JPS6225146B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following general formula [wherein R is a halogen atom, an alkyl group, a cyano group, an amino group, a nitro group, an optionally protected formyl group, an optionally protected acetyl group,
-MgX, -COCHO, ^-COOR1 , optionally substituted oxazoline group,

【formula】

【formula】

【formula】

【formula】 or

[Formula] is shown. [However, X represents a halogen atom, and R ¹ represents a hydrogen atom, a salt-forming cation, or an ester-forming group. (Hereinafter, R ¹ has the same meaning.); R ² is a hydrogen atom or a methyl group; R ³ is a cyano group, a halogen atom, an optionally protected hydroxyl group, an optionally protected formyl group, a protected an optional acetyl group, -COOR ¹ (however,
When R ² is a methyl group and R ⁴ is a hydrogen atom, this R ¹
is an ester-forming group. ), -COCOOR ¹ , an optionally substituted oxazoline group,

[Formula] −CH ₂ OH, −COCONH ₂ , −COCN, −MgX or

[Formula] (where R ¹⁰ and R ¹¹ are a hydrogen atom or an alkyl group, or R ¹⁰ and R ¹¹ taken together to form a ring with the adjacent nitrogen atom); R ⁴ is a hydrogen atom or an optionally protected hydroxyl group, halogen atom, amino group, dialkylamino group or -COOR ¹ ; R ⁵ is a hydrogen atom,
an alkyl group, an alkoxy group, a hydroxyl group, a carbamoyl group or a cyano group; R ⁶ is a hydrogen atom or -
COOR ¹ ; R ⁷ is a cyano group, carbamoyl group, or -COOR ¹ ; R ⁸ is an optionally protected hydroxyl group or -COOR ¹ ; R ⁹ is -COOR ¹ or

[Formula] (However, R ¹² represents a hydroxyl group which may be protected.) ] ] This relates to a novel 4-(3-methyl-2-thienyl)benzene derivative represented by the following. The present inventors previously reported that 2-[4-(3-methyl-2
-Thienyl)phenyl]propionic acid≪≫ and its non-toxic salts have favorable properties such as excellent anti-inflammatory and analgesic effects, low toxicity and side effects, and can be used for extended periods, making them extremely useful as anti-inflammatory and analgesic agents. I discovered something (Special application 1977-
No. 138943). The compound of the formula <<>> of the present invention can be obtained by a reaction known per se to obtain its useful 2-[4-(3-methyl-2-
It is an extremely useful substance as an intermediate derived from thienyl)phenyl]propionic acids. The present invention will be explained in detail below. In the present specification, halogen atoms include chloro, bromo, iodo, etc.; alkyl groups include methyl, ethyl, propyl, butyl, and other alkyl groups; optionally protected formyl groups include - CHO or expression

[Formula] or

Those represented by [Formula] (wherein R ¹³ and R ¹⁴ represent an alkyl group or an alkenyl group, and n represents 2 or 3); optionally protected acetyl groups include:
For example −COCH ₃ or the formula

[Formula] or

[Formula] (In the formula, R ¹³ , R ¹⁴ and n have the above-mentioned meanings.) The optionally substituted oxazoline group is represented by the formula

[expression] or

[Formula] (In the formula, R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ represent a hydrogen atom or an alkyl group.) Salt-forming cations include lithium, sodium A cation that forms a salt with a carboxyl group such as , potassium, magnesium, calcium, or zinc; As an ester-forming group, a group that forms an ester with a carboxyl group such as an alkyl group or an aralkyl group; may be protected. Examples of hydroxyl groups include hydroxyl group, acetoxy group, benzoyloxy group;
Examples of R ¹⁰ and R ¹¹ taken together to form a ring with the adjacent nitrogen atom include morpholino and hyperdino groups; examples of alkoxy groups include methoxy,
Alkoxy groups such as ethoxy, propoxy and butoxy; dialkylamino groups include dialkylamino groups such as dimethylamino, diethylamino and methylethylamino; and alkenyl groups include alkenyl groups such as allyl and propenyl. In addition, some of the compounds represented by the general formula <<> of the present invention include asymmetric carbon atoms, and these compounds naturally exist in optical isomers and racemic forms, but the present invention encompasses both of them. be done. The compounds of the formula <<>> of the present invention are produced and utilized, for example, by the reactions shown in the following (1) to (25). (In the formula, M is a metal atom such as Na, K, Zn, Al, etc.
For example, R ²¹ is an alkyl group, X is a halogen atom, and R ²² is

[Formula], R ²³ is − COCH ₃ , −NH ₂ , −COOH, −COOR ²¹ −CN, −
NO ₂ , halogen atom, -CHO, -COCHO, -
COCOOH, −COCOOR ²¹ , R ¹⁰ , R ¹¹ , R ¹³
and R ¹⁴ have the meanings given above. ) The Grignard reactions of reactions (1) to (4) and (7) to (9) are methods discovered for the first time by the present inventors. That is, the expression

