JP3357147B2 - Method for producing 5-phenylpentanoic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 5-phenylpentanoic acid using 3-phenylpropanal, which can be easily obtained industrially, as a starting material. 5-Phenylpentanoic acid is a compound useful as a raw material for cardiovascular drugs such as cholesterol absorption inhibitors and other synthetic intermediates.

[0002]

2. Description of the Related Art Conventionally, the following method has been known as a method for synthesizing 5-phenylpentanoic acid.

Reaction of benzene with 5-valerolactone using anhydrous aluminum chloride as a catalyst (CS 1803)
77 (15 Aug 1979)).

Reaction of benzene with ω-chloropentanoic acid using a Friedel-Craft catalyst (Iz
v. Akad. Nauk SSSR, Ser. Khi
m. , (2), 367-71 (1987)).

[0005] Lithium-copper chloride complex catalyst presence, a method of reacting a 2-phenylethyl Grignard reagent with 3-Bed Romopuropion magnesium chloride salt (Tetrahedron Lett., (51) , 4
697 (1976)).

[0006] In the presence of a Friedel-Craft catalyst, benzene is reacted with glutaric anhydride,
emmensen reduction method (J. Org. Che)
m. , 38 , 1445 (1973 ) ).

[0007] However, in order to produce 5-phenylpentanoic acid on an industrial scale, the above-mentioned conventional method has many problems to be solved. For example, in the reactions (1) and (2), it is necessary to use an equimolar or more catalyst. Therefore, wastewater treatment for collecting these is required. In the above method, 4-phenyl-4-methylbutanoic acid is produced as a by-product at a rate of 3 to 8%, and the removal method is also complicated (CS 216872 B (31 Oct 19).
84)). Uses an extremely expensive lithium-copper chloride complex catalyst and uses a large amount of magnesium, and thus cannot be said to be an industrially inexpensive synthesis method. Although the yield is high, it is necessary to use harmful reagents such as zinc amalgam in Clemmensen reduction.

[0008]

An object of the present invention is to produce 5-phenylpentanoic acid, which is expected to be effectively used in the field of medicine and the like, in an industrially inexpensive manner without using harmful reagents. The aim is to provide a way to do so.

[0009]

SUMMARY OF THE INVENTION According to the present invention, the above-mentioned object is achieved by the condensation reaction of 3-phenylpropanal with malonic acid and 5-phenyl-2-pentenoic acid and / or 5-phenyl-2-pentenoic acid.
It has been found that this can be achieved by preparing phenyl-3-pentenoic acid and then subjecting the 5-phenyl-2-pentenoic acid and / or 5-phenyl-3-pentenoic acid to a hydrogenation reaction.

Conventionally, it has been known that an unsaturated carboxylic acid having two carbons extended from an aldehyde can be obtained by a condensation reaction of an aldehyde and malonic acid (generally, Doebner).
Called the reaction). However, it is reported that the synthesis of 5-phenylpentanoic acid utilizes the condensation reaction of 3-phenylpropanal and malonic acid, and that this reaction can be a very effective industrial method for producing 5-phenylpentanoic acid. There is no. Incidentally, Katsura skins aldehyde with malonic acid to condensation reaction, followed by the synthesis of 5-phenyl pentanoic acid reduction with Raney nickel is known, this method has been reported to frequently purification gives hard oil (J. Org. Chem., 38 , 1445 (197)
3)). From such findings, it was completely unexpected that high-purity 5-phenylpentanoic acid can be efficiently produced by using 3-phenylpropanal, which is a hydrogenated product of cinnamaldehyde.

In the condensation reaction of 3-phenylpropanal and malonic acid according to the method of the present invention, a base is usually used as a catalyst. Examples of the base include organic amines such as pyridine, picoline, piperidine, trimethylamine, triethylamine, tripropylamine, and tributylamine. These can be used alone or as a mixture. The base is usually used in an amount of 0.1 mol times or more based on 3-phenylpropanal. There is no problem even if a large amount of the base is used, for example, as a reaction solvent, but it is practical to use the base within a range of 4 mol times or less from an economic viewpoint.

