JP2003206247A - Method of producing cyclopropylethanol - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of producing cyclopropylethanol inexipensively with industrial advantage. <P>SOLUTION: 3-Cyclopropyl-2,3-epoxy propionate is solvolyzed, the product is treated with an acid to form cyclopropylacetaldehyde. Then, the resultant cyclopropylacetaldehyde is reduced to give cyclopropylethanol. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing cyclopropylethanol. The cyclopropyl ethanol obtained by the present invention is useful as a synthetic intermediate for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art As a method for producing cyclopropylethanol, for example, (1) a method in which diazomethane is allowed to act on homoallyl alcohol (see Non-Patent Document 1), and (2) butadiene is allowed to act on dibromocarbene to obtain 1 ，
A method of debrominating 1-dibromo-2-vinylcyclopropane with metallic sodium-alcohol to synthesize vinylcyclopropane, and then hydroborating and oxidizing vinylcyclopropane (see Non-Patent Document 2), (3) Cyclo A method of synthesizing propyllithium and ethylene oxide (see Non-Patent Document 3) is known.

[0003]

[Non-Patent Document 1] Journal of Organic Synthesis (J. Org. Synth.), 1978,
Vol. 43, p. 3496

[Non-Patent Document 2] Journal of Organic Synthesis (J. Org. Synth.), 1967,
Volume 32, Page 940

[Non-Patent Document 3] American Society (Am.
Soc. ), 1959, Vol. 81, p. 4895

[0004]

In the above method (1), explosive diazomethane is used, and in the method (2), it is necessary to use carcinogenic bromoform to generate dibromocarbene. Yes, and uses ignitable metallic sodium. Method (3)
Uses ethylene oxide, which is a toxic gas.
Therefore, none of these methods is an industrially advantageous method for producing cyclopropylethanol.

An object of the present invention is to provide a method for producing cyclopropylethanol inexpensively and industrially advantageously.

[0006]

The present invention provides 3-cyclopropyl-2,3-epoxypropionic acid ester (3-
Cyclopropyl-2-oxiranecarboxylic acid ester)
Is subjected to solvolysis, and the product is treated with an acid to obtain cyclopropylacetaldehyde, and the obtained cyclopropylacetaldehyde is reduced, which is a method for producing cyclopropylethanol.

Further, the present invention is a method for producing cyclopropyl ethanol characterized by reducing cyclopropyl acetaldehyde.

The present invention relates to 3-cyclopropyl-2,3-
It includes a process for producing cyclopropylacetaldehyde, which comprises subjecting an epoxypropionic ester to solvolysis and subjecting the product to acid treatment.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION (A) 3-Cyclopropyl-2,
3-Epoxypropionic acid ester is subjected to solvolysis, and the product is treated with an acid to obtain cyclopropylacetaldehyde. The 3-cyclopropyl-2,3-epoxypropionic acid ester used in the present invention is the ester thereof. There is no particular limitation as long as the group can undergo solvolysis, and examples thereof include methyl ester, ethyl ester, propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, pentyl ester and hexyl ester.

The solvolysis is carried out in the presence of a base. Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate and sodium hydrogen carbonate.
An alkali metal hydrogencarbonate such as potassium hydrogencarbonate is used. The amount of base used is 3-cyclopropyl-
It is preferably in the range of 0.5 to 10 moles per 1 mole of 2,3-epoxypropionic acid ester, and 0.5 to
It is more preferably in the range of 1.5 mol.

Examples of the acid used in the acid treatment include hydrochloric acid,
Examples thereof include inorganic acids such as sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, chloroacetic acid, propionic acid, butyric acid, formic acid, oxalic acid and malonic acid; and acidic ion exchange resins. The amount of the acid used is preferably in the range of 1 to 10 mol, and more preferably in the range of 1 to 1.5 mol, per 1 mol of 3-cyclopropyl-2,3-epoxypropionic acid ester. .

The above reaction is carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction,
For example, water; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; ethers such as diisopropyl ether, tetrahydrofuran and dioxane are used. The amount of the solvent used is not particularly limited, but is preferably in the range of 1 to 100 times by weight, and preferably in the range of 1 to 10 times by weight, of the 3-cyclopropyl-2,3-epoxypropionic acid ester. Is more preferable.

