JP2000119221A - Method for producing (2,4,5-trifluoro-3-methoxybenzoyl) acetic acid ester derivative and intermediate for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially and easily executable (2,4,5-
Provided is a method for producing a trifluoro-3-methoxybenzoyl) acetic acid ester derivative. SOLUTION: A malonic ester derivative is condensed with a carboxylic acid of a methoxyphthalic acid monoester derivative represented by the general formula I to obtain a benzoylmalonic ester derivative represented by the general formula II, and the general formula II is hydrolyzed. To form an acetylbenzoic acid compound represented by the formula III, and then decarboxylate the formula III to obtain an acetophenone compound represented by the formula IV,
A method for producing a benzoylacetic acid ester derivative represented by the general formula V, wherein the IV is alkoxycarbonylated. Embedded image (In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents lower alkyl.)

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention is an intermediate useful for the production of pharmaceuticals, especially quinolone antibacterial agents (2,
The present invention relates to a method for producing 4,5-trifluoro-3-methoxybenzoyl) acetic acid ester, a benzoylmalonate derivative, an acetylbenzoic acid derivative and an acetophenone derivative which are intermediates for producing the same.

[0002]

2. Description of the Related Art (2,4,5-trifluoro-3-methoxybenzoyl) acetic acid ester derivatives are important compounds as intermediates for pharmaceuticals, especially for quinolone antibacterial agents. Generally, the compound is produced by a method in which a malonic acid derivative is condensed with 2,4,5-trifluoro-3-methoxybenzoic acid (Japanese Patent Application Laid-Open No. 62-252772).
No., JP-A-63-198664). Many methods for producing the starting material 2,4,5-trifluoro-3-methoxybenzoic acid in this production method are known. For example (1)
A method of producing from pentafluorobenzonitrile through 8 steps (JP-A-63-198664), (2) 2,3
-Halogenation of dihalogeno-5,6-difluoroanisole with metal cyanide to give 2-halogeno-3-cyano-
5,6-difluoroanisole, followed by addition of water to give 2-halogeno-3-carbamoyl-5,6-difluoroanisole, which is hydrolyzed to produce (Japanese Patent Application Laid-Open No. 62-252772, Kaisho 64-16746
) And (3) a method of producing tetrafluorophthalic acid as a starting material through four steps of hydroxylation, decarboxylation, alkylation, and hydrolysis (JP-A-63-264439 and JP-A-63-264440). , (4) a method of producing 3,5,6-trifluoro-4-methoxyphthalic acid by decarboxylation (JP-A-3-279348, JP-A-7-24259)
No. 4) is known.

[0003]

SUMMARY OF THE INVENTION A method for producing (2,4,5-trifluoro-3-methoxybenzoyl) acetic acid ester derivative and, consequently, a method for producing 2,4,5-trifluoro-3-methoxybenzoic acid are disclosed. There are the following problems.
The method (1) has long steps and is industrially disadvantageous.
The method (2) is based on the method of using 2,3-dihalogeno-
It is not easy to obtain 5,6-difluoroanisole,
Further, a metal cyanide compound which is difficult to handle and treat is used. The method (3) requires a pressure-resistant reaction vessel because the decarboxylation step is performed under pressurized conditions, and uses dimethyl sulfate, a specific chemical substance that is complicated to handle industrially, during alkylation. . In method (4), 3,5,6-
It is difficult to carry out the decarboxylation of trifluoro-4-methoxyphthalic acid with good selectivity, and as a result of the inventors' detailed study of this decarboxylation reaction, it was found that an undesirable by-product (2,3,5- It is clear that 20 to 30% of trifluoro-4-methoxybenzoic acid is contaminated, and it is difficult to efficiently remove this by-product. Further, demethylation of a methoxy group cannot be avoided, and industrial Disadvantageous.

The problem to be solved by the present invention is to provide an industrially and easily practicable (2,4,5-trifluoro-3)
-Methoxybenzoyl) acetic acid ester derivative.

