JP3061599B2 - Method for producing ketones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the production of ketones having an isoxazole ring, which are intermediates of aminoketones useful as central muscle relaxants.

[0002]

2. Description of the Related Art In a process for producing ketones from secondary alcohols, heavy metals such as chromic acid are generally known as oxidizing agents. However, heavy metals are biologically or otherwise harmful, and their use in pharmaceutical manufacturing is not preferred.

As a method of using another oxidizing agent not using a heavy metal, for example, a method of using a combination of sodium hypochlorite and a phase transfer catalyst (GA Lee et al.
ahedron Letters, p.1641, 197
6 years) or a method using calcium hypochlorite in the presence of a solvent such as acetic acid (SD Nwavkwa et al., Tetr).
ahedron Letters, 35, 1982.
However, these oxidation methods could not produce ketones of the general formula [3] from alcohols of the general formula [1].

On the other hand, there is known a method for producing ketones from alcohols represented by the general formula [1] using sodium hypochlorite in the presence of pyridines (JP-A-4-210974). However, the reaction rate is low and it cannot be said that it is satisfactory for an industrial production method.

[0005]

SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems of the prior art, and an improved intermediate for producing aminoketones useful in the pharmaceutical field. It is intended to provide an industrial manufacturing method.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems. As a result, the alcohols represented by the general formula [1] were converted to pyridines in an organic solvent using hypohalites. In the method for producing ketones of the general formula [3] in the presence, the reaction is carried out while controlling the pH of the reaction solution within a specific range, whereby by-products, decomposed products and the like are not generated, and the reaction rate is high. Thus, the present inventors have found a method capable of synthesizing the desired product and producing the ketone represented by the general formula [3] in high yield, and completed the present invention.

That is, the present invention provides the following general formula [1]

Embedded image Wherein R ₁ and R ₃ are each independently a hydrogen atom; a halogen atom; a lower alkyl group; a pyridyl group; a furyl group optionally substituted with a lower alkyl group; a thienyl optionally substituted with a lower alkyl group. A group substituted with a halogen atom, lower alkoxy group, lower alkyl group, trifluoromethyl group, cyano group, nitro group, amino group, dimethylamino group, acetamido group, methanesulfonylamide group, acetyl group or lower alkoxycarbonyl group A phenyl group; a naphthyl group; a benzyl group; a benzoyl group. R ₂ and R ₄ are a hydrogen atom; a lower alkyl group; a benzyl group; a methoxy group; a phenyl group;
A lower alkyl group which may be substituted with a trifluoromethyl group or a lower alkoxy group; a cyclopropylmethyl group; or a group wherein R ₂ and R ₄ are linked to form an alicyclic 5- or 6-membered ring It may be. In a solvent in the presence of pyridines, an alcohol represented by the following general formula [2] M (OX) n [2] wherein M is an alkali metal or an alkaline earth metal; Represents a halogen atom. n represents 1 when M is an alkali metal, and 2 when M is an alkaline earth metal. ] With a hypohalite represented by the general formula [3]

Embedded image In the method for producing ketones represented by [R ₁ , R ₂ , R ₃ and R ₄ are the same as described above], this is a method for producing ketones which react while controlling the pH of the reaction solution to 7 to 9. .

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Specific embodiments of the present invention are as follows. After dissolving the alcohol represented by the general formula [1] in an organic solvent, a small amount of hypohalite and pyridine are added, and the hypohalite is used as an alkaline pH adjuster for the reaction. React while controlling within the range of ~ 9. After completion of the reaction, the organic solvent layer is separated, washed with a reducing agent such as sodium bisulfite, distilled off under reduced pressure, and recrystallized with an alcohol such as ethanol.

The alcohol represented by the general formula [1] used in the present invention can be produced by the method described in JP-A-4-210974. For example, 5- (1-hydroxybutyl) -3-phenylisoxazole having isoxazole is specifically prepared by dissolving benzaldoxime and 1-hexyn-3-ol in an organic solvent, and adding 12% It can be synthesized by dropping and reacting an aqueous solution of sodium chlorite. After completion of the reaction, the reaction mixture was extracted with dichloromethane, the organic layer was washed with water, dried over anhydrous sodium sulfate, the organic solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 5- (1-hydroxybutyl)- 3-Phenylisoxazole is obtained as an oil.