The reaction temperature for solvolysis is -20 ° C to 15 ° C.
It is preferably in the range of 0 ° C, more preferably in the range of 0 to 70 ° C. The reaction time for solvolysis depends on the type and amount of base and solvent used, but is usually 1
It is in the range of 0 minutes to 24 hours. The reaction temperature by the acid treatment is preferably in the range of -20 ° C to 100 ° C, and 0
More preferably, it is in the range of -50 ° C. The reaction time by the acid treatment varies depending on the type and amount of the acid and solvent used, but is usually in the range of 10 minutes to 24 hours.

In the above reaction, for example, 3-cyclopropyl-2,3-epoxypropionic acid ester, a base and a solvent are mixed and stirred under reduced pressure or normal pressure at a predetermined temperature, and then an acid is added to the reaction system. By doing.

The reaction mixture of cyclopropylacetaldehyde thus obtained may be subjected to the next reduction reaction as it is, but cyclopropylacetaldehyde may be isolated and purified from the reaction mixture and then subjected to the reduction reaction. Isolation / purification of cyclopropylacetaldehyde from the reaction mixture is carried out by a method generally used for isolation / purification of organic compounds. For example, the reaction mixture is poured into water and extracted with an aliphatic hydrocarbon such as hexane; an aromatic hydrocarbon such as toluene; a halogenated hydrocarbon such as dichloromethane; an ether such as diethyl ether or diisopropyl ether. After concentrating the liquid,
Purify by distillation, silica gel column chromatography, etc.

(B) Step of obtaining cyclopropyl ethanol by reducing cyclopropylacetaldehyde The reducing method is not particularly limited as long as it can reduce the aldehyde group, but for example, (a) metal-hydrogen complex compound is used for reduction. A method of (b) catalytic hydrogenation,
(C) A method of reacting with a secondary alcohol in the presence of aluminum alkoxide is adopted. Hereinafter, these reduction methods will be described.

(A) Method of reduction with metal-hydrogen complex compound Examples of the metal-hydrogen complex compound include sodium borohydride, sodium trimethoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, and sodium triethoxyaluminum hydride. , Sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and the like are used. The amount of the metal-hydrogen complex compound used is preferably in the range of 0.1 to 10 mol, and more preferably in the range of 0.25 to 2.0 mol, per 1 mol of cyclopropylacetaldehyde.

The reaction is preferably carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and for example, ethers such as diisopropyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene, xylene and mesitylene are preferably used. As the metal-hydrogen complex compound, for example, when sodium borohydride, sodium trimethoxyborohydride, or sodium borohydride is used, as a solvent, other than the above ethers or aromatic hydrocarbons, water or methanol, ethanol, propanol is used. Alcohols such as isopropanol, butanol and the like can also be used. The amount of solvent used is not particularly limited, but is 1 with respect to cyclopropylacetaldehyde.
It is preferably in the range of 1 to 100 times by weight, more preferably in the range of 1 to 10 times by weight.

The reaction temperature is preferably in the range of -70 ° C to 100 ° C, more preferably in the range of -20 ° C to 50 ° C. The reaction time varies depending on the kind and the amount of the metal-hydrogen complex compound and the solvent used, but is usually in the range of 10 minutes to 24 hours.

The reaction is carried out, for example, by mixing cyclopropylacetaldehyde and a solvent, stirring at a predetermined temperature, and then adding a metal-hydrogen complex compound to the mixture, or by mixing the metal-hydrogen complex compound and a solvent at a predetermined temperature. By stirring and then adding cyclopropylacetaldehyde to the mixture.

(B) Method of catalytic hydrogenation It is carried out in the presence of a hydrogenation catalyst. As a hydrogenation catalyst,
For example, Raney nickel, Raney cobalt, activated carbon-supporting rhodium, platinum oxide, activated carbon-supporting platinum, hexachloroplatinum, copper chromite and the like are used. The amount of hydrogenation catalyst used is 0.0 based on cyclopropylacetaldehyde.
It is preferably in the range of 1 to 20% by weight, and 0.1 to 5
It is more preferably in the range of% by weight.

The reaction is preferably carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include water; alcohols such as methanol, ethanol, propanol, isopropanol, butanol; diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane; esters such as methyl acetate and ethyl acetate are used. The amount of the solvent used is not particularly limited, but is preferably in the range of 1 to 100 times the weight of cyclopropylacetaldehyde,
The range of 10 times the weight is more preferable.

The reaction temperature is preferably in the range of 0 to 100 ° C, more preferably 20 to 60 ° C. The reaction time varies depending on the type and amount of the hydrogenation catalyst and the solvent used, but is usually in the range of 10 minutes to 24 hours.

