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

Abstract

The present invention relates to a process for preparing 2-alkoxy-4-amino-5-methyl-pyridines of formula (I) and / or 2-alkoxy-4-alkylamino-5-methyl-pyridines of formula (II) from the corresponding 2-halo-amino-pyridines and the corresponding alcohols in the presence of a base, and to the corresponding resulting compounds.

Description

Technical Field

[0001] The present invention relates to a process for preparing 2-alkoxy-4-amino-5-methylpyridines of formula (I) and / or 2-alkoxy-4-alkylamino-5-methylpyridines of formula (II) from the corresponding 2-haloaminopyridines and a suitable alcohol in the presence of a base or the corresponding alkoxide, and to the compounds resulting therefrom. Background Art

[0002] 2-Alkoxy-4-amino-5-methylpyridines and 2-alkoxy-4-alkylamino-5-methylpyridines are starting materials for the synthesis of pharmaceutical and agrochemical active ingredients. Such structural elements are found, for example, in the acetyl-CoA carboxylase inhibitors in WO2014 / 114578A2, which can be used for treating, for example, diabetes or obesity. As an active ingredient in WO 2014 / 124230 A2, such 2-alkoxy-4-amino-5-methylpyridines of formula (I) are disclosed as starting materials for preparing active ingredients from the group of ERK kinase inhibitors, which kinase inhibitors can be used for treating cancer.

[0003] So far, no method for preparing such 2-alkoxy-4-amino-5-methylpyridines and / or 2-alkoxy-4-alkylamino-5-methylpyridines is known from the literature.

[0004] There is therefore a need for a process for preparing 2-alkoxy-4-amino-5-methylpyridines of formula (I) and / or 2-alkoxy-4-alkylamino-5-methylpyridines of formula (II), by means of which these pyridine derivatives can be prepared in an efficient manner in an industrial process. Summary of the Invention

[0005] Surprisingly, a process for preparing 2-alkoxy-4-amino-5-methylpyridines of formula (I) and / or 2-alkoxy-4-alkylamino-5-methylpyridines of formula (II) has been found, which comprises reacting 2-halo-4-amino-5-methylpyridines of formula (III) in the presence of an alcohol and a base to give these products in good yield and high purity.

[0006] The present invention thus relates to a process for preparing the following compounds: a compound of formula (I)

[0007]

[0008] and / or a compound of formula (II),

[0009]

[0010] wherein R 1is a straight-chain or branched C1-C 10 -alkyl, preferably a straight-chain or branched C1-C6-alkyl, which may be unsubstituted, mono-substituted or multi-substituted,

[0011] or wherein R 1 is a C3-C8-cycloalkyl, which may be unsubstituted, mono-substituted or multi-substituted,

[0012] or wherein R 1 is an aralkyl, which may be unsubstituted, mono-substituted or multi-substituted,

[0013] The method comprises at least reacting a compound of formula (III)

[0014]

[0015] wherein X is Cl or Br, preferably Cl,

[0016] with a compound of formula (IV),

[0017] R 1 OH(IV)

[0018] wherein the group R 1 has the definition specified for formula (I),

[0019] The reaction is carried out in the presence of a base and optionally in the presence of a solvent.

[0020] In the compound of formula (II), the group R 1 in the substituent "O-R 1 " at the 2-position of the pyridine ring and the group R 1 in the substituent "NH-R 1 " at the 4-position of the pyridine ring are preferably the same in one molecule. In the method according to the invention, if a mixture of compounds of formula (IV) and / or (V) with different R 1 groups is used, compounds containing different R

[0021] According to the straight-chain C1-C 1 -alkyl of R 10 is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.

[0022] According to the unsubstituted straight-chain or branched C1-C 1 -alkyl of the group R 10 is preferably methyl, ethyl or n-propyl. According to the substituted straight-chain alkyl of the group R 1 is preferably cyclopropylmethyl or 1,1-difluoroethyl.

[0023] According to R 1 The straight-chain or branched C1-C6-alkyl groups are, for example, 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 or 3-ethyl-1-butyl.

