KR101114893B1 - - Process for preparing pyridine-substituted amino ketal derivatives - Google Patents

Abstract

The present invention provides high purity and high yields of derivatives of 1- (pyridinyl) -1,1-dialkoxy-2-aminoethane of formula (I) to isolate acetylpyridine tosyl oxime of formula (XI) which is a dangerous product from a safety standpoint. And an effective method which can be prepared in free base form without the use of the present invention.

1- (pyridinyl) -1,1-dialkoxy-2-aminoethane, amino ketal derivative, pyridine

Description

Process for preparing pyridine-substituted amino ketal derivatives

The present invention provides a process for preparing pyridinyl-substituted dialkoxyaminoethane derivatives of the formula (I) and intermediates in 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 at position 3 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. See J. Am. Soc., 1938, 753-755.

In formula (III) above, R ″ is H or SH.

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

Known methods for preparing compounds of formula (I) are based on the action of alkali metal alkoxides on p-toluenesulfonic acid esters of ketoxime in alcohol solutions, for example, amino ketal derivatives of formula (I) 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].

1- (pyridinyl) -1,1- of formula I using the example of 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethane dihydrochloride of formula IV by the following three step process: The preparation of dialkoxy-2-aminoethane derivatives is described in US Pat. No. 5,792,871:

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

Alternatively, the oxime 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% due to 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 prolonged storage at room temperature, releasing a large amount of energy (the decomposition energy of 3-acetylpyridine tosyl oxime is about 1000 J / g). For storage of toxime 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 the 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, the solvent must be changed frequently 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 is straight or branched, or R ¹ and R ² together with the oxygen atom form a ketal ring. Wherein R ¹ and R ² together are a (C ₂ -C ₄ ) -alkylidene group and the pyridine radical is substituted at position 2, 3 or 4, preferably position 3 There is provided a process for preparing a dill-1,1-dialkoxy-2-aminoethane derivative, the process comprising process steps (a), (b) and (c). In process step (a), an aqueous solution of a hydroxylammonium compound (eg, hydroxylammonium chloride or hydroxylammonium sulfate) or an aqueous solution of hydroxylamine is added and an inorganic base comprising M ^{n +} is added to the formula an acetylpyridine of the V-acetylpyridine oxime metal salt of the formula IX (wherein n is 1 or 2, M ^{n +} is when n is 1, an alkali metal ^ion, and when n is 2, and the alkaline earth metal ions, preferably Is Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ ).

R ¹ and R ² in formula (I) 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.

Ketal rings containing a (C ₂ -C ₄ ) -alkylidene group are, for example, [1,3] dioxolane or [1,3] dioxane radicals.

The production process can be carried out batchwise or continuously by the addition of single or multicomponents. Compounds of formula (IX) may be isolated or further processed into solutions or suspensions.

M ^{n +} is, for example, Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ . Inorganic bases comprising M ^{n +} are, for example, alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates, or alkali or alkaline earth metal hydrogencarbonates or mixtures thereof, preferably lithium hydroxide, sodium hydroxide, hydroxides. 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-toluene of formula (X) comprising leaving group Y in an aqueous solution, aqueous suspension or separated solid of an acetylpyridine oxime metal salt of formula (IX) in a suitable solvent that is water immiscible, poorly water soluble or water insoluble Reaction with sulfonic acid derivative solution yields acetylpyridine tosyl oxime of formula (XI). The reaction proceeds in a two phase mixture of water and a suitable water insoluble solvent, optionally with one or more phase transfer catalysts, for example quaternary ammonium or phosphonium salts, preferably quaternary ammonium salts of formula XII or formula XIII Phosphonium salts; Or hydrates of the salts of formula XII or formula XIII.

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 or hexafluoroantimo Nate.

The reaction in the biphasic mixture is preferably carried out using one or more phase transfer catalysts, but may also be carried out without phase transfer catalysts.

