JPS6245868B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [] [In the formula, X ¹ represents a halogen atom or a group consisting of -Mg-halogen atom. ] In the presence of a catalyst, a compound represented by the general formula [] [In the formula, R ¹ is a halogen atom, an alkyl group, or a general formula or A group represented by [formulas [] to [], M represents a metal atom,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ and R ¹⁰ are hydrogen atoms or alkyl groups, R ⁷ and R ⁸ are alkyl groups or alkenyl groups, or R ⁷ and R ⁸ are adjacent

[Formula] A group which may be combined with the group to form a ring, R ¹¹ represents a hydrogen atom or a methyl group, and Y represents an oxygen atom or a sulfur atom. ]
, X ² represents a halogen atom or a group consisting of -Mg-halogen atom. However, in the formula [] above,
When X ¹ is a halogen atom, X ² represents a -Mg-halogen atom, or when X ¹ is a -Mg-halogen atom, X ² represents a halogen atom. ] General formula [ ] characterized by reacting with a compound represented by [In the formula, R ¹ has the meaning described above. ] It is related with the novel manufacturing method of the (3-methyl-2-thienyl) benzene derivative represented by these. The purpose is to provide an industrially advantageous method for obtaining a compound represented by the general formula [] that is useful as a pharmaceutical agent such as an anti-inflammatory analgesic agent or as an intermediate thereof. Previously, 2-(4-heterocyclic phenyl)propionic acids, their intermediates and processes for their production have been described in British Patent No. 1119334. The present inventors have previously discovered that novel 2-[4-(3-methyl-2-thienyl)phenyl]propionic acids covered by the British patent but without specific description have anti-inflammatory, analgesic, anti-rheumatic and It was discovered that it is extremely useful as an anti-inflammatory and analgesic agent, having strong main effects such as antipyretic action, low toxicity, few side effects such as gastrointestinal disorders, and can be used continuously for a long period of time. No. 52-138943 "Japanese Patent Application Publication No. 54-81260"). Therefore, the present inventors investigated 2-[4-(3-methyl-
In order to develop an industrial method for producing 2-thienyl)phenyl]propionic acids and their intermediates, a known method was used, namely, the condensation reaction of a heterocycle and a benzene derivative described in the above-mentioned British patent (Gomberg-Batschmann-Hay reaction). ；Gomberg−
Bachmann-Hey Reaction), then various substituents bonded to the benzene ring.

[Formula] Reactions to convert into groups, and various substituents bonded to the benzene ring described in numerous literatures.

As a result of various studies on known reactions for converting into [formula] groups, the yield of the target product was particularly low in the condensation reaction of a 3-methylthiophene ring and a benzene derivative by the Gomberg-Batschmann-Hey reaction shown in the following formula. Also, a compound of the following formula in which a phenyl derivative is bonded to the 5-position of the 3-methylthiophene ring (In the formula, R' has the same meaning as described below) was produced as a by-product, and it was therefore found that this method was not preferred as an industrial method for producing 4-(3-methyl-2-thienyl)benzene derivatives. [In the formula, Z represents a halogen atom, and R' represents a substituent that can be applied regardless of the reaction. ] Therefore, the present inventors conducted research to develop a new method for industrially advantageous condensation of a 3-methylthiophene ring and a benzene derivative. It was discovered that the compound represented by the general formula [] can be obtained in high purity and in high yield without contamination with the above-mentioned isomers by reacting the compound represented by the above in the presence of a catalyst. completed. According to the method of the present invention, in the general formula []
Similarly, when R ¹ is a group such as a protected formyl, acetyl group, oxazoline group, or -COOM group (where M represents a metal atom), or a substituted alkyl group containing these, it can be handled without participating in the reaction. A compound of the general formula [] can be obtained with high purity and high yield, especially when R ¹ contains a protected formyl group, oxazoline group, or -COOM group (where M has the meaning described above). If a compound represented by the general formula [] which is a substituted alkyl group is used, highly pure 2-[4-
It has advantages such as being able to obtain (3-methyl-2-thienyl)phenyl]propionic acids in high yield. The method of the present invention, which has various advantages as described above, is extremely useful as an industrial method for producing 4-(3-methyl-2-thienyl)benzene derivatives compared to conventional methods. To explain the present invention in detail, in the general formula [], examples of R ¹ include a halogen atom, an alkyl group such as methyl or ethyl, or a group represented by the general formula shown below. In the above formulas [] to [], R ² , R ³ .R ⁴ , R ⁵ ,
R ⁶ , R ⁹ and R ¹⁰ are hydrogen atoms or alkyl groups such as methyl, ethyl, propyl or butyl,
Y is an oxygen atom or a sulfur atom, R ⁷ and R ⁸ are an alkyl group such as methyl, ethyl, propyl or butyl, or an alkenyl group such as vinyl or allyl, or R ⁷ and R ⁸ are adjacent

