KR20050101205A - Process for preparing pyridine-substituted amino ketal derivatives - Google Patents

Abstract

The present invention relates to an efficient process for preparing derivatives of 1-(pyridinyl)-1, 1- dialkoxy-2-aminoethane of the formula (I), with which compounds of the formula (I) can be prepared in high purity and yield and in the form of the free base without isolating the acetylpyridine oxime of the formula (XI) which is a critical product from a safety point of view as a solid.

Description

Process for preparing pyridine-substituted amino ketal derivatives

The present invention provides a process for the preparation of pyridinyl-substituted dialkoxyaminoethane derivatives of the formula (I) and the intermediates of the process according to the invention.

Compounds of formula (I) are intermediates in the preparation of pharmaceutically active ingredients. For example, US Pat. No. 5,792,871 describes the synthesis of derivatives of compounds of formula I wherein the pyridine radical is substituted in the 3-position and R 'is (C ₁ -C ₃ ) -alkyl. According to US Pat. No. 5,792,871, compounds of formula II can be obtained from these derivatives.

The compounds of formula (I) are also used to prepare pyridinimidazole derivatives of formula (III) as building blocks (J. Am. Soc., 1938, 753-755).

In formula (III) above, R ″ is H, SH.

Pyridinoimidazole derivatives of formula III have been used to prepare novel macrolide antibiotics, for example, telitthromycin (US Pat. No. 5,635,485).

Known methods of preparing compounds of formula (I) include the action of alkali metal alkoxides on p-toluenesulfonic acid esters of ketoxime in alcoholic solutions, for example, amino ketal derivatives of formula (I) acting as intermediates in the preparation of amino ketone rings. F.moller: amine durch Umlagerungsreaktionen (Neber-Umlagerung) [Amines by rearrangement reactions (Neber rearrangement)], Houben-Weyl 11/1: Stickstoffverbindungen II [Nitrogen compounds II] (1957), p. 903-905.

Preparation of the 1- (pyridinyl) -1,1-dialkoxy-2-aminoethane derivative of the formula (I) is carried out by the following three step process: 1- (3-pyridinyl) -1,1-diethoxy- of the formula (IV) It is described in US Pat. No. 5,792,871 using an example of 2-aminoethane dihydrochloride:

In this process, 3-acetylpyridine of formula V is initially oxime with hydroxylammonium chloride in methanol. The 3-acetylpyridine oxime of formula VI obtained using solvent replacement is converted to pyridine and dried by a number of distillation processes and further pyridine addition (water content <5 mol%).

Alternatively, oximelation is carried out directly in pyridine and dried in the same way. Thereafter, the obtained mixture of hydrochloride of 3-acetylpyridine oxime of formula VI and pyridine is reacted with tosyl chloride of formula VII to obtain 3-acetylpyridine tosyl oxime of formula VIII, precipitated from the mixture with water and separated. do.

The tosyl oxime of formula (VIII) is then reacted with potassium ethoxide in ethanol at Never rearrangement to yield an amino ketal. The resulting p-toluenesulfonic acid potassium salt is diluted with methyl tert-butyl ether, then filtered and the filtered solution is mixed with hydrogen chloride dissolved in ether. This precipitates 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethane dihydrochloride of formula IV as an orange solid.

According to US Pat. No. 5,792,871, the purity of the isolated product is> 95% as a result of unidentified impurities as determined by ¹ H and ¹³ C NMR data. For further reactions, amino ketal dihydrochloride (IV) is suspended in water and mixed with sodium hydroxide solution to prepare the amino ketals required as free base for further coupling reactions.

