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

Abstract

The present invention relates to a method for preparing 2-alkoxy-4-amino-5-methylpyridines of the formula (I) and/or 2-alkoxy-4-alkylamino-5-methylpyridines of the formula (II) from the corresponding 2-haloaminopyridines and the appropriate alcohols in the presence of base, and to the compounds resulting therefrom.

Claims

1. A method for preparing compounds of the formula (I) ##STR00008## and/or compounds of the formula (II), ##STR00009## in which R.sup.1 is linear or branched C.sub.1-C.sub.10-alkyl, or in which R.sup.1 is C.sub.3-C.sub.8-cycloalkyl which may be unsubstituted, monosubstituted or polysubstituted, or in which R.sup.1 is aralkyl which may be unsubstituted, monosubstituted or polysubstituted, comprising at least the step of reacting a compound of the formula (III), ##STR00010## in which X is Cl or Br, with a compound of the formula (IV),
R.sup.1OH  (IV) in which the radical R.sup.1 has the definition specified for formula (I), in the presence of a base.

2. The method as claimed in claim 1, characterized in that the base is selected from a group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, and mixtures thereof.

3. The method as claimed in claim 1, wherein the reaction is performed in the presence of a base and a solvent selected from a group consisting of toluene, o-, m-, p-xylene, ethylbenzene, ethoxybenzene, the compounds of the formula (IV), water and mixtures thereof.

4. The method as claimed in any of claim 1, wherein the reaction is carried out at temperatures of 100° C. to 180° C.

5. The method as claimed in any of claim 1, wherein 1 to 10 mol of the compound of the formula (IV) are used per mole of the compound of the formula (III).

6. The method as claimed in any of claim 1, wherein 1.5 to 6 mol of the base are used per mole of the compound of the formula (III).

7. The method as claimed in claim 1, further comprising the steps of a) providing at least the base, b) adding the compound of the formula (III), without solvent or as a solution, to at least the base of step a) at temperatures of 0 to 170° C., providing a mixture, and c) reacting the mixture provided in step b) at temperatures of 120 to 170° C.

8. The method as claimed in claim 1, further comprising the steps of a) providing a mixture of the base selected from a group consisting of the compound of the formula (V), NaOH, and KOH and the compound of the formula (IV), and b) adding the compound of the formula (III) to the mixture provided in step a) at temperatures of 120 to 170° C., and c) reacting the mixture provided in step b) at temperatures of 120 to 170° C.

9. The method as claimed in claim 1, wherein at least the base and the compound of the formula (III) are mixed and this mixture is heated to 120 to 170° C.

10. The method as claimed in claim 9, wherein at least the base, selected from the compound of the formula (V), NaOH or KOH, solvent selected from toluene, o-, m-, p-xylene, ethylbenzene, ethoxybenzene or water, and the compound of the formula (IV) are mixed and this mixture is heated to 120 to 170° C.

11. The method as claimed in any of claim 1, wherein at least the compound of the formula (III) is initially charged and then base and the compound of the formula (IV) is added.

12. The method as claimed in claim 11, wherein at least the compound of the formula (III) and solvent selected from toluene, o-, m-, p-xylene, ethylbenzene, ethoxybenzene or water are initially charged and then the compound of the formula (V) as base and the compound of the formula (IV) are added.

13. The method as claimed in any of claim 1, wherein a liquid phase is distilled off during the reaction.

14. A compound of the formula (I) and/or formula (II), as defined in claim 1.

15. The compound as claimed in claim 14, wherein in formula (I) ##STR00011## R.sup.1 is linear or branched C.sub.1-C.sub.6-alkyl, selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl and 3-ethyl-1-butyl, wherein the linear or branched C.sub.1-C.sub.6-alkyl may be unsubstituted, monosubstituted or polysubstituted, or in which R.sup.1 is C.sub.3-C.sub.8-cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2-methylcycloheptyl, 3-methylcycloheptyl, 4-methylcycloheptyl, 2-ethylcyclobutyl, 3-ethylcyclobutyl, 2-ethylcyclopentyl, 3-ethylcyclopentyl, 2-ethylcyclohexyl, 3-ethylcyclohexyl, 4-ethylcyclohexyl, 2-propylcyclobutyl, 3-propylcyclobutyl, 2-propylcyclopentyl, 3-propylcyclopentyl, 2-butylcyclobutyl, 3-butylcyclobutyl, 2-hydroxycyclopropyl and 2-fluorocyclopropyl, wherein the C.sub.3-C.sub.8-cycloalkyl may be unsubstituted, monosubstituted or polysubstituted, or in which R.sup.1 is aralkyl which may be unsubstituted, monosubstituted or polysubstituted.