[0024] The straight-chain or branched C1-C 10 -alkyl or C1-C6-alkyl can be unsubstituted. It can also be mono-substituted or multi-substituted. Examples of mono-substituted C1-C6-alkyl groups are 2-methoxy-1-ethyl, 2-ethoxy-1-ethyl, 3-methoxy-1-propyl, 3-ethoxy-1-propyl or 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 1,1-difluoroethyl or 2,2-difluorocyclopropylmethyl.

[0025] According to R 1 The C3-C8-cycloalkyl groups according to R are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

[0026] The C3-C8-cycloalkyl can also be unsubstituted, mono-substituted or multi-substituted. Examples of mono-substituted C3-C8-cycloalkyl groups are 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, 2-fluorocyclopropyl.

[0027] According to R 1 The aralkyl groups according to R include two alkyl groups substituted by an aromatic group or by a heteroaromatic group and are, for example, benzyl, phenethyl, 2-furanylmethyl, 3-furanylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl or 2-naphthylmethyl. According to R 1The aralkyl group is preferably benzyl, 2-furanylmethyl, 3-furanylmethyl or 3-pyridylmethyl.

[0028] In the process according to the invention, the base is selected from alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates or alkaline earth metal carbonates or compounds of formula (V)

[0029] R 1 OM (V),

[0030] wherein the group R 1 has the definition specified for formula (I) and M is an alkali metal, in particular potassium or sodium, particularly preferably sodium,

[0031] or mixtures thereof. In the process according to the invention, the base can be used as a pure substance in solid or liquid form and in dissolved or suspended form in a liquid medium. The alkali metal alkoxide of formula (V) used in the reaction is typically in the form of its alcohol solution or used without a solvent.

[0032] The process according to the invention is typically carried out in the presence of a solvent. In this case, the undissolved components can be present in the reaction mixture at the start of the reaction, during the reaction or at the end of the reaction. Suitable solvents are toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, ethoxybenzene, compounds of formula (IV), water or mixtures thereof. For the process according to the invention, the solvents used are preferably toluene, p-xylene or compounds of formula (IV), water or mixtures thereof.

[0033] The reaction partners, i.e. the compounds of formula (III) and the compounds of formula (IV), react in the process according to the invention at a temperature of for example 100 °C to 180 °C, preferably 120 °C to 160 °C. In this case, the reaction partners can initially be mixed individually or separately as pure substances or dissolved or suspended in a solvent at room temperature. Subsequently, the reaction mixture can be heated to the desired reaction temperature, where the solvent can or cannot be distilled off simultaneously and / or in stages. In another embodiment of the process according to the invention, the base and the mixture of the compound of formula (III) and the solvent can already be heated to a temperature above ambient temperature and then the compound of formula (IV) is added. The addition is carried out, for example, in portions or continuously. Preferably, the compound of formula (IV) is added continuously.

[0034] In a preferred embodiment, the process according to the invention is carried out such that in step a), initially at least an alkali, preferably a compound of formula (V), and optionally a solvent, are charged, for example as a solution in the corresponding alcohol or without a solvent, and in step b), a compound of formula (III) is added to the mixture from step a) as a solution or without a solvent at a temperature of from 0 °C to 170 °C, preferably from 20 °C to 160 °C, and in step c) the mixture obtained from step b) is reacted at a temperature of from 120 °C to 170 °C, preferably from 130 °C to 160 °C. The compound of formula (III) is typically added in one step, in two or more steps or continuously.

[0035] Typically, the process according to the invention is carried out such that 1 to 10 mol, preferably 1 to 6 mol, particularly preferably 2 to 4 mol, of a compound of formula (IV) are used per mole of the compound of formula (III).

[0036] Also typically, in the process according to the invention, 1.5 to 6 mol, preferably 2 to 5 mol, particularly preferably 2.5 to 4 mol, of an alkali are used per mole of the compound of formula (III).

