JPH01222078A - Production of alpha-aryl acetic acids - Google Patents

Abstract

PURPOSE:To safely and efficiently obtain the alpha-aryl acetic acids expressed by specific formula by subjecting the ketone deriv. expressed by specific formula to electrode oxidation in the presence of iodine or iodine compd. and acetal forming reagent. CONSTITUTION:The ketone deriv. expressed by general formula I is subjected to the electrode oxidation in the presence of the iodine or the iodine compd. and the acetal forming reagent by adding a supporting electrolyte at need thereto. The compd. expressed by above-mentioned formula is exemplified by for example, the compd. expressed by formula I'. The alpha-aryl acetic acids expressed by formula II, for example, the alpha-isopropylphenylmethyl acetate expressed by formula II' are obtd. by the above-mentioned electrode reaction. The alpha-aryl acetic acids expressed by formula II are useful as the raw material for drugs having an antipyretic effect and anti-inflammatory and analgesic effects and synthetic pyrethroid insecticides. The above-mentioned acetal forming reagent is exemplified by, for example, orthomethyl acetic acid, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing α-arylacetic acids useful as raw materials for pharmaceuticals and synthetic pyrethroid insecticides having antipyretic and anti-inflammatory and analgesic effects.

BACKGROUND ART Conventionally, as a method for producing α-alkylaryl acetic acid derivatives, a method in which an arylacetic acid ester and an alkylating agent are reacted in the presence of a strong base is generally known [for example, J.
, Org, Chew,, 28°3108 (19
63)). However, this method is difficult to handle because (1) the strong base used is expensive or highly dangerous, and (2) the selectivity for the desired alkylation is not high enough, resulting in purification of the product. It has drawbacks such as requiring a large amount of energy.

On the other hand, the general formula [wherein Ar represents an aryl group, a heterocyclic group, or a fused heterocyclic group, and these may have a substituent.

The substituents include 01-C6 linear or branched alkyl groups, 03-C6 alicyclic groups, 02-C6 linear or branched unsaturated hydrocarbon groups, aryl groups, Heterocyclic group, aralkyl group, /%rogen, alkoxy group, aryloxy group, acyl group, acyloxy group, carboxyl group, alkoxycarbonyl group, nitro group, cyano group, sulfonic acid group, protected hydroxyl group, protected amino group, a protected sulfonic acid group, or a protected thiol group, and the number of the substituents is 1 to 3, and these may be the same or different. R1 and R2 are the same or different, and represent a hydrogen atom, a linear or branched alkyl group, an alicyclic group, a linear or branched unsaturated hydrocarbon group, an aryl group, or an aralkyl group. show. ] From the ketone derivative represented by the general formula [where Ar, R3 and R4 have the same meanings as Ar5R' and R2, and R5 represents a hydrogen atom or a lower alkyl group. ] As a method for producing α-arylacetic acids represented by 3
taurim compound (JP-A No. 51-23249,
Publication No. 52-105149) and tetravalent lead compounds (S
Synthesis, 456 (1982), Japanese Patent Application Publication No. 1987
-163337) and trivalent aromatic iodine compounds (JP-A-59-163345) or iodine (JP-A-62-2) in the presence of orthocarboxylic acid esters.
38233) as an oxidizing agent is known. However, the former method requires a stoichiometric amount or more of a highly toxic heavy metal salt, which poses a major problem in terms of pollution control, and is difficult to implement on an industrial scale. In addition, even in the latter method using iodine compounds or iodine, these oxidizing agents have weak activity, so it is necessary to use more than an equivalent amount (approximately double the amount), and only a limited range of compounds can be actually used. The reaction does not proceed. Moreover, the selectivity and yield are not necessarily satisfactory.

Problems to be Solved by the Invention An object of the present invention is to provide a safe and efficient method for producing α-arylacetic acids without the drawbacks of the conventional methods described above.

Means for Solving the Problems The present inventor has developed the general formula (I
) As a result of intensive studies on an efficient method for synthesizing α-esteryl acetic acids represented by general formula (II) from ketone derivatives represented by The present inventors have discovered that this compound has high activity and selectivity, and have completed the present invention.

