JPH0547526B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing acetic acid derivatives such as propionic acid derivatives that have anti-inflammatory and analgesic effects. For more details, see general formula (1) (In the formula, Ar represents a substituted or unsubstituted aryl group or a heterocyclic group, R represents hydrogen or an alkyl group, R' and R ² may be the same or different, and represent an alkyl group or R' R ² may be combined to form a cyclic acetal) A compound represented by (a) a basic substance or amide and (b) general formula (2) or (3) XSOX′ (2) XSO ₂ ' (3) (wherein X and X' are the same or different and often represent a halogen atom or a trifluoromethyl group) or a rearrangement reaction in the presence of sulfur dioxide and a halogen. General formula (4) The present invention relates to a method for producing an acetic acid derivative represented by the formula (wherein Ar and R have the same meanings as defined above, and R ³ represents hydrogen, an alkyl group, or a substituted alkyl group). The aryl group in Ar has 6 to 10 carbon atoms.
aryl such as phenyl, naphthyl, and the like. The substituent of substituted aryl has 1-carbon atoms.
5 alkyl such as methyl, ethyl, 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.), alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy , butoxy, phenoxy, halogen such as chlorine atom, fluorine atom, bromine atom, aryl group such as phenyl group, substituted phenyl group (substituents are defined herein), acyl group having 1 to 7 carbon atoms such as acetyl,
Propionyl, phenylcarbonyl, etc., carbon number 2
-7 acyloxy groups such as benzoyloxy,
Includes acyloxy groups such as acetyloxy, such as benzoyloxy, acetyloxy, hydroxyl, amino, cyclohexyl, nitro, heterocyclic groups containing N, O or S, and heterocyclic groups include 5 to 5 containing oxygen, sulfur or nitrogen. Includes a 6-membered ring or a group to which a substituent of the substituted aryl, the aryl group, or another heterocyclic group is bonded, and the following groups (there are also groups included in the above definition, but these are shown as representative examples) is also included in Ar. (R ⁴ represents hydrogen or a halogen atom, R ⁵ represents a fluorine or chlorine atom, and Ac represents an acetyl group). Examples of the alkyl group for R ¹ , R ² , and R include alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, and pentyl. A hydroxyl group etc. are illustrated as a substituent of a substituted alkyl group. 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 antiinflammatory and analgesic effects.
[Falmacia, Vol.11.No.7, 515 (1975), Tokyo Tech News (Chemical Industry Data) Vol.13, No.4, 85
(1975)]. Further, 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. [Tsuchibashi et al., Tetrahedron
Letters, 22 No.43, 4305 (1981). ] Using easily synthesized compound (1) as a raw material, the compound can be synthesized without adding the tosylation step as described above.
As a result of research into methods for obtaining (4), a method was discovered that could be produced industrially with great advantage. According to the present invention, a high yield can be obtained by rearranging 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 by This reaction is a completely new rearrangement reaction between the 1st and 2nd positions. When carrying out the present invention, basic substances or amides and compounds are added to compound (1) dissolved in an organic solvent.
(2) or (3) or 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, and examples thereof include aromatic hydrocarbons such as benzene and toluene, and halogenated compounds such as methylene chloride and chloroform. Examples of basic substances include primary, secondary, and tertiary amines of aromatic or aliphatic amines such as pyridine, γ-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
(Product name: Diaion) etc. 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, but at least 1
It is preferable to use twice the molar amount. Depending on the type, it can also be used as a solvent. These may be used alone or as a mixture. As the compound (2) or the compound (3), thionyl bromide, thionyl chloride, sulfuryl chloride, trifluoromethanesulfonyl chloride (ClSO ₂ CF ₃ ), etc. can be used.
Industrially, thionyl chloride and sulfuryl chloride are advantageously used. As the halogen, chlorine, bromine, etc. are used, preferably in an amount of 1 to 3 times the mole of compound (1). The reaction is carried out at a temperature of -100 to 150°C, preferably -60 to 100°C. In this temperature range, reaction times are 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, by coexisting activated carbon or the like, the reaction proceeds smoothly. 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.