[Formula] and

It can be produced by reacting [Formula] (wherein X and R have the above-mentioned meanings) in the presence of a catalyst. In this case, the solvent used is not limited as long as it does not participate in the Grignard reaction, and examples thereof include tetrahydrofuran, dioxane, diethyl ether, and the like. Further, the catalyst may be a palladium compound, a nickel compound, a platinum compound, etc., such as palladium chloride.
Although the reaction temperature and time are not particularly limited, the reaction is carried out under reflux of the solvent for 30 minutes to several hours. Furthermore, if R is inconvenient during the Grignard reaction, it can be converted into a suitable group by a conventional method, and then converted into a desired group after the reaction. The other reactions are reactions known per se. The reactions (1) to (25) above can be easily carried out by referring to the following production examples and matters described in known literature, and the compounds of the present invention can be obtained. Next, the compound of the present invention will be explained with reference to production examples. Production example 1 (1) Synthesis of 4-(3-methyl-2-thienyl)acetophenone (i) Method (i) 27 g of hydrochloride of 4-aminoacetophenone
(0.157 mol) in methanol 30 ml, acetic acid 30 ml and 3-methylthiophene 150 g (1.53 mol)
Then, 28 g (0.237 mol) of isoamyl nitrite was added thereto. While stirring, 15 g (0.183 mol) of anhydrous sodium acetate is added in portions at room temperature. Meanwhile, water cooling to 20-30℃
Try to keep it. After adding the entire amount, the mixture was stirred for 4 hours, the solvent was distilled off under reduced pressure, and the residue was extracted with diisopropyl ether. After washing the organic layer with alkaline water, it was dehydrated with anhydrous magnesium sulfate, then treated with activated carbon, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain pale yellow 4-(3
-Methyl-2-thienyl)acetophenone 20
g (yield 58.8%). Boiling point 180-182℃/6mmHg I・R (liquid film); νC=O 1665cm ^-1 NMR (CDCl ₃ ); 60MHz Internal standard TMS τ value; 7.68 (s, 3-position CH ₃ of thiophene,
3H) 7.44 (s, -CO CH ₃ , 3H) 3.16 (d, thiophene 4-position H 1H, J=
5Hz) 2.83 (d, thiophene 5th position H 1H, J=
5Hz) 2.55 (d, benzene 3rd, 5th position H 2H, J
=8Hz) 2.11 (d, benzene 2, 6th position H 2H, J
=8Hz) (ii) Method (ii) 3-methylthiophene 150g (1.53mol)
4-acetylbenzenediazonium tetrafluoroborate obtained from the diazonium salt of 4-aminoacetophenone and 42% hydrofluoric acid was mixed with 50 ml of methanol and cooled to -10 to 0°C. Add 43g (0.183 mole). Next, 70 ml of a methanol solution containing 9.9 g (purity 95%) (0.183 mol) of powdered sodium methylate was mixed with -10 to 0 with stirring.
Add slowly at ℃. During this time, nitrogen gas is generated intensely. After the dropwise addition, the temperature was gradually raised to room temperature, and after stirring at 20 to 30°C for 3 hours, the solvent and excess 3-methylthiophene were distilled off under reduced pressure. After diisopropyl ether is added to the residue and extracted by heating, the organic layer is washed with alkaline water, then dried with saturated brine, and the solvent is distilled off. If you process in the same way as method (1) below, 4
-(3-Methyl-2-thienyl)acetophenone 21 g (yield 53%) is obtained. (iii) Method (iii) 3-methylthiophene 120g (1.22mol)
and 40 g (0.296 mol) of 4-aminoacetophenone were mixed and suspended and dispersed. To this was added 41.5 g of isoamyl nitrite (0.355 g) at 20°C with stirring.
mol) is gradually added dropwise. After dropping the entire amount, react under reflux for 1 hour, recover excess 3-methylthiophene by atmospheric distillation, and treat the residue in the same manner as method (1) or (2) to obtain 4-(3 -Methyl-2-thienyl)acetophenone 23 g (yield 36%) are obtained. (2) Synthesis of methyl 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidylate. 20 g (0.0925 mol) of 4-(3-methyl-2-thienyl)acetophenone is dissolved in 150 ml of tetrahydrofuran, and then 20 g (0.184 mol) of methyl monochloroacetate is added and dissolved. This is cooled to -5 to 0°C, and 10.5 g (0.185 mol) of sodium methylate (95% purity) is gradually added at the same temperature. After adding the entire amount, stir at the same temperature for 1 hour, further stir at room temperature for 1 hour, and then stir for 30 minutes.
Reflux for minutes. After the solvent was distilled off under reduced pressure, 100 ml of diisopropyl ether and 50 ml of water were added, and the organic layer was separated and passed through Celite to remove trace amounts of insoluble matter. After drying the obtained organic layer with magnesium sulfate and distilling off the solvent, almost pure oily 3-methyl-3-[4-(3-methyl-2
-thienyl)phenyl]methylglycidylate 25
g (yield 92%). I.R (liquid film); νC=O 1750cm ^-1 (3) Synthesis of 3-methyl-3[4-(3-methyl-2-thienyl)phenyl]glycidylic acid. Caustic potash (85% purity) 7.5g (0.115mol)
3-methyl-3 in 100 ml of ethanol solution containing
- After adding 30 g (0.104 mol) of methyl [4-(3-methyl-2-thienyl)phenyl]glycidylate, reflux is carried out for 1 hour. After distilling off the ethanol, add 200 ml of water, then add 100 ml of benzene to remove insoluble matter, shake well, and adjust the separated aqueous layer to pH 3 with 10% hydrochloric acid to produce an oil. After extracting this with diisopropyl ether and separating the organic layer,
After drying over magnesium sulfate, the diisopropyl ether was distilled off under reduced pressure to obtain 17 g (yield: 60%) of oily 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl)glycidylic acid. I.R (liquid film); νC=O 1720cm ^-1 (4) Synthesis of 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde. 3-Methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidylic acid 17g (0.062
mol) in 100 ml of toluene and refluxed for 1 hour. After the generation of carbon dioxide gas has stopped, cool it down, add 100 ml of 10% sodium bicarbonate solution to the reaction solution, and wash the organic layer. Next, the organic layer is dehydrated with saturated brine, treated with activated carbon, and the solvent is distilled off under reduced pressure.
Add 100 ml of n-hexane to this residue, heat to reflux, perform heating extraction, and separate from insoluble matter. Furthermore, 50% n-hexane was added to this residual insoluble matter.
Perform the same operation twice using ml address. If the collected n-hexane is distilled off, almost pure 2-
[4-(3-methyl-2-thienyl)phenyl]
12 g (85% yield) of propionaldehyde are obtained. I/R (liquid film); νC=O 1715cm ^-1 Production example 2 (1) 2,3-dimethyl-3-[4-(3-methyl-
Synthesis of methyl 2-thienyl)phenylglycidylate. tert. 5.0 g (0.0232 mol) of 4-(3-methyl-2-thienyl)acetophenone and 8.5 g (0.0693 mol) of methyl α-chloropropionate.
- 6.5 g (0.058 mol) of potassium tert.-butoxide are added slowly at 20-30 DEG C., dissolved in 30 ml of butanol. After the addition, the mixture is stirred at room temperature for 1 hour and then for 1 hour under reflux. After the reaction is completed, tert.-butanol is distilled off under reduced pressure, and 30 ml of cyclohexane and 30 ml of water are added to the residue for extraction.
After washing with water and drying over anhydrous magnesium sulfate, cyclohexane is distilled off under reduced pressure to obtain an almost pure oily 2,3-dimethyl-3-[4-(3-
7.1 g (100% yield) of methyl-2-thienyl)phenyl]glycidylate are obtained. I/R (liquid film); νC=O 1730, 1750 cm ^-1 NMR (CDCl ₃ ) 60 MHz, internal standard TMS cis, trans mixture τ value; 8.76 (s,

