JPS5919550B2 - (E)-2-[p-(β-2-thienylvinyl)phenyl]propionic acid and its production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of the general formula (I) c■c/HcH, which have anti-inflammatory, analgesic, fever-lowering, and platelet aggregation inhibiting effects.

The present invention relates to (l-2-[p-(β-2-thienylvinyl)phenyl]propionic acid represented by ゜"'H' 0 and HCOOH and a method for producing the same.

The present inventors have been conducting research on new pharmaceuticals with the aim of developing new anti-inflammatory agents, and now we have discovered that D-2-[p-(β-2-thienyl) has an excellent effect as an anti-inflammatory agent. Invented vinyl)phenyl]propionic acid.

That is, the compound of the present invention has about 1 to 2 times the anti-inflammatory effect measured by the carrageenan edema method, and about 3 times the analgesic effect measured by the phenylquinone rich cider method, compared to isobutylphenylpropionic acid, which is useful as an anti-inflammatory agent. It is effective and has low toxicity. Field-2-[p-β-2 of the present invention
-thienylvinyl)phenyl]propionic acid can be produced by the following two methods. (1) See c■/H (■) □C0CH3 / X-CH2COOR011) Gate ■; Me:.

0, alkali [wherein R is a lower alkyl group, M is an alkali or 1
/2 alkaline earth metal, X represents chlorine, bromine, or iodine.

[representing]] Method of (1) Step (g)-p-(β-2-thienylvinyl)acetophenone () is treated under anhydrous conditions in an inert atmosphere such as nitrogen,
In the presence of an alkaline condensing agent, the α-halogenated acetic acid ester is reacted.

(Dalzene Condensation) Examples of the alkaline condensing agent include soda amide, potassium amide, sodium hydride, sodium methoxide, sodium isopropoxide, potassium t-butoxide, and lithium diethylamide.

As the solvent, alkanols such as methanol, ethanol, isopropanol and butanol, ether, hydrocarbons such as toluene and xylene, and light oil are used. Among these condensing agents and solvents, it is preferred to use isopropanol, sodium isopropoxide, or potassium t-butoxide in t-butanol. The reaction temperature ranges from 0°C to the reflux temperature of the solvent, but the optimum temperature varies depending on the aging agent and solvent used, and is preferably from 0°C to around room temperature. The α-halogenated acetate ester represents a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. If this ester group R3 is the same as the alkanol from which the alkoxide condensing agent is prepared, the reaction product can be sufficiently pure. In the second step, by water decomposition, a salt of general formula (2) is produced.

Examples of the alkali used include alkali hydroxides such as sodium hydroxide and potassium hydroxide, and alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide. The sodium, potassium and calcium salts are representative of the hydrolysis products of the esters and can be isolated from aqueous solutions by precipitation in aqueous alkanols. 3rd step: The isolated glycidate salt (V) is added to an aqueous solution with a pH of 6 to 8.
90-140℃ in an inert atmosphere such as nitrogen gas,
Preferably, by heating and refluxing at 110 to 120°C for 3 to 6 hours, decarboxylation and ring closure reactions occur, yielding the aldehyde compound (b).

The fourth step is to oxidize the aldehyde compound (b) to obtain the desired (Nouichi)
p-(β-2-thienylvinyl)phenyl]propionic acid (1) is obtained.

Oxidizing agents include potassium permanganate, hydrogen peroxide,
Oxygen gas or the like is added to the aldehyde compound (b) for 2 to 2 hours under a catalyst of nitric acid, chromic anhydride, silver oxide, or cobalt acetate.
Use 5 times the mole, preferably about 2 times the mole. Among these oxidizing agents, silver oxide is preferred. Methanol as a solvent,
A mixed solvent of alkanols such as ethanol, propanol, and isopropanol and water is used, but a system of ethanol/water or methanol/water is preferable.

When the aldehyde compound (b) shows poor solubility in those solvents, tetrahydrofuran, dioxane, etc. may be added. For the oxidation reaction, an aqueous solution of sodium hydroxide, for example, as an alkali is added dropwise to a water-ethanol mixture of the aldehyde compound (7) and silver oxide, and the reaction is carried out at room temperature for 2 to 3 hours.
After stirring, silver oxide is filtered off, volatile solvents such as ethanol are distilled off from the filtrate, and the resulting aqueous layer is washed with a water-immiscible solvent such as ether. It is extracted with a suitable solvent such as ether, n-hexane, ethyl acetate, or a mixed solvent of these two, evaporated to dryness, and purified by crystallization using light oil or the like.

Method (2) When morpholin is used as the secondary amine in step (1), morpholin and sulfur are added to (p-(β-2-thienylvinyl)acetophenone) and placed on a water bath or Carbothiomorpholide (a) is obtained by heating in an oil bath at normal pressure.