[Formula] A group that may be combined with the group to form a ring, R ¹¹ is a hydrogen atom or a methyl group, M is lithium, sodium, potassium, magnesium, calcium, aluminum, zinc,
Tin, lead, antimony, bismuth, copper, nickel, cobalt, iron, manganese, chromium, titanium,
Represents a metal atom that forms a salt with a carboxyl group such as cadmium or silver. Catalysts that can be used in the reaction include, for example, palladium black, palladium carbon, palladium halides (palladium chloride or palladium bromide, etc.).
Or, the general formula M ² (PR ¹² ₃ ) ₄ [] M ² (PR ¹² ₃ ) ₂ R ¹³ X [XI] M ² (R ¹² ₂ P-R ¹⁴ _-PR ¹² ₂ ⁾ (acac) [] [In the formula, M ² is a metal atom such as palladium, nickel, or platinum, and R ¹² and R ¹³ are phenyl or phenooxy which may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom. , phenyl lower alkyl, phenyl lower alkoxy or cycloalkyl group, X represents a halogen atom, R ¹⁴ represents a C _1-10 alkylene group or lower alkenylene group, and acac represents an acetoacetonate group. ] Examples include palladium, nickel or platinum catalysts represented by the following. Furthermore, for example, the above formula [] ~
Specific examples of the catalysts represented by [] include tetrakis(triphenylphosphine)palladium, iodo(phenyl)bis(triphenylphosphine)palladium, bromo(phenyl)bis(triphenylphosphine)palladium, and tetrakis(triphenylphosphine)palladium. (triethylphosphine)palladium, iodo(p-fluorophenyl)bis(triphenylphosphine)palladium, tetrakis(tributylphosphine)palladium, tetrakis(tricyclohexylphosphine)palladium or dichloro[1,2-bis(diphenylphosphine)palladium] enylphosphino)
Palladium catalysts such as [ethane]palladium; nickel catalysts such as tetrakis(triethylphosphine)nickel or nickel acetoacetonate; platinum catalysts such as tetrakis(triethylphosphine)platinum; and the like. Palladium catalysts are particularly preferred. In addition, some of the compounds represented by the general formula [ ] of the present invention contain asymmetric carbon atoms, and these compounds naturally have optical isomers and racemates, but the present invention does not include any of them. Included. Next, embodiments of the present invention will be described. The compound represented by the general formula [] and the compound represented by the general formula [] are reacted in the presence of a catalyst. At that time, the solvent used is tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, or a mixture of two or more thereof. Examples include solvents that do not participate in the reaction, such as solvents. The amount of the catalyst used is usually 1/10 to 1/10000 molar equivalent, preferably 1/1000 molar equivalent, relative to the compound represented by the general formula []. The reaction time and reaction temperature are not particularly limited, but under refluxing of the solvent, 30
It is preferable to react for minutes to several hours. Furthermore, since the method of the present invention uses a Grignard reagent, it is preferably carried out under anhydrous conditions and under a nitrogen stream. After the completion of the reaction, the desired (3-methyl-2-thienyl)benzene derivative represented by the general formula [] can be obtained by carrying out the chemical separation and purification that is normally carried out. By converting R ¹ , various (3-methyl-2-thienyl)benzene derivatives can be obtained. For example, when R ¹ in general formula [] is a group represented by formula [], hydration at room temperature or under heating using hydrochloric acid, sulfuric acid, acetic acid, p-toluenesulfonic acid, trichloroacetic acid, phosphoric acid, etc. Disassemble or
easily by dealcoholization reaction in the presence of acetic acid, oxalic acid, or formic acid, etc.

【formula】 or

[Formula] can be converted to the base, like this obtained by

The [Formula] group can be further oxidized with commonly used oxidizing agents (potassium permanganate, silver oxide, hydrogen peroxide, chlorous acid, hypochlorous acid, sodium chlorite, sodium hypochlorite, nitric acid, etc.). If you do it easily

[Formula] Can be converted into a base, or Ta

[Formula] group is formed by haloform reaction.

[Formula] can be converted into a group. Furthermore, when R ¹ is a group represented by formula [],
By using a mineral acid, in the case of a group represented by the formula [], by alkali or acid hydrolysis using alkali hydroxide or hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trichloroacetic acid, etc.