[Formula] 3H) 8.36(s,

[Formula] 3H) 7.66 (s, 3rd position _CH 3 of thiophene, 3H) 6.22 (s, -COO CH ₃ , 3H) 3.19 (d, 4th position H of thiophene, 1H, J=
5Hz) 2.91 (d, 5th position H of thiophene, 1H, J=
5Hz) 2.66 (s, 2nd, 3rd, 5th, 6th position H of benzene,
4H) (2) Synthesis of 3-[4-(3-methyl-2-thienyl)phenyl]-2-butanone. 2,3-dimethyl-3-[4-(3-methyl-
2-thienyl)phenyl]methyl glycidylate
Dissolve 7.1g (0.0235mol) in 21ml of ethanol and add 1.7g of sodium methylate at room temperature.
(0.0315 mol) and stirred, then 0.5 ml of water.
Add and gradually heat to reflux for 30 minutes. Ethanol was distilled off from the reaction mixture under reduced pressure, and the residue was dispersed in 40 ml of xylene.
ml and heated under reflux for 4 hours. After the reaction, the xylene layer is washed with water, then with 20 ml of 1N aqueous sodium hydroxide solution, washed again with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under pressure to obtain an oily 3- [4-(3-
4.3 g (yield 76%) of methyl-2-thienyl)phenyl]-2-butanone are obtained. I/R (liquid film); νC=O 1705cm ^-1 NMR (CCl ₄ ) 60MHz, internal standard TMS τ value; 8.64 (d,

[Formula] 3H, J=7Hz) 8.00 (s, -CO CH ₃ , 3H) 7.70 (s, 3rd position CH ₃ of thiophene, 3H) 6.35 (q,

[Formula] 1H, J = 7Hz) 3.24 (d, H at the 4th position of thiophene, 1H, J =
5Hz) 2.97 (d, 5th position H of thiophene, 1H, J=
5Hz) 2.90 (d, 2nd and 6th positions of benzene H, 2H, J
=9Hz) 2.68 (d, 3rd and 5th positions of benzene H, 2H, J
=9Hz) Production Example 3 (1) Synthesis of 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde. 5.0 g (0.0232 mol) of 4-(3-methyl-2-thienyl)acetophenone was dissolved in acetonitrile.
Then, 8.7 g (0.046 mol) of trimethylsulfonium methyl sulfate was added, and sodium methylate was further dissolved with stirring at room temperature.
Add 2.5 g (0.0464 mol) and continue stirring for 1 hour. Then, the solvent is distilled off under reduced pressure, and 20 ml of toluene is added to the residue, which is washed several times with water. After drying over anhydrous magnesium sulfate and distilling off the solvent under reduced pressure, almost pure oily 2-
[4-(3-methyl-2-thienyl)phenyl]
-2-Methyloxirane 5.2g (yield 97.4%)
get. Dissolve this in 25 ml of toluene, add 0.5 g of Molecular Sieves 4A crushed in a mortar, and reflux for 1 hour. Separate the monocular sieves and distill off the solvent under reduced pressure. -[4-(3-methyl-2-thienyl)phenyl]propionaldehyde 5.1 g (yield 98
%). I・R (liquid film); νC=O 1715cm ^-1

[Formula] 2705, 2805cm ^-1 NMR (CCl ₄ ) 60MHz, internal standard TMS τ value; 8.63 (d,

[Formula] 3H, J=7Hz) 7.77 (s, 3rd position CH ₃ of thiophene, 3H) 6.46 (q,

[Formula] 1H, J = 7Hz) 3.21 (d, H at the 4th position of thiophene, 1H, J =
5Hz) 2.93 (d, 5th position H of thiophene, 1H, J=
5Hz) 2.90 (d, 2nd and 6th positions of benzene H, 2H, J
=8Hz) 2.61 (d, 3rd and 5th positions of benzene H, 2H, J
=8Hz) 0.45(d,

