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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 700C -8O0C. Iron (750gm, 13.42moles) was added and the temperature maintained at 700C to 8O0C. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residual mass was diluted with water (5 litres). The pH of the aqueous layer was adjusted between 8.0-8.5 by addition of aqueous sodium carbonate solution and organic layer was separated. The aqueous layer was washed with ethyl acetate (2 litres). The organic layer after optional charcoal treatment was concentrated under reduced pressure to give 3-Amino-2-chloro-4-methyl pyridine of formula (III).Yield: 750gm %Yield: 90.79% HPLC purity: 99.25%.
90.1 - 96.7%
Example 12: 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 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 65C. Iron (195gms, 3.49moles) was added and the temperature maintained at 65C. 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 <DP n="24"/>added to the reaction mixture and stirred. The organic layer was separated and concentrated. 3-Amino-2-chloro-4-methyl pyridine of formula (III) thus obtained was dried.Yield: 74.4gms~79.9gms %Yield: 90.1-96.7% HPLC purity: 99%.
90.7 - 96.8%
Example 10: 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 70C-80C. Iron (1813 gms, 32.45moles) was added and the temperature maintained at 700C to 800C. 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 added to the reaction mixture and stirred. The EPO <DP n="23"/>organic layer was separated and concentrated. Cyclohexane (3.116 kg) was added to the residue with stirring and the resulting mixture after stirring at 10-150C for 60 minutes was filtered, washed with cyclohexane and dried to give 3-Amino-2-chloro-4-methyl pyridine of formula (III). Yield: 15 OOgms to 1600gms %Yield: 90.7 to 96.8% HPLC purity: 99%.
72.60%
With sodium dithionite; In methanol; water; at 70 - 80℃;Product distribution / selectivity;
Example-2: Preparation of 3-Amino-2-chloro-4-methyl pyridine of formula (III) EPO <DP n="19"/>Second method: Reduction with sodium dithionite2-Chloro-3-nitro-4-methylpyridine (II; lOOgm, 0.575moles), was dissolved in methanol (1000 ml) and heated to 70C-80C. Sodium dithionite (300gm, 1.725moles) dissolved in water (1000 ml) was added gradually to the reaction mixture and the temperature maintained at 700C to 8O0C. After completion of reaction, the reaction mixture was concentrated under reduced pressure, residue extracted with ethyl acetate (1000 ml) and the separated organic layer was then concentrated under reduced pressure to give 3-Amino-2-chloro-4-methyl pyridine of formula (III). Yield: 60gm % Yield: 72.60%HPLC purity: 99.25%.
With sodium hydroxide; acetic acid; In hydrogenchloride; water;
b 3-Amino-2-chloro-4-methylpyridine 16.2 g of 2-chloro-4-methyl-3-nitropyridine was added to 470 ml of acetic acid and the resulting mixture stirred at room temperature for 15 min. A solution of 160 g of stannic chloride dihydrate in 200 ml of concentrated hydrochloric acid was then added in one portion and the resulting mixture stirred overnight at room temperature. This mixture was then diluted to 1 liter with water and 10N sodium hydroxide was added slowly with cooling until the white precipitate of tin hydrochloride dissolved. The product was extracted with methylene chloride, dried (sodium sulfate) and concentrated to give 12.8 g of a yellow oil, which solidified on standing, of almost pure 3-amino-2-chloro-4-methylpyridine suitable for use in the next reaction.
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