[0037] In the process according to the invention, for example in step a), initially at least an alkali selected from compounds of formula (V), NaOH or KOH, preferably as a solution in the corresponding alcohol or without a solvent, an alcohol of formula (IV) and optionally a solvent can be charged. In step b), a compound of formula (III), optionally as a mixture with a compound of formula (IV), can be added to the mixture from step a) at a temperature of from 120 °C to 170 °C, preferably from 130 °C to 160 °C. The compound of formula (III) is typically added in one step, in two or more steps or continuously. The mixture obtained from step b) can be reacted at a temperature of from 120 °C to 170 °C, preferably from 130 °C to 160 °C. In this case, the solvent can be distilled off either simultaneously and / or in stages. Typically, steps a), b) and c) are carried out continuously.

[0038] In the process according to the invention and in a further preferred embodiment, for example, the alkali, optionally the solvent and the compound of formula (III) are mixed and this mixture is heated to from 120 °C to 170 °C, preferably from 130 °C to 160 °C. In this case, the solvent can be distilled off either simultaneously and / or in stages. The reaction mixture is preferably maintained at this temperature until no further reaction occurs. The chemical reaction is typically monitored by gas chromatography, thin layer chromatography, infrared spectroscopy or HPLC.

[0039] In the process according to the invention, preferably and by way of example, initially at least a base selected from the group consisting of the compounds of formula (V), NaOH or KOH; a solvent selected from toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, ethoxybenzene or water; and a compound of formula (IV) are mixed, and this mixture is heated to 120 °C to 170 °C, preferably 130 °C to 160 °C. If a compound of formula (V) is used as the base, then preferably a compound of formula (IV) (which contains the same group R as formula (V)) is used as the solvent. In this embodiment, for example, in the case of sodium benzylate as the base, benzyl alcohol is used as the solvent. 1 )

[0040] In the process according to the invention, for example, initially at least a compound of formula (III) and optionally a solvent are charged, and then a base and a compound of formula (IV) are added. During the addition, the base can be present as a pure substance, in dissolved form or in suspended form.

[0041] The process according to the invention is preferably carried out such that initially at least a compound of formula (III) and a solvent selected from toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, ethoxybenzene are charged, and then a compound of formula (V) as the base and a compound of formula (IV) are added. During the reaction in the process according to the invention, the liquid phase is preferably distilled off. In this case, the distillation during the reaction can be carried out at ambient temperature, under pressure or under reduced pressure. The distillation during the reaction is preferably carried out at a pressure of 0.0001 to 0.1 MPa. A person skilled in the art typically selects the pressure according to the melting point of the solvent and the desired reaction temperature.

[0042] If the reaction temperature is above the melting point of the reaction mixture or of the individual components of the reaction mixture at ambient pressure, the reaction is typically carried out in a pressure-sealed device (e.g., in an autoclave) under autogenous pressure or under a pressure generated, for example, by nitrogen.

[0043] The process according to the invention is preferably carried out in the absence of copper compounds, for example in the absence of copper iodide. In an alternative embodiment, the process according to the invention is preferably carried out in the absence of a catalyst, for example in the absence of transition metal compounds. Surprisingly, using the process according to the invention, even in the absence of copper compounds such as copper iodide and / or in the absence of a catalyst such as transition metal compounds, a high yield of the compound of formula (I) and / or the compound of formula (II) is obtained.

[0044] After completion of the reaction of the compound of formula (III), the reaction product, i.e., the compound of formula (I) and / or the compound of formula (II), is obtained from the reaction mixture, for example, by:

[0045] a) Add water to the reaction mixture, which has been controlled to a temperature from ambient temperature to the maximum reaction temperature, preferably cooled to 15 °C to 100 °C, and

[0046] b) Add an acid, such as hydrochloric acid, thereby adjusting the pH of the mixture to, for example, pH 7 to 9, and

[0047] c) Add water and a solvent that is slightly miscible with water, such as toluene or xylene, to the mixture, and mix the resulting mixture, and

[0048] d) Subsequently, after phase separation, separate the organic phase, optionally wash it with water and then optionally release the organic phase from the water, and

[0049] e) Then remove the volatile components of the organic phase, for example by distillation, to obtain a crude product, and

[0050] f) Subsequently separate the product from the crude product by fractional distillation or crystallization.