[Formula] 1H, J=1Hz) Production Example 4 (1) Synthesis of 5-[4-(3-methyl-2-thienyl)phenyl]-5-methylhydantoin. 5.0g (0.0232mol) of 4-(3-methyl-2-thienyl)acetophenone in 50ml of ethanol
and 34 ml of water, add 11 g of ammonium carbonate and 3.1 g of potassium cyanide, and react at 60 to 65°C for 10 hours. After the reaction is completed, ethanol is distilled off to obtain a white solid. If this is decomposed in water and washed with water,
6.1 g of crystalline 5-[4-(3-methyl-2-thienyl)phenyl]-5-methylhydantoin
(yield 96%). Melting point ^201-202.5 ℃ ( ^{recrystallized} from ethyl acetate) I.R. Synthesis of 2-thienyl)phenyl]-propionic acid. 5-[4-(3-methyl-2) obtained in (1) above
-thienyl)phenyl]-5-methylhydantoin 5.0g (0.0183mol) in sodium hydroxide
Add to a solution prepared from 3.0 g and 30 ml of water, and heat and hydrolyze at 170°C for 4 hours in a bomberol. After the reaction is completed, crystals are precipitated by cooling to room temperature. This reaction solution was adjusted to PH5 with hydrochloric acid,
If the crystals are taken and washed with water, 2-amino-2-[4-(3-methyl-2-thienyl)
4.4 g (yield 92%) of phenyl]propionic acid are obtained. Melting point: 250°C or higher (3) Synthesis of 2-dimethylamino-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid. 2-Amino-2-[4-(3) obtained in (2) above
4.0 g (0.0153 mol) of -methyl-2-thienyl)phenyl]propionic acid was added to a mixture of 8 ml of formic acid and 5 ml of formaldehyde (40%), and after refluxing for 1 hour, the solvent was distilled off under reduced pressure.
A white solid is obtained. If this is washed with acetone, 2-dimethylamino-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid
Obtain 3.6 g (81% yield). Production Example 5 (1) Synthesis of 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde. 1.3 g (0.0535 mol) of magnesium chips are dispersed in 20 ml of anhydrous tetrahydrofuran, and then 5.0 g of ethyl bromide is gradually added dropwise with stirring. After the addition is complete, the mixture is refluxed for an additional 30 minutes. After the reaction was completed, this solution was cooled to 0°C, 5.0 g of chloromethyl ethyl ether was added dropwise while maintaining the temperature at 0 to 10°C, and then 4-(3-methyl-2-
A solution of 5.0 g (0.0232 mol) of thienyl)acetophenone dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise at the same temperature, and the mixture was stirred at room temperature for 2 hours. This reaction mixture is poured into a solution of 5.0 g of ammonium chloride in 50 ml of water, and 50 ml of diethyl ether is added. The ether layer is separated, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. 20ml of acetic acid to the residue
After refluxing for 4 hours, the solvent was distilled off under reduced pressure. If the residue is purified by silica gel column chromatography (developing solvent: benzene; n-hexane = 2:1), 2-[4-(3-
2.5 g (47% yield) of methyl-2-thienyl)phenyl]propionaldehyde are obtained. Production Example 6 (1) Synthesis of 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidonitrile. 15 g (0.0694 mol) of 4-(3-methyl-2-thienyl)acetophenone was dissolved in 50 ml of xylene, followed by 6.6 g of chloroacetonitrile.
(0.0847 mol) is added. This solution is −20 to −
Cool to 10°C, and add 3.34 g of sodium tertiary amylate (3.34 g of sodium amide and 7.5 g of tertiary amyl alcohol) in 110 ml of xylene at 60°C.
Adjusted by stirring for hours. ) Solution at -5~0℃
While holding the bottle, gradually drip the liquid. After dropping the entire amount, stir at the same temperature for 1 hour, and then at room temperature for 1 hour, and then add 40 ml of water. Next, the reaction mixture is filtered, the organic layer is separated, 30 ml of xylene is added to the aqueous layer, the organic layer is separated, both organic layers are combined, and after drying over anhydrous magnesium sulfate, the solvent is removed under reduced pressure. Distilled into. The resulting residue was purified by silica gel column chromatography (developing solvent: benzene:hexane = 2:1) to obtain oily 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl ] Obtain 6.9 g of glycidonitrile (yield 39%). I/R (liquid film); νC≡N 2250cm ^-1 NMR (CDCl ₃ ) 60MHz, internal standard TMS τ value; 8.10, 8.02 (s,

[Formula] trans, cis, 3H) 7.67 (s, 3-position CH ₃ of thiophene, 3H) 6.71, 6.63 (s,

