2 to 3 hours to obtain a reaction mixture.The resulting cold reaction mixture was added dropwise to water (150 mL)Control temperature of 100 degrees or less; dropping finished, 70 ~ 80 ° C to continue the reaction 2 hours; cooling to 5 ° C, With concentrated hydrochloric acid adjusted pH value of 6.5 to 7; suction filtration, The filter cake was washed with ice water; the filter cake was added to 75 mL of water, Heated to 60 to 70 ° C, stirred for 30 minutes, Slowly cooled to 0 ~ 5 , the precipitation of crystals, filtration, The filter cake was washed with ice water, dried in vacuo, To obtain 41.5 g of 2-chloro-3-amino-4-methylpyridine, HPLC purity was 99.9percent.First, 21.6 g of 3-amino-4-methylpyridine was added to the reaction kettle, In the cold water bath slowly dropping 72mL concentrated hydrochloric acid, Stirring to clarify after warming to 40 ° C, 30 ~ 60min slowly dropping 30mL 30percent hydrogen peroxide, temperature control reaction 2h.After completion of the reaction, the system ρΗ = 3 was adjusted with 45percent sodium hydroxide solution, extracted with trichloromethane, dried and removed to obtain the crude product. Recrystallization from petroleum ether or n-hexane gave white or pale yellow needle-like crystals of 2-chloro-3-amino-4-methylpyridine with a purity of 99.0percent, a yield of 83.2percentStep 2[00286] 2-chloro-4-methyl-pyridin-3 -ylamine : A solution of 4-methylpyridin-3 -amine(200 g, 1.85 mol, 1.00 equiv) in concentrated hydrochloric acid (3 L) was placed in a 5 L 3- necked round-bottom flask. Hydrogen peroxide (30percent) (210 g, 1.85 mol, 1.00 equiv) was added dropwise to the solution while maintaining the temperature at 20 °C. The resulting solution was allowed to react overnight at ambient temperature. Saturated aqueous sodium carbonate was added to the solution, till a pH of 8 was reached. The solution was filtered, and the filter cake was washed with water (100 ml x3). The filter cake was dissolved in ethyl acetate (300OmL) and dried over sodium sulfate. The solution was filtered, and the filtrate was concentrated in vacuo F) Example-1 : Preparation of 3-Aniino-2-chloro-4-methyl pyridine of formula (III)First method: Reduction with Iron in acetic acid.2-Chloro-3-nitro-4-methylpyridine (II; lOOOgm, 5.75moles), was dissolved in acetic acid(10 litres) and heated to 70Preparation of 3-Amino-2-chloro-4-methyl pyridine of formula (III)First method: Reduction of 2-chloro-3-nitro-4-methyl pyridine with Iron and hydrochloric acid in an aqueous medium.2-Chloro-3-nitro-4-methylpyridine (II; lOOgm, 0.579moles), was suspended in methanol (1000 ml). Hydrochloric acid (550ml; 15.06 moles ) was added to the mixture and heated to 65°C. Iron (195gms, 3.49moles) was added and the temperature maintained at 65°C. The reaction mixture was monitored by thin layered chromatography and after completion of reaction; the reaction mixture was cooled to ambient temperature. Ethyl acetate was EPO Preparation of 3-Amino-2-chloro-4-methyl pyridine of formula (III)First method: Reduction of 2-chloro-3-nitro-4-methyl pyridine with Iron and phosphoric acid in an aqueous medium.2-Chloro-3-nitro-4-methylpyridine (II; 2000gm, 11.59moles), was suspended in water (20 litres). Orthophosphoric acid (4.545kg; 46, 36 moles ) was added to the mixture and heated between 70°C-80°C. Iron (1813 gms, 32.45moles) was added and the temperature maintained at 70Example-2: Preparation of 3-Amino-2-chloro-4-methyl pyridine of formula (III) EPO

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Molecular Weight:142.58
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:142.0297759
Monoisotopic Mass:142.0297759
Topological Polar Surface Area:38.9
Heavy Atom Count:9
Complexity:97.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes