JP2003306471A - Method for producing 2-cyclopropylethylamine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing 2- cyclopropylethylamine. <P>SOLUTION: The method for producing the 2-cyclopropylethylamine comprises solvolyzing an ester of 3-cyclopropyloxiranecarboxylic acid in the presence of a base, treating the product with an acid to provide cyclopropylacetaldehyde, reacting the obtained cyclopropylacetaldehyde with hydroxylamine or a salt thereof to provide cyclopropaneacetaldehyde oxime, and reducing the obtained cyclopropaneacetaldehyde oxime. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 2-cyclopropylethylamine. The 2-cyclopropylethylamine obtained by the present invention is useful as a synthetic intermediate for various pharmaceuticals (US Pat. No. 5,866,657).
No. 3, specification, WO97 / 40024, etc.).

[0002]

2. Description of the Related Art Conventionally, as a method of producing 2-cyclopropylethylamine, a method of treating 4-phthalimido-1-butene with diazomethane using palladium acetate and treating the obtained 2-phthalimidoethylcyclopropane with hydrazine. Are known (US Pat. No. 5,866,565).
73 specification).

[0003]

The above-mentioned conventional method uses explosive diazomethane and is not an industrially advantageous method for producing 2-cyclopropylethylamine.

An object of the present invention is to provide a method for producing 2-cyclopropylethylamine industrially advantageously.

[0005]

The present invention is a method for producing 2-cyclopropylethylamine, which comprises reducing cyclopropylacetaldehyde oxime.

Further, according to the present invention, 3-cyclopropyloxiranecarboxylic acid ester is subjected to solvolysis in the presence of a base, and the product is treated with an acid to obtain cyclopropylacetaldehyde. A method for producing 2-cyclopropylethylamine, which comprises reacting with hydroxylamine or a salt thereof to obtain cyclopropylacetaldehyde oxime, and reducing the obtained cyclopropylacetaldehyde oxime.

Further, according to the present invention, cyclopropylacetaldehyde oxime was obtained by subjecting 3-cyclopropyloxiranecarboxylic acid ester to solvolysis in the presence of a base, and reacting the product with a hydroxylamine salt to obtain cyclopropylacetaldehyde oxime. A method for producing 2-cyclopropylethylamine, which comprises reducing cyclopropylacetaldehyde oxime.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The step (A) of obtaining cyclopropylacetaldehyde by subjecting 3-cyclopropyloxiranecarboxylic acid ester to solvolysis in the presence of a base and subjecting the product to acid treatment will be described.

The 3-cyclopropyloxiranecarboxylic acid ester is not particularly limited as long as its ester group can undergo solvolysis, and examples thereof include methyl ester, ethyl ester, propyl ester, isopropyl ester and n-butyl. Examples thereof include esters, isobutyl esters, pentyl esters, hexyl esters and the like.

Examples of the solvent include water; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; ethers such as diisopropyl ether, tetrahydrofuran and dioxane. The amount of the solvent used is not particularly limited, but is 1 to 3 cyclopropyl oxirane carboxylic acid ester.
It is preferably in the range of 100 times by weight, more preferably in the range of 1 to 10 times by weight.

Examples of the base include sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide and lithium hydroxide; Alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; Alkali hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate Salt or the like is used. The amount of base used is 3
-It is preferably in the range of 0.5 to 10 mol per 1 mol of cyclopropyl oxirane carboxylic acid ester,
It is more preferably in the range of 0.5 to 1.5 mol.

Cyclopropylacetaldehyde is obtained by adding an acid to the system containing the product obtained by solvolysis. Examples of the acid include inorganic acids such as hydrochloric acid, 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; acidic ion exchange resins. The amount of acid used is 3
-It is preferably in the range of 1 to 10 mol with respect to 1 mol of cyclopropyl oxirane carboxylic acid ester, and 1 to
It is more preferably in the range of 1.5 mol.