That is, the present invention is directed to the general formula [wherein Ar5R' and R2 are the same as above. A general method characterized by electrode oxidizing a ketone derivative represented by ] in the presence of a metal or iodine compound and an acetalizing reagent in an organic solvent or a water-containing organic solvent, with the addition of a supporting electrolyte if necessary. Formula % Formula % () [In the formula, A r s R3, R' and R5 are the same as above.

] This relates to a method for producing α-arylacetic acids represented by the following.

According to the method of generating iodine active species by the electrode oxidation method of the present invention, the required amount of iodine or an iodine compound is sufficient to be less than an equivalent amount. Furthermore, the range of applicable compounds is wide, and the yield and selectivity are also very satisfactory.

In the present invention, Ar represents an aryl group, a heterocyclic group, or a fused heterocyclic group, which may have a substituent. The aryl group represents a phenyl group or a polynuclear aromatic hydrocarbon group, and specific examples of the polynuclear aromatic hydrocarbon group include α-naphthyl, β-naphthyl, anthranyl, and pyrenyl groups.

A heterocyclic group or a fused heterocyclic group refers to a cyclic aromatic group containing oxygen, nitrogen, sulfur atoms, etc., such as furyl, pyrrolyl, pyridyl, oxasilyl, thienyl, thiadiazolyl, thiazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl, carbazolyl. , benzocarbazolyl, quinoxalinyl, quinazolinyl, benzoxasilyl, benzothiazolyl, indolyl, intridinyl group, and the like.

Substituents for these aryl groups, heterocyclic groups, and fused heterocyclic groups include 01-C6 linear or branched alkyl groups, 03-C6 alicyclic groups, and C2-C6 linear or branched alkyl groups. Branched unsaturated hydrocarbon group, aryl group, heterocyclic group, aralkyl group, halogen, alkoxy group, aryloxy group, acyl group, acyloxy group, carboxyl group,
an alkoxycarbonyl group, a nitro group, a cyano group, a sulfonic acid group, a protected hydroxyl group, a protected amino group, a protected sulfonic acid group or a protected thiol group,
The number of the substituents is 1 to 5, and these may be the same or different. The linear or branched alkyl group of c1 to C is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, amyl,
Examples include isoamyl and hexyl groups. Examples of the 03-C6 alicyclic group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of the C2-C6 straight-chain or branched unsaturated hydrocarbon group include vinyl, ethynyl, propenyl, propynyl, butenyl, butynyl, pentenyl, pentagenyl, pentynyl, hexenyl, hexynyl, and the like.

Examples of the aryl group and heterocyclic group include the groups exemplified in the definition of Ar above. Aralkyl groups include benzyl, phenethyl, diphenylmethyl,
Examples include triphenylmethyl and naphthylmethyl groups. Halogens are fluorine, chlorine, bromine, and iodine. Examples of the alkoxy group include lower alkoxy groups such as methoxy, ethoxy, propoxy, impropoxy, and butoxy groups. Examples of the aryloxy group include phenoxy, tolyloxy, naphthyloxy, anthranyloxy, and pyrenyloxy groups. Examples of the acyl group include formyl, acetyl, propionyl, benzoyl, toluoyl, and furoyl groups; examples of the acyloxy group include formyloxy, acetyloxy,
Examples include propionyloxy, benzoyloxy, toluoyloxy, and furoyloxy groups. As the alkoxycarbonyl group, lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl groups,
Examples include phenoxycarbonyl, benzyloxycarbonyl, and phenethyloxycarbonyl groups. Protected hydroxyl groups include acyl groups such as formyl, acetyl, propionyl, benzoyl, toluoyl, and furoyl groups, cyclic ether groups such as tetrahydrofuranyl and tetrahydropyranyl groups, and lower alkoxymethyl groups such as methoxymethyl and ethoxymethyl groups. Examples include groups. Protected amino groups include lower alkyl groups such as methyl, ethyl, propyl, isopropyl and amyl groups, aralkyl groups such as benzyl, phenethyl and phenylpropyl groups, formyl, acetyl, propionyl, benzoyl, toluoyl and furoyl groups. Examples include acyl groups such as Examples of protecting groups for protected sulfonic acid groups and protected thiol groups include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and acyl groups, and aralkyl groups such as phenyl, benzyl, and phenethyl groups. can do.