16. The compound as claimed in claim 14, wherein in formula (II) ##STR00012## R.sup.1 is linear or branched C.sub.1-C.sub.6-alkyl selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl and 3-ethyl-1-butyl, wherein the linear or branched C.sub.3-C.sub.6-alkyl may be unsubstituted, monosubstituted or polysubstituted, or in which R.sup.1 is C.sub.1-C.sub.8-cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2-methylcycloheptyl, 3-methylcycloheptyl, 4-methylcycloheptyl, 2-ethylcyclobutyl, 3-ethylcyclobutyl, 2-ethylcyclopentyl, 3-ethylcyclopentyl, 2-ethylcyclohexyl, 3-ethylcyclohexyl, 4-ethylcyclohexyl, 2-propylcyclobutyl, 3-propylcyclobutyl, 2-propylcyclopentyl, 3-propylcyclopentyl, 2-butylcyclobutyl, 3-butylcyclobutyl, 2-hydroxycyclopropyl and 2-fluorocyclopropyl, wherein the C.sub.1-C.sub.8-cycloalkyl may be unsubstituted, monosubstituted or polysubstituted, or in which R.sup.1 is aralkyl, which may be unsubstituted, monosubstituted or polysubstituted.

Description

EXAMPLES

Example 1a: Preparation of 4-amino-2-benzyloxy-5-methylpyridine/4-benzylamino-2-benzyloxy-5-methylpyridine (Inventive)

[0100] 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 ca. 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 1 hour. Subsequently, the vacuum was improved at 150° C. until distillation began. Distillation continued under these conditions until the top temperature reached or exceeded 100° C.

[0101] At 150° C. and under standard pressure, the solution of 10 g (0.07 mol) of 4-amino-2-chloro-5-methylpyridine in 20 g (0.18 mol) of benzyl alcohol was then metered in over 2 hours. After metering, the reaction mixture was stirred further at 150° C. until conversion was complete.

[0102] After cooling to room temperature and addition of 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.

[0103] After concentration of the organic phase under reduced pressure up to a bottom temperature of 140° C. and 10 mbar, 18 g of a beige oil comprising 40% by weight 4-amino-2-benzyloxy-5-methylpyridine (0.03 mol) and 55% by weight 4-benzylamino-2-benzyloxy-5-methylpyridine (0.03 mol) (48% and 46% theoretical yield respectively) remained. .sup.1H-NMR and GC-MS verify the chemical structures.

Example 1b: Preparation of 4-amino-2-benzyloxy-5-methylpyridine/4-benzylamino-2-benzyloxy-5-methylpyridine (Inventive)

[0104] A mixture of 60 g (0.55 mol) of benzyl alcohol and 9 g (0.22 mol) of sodium hydroxide was heated to ca. 150° C. with distillate removal. 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 1 hour. Subsequently, the vacuum was improved at 150° C. until distillation began. Distillation continued under these conditions until the top temperature reached or exceeded 100° C.

[0105] At 150° C. and under standard pressure, the solution of 10 g (0.07 mol) of 4-amino-2-chloro-5-methylpyridine in 20 g (0.18 mol) of benzyl alcohol was then metered in over 2 hours. After metering, the reaction mixture was stirred further at 150° C. until conversion was complete.

[0106] After cooling to room temperature and addition of 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.

[0107] After concentrating the organic phase under reduced pressure up to 140° C. bottom temperature and 10 mbar, 17 g of a beige oil comprising 45% by weight 4-amino-2-benzyloxy-5-methylpyridine (0.04 mol) and 49% by weight 4-benzylamino-2-benzyloxy-5-methylpyridine (0.03 mol) (53% and 40% theoretical yield respectively) remained.

Example 1c: Preparation of 4-amino-2-benzyloxy-5-methylpyridine/4-benzylamino-2-benzyloxy-5-methylpyridine (Inventive)

[0108] A mixture of 60 g (0.55 mol) of benzyl alcohol and 18 g (0.22 mol) of an aqueous 50% sodium hydroxide solution was heated to ca. 150° C. with distillate removal. 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 1 hour. Subsequently, the vacuum was improved at 150° C. until distillation began. Distillation continued under these conditions until the top temperature reached or exceeded 100° C.

[0109] At 150° C. and under standard pressure, the solution of 10 g (0.07 mol) of 4-amino-2-chloro-5-methylpyridine in 20 g (0.18 mol) of benzyl alcohol was then metered in over 2 hours. After metering, the reaction mixture was stirred further at 150° C. until conversion was complete.

[0110] After cooling to room temperature and addition of 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.