The process described above has several disadvantages when scaled up industrially: First, the intermediate obtained in each step must be dried by a distillation process. Second, the 3-acetylpyridine tosyl oxime intermediate of formula VIII is very easily decomposed upon extended storage at room temperature to release a large amount of energy (about 1000 J / g of 3-acetylpyridine tosyl oxime), and also toluene sulfonic acid Regarding storage of ketoxime esters, see F. moller: amine durch Umlagerungsreaktionen (Neber-Umlagerung), Houben-Weyl 11/1: Stickstoffverbindungen II (1957), p. 903-905. Third, 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethane dihydrochloride (IV) prepared by this method is contaminated by byproduct, which is confirmed by strong coloring. Fourth, to obtain free 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethane, the isolated salt (IV) must be released with the auxiliary base in a further process. Fifth, there are frequent solvent changes during the process. Thereafter, the solvent mixture which causes environmental pollution must be worked up again very expensively.

It is an object of the present invention to find a method for synthesizing a compound of formula I more effectively and safely.

Thus, in the present invention, R ¹ and R ² are each independently (C ₁ -C ₆ ) -alkyl, wherein the alkyl group may be straight or branched, or R ¹ and R ² together with the oxygen atom are R ¹ And R ² together form a ketal ring wherein (C ₂ -C ₄ ) -alkylidene group, wherein the pyridine radical is substituted in the 2-, 3- or 4-position, preferably in the 3-position Provided is a method for preparing a 1-pyridyl-1,1-dialkoxy-2-aminoethane derivative, which method comprises an aqueous solution of a hydroxylammonium compound (eg, hydroxylammonium chloride or hydroxylammonium sulfate). ) Or by using an aqueous solution of hydroxylamine and adding an inorganic base comprising M ^{n +} to convert the acetylpyridine of formula V to the acetylpyridine oxime metal salt of formula IX, wherein n is 1 or 2 and M ^{n +} is n If 1, alkali metal or if n is 2, alkaline earth In an ion, and preferably it includes a process comprising: conversion with Li ^+, Na ^+, a K ⁺ or Ca ²⁺⁾ (a).

R ¹ and R ² are each preferably a (C ₁ -C ₆ ) -alkyl radical. Especially preferably R ¹ and R ² are the same and each is a (C ₁ -C ₆ ) -alkyl radical. (C ₁ -C ₆ ) -alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-hexyl.

The ketal ring containing a (C ₂ -C ₄ ) -alkylidene group is, for example, a [1,3] dioxalan or [1,3] dioxane radical.

The preparation can be carried out either batchwise or continuously by single or multicomponent metering. Compounds of formula (IX) may be isolated or have additional processes as solutions or suspensions.

M ^{n +} is, for example, Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ . Inorganic bases comprising M ^{n +} are, for example, alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal carbonates or alkali metal or alkaline earth metal hydrogencarbonates or mixtures thereof, preferably lithium hydroxide, sodium hydroxide, hydroxide Potassium, calcium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate.

Preferably 98 to 120 moles, more preferably 99 to 101 moles of hydroxylamine or hydroxylammonium compound per 100 moles of acetylpyridine; And 200 to 300 moles of inorganic base comprising M ⁺ , more preferably 200 to 220 moles, or 100 to 150 moles of inorganic base comprising M ²⁺ , more preferably 100 to 110 moles.

In process step (b), p-toluenesulfonic acid derivatives comprising the leaving group Y in an aqueous solution, aqueous suspension or separated solid of an acetylpyridine metal salt of formula IX in a water immiscible, poorly water soluble or water insoluble solvent ( Optionally one or more phase transfer catalysts, for example quaternary ammonium or phosphonium salts, preferably quaternary ammonium salts of formula XII or phosphonium of formula XIII, in a biphasic mixture of water and a suitable solvent salt; Or by reacting with a hydrate of formula (XII) or (XIII) to obtain an acetylpyridine metal salt of formula (IX).

In Formula X above,

Y is F, Cl or Br, preferably Cl.

In the above formulas XII and XIII,

R ³ to R ¹⁰ are the same or different and each independently

a) straight or branched (C ₁ -C ₂₀ ) -alkyl,

b) benzyl or

c) phenyl,

X ⁻ is an anion such as fluoride, chloride, bromide, iodide, hydroxide, hydrogensulfate, tetrafluoroborate, acetate, trifluoromethanesulfonate, nitrate, hexafluoroantimo Acetates, preferably methyltributylammonium chloride.