High quality compound (4) can be obtained in high yield by concentrating the chloroform solution and fractionating the target substance using silica gel chromatography. 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 ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, 20 ml of chloroform and 20 ml of water were added to the residue, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The oily residue was subjected to silica gel chromatography (developed with n-hexane-ethyl acetate solvent).
2-(4-isobutylphenyl)
1.62 g of methyl propionate was obtained. (Yield 72%) Example 2 2.52 g of α-hydroxy-p-isobutylpropiophenone dimethyl acetal and 2.02 g of triethylamine were dissolved in 50 ml of methylene chloride, 1.75 ml of sulfuryl chloride was added at -50°C, and the Stir for hours. Then add 20% of saturated sodium bicarbonate aqueous solution.
ml was added and the liquid was separated. The organic layer was dried over anhydrous sodium sulfate and then 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 acetal 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 added at -50°C. Stirred at temperature for 3 hours. Hereinafter, the same post-processing as in Example 1 was performed, and 2
-(4-biphenylyl)methyl propionate 2.10
I got g. (Yield: 87.5%) Example 4 To a solution in which 250 mg of α-hydroxy-p-isobutylpropiophenone dimethyl acetal and 200 mg of diisopropylamine were dissolved in 4 ml of methylene chloride, 300 mg of sulfuryl chloride was added dropwise under ice cooling. After stirring at the same temperature for 1 hour, quantitative analysis using gas chromatography revealed that 2-
Methyl (4-isobutylphenyl)propionate was produced at a production rate of 81%. Gas chromatography conditions Column 2% DEGS on Gas Chrom Q 3mmφ 1.5m Glass Column temperature 100→200℃ Inlet temperature 200℃ In addition, samples were prepared using N,O-bis(trimethylsilyl)acetamide, hexamethyldisilazane, and trimethylsilyl chloride. After performing trimethylsilylation, analysis by gas chromatography under the following conditions revealed that 2-(4-isobutylphenyl)propionic acid was produced. Gas chromatography conditions Column 2% SE-52 on Chromosolb W 3mmφ 3m Glass Column temperature 165→260℃ Inlet temperature 270℃ Example 5 250mg of α-hydroxy-p-isobutylpropiophenone dimethyl acetal was dissolved in 2ml of toluene. 200 mg of potassium acetate was added. When 200 mg of sulfuryl chloride was added dropwise to this suspension under ice cooling and treated in the same manner as in Example 4, methyl 2-(4-isobutylphenyl)propionate was produced at a production rate of 78%. Example 6 The results obtained by reacting with the raw materials and conditions shown in the table are shown in the table.

【table】

[Table] The numerical values of compound (2) or (3) and base indicate the equivalent amount to compound (1), and the reactions were all carried out 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-acetoxypropiophenone dimethyl acetal was dissolved in a mixed solvent of 2 ml of N,N-dimethylformamide and 20 ml of toluene and cooled to -50°C. Then, 1.75 ml of sulfuryl chloride was added and stirred 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 2-
Methyl (p-acetoxyphenyl)propionate
1.78g (80% yield) was obtained. This was heated in 20 ml of 1N aqueous sodium hydroxide solution at 50°C for 1 hour. Afterwards, the pH was adjusted to 3 using concentrated hydrochloric acid. This solution was extracted with 50 ml of chloroform. The extract was concentrated under reduced pressure to give 2-(p-hydroxyphenyl)
1.2 g (90% yield) of propynic acid was obtained. mp 128.7°C (acetic acid to water-based recrystallized product) Example 8 2.52 g of α-hydroxy-P-isobutylpropiophenone dimethyl acetal and pyridine
Dissolve 2.4 g in 25 ml of methylene chloride. activated carbon
After adding 0.25g and cooling to -40℃, sulfur dioxide 0.96
g and 1.06 g of chlorine were added and stirred at the same temperature for 3 hours. After the reaction was completed, the mixture was washed with an aqueous sodium bicarbonate solution, the organic layer was separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was purified by silica gel chromatography (developed with n-hexane-ethyl acetate) to obtain 2-(4-
Methyl isobutylphenyl)propionate 1.60g
I got it. Add this to 1N sodium hydroxide aqueous solution 20
ml at 50°C for 1 hour. 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-isobutylphenyl)propionic acid. Melting point: 75-76°C (acetic acid to water-based recrystallized product) Example 9 2.52 g of α-hydroxy-P-isobutylpropiophenone dimethyl acetal and 1.5 g of triethylamine were dissolved in 25 ml of methylene chloride. After adding 0.25g of activated carbon and cooling to -50℃, sulfur dioxide
0.96 g and 1.3 g of chlorine were added and 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 found.
