JPH05331106A - Production of phenylacetic acid derivative - Google Patents

Abstract

PURPOSE:To readily obtain a phenylacetic acid derivative which is an important synthetic intermediate for fine chemicals including medicines and agricultural chemicals in high yield without using an expensive (methylsulfinyl) (methylthio) methane (FAMSO) and producing toxic mercaptan derivatives. CONSTITUTION:A compound of formula I (R<1> and R<2> are H, lower alkyl, lower alkoxy, aryl, substituted aryl, halogen or R<1> and R<2> together may form alkylenedioxy ring) is made to react with prussic acid in a molar amount of preferably about 1-10 times, especially about 1-2 times based on the substrate to provide a compound of formula II, which is then hydrolyzed with an acid such as a mineral acid or an organic acid, preferably concentrated hydrochloric acid to afford a compound of formula III (R<3> is H or lower alkyl). The OH at the alpha-position of the resultant compound is further acetylated with an acetylating reagent such as acetic anhydride, glacial acetic acid or acetyl chloride and the obtained compound is then subjected to hydrogenolysis using a solid catalyst such as Pd/C, Pt/C, Ru/C or Pd/Al2O3, preferably 5% Pd/C to industrially and advantageously provide the objective compound of formula IV.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for selectively producing a phenylacetic acid derivative which is an important synthetic intermediate for fine chemicals such as pharmaceuticals and agricultural chemicals. Particularly, 2,3-methylenedioxyphenylacetic acid advantageously obtained according to the present invention is an inhibitor of acylcoenzyme A cholesterol acyltransferase (ACAT). 1
It is a useful intermediate of a -phenylalkyl-3-phenylurea derivative (Japanese Patent Application No. 3-2821).

[0002]

2. Description of the Related Art Conventionally, as a method for producing a phenylacetic acid derivative by subjecting an arylaldehyde derivative to a carbon-charging reaction, the arylaldehyde derivative has FAMSO (Formaldehyde).
dimethyl acetyl s-o
xide) is known to act. (Bul
l. Chem. Soc. Jpn. , 52 (7) 201
3.1979 and Tetrahedron. Lette
rs. , (15), 1383, 1972). However, this method is: 1) FAMSO is expensive, and its production amount is small, and it is difficult to apply it to a large-scale synthetic reaction. 2) In the course of the reaction, harmful mercaptan derivatives are produced, and a large-scale operation and equipment for detoxification treatment are required. 3) Although the reaction is expressed in one step, it is a method that actually goes through two steps and the operation is complicated. 4) The obtained phenylacetic acid derivative contains a small amount of mercaptan derivative and has a problem of bad odor, and therefore requires considerable purification. However, it is industrially disadvantageous.

[0003]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have made cyanuric acid act on an aryl aldehyde derivative and subsequently hydrolyzed it to give an α-hydroxycarboxylic acid derivative, which is used as it is. , Or α
It was found that a phenylacetic acid derivative can be easily obtained in a high yield without producing a harmful mercaptan derivative by carrying out hydrogenolysis after acetylating the hydroxyl group at the position, and completed the present invention.

That is, the gist of the present invention is the following general formula (I):
The arylaldehyde derivative represented by the formula (1) is treated with cyanic acid to obtain a mandelonitrile derivative represented by the following general formula (II), and the obtained mandelonitrile derivative is hydrolyzed and represented by the following general formula (III). And a method of producing a phenylacetic acid derivative represented by the following general formula (IV), characterized in that the α-hydroxycarboxylic acid derivative is hydrolyzed.

[0005]

[Chemical 3]

(In the general formulas (I) to (IV), R ¹ and R ² each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, an aryl group, a substituted aryl group or a halogen atom, and R ³ represents hydrogen. Represents an atom or a lower alkyl group, wherein R ¹ and R ² may combine to form an alkylenedioxy ring), and hydrocyanic acid acts on the arylaldehyde derivative represented by the above general formula (I). To obtain a mandelonitrile derivative represented by the general formula (II), and the obtained mandelonitrile derivative is hydrolyzed to obtain an α-hydroxycarboxylic acid derivative represented by the general formula (III). A phenylacetic acid derivative represented by the above general formula (IV), characterized in that the α-hydroxyl group of the α-hydroxycarboxylic acid derivative is acetylated and then hydrolyzed. Exists in the manufacturing method.

The present invention will be described in more detail below. The aryl aldehyde derivative used in the present invention is represented by the following general formula (I).

