JPS63154647A - Production of ester derivative - Google Patents

Abstract

PURPOSE:To obtain a compound useful as an acidic anti-inflammatory agent having slight side effects such as gastric ulcer formation, central action, etc., economically and in high yield, by reacting a vinyl ester derivative with an aromatic substituted alkylcarboxylic acid in the presence of an acid derivative. CONSTITUTION:A vinyl ester derivative shown by formula I (R1 is 1-15C alkyl or alkenyl) is reacted with a compound shown by the formula R2-COOH [R2 is 1-(2-fluoro-4-biphenyl)ethyl, 1-(p-chlorobenzyl)-5-methoxy-2-methyl-indolylmethyl, etc.] in the presence of a catalyst such as protonic acid (e.g. phosphoric acid) or Lewis acid (e.g. boron trifluoride), etc., to give the aimed substance shown by formula II. The reaction is carried out at -20-150 deg.C for 0.5-30hr. A blending ratio of the carboxylic acid derivative and the vinyl ester derivative in a molar ratio is 1:15-1:150.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a method for producing ester derivatives.

More specifically, the present invention relates to a method for producing an acidic anti-inflammatory agent ester derivative.

[Conventional technology]

Flurbiprofen, ibuprofen, indomethacin, sulindac diclofenac, and the like are commercially available as aromatic substituted alkane carboxylic acids that are acidic anti-inflammatory agents.

These acidic anti-inflammatory agents are used as anti-inflammatory, analgesic and antipyretic agents.

In recent years, ester derivatives with a double ester structure, such as flurbiprofen, ibuprofen, indomethacin, and diclofenac, have gained attention compared to these acidic anti-inflammatory drugs in terms of reducing side effects such as gastric ulcer formation and central effects, and enhancing drug efficacy. It has been found by the present applicant to be far superior (see Japanese Patent Application Laid-open Nos. 59-152348 and 60-28957).

The above-mentioned double ester structure means that, as shown in the general formula (8), one of the acid moieties is an acetic acid or propionic acid derivative of an acidic anti-inflammatory agent, and the other is an alkanoic acid or a dihydric acid consisting of a straight chain and a branched chain. It has an acylar structure in which alkenylic acid and alkagenylic acid each having a double bond are bonded to the 1-position of an ethyl group.

Methods for producing ester derivatives having a double ester structure are already known. However, the method for producing an ester derivative of flurbiprofen having a double ester structure (
JP-A-59-15234), method for producing ester derivatives of indomethacin and diclofenac (JP-A-60-28957 and U.S. Pat. No. 4,603)
, 217) and the method for producing an ester derivative of sulindac (see British Patent No. 1.345.628), an acidic anti-inflammatory agent and 1,1-acyloxy-, which is not commercially available as an industrial raw material, are used. The desired ester derivative is produced by reacting haloethane in the presence of a base. Therefore, when producing the ester derivative, it is necessary to prepare the haloethane derivative.

In the process of preparing haloethane derivatives, haloethane derivatives are prepared by Planckélé reaction using acid chloride and acetaldehyde or by addition of hydrogen chloride to vinyl ester derivatives, but in the case of Planckélé reaction, the reagent used, acetaldehyde, is reactive. As the reaction is rapid and abruptly exothermic, it is difficult to control the reaction well, resulting in low yields and the presence of many by-products. In the case of adding hydrogen chloride, a special reaction equipment is required due to the use of corrosive hydrogen chloride, and care must be taken from the safety of the equipment and the working environment, especially to avoid exposing workers to harmful gases. There were some drawbacks.

Then, in the step of reacting the haloethane derivative with an acidic anti-inflammatory agent, a step of preparing the haloethane derivative is required before the step of obtaining the desired ester derivative. Therefore, from an economic point of view, this method is not suitable as an industrial method for producing an ester derivative. This is disadvantageous in that manufacturing costs are high.