R1 and R2 are the same or different and represent a hydrogen atom, a straight or branched alkyl group, an alicyclic group, a straight or branched unsaturated hydrocarbon group, an aryl group or an aralkyl group. represents a group, and may form a ring with a carbon chain or a carbon chain containing a heteroatom.

Specific examples of straight chain or branched alkyl groups include:
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, decyl groups, etc. can be shown. Examples of the alicyclic group include cyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, cyclohexyl, and 4-isopropylcyclohexyl groups. Examples of linear or branched unsaturated hydrocarbon groups include vinyl, ethynyl, propenyl, propynyl, butenyl, butynyl, pentenyl, pentagenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptenyl, decenyl,
Examples include prenyl and geranyl groups. Examples of the aryl group include phenyl, naphthyl, anthranyl, and pyrenyl groups, and examples of the aralkyl group include benzyl, phenethyl, and phenylpropyl groups. These groups may also have at least one substituent, including halogens such as fluorine, chlorine, bromine, and iodine, lower alkoxy groups such as methoxy, ethoxy, and propoxy, acyl groups such as formyl and acetyl groups, and formyl groups. Examples include acyloxy groups such as oxy and acetyloxy groups, amino groups such as amino, methylamino, dimethylamino and diethylamino groups, and cyano groups.

In carrying out the present invention, the ketone derivative represented by the above general formula (I) is electrolytically oxidized in the presence of iodine or an iodine compound and an acetalizing reagent. The iodine compound used is
A wide variety of conventionally known products can be used, including alkyl metal iodides such as sodium iodide and potassium iodide, hypoiodites such as sodium hypoiodite and potassium hypoiodite, sodium iodate, and potassium iodate. iodates such as sodium periodate, inorganic iodine compounds such as periodates such as potassium periodate, methyl iodide, ethyl iodide, isopropyl iodide, iodobenzene, benzyl iodide, triphenyl iodide Organic iodine compounds such as methyl, acetyl iodide, benzoyl iodide, short methane, triiodomethane, organic silicon iodides such as trimethylsilyl iodide, trivalent iodine compounds such as ammonium iodide, iodobenzene dichloride, iodobenzene diacetate, etc. These can be used singly or in combination of two or more. The amount of iodine or iodine compound to be used may be at least 0.01 times the mole of compound (I), but preferably 0.01 times the amount of iodine or iodine compound used in order to allow the reaction to proceed more efficiently and selectively. 1~
It is used in a range of 0.25 times the mole.

Examples of acetalization reagents include lower alkyl ortho-lower carboxylic acid esters such as methyl orthoformate, ethyl orthoformate, propyl orthoformate, methyl orthoacetate, ethyl orthoacetate, propyl orthoacetate, methyl orthopropionate, and ethyl orthopropionate, and dimethyl acetone. Lower dialkyl acetals of ketones such as acetal, acetone diethyl acetal, methyl ethyl ketone dimethyl acetal, methyl ethyl ketone diethyl acetal,
Lower dialkyl esters of carbonic acid such as dimethyl carbonate and diethyl carbonate, lithium methoxide, sodium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, barium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide,
Alkali metal or alkaline earth metal alkoxides such as magnesium ethoxide, calcium ethoxide, barium ethoxide, lithium propoxide, sodium propoxide, potassium propoxide, magnesium propoxide, calcium propoxide, barium propoxide, trimethyl phosphate, Examples include lower alkyl phosphates such as triethyl phosphate and tripropyl phosphate, lower alkyl phosphites such as trimethyl phosphite, triethyl phosphite, and tributyl phosphite, and these may be used alone or in combination of two or more. used as The amount of the acetalization reagent used is usually 1 to 10 times the mole of compound (I), preferably 2 to 10 times the mole.
It is 8 times the mole.