Process step (b) may be carried out batchwise or continuously, preferably continuously, in which case the concentration of the compound of formula XI, which is dangerous for safety reasons, is kept low. The 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 biologically purified. Thereafter, optionally, the aqueous phase can 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, tetraethylammonium chloride, n-butyltriethylammonium chloride, methyltriisopropylammonium 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), methyltri- n-octylammonium hydroxide, methyltricaprylammonium chloride, methyltricaprylammonium hydroxide, dimethylbenzyl (C8-C18) -alkyl chloride, tetra-n-propylammonium chloride, triethylhexylammonium chloride, tri Ethyl-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-butylammonium bromide, tetra-n-butylammonium chloride, tetra -n-butylammonium hydrogensulfate, tetramethylammonium iodide, tetramethylammonium hydroxide pentahydrate, tetramethylammonium hydroxide, methyltriethylammonium bromide, tetramethylammonium chloride monohydrate, tetramethylammonium bromide, Tetramethylammonium iodide, tetramethylammonium tetrafluoroborate, (n-hexyl) trimethylammonium bromide, phenyltrimethylammonium chloride, phenyltrimethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium iodide, benzyl tree Methylammonium hydroxide, (n-octyl) trimethylammonium bromide, (N-nonyl) trimethylammonium bromide, tetra-n-propylammonium bromide, phenyltriethylammonium iodide, (n-decyl) trimethylammonium bromide, benzyl Triethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium tetrafluoroborate, benzyltriethylammonium hydroxide, (n-dodecyl) trimethylammonium chloride, (n-dodecyl) trimethylammonium bromide, benzyl tree -n-propylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium acetate, tetra-n-butylammonium hydrogensulfate, tetra-n-butylammonium hydride Roxoxide, tetra-n-butylammonium trifluoromethanesulfonate, (n-tetradecyl) trimethylammonium chlora Id, (n-tetradecyl) trimethylammonium bromide, (n-hexadecyl) trimethylammonium bromide, tetra-n-pentylammonium chloride, tetra-n-pentylammonium iodide, benzyltri-n-butylammonium chloride, benzyl Tri-n-butylammonium bromide, (n-hexadecyl) pyridinium chloride monohydrate, (n-hexadecyl) pyridinium bromide monohydrate, tetra-n-hexylammonium bromide, tetra-n-hexylammonium hydrogensulfate, Tetra-n-octylammonium bromide, tetra-n-dodecylammonium iodide or tetra-n-dodecylammonium nitrate.

Examples of phosphonium salts of formula (XIII) include tetra-n-butylphosphonium chloride, tetraphenylphosphonium bromide, methyltri-n-octylphosphonium chloride, methyltriphenylphosphonium bromide, ethyl-tri-n-octylphosphonium bromide , Tetra-n-butylphosphonium bromide, tetraphenylphosphonium chloride, tetraphenylphosphonium iodide, tetraphenylphosphonium hexafluoroantimonate, tetraphenylphosphonium tetrafluoroborate, (n-hexadecyl) Tri-n-butylphosphonium bromide or triphenylmethyltriphenylphosphonium chloride.

Suitable solvents that are water immiscible or 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 above.

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 metal salt (IX) and a solvent phase comprising p-toluenesulfonic acid derivative (X). If a phase transfer catalyst is used, the catalyst may be present in the aqueous phase or the solvent phase, or in separate phases of these two phases. The biphasic mixture is stirred and / or mixed by conventional batch or continuous processes so that the phases are dispersed well.

The reaction temperature of the process step (b) is preferably from 0 to 50 ° C., more preferably from 5 to 30 ° C., in a batch process, from 0 to 60 ° C., more preferably from 5 to 40 ° C. in the case of a continuous process. to be.

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 addition to a compound of formula XI is converted to a 1- (pyridinyl) -1,1-dialkoxy-2-aminoethane derivative of formula I, wherein the alkoxide is R ¹ O ⁻ and / or R ² O ⁻ and , Alcohol is R ¹ OH and / or R ² OH, and R ¹ and R ² are 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 step is carried out, 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 salt 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.

The amino ketal derivatives of formula (I) are then separated in high purity form by crystallization of the distillation residue obtained by vacuum distillation or rectification or by preliminary 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 flex 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 can 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.

Crystallization can be carried out in conventional manner with or without organic solvents. Melting 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 free base; Second, the selected reaction conditions allow the oxime and tosylation reactions to be carried out in a continuous process which always produces only a small amount of the intermediate of formula (XI) from a safety point of view and does not separate 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 free base form using a method suitable for an 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

1 (a): In the reactor, three components of 174 g of 40% hydroxylammonium chloride solution, 121 g of 3-acetylpyridine and 245 g of 33% sodium hydroxide solution were added and reacted at 15 to 25 ° C. The resulting sodium salt solution of 3-acetylpyridine oxime is reacted with 2 g of methyltributylammonium chloride.