In the above-mentioned method of performing the reaction while controlling the pH, there is no particular limitation, but a commercially available pH controller may be used. There is no restriction on the model to be used, but it is preferable that the apparatus has a function such as an interval timer for controlling the flow rate by operating the pump at the upper and lower limits.

The pH controller is set so that an acidic solution is added at the upper limit and hypohalites are added at the lower limit. The flow rate may be adjusted by an interval timer while checking heat generation and the like.

Specific examples of the solvent used in the present invention include hydrocarbons such as hexane, pentane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, methanol, ethanol and n-propanol. Primary alcohols, tetrahydrofuran, ethers such as dioxane, chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, halogenated hydrocarbons such as 1,1,2-trichloroethane, Esters such as methyl acetate, ethyl acetate and propyl acetate, and water, acetonitrile, dimethylformamide, dimethyl sulfoxide, N-methyl-2-
Pyrrolidone and the like are preferred, and more preferred are halogenated hydrocarbons such as chloroform and dichloromethane.

The amount of the solvent used depends on the type of the solvent, but if the amount is too small, the reaction does not proceed sufficiently. It is usually at least 2 times, more preferably at least 3 times, the weight of alcohols. The upper limit is not particularly limited, but using too much is economically undesirable. Usually, it is better to use the alcohol at 20 times or less by weight.

Hypohalites added as an alkaline solution while adjusting the pH of the reaction solution are represented by the following general formula [2] M (OX) n [2].

In the general formula [2], M represents an alkali metal or an alkaline earth metal. Examples of the alkali metals include lithium, sodium, potassium,
Cesium and the like can be mentioned. Examples of the alkaline earth metal include magnesium, calcium, strontium, barium and the like.

The group X represents a halogen atom, and examples thereof include chlorine, bromine and iodine. n is 1 when M is an alkali metal, and 2 when M is an alkaline earth metal.
Is shown. Specifically, alkali metals are sodium hypochlorite, potassium hypochlorite, lithium hypochlorite, sodium hypobromite, potassium hypobromite, and alkaline earth metals are calcium hypochlorite, Magnesium hypochlorite, strontium hypochlorite, calcium hypobromite, and magnesium hypobromite are preferable, and more preferably, an aqueous solution of an alkali metal such as sodium hypochlorite and potassium hypochlorite is used. it can.

Examples of the acidic pH adjuster include mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid, and propionic acid. Acids are preferred, and more preferred are mineral acids such as hydrochloric acid and sulfuric acid.

The concentration of the acidic solution for controlling the pH of the reaction solution is not particularly limited. However, if the pH is controlled with an acid solution having a very low concentration, the efficiency of the reaction vessel and the like is deteriorated, which is not preferable. PH in very concentrated acid solution
When the pH is controlled, it is difficult to control the pH of the reaction solution, it is difficult to control the heat generation due to the neutralization reaction with hypohalites, and the decomposition of the raw material and the target product tends to occur.
Therefore, preferably 5 to 20%, more preferably 8 to 1%.
It is preferable to use a 5% aqueous solution.

The amount of hypohalites added at the beginning of the reaction is not particularly limited, but the pH of the mixed solution is measured using a pH electrode.
Any amount can be used as long as H can be measured. If a large amount of hypohalites are added at once, salts are easily formed and the subsequent reaction does not proceed sufficiently. In addition, a large amount of acid is added to lower the pH, and the decomposition of hypohalites and target substances due to heat generation is likely to occur.

Pyridine to be added to the reaction solution of the alcohol represented by the general formula [1] is represented by the following general formula [4]

Embedded image (In the general formula [4], Y and Z independently represent a hydrogen atom or a lower alkyl group).

