JP4709741B2 - Process for producing pyridine-substituted aminoketal derivatives - Google Patents

Description

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

The compounds of formula (I) are intermediates in the production of active pharmaceutical ingredients. For example, Patent Document 1 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 Patent Document 1, starting from these derivatives, compounds of the formula (II) are obtained.

式中、Ｒ”はＨ、ＳＨである。 Further, the compound of the formula (I) is used as a structural unit for producing a pyridinoimidazole derivative of the formula (III) (Non-patent Document 1).

In the formula, R ″ is H or SH.

  The pyridinoimidazole derivative of the formula (III) has been used for the production of novel macrolide antibiotics, for example tethromycin (patent document 2).

  Known methods for preparing compounds of formula (I) are based on the action of alkali metal alkoxides on ketoxime p-toluenesulfonate in alcoholic solutions, for example aminoketal derivatives of formula (I) are cyclic aminoketones It occurs as an intermediate during the production of (Non-patent Document 2).

The preparation of 1- (pyridinyl) -1,1-dialkoxy-2-aminoethane derivatives of formula (I) is described in US Pat. Prepared in the following three-step process using diethoxy-2-aminoethane dihydrochloride:

In this method, 3-acetylpyridine of formula (V) is first oximed with hydroxylammonium chloride in methanol. The resulting 3-acetylpyridine oxime of formula (VI) is converted to pyridine by changing the solvent and dried by addition of many distillation operations and addition of fresh pyridine (water content <5 mol%).

Alternatively, oximation is carried out directly in pyridine and drying is carried out in the same way. The resulting mixture of 3-acetylpyridine oxime hydrochloride of formula (VI) and pyridine is subsequently reacted with tosyl chloride of formula (VII) to precipitate 3-acetyl of formula (VIII) precipitated from the mixture with water. Pyridine tosyl oxime is obtained and separated.

  The resulting tosyl oxime of formula (VIII) is subsequently reacted with potassium ethoxide in ethanol by Naver transfer to give the amino ketal. The obtained p-toluenesulfonic acid potassium salt is diluted with methyl tert-butyl ether, filtered, and the filtered solution is mixed with hydrogen chloride dissolved in ether. This precipitates 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethanedihydrochloride of formula (IV) as an orange solid.

According to U.S. Pat. No. 6,057,059, the purity of the isolated product can only be estimated using ¹ H and ¹³ C NMR data and is greater than 95% as a result of unknown impurities. For further reaction, the amino ketal dihydrochloride (IV) is suspended in water and mixed with sodium hydroxide solution to produce the amino ketal as the free base required for the next coupling reaction.

The above method has several disadvantages for scaling up to an industrial scale. First, each of the resulting intermediates must be dried by a distillation operation. Secondly, the 3-acetylpyridine tosyloxime intermediate of formula (VIII) decomposes very easily upon release for a long time at a temperature higher than room temperature and releases a large amount of energy (the decomposition energy of 3-acetylpyridine tosyloxime is about 1000 J / G, see warning on storage of toluenesulfonic acid ketoxime ester in Non-Patent Document 2). Thirdly, 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethanedihydrochloride prepared in this way is contaminated with by-products and is confirmed by strong coloration. Fourth, to obtain free 1- (3-pyridinyl) -1,1-diethoxy-2-aminoethane, the isolated salt (IV) must be liberated with an auxiliary base in an additional step. I must. Fifth, there is frequent solvent exchange during the process. The solvent mixture must therefore be processed again at a very high cost, which becomes an environmental pollution.
US Pat. No. 5,792,871 US Pat. No. 5,635,485 J. et al. Am. Soc. 1938, 753-755. F. Moeller: Amine durch Umagerun sreaktionen (Never-Umagerung) [Amines by rearrangement reactions (Neber rienrangement) (Never-90 rend)

  The object of the present invention is to find a more efficient and safe method for the synthesis of compounds of formula (I).