Although it is not necessary to use any particular solvent, pyridine, dioxane, etc. may be used as an auxiliary solvent. of raw materials (
g)-p-(β-2-thienylvinyl)acetophenone (), morpholin is 2 to 5 times the mole, preferably 2 to 2.5 times the monomer, and sulfur is 2 to 3 times the mole, preferably 2 to 2 Use about .5 times the mole. Reaction temperature is 80-15
At 0°C, reflux temperature is preferred. The reaction time is 3 to 24 hours, preferably 3 to 4 hours. When using a secondary amine such as dimethylamine or diethylamine instead of morpholine, the (t)-p-(β-2-
If sulfur and the above-mentioned amines are added to thienylvinyl)acetophenone () and heated in a closed tube, carbothamide (M[B, c) is obtained.

The reaction temperature is 180-200°C and the reaction time is 12-24 hours.

When ammonium polysulfide is used instead of secondary amines and sulfur, ammonium polysulfide is added to the raw material (t)-p-(β-2-thierruvinyl)acetophenone (1), and the mixture is heated to 200 to 250°C in a closed tube. , carboxamide (MId) is obtained by heating for 5 to 24 hours.

Ammonium polysulfide is used in an amount of 1.8 to 2.0 times the mole of the raw material. Dioxane, ethanol, pyridine, etc. are used as the solvent. These carbothioamides (A
, b, c) or the carboxamide compound (d) is isolated or not isolated and used as it is in the next hydrolysis step. In the hydrolysis step (2), the carbothioamide (A, b, c) is hydrolyzed with a strong acid such as hydrochloric acid or a strong base such as sodium hydroxide or potassium hydroxide.

Hydrolysis can be carried out following the first step by adding a strong acid such as hydrochloric acid or a caustic alkali to the reaction solution in the first step, or if the p-rubothioamide compound is isolated, it can be dissolved in a solvent such as acetic acid or dioxane and treated with acid or Perform hydrolysis with alkali. After the hydrolysis reaction, in the case of acid hydrolysis, the organic solvent such as acetic acid or dioxane used as a solubilizing agent is distilled off under reduced pressure, and after concentration, a water-immiscible solvent such as ether, benzene, chloroform, or dichloromethane is added. The product is separated by extraction with an organic solvent such as petroleum ether. On the other hand, in the case of alkaline hydrolysis, after acidification with hydrochloric acid or the like, the precipitate or oily substance that precipitates is separated by filtration or extraction with a solvent immiscible with water. Hydrolysis of carboxamide (CVfXid) (6 circles) This was carried out by heating and refluxing the above caustic alkali dissolved in an alcoholic aqueous solution such as methanol or ethanol, and after the reaction was completed, the alcohol was distilled off, and the concentrated liquid was cooled with ice-cooled hydrochloric acid. The free acid that precipitates is separated and purified. Hydrolysis reaction time is approximately 10-24 hours.

Next, in the third step, the methylation reaction, after esterifying the carboxyl group of the compound, the corresponding raw material is reacted with an alkaline condensing agent in a polar or non-polar solvent in a nitrogen stream at room temperature or during cooling. Anion is generated.
The generation of the anion is easily confirmed by coloring, and the generation time takes 30 minutes to 1 hour. When the anion-forming gas is reacted with methyl halide, an α-monoalkylated product is obtained. The solvent used is polar solvent such as dimethylformamide, dimethyl sulfoxide, liquid ammonia, etc.
In addition, non-polar solvents include benzene, toluene, n-hexane, ether, diglyme, monoglyme, etc.
Alternatively, a mixed solvent thereof may be used.

Further, as the alkali condensing agent, alkali metal hydrides such as sodium hydride, potassium hydride, and lithium hydride, metal amides such as sodium amide and potassium amide, and the like are used. The α-moy alkylated form of the obtained intermediate, that is, the ester form, can be easily converted into (day-2-[p-(β-2
-thienylvinyl)phenyl]propionic acid is obtained.

Examples of acids used include hydrochloric acid and sulfuric acid, and examples of bases include sodium hydroxide and potassium hydroxide. As the solvent, alcohols such as methanol, ethanol, isopropanol, dioxane, acetic acid, water, etc. are used. Hydrolysis is carried out by heating under reflux for 1 to 4 hours.

After the reaction is complete, in the case of acid hydrolysis, it is poured into water and extracted with an organic solvent, or in the case of base hydrolysis, the organic solvent is distilled off, water is added, and then acidified with hydrochloric acid etc. to form crystals. Separate. 0-2 obtained by the present invention
-[p-(β-2-thienylvinyl)phenyl]propionic acid can also be obtained as an alkali metal salt such as sodium, potassium, or lithium, or an alkaline earth metal salt such as calcium or barium by a conventional method.

