JPS60218332A - Production of acetic acid derivative - Google Patents

Abstract

PURPOSE:The rearrangement reaction of an alpha-hydroxyacetal derivative is carried out in the presence of a combination of a basic substance or amide with thionyl or sulfuryl chloride to obtain advantageously a propionic or acetic acid derivative with anti-inflammatory analgesic action. CONSTITUTION:The rearrangement reaction of a compound of formula I (Ar is substituted or unsubstituted aryl or heterocycle; R is H, alkyl; R<1>, R<2> are alkyl or incorporate to form a cyclic acetal) is carried out in the presence of (A) a basic substance such as pyridine or an amide such as dimethylformamide and (B) (i) a compound of XSOX' (X, X' are halogen, CF3), (ii) a compound of XSO2X' or (iii) sulfur dioxide and halogen to enable the industrially very advantageous production of the objective compound of formula II (R<3> is H, alkyl, substituted alkyl) from readily synthesized starting substance without tosylation process.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing acetic acid derivatives such as propionic acid derivatives having anti-inflammatory and analgesic effects.

More specifically, the general formula (1) (wherein, Ar represents a substituted or unsubstituted aryl group or a heterocyclic group, R represents hydrogen or an alkyl group, and R'
and R2 may be the same or different and represent an alkyl group, or R' and R2 may be combined to form a cyclic acetal). )■-Represented by the general formula 2) or (3) compound or ■ general formula (4) characterized by carrying out a rearrangement reaction in the presence of sulfur dioxide and halogen;
) (wherein, Ar has the same meaning as above, and R3 represents hydrogen, an alkyl group, or a substituted alkyl group).

The aryl group in Ar includes aryl having 6 to 10 carbon atoms, such as phenyl and naphthyl. Substituents for substituted aryl include alkyl having 1 to 5 carbon atoms, such as methyl, ethyl, and propyl.

Butyl, isobutyl, pentyl, etc., substituted alkyl (the alkyl moiety has the same meaning as above, and substituents include tehaphenyl, halogen, hydroxyl, amino, etc.),
Alkoxy having 1-6 carbon atoms, such as methoxy, ethoxy,
Propoxy, butoxy.

Phenoxy, halogens such as chlorine, fluorine, bromine, aryl groups such as phenyl, substituted phenyl (substituents are defined herein).

Acyl groups having 1 to 7 carbon atoms, such as acetyl, propionyl, phenylcarbonyl, and hydroxyl.

A heterocyclic group containing amino, cyclohexyl, nitro, N, 0 or S is included, and the heterocyclic group includes a 5- to 6-membered group containing oxygen, sulfur or nitrogen, or a substituent of the above-mentioned substituted aryl, and the above-mentioned aryl group. Alternatively, groups to which other heterocyclic groups are bonded are included, and the following groups (including groups included in the above definition, but shown as representative examples) are also included in Ar.

(R' represents hydrogen or a halogen atom, R5 represents a fluorine or chlorine atom, and 8c represents an acetyl group). Examples of the alkyl group in R', R'', and R include an alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, and pentyl. Examples of the substituent in the substituted alkyl group include a hydroxyl group, etc. be done.

In the following, the compounds represented by the general formulas (1,), '(2)... will be referred to as compounds (1), (2)...

Compound (4) is known as an extremely useful drug having antipyretic or antiinflammatory and analgesic effects. I:7AJ
Lr7shi7, Vol, 11. No, 7. 515 (
1975), Tokyo Technological Test News (Chemical Industry Materials) Vol.
13, No, 4. 85 (1975))
. Moreover, a part of compound (4) can also be used as a raw material for other compound (4). It also serves as a raw material for the acid part of pyrethroid compounds (insecticides).

Conventionally, various methods have been known for producing compound (4).

Among these, using compound (1) as a raw material, compound (4)
The only known method for producing compound (4) is to tosylate the hydroxyl group of compound (1) and then heat-treat it in, for example, an aqueous calcium carbonate solution. [Kamiyokora, Tetrahedron Let
ters, 22 & 43.4305 (1981).

] As a result of research into a method for obtaining compound (4) using easily synthesized compound (1) as a raw material without adding the tosylation step as described above, an industrially extremely advantageous production method was discovered. It was.

According to the present invention, a high yield can be obtained by carrying out a rearrangement reaction of compound (1) in the presence of (a) a basic substance or amide and (b) ■ compound (2) or (3) or ■ sulfur dioxide and a halogen. You can get the compound (Xun).