[Problem that the invention seeks to solve]

Therefore, the present inventors have conducted intensive research to solve the above-mentioned problems, and as a result, in the presence of a suitable catalyst such as a protic acid or a Lewis acid, the vinyl ester derivative is converted into an aromatic substituted alkyl carboxylic acid. The present inventors have discovered a new synthetic method for producing an ester derivative having a double ester structure by reacting with an acidic anti-inflammatory agent, and have completed the present invention.

[Means for solving problems]

That is, the present invention provides formula (I): CH2-CHOC-R+ m (wherein R
1 represents an alkyl or alkenyl group having 1 to 15 carbon atoms) and a vinyl ester derivative of the formula (■): R2-COOH(If) (wherein R2 is 1-(2- Fluoro-4-biphenylyl)ethyl group, 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl group, 2-(2
,6-dichloroanilino)phenylmethyl group, 1-(4
-isobutylphenyl)ethyl group or (z)-5-fluoro-2-methyl-1-([p-(methylsulfinyl)phenyl]methylene] -LH-3-indenylmethyl group) The formula (10° OCH30 II II II R2-C-0-CH-0-C-R+ (110 (in the formula, R1 is 1 to 15 an alkyl or alkenyl group having carbon atoms, R2 is a 1-(2-fluoro-4-biphenylyl)ethyl group, 1-(p-chlorobenzoyl)-
5-methoxy-2-methyl-3-indolylmethyl group,
2-(2,8-dichloroanilino)phenylmethyl group,
1-(4-isobutylphenyl)ethyl group or (z
)-5-fluoro-2-methyl-1, -C' (p-(
Methylsulfinyl)phenyl]methylene)-1H-3
-indenylmethyl group).

〔Example〕

The vinyl derivative used in the present invention may be one that is widely available commercially.

Examples include vinyl acetate, vinyl propionate, vinyl butyrate, vinyl pivalate, vinyl palmitate, vinyl crotonate or vinyl turbate.

Examples of acidic anti-inflammatory agents that are carboxylic acid derivatives represented by formula (■) include 2-((2-fluoro)-4-biphenylyl)propionic acid (flurbiprofen),
1. -(p-chlorobenzoyl)-5-methoxy-2-
Methyl-3-indolyl acetic acid (indomethacin), 2
-(2,B-dichloroanilino)phenylacetic acid (diclofenac), 2-(4-isobutylphenyl)propionic acid (ibuprofen), (z)-5-fluoro-2
-Methyl-1[[p-(methylsulfinyl)phenyl]methylene) -LH-3-indenyl acetic acid (Sulindac), etc., but substances other than those listed above may also be used.

As acid catalysts, protic acids include phosphoric acid or I)-
Toluenesulfonic acid and Lewis acids such as boron trifluoride ether complex, zinc chloride, aluminum chloride, stannous chloride, and titanium tetrachloride have fewer side reactions and increase the electrophilicity of double bonds, resulting in high yields. This is preferable because it gives Among these, in order to obtain a particularly high yield, it is particularly preferable to use boron trifluoride ether complex or phosphoric acid because side effects such as ester hydrolysis and transesterification are less likely to occur.

Although the reaction of the present invention can be carried out in a normal pressure system or a pressurized system, it is necessary to carry out the reaction in an inert gas atmosphere such as argon gas. The reaction pressure can be carried out in the range of normal pressure to 100 atm, but normal pressure is preferable since there is a risk that the vinyl ester derivative will undergo a polymerization reaction at high pressure.

The reaction temperature of the reaction of the present invention is not particularly limited, but -2
0 to 150°C is preferred, and 0 to 120°C is particularly preferred. At temperatures below 0°C, carboxylic acid derivatives begin to precipitate, and the reaction system is not homogenized, resulting in slow reaction progress.
If it is larger than 0'C, harsh reaction conditions will result, and undesirable reactions such as hydrolytic transesterification and vinyl ester polymerization will proceed. Essentially, the molar ratio of the carboxylic acid derivative represented by the formula (II) and the vinyl ester derivative represented by the formula (■) is 1:1, but when the vinyl ester derivative is used as a solvent, is preferable in that the reaction equilibrium shifts to the product system and leads to improved yield, so the molar ratio may be 1 = 1 to 1:300, but usually it is 1:15 to 1:150. .