It was generating. Gas chromatography conditions Column 2% DEGS on Ges chrom Q 3mmφ 1.5m, Glass Column temperature 100℃→200℃ Inlet temperature 200℃ In addition, the concentrated dry product of the above water layer was treated with N,O-bis(trimethylsilyl)acetamide, hexa After performing trimethylsilylation using methyldisilazane and trimethylsilyl chloride, analysis by gas chromatography was performed under the following conditions.
2-(4-isobutylphenyl)propionic acid was produced. Gas chromatography conditions Column 2%SE-52 on chromosorb W 3mmφ 3m, Glass Column temperature 165℃→260℃ Inlet temperature 270℃ Example 10 α-hydroxy-P-isobutylpropiophenone dimethyl acetal 0.25g, isopropylamine 0.18g 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 and stirred at the same temperature for 3 hours. Below, the same post-treatment as in Example 8 was carried out, and 2
0.19 g of methyl -(4-isobutylphenyl)propionate was produced. Example 11 11 g of N,N-dimethylformamide was added to 2.52 g of α-hydroxy-P-isobutylpropiophenone dimethyl acetal, and 18 ml of sulfur dioxide and 1.1 g of chlorine were added at -50°C. The temperature was raised to 10°C over 2 hours, and 20ml of chloroform was added. Thereafter, the same post-treatment as in Example 8 was carried out, and 1.1 g of methyl 2-(4-isobutylphenyl)propionate was produced. Example 12 α-hydroxy-p-isobutylpropiophenone dimethyl acetal 0.25g, pyridine 0.24g
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. Afterwards, the same post-processing as in Example 8 was carried out, and 2-(4
-Methyl isobutylphenyl)propionate 0.12
g was produced. Example 13 2.54 g of α-hydroxy-P-acetoxypropiophenone dimethyl acetal, 2.4 g of pyridine
was dissolved in 20 ml of methylene chloride. Activated carbon 0.3g
After cooling to -50°C, 1 g of sulfur dioxide and 1.2 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 1.3 g of methyl 2-(4-acetoxyphenyl)propionate.
This was heated at 50°C in 20ml of 1N sodium hydroxide aqueous solution.
Heated for 1 hour. 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.
2-(P-hydroxyphenyl)propionic acid 0.9
I got g. Melting point: 128.5°C (acetic acid to water-based recrystallized product) Example 14 2.45 g of α-hydroxy-P-phenylpropiophenone dimethyl acetal and 2.4 g of pyridine were dissolved in 25 ml of methylene chloride. 0.3 g of activated carbon was added, and after cooling to -40°C, 0.96 g of sulfur dioxide and 1.1 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 2.0 g of methyl 2-(P-biphenylyl)propionate. This was heated at 50° C. for 1 hour in 20 ml of a 1N aqueous sodium hydroxide solution. Adjust the pH to 3 with concentrated hydrochloric acid and add 50ml of chloroform.
Extracted with. 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)

Claims (1)

[Claims] 1 (In the formula, Ar represents a substituted or unsubstituted aryl group or a heterocyclic group, R represents hydrogen or an alkyl group, R′ and R ² may be the same or different, and represent an alkyl group, or R′ and R ² may be combined to form a cyclic acetal) A compound represented by (a) a basic substance or amide and (b) general formula (2) or (3) XSOX′ (2) XSO ₂ ' (3) (wherein X and X' are the same or different and often represent a halogen atom or a trifluoromethyl group) or a general compound characterized by carrying out a rearrangement reaction in the presence of sulfur dioxide and a halogen. Formula (4) A method for producing an acetic acid derivative represented by the formula (wherein Ar and R have the same meanings as above, and R ³ represents hydrogen, an alkyl group, or a substituted alkyl group).