This reaction is a completely new rearrangement reaction at the 1 and 2 positions.

In carrying out the present invention, a basic substance, an amide compound (2) or (3), or sulfur dioxide is added to the compound (1) dissolved in an organic solvent, and if necessary, a halogen is added and reacted. A rearrangement reaction of compound (1) is carried out.

As the organic solvent used in the reaction, any solvent inert to the reaction can be used, such as benzene.

Aromatic hydrocarbons such as toluene, methylene chloride.

Examples include halogenated compounds such as chloroform.

Examples of basic substances include primary, secondary, and tertiary amines of aromatic or aliphatic amines such as pyridine, T-picoline, imidazole, triethylamine, diisopropylamine, and isopropylamine, and alkoxides such as t-buto-bovine dipotassium. and potassium acetate and sodium benzoate.

Examples include organic acid alkali metal salts or alkaline earth metal salts such as calcium benzoate. Furthermore, metal amides such as sodium amide and basic resins such as weakly basic resin wA-al (trade name: Diaion) are also used.

Examples of amides include dimethylformamide, dimethylacetamide, pyrrolidone, and N-benzylpyrrolidone.

The amount of these basic substances and amides to be used varies depending on the type thereof, but it is preferable to use at least 1 mole per mole of compound (1). Depending on the type, it can also be used as a solvent. These may be used alone or as a mixture.

Compound (2) or compound (3) includes thionyl bromide, thionyl chloride, sulfuryl chloride, trifluoromethanesulfonyl chloride ((IsO
□CFs) etc. can be used. Industrially, thionyl chloride and sulfuryl chloride are advantageously used.

As the halogen, chlorine, bromine, etc. are used, and preferably 1 to 3 times the mole of compound (1) is used.

The reaction is carried out at -100 to 150°C, preferably -60 to 100°C.
It is carried out within the range of In this temperature range, the reaction time is generally 1 minute to 20 hours. In particular, when sulfuryl chloride is used, the reaction proceeds quickly and the rearrangement reaction is completed in a short time. Furthermore, the reaction proceeds smoothly by coexisting activated carbon or the like.

The reaction product thus obtained is isolated and produced by a conventional method. For example, if a salt of a hydrohalic acid and a base is insoluble, the reaction solution is filtered to remove them.

If these salts are dissolved, post-treatment is performed as is. In the post-treatment, if necessary, the reaction solution is concentrated to remove the solvent or excess amines and amides. Water is added to the residue and the product is extracted with an organic solvent such as chloroform. Concentrate the chloroform solution, and fractionate the target substance using silica gel chromatography to obtain a high-quality compound (
4) can be obtained in high yield.

Examples are shown below.

Example 1 2.52 g of α-hydroxy-p-isobutylpropiophenone dimethyl acecule was dissolved in 20 ml of pyridine, 1.43 g of thionyl chloride was added under water cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and chloroform 2 was added to the residue.
20ml of 0mk water was added and the mixture was separated.

The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.

The oily residue was purified by silica gel chromatography (developed with n-hexane-ethyl acetate solvent) to obtain 2-
Methyl (4-isobutylphenyl)propionate 1.6
2 g was obtained. (Yield 72%) Example 2 α-hydroxy-p-isobutylpropiophenone dimethyl acetal 2.52 g, ) ethylamine 2.0'
2 g was dissolved in 50 ml of methylene chloride, 1.75 ml of sulfuryl chloride was added at -50°C, and the mixture was stirred at the same temperature for 3 hours. Then, 20 ml of saturated aqueous sodium hydrogen carbonate solution was added to decompose. The organic layer was dried over anhydrous sulfuric acid and concentrated under reduced pressure. The oily residue was purified in the same manner as in Example 1 to obtain 1.85 g of methyl 2-(4-isobutylphenyl)propionate. (Yield 84%) Example 3 2.72 g of α-hydroxy-p-phenylpropiophenone dimethyl acecool was dissolved in a mixed solvent of 25 ml of pyridine and 25 ml of methylene chloride, and 1.75 ml of sulfuryl chloride was dissolved at -50°C. The mixture was added and stirred at the same temperature for 3 hours. Thereafter, the same post-treatment as in Example 1 was performed to obtain 2.10 g of methyl 2-(4-biphenylyl)propionate.