The temperature of the solvolysis reaction is -20 to 150.
It is preferably in the range of 0 ° C, more preferably in the range of 0 to 70 ° C. The time for the solvolysis reaction varies depending on the types and amounts of the base and solvent used, but is usually preferably in the range of 10 minutes to 24 hours. The acid treatment temperature is preferably in the range of -20 to 100 ° C, and 0 to
More preferably, it is in the range of 50 ° C. The time required for the acid treatment varies depending on the types and amounts of the acid and solvent used, but is preferably in the range of usually 10 minutes to 24 hours.

In the above reaction, for example, 3-cyclopropyl oxirane carboxylic acid ester, a base and a solvent are mixed and stirred under reduced pressure or normal pressure at a predetermined temperature, and then,
It is carried out by adding an acid to the reaction system.

The reaction mixture containing cyclopropylacetaldehyde thus obtained may be used as it is for the next reaction with hydroxylamine or a salt thereof.
It is also possible to isolate and purify cyclopropylacetaldehyde from the reaction mixture and use it in the next reaction. Isolation and purification of cyclopropylacetaldehyde from the reaction mixture can be carried out by a method generally used for isolation and 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.

Next, the step (B) of obtaining cyclopropylacetaldehyde oxime by reacting cyclopropylacetaldehyde with hydroxylamine or a salt thereof will be described.

As the salt of hydroxylamine, commercially available products can be used. Examples of the hydroxylamine salt include hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine phosphate and the like.
Free hydroxylamine is readily prepared by treating the salt of hydroxylamine with a base. Therefore, when using a salt of hydroxylamine, the reaction is carried out in the presence of a base. As the base, any one can be used as long as it can convert a salt of hydroxylamine into free hydroxylamine, for example, lithium hydroxide,
Examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Among these, it is preferable to use sodium hydroxide or sodium carbonate. The amount of the base used is preferably in the range of 1 to 5 mol, and more preferably in the range of 1 to 1.5 mol, based on 1 mol of the salt of hydroxylamine. The amount of hydroxylamine or its salt used is not particularly limited, but it is preferably in the range of 0.5 to 2 mol per 1 mol of cyclopropylacetaldehyde.

The reaction is preferably carried out in the presence of a solvent.
As the solvent, for example, water; alcohols such as methanol and ethanol are used. Of these, it is preferable to use water. The amount of the solvent used is not particularly limited, but is preferably an amount that does not impair the operability and volume efficiency of the reaction, and is preferably in the range of 1 to 10 times the weight of cyclopropylacetaldehyde.

The above reaction is carried out, for example, by adding cyclopropylacetaldehyde to a reaction vessel equipped with a stirrer in which hydroxylamine or a salt thereof, a solvent and, if desired, a base are previously charged.

The reaction temperature is preferably in the range of about 0 to 100 ° C, more preferably 10 to 60 ° C. Also, the reaction time depends on the reaction conditions,
It is preferably in the range of 0.5 to 10 hours.

Isolation and purification of the cyclopropylacetaldehyde oxime thus obtained from the reaction mixture can be carried out by a method generally used for isolation and 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,
It can be purified by distillation, silica gel column chromatography and the like. Further, the extract can be directly used for the next reduction reaction.

Next, the step (C) for obtaining cyclopropylacetaldehyde oxime by subjecting 3-cyclopropyloxiranecarboxylic acid ester to solvolysis and reacting the product with a hydroxylamine salt will be described.

The solvolysis reaction of 3-cyclopropyloxiranecarboxylic acid ester can be carried out in the same manner as the solvolysis reaction in step (A).

The reaction between the product obtained by solvolysis and the hydroxylamine salt is carried out in the presence of a base. Any base can be used as long as it can convert a salt of hydroxylamine into free hydroxylamine, and examples thereof include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium carbonate. , Carbonates of alkali metals such as sodium carbonate and potassium carbonate. Among these, it is preferable to use sodium hydroxide or sodium carbonate. The amount of the base used is 1 to 1 mol of the salt of hydroxylamine.
It is preferably in the range of 5 mol, more preferably in the range of 1 to 1.5 mol. The amount of the salt of hydroxylamine used is not particularly limited, but is preferably in the range of 0.5 to 2 mol per 1 mol of 3-cyclopropyloxiranecarboxylic acid ester.