Specific examples of the pyridines include pyridine, 2-picoline, 3-picoline, 4-picoline,
Examples thereof include 2,5-dimethylpyridine, 2,3-dimethylpyridine, 2,4-dimethylpyridine, 3,5-dimethylpyridine, 3-ethylpyridine, and 4-ethylpyridine.

The most preferred method for adding pyridines to the reaction solution is to add them all at once in the initial stage. The method of dividingly adding during the reaction is not preferable because the reaction rate is high and the reaction rate is lowered due to the shortage of pyridines.

The amount of the pyridine to be added is usually 0.01 to 0.01 in a molar ratio to the alcohol of the general formula [1].
10 is preferable, and 0.1 to 5 is more preferable.
If it is less than 0.01, the reaction does not proceed sufficiently, and if it exceeds 10, it is not economically preferable.

The pH at which the ketones are reacted is preferably in the range of 7 to 9, and more preferably in the range of 7.5 to 8.5. If the pH exceeds 9, the progress of oxidation is slow and the reaction time is undesirably long. If the pH is less than 7, hypohalites are decomposed, which is not preferable.

The amount of hypohalites added as an alkaline solution while adjusting the pH of the reaction solution is preferably 1 to 5, more preferably 2 to 3 in molar ratio with respect to the alcohol of the general formula [1]. It is. If the molar ratio is less than 1 mole, the reaction is not completed due to the lack of hypohalites. Use of more than 5 mole ratio is not preferable from an economical point of view.

The reaction temperature is preferably from 0 to 60 ° C, more preferably from 5 to 20 ° C. If the temperature is lower than 0 ° C., the progress of the reaction is slow and the reaction time is undesirably long. If the temperature is higher than 60 ° C., the decomposition of hypohalites and the side reaction of the target product are likely to occur, which is not preferable.

The end point of the reaction can be easily determined by adding a predetermined amount of hypohalites and then using a means such as liquid chromatography.

In the method of the present invention, as a method for isolating ketones from the reaction solution in which ketones of the general formula [3] are formed, the separated organic solvent layer is treated with a reducing agent such as sodium hydrogen sulfite. After washing, the ketones may be replaced with an organic solvent or the like having low solubility, the solution may be cooled and crystallized, and isolated by a solid-liquid separation operation such as suction filtration.

Hereinafter, the method of the present invention will be specifically described with reference to examples. Liquid chromatography analysis conditions Column ODS A-314 (YMC) Column temperature 35 ° C. Detection UV 254 nm Eluent 10.5 mM potassium dihydrogen phosphate / acetonitrile = 3/7 Eluent flow rate 1.3 ml / min. Reference Example 1 Synthesis of 5- (1-hydroxylbutyl) -3-phenylisoxazole

Embedded image 49.8 g (411 mmol) of benzaldoxime and 46.0 g (469 mmol of 1-hexyn-3-ol)
l) was dissolved in 250 ml of dichloromethane. below freezing,
290 g of a 12% aqueous NaOCl solution (467 m
mol) was added dropwise over 30 minutes. After the completion of the dropwise addition, the reaction was continued at 20 ° C. for 2 hours. After completion of the reaction, the mixture was extracted with dichloromethane, and the organic layer was washed. After drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform) to give the desired product, 5- (1-hydroxybutyl) -3-phenylisoxazole, as an oil. Yield 64.8 g (Yield 72.5%) ¹ H-NMR (CDCl ₃ , 270 MHz): δ 0.7
To 1.1 (3H, m), 1.1 to 2.1 (4H, m),
3.8 (1H, m), 4.8 (1H, t, J = 7H
z), 6.4 (1H, s), 7.2-7.5 (3H,
m), 7.5-7.9 (2H, m).