[Formula] trans, cis, 1H) 3.10 (d, H at 4th position of thiophene, 1H, J=
5Hz) 2.82 (d, 5th position H of thiophene, 1H, J=
5Hz) 2.25-2.91 (m, benzene 2, 3, 5, 6
position H, 4H) (2) 2-acetoxy-3-methyl-3-[4-(3
Synthesis of -methyl-2-thienyl)phenyl]acrylonitrile. 3-Methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidonitrile 3.7g
2-Hydroxy-3-methyl-3-[4-(3-
Methyl-2-thienyl)phenyl]-3-chloropropionitrile is produced. Then, after volatilizing the remaining hydrogen chloride by passing dry nitrogen gas, 1.43 g of pyridine was added to the reaction solution.
(0.0181 mol) and 1.70 g (0.0167 mol) of acetic anhydride, then 2.1 g of triethylamine.
(0.0207 mol) and reflux for 15 hours. The reaction solution is washed with hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain oily 2-acetoxy-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl. ]Acrylonitrile
Obtain 4.2 g (92% yield). I/R (liquid film); νC≡N 2230cm ^-1 νC=O 1770cm ^-1 Production example 7 2-hydroxy-3-[4-(3-methyl-2-
Synthesis of methyl thienyl)phenyl]-3-butenoate. Methyl 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidylate 7.0g
(0.0243 mol) is dissolved in 35 ml of toluene, 0.45 ml of dioxane solution containing 0.05 ml of concentrated sulfuric acid is added at room temperature, and the reaction is stirred for 30 minutes. Next, the reaction solution is washed with water, dried over anhydrous magnesium sulfate, and concentrated to obtain oily 2-hydroxy-3-[4-(3
-Methyl-2-thienyl)phenyl]-3-butenoate (7.0 g) is obtained. I/R (liquid film); νOH 3480cm ^-1 νC=O 1740cm ^-1 Production example 8 (1) 2-ethoxy-3-methyl-3-[4-(3-
Synthesis of methyl-2-thienyl)phenyl]acrylonitrile. 3-Methyl-3-[4-(3-methyl-2-thienyl)phenyl]glycidonitrile 2.55g
(0.010 mol) in 30 ml of toluene, saturated with dry hydrogen chloride and stirred for 1 hour. The remaining hydrogen chloride is then volatilized by passing dry nitrogen gas through it. Next, sodium amide
0.50g (0.013mol) and 2.18g of bromoethane
(0.020 mol), stirred at room temperature for 5 hours, further added 1.5 g (0.015 mol) of triethylamine, and refluxed for 5 hours. Add 100 ml of water to the reaction mixture and shake thoroughly. The organic layer is separated, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain oily 2-ethoxy-3-methyl-3-[4-(3-methyl-2-thienyl).
Phenyl] acrylonitrile 2.4g (yield 85
%). I.R (liquid film); νC≡N 2250 cm ⁻¹ (2) Synthesis of 3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]-2-oxopropionitrile. 2.4 g (0.0085 mol) of 2-ethoxy-3-methyl-3-[4-(3-methyl-2-thienyl)phenyl]acrylonitrile obtained in (1) above
was dissolved in 30 ml of toluene, 4 ml of concentrated hydrochloric acid and 4 ml of methanol were added, and the mixture was stirred under reflux for 6 hours.
After the reaction is complete, add 50 ml of water to the reaction mixture and separate the organic layer. Furthermore, add 20 ml of toluene to the aqueous layer and separate the organic layer. Both organic layers were combined, thoroughly washed with 50 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily 3-methyl-3-[4-(3-methyl-2-thienyl). 1.8 g (yield: 84%) of phenyl]-2-oxopropionitrile are obtained. I/R (liquid film); νC≡N 2210cm ^-1 νC=O 1755cm ^-1 Production example 9 (1) Synthesis of {1-[4-(3-methyl-2-thienyl)phenyl]ethylidene}methyl cyanoacetate . 4-(3-methyl-2-thienyl)acetophenone 4.32 g (0.020 mol), methyl cyanoacetate 2.26 g (0.0228 mol), ammonium acetate 0.23
g (0.003 mol) and 1.80 g (0.030 mol) of acetic acid are dissolved in 50 ml of benzene, and while the mixture is stirred under reflux, the water produced by the reaction is removed by azeotroping with the benzene. After 4 hours, 0.23 g (0.003 mol) of ammonium acetate and 0.60 g (0.010 mol) of acetic acid were added.
mol) into the reaction vessel and heated for an additional 6 hours. The reaction solution was cooled, 50 ml of water was added, and after vigorous shaking, the separated benzene layer was dried over anhydrous sodium sulfate, and the benzene was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography to convert benzene:hexane=
If you elute with a ratio of 2:1 and concentrate the desired fraction, {1-[4-(3-methyl-2-thienyl)
Phenyl〈ethylidene〉methyl cyanoacetate 5.00
g (yield 84%). I/R (liquid film); νC≡N 2250cm ^-1 NMR (CDCl ₃ ); 60MHz, internal standard TMS τ value: 7.69 (s, 3rd position CH ₃ of thiophene, 3H) 7.49, 7.35 (s,

[Formula] cis, trans, 3H) 6.37, 6.18 (s,

[Formula] cis, trans, 3H) 3.19 (d, H at the 4th position of thiophene, 1H, J=
5Hz) 2.89 (d, 5th position H of thiophene, 1H, J=
5Hz) 2.57 (s, 2nd, 3rd, 5th, 6th position H of benzene,
4H) (2) Synthesis of 3-[4-(3-methyl-2-thienyl)phenyl]-2,3-epoxy-2-methoxycarbonyl-butyramide. {1-[4-(3-methyl-2-thienyl)phenyl]ethylidene}methyl cyanoacetate 5.00g
(0.0168 mol) and dipotassium phosphate 1.68 g
(0.0096 mol) in 20 ml of methanol, 55
Warm to ~60°C. While vigorously stirring, 7.25 ml (0.064 mol) of 30% hydrogen peroxide solution was gradually added over 1 hour. After dropping, add another 1 at the same temperature.
Stir for an hour. Add 20ml of water and 70ml of benzene,
After shaking thoroughly, the separated benzene layer was washed with 10 ml of a 10% aqueous sodium thiosulfate solution, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3-[4-(3-methyl- 2-thienyl)phenyl]-2,3-epoxy-2-methoxycarbonyl-butyramide 4.98 g (yield
89%). I.R (liquid film); νC=O 1750, 1680 cm ^-1 (3) Synthesis of 3-[4-(3-methyl-2-thienyl)phenyl]-2-oxo-butyramide. 3.32 g (0.010 mol) of 3-[4-(3-methyl-2-thienyl)phenyl]-2,3-epoxy-2-methoxycarbonyl-butyramide was dissolved in 5 ml of methanol, and then 15 ml of 1N potassium hydroxide methanol solution was dissolved. (0.015 mol) is added slowly and stirred for 1 hour at room temperature. After distilling off methanol under reduced pressure, add 40 ml of water, then add 20 ml of benzene to remove impurities, and shake well. Add 17ml of 1N hydrochloric acid (0.017ml) to the separated aqueous layer.
mol) gradually, and while stirring, heat to 90°C to decarboxylate. After heating for 1 hour, it was cooled and extracted with 70 ml of diethyl ether. The organic layer was separated, dried over anhydrous magnesium sulfate, and the diethyl ether was distilled off under reduced pressure to obtain 3-
[4-(3-methyl-2-thienyl)phenyl]
-2-oxo-butyramide 2.1 g (yield 77
%). Melting point 116-117℃ (recrystallized from n-hexane-benzene) I・R (KBr); νC=O 1650, 1705 cm ^-1 NMR (CDCl ₃ ); 60 MHz, internal standard TMS τ value; 8.56 (d,