The reaction is preferably carried out in the presence of a solvent.
As the solvent, for example, water; alcohols such as methanol and ethanol are used. Of these, it is preferable to use water. The amount of the solvent used is not particularly limited, but it is desirable to use an amount that does not impair the operability and volumetric efficiency of the reaction, and is in the range of 1 to 10 times the weight of 3-cyclopropyloxiranecarboxylic acid ester. Is preferred.

The reaction temperature is preferably in the range of about 0 to 100 ° C, more preferably 10 to 60 ° C. Also, the reaction time depends on the reaction conditions,
It is preferably in the range of 0.5 to 10 hours.

In the above reaction, for example, 3-cyclopropyloxiranecarboxylic acid ester, a base and, if necessary, a solvent are mixed and stirred under reduced pressure or atmospheric pressure at a predetermined temperature, and then hydroxylamine is added to the reaction system. This is done by adding salt or an aqueous solution thereof.

The isolation / purification of the cyclopropylacetaldehyde oxime thus obtained from the reaction mixture can be carried out by a method generally used for the 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,
It can be purified by distillation, silica gel column chromatography and the like. Further, the extract can be directly used for the next reduction reaction.

Next, the step (D) of obtaining 2-cyclopropylethylamine by reducing cyclopropylacetaldehyde oxime will be described.

The reduction method is not particularly limited as long as it is a method of reducing an oxime to obtain an amine. The reduction reaction of cyclopropylacetaldehyde oxime can be carried out by hydrogenation under the presence of a catalyst such as Raney nickel, Raney cobalt, platinum oxide, activated carbon-supported platinum, activated carbon-supported palladium under normal pressure or pressure. The amount of the catalyst used is preferably in the range of 1 to 50% by weight, more preferably 5 to 25% by weight, based on the cyclopropylacetaldehyde oxime.
Hydrogen pressure is 0 kg / cm ² (normal pressure) to 20 kg / cm ^2.
The range is preferably.

The reaction is preferably carried out in the presence of a solvent. As the solvent, for example, methanol, ethanol,
It is preferable to use alcohols such as isopropanol; ethers such as diisopropyl ether and dioxane; aromatic hydrocarbons such as toluene, xylene and mesitylene; esters such as ethyl acetate and butyl acetate.
Although the amount of the solvent used is not particularly limited, it is preferably in the range of 1 to 100 times by weight, more preferably 5 to 20 times by weight of the cyclopropylacetaldehyde oxime.

The reaction temperature is preferably in the range of 0 to 150 ° C, more preferably 25 to 100 ° C. The reaction time varies depending on the type and amount of the catalyst and solvent used, the hydrogen pressure, the reaction temperature, etc., but is 10 minutes to 2 minutes.
It is preferably in the range of 4 hours.

The reaction is carried out, for example, by mixing cyclopropylacetaldehyde oxime, a catalyst and a solvent and stirring at a predetermined temperature and a predetermined hydrogen pressure.

As another reduction method, a method of reducing cyclopropylacetaldehyde oxime using a metal hydride such as lithium aluminum hydride can be adopted. The amount of lithium aluminum hydride used is preferably in the range of 0.25 to 5 times mol, and more preferably in the range of 0.5 to 2 times mol, of the cyclopropylacetaldehyde oxime.

The reaction is preferably carried out in the presence of a solvent. As the solvent, it is preferable to use ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether and dioxane. Although the amount of the solvent used is not particularly limited, it is preferably in the range of 1 to 100 times by weight, more preferably 5 to 20 times by weight of the cyclopropylacetaldehyde oxime.

The reaction temperature is preferably 25 ° C. to the reflux temperature of each solvent. The reaction time varies depending on the type and amount of the lithium aluminum hydride and the solvent used, the reaction temperature, etc., but is preferably in the range of 10 minutes to 24 hours.