(Yield 87.5%) Example 4 300 mg of sulfuryl chloride was added dropwise to a solution of 250 mg of α-hydroxy-p-isobutylpropiophenone dimethyl acecool and 200 μm of diisopropylamine dissolved in 4 ml of methylene chloride under ice cooling. did. 1 at the same temperature
After stirring for a period of time, quantitative analysis using gas chromatography revealed that 2-(4-inbutylphenyl)
Methyl propionate was produced at a production rate of 81%.

THF: Tetrahydrofuran EM: Methylene chloride DFA: N,N-dimethylformamide P: Pyridine tBuOK: t-Butyloxypotassium φCOON
a: The numerical values of sodium benzoate compound (2) or (3) and the base indicate the equivalent amount to compound (1), and the reaction was allowed to proceed for 3 hours.

Yield indicates the yield of the target product corresponding to the raw material.

Example 7 2.54 g of α-hydroxy-p-acetylated biophenone dimethylacecool was dissolved in a mixed solvent of 2 ml of N,N-dimethylformamide and 20 ml of toluene.
Cooled to -50°C. Next, sulfuryl chloride 1.75
Add m1 and stir at the same temperature for 3 hours. After the reaction was completed, the same post-treatment as in Example-1 was carried out to obtain methyl 2-(p-acetoxyphenyl)propionate. '78 g (80% yield) was obtained. This is IN-sodium hydroxide aqueous solution 20
The mixture was heated in +++1 at 50°C for 1 hour. Afterwards, the pH was adjusted to 3 using concentrated hydrochloric acid. This solution was mixed with 50% chloroform.
Extracted with m1. The extract was concentrated to 2-(p
1.2 g (90% yield) of -hydroxyphenyl)propionic acid were obtained.

m, p, 128.7°C (acetic acid to aqueous recrystallized product) Example 8
2.52 g of α-hydroxy-P-inbutylpropiophenone dimethylacecool and 2.4 g of pyridine are dissolved in 25 ml of methylene chloride. Activated carbon 0.25 g
After cooling to -40°C, 0.96 g of sulfur dioxide and 1.06 g of chlorine were added, and the mixture was stirred at the same temperature for 3 hours.

The reaction completed solution was washed with water with hydrogen carbonate solution, the organic layer was separated, and the organic layer was dried over anhydrous sodium sulfate.
It was concentrated under reduced pressure. The oily residue was purified by silica gel chromatography (developed with n-hexane-ethyl acetate solvent) to obtain 1.60 g of methyl 2-(4-inbutylphenyl)propionate. This was heated at 50° C. for 1 hour in 20 ml of IN-sodium hydroxide aqueous solution. The pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was extracted with 50 ml of chloroform. The extract was concentrated under reduced pressure to give 2-(P-inbutylphenyl).
1.3 g of propionic acid was obtained.

Melting point: 75-76°C (acetic acid to water-based recrystallized product) Example 9 α-Hydroxy-P-isobutylpropiophenone dimethylacecool 2.52g, ) ethylamine 1.5g
was dissolved in 25 ml of methylene chloride.

Add 0.25 g of activated carbon, cool to -50°C, add 0.96 g of sulfur oxide and 1.3 g of chlorine, and heat at the same temperature.
Stir for hours. The reaction-completed solution was washed with an aqueous sodium hydrogen carbonate solution, and the organic layer was separated.

After drying the organic layer over anhydrous sodium sulfate, the organic layer was quantitatively determined using gas chromatography, and 1.8 g of methyl 2-(4-inbutylphenyl)propionate was produced.

Gas chromatography conditions column 2% DECS on Gas chrom
(J3Q φ 1.5 m, Glass Column temperature 100℃←200℃ Inlet temperature 200℃ In addition, the concentrated dry product of the above aqueous layer was purified using N,0-bis(trimethylsilyl)acetamidohexamethylenedisilazane trimethylsilyl chloride. After performing trimethylsilylation, analysis by gas chromatography was performed under the following conditions, and 2-(4-isobutylphenyl)propionic acid was produced.4 Gas chromatography condition column 2%SE E-52on chromosorb
W3 order φ 3 m, Glas's Column temperature 165°C-260°C Inlet temperature 270°C Example 10゜α-Hydroxy-P-isobutylpropiophenone dimethyl acetal 0.25g, isopropylamine 0.1
8 g was dissolved in 6 ml of methylene chloride.

0.03 g of activated carbon was added and the mixture was cooled to -20°C. 0.1 g of sulfur dioxide and 0.11 g of chlorine were added at the same temperature.
Stir for hours. Example 8 below. Perform the same post-processing as
Methyl 2-(4-butylphenyl)propionate 0
．． 19 g was produced.