[Formula] 3H, J=7Hz) 7.74 (s, 3rd position CH ₃ of thiophene, 3H) 5.19 (q,

[Formula] 1H, J=7Hz) 3.54~4.14 (broad,

[Formula] 2H) 3.20 (d, 4-position H of thiophene, 1H, J=
5Hz) 2.91 (d, 5th position H of thiophene, 1H, J=
5Hz) 2.74 (s, 2nd, 3rd, 5th, 6th place of benzene
position, H, 4H) 2-[4-(3-methyl-2-
Crude crystals of thienyl) phenyl propionic acid
Obtain 1.43 g (81% yield). Production Example 10 (1) Synthesis of diethyl [4-(3-methyl-2-thienyl)phenyl]malonate. 1.4g of metallic sodium in 50ml of ethanol
(0.06 mol) was added and dissolved, and then 10 g of ethyl 4-(3-methyl-2-thienyl)phenylacetate [I・R (liquid film); νC=O 1735 cm ^-1 ]
(0.038 mol) and then 14.3 mol of diethyl carbonate
g (0.121 mol) and stirred at 50-60°C for 30 minutes. Next, ethanol was distilled off under reduced pressure, and 15 ml of 1N hydrochloric acid and benzene were added to the residue.
After adding 50 ml and thoroughly shaking, the organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (developing solvent: benzene:n-hexane=2:1) to obtain oily diethyl [4-(3-methyl-2-thienyl)phenyl]malonate (7.8 g (yield
58%). I/R (liquid film); νC=O 1735cm ^-1 (2) Synthesis of α-methyl-α-[4-(3-methyl-2-thienyl)phenyl] diethyl malonate. 0.40g of metallic sodium in 25ml of methanol
(0.017 mol) is added and dissolved, and to this, the above (1)
5 g of diethyl [4-(3-methyl-2-thienyl)phenyl]malonate (0.015
After 10 minutes, 6.7 g (0.047 mol) of methyl iodide was added and stirred at room temperature for 2 hours. Next, 10 ml of 1N hydrochloric acid and 30 ml of benzene were added, and after thorough shaking, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily α-methyl-α-
[4-(3-methyl-2-thienyl)phenyl]
4.3 g (yield 83%) of diethyl malonate is obtained. I/R (liquid film); νC=O 1735cm ^-1 Production example 11 (1) 2-[1-(4-iodophenyl)ethyl]-
Synthesis of 4,4-dimethyl-2-oxazoline. 2-(4-iodophenyl)propionic acid 25
g was dissolved in 50 ml of chloroform, then 16.1 g of thionyl chloride was added and refluxed for 2 hours. After the reaction is completed, excess thionyl chloride and chloroform are distilled off under reduced pressure. Next, the obtained residue was dissolved in 50 ml of chloroform, and while maintaining the temperature from 0 to 10°C, it was added to a solution of 20 g of 2-amino-2-methyl-1-propanol dissolved in 50 ml of chloroform.
It takes 30 minutes to drip. Stir for 15 minutes after dropping,
After washing with 100 ml of water and drying the chloroform layer over anhydrous magnesium sulfate, 17.7 g of phosphorus oxychloride is added dropwise to react at 10 to 20°C. After dropping, stir at room temperature for 1 hour, and add 100% water to the reaction mixture.
ml, and while stirring vigorously and keeping the temperature at 10-20°C, add 20% aqueous sodium hydroxide solution and adjust the pH to 12. Next, the organic layer is separated, dried over anhydrous magnesium sulfate, and the solution is concentrated to dryness to obtain 2-
[1-(4-iodophenyl)ethyl]-4.4
-dimethyl-2-oxazoline 28.8g (yield
96.5%). I・R(KBr) νC=N 1645cm ^-1 (2) 2-[1-[4-(3-methyl-2-thienyl)phenyl]ethyl]-4,4-dimethyl-
Synthesis of 2-oxazoline. 2-[1-(4-iodophenyl)ethyl]-
8.0 g of 4,4-dimethyl-2-oxazoline is dissolved in 24 ml of anhydrous tetrahydrofuran, then 0.080 g of palladium chloride is added and heated to 60-65°C. Separately, prepare a Grignard reagent from 5.2 g of 2-bromo-3-methylthiophene, 0.8 g of ground magnesium, and 15 ml of anhydrous tetrahydrofuran, and add the Grignard reagent to the solution obtained above for 30 minutes while maintaining a temperature of 60 to 65°C. drip. After further completing the reaction at the same temperature for 1 hour, the solvent was distilled off under reduced pressure, and to the resulting residue were added 50 ml of benzene, 50 ml of water, and 5 ml of hydroacetic acid, and after shaking thoroughly, the organic layer was separated. The sample was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain oily 2-[1-[4-(3-
Methyl-2-thienyl)phenyl]ethyl]-
4,4-dimethyl-2-oxazoline 6.8g
(yield 93.3%). I/R (liquid film); νC=N 1645cm ^-1 Production Example 12 Synthesis of 4-(3-methyl-2-thienyl)bromobenzene. Add 5.8 g (0.239 mol) of magnesium chips to 200 ml of anhydrous tetrahydrofuran, and then add 39 g of 2-bromo-3-methylthiophene under a nitrogen stream.
(0.220 mol) is gradually added. After dropping the entire amount, heat under reflux for 30 minutes to conclude 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 ℃. After dropping, most of the solvent was distilled off, 150 ml of 10% aqueous hydrochloric acid solution was added to the residue, and then 100 ml of benzene was added to separate the organic layer, which was washed successively with water and an aqueous alkali 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°C/16-17mmHg Production example 13 Synthesis of 4-(3-methyl-2-thienyl)phenylacetic acid. Add 3.1 g (0.13 mol) of magnesium chips to 65 ml of anhydrous tetrahydrofuran, and add 21 g (0.12 mol) of 2-bromo-3-methylthiophene while stirring at room temperature.
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 86.3%) of phenylacetic acid is obtained. Melting point 126-127℃ (recrystallized from benzene) I・R (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, 4-position H of thiophene, 1H, J = 5
Hz) 2.83 (d, H at the 5th position of thiophene, 1H, J = 5
Hz) 2.64 (s, H at the 2, 3, 5, and 6 positions of benzene,
4H) Production Example 14 Synthesis of 4-(3-methyl-2-thienyl)chlorobenzene. 2-Bromo-3-