If the vinyl ester derivative is blended in an amount lower than the blending ratio of 1:15, the reaction system will not be homogeneous;
The progress of the reaction is slowed down and further localized reactions occur, leading to the production of impurities. Furthermore, if the amount is added in an amount larger than the amount determined by the feeding amount ratio of 1:150, the dilution rate of the carboxylic acid derivative becomes high, making it difficult for the reaction to proceed.

The amount of catalyst to be added varies depending on the type of catalyst, but it is usually preferably 1 mol % to 20 mol %.

If it is less than 1 mol %, the reaction progresses slowly, and if it is more than 20 mol %, undesirable side reactions tend to proceed.

The reaction time varies depending on the reaction temperature, reaction raw materials, type of catalyst, blending ratio of raw materials, and concentration of catalyst, but is generally 0.
．． It is 5 to 30 hours. If the reaction time is less than 0.5 hours, the reaction will not be completed, and if it is longer than 30 hours, other side reactions will proceed.

The order of addition of each component is to dissolve the carboxylic acid derivative represented by the formula (1) into the vinyl ester derivative represented by the formula (■), and then add the catalyst, or add the catalyst in advance by adding the catalyst to the vinyl ester derivative represented by the formula fl). It is preferable to dissolve the resulting carboxylic acid derivative and then add the solution to the vinyl ester derivative represented by formula +11 in order to suppress side reactions and improve yield.

The ester derivative represented by the obtained formula includes all optical isomers and mixtures thereof.

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

The characteristic values of the obtained ester derivatives are shown in Table 1.

Example 1 Production of 1-acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate 2-(2-fluoro-4-biphenylyl)propionic acid (hereinafter referred to as FP) 2.44 in an argon gas atmosphere
g (10 mmol) of dehydrated vinyl acetate 20 m
1 (216 ml Ilol), then add 4
After adding 0.2 ml of 7% boron trifluoride ether complex, the mixture was stirred at room temperature for 6 hours, and then heated and stirred at 80° C. for 1 hour. After the reaction is complete, add 50% ether to the reaction solution.
ml of 5% potassium carbonate aqueous solution to remove FP. After successively washing with 20 ml of saturated brine and dehydrating the organic layer with an appropriate amount of anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5.87 g of a brown oil. The oil was subjected to silica gel column chromatography to obtain a transparent oil of 1-acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate (hereinafter, compound 1).
2.48 g was obtained. The yield was 75% based on FP. However, for the silica gel column, 60 g of Merck Kiesel Gel 60 (manufactured by Merck & Co., Ltd.) was used as the eluent, and cyclohexane:ethyl acetate 100:2
A mixed solution was used.

The characteristic values of Compound 1 in Table 1 are those obtained by the method of Example 1.

Example 2 1-propionyloxyethyl 2-(2-fluoro-4
-Production of biphenylyl) propionate FP O,81
g (2.5 mmol), 7 ml (84.3 mmol) of dehydrated vinyl propionate and 0.05 ml of 47% boron trifluoride ether complex, reacted, treated and purified in the same manner as in Example 1 to obtain a transparent product. Oily 1-propionyloxyethyl 2-(2-fluoro-4
-biphenylyl) propionate (hereinafter referred to as compound 2) was obtained. Yield is 62% based on FP.
．． It was 9%.

Example 3 Preparation of 1-butyryloxyethyl 2-(2-fluoro-4-biphenylyl)propionate PP 0.61 g (2.5 ml 1 ol), dehydrated vinyl butyrate 10 ml (78.9 ml 1 ol)
and 47% boron trifluoride ether complex 0.05ml
1-butyloxyethyl 2-(2
-Fluoro-4-biphenylyl) propionate (hereinafter referred to as compound 3) was obtained in an amount of 0.77 g. The yield was 85.8% based on PP.