Example 11 11 g of N,N-dimethylformamide was added to 2.52 g of α-hydroxy-P-isobutypropiophenone dimethylacecool, and 18 ml of sulfur dioxide and 1.1 g of chlorine were added at -50°C. Raise the temperature to 10℃ in 2 hours,
20ml of chloroform was added. Thereafter, the same post-treatment as in Example 8 was performed, and 1.1 g of methyl 2-(4-inbutylphenyl)propionate was produced.

Example 12. 'α-Hydroxy-P-isobutylprobiophene nondimethyl acetal 0.25 g, pyridine 0.24
g was dissolved in methylene chloride. 0.25 g of activated carbon was added and cooled to -20°C. 0.96 g of sulfur dioxide and 0.29 g of bromine were added, and the mixture was stirred at 0°C for 4 hours.

Thereafter, the same post-treatment as in Example 8 was carried out, and 0.12 g of methyl 2-(4-inbutylphenyl)propionate was produced.

Example 13 2.54 g of α-hydroxy-P-acetoxypropiophenone dimethylacecool and 2.4 g of pyridine were dissolved in 20 ml of methylene chloride. 0.3 g of activated carbon was added, and after cooling to -50° C., 1 g of sulfur dioxide and 1.2 g of chlorine were added, and the mixture was stirred at the same temperature for 5 hours.

Thereafter, the same post-treatment as in Example 7 was performed to obtain 1.3 g of methyl 2-(4-a7toxyphenyl)propionate.

This was heated at 50°C in 20ml of IN-sodium hydroxide aqueous solution.
Heated for 1 hour. Adjust the pH to 3 with concentrated hydrochloric acid and add chloroform to 5
Extracted with 0ml. The extract was concentrated under reduced pressure to obtain 2-(
0.9 g of P-hydroxyphenyl)propionic acid was obtained.

Melting point: 128.5°C (acetic acid to water-based recrystallized product) Example 14 2.45g of α-hydroxy-P-phenylpropiophenone dimethyl acetal and 2.4g of pyridine were dissolved in 25n+1 methylene chloride. Added 0.3g of activated carbon.
After cooling to -40°C, 0-96 g of sulfur dioxide and 1.1 g of chlorine were added and stirred at the same temperature for 5 hours.

Thereafter, the same post-treatment as in Example 7 was performed to obtain 2.0 g of methyl 2-(P-biphenylyl)propionate.

This was mixed at 50°C in 20ml of IN aqueous sodium hydroxide solution.
heated for an hour. Adjust the pH to 3 with concentrated hydrochloric acid and add 50% chloroform.
Extracted with ml. The extract was concentrated under reduced pressure to obtain 2-(P-
1.6 g of biphenylyl propionic acid were obtained.

Melting point 146-146.5℃ (acetic acid to water-based recrystallized product) 1st
Continued page■Int, CI,' Identification code Internal reference number 491/
IJ) 2 8115-4C Procedural Amendment (V) June 1, 1980 1, Indication of Case 1981 Patent Application No. 7555. ．． No. 1, No. 2, Name of the invention Process for producing acetic acid derivatives 3, Relationship with the person making the amendment Case Patent applicant postal code 100 Address 6-1 Otemachi-chome, Chiyoda-ku, Tokyo Name (1
02), Kyowa Hakko Kogyo Co., Ltd. Specification, Scope of Claims and Detailed Description of the Invention Column Description 1, Title of Invention Process for Producing Acetic Acid Derivatives 1 Claim (1) OR' ■ (In the formula, Ar represents a substituted or unsubstituted aryl group or a heterocyclic group, R represents hydrogen or an alkyl group, and R'
and R2 may be the same or different (represent an alkyl group, or R' and R2 may be combined to form a cyclic acetal). (2) or (3) xsox' (2) The general formula (4) is characterized by carrying out a rearrangement reaction in the presence of sulfur and halogen.
) (In the formula, Ar has the same meaning as above, and R3 represents hydrogen, an alkyl group, or a substituted alkyl group) and is represented by 4-fold 11
11 Wood manufacturing methods.

3. Detailed Description of the Invention The present invention relates to a novel method for producing acetic acid derivatives such as propionic acid derivatives having anti-inflammatory and analgesic effects.

