JPS649988B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula () (In the formula, Ar means p-tolyl group or p-chlorophenyl group, R ₁ means methyl group or ethyl group, or together with other R ₁ means ethylene group or trimethylene group, R ₂ means a hydrogen atom or a methyl group, R ₃ is a hydrogen atom,
It means a methyl group or an ethyl group, and R ₄ means an alkyl group having 1 to 6 carbon atoms. ) It relates to a pyrrole acetic acid derivative represented by

Compounds of formula () have a pronounced anti-inflammatory effect and have a general formula () (In the formula, Ar, R ₂ and R ₃ have the same meanings as above.) Useful as a synthetic intermediate for the 5-aroylpyrrole-2-acetic acid derivative (see JP-A No. 46-418) It is.

By hydrolyzing the compound of formula (), the compound of formula () can be obtained in good yield. This hydrolysis can be carried out according to a conventional method, for example, by bringing the compound of formula () into contact with water in the presence of a base, and then making the reaction solution acidic.
Examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, sodium carbonate,
Examples include alkali carbonates such as potassium carbonate. Examples of the solvent include water, lower alcohols such as methanol, ethanol, isopropyl alcohol, and mixtures thereof. The reaction temperature is usually room temperature to 120°C. In this reaction,
A salt represented by formula (') can be obtained by freeze-drying a reaction solution obtained by contacting the compound of formula () with water in the presence of a base.

(In the formula, Ar, R ₁ , R ₂ , R ₃ and R ₄ have the same meanings as defined above.) The compound of formula () can be produced, for example, by the following production method.

(In the formula, Ar, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the same meanings as defined above.) The conversion of the compound of formula () to the compound of formula () is carried out using the conventional Friedel- It can be carried out under Crafts reaction conditions. For example, dichloromethane,
A compound of formula () in the presence of a Lewis acid such as aluminum chloride, stannic chloride, ferric chloride, boron trifluoride, zinc chloride in a solvent such as 1,2-dichloroethane, carbon disulfide. This is preferably carried out by reacting with a compound represented by ArCOCl. The reaction temperature is usually -20 to 30°C.

Conversion of a compound of formula () to a compound of formula () can be carried out according to a conventional ketalization method, for example, by combining a compound of formula () with excess methanol, ethanol, ethylene glycol, trimethylene glycol, The reaction is carried out by reacting methyl orthoformate or ethyl orthoformate in the presence of a catalyst without a solvent or in an appropriate solvent. Examples of the catalyst include p-toluenesulfonic acid, hydrogen chloride, and concentrated sulfuric acid. Examples of solvents include hydrocarbons such as benzene, toluene, xylene, and cyclohexane, tetrahydrofuran,
Examples include ethers such as dioxane. The reaction temperature is usually 50-140°C. When alcohols such as methanol are used as the ketal component, it is a dehydration reaction, so it is desirable to remove the generated water from the reaction system.
Dean-Stark traps or dehydrating agents (eg, anhydrous calcium chloride, molecular sieves) are used.

Conversion of a compound of formula () to a compound of formula () is carried out by electrolytically oxidizing the compound of formula () in methanol or emethanol or chemically methoxylating or ethoxylating the compound.

The electrolytic oxidation of the compound of formula () is usually carried out in a membraneless electrolytic cell using a gold, platinum or carbon electrode, preferably a platinum electrode, as the anode and a copper or carbon electrode as the cathode. Although it is convenient to use methanol or ethanol in an excess amount to also serve as an electrolytic solvent, dioxane, dimethylformamide, or the like may also be used as an electrolytic solvent.
This electrolytic oxidation is preferably carried out in the presence of a supporting electrolyte such as ammonium bromide, ammonium chloride, or sodium methoxide. The supporting electrolyte is usually used in an amount of 0.01 to 0.1 equivalent to the compound of formula (). The voltage between the terminals is usually chosen in the range of 10 to 100 volts. Current density is 30~100m
A range of A/cm ² is preferred. The reaction temperature is usually -50~
It is 20℃.

