Process for preparing 2-alkoxy-4-amino-5-methyl-pyridines and/or 2-alkoxy-4-alkylamino-5-methyl-pyridines

[0107] example

[0108] Example 1a: Preparation of 4-amino-2-benzyloxy-5-methylpyridine/4-benzylamino-2-benzyloxy-5-methylpyridine (the present invention)

[0109] A mixture of 60 g (0.55 mol) of benzyl alcohol and 40 g (0.22 mol) of a 30% methanolic sodium methoxide solution was heated to about 150°C and the methanol produced was distilled off. After reaching 150° C., a vacuum of 90 mbar was applied, with continuous removal of distillate, and the mixture was stirred under these conditions for a further hour. Subsequently, the vacuum was increased at 150°C until distillation started. Distillation was continued under these conditions until the maximum temperature reached or exceeded 100°C.

[0110] A solution of 10 g (0.07 mol) of 4-amino-2-chloro-5-methylpyridine in 20 g (0.18 mol) of benzyl alcohol is then metered in over 2 hours at 150° C. and under standard pressure. After metering, the reaction mixture was stirred again at 150°C until conversion was complete.

[0111] After cooling to room temperature and adding 40 g of water and 60 g of toluene, the mixture was acidified to pH 9 with 30% aqueous hydrochloric acid. The organic phase remaining after removal of the aqueous phase was washed once with 40 g of water.

[0112] After concentrating the organic phase under reduced pressure to a minimum temperature of 140° C. and 10 mbar, 18 g remain containing 40% by weight of 4-amino-2-benzyloxy-5-methylpyridine (0.03 mol) and 55% by weight of 4-benzylamino-2-benzyloxy-5-methylpyridine (0.03 mol) (theoretical yields 48% and 46%, respectively) as a beige oil. 1 H-NMR and GC-MS verify the chemical structure.

[0113] Example 1b: Preparation of 4-amino-2-benzyloxy-5-methylpyridine/4-benzylamino-2-benzyloxy-5-methylpyridine (the present invention)

[0114] A mixture of 60 g (0.55 mol) benzyl alcohol and 9 g (0.22 mol) sodium hydroxide was heated to about 150°C while removing the distillate. After reaching 150° C., a vacuum of 90 mbar was applied, with continuous removal of distillate, and the mixture was stirred under these conditions for a further hour. Subsequently, the vacuum was increased at 150°C until distillation started. Distillation was continued under these conditions until the maximum temperature reached or exceeded 100°C.

[0115] A solution of 10 g (0.07 mol) of 4-amino-2-chloro-5-methylpyridine in 20 g (0.18 mol) of benzyl alcohol is then metered in over 2 hours at 150° C. and under standard pressure. After metering, the reaction mixture was stirred again at 150°C until conversion was complete.

[0116] After cooling to room temperature and adding 40 g of water and 60 g of toluene, the mixture was acidified to pH 9 with 30% aqueous hydrochloric acid. The organic phase remaining after removal of the aqueous phase was washed once with 40 g of water.

[0117] After concentrating the organic phase under reduced pressure to a minimum temperature of 140° C. and 10 mbar, 17 g remain containing 45% by weight of 4-amino-2-benzyloxy-5-methylpyridine (0.04 mol) and 49% by weight of 4-benzylamino-2-benzyloxy-5-methylpyridine (0.03 mol) (53% and 40% theoretical yields, respectively) as a beige oil.

[0118] Example 1c: Preparation of 4-amino-2-benzyloxy-5-methylpyridine/4-benzylamino-2-benzyloxy-5-methylpyridine (the present invention)

[0119] A mixture of 60 g (0.55 mol) benzyl alcohol and 18 g (0.22 mol) 50% aqueous sodium hydroxide solution was heated to approximately 150°C while removing distillate. After reaching 150° C., a vacuum of 90 mbar was applied, with continuous removal of distillate, and the mixture was stirred under these conditions for a further hour. Subsequently, the vacuum was increased at 150°C until distillation started. Distillation was continued under these conditions until the maximum temperature reached or exceeded 100°C.

[0120] A solution of 10 g (0.07 mol) of 4-amino-2-chloro-5-methylpyridine in 20 g (0.18 mol) of benzyl alcohol is then metered in over 2 hours at 150° C. and under standard pressure. After metering, the reaction mixture was stirred again at 150°C until conversion was complete.

[0121] After cooling to room temperature and adding 40 g of water and 60 g of toluene, the mixture was acidified to pH 9 with 30% aqueous hydrochloric acid. The organic phase remaining after removal of the aqueous phase was washed once with 40 g of water.

[0122] After concentrating the organic phase under reduced pressure to a minimum temperature of 140° C. and 10 mbar, approximately 17 g remain containing 60% by weight of 4-amino-2-benzyloxy-5-methylpyridine (0.05 mol) and 35% by weight of 4-benzylamino-2-benzyloxy-5-methylpyridine (0.02 mol) (65% and 28% theoretical yields, respectively) as a beige oil.