[0051] In this variant, after step a) and before step b) - if the process according to the invention is carried out in the presence of the solvent of formula (IV) - the solvent of formula (IV) is removed from the reaction mixture, for example by distillation. In another variant, for example - if the process according to the invention is carried out in the presence of the solvent of formula (IV),

[0052] a) Adjust the pH of the reaction mixture to, for example, pH 7 to 9 by adding an acid, such as hydrochloric acid, and

[0053] b) Then further, add the solvent of formula (IV), such as ethanol, to the reaction mixture, whereby the product can precipitate as a solid, and

[0054] c) Subsequently render the reaction mixture free of volatile components, for example by distillation, to obtain a crude product, and

[0055] d) Then optionally separate the product from the crude product by fractional distillation or crystallization.

[0056] In another variant, the compound of formula (I) and / or the compound of formula (II) is / are separated from the reaction mixture, for example, by:

[0057] a) Preferably filter off the crude product as a solid precipitate from the reaction mixture, which has been controlled to a temperature from ambient temperature to the maximum reaction temperature, preferably cooled to 15 °C to 70 °C, and

[0058] b) Then optionally separate the product from the crude product by fractional distillation or crystallization.

[0059] In this variant, before step a), a solvent such as ethanol can optionally be added to the reaction mixture which has been controlled to a temperature between ambient temperature and the maximum reaction temperature, preferably cooled to 15 °C to 70 °C. Also in this case, before step a), the pH of the mixture can optionally be adjusted to, for example, pH 7 to 9 by adding an acid such as hydrochloric acid.

[0060] The invention also includes compounds of formula (I) or formula (II) obtained by the process according to the invention.

[0061] The invention preferably includes compounds of formula (I),

[0062]

[0063] wherein R 1 is a straight-chain or branched C1-C6-alkyl group, preferably a C3-C6-alkyl group, or is a group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methyl-1-butyl, 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 or 3-ethyl-1-butyl,

[0064] wherein the straight-chain or branched C1-C6-alkyl group can be unsubstituted, monosubstituted or polysubstituted,

[0065] or wherein R 1 is a C3-C8-cycloalkyl group selected from the group consisting of

[0066] cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0067] 2-methylcyclobutyl, 3-methylcyclobutyl,

[0068] 2-methylcyclopentyl, 3-methylcyclopentyl,

[0069] 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,

[0070] 2-methylcycloheptyl, 3-methylcycloheptyl, 4-methylcycloheptyl,

[0071] 2-ethylcyclobutyl, 3-ethylcyclobutyl,

[0072] 2-ethylcyclopentyl, 3-ethylcyclopentyl,

[0073] 2-ethylcyclohexyl, 3-ethylcyclohexyl, 4-ethylcyclohexyl,

[0074] 2-propylcyclobutyl, 3-propylcyclobutyl,

[0075] 2-propylcyclopentyl, 3-propylcyclopentyl,

[0076] 2-butylcyclobutyl, 3-butylcyclobutyl,

[0077] 2-hydroxycyclopropyl or 2-fluorocyclopropyl,

[0078] wherein the C3-C8-cycloalkyl may be unsubstituted, monosubstituted or polysubstituted,

[0079] or wherein R 1 is an aralkyl group, preferably benzyl, phenethyl, 2-furanylmethyl, 3-furanylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl or 2-naphthylmethyl, which may be unsubstituted, monosubstituted or polysubstituted.

[0080] These compounds of formula (I) are accessible in high yield and purity by the process described above according to the invention.