Chemical methoxylation or ethoxylation of the compound of formula () is usually carried out by adding an equimolar to slightly excess amount of halogen (e.g. chlorine, bromine) to the compound of formula (V) in methanol or ethanol in the presence of a base. This is done by reacting. It is convenient to use methanol or ethanol in an excess amount so that it also serves as a reaction solvent, but dichloromethane, diethyl ether, etc. may also be used as a reaction solvent. Examples of bases include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium methoxide, and sodium ethoxy. Examples include alkali metal alkoxides such as hydrogen, triethylamine, and organic bases such as pyridine. The amount of the base used is usually a slightly excess amount of more than 2 moles per mole of halogen. The reaction temperature is usually -50 to 20°C.

Although the compound of formula () is obtained as a mixture of stereoisomers, it can be used in the next reaction without being separated into each isomer.

Conversion of a compound of formula () to a compound of formula () is carried out by reducing the compound of formula (). Catalytic reduction is preferred as the reduction means;
It is usually carried out at room temperature in the presence of a catalyst such as Raney nickel, palladium-carbon, palladium-calcium carbonate, or platinum oxide. Alcohols such as methanol and ethanol are suitable as the reaction solvent. When Raney nickel is used as a catalyst, it is preferable to carry out the reaction under increased pressure, for example at 5 to 100 atmospheres. When a compound of formula () which is a mixture of stereoisomers is used, the compound of formula () is also obtained as a mixture of stereoisomers, which can be used as is in the next step reaction.

Conversion of the compound of formula () to the compound of formula () is carried out by contacting the compound of formula () with water in the presence of an acid. This reaction can be carried out in a homogeneous system using water-miscible organic solvents such as lower alcohols (e.g. methanol, ethanol), dioxane, and tetrahydrofuran, or in a homogeneous system using water-immiscible organic solvents such as diethyl ether, ethyl acetate, and dichloromethane. Even in the heterogeneous system used, the process proceeds smoothly. Examples of acids include hydrochloric acid,
Examples include sulfuric acid, methanesulfonic acid, citric acid, or strongly acidic ion exchange resins having sulfonic acid groups. The reaction temperature is usually 0 to 50°C.

Conversion of a compound of formula () to a compound of formula () is carried out by reacting a compound of formula () with an amine represented by H ₂ N-R ₃ in a suitable solvent in the presence of a catalyst. be exposed. Examples of the catalyst include organic acids such as acetic acid, citric acid, tartaric acid, and p-toluenesulfonic acid, and Lewis acids such as titanium tetrachloride, stannic chloride, and aluminum chloride. When the catalyst is an organic acid, lower alcohols (e.g. methanol, ethanol) are suitably used as the reaction solvent, and the reaction temperature is usually 0 to 0.
It is 50℃. When the catalyst is a Lewis acid, the reaction is preferably carried out under anhydrous conditions, anhydrous benzene or dichloromethane is preferably used as the reaction solvent, and the reaction temperature is usually -10 to 50°C.

Isolation and purification of the product in each step of the above production method can be carried out according to conventional methods, but it is not necessary to purify each step, and the product may be used in the next step reaction in the form of a crude product. .

The present invention will be explained in more detail with reference to Reference Examples and Examples below, but the present invention is not limited to these Examples. The compounds were identified using elemental analysis values, mass spectra, IR spectra, NMR spectra, etc.

Reference Example 1 Methyl 5-(p-toluoyl)furan-2-acetate 22.2 g of p-toluoyl chloride was dissolved in 30 ml of dry dichloromethane, and while keeping the temperature below 0°C,
Add 29 ml of anhydrous stannic chloride dropwise while stirring. After dropping, stir at 0°C for 1 hour. This solution was then added with 18.3 g of methyl furan-2-acetate and 30 g of dichloromethane.
ml solution dropwise over 1 hour at -10 to -5°C. The reaction solution was stirred for an additional hour at -5°C, then poured into 200 ml of ice water, and the dichloromethane layer was separated.
The dichloromethane layer is washed successively with 10% potassium bicarbonate and water, dried over magnesium sulfate, and the solvent is distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform to obtain the desired product 29.5.
I got g. This product was oily, but it solidified when left in the refrigerator for a long time.