The reaction is carried out, for example, by mixing cyclopropylacetaldehyde oxime, lithium aluminum hydride and a solvent and stirring at a predetermined temperature.

The 2-cyclopropylethylamine 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 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 the liquid is concentrated, it is purified by distillation, silica gel column chromatography or the like. It is also possible to purify by distilling the reaction mixture as it is.

The 3-cyclopropyl oxirane carboxylic acid ester used in the present invention can be prepared, for example, by reacting cyclopropanecarbaldehyde with an α-haloacetic acid ester in the presence of a base (Japanese Patent Laid-Open No. Hei 11). -228859 gazette).

[0040]

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-cyclopropyloxiranecarboxylate 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 and cyclopropanecarbaldehyde were added. 21 g (0.30 mol) was 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 to obtain 29.8 g (0.21 mol, yield 70.0%) of methyl 3-cyclopropyloxiranecarboxylate having the following physical properties as a fraction at 70 to 73 ° C. (6 mmHg). .

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 (2H, m), 0.
46-0.41 (2H, m)

Example 1 Synthesis of cyclopropylacetaldehyde Internal volume of 200 ml equipped with condenser, thermometer and stirrer
In a three-necked flask containing 5N sodium hydroxide solution 4
8 ml (0.24 mol) was added, 28.4 g (0.2 mol) of methyl 3-cyclopropyloxiranecarboxylate obtained in the same manner as in Reference Example 1 was added dropwise at 25 ° C. over 2 hours, and after completion of the addition, The mixture was stirred at 25 ° C for 1 hour. Then, 48 ml (0.24 mol) of 1.86 N hydrochloric acid was added to 2
Drip at 5 ° C over 1 hour, and after dropping is complete, add 30 ° C at 25 ° C.
Stir for minutes. The obtained reaction mixture was extracted 3 times with 50 ml of diethyl ether, and the extract was saturated with 50 ml of brine.
After washing with ml, the extract was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel 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 cyclopropylacetaldehyde oxime 4.1 g of hydroxylamine sulfate was placed in a three-necked flask having an internal volume of 50 ml equipped with a condenser, a thermometer and a stirrer.
(25.0 mmol) and 50 g of water were added, followed by neutralization with 2.0 g (50.0 mmol) of sodium hydroxide. After stirring at room temperature for 30 minutes, 4.2 g (5%) of cyclopropylacetaldehyde obtained in the same manner as in Example 1.
0.0 mmol) was added over 15 minutes, and after the addition was completed,
The mixture was stirred at 25 ° C for 2 hours. The obtained reaction mixture was extracted 3 times with 15 ml of isopropyl ether, the extract was washed with 15 ml of saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel chromatography and 4.7 g (47.5 mmo) of cyclopropylacetaldehyde oxime having the following physical properties.
1, yield 95%) was obtained.

¹ H-NMR (270 MHz, CDCl ₃
, TMS, ppm) δ: 7.80-6.90 (1H,
m), 7.20-6.60 (1H, m), 2.20-
1.75 (2H, m), 0.80-0.60 (1H,
m), 0.50-0.33 (2H, m), 0.13-
0.03 (2H, m)

Example 3 Synthesis of cyclopropylacetaldehyde oxime Internal volume of 200 ml equipped with condenser, thermometer and stirrer
In a three-necked flask containing 5N sodium hydroxide solution 4
8 ml (0.24 mol) was added, 28.4 g (0.2 mol) of methyl 3-cyclopropyloxiranecarboxylate obtained in the same manner as in Reference Example 1 was added dropwise at 25 ° C. over 2 hours, and after completion of the addition, The mixture was stirred at 25 ° C for 1 hour. Next, 18 g of hydroxylamine sulfate (0.11 mo
l) was added at 25 ° C. over 30 minutes, and after the addition was completed, 25
The mixture was stirred at 0 ° C for 2 hours. The obtained reaction mixture was extracted 3 times with 50 ml of isopropyl 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 chromatography to obtain 13.9 g (0.14 mol, yield 70.3%) of cyclopropylacetaldehyde oxime having the following physical properties.