A solvent is not necessarily required for this condensation reaction, but a solvent can be used as long as 3-phenylpropanal or malonic acid is dissolved and the condensation reaction is not hindered. Specific examples of the solvent include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene; and ethers such as tetrahydrofuran, tetrahydropyran, 4-methyltetrahydropyran, dioxane, ethyl ether, and ethylene glycol dimethyl ether.

[0013] The condensation reaction is usually carried out in a temperature range from room temperature to 150 ° C. Although the condensation reaction can be carried out in a temperature range higher than this, a decrease in the selectivity of the reaction is generally recognized.

Although the reaction time varies depending on the reaction conditions, when 3 equivalents of pyridine are used as a base and the condensation reaction is carried out at 115 ° C., the reaction is completed within 4 hours.

The condensation reaction is carried out by the above-mentioned method. The consumption of malonic acid or 3-phenylpropanal, which is the end point of the reaction, can be confirmed by thin layer chromatography or gas chromatography.

After confirming the completion of the condensation reaction, the reaction can be stopped, for example, by pouring the reaction solution into water.
Next, the target substance is converted into a water-soluble compound with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and then oily impurities are separated and removed with an extractant such as ethyl ether, isopropyl ether, toluene and hexane. Then, the pH of the system is adjusted to 2 or less with a mineral acid such as hydrochloric acid or sulfuric acid in an aqueous alkaline solution, and the released 5-phenyl-2-pentenoic acid and / or 5-phenyl-3-pentenoic acid are converted into methylene chloride, ethyl ether , Isopropyl ether and the like. The extractant is distilled off from the extract to isolate 5-phenyl-2-pentenoic acid and / or 5-phenyl-3-pentenoic acid. This can be highly purified by means such as column chromatography or recrystallization. In the method of the present invention, 5-phenyl-2-pentenoic acid and / or 5-phenyl-3-pentenoic acid isolated by the above method may be used for the next reaction without purification. it can.

Then, 5-phenylpentanoic acid is produced by subjecting 5-phenyl-2-pentenoic acid and / or 5-phenyl-3-pentenoic acid to a hydrogenation reaction. As the hydrogenation reaction, catalytic hydrogenation of hydrogen using a catalyst is generally industrially advantageous. Examples of usable catalysts include palladium carbon, Raney nickel, and other catalysts usually used in hydrogenation reactions. The catalyst is usually used in an amount of 0.01% by weight or more based on 5-phenyl-2-pentenoic acid and / or 5-phenyl-3-pentenoic acid. From an economic point of view, it is practical to use the catalyst in the range of 0.1% to 2% by weight.

In the hydrogenation reaction, 5-phenyl-
An organic solvent is preferably used for dissolving 2-pentenoic acid and / or 5-phenyl-3-pentenoic acid. As an organic solvent, it is necessary to dissolve 5-phenyl-2-pentenoic acid and / or 5-phenyl-3-pentenoic acid and not to inhibit the hydrogenation reaction. Specific examples thereof include aliphatic esters such as ethyl acetate and butyl acetate; aliphatic alcohols such as methanol and ethanol; and tetrahydrofuran. These organic solvents may be used alone or in combination.

The hydrogenation reaction is generally carried out in a temperature range from room temperature to 100 ° C. Note that the catalytic hydrogenation reaction can be carried out in a temperature range higher than this, but there is a general tendency to decrease the selectivity of the reaction.

The pressure of hydrogen is higher than normal pressure, especially 2 to 10
It is practical to perform the reaction in the range of the atmospheric pressure from the viewpoint of the reaction rate or the economical viewpoint.

The end point of the hydrogenation reaction is determined by means of gas chromatography or the like using 5-phenyl-2-pentenoic acid and / or 5-phenyl-2-pentenoic acid.
Alternatively, it can be followed by confirming the consumption of 5-phenyl-3-pentenoic acid.

After confirming the end point of the hydrogenation reaction, the catalyst is separated by filtration and the filtrate is distilled off under normal pressure or reduced pressure to isolate 5-phenylpentanoic acid.

The 5-phenylpentanoic acid thus isolated can be highly purified by means such as distillation under reduced pressure or recrystallization.