[0005]

The inventors of the present invention have conducted intensive studies and, as a result, derived the carboxyl group at the 2-position of the methoxyphthalic acid monoester derivative represented by the following general formula I into an acetyl group, followed by decarboxylation. 2, represented by the following formula IV
A selective decarboxylation method for producing a 4,5-trifluoro-3-methoxyacetophenone derivative was found. Furthermore, an alkoxycarbonyl group is introduced into the acetyl group of the 2,4,5-trifluoro-3-methoxyacetophenone derivative represented by the formula IV to give a highly pure compound represented by the following general formula V (2,4,5-
A method for obtaining a trifluoro-3-methoxybenzoyl) acetic acid ester derivative was developed, and the present invention was completed.

[0006]

Embedded image

(Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different and each represents a lower alkyl.) The present invention has been made to solve the problems of the prior art. (2,4,5-trifluoro-3) represented by the general formula V useful for producing an antibacterial agent, particularly an 8-methoxyquinolone carboxylic acid derivative known to have excellent antibacterial activity. A novel method for producing a (methoxybenzoyl) acetic acid ester derivative is provided.

A benzoylmalonate derivative represented by the general formula II, which is a production intermediate not described in the literature, wherein R ¹ , R ² and R ³ are the same or different and each represent a lower alkyl. ), An acetylbenzoic acid compound represented by the formula III and an acetophenone compound represented by the formula IV.

[0009]

Embedded image

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The steps of the present invention will be described below. In the present invention, the lower alkyl group is an alkyl group having 1 to 6 carbon atoms, and more preferably an alkyl group having 1 or 2 carbon atoms. The methoxyphthalic acid monoester derivative represented by the general formula I as a starting material of the present invention is disclosed in JP-A-7-2.
No. 42594, and can be easily produced by a usual method.

The benzoylmalonic ester derivative represented by the general formula II is produced by adding a methoxyphthalic acid monoester derivative represented by the general formula I without solvent or toluene,
The acid chloride is prepared by reacting a suitable chlorinating agent such as thionyl chloride or oxalyl chloride in an inert solvent such as methylene chloride or tetrahydrofuran, or in an inert solvent such as toluene, methylene chloride or tetrahydrofuran. In the presence of a base such as triethylamine, a chloroformic acid ester is reacted to form a mixed acid anhydride, and a malonic acid ester is obtained in the presence of a suitable base for the obtained acid chloride or mixed acid anhydride, for example, magnesium alcoholate. It is carried out by condensation. This condensation reaction is carried out in an inert solvent such as toluene, diethyl ether or tetrahydrofuran at -50 ° C to 50 ° C.
C., preferably in the range of -20.degree.
The reaction is completed in minutes to 5 hours.

The preparation of the acetylbenzoic acid derivative represented by the formula III is carried out by preparing a benzoylmalonic ester derivative represented by the general formula II using a suitable acid, for example, sulfuric acid or hydrochloric acid, in acetic acid, water, alcohol or a mixture thereof. This is carried out by hydrolysis. The hydrolysis is carried out from room temperature to the boiling point of the solvent, and the reaction is completed in 10 minutes to 5 hours.

The preparation of the acetophenone compound represented by the formula IV is carried out by using the acetylbenzoic acid compound represented by the formula III without solvent or N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, In a solvent such as dimethyl sulfoxide, xylene, toluene, chlorobenzene, or quinoline, if necessary, a copper compound such as cupric oxide, copper powder, triethylamine, trioctylamine, diisopropylethylamine, or a tertiary amine such as N-methylpyrrolidine; It is carried out by adding a carbonate such as sodium bicarbonate or potassium carbonate and decarboxylation. This decarboxylation reaction is carried out from room temperature to the boiling point of the solvent, and the reaction is completed in 10 minutes to 5 hours.

The benzoyl acetic acid ester derivative represented by the general formula V is produced by adding the acetophenone derivative represented by the formula IV without solvent or toluene, benzene, tetrahydrofuran, dioxane, diethyl ether, ethylene glycol dimethyl ether, N, N-dimethylformamide ,
In a solvent such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, sodium hydride, potassium hydride, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) ) In the presence of a base such as amide, lithium diisopropylamide, sodium tert-butoxide and potassium tert-butoxide, an alkoxycarbonylating agent such as an alkoxycarbonylphosphonate, a cyanoformate, a chloroformate or a carbonate is allowed to act. Can be carried out. This alkoxycarbonylation is -7
The reaction is carried out at 8 ° C to the boiling point of the solvent, and the reaction is completed in 10 minutes to 5 hours.