[Formula] Can be converted into a group. The method of the present invention will be further explained in detail by giving examples and reference examples. Example 1 Synthesis of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid 27.8 g (0.157 mol) of 2-bromo-3-methyl-thiophene in 84 ml of anhydrous tetrahydrofuran
and 4.2 g (0.173 mol) of magnesium chips to prepare a Grignard reagent. Meanwhile, 34 g (0.111 mol) of 2-(p-iodophenyl)propionic acid was dissolved in 125 ml of 1N aqueous sodium hydroxide solution, and 9.2 g of anhydrous zinc chloride was dissolved in 125 ml of 1N sodium hydroxide aqueous solution.
(0.0675 mol) to form zinc salt. 100 ml of toluene is added to this to extract the zinc salt, and after azeotropic dehydration, the solvent is distilled off under reduced pressure, and 100 ml of anhydrous tetrahydrofuran is added to the residue. Next, 0.035 g of palladium chloride is added, the temperature is raised to 60 to 65°C, and while stirring, the Grignard reagent prepared above is added dropwise to react. After dropping the entire amount, the mixture was refluxed for 2 hours, and then cooled to room temperature. After cooling, the solvent is distilled off under reduced pressure, 100 ml of water, 12.5 ml of concentrated hydrochloric acid and 100 ml of toluene are added to the residue, and after stirring, the organic layer is separated. The resulting organic layer was washed several times with water and then
Extract the alkali-soluble matter using 125 ml of 1N aqueous sodium hydroxide solution. Add 100 ml of cyclohexane to this aqueous layer, adjust the pH to 4 with 6N hydrochloric acid while stirring, and separate the organic layer. After washing this organic layer with water, it is dried over anhydrous magnesium sulfate, and the solution is stirred at 10 to 20°C to precipitate crystals. If you take this crystal, 2-[4-(3-methyl-2
26 g of -thienyl)phenyl]propionic acid are obtained. Melting point 98-99℃ (recrystallized from a mixed solvent of cyclohexane-ethanol) IR (KBr); νC=O 1700cm ^-1 Elemental analysis amount (C ₁₄ H ₁₄ O ₂ S) C H (%) Theoretical value 68.27 5.73 Actual value 68.15 5.73 Furthermore, if the above filtrate is concentrated and the target compound is recovered, the target compound can be obtained with a yield of 95%. Example 2 Synthesis of 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde 2-promo-3-methylthiophene 27.8g
(0.157 mol) and 4.2 g (0.173 mol) of magnesium chips are reacted in 84 ml of anhydrous tetrahydrofuran to prepare a Grignard reagent. On the other hand, 40.6 g (0.133 mol) of 2-(4-iodophenyl)propionaldehyde dimethyl acetal obtained in Reference Example 1-(2) was dissolved in 122 ml of anhydrous tetrahydrofuran, and palladium chloride
Add 0.04g, raise the temperature to 55℃~60℃,
The Grignard reagent prepared above is added dropwise to this while maintaining the temperature at °C. After completion of the dropwise addition, the temperature was maintained at the same temperature for 1 hour, and then the solvent was distilled off under reduced pressure. Add 120 ml of cyclohexane, 80 ml of water and 5 ml of glacial acetic acid to the residue, stir thoroughly, separate the organic layer, wash with water, and concentrate the solution. Add 250 ml of glacial acetic acid to the residue and react under heating and reflux for 4 hours. After the reaction, the solvent is distilled off under reduced pressure to obtain an oily, almost pure 2-[4-
29.7 g (yield 97%) of (3-methyl-2-thienyl)phenyl]propionaldehyde are obtained. IR (liquid film); νC=O 1715cm ^-1 νCH 2705cm ^-1 (-CHO) If this is oxidized by a conventional method, 2-[4-(3-
Methyl-2-thienyl)phenyl]propionic acid is obtained. Example 3 Synthesis of 4-(3-methyl-2-thienyl)bromobenzene 5.8 g (0.239 mol) of magnesium chips were added to 200 ml of anhydrous tetrahydrofuran, and then 39 g of 2-bromo-3-methylthiophene was added under a nitrogen stream.
(0.220 mol) is gradually added. After dropping the entire amount, heat under reflux for 30 minutes to complete the reaction. Then, excess magnesium pieces are separated through glass wool to prepare Grignard reagent. Next, 50 g of p-iodobromobenzene (0.177
mol) and palladium chloride (0.05 g) were dissolved in 150 ml of anhydrous tetrahydrofuran, and the Grignard reagent prepared above was added dropwise at 50-60°C.
React at 60℃. After the addition, the solvent was partially distilled off, and 150 ml of 10% hydrochloric acid was added to the residue, followed by 100 ml of benzene. The organic layer was separated, washed sequentially with water and an aqueous alkaline solution, and the solvent was removed under reduced pressure. To leave. This residue is purified by silica gel column chromatography (developing solvent: n-hexane) and distilled to obtain 32.6 g (yield: 72.9%) of 4-(3-methyl-2-thienyl)bromobenzene. Boiling point 171-175℃/16-17mmHg Example 4 Synthesis of 4-(3-methyl-2-thienyl)phenylacetic acid 3.1 g (0.13 mol) of magnesium chips was added to 65 ml of anhydrous tetrahydrofuran, and 2- Bromo-3-methylthiophene 21g (0.12