1 (b): This solution was then subjected to a continuous process (recirculation via a partially mixed withdrawal static mixer) at an internal temperature of 35 to 38 ° C. with a solution of 193 g of p-toluenesulfonyl chloride and 655 g of toluene; React. The biphasic mixture obtained is then passed through a separation zone and the solvent phase is separated from the aqueous phase.

1 (c): The solvent phase is added directly to a solution of 940 g of initially charged methanol (or methanol / toluene mixture from first solvent distillation, 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 continued to react for an additional 5 to 10 hours. Methanol is distilled from the reaction mixture as an azeotropic mixture with toluene (first solvent distillation) at 70-90 ° C. and atmospheric pressure. The boiling boiler 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 an internal temperature of 120-130 ° C. Then, 10 to 20 g of polyethylene glycol 600 was added to the distillation residue and 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane was added at 1 to 10 mbar and 100 to 160 ° C internal evaporator temperature. Distillate via a short column as a water-clear liquid. 157.3 g of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane are obtained with a purity of 98-99% (as measured by reference, by means of titration, HPLC-MS and NMR). 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

2 (a): In the reactor, three components of 174 g of 40% hydroxylammonium chloride solution, 121 g of 3-acetylpyridine and 245 g of 33% sodium hydroxide solution were added and reacted at 15 to 25 ° C. The resulting sodium salt solution of 3-acetylpyridine oxime 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 via a partially recovered 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 added directly to a solution of 940 g of initially charged methanol (or methanol / toluene mixture from the first solvent distillation, see below) and 48 g of sodium hydroxide. The temperature is maintained in the range of 20 to 40 ° C. The reaction solution is continued to react for an additional 5 to 10 hours. Methanol is distilled from the reaction mixture as a boiling mixture with toluene (first solvent distillation). The azeotropic 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 an internal temperature of 120-130 ° C. Then, 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 ^{n +} is an alkali metal ion or alkaline earth metal ion) (a);

An acetylpyridine oxime metal salt of formula (IX), an aliphatic or aromatic hydrocarbon solvent, unsubstituted or substituted by one or more substituents selected from the group consisting of (C ₁ -C ₄ ) -alkyl groups, fluorine, chlorine and bromine, or Reacting with a solution of p-toluenesulfonic acid derivative of formula X containing leaving group Y in a water immiscible, poorly water soluble or water insoluble solvent which is a mixture of to obtain acetylpyridine tosyl oxime of formula XI, wherein (B) proceeding with or without one or more phase transfer catalysts in a two-phase mixture of water and the solvent; And Compounds of formula (XI) are converted to compounds of formula (I) by adding to the mixture of alkali metal alkoxides, alkali metal hydroxides, alkaline earth metal alkoxides or alkaline earth metal hydroxides with alcohols without separating the acetylpyridine tosyl oximes of formula (XI) step (c) (wherein the alkoxide is R ¹ O of ^-, R ² O ^-, or these both, and an alcohol R ¹ OH, R ² OH or are these two, R ¹ and R ² are the compounds of formula (I) Wherein each process step (a) to (c) is carried out continuously or in an independent batch, wherein 1- (pyridinyl) -1,1-dialkoxy of formula (I) Method for producing 2-aminoethane derivative. Formula I

In Formula I above, R ¹ and R ² are each independently (C ₁ -C ₆ ) -alkyl wherein the alkyl group is straight or branched, or R ¹ and R ² together with the oxygen atom form a ketal ring wherein R ¹ and R ² Together is a (C ₂ -C ₄ ) -alkylidene group, The pyridine radical is substituted at position 3. X

In Formula X above, Y is F, Cl or Br. XI

delete The method of claim 1, wherein R ¹ and R ² are each (C ₁ -C ₆ ) -alkyl. 2. Process according to claim 1, wherein in process step (a) hydroxylamine, hydroxylammonium chloride or hydroxylammonium sulfate are used. The process of claim 1 wherein M ^{n +} in process step (a) represents Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ . The process of claim 1 wherein the inorganic base comprising M ^{n +} in process step (a) is lithium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, potassium carbonate or calcium hydroxide. The process of claim 1 wherein the leaving group Y is Cl in process step (b). The process of claim 1 wherein the phase transfer catalyst in process step (b) is a quaternary ammonium salt of formula XII or a phosphonium salt of formula XIII. XII

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. 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 The side or cesium ethoxide is used. The process according to claim 1, wherein in process step (c) the acetylpyridine tosyl oxime of formula (XI) is used without prior drying. delete delete delete delete delete delete delete delete delete