Accordingly, the present invention is a 1-pyridinyl-1,1-dialkoxy-2-aminoethane derivative of the formula (I), wherein R ¹ and R ² are each independently (C ₁ -C ₆ ) -alkyl (here The alkyl group can be linear or branched) or R ¹ and R ² together with an oxygen atom are cyclic ketals (where R ¹ and R ² together (C ₂ -C ₄₎ - form an alkylidene group is), pyridine groups 2-, 3- or 4-position, preferably 3-position to provide a process for producing the derivatives substituted, said process Is
In step (a), an acetylpyridine of formula (V) is converted to an inorganic base containing M ^{n +} simultaneously or after using an aqueous solution of a hydroxylammonium compound, for example hydroxylammonium chloride or hydroxylammonium sulfate, or an aqueous solution of hydroxylamine. In addition, an acetylpyridine oxime metal salt of formula (IX), where n is 1 or 2, and M is an alkali metal when n = 1, or an alkaline earth metal when n = 2, preferably Is Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ ).

R ¹ and R ² are preferably (C ₁ -C ₆ ) -alkyl groups. It is particularly preferred that R ¹ and R ² are the same and each is a (C ₁ -C ₆ ) -alkyl group. A (C ₁ -C ₆ ) -alkyl group is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or n-hexyl.

Cyclic ketals containing a (C ₂ -C ₄ ) -alkylidene group are for example [1,3] dioxolane or [1,3] dioxane groups.

  Manufacture can be performed batchwise or continuously by single or multiple component metering. The compound of formula (IX) can be isolated or further processed as a solution or suspension.

M ^{n +} is, for example, Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ . The inorganic base containing M ^{n +} is, for example, an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal hydrogen carbonate, or a mixture thereof, preferably Lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, or potassium carbonate.

For 100 moles of acetylpyridine, 98-120 moles of hydroxylamine or hydroxylammonium compound, more preferably 99-101 moles; and also 200-300 moles, more preferably 200-220 moles, of an inorganic base containing M ⁺ , or It is preferable to use 100 to 150 mol, more preferably 100 to 110 mol, of an inorganic base containing M ²⁺ .

（式中、ＹはＦ、Ｃｌ又はＢｒ、好ましくはＣｌ）の溶液と反応させて、式（ＸＩ）のアセチルピリジントシルオキシムを得る：

In process step (b), an aqueous solution, aqueous suspension or isolated solid of an acetylpyridine metal salt of formula (IX) is removed with a leaving group Y in a suitable solvent which is insoluble or slightly soluble in water. Containing p-toluenesulfonic acid derivative (X)

(Wherein, Y is F, Cl or Br, preferably Cl) by the solution and reaction of obtaining the acetylpyridine tosyl oxime of the formula (XI):

The reaction proceeds in a two-phase mixture of water and a suitable water-insoluble solvent, and the reaction is optionally one or more phase transfer catalysts such as quaternary ammonium salts or phosphonium salts, preferably of formula (XII ) Quaternary ammonium salts or phosphonium salts of formula (XIII) or hydrates of salts of formula (XII) or formula (XIII).

In which R ³ to R ¹⁰ are the same or different and are each independently a) a linear or branched (C ₁ -C ₂₀ ) -alkyl;
b) benzyl, or c) phenyl, and X ⁻ is an anion such as fluorine, chlorine, bromine, iodine, hydroxy acid, hydrogen sulfate, tetrafluoroboric acid, acetic acid, trifluoromethanesulfonic acid, nitric acid, hexafluoroantimonate ion. is there.

  The reaction in the two-phase mixture is preferably carried out using one or more phase transfer catalysts, but it proceeds even without a phase transfer catalyst.

  Step (b) can be carried out batchwise or continuously, but is preferably carried out continuously, in which case the concentration of the compound of formula (XI), which is important from the viewpoint of safety, is kept low. The resulting mixture of solvent and aqueous phase is subsequently separated by conventional methods of phase separation. The aqueous phase contains the used metal salt dissolved. The aqueous phase is sent for biological purification. In some cases, the aqueous phase is subsequently washed one or more times with a suitable water-insoluble solvent, and the solvent phases are combined and further processed together. The solvent phase contains a compound of formula (XI).