mol) is reacted dropwise, and the excess magnesium pieces are separated through glass wool to obtain a Grignard reagent. Next, 29 g of 4-iodophenyl acetic acid zinc salt was removed by azeotropic dehydration with xylene.
(0.099 mol) and 0.018 g of palladium chloride are added to 150 ml of anhydrous tetrahydrofuran, heated to 60°C, and the Grignard reagent obtained above is added dropwise over 30 minutes. After dropping, stir at 70-80℃ for 2 hours,
After cooling to 30℃, the solvent was distilled off under reduced pressure, and the residue was diluted with water.
Add 100ml and then add 10% hydrochloric acid to adjust the pH to 3.0. Add 200 ml of benzene to this, separate the organic layer, dry over anhydrous magnesium sulfate, distill off the solvent under reduced pressure, add benzene to the residue, crystallize it, and the 4-(3-methyl- 2-thienyl)
21.8 g (yield 95%) of phenylacetic acid is obtained. Melting point 126-127℃ (recrystallized from benzene) IR (KBr); νC=O 1700cm ^-1 NMR (CDCl ₃ ) 60MHz, internal standard TMS τ value 7.71 (s, 3-position CH ₃ of thiophene,
3H) 6.33 (s, - CH ₂ COOH, 2H) 3.12 (d, H at the 4-position of thiophene,
1H, J=5Hz) 2.83 (d, 5th H of thiophene,
1H, J = 5Hz) 2.64 (s, 2, 3, 5, 6 of benzene
Example 5 Synthesis of 4-(3-methyl-2-thienyl)chlorobenzene 1.9 g (0.078 mol) of magnesium chips was added to 60 ml of anhydrous tetrahydrofuran, and while stirring, the 2-
13.3 g (0.075 mol) of bromo-3-methylthiophene was gradually added dropwise to react. After finishing dropping,
Heat under reflux for 30 minutes and remove excess magnesium with glass wool to obtain Grignard reagent. Meanwhile, 15 g (0.063 mol) of p-chloroiodobenzene was dissolved in 60 ml of anhydrous tetrahydrofuran.
Add 0.03g of palladium chloride and add 55% while stirring.
Raise the temperature to ~60°C. The Grignard reagent prepared above is gradually added dropwise to this solution for reaction. After dropping, heat at 60-70°C for 20 minutes and then cool.
After separating the salts precipitated at this time and washing with 30 ml of tetrahydrofuran, the entire liquid was concentrated under reduced pressure, and the resulting residue was poured into 100 ml of 5% hydrochloric acid.
Next, 80 ml of n-hexane was added, and after thorough shaking, the organic layer was separated. The obtained n-hexane solution is further washed successively with 100 ml of 5% hydrochloric acid and 100 ml of 5% aqueous sodium hydroxide solution, and the obtained organic layer is dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. . The resulting residue was distilled under reduced pressure to obtain 12.5 g (yield: 95%) of 4-(3-methyl-2-thienyl)-chlorobenzene. Boiling point 162-164℃/17mmHg Example 6 (1) 2-[1-[4-(3-methyl-2-thienyl)phenyl]ethyl]-4,4-dimethyl-
Synthesis of 2-oxazoline 2-[1-(4-iodophenyl)ethyl]-4,4-dimethyl-2-
8.0 g (0.0243 mol) of oxazoline is dissolved in 24 ml of anhydrous tetrahydrofuran, then 0.08 g of palladium chloride is added and heated to 60-65°C. On the other hand, 2-bromo-3-methylthiophene
5.2g (0.0294mol), 0.8g of magnesium chips
(0.0329 mol) and anhydrous tetrahydrofuran
Prepare Grignard reagent from 15 ml and dropwise add this Grignard reagent to the solution obtained above over 30 minutes while maintaining the temperature at 60-65°C. After further completing the reaction at the same temperature for 1 hour, the solvent was distilled off under reduced pressure, and 50 ml of benzene and 50 ml of water were added to the resulting residue.
After adding 5 ml of glacial acetic acid and shaking thoroughly, the organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily 2-[1-[4-( 3-Methyl-2-thienyl)phenyl]ethyl]-4,4-dimethyl-
6.8 g of 2-oxazoline (yield 93.3%) is obtained. IR (liquid film); νC=N 1645cm ^-1 (2) Synthesis of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid 2-[1-[ obtained in (1) above] 4-(3-methyl-2-thienyl)phenyl]ethyl]-4,
4-dimethyl-2-oxazoline 6.0g (0.020
mol) in 30 ml of glacial acetic acid, 6 ml of water and 2 ml of concentrated sulfuric acid.
ml of a mixed solution and heated under reflux for 4 hours. After the reaction is complete, 50 ml of water and 50 ml of benzene are added to the reaction mixture, thoroughly shaken, the organic layer is separated and washed with water, and then 25 ml of 1N aqueous sodium hydroxide solution is added. After shaking this solution thoroughly, separate the aqueous layer, add 20 ml of benzene,
Add 25 ml of 1N hydrochloric acid to neutralize. Next, the organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. By adding a small amount of n-hexane to the resulting residue and crystallizing it, 4.0 g of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (yield: 82