More specifically, the general formula (1) (wherein, Ar represents a substituted or unsubstituted aryl group or a heterocyclic group, R represents hydrogen or an alkyl group, and R'
and R2 may be the same or different and represent an alkyl group, or R' and R2 may be combined to form a cyclic acetal). ) ■ - Compound represented by general formula 2) or (3) XSOX' (2) or ■ General formula (4) characterized by carrying out a rearrangement reaction in the presence of sulfur dioxide and halogen.
) (wherein Ar has the same meaning as above, and R3 represents hydrogen, an alkyl group, or a substituted alkyl group).

The aryl group in Ar includes aryl having 6 to 10 carbon atoms, such as phenyl and naphthyl. Substituents for substituted aryl include alkyl having 1 to 5 carbon atoms, such as methyl, ethyl, and propyl.

Butyl, isobutyl, pentyl, etc., substituted alkyl (the alkyl moiety has the same meaning as above, examples of substituents include phenyl, halogen, hydroxyl, amino, etc. 8 and 6),
Carbon number 1-60:) T) bD +? Examples: methoxy, ethoxy, propoxy, butoxy.

Phenoxy, halogens such as chlorine, fluorine, bromine, aryl groups such as phenyl, substituted phenyl (substituents are defined herein).

Acyl groups having 1-7 carbon atoms, such as acetyl, propionyl, phenylcarbonyl, etc., acyloxy groups, such as benzoyloxy, acetyloxy, hydroxyl, amino,
A heterocyclic group containing cyclohexyl, nitro, N, 0 or S is included, and the heterocyclic group includes a 5- to 6-membered ring containing oxygen, sulfur or nitrogen, a substituent of the above-mentioned substituted aryl, the above-mentioned aryl group, or Groups to which other heterocyclic groups are bonded are included, and the following groups (including groups included in the above definition, but shown as representative examples) are also included in Ar.

(R' represents hydrogen or a halogen atom, R5 represents a fluorine or chlorine atom, and Aclt represents an acetyl group). Examples of the alkyl group in R', R", and R include an alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, and pentyl. Examples of the substituent of the substituted alkyl group include a hydroxyl group, etc. Ru.

In the following, compounds represented by general formulas (1), (2>...) are referred to as compounds (1), (2)...

Compound (4) is known as an extremely useful drug having antipyretic or anti-inflammatory and analgesic effects. [Pharmacia, Vol. 11. No, 7. 515 (197
5), Tokyo Tech Test News (Chemical Industry Materials) Vol. 13.
No, 4. '85 (1975)). Also, the compound (4
) can also be used as a raw material for other compound (4). It also serves as a raw material for the acid part of pyrethroid compounds (insecticides).

Conventionally, there are various methods for producing compound (4).

method is known.

Among these, using compound (1) as a raw material, compound (4)
The only known method for producing compound (4) is to tosylate the hydroxyl group of compound (1) and then heat-treat it in, for example, an aqueous calcium carbonate solution. [Uploaded, Tetrahedron etc.
ters, 22 No., 43. 4305 (1981
). ] Using easily synthesized compound (1) as a raw material,
The compound (
As a result of research into a method for obtaining 4), an extremely advantageous industrial manufacturing method was discovered.

According to the present invention, a high yield can be obtained by carrying out a rearrangement reaction of compound (1) in the presence of (a) a basic substance or amide and (b) ■ compound (2) or (3) or ■ sulfur dioxide and a halogen. Compound (4) can be obtained. This reaction is a completely new rearrangement reaction at the 1.2-position.When carrying out the present invention, a basic substance or an amide and a compound (2) or (3) are added to the compound (1) dissolved in an organic solvent.
Alternatively, sulfur dioxide and halogen are added and reacted to carry out a rearrangement reaction of compound (1).

As the organic solvent used in the reaction, any solvent inert to the reaction can be used, such as benzene.

Aromatic hydrocarbons such as toluene, methylene chloride.

Examples include halogenated compounds such as chloroform.

Examples of basic substances include primary, secondary, and tertiary amines of aromatic or aliphatic amines such as pyridine, T-picoline, imidazole, triethylamine, diisopropylamine, and isopropylamine, as well as alkoxides such as potassium t-butoxy. , potassium acetate, sodium benzoate.

Examples include organic acid alkali metal salts or alkaline earth metal salts such as calcium benzoate. Furthermore, metal amides such as sodium amide and basic resins such as weakly basic resin WA-31 (trade name: Diaion) are also used.