The reaction in two phases is preferably carried out using one or more phase transfer catalysts, but is also carried out without phase transfer catalysts.

Process step (b) may be effected batchwise or continuously, preferably continuously, in which case the concentration of the dangerous compound of formula XI from the safety point of view is kept low. The resulting mixture of solvent and aqueous phase is then separated using conventional phase separation methods. The aqueous phase includes the dissolved metal salts used. The aqueous phase is sent to biological purification. Thereafter, the aqueous phase may optionally be washed one or more times with a suitable water insoluble solvent, combined with the solvent phase and further reacted together. The solvent phase comprises a compound of formula XI.

In process step (b), it is preferred to use from 0.1 to 50 moles, preferably from 0.2 to 10 moles of phase transfer catalyst per 100 moles of 3-acetylpyridine oxime salt of formula (IX).

Examples of quaternary ammonium salts of formula XXII include tetramethylammonium bromide, tetramethylammonium chloride, tetraethyl-ammonium chloride, n-butyltriethylammonium chloride, methyltriisopropyl-ammonium chloride, methyltri-n-butylammonium chloride ( Aliquat® 175), methyltri-n-butylammonium bromide, methyltri-n-butylammonium hydrogensulfate, methyltetra-n-butylammonium chloride, methyltri-n-octyl-ammonium chloride (Aliquat® 336), methyl Tri-n-octylammonium hydroxide, methyltricaprylammonium chloride, methyltricaprylammonium hydroxide, dimethylbenzyl (C8-C18) -alkyl chloride, tetra-n-propylammonium chloride, triethylhexylammonium chloride Triethyl-n-octylammonium chloride, triethyl-n-octylammonium bromide, triethyl-n-decylammonium bromide, Triethyl-n-hexadecylammonium bromide, phenyltriethylammonium chloride, ethyltri-n-octylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butyl-ammonium bromide, tetra-n-butylammonium chloride, Tetra-n-butyl-ammonium hydrogensulfate, tetramethylammonium iodide, tetramethyl-ammonium hydroxide pentahydrate, tetramethylammonium hydroxide, methyltriethylammonium bromide, tetramethylammonium chloride monohydrate, tetramethyl Ammonium bromide, tetramethylammonium iodide, tetramethylammonium tetrafluoroborate, (n-hexyl) trimethyl-ammonium bromide, phenyltrimethylammonium chloride, phenyltrimethyl-ammonium iodide, benzyltrimethylammonium chloride, benzyltrimethyl-ammonium Iodide, benzyl Trimethylammonium hydroxide, (n-octyl) -trimethyl-ammonium bromide, (N-nonyl) trimethylammonium bromide, tetra-n-propyl-ammonium bromide, phenyltriethylammonium iodide, (n-decyl) trimethyl- Ammonium bromide, benzyltriethylammonium chloride, benzyltriethyl-ammonium bromide, benzyltriethylammonium tetrafluoroborate, benzyl-triethylammonium hydroxide, (n-dodecyl) trimethylammonium chloride, (n-dodecyl) Trimethylammonium bromide, benzyltri-n-propylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium acetate, tetra-n-butylammonium hydrogensulfate, tetra -n-butylammonium hydroxide, tetra-n-butylammonium trifluoromethane-sulfonate, (n-tetradecyl) -trimethylarm Chloride, (n-tetradecyl) trimethylammonium bromide, (n-hexadecyl) trimethyl-ammonium bromide, tetra-n-pentylammonium chloride, tetra-n-pentyl-ammonium iodide, benzyltri-n-butylammonium Chloride, benzyltri-n-butyl-ammonium bromide, (n-hexadecyl) pyridinium chloride monohydrate, (n-hexadecyl) pyridinium bromide monohydrate, tetra-n-hexylammonium bromide, tetra-n-hexylammonium Hydrogensulfate, tetra-n-octyl-ammonium bromide, tetra-n-dodecylammonium iodide or tetra-n-dodecyl-ammonium nitrate.