%). Example 7 (1) Synthesis of 4-(3-methyl-2-thienyl)ethylbenzene 1.85 g (0.0761 mol) of ground magnesium was added to 30 ml of anhydrous tetrahydrofuran, and 12.5 g of 2-bromo-3-methylthiophene was added with stirring. g
(0.071 mol) and react. After starting the reaction, the remaining half amount of 2-bromo-3-methylthiophene was gradually added dropwise, and after the addition was completed, the mixture was further refluxed with stirring for 1 hour. 15.0 g (0.0647 mol) of 4-iodoethylbenzene is dissolved in 50 ml of anhydrous tetrahydrofuran and 0.012 g of palladium chloride is added. this mixture
While maintaining the temperature at 55-60°C, the Grignard reagent obtained above was added dropwise, and the mixture was refluxed with stirring for 1 hour. After the solvent is distilled off under reduced pressure, 100 ml of benzene, 5 ml of acetic acid and 100 ml of water are added, and after thorough shaking, the organic layer is separated and washed with 100 ml of water. After drying the benzene solution obtained in this way over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the 4-(3
-Methyl-2-thienyl)ethylbenzene 12.0g
(yield 92%). NMR (CCl ₄ ); 60 MHz, internal standard TMS τ value 8.80 (t, −CH ₂ CH ₃ , 3H, J = 7 Hz) 7.78 (s, 3rd position CH ₃ of thiophene, 3H) 3.42 (q, − CH ₂ CH ₃ , 2H, J = 7Hz) 3.33 (d, 4th position H of thiophene, 1H, J
=5Hz) 3.08 (d, 5th position H of thiophene, 1H, J
=5Hz) 3.00 (d, 2nd and 6th position H of benzene, 2H,
J = 9Hz) 2.77 (d, H at the 3rd and 5th positions of benzene, 2H,
J=9Hz) (2) Synthesis of 4-(3-methyl-2-thienyl)acetophenone 4.04 g (0.020 mol) of 4-(3-methyl-2-thienyl)ethylbenzene obtained in (1) above was dissolved in acetic acid. 2.66g of selenium dioxide dissolved in 30ml
After adding (0.024 mol), the mixture was refluxed for 4 hours while stirring. The reaction mixture was cooled to room temperature and filtered through Celite. Add 50 ml of benzene and 70 ml of water to the solution, shake thoroughly, and then wash the separated organic layer with 50 ml of water. After drying the benzene solution obtained in this way over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (developing solvent: benzene: n-hexane = 2:1). If purified, 4-(3-methyl-2-thienyl)
2.68 g (yield 62%) of acetophenone is obtained. IR (liquid film); νC=O 1675 cm ^-1 Example 8 (1) Synthesis of 4-(3-methyl-2-thienyl)benzoic acid 24.8 g (0.1 mol) of 4-iodobenzoic acid was dissolved in 1N-
A solution of 7.5 g (0.055 mol) of zinc chloride dissolved in 10 ml of water was added under stirring to a solution of 105 ml of sodium hydroxide aqueous solution, and the precipitated crystals were collected, washed with water, and then added to 200 ml of toluene. suspend,
Azeotropically dehydrate for 2 hours with stirring. After cooling, collect the crystals, suspend them in 150 ml of anhydrous tetrahydrofuran, add 0.03 g of palladium chloride, and heat at 60-65°C.
Add 63 ml of anhydrous tetrahydrofuran, 21.3 ml of 2-bromo-3-methylthiophene to this solution while maintaining
g (0.12 mol) and 3.2 g of ground magnesium
Grignard reagent prepared from (0.13 mol)
It takes 30 minutes to drip. After the addition is complete, the mixture is stirred at 60 to 65°C for an additional hour to complete the reaction. After the reaction, the solvent was distilled off under reduced pressure, 200 ml of chloroform and 130 ml of 1N hydrochloric acid were added to the residue, stirred thoroughly, and the organic layer was separated, washed thoroughly with water, and further
Add 105 ml of 1N hydrochloric acid, shake thoroughly, and separate the aqueous layer. This aqueous layer is neutralized by adding 105 ml of 1N hydrochloric acid, and the precipitated crystals are collected, washed with water, and dried, yielding 20.9 g of almost pure 4-(3-methyl-2-thienyl)benzoic acid. (yield 96%). Melting point 147-148℃ IR (KBr); νC=O 1680cm ^-1 (2) Synthesis of 4-(3-methyl-2-thienyl)acetophenone 4-(3-methyl-2-thienyl)benzoic acid
60 ml of benzene, 17.85 g (0.15 mol) of thionyl chloride and 3 drops of dimethylformamide are added to 21.8 g (0.1 mol) and refluxed for 2 hours. After the reaction is complete,
If the solvent is distilled off under reduced pressure, 4-(3-methyl-
2-thienyl)benzoic acid chloride is obtained. Meanwhile, mix 2.7 g (0.11 mol) of magnesium chips, 14.5 ml of ethanol, and 0.3 ml of carbon tetrachloride.
Stir for 2 hours. Add 19.2 g (0.12 mol) of diethyl malonate to this mixed solution in anhydrous tetrahydrofuran.
Add the solution dissolved in 90 ml and reflux for 1 hour.
The 4-(3-methyl-2-thienyl)benzoic acid chloride obtained above was added dropwise to the reaction mixture thus obtained at 0 to 10°C over a period of 30 minutes.
Stir and react for an additional 30 minutes. After the reaction is complete, the solvent is distilled off, and 100 ml of acetic acid, 20 ml of water and 7 ml of concentrated sulfuric acid are added to the residue, followed by refluxing for 2 hours. After the reaction, the solvent was distilled off under reduced pressure and the residue was added with toluene.