The benzoyl acetic acid ester derivative represented by the general formula V can be produced as an intermediate for producing an 8-methoxyquinolone carboxylic acid antibacterial agent by the following known production method (Japanese Patent Application Laid-Open No. 62-252772). Important 1-cyclopropyl-6,7-difluoro-8-methoxy-4
-Oxo-3-quinoline carboxylic acid ester derivatives.

[0016]

Embedded image

[0017]

EXAMPLES Next, the compounds of the present invention and the method for producing the same will be described in detail with reference to Examples.

Example 1 (3,4,6-trifluoro-5-methoxy-2-methoate )
Xyloxycarbonylbenzoyl ) malonate A: 45.0 g of 3,5,6-trifluoro-4-methoxyphthalic acid monomethyl ester and thionyl chloride 225
of N, N-dimethylformamide 0.5m
and stirred at an external bath temperature of 40 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue acid chloride was dissolved in 200 ml of toluene.
Was dissolved.

A solution of 30.0 g of diethyl malonate in 400 ml of toluene was added to 23.4 g of magnesium ethoxide, and the mixture was stirred at 50 ° C. for 2 hours. While the reaction solution was cooled on a saline-ice bath, the above-mentioned toluene solution of acid chloride was added dropwise, followed by stirring at room temperature for 2 hours. 1 mol /
400 ml of 1 hydrochloric acid was added, the toluene layer was separated, and the aqueous layer was extracted with toluene. The toluene layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give yellow oily diethyl (3,4,6-trifluoro-5-methoxy-2-methoxycarbonylbenzoyl) malonate.
8 g were obtained. Yield 99%.

B: 4.66 g of 3,5,6-trifluoro-4-methoxyphthalic acid monomethyl ester was dissolved in 100 ml of methylene chloride, one drop of N, N-dimethylformamide was added, and 2.30 ml of oxalyl chloride were added. Then, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residual acid chloride was dissolved in 25 ml of toluene.

A solution of 3.10 g of diethyl malonate in 50 ml of toluene was added to 2.42 g of magnesium ethoxide, and the mixture was stirred at 50 ° C. for 1 hour. While the reaction solution was cooled on a salt-ice bath, the toluene solution of the above acid chloride was added dropwise, and the mixture was stirred at -5 ° C to -8 ° C for 1 hour, and further at room temperature for 1 hour. 50 ml of 1 mol / l hydrochloric acid was added to the reaction solution, the toluene layer was separated, and the aqueous layer was extracted with toluene.
The toluene layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7.45 g of yellow oily diethyl (3,4,6-trifluoro-5-methoxy-2-methoxycarbonylbenzoyl) malonate. Was. Yield quantitative.

C: 2.75 g of 3,5,6-trifluoro-4-methoxyphthalic acid monomethyl ester was dissolved in 50 ml of methylene chloride, one drop of N, N-dimethylformamide was added, and then 1.14 ml of thionyl chloride was added. After that, the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure,
The residual acid chloride was dissolved in 13 ml of toluene.

A solution of 1.83 g of diethyl malonate in 26 ml of toluene was added to 1.43 g of magnesium ethoxide, and the mixture was stirred at 50 ° C. for 1.5 hours. While the reaction solution was cooled on a saline-ice bath, the above-mentioned toluene solution of acid chloride was added dropwise, followed by stirring at room temperature for 2 hours. 1 mo to the reaction solution
20 ml of 1 / l hydrochloric acid was added, the toluene layer was separated, and the aqueous layer was extracted with toluene. Combine the toluene layers, wash with water,
After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to give yellow oily diethyl (3,4,6-trifluoro-5-methoxy-2-methoxycarbonylbenzoyl) malonate as 4.2.
1 g was obtained. Yield 100%.