The reaction is carried out, for example, by mixing cyclopropylacetaldehyde, a hydrogenation catalyst and a solvent, and hydrogenating under normal pressure or under pressure. Hydrogen pressure is 1-5
It is preferably in the range of 0 kg / cm ² (0.098 to 4.9 MPa).

(C) Method of reacting with secondary alcohol in the presence of aluminum alkoxide As the aluminum alkoxide, for example, aluminum trimethoxide, aluminum triethoxide, aluminum isopropyloxide, aluminum tri-n-butoxide, aluminum diisopropylate. Mono sec-
Butyrate is used. Among these, it is preferable to use aluminum isopropoxide. The amount of the aluminum alkoxide used is preferably selected in the range of 0.1 to 100 mol% with respect to cyclopropylacetaldehyde, and is preferably selected in the range of 1 to 10 mol%. Is more preferable.

As the secondary alcohol, for example, isopropanol, 2-butanol, 2-pentanol, cyclobutanol, cyclopentanol, cyclohexanol and the like are used. Among these, it is preferable to use isopropanol. The amount of the secondary alcohol used is 1.0 to 1 mol of cyclopropylacetaldehyde.
It is preferably in the range of 100 mol, and more preferably in the range of 1.0 to 10 mol.

The reaction is carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction, for example, aliphatic hydrocarbons such as hexane, heptane, octane; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene; diisopropyl ether, tetrahydrofuran, dioxane, etc. Ether, etc. are used. The amount of the solvent used is not particularly limited, but is 1 to 10 relative to cyclopropylacetaldehyde.
It is preferably in the range of 0 times the weight, and more preferably in the range of 1 to 10 times the weight.

The reaction temperature is preferably in the range of 0 to 150 ° C. The reaction time is aluminum alkoxide,
Although it depends on the type and amount of the secondary alcohol and solvent used, it is usually in the range of 30 minutes to 20 hours.

The reaction is carried out, for example, by mixing cyclopropylacetaldehyde, aluminum alkoxide, secondary alcohol and, if necessary, a solvent, and stirring the mixture at a predetermined temperature under normal pressure or reduced pressure. When the ketone by-produced by the reaction has a boiling point lower than that of cyclopropylethanol, it is more preferable to carry out the reaction while distilling off the ketone.

The cyclopropylethanol thus obtained can be isolated / purified by a method generally used for the isolation / purification of organic compounds. For example, the reaction mixture is poured into water, and an aliphatic hydrocarbon such as hexane;
Extraction is performed with an aromatic hydrocarbon such as toluene; a halogenated hydrocarbon such as dichloromethane; an ether such as diethyl ether and diisopropyl ether, and the obtained extract is concentrated and then purified by distillation, silica gel column chromatography and the like.

The 3-cyclopropyl-2,3-epoxypropionic acid ester used in the present invention can be produced by reacting cyclopropanecarbaldehyde with an α-haloacetic acid ester in the presence of a base ( (See Japanese Patent Laid-Open No. 11-228559).

[0032]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 Synthesis of methyl 3-cyclopropyl-2,3-epoxypropionate In a three-necked flask having an internal volume of 300 ml equipped with a thermometer and a stirrer, 87 g (0.45 mol) of 28% sodium methoxide in methanol was added. And 21 g (0.30 mol) of cyclopropanecarbaldehyde were added, and -10
After cooling to ℃, methyl chloroacetate 48.9 in the reaction solution.
g (0.45 mol) was added dropwise over 3 hours. After completion of dropping, the reaction solution was heated to room temperature and stirred at room temperature for 5 hours. 12 g (0.20 mol) of acetic acid was added to neutralize the remaining sodium methoxide, and the reaction solution was added to 140 g of water.
Poured into. 50 ml of ethyl acetate was added to the obtained reaction mixture.
The extract was washed with 50 ml of saturated saline solution, dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure, and 70-73 ° C [6 mmHg (8.
Methyl 3-cyclopropyl-2,3-epoxypropionate 2 having the following physical properties as a fraction of
9.8 g (0.21 mol, yield 70.0%) was obtained.