Add 100ml and 100ml of water and shake thoroughly. Next, the organic layer was separated, washed with 50 ml of 1N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, concentrated, and distilled under reduced pressure (159-163°C/mmH).
g) 17.7 g (yield 82%) of crystalline 4-(3-methyl-2-thienyl)acetophenone is obtained. Melting point 36℃ IR (KBr); νC=O 1685cm ^-1 Example 9 Synthesis of d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid d-2-(4-iodophenyl)propionic acid
Dissolve 7.8g (0.028mol) in 28ml of 1N sodium hydroxide aqueous solution and add 2.0g of anhydrous zinc chloride.
(0.015mol) to form zinc salt. To this, 23.4 ml of toluene is added, the zinc salt is extracted, and after azeotropic dehydration, the solvent is distilled off under reduced pressure, and 23.4 ml of anhydrous tetrahydrofuran is added to the residue. On the other hand, in 17.8 ml of anhydrous tetrahydrofuran, 2-
Bromo-3-methylthiophene 5.9g
(0.033mol) and ground magnesium 0.87g
(0.036mol) and prepare the Grignard reagent. 0.008 g of palladium chloride is added to the anhydrous tetrahydrofuran solution of the zinc salt of d-2-(4-iodophenyl)propionate obtained previously, the temperature is raised to 60-65°C, and the prepared Grignard reagent is added dropwise to react with stirring. After dropping the entire amount, the mixture was refluxed for 2 hours, and then cooled to room temperature. After cooling, the solvent was distilled off under reduced pressure, and water was added to the residue.
ml, concentrated hydrochloric acid 3.0 ml and toluene 23.4 ml and stirred, and then the organic layer was separated. The resulting organic layer was washed several times with water and then 1N
- Extract the alkali solubles using 28.0 ml of aqueous sodium hydroxide solution. Add 23.4 ml of cyclohexane to this extract, and add 6N hydrochloric acid to pH 4 with stirring.
and separate the organic layer. This organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain 6.2 g of an oil. Add 43 ml of hexane to this oil, and add a trace amount of d-2-[4-(3-
Add methyl-2-thienyl)propionic acid and add 30
Stir for a minute. If you take the formed crystal, d-
6.0 g (0.024 mol) of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid is obtained. Melting point 62-63°C (recrystallized from a mixed solvent of cyclohexane-hexane) IR (KBr); νC=O 1700cm ^-1 [α] ²⁰ _D = +51.2° (C = 2.01, ethanol) Reference example 1 (1) Synthesis of 2-(4-iodophenyl)propionaldehyde 47.7 g (0.194 mol) of 4-iodoacetophenone and 42.1 g (0.388 mol) of methyl monochloroacetate were dissolved in 143 ml of toluene, and sodium methane was added while cooling to -10 to 0°C. 18.9 g (0.35 mol) of Lato was added in portions over 1 hour. And 0
React with stirring at ~10°C for 1 hour, at room temperature for 1 hour, and at 50-60°C for 1 hour. After the reaction is complete, add 100 ml of water to the reaction mixture cooled to room temperature, shake thoroughly, separate the organic layer, and evaporate the solvent under reduced pressure to obtain oily 3-methyl-3-(4-iodophenyl). ) to obtain methyl glycidylate. A solution of 10.8 g of sodium hydroxide dissolved in 143 ml of ethanol is added to this, and the mixture is gradually heated and refluxed for 30 minutes.
Next, the reaction mixture is cooled to 10-15°C, and the precipitated crystals are collected and washed successively with ethanol and toluene. The crystals are suspended and dispersed in 143 ml of toluene, and 12.8 ml of glacial acetic acid is added dropwise under heating and refluxing, and refluxing is continued until no carbon dioxide gas is generated. The reaction mixture was then cooled to room temperature, washed with 100 ml of water, and further washed with 0.1N aqueous sodium hydroxide solution.
Wash with 50ml. Subsequently, the solvent is distilled off under reduced pressure and distilled under reduced pressure (153-156°C/15mmHg).
34 g (yield 67.4%) of 2-(4-iodophenyl)propionaldehyde are obtained. IR (liquid film); νC=O 1720cm ^-1 νCH 2710cm ^-1 , 2805cm ^-1 (2) Synthesis of 2-(4-iodophenyl)propionaldehyde dimethyl acetal 2-(4-iodophenyl)propionaldehyde 39.2g (0.151 mol) ) was dissolved in 39.2 ml of methanol, 0.2 g of p-toluenesulfonic acid was added, and the mixture was stirred at room temperature for 10 minutes. Then methyl orthoformate
19.2 g (0.18 mol) was added and stirred at the same temperature for 30 minutes. After the reaction was completed, 1.0 g of sodium methylate was added, the solvent was distilled off under reduced pressure, and the solution was distilled under reduced pressure (155-160
℃/15mmHg), 2-(4-iodophenyl)propionaldehyde dimethyl acetal
43.2 g (yield 93.6%) is obtained. NMR (CDCl ₃ ) 60MHz, internal standard TMS τ value 8.79 (d,