[0111] After concentrating the organic phase under reduced pressure up to 140° C. bottom temperature and 10 mbar, ca. 17 g of a beige oil comprising 60% by weight 4-amino-2-benzyloxy-5-methylpyridine (0.05 mol) and 35% by weight 4-benzylamino-2-benzyloxy-5-methylpyridine (0.02 mol) (65% and 28% theoretical yield respectively) remained.

Example 1d: Preparation of 4-amino-2-benzyloxy-5-methylpyridine (Inventive)

[0112] A mixture of 57.5 g (0.53 mol) of benzyl alcohol, 65 g (0.61 mol) of xylene, 19 g (0.47 mol) of sodium hydroxide and 25 g (0.18 mol) of 4-amino-2-chloro-5-methylpyridine was heated to 147° C. at standard pressure with distillate removal and the mixture was further stirred at this temperature until conversion was complete.

[0113] After cooling to ca. 100° C., the distillate produced and also 20 g of xylene and 60 g of water were added and the mixture was controlled to a temperature of ca. 60° C. After removing the lower phase at ca. 60° C., the remaining organic phase was washed once with 75 g of water.

[0114] After concentrating the organic phase under reduced pressure up to 60° C. bottom temperature and 20 mbar, ca. 79 g of a beige liquid comprising 40% by weight 4-amino-2-benzyloxy-5-methylpyridine (0.15 mol, 88% theoretical yield) remained. The ratio of 4-amino-2-benzyloxy-5-methylpyridine to 4-benzylamino-2-benzyloxy-5-methylpyridine was ca. 98:2.

Example 1e: Preparation of 4-amino-2-benzyloxy-5-methylpyridine (Inventive)

[0115] 23 g (0.21 mol) of benzyl alcohol were heated to ca. 120° C. At ca. 120° C. and under standard pressure, the solution of 10 g (0.07 mol) of 4-amino-2-chloro-5-methylpyridine in 53 g of methanol was metered in over 2-3 hours so that the methanol was rapidly distilled off. After metering, distillation was continued with heating at an internal temperature of ca. 120° C. until no more distillate accrued.

[0116] After addition of 24 g of xylene and 14.2 g (0.18 mol) of an aqueous 50% sodium hydroxide solution, the mixture was heated slowly to 144° C. and the resulting aqueous phase in the biphasic distillate was separated out. Subsequently, this was adjusted to full distillate removal and the mixture further heated to 147° C.

[0117] The reaction mixture was stirred at 147° C. for 16 hours, then cooled to 90-100° C. and 13 g of xylene and 26 g of demineralized water were added. After cooling to ca. 60° C., the aqueous phase was removed and 30 g of demineralized water were added to the organic phase. After acidifying with 30% aqueous hydrochloric acid to pH 8-9, the aqueous phase was again removed.

[0118] After concentrating the organic phase under reduced pressure up to 60° C. bottom temperature and 100 mbar, ca. 54 g of a red-brown liquid comprising ca. 26% by weight 4-amino-2-benzyloxy-5-methylpyridine (0.07 mol) and 1.7% by weight 4-benzylamino-2-benzyloxy-5-methylpyridine (3 mmol) (93% and 4% theoretical yield respectively) remained.

Example 2a: Preparation of 4-amino-2-ethoxy-5-methylpyridine (Inventive)

[0119] In an autoclave, the 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 autogenous pressure and the mixture was stirred under these conditions for 15 hours.

[0120] After cooling to room temperature, the reaction mixture was neutralized with 30% aqueous hydrochloric acid and 120 g of ethanol were added. The precipitated solid was filtered off and the mother liquor was concentrated to dryness. The solid remaining after evaporating the mother liquor was taken up in methylene chloride and insoluble fractions were filtered off. The mother liquor was again concentrated to dryness. There remained ca. 8.4 g of a beige oil comprising 85% by weight 4-amino-2-ethoxy-5-methylpyridine (0.05 mol) in addition to 10% by weight 4-ethylamino-2-ethoxy-5-methylpyridine (4 mmol) (55% and 5% theoretical yield respectively).

[0121] The crude product was further purified by recrystallization from tert-butyl methyl ether/n-hexane. This gave a pale beige solid having a content of ca. 95% by weight 4-amino-2-ethoxy-5-methylpyridine.

Example 2b: Preparation of 4-amino-2-ethoxy-5-methylpyridine (Inventive)

[0122] 120 g (0.35 mol) of a 20% ethanolic solution of sodium ethoxide was added over ca. 2 hours to a mixture of 25.2 g (0.18 mol) of 4-amino-2-chloro-5-methylpyridine and 86 g (0.70 mol) of phenetol with distillate removal at 120° C. After metering, the mixture was heated to 170° C. and stirred at this temperature until full conversion.