  In the step (b), it is preferable to use 0.1-50 mol, preferably 0.2-10 mol, of the phase transfer catalyst with respect to 100 mol of the 3-acetylpyridine oxime salt of the formula (IX).

Examples of quaternary ammonium salts of formula (XXII) are tetramethylammonium bromide, tetramethylammonium chloride, tetraethylammonium chloride, n-butyltriethylammonium chloride, methyltriisopropylammonium chloride, methyltri-n-butylammonium chloride ( Aliquat (R) 175), methyltri-n-butylammonium bromide, methyltri-n-butylammonium hydrogen sulfate, methyltetra-n-butylammonium chloride, methyltri-n-octylammonium chloride (Aliquat (R) 336) , hydroxide methyltri -n- octyl ammonium, methyl tricapryl ammonium chloride, methyl tricapryl ammonium hydroxide, chloride dimethylbenzyl (C ₈ -C ₁₈₎ - alkyl, chlorides tetra -N-propylammonium chloride, triethylhexylammonium chloride, triethyl-n-octylammonium chloride, triethyl-n-octylammonium bromide, triethyl-n-decylammonium bromide, triethyl-n-hexadecylammonium bromide, phenyltriethyl chloride Ammonium, ethyl tri-n-octylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, tetra-n-butylammonium hydrogen sulfate, 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, benzyltrimethyl hydroxide Ammonium, (n-octyl) trimethylammonium bromide, (N-nonyl) trimethylammonium bromide, tetra-n-propylammonium bromide, phenyltriethylammonium iodide, (n-decyl) trimethylammonium bromide, benzyltriethyl chloride Ammonium, benzyltriethylammonium bromide, benzyltriethylammonium tetrafluoroborate, benzyltriethylammonium hydroxide , Trimethylammonium chloride (n-dodecyl) trimethylammonium bromide, benzyltri-n-propylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-acetate n-Butylammonium, hydrogen sulfate tetra-n-butylammonium hydroxide, tetra-n-butylammonium hydroxide, tetra-n-butylammonium trifluoromethanesulfonate, (n-tetradecyl) trimethylammonium chloride, bromide (n-tetradecyl) Trimethylammonium, (n-hexadecyl) trimethylammonium bromide, tetra-n-pentylammonium chloride, tetra-n-pentylammonium iodide, benzyltri-n-butylammonium chloride, benzyltri-bromide n-butylammonium chloride, (n-hexadecyl) pyridinium chloride monohydrate, (n-hexadecyl) pyridinium bromide monohydrate, tetra-n-hexylammonium bromide, tetra-n-hexylammonium hydrogen sulfate, bromide Tetra-n-octylammonium, tetra-n-dodecylammonium iodide or tetra-n-dodecylammonium nitrate.

  Examples of phosphonium salts of the formula (XIII) are tetra-n-butylphosphonium chloride, tetraphenylphosphonium bromide, methyltri-n-octylphosphonium chloride, methyltriphenylphosphonium bromide, ethyltri-n-octylphosphonium bromide, odor Tetra-n-butylphosphonium chloride, tetraphenylphosphonium chloride, tetraphenylphosphonium iodide, tetraphenylphosphonium hexafluoroantimonate, tetraphenylphosphonium tetrafluoroborate, (n-hexadecyl) tri-n-butylphosphonium bromide or trichloride Phenylmethyltriphenylphosphonium.

Suitable water-immiscible or slightly poorly water-soluble or water-insoluble solvents are, for example, aliphatic or aromatic hydrocarbons, which are unsubstituted or one or more (C ₁ -C ₄ )- Alkyl groups such as methyl or substituted with one or more substituents selected from fluorine, chlorine and bromine, preferably toluene, xylene (as pure isomer or as a mixture of isomers), ethylbenzene, heptane Or dichloroethane. Mixtures of the aforementioned suitable solvents are also suitable.