[Formula], 3H, J=7Hz) 6.79~7.29 (m,

[Formula], 1H, J=7Hz) 6.85 to 6.75 (a,

[Formula], 3H, 3H) 5.80(d,

[Formula], 1H, J=7Hz) 3.19 (d, H at the 2 and 6 positions of benzene, 2H,
J = 8 Hz) 2.58 (d, H at the 3rd and 5th positions of benzene, 2H,
J=8Hz) Reference Example 2 (1) Synthesis of 2-(4-iodophenyl)propionic acid Dissolve 34g (0.131 mol) of 2-(4-iodophenyl)propionaldehyde in 100ml of ethylene chloride, and add 16.5g (0.170 mol) of sulfamic acid to this. mol) in 85 ml of water. While stirring, a solution of 15.2 g (0.168 mol) of sodium chlorite dissolved in 22 ml of water is added dropwise while maintaining the temperature at 10-15°C. After stirring for 10 minutes, 15 g (0.144 mol) of sodium hydrogen sulfite is added little by little, and the organic layer is separated and washed with water. Next, add 150 ml of 1N aqueous sodium hydroxide solution, separate the aqueous layer, and add 6N aqueous solution.
- If the pH is adjusted to 3.0 with hydrochloric acid, white crystals will precipitate. If you take this, wash it with water, and dry it, 2-
(4-iodophenyl)propionic acid 34g (yield
94%). Melting point 101-102℃ (recrystallized from cyclohexane) IR (KBr); νC=O 1685cm ^-1 (2) Synthesis of zinc salt of 2-(4-iodophenyl)propionic acid 2-( obtained in (1) above) 4-iodophenyl)
Dissolve 34 g (0.123 mol) of propionic acid in 125 ml of 1N aqueous sodium hydroxide solution and 100 ml of toluene.
and a solution of 9.2 g (0.067 mol) of zinc chloride dissolved in 10 ml of water. Then, after stirring thoroughly,
The organic layer is separated, subjected to azeotropic dehydration, and then the solvent is distilled off under reduced pressure to obtain 37.5 g of syrupy zinc salt of 2-(4-iodophenyl)propionic acid (yield 99%).
get. Reference example 3 2-[1-(4-iodophenyl)ethyl]4,
Synthesis of 4-dimethyl-2-oxazoline 25 g (0.091 mol) of 2-(4-iodophenyl)propionic acid obtained in Reference Example 2-(1) was dissolved in 50 ml of chloroform, and then 16.1 g of thionyl chloride was dissolved.
(0.135 mol) and refluxed for 2 hours. After the reaction is completed, excess thionyl chloride and chloroform are distilled off under reduced pressure. Then, the obtained residue was dissolved in 50 ml of chloroform, and 2-amino-2-methyl-1-
20g (0.225mol) of propanol in chloroform
Add dropwise to 50 ml of solution at 0 to 10°C over 30 minutes. After dropping, stir for 15 minutes and add water.
Wash with 100 ml of water, separate the chloroform layer, dry with anhydrous magnesium sulfate, and add phosphorus oxychloride.
17.7g (0.115 mol) is added dropwise to react at 10-20°C. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour, 100 ml of water was added to the reaction mixture, and while stirring vigorously, a 20% aqueous sodium hydroxide solution was added while maintaining the temperature at 10 to 20°C to adjust the pH to 12. Next, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solution was concentrated to dryness to obtain 2-[1-(4-iodophenyl).
ethyl]-4,4-dimethyl-2-oxazoline
Obtain 28.8 g (96.5% yield). IR (KBr); νC=N 1645 cm ^-1 Reference Example 4 (1) Synthesis of 2-(4-iodophenyl)-2-methyloxirane In a solution of 30 g (0.483 mol) of dimethyl sulfide dissolved in 30 ml of acetonitrile, 30 g (0.238 mol) of dimethyl sulfate was added dropwise at 40 to 50°C over 30 minutes, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was cooled to 25°C, and 30 g (0.122 mol) of 4-iodoacetophenone and 90 ml of acetonitrile were added.
Add sodium methoxide 13.2 while stirring.
g (0.244 mol) is added. Stir at room temperature for 30 minutes to complete the reaction. After the reaction was completed, dimethyl sulfide and acetonitrile were distilled off, 120 ml of cyclohexane and 120 ml of water were added to the residue, thoroughly shaken, the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. If you leave it in
31.5 g (yield 99%) of oily 2-(4-iodophenyl)-2-methyloxirane is obtained. Note that if this oily substance is left at room temperature, it will gradually solidify. Melting point 44-45℃ (recrystallized from n-hexane) (2) Synthesis of 2-(4-iodophenyl)propionaldehyde 2-(4-iodophenyl)- obtained in (1) above
Dissolve 15 g (0.058 mol) of 2-methyloxirane in 75 ml of toluene, add 1.5 g of crushed molecular sieves 4A, and reflux for 4 hours. After the reaction is complete, separate the molecular sieves, concentrate the liquid, and distill under reduced pressure (152-160℃/15mmHg) to obtain
12.5 g (83% yield) of oily 2-(4-iodophenyl)propionaldehyde are obtained. Reference Example 5 Synthesis of d-2-(4-iodophenyl)propionic acid 16.0g cinchonidine in 90ml ethanol
(0.0544 mol) was heated and dissolved, and then 30.0 g (0.109 mol) of 2-(4-iodophenyl)propionic acid obtained in Reference Example 2-(1) was added to this solution, and after heating and dissolving, 39.0 g of ethyl acetate was added. ml under heating. The solution is stirred for 1 hour at 60°±2°C to precipitate crystals, and then gradually cooled to room temperature. If you remove the precipitated crystals, you will find 20.5 g of cinchonidine salt of d-2-(4-iodophenyl)propionic acid.
(0.036mol) is obtained. The obtained salt is suspended in methyl acetate with stirring and added to dilute hydrochloric acid. After that, the organic layer is separated, washed with water, dried over anhydrous magnesium sulfate, concentrated to dryness, and has an optical purity of 90%.
-2-(4-iodophenyl)propionic acid 9.8g
(0.0355mol) is obtained. If this crystal is recrystallized from a mixed solvent of ethanol and cyclohexane, d-2-
(4-iodophenyl)propionic acid 7.8g
(0.028mol) is obtained. Melting point 138-139℃ [α] ²⁰ _D = +40.5° (C = 2.82, ethanol)