Examples of phosphonium salts of formula (XIII) include tetra-n-butyl-phosphonium chloride, tetraphenylphosphonium bromide, methyltri-n-octyl-phosphonium chloride, methyltriphenylphosphonium bromide, ethyl-tri-n-octylphosph Phonium bromide, tetra-n-butylphosphonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium iodide, tetraphenylphosphonium hexafluoroantimonate, tetraphenylphosphonium tetrafluoroborate, (n-hexa Decyl) tri-n-butylphosphonium bromide or triphenylmethyltriphenylphosphonium chloride.

Suitable solvents that are water immiscible, poorly water soluble, or water insoluble include, for example, unsubstituted or one or more (C ₁ -C ₄ ) -alkyl such as methyl; Or aliphatic or aromatic hydrocarbons substituted by one or more substituents selected from the group consisting of fluorine, chlorine and bromine, preferably toluene, xylene (a pure isomer or mixture of isomers), ethylbenzene, heptane or dichloromethane. Also suitable are mixtures of the suitable solvents mentioned.

Preference is given to using from 0.6 to 1.1 kg of a suitable solvent per mole of p-toluenesulfonic acid derivative (X). In the reaction of 100 moles of the acetylpyridine oxime salt of formula (IX), it is preferable to use 99 to 150 moles, more preferably 100 to 110 moles of p-toluenesulfonic acid derivative (X).

The term "biphasic mixture" denotes a mixture of two liquid phases-an aqueous phase comprising acetylpyridine oxime salt (IX) and a solvent phase comprising p-toluenesulfonic acid derivative (X). If a phase transfer catalyst is used, it may be present in the aqueous phase or the solvent phase, or separately in two phases. The biphasic mixture is stirred and / or mixed by conventional batchwise or continuous process operation to ensure good dispersion of the phase.

The reaction temperature in process step (b) is preferably from 0 to 50 ° C., more preferably from 5 to 30 ° C., for batch processes, from 0 to 60 ° C., more preferably from 5 to 40 ° C. for continuous processes. ℃.

In process step (c), a mixture of an alkali metal alkoxide, alkali metal hydroxide, alkaline earth metal alkoxide or alkaline earth metal hydroxide with an alcohol is dried or the solvent phase comprising acetylpyridine tosyl oxime of formula XI which is not previously dried. by weighing a 1- (pyridinyl) of formula I a compound of formula XI -1,1- dialkoxy-2-amino-ethanol was converted to the derivative, wherein the alkoxide is R ¹ O ^- and / or R ² O ^- And the alcohol is R ¹ OH and / or R ² OH and R ¹ and R ² as defined for compounds of formula (I).

In process step (c), 99 to 500 moles of alkali metal alkoxides, more preferably 100 to 200 moles per 100 moles of acetylpyridine tosyl oxime of formula (XI); 99 to 500 moles, more preferably 100 to 300 moles of alkali metal hydroxide; 50 to 250 moles, more preferably 50 to 100 moles of alkaline earth metal alkoxide; Or 50 to 250 moles, more preferably 50 to 150 moles, of alkaline earth metal hydroxides.

In process step (c), alkali metal hydroxides or alkoxides, in particular lithium hydroxide, lithium methoxide, lithium ethoxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxide, hydroxide Preference is given to using cesium, cesium methoxide or cesium ethoxide.

The choice of alkoxides and / or alcohols depends on the introduction of the desired alkoxy group. For example, in the preparation of 1- (pyridinyl) -1,1-dimethoxy-2-aminoethane, the mixture may be an alkali metal or alkaline earth metal methoxide in methanol; Or alkali metal hydroxides in methanol are used. In the preparation of compound 1- (pyridinyl) -1-([1,3] dioxalan) -2-aminoethane, wherein R ¹ and R ² together with the oxygen atom form a ketal ring, for example alkali in glycol Metal hydroxides are used.

It is preferred that 0.3 to 3 kg, preferably 0.5 to 1.5 kg, of the corresponding alcohol is used per mole of acetylpyridine oxime tosylate of formula (XI). The conversion is effected, for example, in a temperature range of 0 to 90 ° C, more preferably 10 to 60 ° C.