  It is preferable to use 0.6 to 1.1 kg of a suitable solvent for 1 mol of the p-toluenesulfonic acid derivative (X). In the reaction of 100 mol of the acetylpyridine oxime salt of formula (IX), it is preferable to use 99-150 mol, more preferably 100-110 mol, of p-toluenesulfonic acid derivative (X).

  The term two-phase mixture refers to a mixture of two liquid phases—an aqueous phase containing acetylpyridine oxime salt (IX) and a solvent phase containing p-toluenesulfonic acid derivative (X). If a phase transfer catalyst is used, it may be present in the aqueous or solvent phase or may be divided between the two phases. The two-phase mixture is agitated and / or mixed in the usual manner for batch or continuous process operations to ensure good distribution of the phases.

  The reaction temperature of the batch operation in the step (b) is preferably 0-50 ° C, more preferably 5-30 ° C, and 0-60 ° C, more preferably 5-40 ° C in the continuous operation.

In step (c), the solvent phase comprising acetylpyridine tosyloxime of formula (XI) is dried after or without prior drying, alkali metal alkoxide, alkali metal hydroxide, alkaline earth metal alkoxide or alkaline earth metal. Metered into a mixture of hydroxide and alcohol (wherein “alkoxide” means R ¹ O ⁻ and / or R ² O ⁻ and alcohol means R ¹ OH and / or R ² OH) And R ¹ and R ² are as defined for compounds of formula (I)), and converted to 1- (pyridinyl) -1,1-dialkoxy-2-aminoethane derivatives of formula (I) To do.

  In step (c), 99-500 moles of alkali metal alkoxide, more preferably 100-200 moles, or 99-500 moles of alkali metal hydroxide, relative to 100 moles of acetylpyridine tosyloxime of formula (XI), Preferably 100-300 moles; or alkaline earth metal alkoxides 50-250 moles, more preferably 50-100 moles; or alkaline earth metal hydroxides 50-250 moles, more preferably 50-150 moles. preferable.

  In step (c), an alkali metal hydroxide or alkoxide, particularly lithium hydroxide, lithium methoxide, lithium ethoxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium methoxide, potassium ethoxy Preferably, cesium hydroxide, cesium hydroxide, cesium methoxide or cesium ethoxide are used.

The choice of alkoxide and / or alcohol depends on the introduction of the desired alkoxy group. For example, for the production of 1- (pyridinyl) -1,1-dimethoxy-2-aminoethane, a mixture of alkali metal or alkaline earth metal methoxide in methanol or an alkali metal hydroxide in methanol is used. For the preparation of the compound 1- (pyridinyl) -1-([1,3] dioxolane) -2-aminoethane in which R ¹ and R ² together with the oxygen atom form a cyclic ketal, for example, alkali metal water in glycol Oxides are used.

  It is preferred to use 0.3-3 kg, preferably 0.5-1.5 kg of the corresponding alcohol per mole of acetylpyridine oximutosylate of the formula (XI). The conversion is performed, for example, within a temperature range of 0-90 ° C, more preferably 10-60 ° C.

  After the reaction, a part of the solvent is first distilled off, and p-toluenesulfonate by-product precipitates at room temperature. Distillation is carried out in the usual way. The solvent mixture distilled off (distilled liquid) can be directly reused in the step (c).

  The alkali metal or alkaline earth metal salt of p-toluenesulfonic acid is removed by a usual filtration method. The remaining solvent portion is removed in a conventional manner by distillation under atmospheric pressure or preferably under reduced pressure.

The amino ketal derivative of formula (I) is subsequently isolated in high purity form, optionally by vacuum distillation or rectification or by crystals from the distillation residue obtained in the previous distillation. For example, a compound of formula (I) in which R ¹ and R ² are each methyl can be purified by distillation.

The yield in vacuum distillation or rectification can optionally be improved by adding flux to the distillation residue. The term flux refers to a liquid or waxy solid whose viscosity is reduced by heating, thus improving the fluidity of the residue to be distilled, but at the same time having a considerably higher boiling point than the product to be distilled. say. The flux used is, for example, polyethylene glycol having a molecular weight greater than 400 (eg polyethylene glycol 600 or polyethylene glycol 1000), paraffin (C _n H _{2n + 2} , where n> 15), polyhydric alcohols (one or more Alcohols with OH groups, such as glycerol) or esters, such as bis-2-ethyl sebacate.