[0123] Example 1d: Preparation of 4-amino-2-benzyloxy-5-methylpyridine (the present invention)

[0124] A mixture of 57.5 g (0.53 mol) benzyl alcohol, 65 g (0.61 mol) xylene, 19 g (0.47 mol) sodium hydroxide and 25 g (0.18 mol) 4-amino-2-chloro-5-methylpyridine under standard pressure The mixture was heated to 147°C while removing the distillate and the mixture was stirred again at this temperature until conversion was complete.

[0125] After cooling to about 100°C, the resulting distillate and also 20 g of xylene and 60 g of water were added and the mixture was controlled to a temperature of about 60°C. After removing the lower phase at about 60°C, the remaining organic phase was washed once with 75 g of water.

[0126] After concentrating the organic phase under reduced pressure to a minimum temperature of 60° C. and 20 mbar, approximately 79 g of 4-amino-2-benzyloxy-5-methylpyridine (0.15 mol, 88 g of 4-amino-2-benzyloxy-5-methylpyridine (0.15 mol, 88 g) remained % theoretical yield) as a beige oil. The ratio of 4-amino-2-benzyloxy-5-methylpyridine to 4-benzylamino-2-benzyloxy-5-methylpyridine was approximately 98:2.

[0127] Example 1e: Preparation of 4-amino-2-benzyloxy-5-methylpyridine (invention)

[0128] 23 g (0.21 mol) of benzyl alcohol were heated to about 120°C. A solution of 10 g (0.07 mol) of 4-amino-2-chloro-5-methylpyridine in 53 g methanol was metered over 2-3 hours at about 120° C. and standard pressure, allowing rapid distillation to remove methanol. After metering, distillation was continued with heating at an internal temperature of about 120°C until no more distillate accumulated.

[0129]After addition of 24 g of xylene and 14.2 g (0.18 mol) of 50% aqueous sodium hydroxide solution, the mixture was slowly heated to 144° C. and the resulting aqueous phase in the biphasic distillate was separated off. Subsequently, it was adjusted for complete distillate removal and the mixture was further heated to 147°C.

[0130] The reaction mixture was stirred at 147°C for 16 hours, then cooled to 90°C-100°C, and 13 g of xylene and 26 g of demineralized water were added. After cooling to about 60°C, the aqueous phase was removed and 30 g of demineralized water were added to the organic phase. After acidification to pH 8-9 with 30% aqueous hydrochloric acid, the aqueous phase was removed again.

[0131] After concentrating the organic phase under reduced pressure to a minimum temperature of 60°C and 100 mbar, approximately 54 g of 4-amino-2-benzyloxy-5-methylpyridine (0.07 mol) are left containing more than 26% by weight and 1.7% by weight of 4-benzylamino-2-benzyloxy-5-methylpyridine (3 mmol) (93% and 4% theoretical yields, respectively) as a reddish-brown liquid.

[0132] Example 2a: Preparation of 4-amino-2-ethoxy-5-methylpyridine (the present invention)

[0133] In an autoclave, a mixture of 12 g (0.08 mol) of 4-amino-2-chloro-5-methylpyridine and 144 g (0.42 mol) of a 20% ethanolic solution of sodium ethoxide was heated to 170°C under spontaneous pressure, and The mixture was stirred under these conditions for 15 hours.

[0134] After cooling to room temperature, the reaction mixture was neutralized with 30% aqueous hydrochloric acid, and 120 g of ethanol was added. The precipitated solid was filtered off and the mother liquor was concentrated to dryness. The solid remaining after evaporation of the mother liquor was taken up in dichloromethane and the insoluble fraction was filtered off. The mother liquor was concentrated to dryness again. The remaining approximately 8.4 g contained 85% by weight of 4-amino-2-ethoxy-5-methylpyridine (0.05 mol) and 10% by weight of 4-ethylamino-2-ethoxy-5 - Methylpyridine (4 mmol) (55% and 5% theoretical yield, respectively) as a beige oil.

[0135] The crude product was further purified by recrystallization from tert-butyl methyl ether/n-hexane. This yielded a light beige solid with a content of 4-amino-2-ethoxy-5-methylpyridine of approximately 95% by weight.

[0136] Example 2b: Preparation of 4-amino-2-ethoxy-5-methylpyridine (the present invention)

[0137] 120 g (0.35 mol) of a 20% ethanolic solution of sodium ethoxide was added to 25.2 g (0.18 mol) of 4-amino-2-chloro-5-methylpyridine and 86 g (0.70 mol) of 4-amino-2-chloro-5-methylpyridine over approximately 2 hours at 120°C ) phenethyl ether mixture while removing the distillate. After metering, the mixture was heated to 170° C. and stirred at this temperature until complete conversion.