Example 4 ■-pivaloyloxyethyl 2-(2-fluoro-4-
Production of (biphenylyl)propionate Reaction and treatment in the same manner as in Example 1 using 61 g (2.5 mmol) of PP O, 13 ml (88.2 mmol) of vinyl bivalate, and 0.05 ml of 47% boron trifluoride niter complex. and by purification, a transparent oily 1-pivaloyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate (hereinafter, compound 4
) I got o, go ge. The yield was 85.4% based on FP.

Example 5 1-balmitoyloxyethyl 2-(2-fluoro-4
-Production of biphenylyl) propionate PP O,81
g (2,50111101), 13 ml (48 mmol) of vinyl palmitate and 0.05 ml of 47% boron trifluoride ether complex were reacted, treated and purified in the same manner as in Example 1 to obtain a transparent oily 1-
Balmitoyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate (hereinafter referred to as compound 5)
I gained 1.18g of. Yield is 89.6% based on FP
Met.

Example 6 1-crotonoyloxyethyl-2-(2-fluoro-
Production of 4-biphenylyl) propionate PP O,6
1g (2.5mmol), vinyl crotonate 5
ml (41.9 mmol) and 0.05 ml of 47% boron trifluoride ether complex, the reaction, treatment and purification were carried out in the same manner as in Example 1 to obtain a transparent oily 1-
Crotonoyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate (hereinafter referred to as compound 6)
I gained 0.56 g. Yield is 82.8 based on PP
%Met.

Example 7 1-(hexa-2,4-genoyloxy)ethyl-2
- Preparation of (2-fluoro-4-biphenylyl)propionate PP O, 81 g (2,5 ma+ol), vinyl turbate 10 ml (89,5 mmol) and 47%
By reacting, treating and purifying in the same manner as in Example 1 using 0.05 ml of boron trifluoride ether complex, 1-(hexa-2,4-genoyloxy)ethyl 2-(2-fluoro 0.23 g of -4-biphenylyl)propionate (hereinafter referred to as compound 7) was obtained.

The yield was 24.1% based on FP.

Example 8 - Production of -acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate 2.44 g (10+ mol) of PP was dissolved in 20 ml (21E1 mmol) of dehydrated vinyl acetate, and 5 ml of p-benzoquinone (0 ,05mmol) and 4
After adding 0.2 ml of 7% boron trifluoride ether complex, the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1 to obtain Compound 1 as a transparent oil.
2.52+r. Yield is 76.5 based on PP
%Met. The characteristic values matched those of Example 1.

Example 9 ■-Production of acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate 2.44 g (10 mmol) of FP was dissolved in 2 Bml (282 mmol) of dehydrated vinyl acetate, and 98 mg (282 mmol) of phosphoric acid was dissolved therein. After adding 1 gaol),
The mixture was heated and stirred at 60°C for 18 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1 to obtain 2.51% of Compound 1 as a transparent oil. I got it. Yield is 76% based on FP
．． It was 1%. The characteristic values matched those of Example 1.

Example 10 Production of 1-acetyloxyethyl 2-(2-fluoro-4-biphenyl)propionate 2.44 g (10 mmol) of PP was dissolved in 26 ml (282 mmol) of dehydrated vinyl acetate, and p-toluene was added to this at room temperature. Sulfonic acid 0.19 g (1
mmol) was added thereto, and the mixture was heated and stirred at 80° C. for 4 hours. After the reaction was completed, the reaction solution was cooled to 20°C, treated and purified in the same manner as in Example 1 to obtain 1.49g of Compound 1 as a transparent oil.
I got it. The yield was 45.0% based on FP.

The characteristic values matched those of Example 1.

