JPH053874B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the following general formula () (In the formula, R represents a C ₁ -C ₅ alkyl group or a hydrogen atom, and R' represents a C ₁ -C ₅ alkyl group) and can be easily obtained by hydrolysis.

The following formula () The present invention relates to a method for producing 5-(1-carboxyethyl)-2-phenylthiophenyl acetic acid. The compound of the present invention has excellent anti-inflammatory and analgesic effects and is expected to be a highly safe and useful anti-inflammatory agent. It is extremely important as an intermediate in the production of 2-(10,11-dihydro-10-oxo-dibenzo[bf]thiepin-2-yl)propionic acid ().

As a method for producing the compound of the present invention, a method via nitrile () (Japanese Patent Application Laid-Open No. 57-106678 and JP-A No. 57-171991) Alternatively, a method via α-halogenopropiophenone derivative () (Japanese Patent Application Laid-open No. 113168-1983) It has been known. However, these methods cannot be said to be industrially advantageous production methods because they use highly toxic reagents and require long reaction steps. As a result of intensive research into a new manufacturing method that can solve these drawbacks, the present inventors discovered a safe and simple manufacturing method and completed the present invention.

The method of the present invention is based on the general formula () (In the formula, R represents a C ₁ to C ₅ alkyl group or a hydrogen atom.) A propiophenone derivative represented by the general formula () (In the formula, A _r is an aromatic hydrocarbon group, X and Y
(each represents a group that leaves as an anion)
In the presence of a trivalent iodine compound represented by the following formula ()′ A _r −=O ()′ (wherein A _r represents an aromatic hydrocarbon group), the general formula () R″C(OR′) ₃ () (In the formula, R′ represents a C ₁ to C ₅ alkyl group,
General formula () characterized by reacting with an orthocarboxylic acid ester represented by R'' represents a hydrogen atom or an alkyl group) (In the formula, RR' has the same meaning as above.) This relates to a method for producing a compound represented by the following.
Furthermore, in the method of the present invention, by hydrolyzing the above-mentioned compound (), the following formula is obtained: The present invention relates to a method for producing 5-(1-carboxyethyl)-2-phenylthiophenyl acetic acid.

Since the method of the present invention uses less toxic substances than the above-mentioned known production methods, there is no need for special considerations regarding equipment, and equipment costs can be reduced. Furthermore, since the number of steps is small and each step has a high yield, it can be said to be an industrially and economically advantageous manufacturing method.

In addition, the raw material propiophenone derivative () is
It can be synthesized by the following method. That is, orthohalogenophenyl acetate () is subjected to a Friedel-Crafts reaction with propionyl chloride to form 2-halogeno-5-propionylphenylacetate (), which is then reacted with thiophenol, and if necessary, hydrated. Obtained by decomposition and esterification.

(In the formula, X represents Cl, Br, R represents a C ₁ to _{C 5} alkyl group or a hydrogen atom, and R' represents C ₁
~ _C5 alkyl group) Next, to explain the present invention in detail, a non-toxic trivalent iodo compound () of a propiophenone derivative (), or ()' such as iodobenzenediacetate or iodosobenzene The reaction with an orthocarboxylic acid ester (such as methyl orthoformate or ethyl orthoformate) starts immediately upon dropping concentrated sulfuric acid, proceeds quantitatively, and is completed in about 1 hour. The reaction proceeds in the same way even if a solvent such as benzene, acetate, or chloroform is added to make the reaction milder. After the reaction is completed, the reaction mixture is extracted with an organic solvent such as ether, the solvent and iodobenzene (bp _0.5 50-53℃ recovery rate 86%) are distilled off under reduced pressure, and the residue is purified by column chromatography. Compound () is obtained in 85% yield. The residue before being subjected to column chromatography is of such a purity that there is no problem even if it is subjected to the next reaction unpurified. The compound () obtained in this way is hydrolyzed in an aqueous solution of an alkali metal hydroxide such as NaOH or an alcoholic aqueous solution of an alkali metal hydroxide, and quantitatively 5-(1-carboxyethyl)-2-
It can lead to phenylthiophenyl acetic acid ().

That is, the manufacturing method of the present invention is ()→()→
(2) The overall yield is 80% or more, and the reaction is very simple, safe, and takes place in a short time, making it a method that is significantly superior to known techniques.

EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

Example 1 5-(1-methoxycarbonylethyl)
-2-Phenylthiophenyl ethyl acetate 5-propionyl-
Ethyl 2-phenylthiophenyl acetate (melting point 46~
47°, ethanol-n-hexane) 6.56 g, methyl orthoformate 60 ml and iodobenzene diacetate
Mix 9.86 g of water and gradually add 1.07 ml of concentrated sulfuric acid dropwise at room temperature. After the addition, the mixture was stirred at room temperature for 1 hour.

After the reaction, add ether to the reaction solution and wash with water. The ether layer was dried with Glauber's salt, and the ether was distilled off under reduced pressure. The residue was further heated at 0.2 mmHg and 100°C at a bath temperature of 200°C.
The fraction below ℃ is distilled off. This residue can be analyzed by NMR, IR
And TLC is almost an object. It can be used as is for the next reaction, but when purified by column chromatography (silica gel, benzene-ethyl acetate 15:1), 5-(1-methoxycarbonylethyl)-2-phenylthiophenyl ethyl acetate 6.09g obtained. Yield 85% IRνneatmaxcm ^-1 : ₁₇₄₀ ( _-CO2CH3 and _-CO2
C ₂ H ₅ NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 8Hz, -
CH ₂ CH ₃ ), 1.48 (3H, d, J = 8Hz,
CHC H ₃ ), 3.64 (3H, S, -CO ₂ CH ₃ ), 3.68
(1H, q, J = 8Hz, CH CH ₃ ), 3.78
(2H, S, -CH ₂ CO ₂ C ₂ H ₅ ), 4.06 (2H, q,
J=8Hz, -CH2CH3 ), 7.00 _~ 7.50(8H _,
Example 2 5-(1-carboxyethyl)-2-phenylthiophenyl acetate 358 mg of ethyl 5-(1-methoxycarbonylethyl)-2-phenylthiophenyl acetate was dissolved in 2N
Reflux for 4 hours in 2.5 ml of NaOH solution. After cooling, 10
Acidify with % sulfuric acid solution.