    Crystallization can be carried out in the usual way with or without organic solvents. A melt or solvent process may be used.

  The advantage of the process of the present invention is that, firstly, the compound of formula (I) can be isolated directly as the free base in high purity and in very good yield. Secondly, depending on the reaction conditions selected, the oximation and tosylation reactions to be carried out are possible in a continuous operation. Continuous operation always produces only a small amount of the intermediate of formula (XI) that is relevant from a safety standpoint, without isolating acetylpyridine tosyloxime, which is important from a safety standpoint, as a solid. This is because, after a short delay, the acetylpyridine tosyloxime is converted directly into the amino ketal of formula (I) which is not important from a safety point of view in a continuous apparatus. The preparation of the compound of formula (I) in high purity (greater than 97%) and high yield (greater than 75% based on the acetylpyridine used) in the form of the free base in a manner suitable for industrial scale. is there. Fourth, because the process uses a solvent that can be reused directly in pure form or in the form of a mixture, the environmental impact is kept very low.

Example 1: Preparation of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane, Method 1
1 (a) In a reactor, 174 g of 40% hydroxylammonium chloride solution, 121 g of 3-acetylpyridine and 245 g of 33% sodium hydroxide solution are reacted within a temperature range of 15-25 ° C. by a three-component metering method. . The resulting sodium salt solution of 3-acetylpyridine oxime is reacted with 2 g of methyltributylammonium chloride.

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

  1 (c) The solvent phase is poured directly into the initially charged solution consisting of 940 g of methanol (or methanol / toluene mixture from the first solvent distillation, see below) and 216 g of 30% sodium methoxide solution. Keep the temperature in the range of 20-40 ° C. The reaction solution is allowed to react for an additional 5-10 hours. Methanol was distilled off from the reaction mixture as an azeotrope with toluene at 70-90 ° C. and atmospheric pressure (first solvent distillation). The azeotropic solvent mixture can be reused in the above reaction (see above). After distillation, the distillation residue is cooled to 25 ° C., p-toluenesulfonic acid sodium salt is subsequently filtered off and washed with 85 g of toluene. The filtrate is subsequently concentrated by distillation under reduced pressure (approximately 100-200 mbar) to an internal temperature of approximately 120-130 ° C. Subsequently, 10-20 g of polyethylene glycol 600 is added to the distillation residue, and 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane is added at 1-10 mbar and a short column at an internal evaporator temperature of 100-160 ° C. After that, it is distilled off as a colorless and transparent liquid. 157.3 g of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane are obtained as having a purity of 98-99% (determined by titration, HPLC-MS and NMR compared to a reference standard). This corresponds to a yield of 85% of theory based on the 3-acetylpyridine used.

Example 2: Preparation of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane, Method 2
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 reactor in a temperature range of 15-25 ° C. by a three-component metering method. 2 g of methyltributylammonium chloride is added to the sodium salt solution of 3-acetylpyridine oxime obtained.

  2 (b) Subsequently, this solution is reacted with a solution of 193 g of p-toluenesulfonyl chloride and 655 g of toluene at an internal temperature of 35 to 38 ° C. in a continuous process (a recycling method through a static mixer while partially taking out). . 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 poured directly into an initially charged solution consisting of 940 g of methanol (or methanol / toluene mixture from the first solvent distillation, see below) and 48 g of 30% sodium hydroxide. Keep the temperature in the range of 20-40 ° C. The reaction solution is allowed to react for an additional 5-10 hours. Methanol was distilled off from the reaction mixture as an azeotrope with toluene (first solvent distillation). The azeotropic solvent mixture can be reused in the above reaction (see above). After distillation, the distillation residue is cooled to 25 ° C., p-toluenesulfonic acid sodium salt is subsequently filtered off and washed with 85 g of toluene. The filtrate is subsequently concentrated by distillation under reduced pressure (approximately 100-200 mbar) to an internal temperature of approximately 120-130 ° C. Subsequently, 10-20 g of polyethylene glycol 600 is added to the distillation residue, and 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane is added at 1-10 mbar and a short column at an internal evaporator temperature of 100-160 ° C. After that, it is distilled off as a colorless and transparent liquid. 148 g of 1- (3-pyridinyl) -1,1-dimethoxy-2-aminoethane are obtained having a purity of 98-99% (determined by titration, HPLC-MS and NMR compared to a reference standard). This corresponds to a yield of 80% of theory based on the 3-acetylpyridine used.