Examples of amides include dimethylformamide, dimethylacetamide, pyrrolidone, and N-benzylpyrrolidone.

The amount of these basic substances and amides to be used varies depending on the type thereof, but it is preferable to use at least 1 mole per mole of compound (1). Depending on the type, it can also be used as a solvent. These may be used alone or as a mixture.

Compound (2) or compound (3) includes thionyl bromide, thionyl chloride, sulfuryl chloride, trifluoromethanesulfonyl chloride (Cj!S
o, CF, ), etc. can be used. Industrially, thionyl chloride and sulfuryl chloride are advantageously used.

As the halogen, chlorine, bromine, etc. are used, and preferably 1 to 3 times the mole of compound (1) is used.

The reaction is carried out at -100 to 150°C, preferably -60 to 100°C.
It is carried out within the range of In this temperature range the reaction time is generally 1 minute to 20 hours. In particular, when sulfuryl chloride is used, the reaction proceeds quickly and the rearrangement reaction is completed in a short time. Furthermore, the reaction proceeds smoothly by coexisting activated carbon or the like.

The reaction product thus obtained is isolated and produced by a conventional method. For example, if a salt of a hydrohalic acid and a base is insoluble, the reaction solution is filtered to remove them. If these salts are dissolved, post-treatment is performed as is.

In the post-treatment, if necessary, the reaction solution is concentrated to remove the solvent or excess amines and amides. Add water to the residue,
The product is extracted with an organic solvent such as chloroform. Concentrate the chloroform solution and fractionate the target substance using silica gel chromatography to obtain high quality compound (4).
can be obtained in high yield.

Examples are shown below.

Example 1 2.52 g of α-hydroxy-p-isobutylpropiophenone dimethyl acetal was dissolved in 20 ml of pyridine, 1.43 g of thionyl chloride was added under water cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and chloroform 2 was added to the residue.
0 ml and 20 ml of water were added to separate the liquids.

The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.

The oily residue was purified by silica gel chromatography (developed with n-hexane-ethyl acetate solvent) to obtain 2-(
Methyl 4-isobutylphenyl)propionate 1.62
I got g. (Yield 72%) Example 2 2.52 g of α-hydroxy-p-isobutylbropiophenone dimethyl acetal, 2.0' ethylamine
2 g was dissolved in 50 ml of methylene chloride, 1.75 ml of sulfuryl chloride was added at -50°C, and the mixture was stirred at the same temperature for 3 hours. Then, 20 ml of saturated aqueous sodium hydrogen carbonate solution was added and the mixture was separated. After drying the organic layer with anhydrous sodium sulfate,
It was concentrated under reduced pressure. The oily residue was purified in the same manner as in Example 1 to obtain 1.85 g of methyl 2-(4-isobutylphenyl)propionate. (Yield: 84%) Example 3 2.72 g of α-hydroxy-p-phenylpropiophenone dimethyl acecool was dissolved in a mixed solvent of 25 ml of pyridine and 25 ml of methylene chloride, and 1.75 n+1 sulfuryl chloride was added at -50°C. The mixture was stirred at the same temperature for 3 hours. Thereafter, the same post-treatment as in Example 1 was performed to obtain 2.10 g of methyl 2-(4-biphenylyl)propionate.

(Yield 87.5%) Example 4 In a solution of 250 mg of α-hydroxy-p-isobutylpropiophenone dimethyl acetal and 200 μl of diisopropylamine dissolved in 4+1 methylene chloride,
While cooling with water, 300 μl of sulfuryl chloride was added dropwise. After stirring at the same temperature for 1 hour, quantitative analysis using gas chromatography revealed that methyl 2-(4-isobutylphenyl)propionate was produced at a production rate of 81%.

Gas chromatography conditions column 2% DEGS on Gas Chro
M-mouth 3mmφ 1.5m Glass.

Column temperature: 100→200°C Inlet temperature: 200°C In addition, the sample was trimethylsilylated using N,O-bis(trimethylsilyl)acetamide, hexamethyldisilazane, and trimethylsilyl chloride, and then subjected to gas chromatography under the following conditions. Analysis revealed that 2-(4-isobutylphenyl)propionic acid was produced. Gas chromatography conditions column 2%SE-52on Chromosol
bl! ! 3II1 mφ 3 m Glass Column temperature 165→260°C Inlet temperature 270°C Example 5 250 mg of α-hydroxy-p-isobutylpropiophenone dimethyl acecool was dissolved in 2 ml of toluene.
200 μ of potassium acetate was added. 200 mg of sulfuryl chloride was added dropwise to this 1 suspension under water cooling and treated in the same manner as in Example 4. As a result, 2-(4-isobutylphenyl)
Methyl propionate was produced at a production rate of 78%.