[0081] The invention preferably further comprises compounds of formula (II),

[0082]

[0083] wherein R 1 is a straight-chain or branched C1-C6-alkyl group, preferably a C3-C6-alkyl group, or is a group selected from the group consisting of

[0084] this group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methyl-1-butyl, 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, 3-ethyl-1-butyl,

[0085] wherein the straight-chain or branched C3-C6-alkyl group may be unsubstituted, monosubstituted or polysubstituted,

[0086] or wherein R 1is a C3-C8-cycloalkyl which is selected from the group consisting of

[0087] cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,

[0088] 2-methylcyclobutyl, 3-methylcyclobutyl,

[0089] 2-methylcyclopentyl, 3-methylcyclopentyl,

[0090] 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl,

[0091] 2-methylcycloheptyl, 3-methylcycloheptyl, 4-methylcycloheptyl,

[0092] 2-ethylcyclobutyl, 3-ethylcyclobutyl,

[0093] 2-ethylcyclopentyl, 3-ethylcyclopentyl,

[0094] 2-ethylcyclohexyl, 3-ethylcyclohexyl, 4-ethylcyclohexyl,

[0095] 2-propylcyclobutyl, 3-propylcyclobutyl,

[0096] 2-propylcyclopentyl, 3-propylcyclopentyl,

[0097] 2-butylcyclobutyl, 3-butylcyclobutyl,

[0098] 2-hydroxycyclopropyl or 2-fluorocyclopropyl,

[0099] wherein the C1-C8-cycloalkyl may be unsubstituted, monosubstituted or polysubstituted,

[0100] or wherein R 1 is an aralkyl, preferably benzyl, phenethyl, 2-furanylmethyl, 3-furanylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl or 2-naphthylmethyl, which may be unsubstituted, monosubstituted or polysubstituted.

[0101] These compounds of formula (II) are accessible by the method described above according to the invention. Typically, higher yields of the compounds of formula (II) are obtained when preferably all components of the reaction are mixed at ambient temperature, i.e., the compound of formula (I), the compound of formula (IV) which functions as a solvent therefor, the compound of formula (V) which functions as a base and as a reactant, and then the mixture is heated to 120 °C to 170 °C, preferably 130 °C to 160 °C, wherein the group R 1 is less sterically challenging, such as methyl or ethyl. If the introduced group R 1Greater spatial challenges, such as benzyl, result in higher yields of the compound of formula (II) when, for example, a compound of formula (III) optionally dissolved in the corresponding alcohol of formula (IV) is added to a solution of an alcoholate of formula (V) at a temperature of from 120°C to 170°C, preferably from 130°C to 160°C.

[0102] Particularly preferred are compounds of the following formula: formula (I)

[0103]

[0104] and / or formula (II),

[0105]

[0106] wherein R 1 is methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl, 2,2-difluorocyclopropylmethyl, benzyl, 1-methoxyethoxy or 1,1-difluoroethyl. Detailed Description

[0107] Examples

[0108] Example 1a: Preparation of 4-amino-2-benzyloxy-5-methylpyridine / 4-benzylamino-2-benzyloxy-5-methylpyridine (of 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 formed was distilled off. After reaching 150°C, a vacuum of 90 mbar was applied while continuously removing the distillate, and the mixture was stirred for a further 1 hour under these conditions. Subsequently, the vacuum was increased at 150°C until distillation began. Distillation was continued under these conditions until the maximum temperature reached or exceeded 100°C.

[0110] At 150°C and under standard pressure, a 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 a period of more than 2 hours. After metering, the reaction mixture was stirred at 150°C until the 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 aqueous 30% 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 of a beige oil remained, 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). 1 The chemical structures were verified by 1H-NMR and GC-MS.

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

[0114] A mixture of 60 g (0.55 mol) of benzyl alcohol and 9 g (0.22 mol) of sodium hydroxide was heated to approximately 150 °C while removing the distillate. After reaching 150 °C, a vacuum of 90 mbar was applied while continuously removing the distillate, and the mixture was stirred for a further 1 hour under these conditions. Subsequently, the vacuum was increased at 150 °C until distillation began. Distillation was continued under these conditions until the maximum temperature reached or exceeded 100 °C.

[0115] At 150 °C and under standard pressure, a 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 a period of more than 2 hours. After metering, the reaction mixture was stirred at 150 °C until the 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 aqueous 30% 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 of a beige oil remained, 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) (theoretical yields 53% and 40% respectively).