13.3 g of methylthiophene was gradually added dropwise to react. After the dropwise addition is completed, the mixture is heated under reflux for 30 minutes and excess magnesium is removed using glass wool to obtain a Grignard reagent. Meanwhile, 15 g of p-chloroiodobenzene is dissolved in 60 ml of anhydrous tetrahydrofuran, 0.03 g of palladium chloride is added, and the temperature is raised to 55-60° C. while stirring. 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 whole solution was concentrated under reduced pressure, the resulting residue was poured into 100 ml of 5% hydrochloric acid, and then 80 ml of 2-hexane was added, and After shaking, separate the organic layer. The resulting 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 resulting 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 Production example 15 (1) Synthesis of 4-(3-methyl-2-thienyl)ethylbenzene. 1.85 g (0.0761 mol) of magnesium chips were added to 30 ml of anhydrous tetrahydrofuran, and 12.5 g of 2-bromo-3-methylthiophene was added under stirring.
(0.071 mol) and react. After starting the reaction, the remaining half of 2-bromo-3-methylthiophene was gradually added dropwise, and after the addition was completed,
Reflux with stirring for an additional hour. Dissolve 15.0 g (0.0647 mol) of 4-iodoethylbenzene in 50 ml of anhydrous tetrahydrofuran,
Add 0.012 g of palladium chloride. The Grignard reagent obtained above is added dropwise to this mixture while keeping it at 55-60°C, and the mixture is refluxed for 1 hour with stirring. After distilling off the solvent under reduced pressure, 100 ml of benzene, 5 ml of acetic acid and 100 ml of water were added, and after shaking thoroughly, the organic layer was separated and water was added.
Wash with 100ml. After drying the benzene solution obtained in this way over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and vacuum distillation (90-93
C/3 mmHg), 12.0 g (yield 92%) of 4-(3-methyl-2-thienyl)ethylbenzene is obtained. NMR (CCl ₄ ); 60 MHz, internal standard TMS τ value; 8.80 (t, -CH ₂ CH ₃ , 3H, J = 7Hz) 7.78 (s, 3-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 positions of benzene H, 2H, J
=9Hz) 2.77(d, 3rd and 5th positions of benzene, 2H, J=
9Hz) (2) Synthesis of 4-(3-methyl-2-thienyl)acetophenone. 40.4 g (0.020 mol) of 4-(3-methyl-2-thienyl)ethylbenzene was dissolved in 30 ml of acetic acid, followed by 2.66 g (0.024 mol) of selenium dioxide.
After adding, 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 thus obtained with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography (developing solvent: benzene:n-hexane=2:1) to obtain 2.68 g (yield: 62%) of 4-(3-methyl-2-thienyl)acetophenone. I/R (liquid film); νC=O 1675cm ^-1 Production Example 16 Synthesis of 4-(3-methyl-2-thienyl)benzoic acid. 24.8 g (0.1 mol) of 4-iodobenzoic acid 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 add anhydrous tetrahydrofuran to this solution while keeping the temperature at 60-65°C.
63ml, 2-bromo-3-methylthiophene 21.3g
(0.12 mol) and 3.2 g (0.13 mol) of magnesium chips
Grignard reagent prepared from mol) is added dropwise over a period of 30 minutes. After the completion of dripping, continue for another 1 hour 60~
Stir at 65°C to complete the reaction. After the reaction, the solvent was distilled off under reduced pressure and 200ml of chloroform was added to the residue.
Add 130 ml of 1N hydrochloric acid, stir well, separate the organic layer, wash thoroughly with water, and add 105 ml of 1N hydrochloric acid.
ml, shake well, and separate the aqueous layer. This aqueous layer is neutralized by adding 105 ml of 1N hydrochloric acid, and the precipitated crystals are crystallized, washed with water and dried to obtain almost pure 4-(3-methyl-2-thienyl)benzoic acid.
Obtain 20.9 g (96% yield). Melting point 147-148°C I.R. (KBr); νC=O 1680 cm ^-1 Reference example (1) Synthesis of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid. 9 g (0.0391 mol) of 2-[4-(3-methyl-2-thienyl)phenyl]propionaldehyde obtained in Production Example 1-(4) was mixed with 90 ml of acetone and water.
Dissolve in 30 ml of mixed solvent and cool and adjust to -5 to 0°C. 6.1 g (0.039 mol) of potassium permanganate are gradually added with stirring while maintaining the same temperature. After adding the entire amount and stirring at the same temperature for 1 hour,
Add 10ml of 30% hydrogen peroxide solution little by little to eliminate the excess potassium permanganate. Next, the reaction solution is passed through Celite to remove manganese dioxide, and then acetone is distilled off by heating. Add 10 ml of 1N caustic soda solution to this concentrated solution, and then add diisopropyl ether for extraction. Adjust the separated aqueous layer to PH7.5,
After removing trace amounts of insoluble matter through Celite, the aqueous layer is neutralized with 10% hydrochloric acid and adjusted to pH 5.5. At this time, the liberated oil is extracted with diisopropyl ether, and the organic layer is dried over magnesium sulfate, then treated with activated carbon, and then the diisopropyl ether is distilled off. The residue has n
-If you add hexane and crystallize, 2-[4-(3
4.5 g (yield: 47%) of crude crystals of -methyl-2-thienyl)phenyl]propionic acid are obtained. Melting point: 96-97°C (recrystallized from n-hexane-cyclohexane) I·R (KBr); νC=O 1700 cm ⁻¹ The structure of this compound was determined by NMR spectrum. NMR (CDCl ₃ ); 60MHz, internal standard TMS τ value; 8.51 (d,