Example 6 THF obtained by reacting the raw materials and conditions shown in the table
: Tetrahydrofuran EM : Methylene chloride DFA : N,N-dimethylformamide P : Pyridine tBuOK : t-butyloxypotassium φCOON
a: The numerical values of sodium benzoate compound (2) or (3) and the base indicate the equivalent amount relative to compound (1), and the reactions were all carried out for 3 hours.

The conversion rate indicates the yield of the target product corresponding to the raw material.

Poststream side 7° 2.54 g of α-hydroxy-p-acetoxypropiophenone dimethyl acetal was dissolved in a mixed lysis solution of 2 ml of N,N-dimethylformamide and 20 ml of toluene.
Cooled to -50°C. Next, sulfuryl chloride 1.75
Add m1 and stir at the same temperature for 3 hours. After the reaction was completed, the same post-treatment as in Example 1 was carried out to obtain 1.78 g (80% yield) of methyl 2-(p-acetoxyphenyl)propionate. This is IN-sodium hydroxide aqueous solution 20
ml and heated at 50°C for 1 hour. Afterwards, the pH was adjusted to 3 using concentrated hydrochloric acid. Add this solution to 50 ml of chloroform.
Extracted with. The extract was concentrated under reduced pressure to obtain 1.2 g (90% yield) of 2-(p-hydroxyphenyl)propionic acid.
I got it.

m, p, 128.7°C (acetic acid to aqueous recrystallized product) Example 8
2.52 g of α-hydroxy-P-isobutylpropiophenone dimethyl acecool and 2.4 g of pyridine are dissolved in 25 ml of methylene chloride. activated carbon 0.25
g added and cooled to -40t: sulfur dioxide 0.96
g and 1.06 g of chlorine were added, and the mixture was stirred at the same temperature for 3 hours.

The reaction-completed solution was washed with an aqueous sodium bicarbonate solution, the organic layer was separated, and the organic layer was dried over anhydrous sulfuric acid and concentrated under reduced pressure. The oily residue was purified by silica gel chromatography (developed with n-hexane-ethyl acetate solvent) to obtain 1.60 g of methyl 2-(4-isobutylphenyl)propionate. This is IN-hydroxylated)
The mixture was heated at 50° C. for 1 hour in 20 ml of IJum aqueous solution. The pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was extracted with 50 ml of chloroform. The extract was concentrated under reduced pressure to obtain 1.3 g of 2-(P-inbutylphenyl)propionic acid.

Melting point: 75-76°C (acetic acid to water-based recrystallized product) Example 9 α-hydroxy-P-inbutylpropiophenone dimethyl acetal 2.52g, ) ethylamine 1.5g
was dissolved in 25 ml of methylene chloride.

0.25 g of activated carbon was added, and after cooling to -50 t, 0.96 g of sulfur dioxide and 1.3 g of chlorine were added, and the mixture was stirred at the same temperature for 3 hours. The reaction-completed solution was washed with an aqueous sodium hydrogen carbonate solution, and the organic layer was separated.

After drying the organic layer over anhydrous sodium sulfate, it was quantified using gas chromatography, and 1.8 g of methyl 2'-(4-isobutylphenyl)propionate was produced.

Gas chromatography conditions column 2% DEGS on Gas chrom
03 mmφ 1.5-m, Glass column temperature 100°C → 200°C Inlet temperature 200°C In addition, the concentrated dry product of the above aqueous layer was purified using N,0-bis(trimethylsilyl)acetamide, hexamethyldisilazane, and trimethylsilyl chloride. After trimethylsilylation, analysis by gas chromatography under the following conditions revealed that 2-(4-isobutylphenyl)propionic acid was produced.

Gas chromad condition column 2%SE -520n chromosorb
W3IIIφ 3 m, Glass column temperature 165°C-260°C Inlet temperature 270°C Example 10゜α-Hydroxy-P-isobutylpropiophenone dimethylacecool 0.25g 1 Isopropylamine 0.1
8 g was dissolved in 5 ml of methylene chloride.