D: 2.64 g of 3,5,6-trifluoro-4-methoxyphthalic acid monomethyl ester was dissolved in 25 ml of methylene chloride, and 1.40 ml of triethylamine and 0.96 ml of ethyl chloroformate were added under ice-water cooling. Then, the mixture was stirred at room temperature for 30 minutes. The insolubles in the reaction solution were removed by filtration, the filtrate was concentrated under reduced pressure, and the mixed acid anhydride of the residue was dissolved in 13 ml of toluene.

A solution of 1.76 g of diethyl malonate in 26 ml of toluene was added to 1.37 g of magnesium ethoxide, and the mixture was stirred at 50 ° C. for 1 hour. The toluene solution of the above acid chloride was added dropwise while cooling the reaction solution on a salt-ice bath, and the mixture was stirred at room temperature for 3 hours. 1 mol /
1 ml of hydrochloric acid was added, the toluene layer was separated, and the aqueous layer was extracted with toluene. The toluene layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give yellow oily diethyl (3,4,6-trifluoro-5-methoxy-2-methoxycarbonylbenzoyl) malonate at 3.6.
8 g were obtained. Yield 91%.

The NMR of the target compound obtained by A is as follows, and the N of the target compound obtained by B, C and D
MR also agreed.

[0027] _{^{1 H-NMR (in CDCl 3}} , δ, ppm): 0.99-1.45 (6H, m, COOCH 2 C H 3 × 2) 3.88-4.49 (10H, m, COOC H ₂ CH ₃ × 2, COOC H ₃ ,
_{OC H 3) 14.0 (0.4H,} br, Ar-C (O H) = C (COOEt) 2)

Example 2 2-acetyl-3,5,6-trifluoro-4-methoxy
27.1 diethyl benzoate (3,4,6-trifluoro-5-methoxy-2-methoxycarbonylbenzoyl) malonate
g of sulfuric acid 14.0 ml, acetic acid 100 ml and water 70 ml
And stirred at an external bath temperature of 100 ° C. for 2.5 hours. 300 ml of ice water was added to the reaction solution, and extracted with methylene chloride. The methylene chloride layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-acetyl- as a pale yellow oil.
3,5,6-trifluoro-4-methoxybenzoic acid
3.7 g were obtained. Yield 83%.

¹ H-NMR (in CDCl ₃ , δ, ppm): 4.20 (3H, t, J = 2.0 Hz, OC H ₃ ) 5.14 (1H, br, COO H )

Example 3 2,4,5-trifluoro-3-methoxyacetopheno
Emissions A: 2-Acetyl-3,5,6 trifluoro-4-
9.00 g of methoxybenzoic acid, 0.577 g of cupric oxide
And 60 ml of dimethyl sulfoxide at 120 ° C.
For 2 hours. After cooling, the reaction solution was added with ethyl acetate 20
0 ml was added, and the insoluble matter was removed by filtration using Celite. Celite and insolubles were washed with ethyl acetate. The filtrate and the washing solution were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to obtain 5.56 g of 2,4,5-trifluoro-3-methoxyacetophenone as a light brown oil. Yield 75%.

B: 10.0 g of 2-acetyl-3,5,6-trifluoro-4-methoxybenzoic acid, 3.39 g of sodium hydrogen carbonate and 60 ml of N, N-dimethylformamide are mixed, and the mixture is mixed at 120 ° C. for 1 hour. The mixture was heated and stirred. The reaction solution was diluted with 200 ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by distillation under reduced pressure to give a light brown oil of 2,4,5-trifluoro-3.
4.85 g of -methoxyacetophenone was obtained. Yield 59
%.

C: A mixture of 500 mg of 2-acetyl-3,5,6-trifluoro-4-methoxybenzoic acid, 0.112 ml of triethylamine and 3 ml of N, N-dimethylformamide was heated and stirred at 130 ° C. for 1 hour. The reaction solution was diluted with 30 ml of ethyl acetate, washed with dilute hydrochloric acid and then with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified by a silica gel column (eluent; hexane: ethyl acetate = 4: 1), and 235 mg of 2,4,5-trifluoro-3-methoxyacetophenone as a light brown oil was obtained.
Obtained. Yield 57%.