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

[0119] A mixture of 60 g (0.55 mol) of benzyl alcohol and 18 g (0.22 mol) of 50% aqueous sodium hydroxide was heated to about 150 °C while removing the distillate. After reaching 150 °C, a vacuum of 90 mbar was applied while continuously removing the distillate, and the mixture was stirred for an additional 1 hour under these conditions. Subsequently, the vacuum was increased at 150 °C until distillation began. Distillation was continued under these conditions until the maximum temperature reached or exceeded 100 °C.

[0120] At 150 °C and under standard pressure, a 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 a period of more than 2 hours. After metering, the reaction mixture was stirred at 150 °C until the 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, there remained approximately 17 g of a beige oil 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) (theoretical yields 65% and 28% respectively).

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

[0124] 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 under standard pressure while removing the distillate, and the mixture was stirred at this temperature until the conversion was complete.

[0125] After cooling to about 100 °C, the distillate produced as well as 20 g of xylene and 60 g of water were added, and the mixture was brought 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, there remained approximately 79 g of a beige oil containing 40% by weight of 4-amino-2-benzyloxy-5-methylpyridine (0.15 mol, 88% theoretical yield). 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 (the present invention)

[0128] 23 g (0.21 mol) of benzyl alcohol was heated to approximately 120 °C. At approximately 120 °C and under standard pressure, a 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 such that methanol was removed by rapid distillation. After metering, distillation was continued while heating at an internal temperature of approximately 120 °C until no more distillate accumulated.

[0129] After adding 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 aqueous phase obtained in the biphasic distillate was separated off. Subsequently, it was adjusted to complete removal of the distillate 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 softened water were added. After cooling to approximately 60 °C, the aqueous phase was removed and 30 g of softened water was added to the organic phase. After acidifying 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, there remained approximately 54 g of a reddish-brown liquid containing greater than 26% by weight of 4-amino-2-benzyloxy-5-methylpyridine (0.07 mol) and 1.7% by weight of 4-benzylamino-2-benzyloxy-5-methylpyridine (3 mmol) (theoretical yields of 93% and 4% respectively).

[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 a 20% ethanolic solution of 144 g (0.42 mol) of sodium ethoxide was heated to 170 °C under autogenous 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. There remained approximately 8.4 g of a beige oil containing 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) (theoretical yields 55% and 5% respectively).

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

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

[0137] At 120 °C, a 20% ethanolic solution of 120 g (0.35 mol) of sodium ethoxide was added to a mixture of 25.2 g (0.18 mol) of 4-amino-2-chloro-5-methylpyridine and 86 g (0.70 mol) of phenetole over a period of about 2 h 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 was 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] There remained approximately 88 g of a brown oil which was purified by fractional distillation under reduced pressure. The highest melting fraction gave 16 g of a colourless liquid which solidified immediately on solidification to give a colourless solid containing 94% by weight of 4-amino-2-ethoxy-5-methylpyridine (0.10 mol) and 4% by weight of 4-ethylamino-2-ethoxy-5-methylpyridine (3 mmol) (theoretical yields 56% and 2% respectively).

[0140] The product fraction was further purified by recrystallization from n-hexane, giving a yield of 97% of theory and being 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) 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.

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

[0144] After adding a further 150 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 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 gave 36 g of a colorless to light beige solid having a purity of approximately 99.8% by weight (0.24 mol, corresponding to an 85% theoretical yield).

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

[0147] In an autoclave, a 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.

[0148] After cooling to room temperature, 150 g of water was added to the reaction mixture, and the mixture was freed from 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 the temperature was controlled at about 50 °C. The aqueous phase was separated at this temperature.

[0149] After adding 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 off at standard pressure, and 12 g of isopropanol was 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 gave 24.4 g of a colorless to light beige solid having a purity of 99% by weight (0.15 mol, corresponding to an 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) 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.

[0153] After cooling to room temperature, 100 g of water was added to the reaction mixture, and it was freed from 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 the temperature was controlled at about 50 °C. The aqueous phase was separated off at this temperature.