0.03 g of activated carbon was added and the mixture was cooled to -20°C. 0.1 g of sulfur dioxide and 0.11 g of chlorine were added and stirred at the same temperature for 3 hours. Example 8 below. Perform the same post-processing as 2.
-Methyl (4-isobutylphenyl)propionate 0.
19 g was produced.

Example 11 11 g of N,N-dimethylformamide was added to 2.52 g of α-hydroxy-P-isobutylpropiophenone dimethylacecool, and 18 ml of sulfur dioxide was added at -50°C.
and 1.1 g of chlorine were added. The temperature was raised to 10° C. over 2 hours, and 20 ml of chloroform was added. Thereafter, the same post-treatment as in Example 8 was carried out, and 1.1 g of 2-(4-isobutylphenyl) was produced.

Example 12.

α-Hydroxy-P-isobutylpropiophenone dimethyl acetal 0.25g. 0.24 g of pyridine was dissolved in methylene chloride. Activated carbon 0. 25 g was added and cooled to -20°C. Sulfur dioxide 0, 9 6
g and bromine 0. 29 g was added and stirred at 0°C for 4 hours.

Thereafter, the same post-treatment as in Example 8 was performed, and 0.12 g of methyl 2-(i-isobutylphenyl)propionate was produced.

Example 13.

α-Hydroxy-P-7toxyp-biophenone dimethyl acetal2. 5 4 g, pyridine 2.4 g
was dissolved in 20 ml of methylene chloride. Activated carbon 0.3g
Add 1 g of sulfur dioxide and 1 chlorine after cooling to -50°C.
．． 2g was added and stirred at the same temperature for 5 hours.

Thereafter, the same post-treatment as in Example 7 was performed to obtain 1.3 g of methyl 2-(4-acetoxyphenyl)propionate.

This was added at 50°C in 20ml of IN-sodium hydroxide aqueous solution.
Heated for 1 hour. Adjust the pH to 3 with concentrated hydrochloric acid and add chloroform to 5
Extracted with 0ml. The extract was concentrated under reduced pressure to obtain 2-(
P-hydroxyphenyl)propionic acid 0. 9 g was obtained.

Melting point: 128.5°C (acetic acid to water-based recrystallized product) Example 14 2.45 g of α-hydroxy-P-phenylpropiophenone dimethyl acecool and 2.4 g of pyridine were dissolved in 25 ml of methylene chloride. Add 0.3g of activated carbon, -
After cooling to 40°C, 0.96 g of sulfur dioxide and 1 chlorine
．． 1 g was added and stirred at the same temperature for 5 hours.

Thereafter, the same post-treatment as in Example 7 was performed to obtain 2.0 g of methyl 2-(P-biphenylyl)propionate.

This was mixed at 50°C in 20ml of IN aqueous sodium hydroxide solution.
heated for an hour. Adjust the pH to 3 with concentrated hydrochloric acid and add 50% chloroform.
Extracted with m1. The extract was concentrated under reduced pressure to obtain 2-(P-
1.6 g of biphenylyl propionic acid were obtained.

Melting point: 146-146.5°C (acetic acid - water-based recrystallized product) Patent applicant (102) Representative of Kyowa Hakko Kogyo Co., Ltd. Mikio Kato Procedural amendment (voluntary) 1980 Bitsuki Taichi, Commissioner of the Patent Office Tonoreo 1. Indication of the case Patent Application No. 75551 filed in 1982 2. Name of the invention Process for producing acetic acid derivatives 3. Relationship with the case by the person making the amendment Patent applicant Zip code 100 Address 6 Otemachi-chome, Chiyoda-ku, Tokyo 1 name
(102) Kyowa Hakko Kogyo Co., Ltd. (TEL: 03
-201-7211 extension 2751) 5. Correction details

Claims (1)

[Scope of Claims] (1) (In the formula, Ar represents a substituted or unsubstituted aryl group or a heterocyclic group, R represents hydrogen or an alkyl group, and R'
and R2 may be the same or different and represent an alkyl group, or R' and R2 may be combined to form a cyclic acetal). (0) ■ - General formula 2) or (3) xsox' (2) XS to X' (3) (In the formula, x and x' may be the same or different and represent a halogen atom or a trifluoromethyl group) or ■ a compound of the general formula (4) characterized by carrying out a rearrangement reaction in the presence of sulfur dioxide and a halogen.
) A method for producing a propionic acid derivative represented by the formula % (4) (wherein Ar has the same meaning as above, and R3 represents hydrogen, an alkyl group, or a substituted alkyl group).