¹ H-NMR (270 MHz, CDCl ₃
, TMS, ppm) δ: 7.80-6.90 (1H,
m), 7.20-6.60 (1H, m), 2.20-
1.75 (2H, m), 0.80-0.60 (1H,
m), 0.50-0.33 (2H, m), 0.13-
0.03 (2H, m)

Example 4 Synthesis of 2-cyclopropylethylamine 500 ml internal volume equipped with a condenser, thermometer and stirrer
In a three-necked flask containing No. 35 g of cyclopropylacetaldehyde oxime obtained in the same manner as in Example 2 (0.3 g
53 mol) and 300 ml of methanol as a solvent, and then Raney Nickel (manufactured by Degussa, BLM)
112W) 5g, and heated to 60 ℃, under normal pressure of hydrogen 7
Stir for hours. After cooling the reaction solution to room temperature, Raney nickel was filtered under nitrogen, and 205 g of the filtrate was analyzed by the internal standard method to give 2-cyclopropylethylamine 24.5.
It was confirmed that g (0.288 mol, reaction yield 81.5%) was obtained. After removing methanol from the filtrate and concentrating it, the concentrate was azeotropically dehydrated with hexane, and the residue was purified by distillation (105 ° C., 760 mmHg), and 22.3 g of 2-cyclopropylethyl having the following physical properties.
(0.263 mol, yield 74.6%) was obtained.

¹ H-NMR (270 MHz, CDCl ₃
, TMS, ppm) δ: 2.74-2.69 (2H,
t, J = 6.92 Hz), 1.70-1.50 (2H,
m), 1.32-1.25 (2H, q, J = 6.92H
z), 0.64-0.57 (1H, m), 0.40-
0.34 (2H, m), 0.06-0.00 (2H,
m)

Example 5 Synthesis of 2-cyclopropylethylamine 200 ml internal volume equipped with a condenser, thermometer and stirrer
To a three-necked flask containing 0.5 g (13.2 mmol) of lithium aluminum hydride and 50 ml of diisopropyl ether, 0.374 g (3.78 mmol) of cyclopropylacetaldehyde oxime obtained in the same manner as in Example 2 was added under stirring. The solution obtained by dissolving in 25 ml of diisopropyl ether was added dropwise, and after completion of the addition, the mixture was stirred under reflux conditions for 5 hours. After cooling the reaction solution to room temperature, 25 g of a 10% hydrochloric acid aqueous solution was added to the reaction solution while paying attention to heat generation and foaming. After stirring at room temperature for 30 minutes, the mixture was made strongly alkaline with sodium hydroxide, the organic layer was separated, and the aqueous layer was extracted 3 times with 10 ml of diisopropyl ether. The organic layer and the extract were combined, dried over sodium sulfate, filtered, and 82 g of the filtrate was analyzed by the internal standard method to give 0.276 g of 2-cyclopropylethylamine.
It was confirmed that (3.25 mmol, reaction yield 85.9%) was obtained.

[0052]

INDUSTRIAL APPLICABILITY According to the present invention, 2-cyclopropylethylamine can be industrially advantageously produced.

Claims (3)

[Claims] 1. A method for producing 2-cyclopropylethylamine, which comprises reducing cyclopropylacetaldehyde oxime. 2. A cyclopropylacetaldehyde is obtained by subjecting 3-cyclopropyloxiranecarboxylic acid ester to solvolysis in the presence of a base, and subjecting the product to acid treatment to obtain cyclopropylacetaldehyde. A method for producing 2-cyclopropylethylamine, which comprises reacting with a salt to obtain cyclopropylacetaldehyde oxime, and reducing the obtained cyclopropylacetaldehyde oxime. 3. A cyclopropylacetaldehyde oxime is obtained by subjecting 3-cyclopropyloxiranecarboxylic acid ester to solvolysis in the presence of a base, and reacting the product with a hydroxylamine salt to obtain cyclopropylacetaldehyde oxime. A method for producing 2-cyclopropylethylamine, which comprises reducing