[0008]

[Chemical 4]

(R ¹ and R ² are as defined above.)
Prussic acid is allowed to act on the aryl aldehyde derivative represented by the general formula (I) to obtain a mandelonitrile derivative, followed by hydrolysis reaction, and an α-hydroxycarboxylic acid derivative represented by the following general formula (III). To get

[0010]

[Chemical 5]

(R ¹ , R ² and R ³ are as defined above.) The amount of hydrocyanic acid used in the reaction for obtaining the mandelonitrile derivative is preferably about 1 to 10 times, more preferably 1 to 10 times, the molar amount of the substrate. It is about twice the molar amount. The reaction temperature is selected so that the reaction proceeds rapidly, but is preferably 0 to 100 ° C, more preferably 10 to 30 ° C. The reaction solvent is not particularly limited as long as it is inert to the reaction, but it is preferable to use a polar solvent such as water or alcohol such as methanol. The pH of the reaction system is not particularly limited, but it is desirable to adjust it to pH 7 to 8 in order to accelerate the reaction. The acid used in the reaction of hydrolyzing the α-hydroxycarboxylic acid derivative represented by the general formula (III) from the mandelonitrile derivative is a mineral acid,
Organic acids and the like are not particularly limited, but concentrated hydrochloric acid is preferable. The reaction temperature is selected so that the reaction proceeds well, but is 20 to
150 degreeC is preferable and 80-100 degreeC is more preferable.
The reaction solvent is not particularly limited as long as it is inert to the reaction, but water is preferably used.

The α-hydroxycarboxylic acid derivative represented by the general formula (III) is subjected to a hydrogenolysis reaction to obtain a phenylacetic acid derivative represented by the following general formula (IV). A solid catalyst such as Pd / C, Pt / C, Ru / C, or Pd / Al ₂ O ₃ is used as the catalyst used to accelerate the hydrocracking reaction, and preferably 5% Pd / C is used. Is good. The reaction conditions are appropriately selected so that the reaction proceeds rapidly, but the amount of the solid catalyst used is 0.01 to 20.0 mol% with respect to the substrate, preferably 1 to 10
Mol%. The hydrogen pressure of the reaction system is normal pressure to 10 kg / cm
² , preferably a low pressure of normal pressure to 5 kg / cm ² . The reaction temperature is preferably room temperature to 100 ° C. The reaction solvent is not particularly limited as long as it is inert to the reaction, but ethanol, acetic acid or the like is preferably used.

[0013]

[Chemical 6]

(R ¹ , R ² and R ³ are as defined above.) When the α-hydroxy group is acetylated before the α-hydroxycarboxylic acid represented by the general formula (III) is hydrolyzed. Examples of the acetylating reagent used include acetic anhydride, glacial acetic acid, acetyl chloride and the like. The reaction temperature is preferably 20 to 150 ° C. In the above general formulas (I) to (IV), the lower alkyl group represented by R ¹ and R ² , the lower alkoxy group and the lower alkyl group represented by R ³ are preferably those having 1 to 8 carbon atoms.

[0015]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded. <Example 1> 2.7 g (40 mm) of (cyanohydrinated) potassium cyanide
ol) was dissolved in 4.4 ml of H ₂ O, and 2.3 ml (40 mmol) of acetic acid was added dropwise under ice cooling. 3.0 g of 2,3-methylenedioxybenzaldehyde (20 mmo
1), a mixed solution of methanol and H ₂ O (1: 1) 3.
4 ml was added, and 0.009 g (0.2
1 mmol) was added, and the aqueous solution of hydrocyanic acid prepared above was added dropwise at room temperature and reacted for 4 hours. After the reaction is complete, add 1
The pH was adjusted to 3 with NHCl, extracted with ethyl acetate, washed with saturated brine, dried and concentrated to give 3.52 g of crude 2,3-methylenedioxymandelonitrile (crude yield: -100%).
Got

(Hydrolysis) 1.19 g (6.7 mmol) of crude 2,3-methylenedioxymandelonitrile was added to 8.5 ml of diethyl ether and 2.0 ml of ethanol (3
4 mmol) was added and dissolved, and at room temperature, HCl gas was blown in until it reached a supersaturated state, and the reaction was performed for 30 minutes as it was. After the reaction was completed, about 12 ml of H ₂ O was added and the mixture was stirred for about 10 minutes. Extract with ethyl acetate, wash with water, dry and concentrate,
Crude ethyl 2,3-methylenedioxymandelate 1.35
g (crude yield: 90%) was obtained.

(Acetylation reaction) Crude ethyl 2,3-methylenedioxymandelate 1.35 g (6.0 mmol)
Was dissolved in 6.8 ml of pyridine, and 1.4 ml of acetic anhydride was added.
(24 mmol) was added and reacted at room temperature for 2.5 hours. After confirming the disappearance of the raw materials, water was added to the reaction solution and the mixture was extracted with ethyl acetate, washed with water, dried and concentrated to give crude 2-acetoxy-2- (2 ', 3'-methylenedioxyphenyl) ethyl acetate. 1.60 g (crude yield: -100%) was obtained.