The NMR of the target compound obtained by A is as follows, and the NMR of the target compound obtained by B and C
Also agreed.

[0034] _{^{1 H-NMR (in CDCl 3}} , δ, ppm): 2.63 (3H, t, J = 5.3Hz, COC H 3) 4.07 (3H, t, J = 1.3Hz, OC H 3 ) 7.42 (1H, ddd, J = 6.2Hz, 8.6Hz, 10.3Hz, C 6 -H)

Example 4 (2,4,5-trifluoro-3-methoxybenzoyi
E ) Ethyl acetate A: A solution of 3.72 g of 2,4,5-trifluoro-3-methoxyacetophenone in 15 ml of toluene was added to a solution of 730 mg of sodium hydride (60%) suspended in 40 ml of toluene. The mixture was heated and stirred at 85 ° C. for 1 hour. The reaction solution was once cooled to room temperature, and 5.74 g of diethyl (ethoxycarbonyl) phosphonate in toluene 15
Then, the mixture was heated and stirred at 80 to 85 ° C. for 1 hour. After cooling, 40 ml of 20% acetic acid was added to the reaction solution, the toluene layer was separated, and the aqueous layer was extracted with toluene. The toluene layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column (eluent; hexane: ethyl acetate = 10: 1) to give (2,2) as a pale yellow oil.
3.72 g of ethyl 4,5-trifluoro-3-methoxybenzoyl) acetate was obtained. Yield 74%.

B: 196 sodium hydride (60%)
mg solution in 3.0 ml of diethyl carbonate
500 mg of 2,4,5-trifluoro-3-methoxyacetophenone was added, and the mixture was stirred at room temperature for 1 hour. 5 ml of 20% acetic acid was added to the reaction solution, the toluene layer was separated, and the aqueous layer was extracted with toluene. The toluene layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column (eluent: hexane: ethyl acetate = 1).
0: 1), and ethyl (2,4,5-trifluoro-3-methoxybenzoyl) acetate as a pale yellow oil was added to 194
mg. Yield 29%.

C: 500 mg of 2,4,5-trifluoro-3-methoxyacetophenone was dissolved in 5 ml of tetrahydrofuran, and lithium bis (triethylsilyl) amide (1) was dissolved in a dry ice-acetone bath while cooling.
(mol / l tetrahydrofuran solution) (2.94 ml) was added dropwise, and the mixture was stirred at -73 ° C for 1 hour. 0.43 ml of hexamethylphosphoric triamide and then 0.29 ml of ethyl cyanoformate were added to the reaction solution, and the mixture was stirred at -73 ° C for 1.5 hours. 3 ml of water was added to the reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (eluent; hexane: ethyl acetate = 4: 1) to obtain 405 mg of pale brown oily ethyl (2,4,5-trifluoro-3-methoxybenzoyl) acetate. Yield 60%.

The NMR of the target compound obtained by A is as follows, and the NMR of the target compound obtained by B and C
Also agreed.

¹ H-NMR (in CDCl ₃ , δ, ppm): 1.34 (3H, t, J = 7.3 Hz, COOCH ₂ CH ₃ ) 4.04 (3H, d, J = 1.0 Hz, OC _{H 3) 4.28 (2H, q} , J = 7.3Hz, COOC H 2 CH 3) 5.82 (1H, s, Ar-C (OH) = C H COOEt) 7.42 (1H, ddd, J = 6.4Hz, 8.6Hz, 11.0Hz, C 6 -H) 12.7 (1H, s, Ar-C (O H) = CHCOOEt)

Reference Example 1 Mono 3,5,6-trifluoro-4-methoxyphthalic acid
Methyl ester 3,4,5,6-tetrafluorophthalic anhydride
0 g was dissolved in methanol (160 ml).
ol / l sodium methoxide methanol solution 45.5
After adding ml, the mixture was further stirred for 1 hour. 4m to reaction liquid
ol / l sodium methoxide methanol solution 50.1
Then, the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 80 ml of 0.5 mol / l hydrochloric acid.
The solution was adjusted to pH 1 by adding concentrated hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is dried under reduced pressure,
46.5 g of 3,5,6-trifluoro-4-methoxyphthalic acid monomethyl ester as a light brown powder was obtained. Yield 9
7%.