¹ H-NMR (270 MHz, CDCl ₃
, TMS, ppm) δ: 3.78 (3H, s), 3.
30 (1H, d, J = 2.0 Hz), 2.97 (1H,
dd, J = 2.0, 5.7 Hz), 1.00-0.80
(1H, m), 0.63-0.56 (1H, m), 0.
46-0.41 (1H, m)

Example 1 Synthesis of cyclopropylacetaldehyde 100 ml internal volume equipped with a condenser, thermometer and stirrer
In a three-necked flask containing 5N sodium hydroxide solution 4
8 ml (0.24 mol) was added, and 28.4 g (0.2 mol) of methyl 3-cyclopropyl-2,3-epoxypropionate obtained in the same manner as in Reference Example 1 was added dropwise at 25 ° C over 2 hours. After completion of dropping, the mixture was stirred at 25 ° C. for 1 hour. Next, 48 ml of 1.86 N hydrochloric acid (0.24 m
ol) is added dropwise at 25 ° C. over 1 hour, and after completion of the addition, 2
The mixture was stirred at 5 ° C for 30 minutes. The obtained reaction mixture was extracted 3 times with 50 ml of diethyl ether, the extract was washed with 50 ml of saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 13.5 g (0.16 mol, yield 80.5%) of cyclopropylacetaldehyde having the following physical properties.

¹ H-NMR (270 MHz, CDCl ₃
, TMS, ppm) δ: 9.90-9.70 (1H,
m), 2.33-2.25 (2H, m), 1.15.
0.95 (1H, m), 0.65-0.58 (2H,
m), 0.21-0.15 (2H, m)

Example 2 Synthesis of cyclopropylethanol 100 ml internal volume equipped with a condenser, thermometer and stirrer
In a three-necked flask of 8.4 g of cyclopropylacetaldehyde obtained in the same manner as in Example 1 (0.1 mo)
1) and 50 ml of diethyl ether were added, and while stirring at 25 ° C., 1.42 g (3
7.5 mmol) was added over 15 minutes. After the addition was completed, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was neutralized with dilute hydrochloric acid, extracted 4 times with 30 ml of diisopropyl ether, the extract was washed with 30 ml of saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, and 7.35 g (85.5 g) of cyclopropylethanol having the following physical properties.
mmol, yield 85.5%).

¹ H-NMR (270 MHz, CDCl ₃
, TMS, ppm) δ: 3.78-3.62 (2H,
m), 1.75-1.56 (1H, m), 1.53-
1.38 (2H, m), 0.80-0.60 (1H,
m), 0.50-0.33 (2H, m), 0.13-
0.03 (2H, m)

Example 3 Synthesis of cyclopropylethanol In a three-necked flask having an internal volume of 1 L equipped with a condenser, a thermometer and a stirrer, 144 m of 5N aqueous sodium hydroxide solution was added.
1 (0.72 mol) was added, and 86.8 g (0.6 mol) of methyl 3-cyclopropyl-2,3-epoxypropionate obtained in the same manner as in Reference Example 1 was added dropwise at 25 ° C over 2 hours. After completion of dropping, the mixture was stirred at 25 ° C. for 1 hour. Then, 387 ml of 1.86 N hydrochloric acid (0.72 m
ol) is added dropwise at 25 ° C. over 1 hour, and after completion of the addition, 2
The mixture was stirred at 5 ° C for 30 minutes. The resulting reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and sodium borohydride 5.68 g was added.
(0.15 mol) was added over 30 minutes. After the addition was completed, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was neutralized with dilute hydrochloric acid, extracted 4 times with 30 ml of diisopropyl ether, the extract was washed with 30 ml of saturated brine, dried over anhydrous sodium sulfate and concentrated. Distill the residue [79
C., 60 mmHg (8.0 kPa)], and 32.5 g of cyclopropylethanol having the following physical properties
(0.38 mol, yield 63.0%) was obtained.

¹ H-NMR (270 MHz, CDCl ₃
, TMS, ppm) δ: 3.78-3.62 (2H,
m), 1.75-1.56 (1H, m), 1.53-
1.38 (2H, m), 0.80-0.60 (1H,
m), 0.50-0.33 (2H, m), 0.13-
0.03 (2H, m)

[0041]

INDUSTRIAL APPLICABILITY According to the present invention, cyclopropylethanol can be produced inexpensively and industrially advantageously.

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Claims (3)

[Claims] 1. A cyclopropylacetaldehyde is obtained by subjecting 3-cyclopropyl-2,3-epoxypropionic acid ester to solvolysis and treating the product with an acid to reduce the obtained cyclopropylacetaldehyde. A method for producing cyclopropylethanol, which is characterized. 2. A method for producing cyclopropylethanol, which comprises reducing cyclopropylacetaldehyde. 3. A process for producing cyclopropylacetaldehyde, which comprises subjecting 3-cyclopropyl-2,3-epoxypropionic acid ester to solvolysis and subjecting the product to acid treatment.