Claims (1)

[Claims] 1. General formula [In the formula, X ¹ represents a halogen atom or a group consisting of -Mg-halogen atom. ] In the presence of a catalyst, a compound represented by the general formula [In the formula, R ¹ is a halogen atom, an alkyl group, or a general formula or A group represented by [formulas [] to [], M represents a metal atom,
R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ and R ¹⁰ are hydrogen atoms or alkyl groups, R ⁷ and R ⁸ are alkyl groups or alkenyl groups, or R ⁷ and R ⁸ are adjacent [Formula] A group which may be combined with the group to form a ring, R ¹¹ represents a hydrogen atom or a methyl group, and Y represents an oxygen atom or a sulfur atom. ]
, X ² represents a halogen atom or a group consisting of -Mg-halogen atom. However, in the formula [] above,
When X ¹ is a halogen atom, X ² is −Mg−
When X ¹ is a halogen atom or a -Mg-halogen atom, X ² represents a halogen atom. ] A general formula characterized by reacting with a compound represented by [In the formula, R ¹ has the meaning described above. ] A method for producing a (3-methyl-2-thienyl)benzene derivative represented by: ^2. The method for producing a (3-methyl-2-thienyl)benzene derivative according to claim 1, wherein X 1 is a -Mg-halogen atom and X ² is a halogen atom. ^3. (3 -Methyl-2-thienyl)benzene derivative manufacturing method. 4 Claim 3 in which R ¹ is [Formula] (where M has the above meaning)
A method for producing a (3-methyl-2-thienyl)benzene derivative described in Section 1. 5. The method for producing a (3-methyl-2-thienyl)benzene derivative according to claim 4, wherein 5 M is a zinc atom. 6. The method for producing a (3-methyl-2-thienyl)benzene derivative according to any one of claims 1 to 5, wherein the catalyst is a palladium, nickel or platinum catalyst. 7. The method for producing a (3-methyl-2-thienyl)benzene derivative according to claim 6, wherein the catalyst is a palladium catalyst.