[0123] 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 removed. 150 g of water was added to the organic phase and the resulting mixture was adjusted to pH 8-9 with 30% aqueous hydrochloric acid. After separating off the aqueous phase, the organic phase was concentrated to dryness at 50° C. and 20 mbar.

[0124] There remained ca. 88 g of a brown oil, which was purified by fractional distillation under reduced pressure. The highest-boiling fraction gave 16 g of a colorless liquid which on cooling immediately solidified to give a colorless solid comprising 94% by weight 4-amino-2-ethoxy-5-methylpyridine (0.10 mol) and 4% by weight 4-ethylamino-2-ethoxy-5-methylpyridine (3 mmol) (56% and 2% theoretical yield respectively).

[0125] The product fraction was further purified by recrystallization from n-hexane in a yield of 97% of theoretical yield and was largely freed from 4-ethylamino-2-ethoxy-5-methylpyridine.

Example 2c: Preparation of 4-amino-2-ethoxy-5-methylpyridine (Inventive)

[0126] In an autoclave, the mixture of 40 g (0.28 mol) of 4-amino-2-chloro-5-methylpyridine, 146 g (3.0 mol) of ethanol and 43 g (1.1 mol) of sodium hydroxide was heated to 145° C. under autogenous pressure and the mixture was stirred under these conditions for 16 hours.

[0127] After cooling to room temperature, 150 g of water were added to the reaction mixture which was freed from alcohol by distillation at standard pressure up to a bottom temperature of ca. 100° C. 150 g of toluene were added to the distillation bottoms and controlled at a temperature of ca. 50° C. The aqueous phase was separated off at this temperature.

[0128] After addition of a further 150 g of water, the resulting mixture was adjusted to pH 8-9 with 30% aqueous hydrochloric acid. Subsequently, at standard pressure, the toluene was separated out and after cooling to room temperature the precipitated solid was filtered off and this was washed once with 100 g of water. After drying under reduced pressure, this gave 36 g of colorless to pale beige solid having a purity of ca. 99.8% by weight (0.24 mol, corresponds to 85% theoretical yield).

Example 3: Preparation of 4-amino-2-propoxy-5-methylpyridine (Inventive)

[0129] In an autoclave, the mixture of 24 g (0.17 mol) of 4-amino-2-chloro-5-methylpyridine, 120 g (2.0 mol) of n-propanol and 25.8 g (0.65 mol) of sodium hydroxide was heated to 145° C. under autogenous pressure and the mixture was stirred under these conditions for 24 hours.

[0130] After cooling to room temperature, 150 g of water were added to the reaction mixture which was freed from alcohol by distillation at standard pressure up to a bottom temperature of ca. 110° C. 90 g of toluene were added to the distillation bottoms and controlled at a temperature of ca. 50° C. The aqueous phase was separated off at this temperature.

[0131] After addition of a further 90 g of water, the resulting mixture was adjusted to pH 8-9 with 30% aqueous hydrochloric acid. Subsequently, the toluene was separated out at standard pressure and 12 g of isopropanol were added to the remaining suspension at ca. 70° C. After cooling to room temperature, the precipitated solid was filtered off and washed once with 60 g of water.

[0132] After drying under reduced pressure, this gave 24.4 g of a colorless to pale beige solid having a purity of 99% by weight (0.15 mol, corresponds to 88% theoretical yield).

Example 4: Preparation of 4-amino-2-isopropoxy-5-methylpyridine (Inventive)

[0133] In an autoclave, the mixture of 24 g (0.17 mol) of 4-amino-2-chloro-5-methylpyridine, 120 g (2.0 mol) of isopropanol and 25.8 g (0.65 mol) of sodium hydroxide was heated to 145° C. under autogenous pressure and the mixture was stirred under these conditions for 24 hours.

[0134] After cooling to room temperature, 100 g of water were added to the reaction mixture which was freed from alcohol by distillation at standard pressure up to a bottom temperature of ca. 110° C. 90 g of toluene were added to the distillation bottoms and controlled at a temperature of ca. 50° C. The aqueous phase was separated off at this temperature.

[0135] After addition of a further 90 g of water, the resulting mixture was adjusted to pH 8-9 with 30% aqueous hydrochloric acid. Subsequently, the toluene was separated out at standard pressure and 12 g of isopropanol were added to the remaining suspension at ca. 70° C. After cooling to room temperature, the precipitated solid was filtered off and washed once with 60 g of water.

[0136] After drying under reduced pressure, this gave 18.1 g of a colorless to pale beige solid having a purity of 99.1% by weight (0.11 mol, corresponds to 65% theoretical yield).