Example 11 Production of 1-acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate FP 2.44 g (10n+n+ol) was dissolved in 26 ml (282 mmo) of dehydrated vinyl acetate and titanium tetrachloride 1. After adding 89 g (10 mmol), the mixture was heated and stirred at 60° C. for 6 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1 to obtain 1.74 g of Compound 1 as a transparent oil. Yield is 52.5% based on FP.
It was 7%. The characteristic values matched those of Example 1.

Example 12 Preparation of 1-acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate PP 2.44 g (10 mmol) was dissolved in dehydrated vinyl acetate 2 [iml (2 g 2 mmol), and zinc chloride 1 was dissolved at room temperature. .36 g (10 mmol.) was added and stirred at 60° C. for 6 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1 to obtain 1-
1.72 g of acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate was obtained. The yield is F
It was 52.1% based on P. Characteristic values are as in Example 1
The characteristic values of

Example 13 Production of 1-acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate 2.44 g (10 mmol) of FP was added to 26 ml of dehydrated vinyl acetate. (282 mmol), and then added 0.13 g of aluminum chloride (282 mmol) at room temperature.
After adding 1 mmol), the mixture was heated and stirred at 60° C. for 6 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1 to obtain 1.53 g of Compound 1 as a transparent oil. The yield was 46.3% based on FP. The characteristic values matched those of Example 1.

Example 14 Production of 1-acetyloxyethyl 2-(2-fluoro-4-biphenylyl)propionate
2.44 g (10 mmol) and 0.2 ml of 47% boron trifluoride neat/l/complex were dissolved, and then this solution was dissolved in 26 ml (282 mmol) of dehydrated vinyl acetate.
After the dropwise addition was completed, the mixture was stirred at room temperature for 17 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1 to obtain Compound 1 as a transparent oil with 2.11. g
I got it. The yield was 63.8% based on FP. The characteristic values matched those of Example 1.

Example 15 Preparation of 1-acetyloxyethyl [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]acetate 1-(p-chlorobenzoyl)-5-methoxy-2-methyl- 1 g of 3-indolyl acetic acid (hereinafter referred to as IM)
(2.8 mmol) in 30 ml (32 mmol) of vinyl acetate.
5 mmol), then added 0.2 ml of 47% boron trifluoride ether complex at room temperature, and dissolved at 25°C for 1 hour.
Stirred for 5 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1 to obtain 1-, which is a transparent yellow oily substance.
Acetyloxyethyl [1-(p-chlorobenzoyl)
1.07 g of -5-methoxy-2-methyl-3-indolyl]acetate (hereinafter referred to as compound 8) was obtained. The yield was 85.9% based on IN.

Example 16 ■-Production of acetyloxyethyl-2-(2,6-dichloroanilino)phenylacetate 2-(2,8-dichloroanilino)phenylacetic acid (hereinafter referred to as DP) 1 g (3,1[ 1111101)
was suspended in vinyl acetate Hml (325 mIIlol) and 47% boron trifluoride ether complex 0 was added at room temperature.
．． 2 ml was added and stirred at 25° C. for 15 hours.

After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1, and a transparent yellow oily substance, 1-acetyloxyethyl 2-(2,6-dichloroanilino)phenylacetate (hereinafter referred to as compound 9), was obtained. ) was obtained by 0.41 g.

The yield was 34.5% based on DP.

Example 17 Production of 1-acetyloxyethyl 2-(4-isobutylphenyl)propionate 1 g of 2-(4-inbutylphenyl)propionic acid (
4,85 mmo+) in 10 ml of dehydrated vinyl acetate (
After adding 0.2 ml of 47% boron trifluoride ether complex at room temperature, the mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1. 0.95 g of transparent oily 1-acetyloxyethyl 2-(4-isobutylphenyl) propionate (hereinafter referred to as compound 10) was obtained.The yield was 67 g based on 2-(4-isobutylphenyl) propionic acid. It was .2%.