E of (t)-2-[p-(β-2-thienylvinyl)phenyl]propionic acid according to the carrageenan edema method of the present invention
D, O value is 23.3~/Kg, (13.8-39.5)
(oral), and the ED, O value according to the phenylquinone enrichment method is 14.1 mf/l (!? (4.31-46
．． 2) (oral). Also, the Born-Cross method (G
．． V. R. BOrnandM. J. CrOss, J. P
hyslOl. The inhibitory effect of Shu-2-[p-(β-2-thienylvinyl)phenyl]propionic acid on platelet aggregation against collagen was determined by the method (1963) and was approximately 1.6 times that of human aspirin. It was hot.
The dosage of the compound of the present invention is appropriately selected depending on the administration method, purpose of administration, etc., but is 1 to 30/I<f!
can be administered separately.

Administration methods include oral, rectal, etc. The dosage form may be administered in a preferred dosage form such as a tablet, powder, capsule, granule, pill, syrup, or suppository.

Upon administration, pharmacologically acceptable excipients, disintegrants, binders, lubricants, etc. may be added. Examples will be described below. Example 1 Production of 8-2-[p-(β-thienylvinyl)phenyl]propionic acid 1st step Ethyl(6)-3-[p-(β-2-thienylvinyl)
-Production of 2,3-epoxybutyrate (D-2-(4-
acetylstyryl) thiophene, 1.25f and monochloroacetic acid ethyl ester, 1.35f, in anhydrous benzene 4
07! Dissolves in Ll.

A potassium t-butoxide solution prepared from potassium metal, 0.43f, and 20% of t-butanol is dropped into the mixed solution at room temperature over a period of 1 hour under nitrogen gas substitution. 1
After day and night reaction, t-butanol was distilled off under reduced pressure, and the residue was poured into ice water and extracted with ether.

Wash with water and dry with anhydrous sodium sulfate. Since this product does not crystallize, it is used in the next step after being treated with silica gel column chromatography. 2nd step Ethyl (T!)-3-[p- (β-2-
thienylvinyl)phenyl]-2,3-epoxybutyrate, 1.6y, was dissolved in 50a of distilled ethanol, and 116m9 of metallic sodium was dissolved in 107m of distilled ethanol! A solution of sodium ethoxide prepared by dissolving in Ll was added all at once, then 5 drops of water were added with a pipette, and the mixture was stirred at room temperature for a day and night.
Washing with diethyl ketone gives a yellowish white powder of 0.65'y.

V. ). ．． Third step (6) - Production of 2-[p-(β-2-thienylvinyl)phenyl]propanal Sodium (t)-3-[p-
(β-2-thienylvinyl)phenyl]-2,3-epoxybutyrate, 0.57y, was suspended in 10cc of water,
Add diluted hydrochloric acid solution dropwise to keep the pH around 7, and raise the pH to 90~90 in an oil bath.
Incubate at 95°C for 2 hours.

After cooling with water and collecting the precipitate by filtration, washing with chloroform, washing with water, and drying (anhydrous sodium sulfate) 4th step 0-2-[p obtained in the process
-(β-2-Thienylvinyl)phenyl]To 1 t of propanol, add 10 ml of ethanol, add tetrahydrofuran to dissolve, and add 0.0 ml of sodium hydroxide to 28 d of water.
An aqueous solution in which 55f7 was dissolved was added dropwise, and after stirring at room temperature for 2 hours, silver oxide was filtered off and the filtrate was collected.

After ethanol is distilled off from the filtrate, the aqueous layer is extracted with ether, and the separated aqueous layer is acidified with concentrated sulfuric acid and extracted with ether. Reference Example 2 (Production of 0-2-[p-(β-2-thienylvinyl)phenyl]propionic acid 1st step ()-Production of p-(β-2-thienylvinino(c)phenylacetothiomorphide) 0.35f of sulfur per 1.0t of 0-2-(4-acetylstyryl)thiophene
and Morpholine 1.01 are mixed and heated for 3 to 4 hours until dissolved in water.

After crystal precipitation, the reaction mixture is washed with ethyl acetate, and insoluble matter is filtered off. 2nd process

Claims (1)

[Claims] 1 (E)-2-[p-(β-2-thienylvinyl)phenyl]propionic acid represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. are available▼. 2 (E)-p-(β-2-thienylvinyl)acetophenone is reacted with α-halogenated acetate in the presence of an alkali condensing agent to obtain the corresponding glycidic acid ester, which is then hydrolyzed in the presence of an alkali to form the corresponding glycidic acid ester. An aqueous solution of this product is heated near neutrality to ring-open and decarboxylate it to form the corresponding aldehyde (formula below), which is then oxidized to form the corresponding acid (E)-2-[p-(β A method for producing -2-thienylvinyl)phenyl]propionic acid. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