¹ H-NMR (in CDCl ₃ , δ, ppm): 3.94 (3H, s, COOC H ₃ ) 4.14 (3 H, t, J = 1.8 Hz, OC H ₃ ) 8.60 ( 1H, br, COO H )

Reference Example 2 1-Cyclopropyl-6,7-difluoro-1,4-di
Hydro-8-methoxy-4-oxo-3-quinolinecal
Bon Ethyl (2,4,5-trifluoro-3-methoxybenzoyl) acetate 6.50 g, ethyl orthoformate 6.30
and 6.00 ml of acetic anhydride.
The mixture was heated and stirred at 0 ° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 15 ml of ethanol, and then 1.79 ml of cyclopropylamine was added dropwise under ice cooling. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give 7.50 g of ethyl 2- (2,4,5-trifluoro-3-methoxybenzoyl) -3-cyclopropylaminoacrylate as an orange oil. Yield 93%.

In a solution of 816 mg of sodium hydride (60%) suspended in 50 ml of tetrahydrofuran, the above-mentioned 2- (2,4,5-trifluoro-3-methoxybenzoyl) -3-cyclopropylamino was cooled with ice water. A solution of 7.00 g of ethyl acrylate in 20 ml of tetrahydrofuran was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with water and then with ethanol, and then dried under reduced pressure to give 1-white powder.
3.75 g of ethyl cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate was obtained. Yield 57%.

Melting point: 177-179 ° C. Elemental analysis value (%): C ₁₆ H ₁₅ F ₂ NO ₄ calculated value; C: 59.44, H: 4.68, N: 4.33 Actual value; C: 59 .42, H: 4.65, N: 4.35

[0045]

According to the production method of the present invention, a compound which is difficult to handle and treat such as a metal cyanide compound and dimethyl sulfate is not used unlike the conventional method, and a special method such as a pressure-resistant reaction vessel is used. No equipment is required, and it is represented by the general formula V (2,4,5-trifluoro-), which is obtained from tetrafluorophthalic anhydride, which is easily available, in a short process, in a high yield, and free of isomers. 3-methoxybenzoyl) acetic acid ester derivatives can be provided.

The present invention relates to a raw material having many problems as industrial waste, for example, an inorganic cyanide compound, a raw material which requires special consideration for leakage in case of an unexpected disaster such as an earthquake or contact with a manufacturing worker, for example, dimethyl sulfate, etc. This is extremely suitable as an industrial production method which eliminates the problem of mixing of undesired isomers without using any of the above.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4H006 AA01 AA02 AB84 AC26 AC44 AC46 AC48 BJ50 BM30 BM71 BP30 BR30 BS30 KA04

Claims (5)

[Claims] 1. A compound of the general formula I (Wherein R ¹ represents a lower alkyl group). A malonic ester derivative is condensed with a carboxylic acid of a methoxyphthalic acid monoester derivative represented by the general formula II. Wherein R ¹ is the same as defined above, R ² and R ³ represent a lower alkyl group, and R ¹ , R ² and R ³ may be the same or different. An acid ester derivative is obtained by hydrolyzing general formula II to give formula III And then decarboxylate the formula III to give an acetylbenzoic acid form of the formula IV Wherein the acetophenone form represented by the formula (IV) is further subjected to alkoxycarbonylation of the formula (IV). (In the formula, R ⁴ represents a lower alkyl group, and R ⁴ represents the above R ¹ ,
R ² and R ³ may be the same or different. )). 2. Formula IV Wherein the acetophenone derivative represented by the formula is alkoxycarbonylated. (Wherein, R ⁴ represents a lower alkyl group). 3. A compound of the general formula II (Wherein, R ¹ , R ² and R ³ are the same or different and each represents a lower alkyl). 4. A compound of formula III An acetylbenzoic acid compound represented by the formula: 5. A compound of formula IV An acetophenone compound represented by