[0138] After cooling to room temperature, 150 g of tert-butyl methyl ether and 150 g of water were added to the reaction mixture, and the aqueous phase was removed. 150 g of water were added to the organic phase and the resulting mixture was adjusted to pH 8-9 with 30% aqueous hydrochloric acid. After separation of the aqueous phase, the organic phase was concentrated to dryness at 50° C. and 20 mbar.

[0139] About 88 g of brown oil remained, which was purified by fractional distillation under reduced pressure. The highest melting point fraction yielded 16 g of a colourless liquid which solidified immediately after curing to yield 4-amino-2-ethoxy-5-methylpyridine (0.10 mol) by weight containing 94% by weight and 4% by weight 4-ethylamino-2-ethoxy-5-methylpyridine (3 mmol) (56% and 2% theoretical yields, respectively) as a colorless solid.

[0140] The product fraction was further purified by recrystallization from n-hexane in 97% theoretical yield and largely free of 4-ethylamino-2-ethoxy-5-methylpyridine.

[0141] Example 2c: Preparation of 4-amino-2-ethoxy-5-methylpyridine (the present invention)

[0142] In an autoclave, a mixture of 40 g (0.28 mol) 4-amino-2-chloro-5-methylpyridine, 146 g (3.0 mol) ethanol and 43 g (1.1 mol) sodium hydroxide was heated to 145 °C under spontaneous pressure , and the mixture was stirred under these conditions for 16 hours.

[0143] After cooling to room temperature, 150 g of water were added to the reaction mixture, which was made free of alcohol by distillation at standard pressure to a minimum temperature of about 100°C. 150 g of toluene were added to the distillation residue and controlled at a temperature of about 50°C. The aqueous phase is separated off at this temperature.

[0144] After adding another 150 g of water, the resulting mixture was adjusted to pH 8-9 with 30% aqueous hydrochloric acid. Subsequently, under standard pressure, the toluene was separated off, and after cooling to room temperature, the precipitated solid was filtered off and washed once with 100 g of water.

[0145] After drying under reduced pressure, this yielded 36 g of a colorless to light beige solid with approximately 99.8% purity by weight (0.24 mol, corresponding to 85% theoretical yield).

[0146] Example 3: Preparation of 4-amino-2-propoxy-5-methylpyridine (the present invention)

[0147] In an autoclave, a mixture of 24 g (0.17 mol) 4-amino-2-chloro-5-methylpyridine, 120 g (2.0 mol) n-propanol and 25.8 g (0.65 mol) sodium hydroxide was heated under spontaneous pressure to 145°C and the mixture was stirred under these conditions for 24 hours.

[0148] After cooling to room temperature, 150 g of water were added to the reaction mixture, which was made free of alcohol by distillation at standard pressure to a minimum temperature of about 110°C. 90 g of toluene was added to the distillation residue and controlled at a temperature of about 50°C. The aqueous phase is separated off at this temperature.

[0149] After adding another 90 g of water, the resulting mixture was adjusted to pH 8-9 with 30% aqueous hydrochloric acid. Subsequently, the toluene was separated off at standard pressure and 12 g of isopropanol were added to the remaining suspension at about 70°C. After cooling to room temperature, the precipitated solid was filtered off and washed once with 60 g of water.

[0150] After drying under reduced pressure, this yielded 24.4 g of a colorless to light beige solid with 99% purity by weight (0.15 mol, corresponding to 88% theoretical yield).

[0151] Example 4: Preparation of 4-amino-2-isopropoxy-5-methylpyridine (the present invention)

[0152] In an autoclave, a mixture of 24 g (0.17 mol) 4-amino-2-chloro-5-methylpyridine, 120 g (2.0 mol) isopropanol and 25.8 g (0.65 mol) sodium hydroxide was heated under spontaneous pressure to 145°C and the mixture was stirred under these conditions for 24 hours.

[0153] After cooling to room temperature, 100 g of water was added to the reaction mixture, which was made free of alcohol by distillation at standard pressure to a minimum temperature of about 110°C. 90 g of toluene was added to the distillation residue and controlled at a temperature of about 50°C. The aqueous phase is separated off at this temperature.

[0154] After adding another 90 g of water, the resulting mixture was adjusted to pH 8-9 with 30% aqueous hydrochloric acid. Subsequently, the toluene was separated off at standard pressure and 12 g of isopropanol were added to the remaining suspension at about 70°C. After cooling to room temperature, the precipitated solid was filtered off and washed once with 60 g of water.

[0155] After drying under reduced pressure, this yielded 18.1 g of a colorless to light beige solid with a purity of 99.1% by weight (0.11 mol, corresponding to 65% theoretical yield).