After the reaction, the solvent portion is initially distilled off and the p-toluenesulfonic acid salt by-product precipitates at room temperature. Distillation is carried out in a conventional manner. The distilled solvent mixture can be directly reused in process step (c).

The p-toluenesulfonic acid alkali metal or alkaline earth metal salt is removed by conventional filtration methods. The remaining solvent fraction is removed by distillation in conventional manner under atmospheric pressure or preferably under reduced pressure.

Thereafter, the amino ketal derivatives of formula (I) are separated in high purity form by crystallization of the distillation residues obtained by vacuum distillation or rectification or by fine distillation. For example, compounds of formula I wherein R ₁ and R ₂ are each methyl can be purified by distillation.

The yield of vacuum distillation or rectification can be improved by optionally adding a flux to the distillation residue. The term "flux" means a liquid or wax solid that, when heated, decreases in viscosity, thus improving the flowability of the residue to be distilled and at the same time having a boiling point considerably higher than the product to be distilled. The flux may be, for example, polyethylene glycol having a molecular weight of at least 400 (eg, polyethylene glycol 600 or polyethylene glycol 1000), paraffin (C _n H _{2n + 2} , n> 15), polyhydric alcohol (having one or more OH groups Alcohols such as glycerol) or esters such as bis-2-ethyl sebacate are used.

Crystallization can be carried out in conventional manner with or without organic solvents. Dissolving or solvent processes may be used.

The advantages of the process according to the invention are, firstly, the direct separation and very good yield of the compounds of formula I of high purity as the free base; Second, the selected reaction conditions allow the oxime and tosylation reactions to be carried out in a continuous process which always results in only a small amount of the intermediate of formula (XI) from a safety point of view and does not separate the dangerous acetylpyridine tosyl oxime as a solid from a safety point of view. After a short delay, directly converting to an amino ketal of formula I, which is not dangerous from a safety point of view in a continuous device; Third, preparation of the compound of formula I in the form of a free base using a method suitable for industrial scale of high purity (at least 97%) and yield (at least 75% based on the acetylpyridine used); And fourth, the use of a solvent which can be directly reused in the process either alone or in the form of a mixture, thus keeping the environmental relevance very small.

Example 1:

Preparation of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane, Method 1

In reactor 1 (a), 174 g of 40% hydroxylammonium chloride solution, 121 g of 3-acetylpyridine and 245 g of 33% sodium hydroxide solution are reacted in a three component metering at 15 to 25 ° C. The obtained 3-acetylpyridine oxime sodium salt solution is reacted with 2 g of methyltributylammonium chloride.

1 (b) The solution is then reacted with a solution of 193 g of p-toluenesulfonyl chloride and 655 g of toluene in a continuous process (recycling method via a partially converted static mixer) at an internal temperature of 35 to 38 ° C. The resulting biphasic mixture is then passed through a separation zone and the solvent phase is separated from the aqueous phase.

The 1 (c) solvent phase is allowed to go directly to 940 g of initially charged methanol (from the first solvent distillation or methanol / toluene mixture, see below) and 216 g of 30% sodium methoxide solution. The temperature is maintained in the range of 20 to 40 ° C. The reaction solution is allowed to continue to react for an additional 5-10 hours. Methanol is distilled from the reaction mixture as an azetrope mixture with toluene (first solvent distillation) at 70-90 ° C. and atmospheric pressure. The azecrope solvent mixture can be recycled to the reaction described above (see above). After distillation, the distillation residue is cooled to 25 ° C., then the p-toluenesulfonic acid sodium salt is filtered off and washed with 85 g of toluene. The filtrate is then concentrated by distillation under reduced pressure (about 100-200 mbar) at 120-130 ° C. Thereafter, 10 to 20 g of polyethylene glycol 600 was added to the distillation residue and 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane was anhydrous at an internal evaporator temperature of 1 to 10 mbar and 100 to 160 ° C. Distillate via a short column as a liquid. 157.3 g of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane are obtained with a purity of 98-99% (measured compared to the reference standard by titration, HPLC-MS and NMR methods). This corresponds to a theoretical yield of 85% based on the 3-acetylpyridine used.