The electrode reaction of the present invention can be carried out by adding a solvent and a supporting electrolyte, if necessary. Examples of solvents include chain or cyclic ethers such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, and lower acetate esters such as methyl acetate, ethyl acetate, and butyl acetate. , dimethylformamide, dimethylacetamide, and other amide compounds can be used.

As the supporting electrolyte, a wide range of substances that are used in ordinary electrode reactions can be used as long as they do not adversely affect the reaction. Specifically, perchlorates such as lithium perchlorate and potassium perchlorate, paratoluene, etc. Quaternary ammonium salts such as tetraethylammonium sulfonate, tetramethylammonium paratoluenesulfonate, tetraethylammonium perchlorate, tetraethylammonium borofluoride, and tetraethylammonium iodide, alkali metals or alkalis of benzenesulfonic acid and toluenesulfonic acid. Examples include salts of earth metals. There is no problem with these supporting electrolytes as long as they are used in an amount that allows electricity to flow efficiently;
It is preferably used in a range of 0.1 to 5 times the mole.

The electrode materials used in this electrode reaction include carbon, platinum,
Common electrode materials such as stainless steel, nickel, titanium, iron, copper, lead dioxide, lead, etc. can be widely used.

This electrode reaction does not require special potential control (
Constant current electrolysis or constant voltage electrolysis may be used. For example, in the case of constant current electrolysis, the current density is 5 to 500 mA/cJ, preferably 10 to 200 mA/cJ.

Theoretically, the amount of electricity may be 1 mol of 2F per starting compound (I), but in order to increase the reaction yield, 1 mol of 2-30F,
Preferably, current can be applied in a range of 2.5 to 10 F per mole.

The present invention can also be carried out while switching the polarity of the anode and cathode, which may provide more desirable results. The equipment used for electrolysis is not particularly limited, and ordinary equipment can be used effectively. The reaction temperature during the electrode reaction is not particularly limited, but preferably the reaction is carried out within a temperature range of 0°C to 50°C.

After the above reaction is completed, for example, a basic sodium thiosulfate aqueous solution is added to the reaction solution, extracted with a solvent, and the extract is concentrated under reduced pressure to obtain almost a single α-arylacetic acid represented by the general formula (n). be able to. If further purification is necessary, methods such as distillation, recrystallization, or column chromatography may be used.

Effects of the Invention The present inventors have discovered that iodine active species generated by electrode oxidation during the production of α-arylacetic acids by oxidative rearrangement reaction of arylalkyl ketones have high activity and selectivity. As a result, the amount of iodine or iodine compound used can be reduced, and a wider range of compounds can be produced compared to conventional techniques, and the yield and selectivity can also be satisfied.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 Compound (I) 648n+g (4.0 mmol), iodine 254 ng (1 mmol), lithium perchlorate trihydrate 300 mg and Add 3 mQ of methyl orthoformate and heat under constant current conditions (50 mA/
A current of 1 mol of 8F was applied to the cT sensor. After the reaction, the reaction solution was poured into a liquid-based aqueous sodium thiosulfate solution (10 mQ) and extracted with methylene chloride (60 mO). After washing the extract with water, it was concentrated under reduced pressure, and the residue was distilled using a small-volume distillation device to obtain α-
714+ng of methyl isopropylphenyl acetate (2)
Obtained.

Yield 93%, boiling point 110°C/4mmHgIR, 2970
,1740,1460,1440°1295.1210
, 1160, 1130°700 Cm' NMR (COOm) δ: 0.70 (d, 6Hz, 6H).

1.02 (d, 6Hz, 3H).

2.70 (m, IH).

3.10 (d, 10Hz, IH).

3.63 (s, 3H).