Example 1 Synthesis of 5-butyryl-3-phenylisoxazole

Embedded image 5- (1-hydroxylbutyl) -3-phenylisoxazole 44.0 g (203 mmol) and pyridine 4.8 g (61 mmol) in dichloromethane 125 ml
Was dissolved. While stirring the solution, add 12%
10 g of aqueous sodium hypochlorite solution was added. In order to control the pH of the above reaction solution in the range of 7.8 to 8.2, a pH controller (Tokyo Rika Instruments Co., Ltd.)
(Type: F-2000). Set the lower limit of the pH controller to 7.8 and the upper limit to 8.2,
12% sodium hypochlorite aqueous solution is added at the lower limit,
The upper limit was set so that 10% aqueous hydrochloric acid was dropped. Also, add (ON) time of the attached interval timer to 10
Seconds, wait time (OFF) is set to 15 seconds, reaction temperature 1
The mixture was reacted at 0 ° C. in the above pH range with 12% sodium hypochlorite and 10% hydrochloric acid while controlling.
The reaction end point was 376 g (606 g) of 12% aqueous NaOCl solution.
mmol; 5- (1-hydroxylbutyl) -3-phenylisoxazole in a molar ratio of 3.0) is pH.
It was the time when it was added by the controller. 12% Na
It took 5.5 hours to complete the addition of the aqueous OCl solution. The reaction solution was separated, the organic solvent layer was washed with a 5% aqueous sodium sulfite solution, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give 5-butyryl-3, which was the desired product.
-Phenyloxazole was obtained as crystals. Yield 39.6 g (Yield 90.4%) Melting point 89-90 ° C. ¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.0
(3H, t, J = 7 Hz), 1.5 to 2.1 (2H,
m), 2.0 (2H, t, J = 7 Hz), 7.2 (1
H, s), 7.3-7.6 (3H, m), 7.6-8.
0 (2H, m).

Comparative Example 1 Synthesis of 5-butyryl-3-phenylisoxazole 44.0 g (203 mmol) of 5- (1-hydroxylbutyl) -3-phenylisoxazole was dissolved in 125 ml of dichloromethane. While stirring this solution,
376 g of 12% aqueous sodium hypochlorite solution
(606 mmol) was added dropwise. Next, the mixed solution (6N-
A solution obtained by adding 4.8 g (61 mmol) of pyridine to 10 ml of hydrochloric acid) was added dropwise over 1 hour while maintaining the internal temperature at 20 ° C. After completion of the reaction, the organic layer was separated and washed with a 5% aqueous sodium bisulfite solution, water and a 1N aqueous hydrochloric acid solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give the desired 5-butyryl-
3-Phenylisoxazole was obtained as crystals. Yield 29.0 g (Yield 66.4%) Melting point 89-90 ° C. ¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.0
(3H, t, J = 7 Hz), 1.5 to 2.1 (2H,
m), 2.0 (2H, t, J = 7 Hz), 7.2 (1
H, s), 7.3-7.6 (3H, m), 7.6-8.
0 (2H, m).

COMPARATIVE EXAMPLE 2 Synthesis of 5-butyryl-3-phenylisoxazole 44.0 g (203 mmol) of 5- (1-hydroxylbutyl) -3-phenylisoxazole and 4.8 g (61 mmol) of pyridine were added to 125 ml of dichloromethane.
Was dissolved. While stirring the solution, add 12%
10 g of aqueous sodium hypochlorite solution was added. In order to control the pH of the above reaction solution in the range of 10.0 to 10.4, the reaction was performed using a pH controller (Tokyo Rika Instruments Co., Ltd. type; F-2000). That p
The lower limit of the H controller was set to 10.0, the upper limit was set to 10.4, the lower limit was set so that a 12% aqueous solution of sodium hypochlorite was added, and the upper limit was set so that 10% hydrochloric acid was dropped. The addition (ON) time of the attached interval timer is set to 10 seconds, the waiting time (OFF) is set to 15 seconds, and the above pH range is adjusted to 12% sodium hypochlorite and 10% hydrochloric acid at a reaction temperature of 10 ° C. The reaction was performed while controlling with water. The reaction end point is 376 g of 12% NaOCl aqueous solution.
(606 mmol 5- (1-hydroxylbutyl) -3
-3.0 molar ratio to phenylisoxazole)
Was added at the pH controller. 12
It took 14.5 hours to complete the addition of the aqueous% NaOCl solution. The reaction solution was separated, and the organic solvent layer was washed with a 5% aqueous solution of sodium sulfite. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give the target compound, 5-butyryl-3-phenylisoxazole. Was obtained as crystals. Yield 21.9 g (50.2% yield) Melting point 89-90 ° C ¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.0
(3H, t, J = 7 Hz), 1.5 to 2.1 (2H,
m), 2.0 (2H, t, J = 7 Hz), 7.2 (1
H, s), 7.3-7.6 (3H, m), 7.6-8.
0 (2H, m).