[Formula] 3H, J=7Hz) 7.75 (s, 3rd position CH ₃ of thiophene, 3H) 6.29 (q,

[Formula] 1H, J = 7Hz) 3.20 (d, thiophene 4th position H 1H, J = 5
Hz) 2.92 (d, thiophene 5th position H 1H, J=5
Hz) 2.70 (s, benzene 2, 3, 5, 6 H
4H) −0.68(s,

[Formula] 1H) (2) d-2-[4-(3-methyl-2-thienyl)
Synthesis of phenyl]propionic acid 24ml of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (6.00 g, 24.4 mmol)
was dissolved in ethyl acetate, and a solution of 2.06 g (12.5 mmol) of D(-)-α-phenylglycine methyl ester dissolved in 18 ml of ethyl acetate was added dropwise at 20° C. over 90 minutes while stirring. The resulting suspension was then stirred at this temperature for 30 minutes, cooled to 10° C. over 30 minutes, and then stirred at the same temperature for an additional 30 minutes. The suspension is filtered and the crystals obtained are washed with 18 ml of pre-chilled ethyl acetate. Then, add these crystals to 40ml of ethyl acetate at 65°C.
Heat to dissolve and cool to 10°C gradually to crystallize. Next, the obtained crystals were filtered, washed with cooled ethyl acetate, and dried at 50°C.
-2.87 g of D(-)-α-phenylglycine methyl ester salt of [4-(3-methyl-2-thienyl)phenyl]propionic acid is obtained. Next, 30 ml of 2.87 g of the above salt was suspended in ethyl acetate, 20 ml of 0.5N hydrochloric acid was added, and the mixture was stirred at 5°C for 10 minutes. The obtained homogeneous ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. 10 mg of seed crystals and 10 ml of n-hexane were added to the oily residue, stirred to crystallize, filtered, and d-2-[4-(3
1.53 g of -methyl-2-thienyl)phenyl]propionic acid are obtained. Melting point 62-63℃ [α] ²⁰ _D = +51.3° (C = 1.56, EtoH)

Claims (1)

[Claims] 1. General formula [wherein R is a halogen atom, an alkyl group, a cyano group, an amino group, a nitro group, an optionally protected formyl group, an optionally protected acetyl group,
-MgX, -COCHO, -COOR ¹ represents an optionally substituted oxazoline group, [Formula] [Formula] [Formula] [Formula] or [Formula]. [However, X represents a halogen atom, and R ¹ represents a hydrogen atom, a salt-forming cation, or an ester-forming group. (Hereinafter, R ¹ has the same meaning in this section.); R ² is a hydrogen atom or a methyl group; R ³ is a cyano group, a halogen atom, an optionally protected hydroxyl group, an optionally protected formyl group. , an optionally protected acetyl group,
-COOR ¹ (However, when R ² is a methyl group and R ⁴ is a hydrogen atom, this R ¹ is an ester-forming group.), -
COCOOR ¹ , an optionally substituted oxazoline group, [Formula] -CH ₂ OH, -COCONH ₂ , - COCN, -MgX or [Formula] (However, R ¹⁰ and R ¹¹ are hydrogen atoms or alkyl groups, or R ¹⁰ and R ¹¹ are combined to form a ring with the adjacent nitrogen atom.); R ⁴ is a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an amino group, a dialkylamino group, or -
COOR ¹ ; R ⁵ is a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a carbamoyl group, or a cyano group; R ⁶ is a hydrogen atom or -COOR ¹ ; R ⁷ is a cyano group, a carbamoyl group, or -COOR ¹ ; R ⁸ is an optionally protected hydroxyl group or −COOR ¹
; R ⁹ is -COOR ¹ or [Formula] (However, R ¹² represents a hydroxyl group that may be protected.)
shows. ] ] 4-(3-methyl-2-thienyl) represented by
Benzene derivative.