[0154] After adding a further 90 g of water, the resulting mixture was adjusted to pH 8 - 9 with aqueous 30% hydrochloric acid. Subsequently, the toluene was separated off at standard pressure, and 12 g of isopropanol was 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 gave 18.1 g of a colorless to light beige solid with a purity of 99.1% by weight (0.11 mol, corresponding to a 65% theoretical yield).

Claims

1. A method for preparing the following compounds: a compound of formula (I) and a compound of formula (II), wherein R 1 is benzyl, the method comprising at least reacting a compound of formula (III) wherein X is Cl or Br, with a compound of formula (IV), R 1 OH(IV) wherein the group R 1 has the definition specified for formula (I), the reaction being carried out in the presence of a base and in the presence of a solvent, wherein the base is selected from alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates or alkaline earth metal carbonates, or a compound of formula (V), R 1 OM(V) wherein the group R 1 has the definition specified for formula (I), and M is an alkali metal or a mixture thereof, and wherein the solvent is selected from toluene, o - xylene, m - xylene, p - xylene, ethylbenzene, phenetole, or a mixture thereof, and wherein the reaction of the compound of formula (III) with the compound of formula (IV) is carried out in the absence of a catalyst selected from transition metal compounds.

2. The method according to claim 1, characterized in that, The reaction is carried out at a temperature of 100 °C to 180 °C.

3. The method according to claim 1 or 2, characterized in that, 1 to 10 mol of the compound of formula (IV) are used per mole of the compound of formula (III).

4. The method according to claim 1 or 2, characterized in that, 1.5 to 6 mol of the base are used per mole of the compound of formula (III).

5. The method according to claim 1 or 2, characterized in that a) initially at least charging the base selected from the compound of formula (V), NaOH or KOH; the compound of formula (IV); and a solvent, and b) adding the compound of formula (III), as a mixture with the compound of formula (IV), to the mixture of step a) at a temperature of 120 °C to 170 °C, and c) reacting the mixture obtained in step b) at a temperature of 120 °C to 170 °C.

6. The method according to claim 1 or 2, characterized in that, At least mixing the base selected from the compound of formula (V), NaOH or KOH; a solvent selected from toluene, o - xylene, m - xylene, p - xylene, ethylbenzene or phenetole; the compound of formula (III) and the compound of formula (IV), and heating this mixture to 120 °C to 170 °C.

7. The method according to claim 1 or 2, characterized in that, Initially at least charging the compound of formula (III) and a solvent, and then adding the base and the compound of formula (IV).

8. The method according to claim 1 or 2, characterized in that, Initially at least charging the compound of formula (III) and a solvent selected from toluene, o - xylene, m - xylene, p - xylene, ethylbenzene or phenetole, and then adding the compound of formula (V) as the base and the compound of formula (IV).

9. The method according to claim 1 or 2, characterized in that, During the reaction, the liquid phase is distilled off.

10. The method according to claim 1, wherein The base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

11. The method according to claim 1, characterized in that, M is potassium or sodium.

12. The method according to claim 1, wherein M is sodium.

13. The method according to claim 2, wherein The reaction is carried out at a temperature of 120 °C to 160 °C.

14. The method according to claim 3, wherein 1 to 6 mol of the compound of formula (IV) are used per mole of the compound of formula (III).

15. The method according to claim 3, characterized in that, 2 to 4 mol of the compound of formula (IV) are used per mole of the compound of formula (III).

16. The method according to claim 4, wherein 2 to 5 mol of the base are used per mole of the compound of formula (III).

17. The method according to claim 4, characterized in that 2.5 to 4 mol of the base are used per mole of the compound of formula (III).

18. The method according to claim 5, wherein At a temperature of 130 °C to 160 °C, the compound of formula (III), as a mixture with the compound of formula (IV), is added to the mixture of step a).

19. The method according to claim 5, wherein The mixture obtained in step b) is reacted at a temperature of 130 °C to 160 °C.

20. The method according to claim 6, characterized in that Heat this mixture to 130°C to 160°C.

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