Comparative Example 3 Synthesis of 5-butyryl-3-phenylisoxazole 54.0 g (203 mmol) of 5- (1-hydroxylbutyl) -3-phenylisoxazole and 4.8 g (61 mmol) of pyridine were added to 125 ml of dichloromethane.
Was dissolved. While stirring the solution, add 12%
10 g of aqueous sodium hypochlorite solution was added. In order to control the pH of the above reaction solution in the range of 6.5 to 6.9, a pH controller (Tokyo Rika Instruments Co., Ltd.)
(Type: F-2000). Set the lower limit of the pH controller to 6.5 and the upper limit to 6.9,
12% sodium hypochlorite aqueous solution is added at the lower limit,
The upper limit was set so that 10% aqueous hydrochloric acid was dropped. Also, add the attached interval timer (ON) time to 10
Seconds, wait time (OFF) is set to 15 seconds, reaction temperature 1
The reaction was carried out at 0 ° C. while controlling the above pH range with 12% sodium hypochlorite and 10% hydrochloric acid. The reaction end point was 376 g (606 m
mol 5- (1-hydroxylbutyl) -3-phenylisoxazole in a molar ratio of 3.0) was added when the pH controller was added. 12% NaO
It took 4.5 hours to complete the addition of the aqueous Cl solution.
The reaction solution was separated, and the organic solvent layer was washed with a 5% aqueous solution of sodium sulfite. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give the target compound, 5-butyryl-3-phenylisoxazole. Was obtained as crystals. Yield 26.7 g (Yield 61.1%) Melting point 89-90 ° C. ¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.0
(3H, t, J = 7 Hz), 1.5 to 2.1 (2H,
m), 2.0 (2H, t, J = 7 Hz), 7.2 (1
H, s), 7.3-7.6 (3H, m), 7.6-8.
0 (2H, m).

Reference Example 2 Synthesis of 5- (1-hydroxypropyl) -3-phenylisoxazole

Embedded image 50.0 g (413 mmol) of benzaldoxime and 39.4 g (468 mmol) of 1-pentyn-3-ol
l) was dissolved in 250 ml of dichloromethane. below freezing,
290 g of a 12% aqueous NaOCl solution (467 m
mol) was added dropwise over 30 minutes. After the completion of the dropwise addition, the reaction was continued at 20 ° C. for 2 hours. After completion of the reaction, the mixture was extracted with dichloromethane, and the organic layer was washed. After drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluted with chloroform) to give 5- (1-hydroxypropyl) -3-phenylisoxazole as a crystal as an objective substance. Yield 65.5 g (Yield: 78.0%) Melting point: 101 to 102 ° C. ¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.0
(3H, t, J = 8 Hz), 1.6 to 2.2 (2H,
m), 3.1 (1H, bs), 4.9 (1H, t, J =
6 Hz), 6.5 (1H, s), 7.3 to 7.6 (3
H, m), 7.7-7.9 (2H, m).