Example 2:

Preparation of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane, Method 2

In reactor 2 (a), 174 g of 40% hydroxylammonium chloride solution, 121 g of 3-acetylpyridine and 245 g of 33% sodium hydroxide solution are reacted in a three component metering at 15 to 25 ° C. The obtained 3-acetylpyridine oxime sodium salt solution is reacted with 2 g of methyltributylammonium chloride.

2 (b) The solution is then reacted with a solution of 193 g of p-toluenesulfonyl chloride and 655 g of toluene at a continuous process (recycling method via a partially converted static mixer) at an internal temperature of 35 to 38 ° C. The resulting biphasic mixture is then passed through a separation zone and the solvent phase is separated from the aqueous phase.

2 (c) The solvent phase is taken directly to 940 g of initially charged methanol (from the first solvent distillation or to a methanol / toluene mixture, see below) and a 48 g solution of sodium hydroxide. The temperature is maintained in the range of 20 to 40 ° C. The reaction solution is allowed to continue to react for an additional 5-10 hours. Methanol is distilled from the reaction mixture as an azetrope mixture with toluene (first solvent distillation). The azecrope solvent mixture can be recycled to the reaction described above (see above). After distillation, the distillation residue is cooled to 25 ° C., then the p-toluenesulfonic acid sodium salt is filtered off and washed with 85 g of toluene. The filtrate is then concentrated by distillation under reduced pressure (about 100-200 mbar) at 120-130 ° C. Thereafter, 10 to 20 g of polyethylene glycol 600 was added to the distillation residue and 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane was anhydrous at an internal evaporator temperature of 1 to 10 mbar and 100 to 160 ° C. Distillate via a short column as a liquid. 148 g of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane are obtained with a purity of 98-99% (measured compared to the reference standard by titration, HPLC-MS and NMR methods). This corresponds to a theoretical yield of 85% based on the 3-acetylpyridine used.

Claims (19)