The 3-phenylpropanal used as a reaction raw material in the present invention can be easily produced by an oxo reaction of styrene or the like (Japanese Patent Laid-Open No. 64-293).
No. 35, Bull. Chem. Soc. Jpn. ,
43 , 2192 (1970); Mol. Cat
l. , 4 , 401 (1978); Mol. Cat
l. , 13 , 323 (1981), etc.).

[0025]

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

Example 1 218 g (1.62 mol) of 3-phenylpropanal and 130 g of malonic acid were placed in a 1-liter three-necked flask.
(1.25 mol), pin lysine 274g (3.22mo
l), take 8.7 g (0.09 mol) of piperidine,
Stir vigorously at room temperature. Next, the internal temperature was raised from room temperature to 70 ° C. over 1 hour. After stirring at 70 ° C. for 1 hour, the internal temperature was increased to about 115 ° C., and the mixture was further stirred for 3 hours. After confirming the disappearance of 3-phenylpropanal by gas chromatography and the disappearance of malonic acid by thin layer chromatography, the reaction mixture was cooled to 5%
-Pour into 1.2 liters of aqueous sodium hydroxide solution and add
Extract with 5 liters of isopropyl ether. After adding 480 g of concentrated hydrochloric acid to the alkaline aqueous layer to adjust the pH to 1 or less, the mixture was extracted with 1.5 liter of isopropyl ether. The isopropyl ether layer was concentrated under reduced pressure to obtain crude 5-phenyl-2-pentenoic acid and 5-phenyl-2-pentenoic acid.
About 200 g of a mixture of phenyl-3-pentenoic acid was obtained.
The ratio of 5-phenyl-2-pentenoic acid to 5-phenyl-3-pentenoic acid was about 2 to 1 by NMR analysis. The resulting mixture of crude 5-phenyl-2-pentenoic acid and 5-phenyl-3-pentenoic acid was used as a raw material for a catalytic hydrogenation reaction without purification.

The crude 5-phenyl-2-pentenoic acid synthesized by the above condensation reaction in a 300 ml autoclave and 5
40 g of a mixture of phenyl-3-pentenoic acid (227 m
mol), 2 g of Pd / C, 80 ml of ethyl acetate, and 80 ml of ethanol. The inside of the system was replaced with nitrogen, and then hydrogen (8 kg / cm ² ) was introduced. Heated to 45 ° C. and stirred for 2 hours. After confirming the disappearance of the mixture of the crude 5-phenyl-2-pentenoic acid and 5-phenyl-3-pentenoic acid by gas chromatography, the reaction mixture was cooled, and Pd / C was filtered using celite. The filtrate was concentrated under reduced pressure to obtain 40 g of crude 5-phenylpentanoic acid. The crude 5-phenylpentanoic acid was distilled under reduced pressure (boiling point: 1 mmHg, 119 ° C) to give a purity of 9
18 g of 9.7% 5-phenylpentanoic acid (102 mm
ol). The reaction yield is 45% based on malonic acid.
Met.

¹ H-NMR (5-phenylpentanoic acid;
_{CDCl 3, ppm) 7.28-7.35 (2H} , m) 7.20-7.24
(3H, m) 2.67 (2H, t, J = 7.0 Hz)
2.42 (2H, t, J = 5.9 Hz) 1.70-1.
75 (4H, m)

Example 2 3.1 g (22 mmol) of 3-phenylpropanal and 2.9 g (28 m) of malonic acid were placed in a 50 ml three-necked flask.
mol), it took a pin lysine 3ml (36mmol).
The internal temperature was raised to about 115 ° C., and the mixture was stirred for 4 hours. 3-
After confirming disappearance of phenylpropanal by gas chromatography, the reaction mixture was cooled, poured into 10 ml of a 5% aqueous sodium hydroxide solution, and extracted with 10 ml of isopropyl ether. The pH of the alkaline aqueous layer was adjusted to 1 or less by adding concentrated hydrochloric acid, followed by extraction with 20 ml of isopropyl ether. The isopropyl ether layer was concentrated under reduced pressure to obtain about 2.5 g of a mixture of crude 5-phenyl-2-pentenoic acid and 5-phenyl-3-pentenoic acid. The crude yield was 65%. The obtained mixture of crude 5-phenyl-2-pentenoic acid and 5-phenyl-3-pentenoic acid was used as a raw material for a catalytic hydrogenation reaction without purification. When a catalytic hydrogenation reaction was performed under the same conditions as in Example 1, 1.9 g (11 mmol) of 5-phenylpentanoic acid was obtained. The reaction yield was 40% based on malonic acid.