The precipitated white crystals were collected, washed with n-hexane, and then recrystallized with ethyl acetate-n-hexane to give 5-(1-carboxyethyl)-2-phenylthiophenyl with a melting point of 147° to 150°. Acetic acid 300
Get mg. Yield 95% IRνKBrmaxcm ^-1 : 1700 (-CO ₂ H) NMR (CDCl ₃ ) δ: 1.50 (3H, d, J=8Hz,
CHCH ₃ ) 3.60 (1H, q, J=8Hz,
CHCH ₃ ) 3.85 (2H, S, -CH ₂ CO ₂ H) 7.20-7.40 (8H, m, Aromatic protons) 9.40 (2H, broad S, -CO ₂ H) Example 3 Methyl 5-(1-methoxycarbonyl ethyl)−
2-Phenylthiophenyl acetate Methyl orthoformate (63ml) and concentrated sulfuric acid (6.28ml)
at 30°C or below, and further methyl 2-phenylthio-
5-propionyl phenyl acetate (31.4g,
100mmol) at below 25℃. Next, add iodobenzene diacetate (38.7 g,
120 mmol) was added over 15 minutes while maintaining the temperature at 33-35°C. After stirring for 15 minutes, water (160 ml) and methylene chloride (160 ml) were added and stirred for 5 minutes. Separate the aqueous layer and extract with methylene chloride (80ml). The combined organic layers were washed with water (160 ml) and saturated brine (160 ml), dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue is subjected to vacuum distillation to recover iodobenzene. After adding sodium iodide (2.99g) to the residue,
Dissolve in acetone (63 ml), add trifluoroacetic anhydride (4.20 g) over 15 minutes under ice-cooling, and stir for another 15 minutes under ice-cooling. After adding ice water (160ml) and methylene chloride (160ml) and stirring,
The aqueous layer was extracted with methylene chloride (40 ml x 2), and the combined organic layers were added to a 15% aqueous sodium thiosulfate solution, water,
and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was adsorbed onto a silica gel column (67 g of silica gel) and eluted with benzene (600 ml) followed by methylene chloride (200 ml) to give the title compound as a yellow oil.
Obtained 31.57g. (Yield 91.7%).

Example 4 5-(1-carboxyethyl)-2-phenylthiophenyl acetate Methyl 5-(1-methoxycarbonylethyl)-2-phenylthiophenyl acetate obtained in Example 3 (31.57 g, 91.7mmol) and
A mixture of 2N NaOH aqueous solution (225 ml) is heated under reflux with stirring until a homogeneous solution is obtained (4 hours required). After cooling, add methylene chloride (160 ml) and adjust the pH to 6.0 with 10% sulfuric acid while stirring. The aqueous layer was separated, washed with methylene chloride (160 ml and 80 ml), and adjusted to pH 1 with 10% sulfuric acid (160 ml).
x2). Add the organic layer to saturated saline (160ml)
, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 25.80 g of yellow crude crystals. The crude crystals were heated and dissolved in ethyl acetate (64.5 ml), hot hexane (77.4 ml) was added, and the mixture was heated at room temperature.
Stir for 1.5 hours. The precipitated crystals were collected by filtration and ethyl acetate-hexane (5:6 (v/v)) (15 ml x 3)
By washing with water and drying under reduced pressure, 20.20 g of the title compound is obtained as pale yellow crystals (yield 69.6%).

Claims (1)

[Claims] 1 General formula () (In the formula, R represents a C ₁ to C ₅ alkyl group or a hydrogen atom.) A propiophenone derivative represented by the general formula () (In the formula, A _r is an aromatic hydrocarbon group, X and Y
(each represents a group that leaves as an anion)
In the presence of a trivalent iodine compound represented by the following formula ()′ A _r −=O ()′ (wherein A _r represents an aromatic hydrocarbon group), a trivalent iodine compound represented by the general formula () R″-C(OR′) ₃ () (In the formula, R′ represents a C ₁ to C ₅ alkyl group,
General formula () characterized by reacting with an orthocarboxylic acid ester represented by R'' represents a hydrogen atom or an alkyl group) A method for producing a compound represented by the formula (wherein R and R' have the same meanings as above). 2 General formula () (In the formula, R represents a C ₁ to C ₅ alkyl group or a hydrogen atom.) A propiophenone derivative represented by the general formula () (In the formula, A _r is an aromatic hydrocarbon group, X and Y
(each represents a group that leaves as an anion)
In the presence of a trivalent iodine compound represented by the following formula ()' A _r -1=O ()' (wherein A _r represents an aromatic hydrocarbon group), the general formula () R″C(OR′) ₃ () (In the formula, R′ represents a C ₁ to C ₅ alkyl group,
R″ represents a hydrogen atom or an alkyl group) and is reacted with an orthocarboxylic acid ester represented by the general formula () (wherein R and R' have the same meanings as above), and then hydrolyzing the compound represented by the general formula (), A method for producing 5-(1-carboxyethyl)-2-phenylthiophenyl acetic acid.