Example 2 Synthesis of 5-propionyl-3-phenylisoxazole

Embedded image 4- (1-hydroxypropyl) -3-phenylisoxazole 41.0 g (202 mmol) and pyridine 4.8 g (61 mmol) in dichloromethane 125 ml
Was dissolved. While stirring the solution, add 12%
10 g of aqueous sodium hypochlorite solution was added. In order to control the pH of the above reaction solution in the range of 7.8 to 8.2, a pH controller (Tokyo Rika Instruments Co., Ltd.)
(Type: F-2000). Set the lower limit of the pH controller to 7.8 and the upper limit to 8.2,
12% sodium hypochlorite aqueous solution is added at the lower limit,
The upper limit was set so that 10% aqueous hydrochloric acid was dropped. Also, add the attached interval timer (ON) time to 10
Seconds, wait time (OFF) is set to 15 seconds, reaction temperature 1
The reaction was carried out at 0 ° C. while controlling the above pH range with 12% sodium hypochlorite and 10% hydrochloric acid. The reaction end point was 376 g (606 m
mol 5- (1-hydroxypropyl) -3-phenylisoxazole in a molar ratio of 3.0) is pH
It was the time when it was added by the controller. 12% Na
It took 5.5 hours to complete the addition of the aqueous OCl solution. The reaction solution is separated, the organic solvent layer is washed with a 5% aqueous sodium sulfite solution, the solvent is distilled off under reduced pressure, and the residue is recrystallized from ethanol to give 5-propionyl-
3-Phenylisoxazole was obtained as crystals. Yield 39.5 g (Yield 97.2%) Melting point 111-112 ° C. ¹ H-NMR (CDCl ₃ , 270 MHz): δ 1.3
(3H, t, J = 8 Hz), 3.1 (2H, q, J = 8)
Hz), 7.2 (1H, s), 7.5 to 8.0 (5H,
m).

[0036]

According to the method of the present invention, ketones having an isoxazole ring can be produced with high yield while suppressing by-products and decomposition products.

Continuation of the front page (72) Inventor Tatsuo Kaiho 1900 Togo, Mobara-shi, Chiba Examiner, Mitsui Toatsu Chemicals Co., Ltd.Examiner, Kazuyuki Yoshizumi (56) References JP-A-4-210974 (JP, A) Field surveyed (Int. Cl. ⁷ , DB name) C07D 261/08 C07D 261/10 CAPLUS (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] [Claim 1] The following general formula [1] Wherein R ₁ and R ₃ are each independently a hydrogen atom; a halogen atom; a lower alkyl group; a pyridyl group; a furyl group optionally substituted with a lower alkyl group; a thienyl optionally substituted with a lower alkyl group. A group substituted with a halogen atom, lower alkoxy group, lower alkyl group, trifluoromethyl group, cyano group, nitro group, amino group, dimethylamino group, acetamido group, methanesulfonylamide group, acetyl group or lower alkoxycarbonyl group A phenyl group; a naphthyl group; a benzyl group; a benzoyl group. R ₂ and R ₄ are a hydrogen atom; a lower alkyl group; a benzyl group; a methoxy group; a phenyl group;
A lower alkyl group which may be substituted with a trifluoromethyl group or a lower alkoxy group; a cyclopropylmethyl group; or a group wherein R ₂ and R ₄ are linked to form an alicyclic 5- or 6-membered ring It may be. In a solvent in the presence of pyridines, an alcohol represented by the following general formula [2] M (OX) n [2] wherein M is an alkali metal or an alkaline earth metal; Represents a halogen atom. n represents 1 when M is an alkali metal, and 2 when M is an alkaline earth metal. ] With a hypohalite represented by the general formula [3]: In the method for producing ketones represented by [R ₁ , R ₂ , R ₃ and R ₄ are the same as described above], a method for producing ketones wherein the reaction is carried out while controlling the pH of the reaction solution to 7 to 9. 2. The method according to claim 1, wherein the alkaline pH adjuster added for controlling the pH is hypohalites. 3. The method according to claim 1, wherein the acidic pH adjuster for controlling the pH is a mineral acid or an organic acid. 4. The process according to claim 1, wherein the amount of hypohalites added to the reaction solution as an alkaline pH adjuster is 1 to 10 in a molar ratio to the alcohols. 5. The process according to claim 1, wherein the amount of the pyridines to be added is 0.01 to 10 in a molar ratio to the alcohols. 6. The method according to claim 1, wherein the reaction temperature is 0 to 60 ° C. 7. The method according to claim 1, wherein R ₁ is a phenyl group, R ₂ is a methyl group, an ethyl group or a propyl group, and R ₃ and R ₄ are hydrogen atoms.