Example 3 3.1 g (22 mmol) of 3-phenylpropanal and 1.8 g (17 m) of malonic acid were placed in a 50 ml three-necked flask.
mol), 4.7 ml of triethylamine (34 mmol)
l) was taken. The internal temperature was raised to about 88 ° C., and the mixture was stirred for 3 hours. After confirming the disappearance of 3-phenylpropanal by gas chromatography, the reaction mixture was cooled and poured into 10 ml of a 5% aqueous sodium hydroxide solution, and 10 m
Extracted with 1 isopropyl ether. After adding concentrated hydrochloric acid to this alkaline aqueous layer to adjust the pH to 1 or less, 20 ml
Extracted with isopropyl ether. The isopropyl ether layer was concentrated under reduced pressure to obtain about 3 g of a mixture of crude 5-phenyl-2-pentenoic acid and 5-phenyl-3-pentenoic acid. The crude yield was 99%. The crude 5-phenyl-2-pentenoic acid obtained here and 5-
The mixture of phenyl-3-pentenoic acid was used as a raw material for a catalytic hydrogenation reaction without purification. When a catalytic hydrogenation reaction was carried out under the same conditions as in Example 1, 1.4 g (7.7 mmol) of 5-phenylpentanoic acid was obtained. The reaction yield was 45% based on malonic acid.

Example 4 3.1 g (22 mmol) of 3-phenylpropanal and 1.8 g (17 m) of malonic acid were placed in a 50 ml three-necked flask.
mol) and 0.8 ml (8.5 mmol) of piperidine and 5 ml of toluene. Raise the internal temperature to about 80 ° C,
Stir for 2 hours. After confirming the disappearance of 3-phenylpropanal by gas chromatography, the reaction mixture was cooled, poured into 10 ml of a 5% aqueous sodium hydroxide solution, and extracted with 20 ml of isopropyl ether. The pH of the alkaline aqueous layer was adjusted to 1 or less by adding concentrated hydrochloric acid, followed by extraction with 20 ml of isopropyl ether. The isopropyl ether layer is concentrated under reduced pressure to give crude 5-phenyl-2-pentenoic acid and 5-phenyl-
About 1.6 g of a mixture of 3-pentenoic acid was obtained. Crude yield 52
%Met. The obtained mixture of crude 5-phenyl-2-pentenoic acid and 5-phenyl-3-pentenoic acid was used as a raw material for a catalytic hydrogenation reaction without purification. When a catalytic hydrogenation reaction was carried out under the same conditions as in Example 1, 0.7 g (3.8 mmol) of 5-phenylpentanoic acid was obtained.
1) was obtained. The reaction yield was 23% based on malonic acid.
Met.

[0032]

According to the present invention, 3-phenylpropanal and malonic acid, which are easily available on an industrial scale, are useful as raw materials for circulatory drugs such as cholesterol absorption inhibitors and other synthetic intermediates. -Phenylpentanoic acid can be produced at low cost without using harmful reagents.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-55-104227 (JP, A) JP-A-62-281840 (JP, A) JP-A-4-108763 (JP, A) JP-A-2- 59541 (JP, A) JP-A-60-139646 (JP, A) JP-A-47-42713 (JP, A) JP-A-60-41628 (JP, A) JP-A-64-79136 (JP, A) JP-B44-25055 (JP, B1) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 57/30 C07C 51/36

Claims (1)

(57) [Claims] 1. A method for producing 5-phenyl-2-pentenoic acid and / or 5-phenyl-2-pentenoic acid by a condensation reaction between 3-phenylpropanal and malonic acid.
Or 5-phenyl-3-pentenoic acid, and then subjecting the 5-phenyl-2-pentenoic acid to a hydrogenation reaction to produce 5-phenylpentane Method for producing acid.