Example 18 ■-Acetyloxyethyl ((z)-5-fluoro-2
-Methyl-7-((p-(methylsulfinyl)phenyl)methylene)-3-indenyl acetate production (z)-5-fluoro-2-methyl-7-([p~(methylsulfinyl)phenyl]methylene )-1H-indene-3-acetic acid 3.5[i g (1,0 mmol) was dissolved in 40 ml (418 mmol) of vinyl acetate, and 0.4 g of 47% boron trifluoride ether complex was dissolved at room temperature.
ml and then stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was treated and purified in the same manner as in Example 1,
Orange, oily ■-acetyloxyethyl [(z)-5
-2.9 g of -fluoro-2-methyl-7-[(p-(methylsulfinyl)phenyl]methylene]-3-indenyl]acetate (hereinafter referred to as compound 11) was obtained. The yield was (z)-5-fluoro -2-methyl-7-[p-(
methylsulfinyl)phenyl]methylene] -LH-
It was 65.4% based on indene 3-acetic acid.

Example 19 ■-Production of propionyloxyethyl (1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl) acetate IM Ig (2,811 mol) was dissolved in vinylpropionate 50 ml (459 mmol). In addition, 0.2 ml of 47% boron trifluoride ether complex was added at room temperature,
The mixture was then stirred at 25°C for 15 hours. After the reaction, the reaction solution was treated and purified in the same manner as in Example 1 to obtain 1-propionyloxyethyl (1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl) acetate as a transparent yellow oil. (hereinafter referred to as compound 12) at 1.1
I gained 3g. The yield was 88.5% based on IM.

Example 20 1-crotonoyloxyethyl (1-(p-chlorobenzoyl-5-methoxy-2-methyl-3-indolyl)
Production of acetate Yellow crystalline 1-crotonoyloxyethyl (L -(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]acetate (hereinafter referred to as compound 13) at 0.8
I gained 1g. The yield was 61.7% based on IM.

Example 21 1(2,4-hexagenoyloxy)ethyl (L-(
p-chlorobenzoyl)-5-methoxy-2-methyl-
Production of 3-indolyl]acetate Example 1 except that 1 g (2.8 mmol) of 1M 1M and 50 ml (347 mmol) of vinyl turbate were used.
1-
(2,4-hexagenoyloxy)ethyl (1-(1
)-chlorobenzoyl)-5-methoxy-2-methyl-
0.44 g of 3-indolyl]acetate (hereinafter referred to as compound 14) was obtained. Yield is 31.3% based on IM.
It was 4%.

Example 22 - Crotonoyluo Beef diethyl 2-<2.6-diku a
Preparation of phenylacetate (loanilino) The reaction, treatment and purification were carried out in the same manner as in Example 1 except that 1 g (Llmmol) of DP and 40 ml (H5mrAol) of vinyl crotonate were used, and an orange oily 1-crotonoyloxyethyl was obtained. -2-(2,8-dichloroanilino)phenylacetate (hereinafter, compound 15
I gained 0.45 g of ). The yield was 35.4% based on DF.

Example 23 1-(2,4-hexagenoyloxy)ethyl-2=
Production of (2,6-dichloroanilino)phenylacetate The reaction, treatment and purification were carried out in the same manner as in Example 1, except that 1 g (3.1 mmol) of DF and 40 ml (278+nmol) of vinyl turbate were used. Oily 1-(2,4-hexagenoyloxy)ethyl-2-
0.24 g of (2°6-dichloroanilino)phenylacetate (hereinafter referred to as compound 1B) was obtained. The yield is D
It was 17.7% based on P.

Comparative number of ■-acetyloxyethyl-2-(2-fluoro-4-
Preparation of FP (biphenylyl) propionate 0.24 g (1 mmol) of FP was dissolved in 4 ml (43.3 mmol) of dehydrated vinyl acetate, 0.03 ml (0.5 mmol) of concentrated sulfuric acid was added under water cooling, and then the solution was dissolved at room temperature. Stirred for 24 hours. After the reaction was completed, the reaction solution was reacted, treated and purified in the same manner as in Example 1 to obtain 0.17 g of transparent and oily Compound 1. The yield was 51.5% based on FP. The characteristic values matched those of Example 1.