(Hydrogenolysis) Crude 2-acetoxy-2-
(2 ', 3'-methylenedioxyphenyl) was dissolved ethyl acetate 1.60g of (6.0 mmol) in ethanol 16 ml, the reaction system by adding 5% Pd-C1.3g H ₂
After that, the hydrogenation reaction was carried out at room temperature and atmospheric pressure. After 1 hour, when H ₂ absorption stopped, the catalyst was filtered off and the solvent was concentrated to obtain 1.25 g of crude ethyl 2,3-methylenedioxyphenylacetate (crude yield: -100%).

<Example 2> The same procedure as in Example 1 was carried out except that the reaction after hydrolysis was carried out as follows. (Hydrolysis) 12 ml of concentrated hydrochloric acid was added to 1.19 g (6.7 mmol) of crude 2,3-methylenedioxymandelonitrile.
₁₂ ml of H ₂ O was added and reacted at 100 ° C. for 1 hour. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, washed with water, dried and concentrated to give crude 2,3-methylenedioxymandelic acid light brown crystals.
22 g (crude yield: 93%) was obtained.

(Acetylation reaction) 1.22 g (6.2 mmol) of crude 2,3-methylenedioxymandelic acid was added to 6.1 ml of pyridine and 1.22 ml of acetic anhydride (1.2 mmo).
1) was added, and the mixture was reacted at room temperature for 2.5 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate, washed with water, dried and concentrated to give the desired crude 2-acetoxy-2- (2 ', 3'-
1.48 g of methylenedioxyphenyl) acetic acid (crude yield:
~ 100%).

(Hydrolysis) Crude 2-acetoxy-2-
(2 ', 3'-Methylenedioxyphenyl) acetic acid 1.4
8 g (6.2 mmol) was dissolved in 15 ml of ethanol, 1.3 g of 5% Pd-C and 0.62 of triethylamine.
g (6.2 mmol) was added to replace the reaction system with H ₂ .
The hydrogenation reaction was carried out at room temperature and atmospheric pressure. After 7 hours, when the H ₂ absorption stopped, the catalyst was filtered off and the solvent was concentrated to give crude 2,3-methylenedioxyphenylacetic acid 1.01 g (crude yield: 90
%) Was obtained.

<Example 3> The same procedure as in Example 2 was repeated except that the acetylation reaction was omitted after the acid hydrolysis and the hydrogenation reaction was performed as follows. (Hydrolysis) 0.2 g (1.0 mmol) of crude 2,3-methylenedioxymandelic acid was dissolved in 2 ml of acetic acid,
The reaction system was replaced with H ₂ by adding 0.22 g of 5% Pd-C, and the hydrogenation reaction was carried out at 100 ° C. and normal pressure. After 2.5 hours, after the H ₂ absorption stopped, the catalyst was filtered off, and the solvent was concentrated and analyzed. As a result, the starting material, 2,3-methylenedioxymandelic acid, remained considerably, and the desired product, 2,3 -The yield of methylenedioxyphenylacetic acid was 13%.

[0023]

The manufacturing method of the present invention makes the FAM expensive.
A phenylacetic acid derivative can be easily obtained in a high yield without using SO and without producing a harmful mercaptan derivative.

Claims (2)

[Claims] 1. A cyanide is allowed to act on an aryl aldehyde derivative represented by the following general formula (I),
The mandelonitrile derivative represented by I) is obtained, and the obtained mandelonitrile derivative is hydrolyzed to obtain an α-hydroxycarboxylic acid derivative represented by the following general formula (III). A method for producing a phenylacetic acid derivative represented by the following general formula (IV), which comprises hydrolyzing an acid derivative. [Chemical 1] (In the general formulas (I) to (IV), R ¹ and R ² each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, an aryl group, a substituted aryl group or a halogen atom,
R ³ represents a hydrogen atom or a lower alkyl group. In addition, R ¹
And R ² may together form an alkylenedioxy ring. ) 2. The following general formula (III): (In the general formula (III), R ¹ and R ² each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, an aryl group, a substituted aryl group or a halogen atom, and R ³ represents a hydrogen atom or a lower alkyl group. Note that R ¹ and R ²
May together form an alkylenedioxy ring. ) Α of an α-hydroxycarboxylic acid derivative represented by
The method according to claim 1, wherein the hydroxyl group at the position is acetylated and then hydrolyzed.