IR (neat): 1740, 1640 cm ^-1 . NMR (CDCl ₃ ) δ: 2.42 (3H, s), 3.76 (3H,
s), 3.86 (2H, s), 6.48 (1H, d), 7.21 (1H,
d), 7.33 (2H, d), 7.93 (2H, d). Reference example 2 5-(α,α-dimethoxy-p-methylbenzyl)furan-2-methyl acetate 14.2 g of methyl 5-(p-toluoyl)furan-2-acetate, 29.2 g of methyl orthoformate, methanol
A mixture of 300 ml and 0.1 g of p-toluenesulfonic acid is heated under reflux for 15 hours. Add 0.1 g of sodium methoxide to the reaction solution, and evaporate the solvent under reduced pressure. The residue was subjected to alumina column chromatography and eluted with hexane-tetrahydrofuran to obtain 14.4 g of the desired product as an oil.

IR (neat): 2830, 1740, 1100, 1080 cm ^-1 NMR (CDCl ₃ ) δ: 2.35 (3H, s), 3.17 (6H,
s), 3.63 (2H, s), 3.68 (3H, s), 6.22 (1H,
d), 6.47 (1H, d), 7.19 (2H, d), 7.50 (2H,
d). Reference example 3 5-(α,α-dimethoxy-p-methylbenzyl)-2,5-dihydro-2,5-dimethoxyfuran-2-methyl acetate A platinum plate (31 mm x 49 mm) was used as the anode, and a copper plate (31 mm) was used as the cathode. 5-(α,α-dimethoxy-p-methylbenzyl)furan-2-methyl acetate was placed in an electrolytic cell set with both electrode plates separated by 2 mm.
3.1g, ammonium bromide 0.3g and methanol
Pour 80ml and bring the internal temperature to -30℃ while stirring with a rotor.
Cool until cool. Current value 0.6 to 0.8A, voltage between terminals 20
Electrify at ~30V for about 3 hours (6-7F/mol). A solution of 0.3 g of sodium methoxide in 5 ml of methanol was added to this reaction solution while cold, and the solvent was distilled off under reduced pressure. After adding diethyl ether to the residue and stirring for a while, insoluble matter was removed. The liquid was concentrated under reduced pressure, and the residue was subjected to alumina column chromatography and eluted with hexane-tetrahydrofuran (10:1) to obtain 3.2 g of the desired product as an oil.

IR (neat): 2830, 1740, 1650 cm ^-1 . NMR (CDCl ₃ ) δ: 2.32 (3H, s), 2.1 ~ 3.7
(17H, m), 5.80 (1H, d), 6.38 (1H, d), 7.1~7.5
(4H, m). Reference example 4 5-(α,α-dimethoxy-p-methylbenzyl)-2,5-dimethoxytetrahydrofuran-2-methyl acetate 5-(α,α-dimethoxy-p-methylbenzyl)-2,5-dihydro- 9.1 g of methyl 2,5-dimethoxyfuran-2-acetate, 50 ml of methanol, and about 3 g of Raney nickel were heated at a hydrogen pressure of 5 Kg/cm ² for 10 minutes.
Shake at room temperature for an hour. Remove the catalyst and concentrate the liquid. The residue was subjected to alumina column chromatography, and hexane-tetrahydrofuran (5:
1) yielded 8.7 g of the target product as an oil.

IR (neat): 2830, 1735, 1070 cm ^-1 . NMR (CDCl ₃ ) δ: 1.6-2.3 (4H, m), 2.34
(3H, s), 2.5-3.7 (17H, m), 7.12 (2H, d), 7.40
(2H, d). Reference example 5 3,6-dioxo-7,7-dimethoxy-7-
Methyl (p-tolyl)heptanoate 5-(α,α-dimethoxy-p-methylbenzyl)-2,5-dimethoxytetrahydrofuran-
Dissolve 1.56 g of 2-methyl acetate in 20 ml of diethyl ether, add 2N hydrochloric acid, and stir overnight at room temperature.
Adjust the pH of the aqueous layer to 7 with 10% sodium hydroxide.
After saturation with common salt, extract with ether three times.
After drying the ether layer over magnesium sulfate, the solvent was distilled off to obtain 1.29 g of the target product as an oil.