[Blank below] [Effects of the Invention] In the method for producing an ester derivative of the present invention, the vinyl ester derivative as a raw material is inexpensive and easily available, and the vinyl ester derivative and an acidic anti-inflammatory agent are directly reacted to produce the ester derivative in one step. It is something that can be obtained.

Furthermore, by using the appropriate catalyst discovered by the present invention, ester derivatives can be obtained in a much more selective manner and in higher yields than conventional methods.

Therefore, the present invention has the advantage that ester derivatives can be produced more economically and industrially than conventional methods.

Procedural amendments (Own ship February 7, 1988 1. Display of patent application No. 300704, filed in 1988. 2. Name of the invention. 3. Process for producing ester derivatives. 3. Relationship with the case. Patent applicant address: Bunkyo, Tokyo. 2-28-8, Honkomagome, Ward Name: Kaken Pharmaceutical Co., Ltd. Representative: Kei Sawa 4 Agent: 540 Address: NS Building 5, 2-37 Tanimachi, Higashi-ku, Osaka
Subject of amendment (1) Contents of amendment in column 6 of "Detailed Description of the Invention" of the specification (1) "Sulindak Jiklo" on page 4, line 5 of the specification is amended to "Slindak, Jiklo".

(2) Correct “alkyl” in line 4 of page 7 to “alkane”.

(3) r 2-((2-fluoro) on page 9, line 13
-" is corrected to "2-(2-fluoro-").

(4) "Hydrolyzed ester" on page 11, line 6 is corrected to "hydrolyzed, ester."

(5) "Blending ratio" on the last line of page 11 will be corrected to "Blending ratio."

(6) Correct “derivative” in the fourth line from the bottom of page 12 to read “solution of derivative”.

(7) In the same page, page 18, line 5, “dissolve” is corrected to “dissolve in”.

(8) Correct rl(2,4-hexa) in line 10 of page 2B to rl-(2,4-hexa).

(9) "Same reaction" on page 28, line 9 is corrected to "similarly."

00) Table 1 on pages 29 to 36 of the same is amended as follows.

[Margin below]

Claims (1)

[Claims] 1 Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 represents an alkyl group or alkenyl group having 1 to 15 carbon atoms) vinyl ester derivative and formula (II): R_2-COOH(II) (wherein R_2 is 1-(2-fluoro-4-biphenylyl)ethyl group, 1-(p-chlorobenzoyl)-5-methoxy-2 -methyl-3-indolylmethyl group, 2-(
2,6-dichloroanilino)phenylmethyl group, 1-(
4-isobutylphenyl)ethyl group or (z)-5-
Formula (III ): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R_1 is an alkyl group or alkenyl group having 1 to 15 carbon atoms, R_2 is 1-(2-fluoro-4-biphenylyl)ethyl group, 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylmethyl group, 2-(2,6-dichloroanilino)phenylmethyl group, 1-(4-isobutylphenyl)ethyl group or (z)-5-fluoro-2-methyl-1-[[p-
(Methylsulfinyl)phenyl]methylene]-1H-
3-indenylmethyl group). 2 R_1 is a methyl group, ethyl group, propyl group, t-butyl group, or pentadecyl group as an alkyl group, and a propenyl group or 1,3- as an alkenyl group.
A method for producing an ester derivative according to claim 1, which comprises a pentadienyl group. 3. The acid catalyst is a Lewis acid selected from the group consisting of boron trifluoride, zinc chloride, aluminum chloride, stannous chloride or titanium tetrachloride, or a proton selected from the group consisting of phosphoric acid or p-toluenesulfonic acid. A method for producing an ester derivative according to claims 1 and 2, which is an acid.