Using an aqueous solution of a hydroxylammonium compound or an aqueous solution of hydroxylamine and adding an inorganic base comprising M ^{n +} , the acetylpyridine of Formula (V) is converted to the acetylpyridine oxime metal salt of Formula (IX), wherein n is 1 or 2 (M) ^wherein M ^{n +} is an alkali metal or alkaline earth metal ion); Optionally one of the acetylpyridine metal salts of formula (IX) in a two-phase mixture of a solution of p-toluenesulfonic acid derivative of formula (X) containing a leaving group Y in a water immiscible, poorly water-soluble or water-insoluble solvent Reacting with the above phase transfer catalyst to obtain acetylpyridine tosyl oxime of formula (XI) (b); And Process step (c), wherein the acetylpyridine tosyl oxime of formula (XI) is added to a mixture of an alkali metal alkoxide, alkali metal hydroxide, alkaline earth metal alkoxide or alkaline earth metal hydroxide with an alcohol to convert into a compound of formula (I), wherein the alkoxide It is R ¹ O ^- and / or R ² O ^-, and the alcohol R ¹ OH and / or R ² OH, and R ¹ and R ² are as defined in compounds of formula I) contains, with each processing step a (a) to (c) are the processes for preparing the 1- (pyridinyl) -1,1-dialkoxy-1-aminoethane derivative of formula (I) which are carried out continuously or in an independent batch mode. Formula I In Formula I above, R ¹ and R ² are each independently (C ₁ -C ₆ ) -alkyl, wherein the alkyl group can be straight or branched, or R ¹ and R ² together with the oxygen atom are R ¹ and R ² together ( A ketal ring, which is a C ₂ -C ₄ ) -alkylidene group, wherein the pyridine radical is substituted in the 2-, 3- or 4-position, preferably in the 3-position. Formula X In Formula X above, Y is F, Cl or Br. Formula XI The method of claim 1 wherein the pyridine radical is substituted at the 3-position. The method of claim 1 or 2, wherein R ¹ and R ² are each (C ₁ -C ₆ ) -alkyl. The process according to claim 1, wherein in process step (a) hydroxylamine, hydroxylammonium chloride or hydroxylammonium sulfate are used. The process according to any one of claims 1 to 4, wherein in process step (a) M ^{n + means} Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ . The process according to any one of claims 1 to 5, wherein the inorganic base comprising M ^{n +} in process step (a) is lithium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate or calcium hydroxide. The process according to any one of claims 1 to 6, wherein the leaving group Y is Cl in process step (b). 8. The process according to claim 1, wherein in process step (b) the phase transfer catalyst is a quaternary ammonium salt of formula XII or a phosphonium salt of formula XII. 9. Formula XII Formula XIII In the above formulas XII and XIII, R ³ to R ¹⁰ are the same or different and each independently a) straight or branched (C ₁ -C ₂₀ ) -alkyl, b) benzyl or c) phenyl, X ⁻ is an anion such as fluoride, chloride, bromide, iodide, hydroxide, hydrogensulfate, tetrafluoroborate, acetate, trifluoromethanesulfonate, nitrate, hexafluoroantimo Acetates, preferably methyltributylammonium chloride. 9. The process according to claim 1, wherein in process step (c) lithium hydroxide, lithium methoxide, lithium ethoxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium Ethoxide, cesium hydroxide, cesium methoxide or cesium ethoxide are used. The process according to claim 1, wherein in process step (c) the acetylpyridine tosyl oxime of formula (XI) is used without prior drying. The acetylpyridine of formula (V) is converted to the acetylpyridine oxime metal salt of formula (IX) using an aqueous solution of hydroxylamine or hydroxylammonium compound and the addition of an inorganic base comprising M ^{n +} , followed by continuous or batchwise reaction. A process for preparing the acetylpyridine oxime metal salt of formula IX. [Formula V] [Formula IX] In Formula IX above, n is 1 or 2, M ^{n +} is an alkali metal ion or alkaline earth metal ion, and the pyridine radical is substituted in the 2-, 3- or 4-position. The method of claim 11, wherein the pyridine radical is substituted at the 3-position. 13. The method of claim 11 or 12, wherein M ^{n +} is Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ . The method according to any one of claims 11 to 13, wherein the inorganic base comprising M ^{n +} is lithium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, potassium carbonate or calcium hydroxide. The process according to claim 11, wherein the reaction is carried out continuously. Optionally one or more phases in a two-phase mixture of an acetylpyridine metal salt of Formula IX, a solution of p-toluenesulfonic acid derivative of Formula X containing a leaving group Y in a suitable solvent that is water insoluble or poorly water soluble, and water and a suitable water insoluble solvent A process for the preparation of a compound of formula (XI), which is carried out continuously or batchwise to react with a transfer catalyst to yield acetylpyridine tosyl oxime of formula (XI). Formula IX In Formula IX above, n is 1 or 2, M ^{n +} is an alkali metal ion or alkaline earth metal ion. Formula X In Formula X above, Y is F, Cl or Br. Formula XI In the above formula (XI), Pyridine radicals are substituted at the 2-, 3- or 4-position. The method of claim 16, wherein at least one phase transfer catalyst is used and the phase transfer catalyst is a quaternary ammonium salt of formula XII or a phosphonium salt of formula XII. Formula XII Formula XIII In the above formulas XII and XIII, R ³ to R ¹⁰ are the same or different and each independently a) straight or branched (C ₁ -C ₂₀ ) -alkyl, b) benzyl or c) phenyl, X ⁻ is an anion such as fluoride, chloride, bromide, iodide, hydroxide, hydrogensulfate, tetrafluoroborate, acetate, trifluoromethanesulfonate, nitrate, hexafluoroantimo Acetates, preferably methyltributylammonium chloride. 18. The method of claim 16 or 17, wherein the pyridine radical is substituted at the 3-position. The method according to claim 16, wherein the reaction is carried out continuously.