Claims (10)

Formula (I):

[Wherein R ¹ and R ² are each independently (C ₁ -C ₆ ) -alkyl (wherein the alkyl group may be linear or branched), or R ¹ and R ² Together with an oxygen atom form a cyclic ketal where R ¹ and R ² together are a (C ₂ -C ₄ ) -alkylidene group, and the pyridine group is 2-, 3- or 4- Substituted at the position] of 1- (pyridinyl) -1,1-dialkoxy-1-aminoethane derivative,
In step (a), an acetylpyridine oxime metal of formula (IX) is added to the acetylpyridine of formula (V) by adding an inorganic base containing M ^{n +} using an aqueous solution of hydroxylammonium compound or an aqueous solution of hydroxylamine. Converted to a salt, where n is 1 or 2, and M ^{n +} is an alkali metal or alkaline earth metal ion;

In step (b), the acetylpyridine oxime metal salt of formula (IX) is converted into a p-toluenesulfonic acid derivative containing a leaving group Y in a suitable solvent that is water-immiscible or slightly water-soluble or water-insoluble ( X)

Reaction with a solution of formula (XI) wherein Y is F, Cl or Br.

Wherein the reaction proceeds in a two-phase mixture of water and a suitable solvent, optionally by use of one or more phase transfer catalysts, and in step (c) The solvent phase containing the compound (XI) obtained in step (b) is added directly to the alkali metal alkoxide, alkali metal hydroxide, alkaline earth metal alkoxide or mixture of alkaline earth metal hydroxide and alcohol. This acetylpyridine tosyl oxime of formula (XI) is converted to a compound of formula (I) (where “alkoxide” means R ¹ O ⁻ and / or R ² O ⁻ and alcohol and Means R ¹ OH and / or R ² OH, and R ¹ and R ² are each as defined for compounds of formula (I)),
And said manufacturing method characterized by performing each of this process (a) thru | or (c) independently continuously or batchwise.   The process according to claim 1, wherein the pyridine group is substituted at the 3-position. The production method according to claim 1 or 2, wherein R ¹ and R ² are each (C ₁ -C ₆ ) -alkyl.   The process according to any one of claims 1 to 3, wherein hydroxylamine, hydroxylammonium chloride or hydroxylammonium sulfate is used in step (a). The process according to any one of claims 1 to 4, wherein in step (a), M ^{n +} means Li ⁺ , Na ⁺ , K ⁺ or Ca ²⁺ . The inorganic base containing M ^{n +} in step (a) is lithium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, potassium carbonate or calcium hydroxide. The manufacturing method of description.   The manufacturing method of any one of Claims 1-6 whose leaving group Y is Cl in a process (b). In step (b), the phase transfer catalyst is a quaternary ammonium salt of formula (XII) or a phosphonium salt of formula (XIII):

[Wherein R ³ to R ¹⁰ are the same or different and are each independently a) a linear or branched (C ₁ -C ₂₀ ) -alkyl,
b) benzyl, or c) phenyl and X, ^- is a anion emission is] The process according to any one of claims 1-7.   In 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 The manufacturing method of any one of Claims 1-8 using a cesium ethoxide.   The process according to any one of claims 1 to 9, wherein in step (c), the acetylpyridine tosyloxime of formula (XI) is used without prior drying.