IR (neat): 2830, 1740, 1720 (broad), 1070cm
^-1 . NMR ( _CDCl3 ) δ: 2.37 (3H, s), 2.6-2.9
(4H, m), 3.26 (6H, s), 3.50 (2H, s), 3.73 (3H,
s), 7.1-7.6 (4H, m). Example 1 - Methyl-5-[α,α-dimethoxy-(p-
methylbenzyl)] pyrrole-2-methyl acetate 3,6-dioxo-7,7-dimethoxy-7
-Methyl (p-tolyl)heptanoate 134mg 30%
Dissolve in 6 ml of methanolic methylamine, and add 7 ml of acetic acid while stirring under ice cooling. After stirring the reaction solution at room temperature for 16 hours, it is added to an aqueous sodium hydroxide solution and extracted with chloroform under alkaline conditions. After drying the chloroform layer over magnesium sulfate, the solvent was distilled off, and the residue was subjected to alumina column chromatography and eluted with hexane to obtain 50 mg of the target product as an oil. It solidified when left in the refrigerator. Melting point 49-51℃ IR (neat): 2840, 1740, 1100, 1070 cm ^-1 . NMR (CDCl ₃ ) δ: 2.30 (3H, s), 3.03 (6H,
s), 3.09 (3H, s), 3.53 (2H, s), 3.66 (3H,
s), 6.03 (1H, d), 6.53 (1H, d), 7.13 (2H,
d), 7.40 (2H, d). Dissolve 2.07 g of methylamine generated from 4.50 g of methylamine hydrochloride and aqueous sodium hydroxide solution in 20 ml of benzene, and then dissolve 3,6-dioxo-7,7-dimethoxy-7-(p-tolyl).
Add 1.29 g of methyl heptanoate and cool to 3°C. While keeping the internal temperature below 10°C, a solution of 0.5 ml of titanium tetrachloride in 10 ml of benzene is added dropwise over 45 minutes. After stirring the reaction mixture overnight at room temperature, the solids are removed and the liquid is concentrated under reduced pressure. The residue was purified by alumina column chromatography to obtain 0.36 g of the target product.

Reference Example 6 1-Methyl-5-(p-toluoyl)pyrrole-2-acetic acid 1-Methyl-5-[α,α-dimethoxy-(p-methylbenzyl)]pyrrole- Suspend 105 mg of 2-methyl acetate and stir at room temperature for 1 day. After extracting the reaction solution with chloroform, the aqueous layer is brought to pH 3 with 10% citric acid, and crystals are precipitated. This was taken, washed with water, and dried to obtain 65 mg of the target product. The IR spectrum of this product matched that of the standard product synthesized according to the method described in Japanese Patent Publication No. 50-37668.

Reference example 7 1-methyl-5-[α,α-dimethoxy-(p-
Suspend 127 mg of methyl 1-methyl-5-[α,α-dimethoxy-(p-methylbenzyl)]pyrrole-2-acetate in 15 ml of water containing 13 mg of sodium hydroxide. , stir at room temperature for 2 days. After the reaction solution was extracted with chloroform, the aqueous layer was filtered and the solution was freeze-dried to obtain 59 mg of a hygroscopic target product.

NMR (D ₂ O) δ: 2.27 (3H, s), 3.04 (9H,
s), 3.37 (2H, s), 6.00 (1H, d), 6.33 (1H,
d), 7.05 (2H, d), 7.33 (2H, d). Reference Example 8 1-Methyl-5-(p-toluoyl)pyrrole-2-acetic acid 1-Methyl-5-[α,α-dimethoxy-(p-
When sodium pyrrole-2-acetate (methylbenzyl) is dissolved in water and 1N hydrochloric acid is added dropwise, crystals are precipitated. This was taken, washed with water, and dried to obtain the desired product. Melting point 158-160℃ (decomposition) IR of this product
The spectrum matched that of the standard product synthesized according to the method described in Japanese Patent Publication No. 50-37668.

Claims (1)

[Claims] 1. General formula (In the formula, Ar means p-tolyl group or p-chlorophenyl group, R ₁ means methyl group or ethyl group, or together with other R ₁ means ethylene group or trimethylene group, R ₂ means a hydrogen atom or a methyl group, R ₃ is a hydrogen atom,
It means a methyl group or an ethyl group, and R ₄ means an alkyl group having 1 to 6 carbon atoms. ) A pyrrole acetic acid derivative represented by