7.73 (m, 5H) Examples 2 to 15 The reaction and post-treatment were carried out in the same manner as in Example 1, except that the starting materials (4 mmol) were replaced with those shown in Table 1, and electrolysis was performed with various amounts of electricity. . The yield of the obtained methyl α-alkylaryl acetate is also shown in Table 1.

Ar -C-CHR' R2(I) ↓ Ar CC02CH3(II) Examples 16 to 34 Using various starting materials (4 mmol) shown in Table 2, 0.4 g (2.8 mmol) of methyl iodide was substituted for iodine. The reaction and post-treatment were carried out in the same manner as in Example 1, except that . The amount of current applied and the yield of the obtained methyl α-alkylaryl acetate are also shown in Table 2.

Example 35 Using 536 mg (4 mmol) of compound (3) as a starting material, 284 mg (2 mmol) of methyl iodide was added in place of iodine.
l) The reaction and post-treatment were carried out in the same manner as in Example 1 except that 597 mg of methyl α-methylphenylacetate (4) was obtained.

Yield 91%. Boiling point 100℃/12 mmHgIR; 3
040, 2990, 2970, 1740°1500.1
460.1420,1335゜1250.1210.1
170,1070°700 cm-' NMR (CC9a) δ: 1.40 (d, 7Hz, 3H).

3.57 (s, 3H).

3.59 (q, 7Hz, IH).

7, 17 (m, 5H) Examples 36-45 Various iodine compounds were used in place of methyl iodide as shown in Table 3. The yield of the obtained (4) is also shown in the same table.

Table 3 Example 46 The reaction and post-treatment were carried out in the same manner as in Example 27 except that two carbon plate electrodes (2 cJ) were used instead of the platinum electrode to obtain 591 mg of the target product (4). Yield 90%.

Example 47 Using 536 mg (4 mmol) of compound (3) as a starting material, iodine was reduced to 57 mg (0.4 mmol) and methyl orthoformate was reduced to 1.3 g (12 mmol).

Furthermore, the reaction and post-treatment were performed in the same manner as in Example 1 except that the amount of electricity was reduced to 1 mole of 3F, and as a result, 551 mg of the target product (4) was obtained. Yield 84%.

Example 48 Compound (5) 936a+g (4,0a
The preparation was carried out in the same manner as in Example 1, except that +mol) was used, and the polarity of the anode and cathode was changed every 7 seconds under constant current conditions (50 mA/cd) at 12F.
1 mol of current was applied. The reaction crude product was taken out in the same manner as in Example 1, and purified by silica gel column chromatography (benzene/ethyl acetate - 10/1) to obtain 908IIIg of compound (6) as a pale yellow oil. Yield 86%.

IR, 2990, 1745, 1515, 1490°12
85.1210.1165.1115cm'' NMR (CCQt) δ: 1.31 (s, 9H).

1.45 (d, 7Hz, 3H).

3.56 (s, 3H).

3.50-3.70 (m, IH).

6.87 (d, 8Hz, 2H).

7.20 (d, 8Hz, 2H) (that's all)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, Ar represents an aryl group, a heterocyclic group, or a fused heterocyclic group, and these have a substituent. Also good. The substituents include C_1 to C_6 linear or branched alkyl groups, C_3 to C_6 alicyclic groups, C_2 to C_6 linear or branched unsaturated hydrocarbon groups, aryl groups,
Heterocyclic group, aralkyl group, halogen, alkoxy group, aryloxy group, acyl group, acyloxy group, carboxyl group, alkoxycarbonyl group, nitro group, cyano group, sulfonic acid group, protected hydroxyl group, protected amino group, It is a protected sulfonic acid group or a protected thiol group, and the number of substituents is 1 to 5, and these may be the same or different. R^1 and R^2 are the same or different, and are a hydrogen atom, a linear or branched alkyl group, an alicyclic group, a linear or branched unsaturated hydrocarbon group, an aryl group, or Indicates an aralkyl group. ] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, Ar, R＾3 and R^4 have the same meanings as the above Ar, R^1 and R^2, and R^5 represents a hydrogen atom or a lower alkyl group. ] A method for producing α-arylacetic acids represented by: