JPH0337539B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing aromatic carboxylic acid amide derivatives. More specifically, the present invention provides compounds of the general formula (R ¹ in the formula is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, R ³ is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and Y can be the same or different. and each is a group selected from a linear or branched lower alkoxyl group having 1 to 4 carbon atoms, a hydroxyl group, and a lower acyloxy group having 2 to 5 carbon atoms, and n is 2 or The present invention relates to a method for producing an aromatic carboxylic acid amide derivative represented by (3). Compounds represented by general formula (1) obtained by the production method of the present invention, especially formula N-(3,4-dimethoxycinnamoyl)anthranilic acid and its pharmacologically acceptable salts, represented by For example, it is extremely useful as a pharmaceutical for the prevention and treatment of bronchial asthma, atopic dermatitis, allergic rhinitis, and the like. The present invention thus relates to a method for efficiently producing the compound of general formula (1) useful as a pharmaceutical. The compound of general formula (1) obtained by the method of the present invention is a known compound, and several methods for its production have already been proposed. Traditionally, this compound has the general formula (R ¹ , Y and n in the formula have the same meanings as above) and a reactive functional derivative of a nuclear-substituted cinnamic acid represented by the general formula (R ³ in the formula has the same meaning as above) A method of reacting aminobenzoic acid and its esters represented by
-40711, No. 57-47906, No. 57-36905). However, this production method has disadvantages in that it is cumbersome to operate, the reaction is carried out under heating conditions, which tends to produce by-products due to decomposition of starting materials, side reactions, etc., and also requires time and effort for purification. In addition, there were several drawbacks, such as the generation of harmful gases such as hydrogen halide when producing acid halides, for example, as reactive functional derivatives of the starting material nuclear-substituted cinnamic acids (2). As a result of research aimed at solving these problems, the present inventors discovered that by applying the Wittig reaction, the desired product could be produced simply, safely, and efficiently with an extremely mild reaction.The present invention is based on the present invention. I was able to accomplish this. That is, according to the present invention, the general formula [In the formula, R ¹ has the same meaning as above, R ² is a lower alkyl group having 1 to 3 carbon atoms, and Z is the formula,

[Formula] or

[Formula] (However, in each formula, X ¹ is an alkyl group having 1 to 10 carbon atoms, a phenyl group, or a substituted phenyl group, X ²
is an alkoxyl group having 1 to 10 carbon atoms, and Hal is a group represented by a chlorine atom, bromine atom, or iodine atom.] A phosphorus compound represented by the following is treated with a basic substance to form the general formula [R ¹ and R ² in the formula have the same meanings as above,
Z′ is the formula (X ¹ ) ₃ P− or

Phosphorus ylide derivative represented by [Formula] (However, in each formula, X ¹ and X ² have the same meanings as above, and B ⁺ is a cation derived from a basic substance) and the general formula, (Y and n in the formula have the same meanings as above) By reacting with a nuclear-substituted benzaldehyde represented by the general formula, An aromatic carboxylic acid amide derivative represented by the formula (R ¹ , R ² , Y and n have the same meanings as above) is produced. Next, by hydrolyzing the ester group by a conventional method and further converting the product into a salt as desired, the product is converted into the general formula (R ¹ and n in the formula have the same meanings as above,
Y′ may be the same or different, each being a linear or branched lower alkoxyl group or hydroxyl group having 1 to 4 carbon atoms) and drugs thereof. Physically acceptable salts can be produced. In the production method of the present invention, the reaction operation is extremely simple, and since the reaction proceeds under mild conditions such as at room temperature or under cooling, there are few by-products and purification is easy. Furthermore, there is no generation of harmful gases such as hydrogen halide gas generated during the production of acid halides. In this manner, the present manufacturing method can manufacture a target object much more easily and efficiently than conventional manufacturing methods. The nuclear-substituted benzaldehyde of general formula (6) used as a raw material in the production method of the present invention is a known compound and can be obtained as a commercial product or easily produced by methods described in literature. Examples of such compounds include 2,3-,2,4-,2,5- or 3,4-dihydroxybenzaldehyde, 2,3-,2,4
-,2,5- or 3,4-diacetoxybenzaldehyde, 2,3-,2,4-,2,5-,3,
4- or 3,5-dimethoxybenzaldehyde,
2,3-,2,4-,2,5- or 3,4-diethoxybenzaldihyde, 2,3-,2,4-,
2,5- or 3,4-dipropoxybenzaldehyde, 2,3-, 2,4-, 2,5- or 3,4
-dibutoxybenzaldehyde, 2-hydroxy-3-methoxybenzaldehyde, 2-hydroxy-4-methoxybenzaldehyde, 2-hydroxy-5-methoxybenzaldehyde, 3-hydroxy-4-methoxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 2-
Acetoxy-3-methoxybenzaldehyde, 2
-acetoxy-4-methoxybenzaldehyde,
2-acetoxy-5-methoxybenzaldehyde, 3-acetoxy-4-methoxybenzaldehyde, 4-acetoxy-3-methoxybenzaldehyde, 2-ethoxy-3-methoxybenzaldehyde, 2-ethoxy-4-methoxybenzaldehyde, 2-ethoxy-5 -Methoxybenzaldehyde, 3-ethoxy-4-methoxybenzaldehyde, 4-ethoxy-3-methoxybenzaldehyde, 2-propoxy-3-methoxybenzaldehyde, 2-propoxy-4-methoxybenzaldehyde, 2-propoxy-5-methoxybenzaldehyde, 3 -Propoxy-4-methoxybenzaldehyde, 4-propoxy-3-methoxybenzaldehyde, 2-butoxy-3-methoxybenzaldehyde, 2-butoxy-4-methoxybenzaldehyde, 2-butoxy-5-methoxybenzaldehyde, 3-butoxy-4- Methoxybenzaldehyde, 4-butoxy-3-methoxybenzaldehyde, 2-isopropoxy-3-methoxybenzaldehyde, 2-isopropoxy-
4-methoxybenzaldehyde, 2-isopropoxy-5-methoxybenzaldehyde, 3-isopropoxy-4-methoxybenzaldehyde, 4
-isopropoxy-3-methoxybenzaldehyde, 2-sec-butoxy-3-methoxybenzaldehyde, 2-sec-butoxy-4-methoxybenzaldehyde, 2-sec-butoxy-5-methoxybenzaldehyde, 3-sec-butoxy-4- Methoxybenzaldehyde, 4-sec-butoxy-3-methoxybenzaldehyde, 2,3,4-,2,
Examples include 4,5-, 2,4,6- or 3,4,5-trimethoxybenzaldehyde. Although the phosphorus compound of general formula (4) used as the other raw material in the production method of the present invention is a new compound, trialkylphosphine, triphenylphosphine, trisubstituted phenylphosphine, trisubstituted phenylphosphine, trisubstituted It can be easily produced by reacting a phosphorus compound such as an alkyl phosphite with an α-haloacylaminobenzoic acid alkyl ester. The phosphines and phosphites used in this reaction are both known compounds and can be obtained as commercially available products or can be produced by methods described in literature. Such compounds include triethylphosphine, tri-n-butylphosphine, tri-n-octylphosphine,
Triphenylphosphine, tris(4-methoxyphenyl)phosphine, tris(4-methylphenyl)phosphine, trimethylphosphite, triethylphosphite, triisopropylphosphite, tri-n-butylphosphite, tri-
Examples include n-decyl phosphite. The production method of the present invention is a type of so-called Wittig reaction, in which a phosphorus ylide derivative (5) obtained by treating a phosphorus compound of general formula (4) with a basic substance is reacted with a nuclear-substituted benzaldehyde (6) to produce an olefin. It produces bonds and obtains the desired product. In this case, the phosphorus ylide derivative (5) is usually produced in the reaction system and subjected to the next reaction without isolation.
In the case of a stable ylide, the next reaction can be performed after isolation and purification. Phosphorus ylide derivative (5) from the phosphorus compound of general formula (4)
The conversion to olefin and the olefin-forming reaction with the nuclear-substituted benzaldehyde of general formula (6) can be carried out according to conventional Wittig reaction and similar reaction methods. That is, the phosphorus compound of general formula (4) is dissolved in an inert organic solvent, a basic substance is added thereto and reacted for a certain period of time, then the nuclear-substituted benzaldehyde of general formula (6) is added, and the mixture is heated at room temperature or under cooling. react to. In this case, compounds such as sodium amide, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium amide, etc. are used as the basic substance. Further, as a solvent, methanol, ethanol, chloroform, methylene chloride, dioxane, diethyl ether, tetrahydrofuran, benzene, toluene, acetonitrile, etc. can be used. When the phosphorus ylide derivative of general formula (5) is a stable ylide, the phosphorus compound of general formula (4) is dissolved or suspended in water or alcohol and reacted with sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. After the phosphorus ylide derivative (5) is produced and isolated and purified, it and the nuclear-substituted benzaldehyde (6) are mixed with an inert organic solvent such as methanol, ethanol, chloroform, methylene chloride, dioxane,
The desired product can be produced by dissolving it in diethyl ether, tetrahydrofuran, benzene, toluene, acetonitrile, acetic acid, ethyl acetate, etc. and reacting it at room temperature or under cooling. Further, the phosphorus compound of general formula (4) is derived from trialkyl phosphite [(2-, 3- or 4
-alkoxylcarbonylphenyl)carbamoylmethyl]phosphonic acid dialkyl esters, in an inert organic solvent such as benzene, toluene, ethanol, pyridine, etc., in the presence of an organic base such as piperidine or a salt thereof such as an acetate. Alternatively, the desired product can also be produced by reacting with a nuclear-substituted benzaldehyde (6) and then hydrolyzing with sodium hydroxide in alcohol. In order to suitably carry out the production method of the present invention, the phosphorus compound represented by the general formula (4) is dissolved in 20 to 40 times the amount of methanol, and a necessary amount or a slightly excessive amount of sodium methoxide is added thereto. Stir for a while at room temperature or under cooling. Next, a nuclear-substituted benzaldehyde represented by the general formula (6) is added to this, and the mixture is stirred at room temperature or under cooling for 2 to 10-odd hours. The solvent was distilled off under reduced pressure, the residue was dissolved in a small amount of alcohol and poured into ice water, and the crystals precipitated as acidified with hydrochloric acid were collected by filtration, washed with water, and recrystallized with an appropriate solvent to obtain the general formula (1' ) is obtained. Furthermore, the obtained product is dissolved or suspended in water or alcohol after purification or as a crude crystal, and a required amount or a slightly excessive amount of sodium hydroxide is added.
Stir at room temperature or under heating for about 10 minutes to several hours.
After concentrating the solvent under reduced pressure, it is acidified with hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water, and recrystallized with an appropriate solvent to obtain the compound represented by the general formula (1''). In the method of the present invention, nuclear substitution When using benzaldehydes (6) having a hydroxyl group, it is preferable to protect the hydroxyl group with an acetyl group or the like before reacting with the ylide derivative of general formula (5). The carboxylic acids (1″) in which R ³ is a hydrogen atom in the compound of general formula (1) obtained by this production method are:
The carboxyl group can be converted into a pharmaceutically acceptable salt, such as a metal salt such as sodium, potassium, calcium, magnesium, etc., by conventional methods. For example, the sodium salt can be easily prepared by adding an equimolar amount of an aqueous solution of sodium hydroxide to an alcoholic solution of the compound of general formula (1'') and heating it for an appropriate period of time. Alternatively, the compound of general formula ( By adding an equimolar amount of sodium hydroxide aqueous solution to an alcoholic solution of the compound 1') and heating for an appropriate period of time, the ester can be hydrolyzed and simultaneously converted into a sodium salt.Production method of the present invention The reaction operation is simple and easy compared to conventional manufacturing methods, and the reaction conditions are mild, so side reactions are difficult to occur, and purification is easy.Furthermore, there is no generation of harmful gases during the entire manufacturing process, including raw materials. The aromatic carboxylic acid amide derivatives produced by the present invention can be widely used for the prevention and treatment of various diseases caused by allergies, such as bronchial asthma, atopic dermatitis, and allergic rhinitis. The present invention will be explained in more detail with reference to Examples and Reference Examples below.The melting points of the products in each Reference Example and Examples are uncorrected.Reference Example 1 Triphenylphosph 20.0 g of ester and 12.0 g of methyl N-chloroacetylanthranilate were mixed in benzene.
It was dissolved in 130 ml and refluxed for 17 hours. After cooling, the precipitated crystals were collected by filtration, washed with benzene and dried to obtain [(2
-Methoxycarbonylphenyl)carbamoylmethyl]triphenylphosphonium chloride 9.0g
I got it. Melting point 163-165℃ (decomposition) Infrared absorption spectrum (KBr) νCO: 1705, 1670cm ^-1 nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 3.70 (3H, s), 5.49 (2H, d, J = 15
Hz), 7.0 to 8.0 (19H, m), 11.62 (1H, s) Elemental analysis value (as C ₂₈ H ₂₅ ClNO ₃ ) C% H% N% Calculated value 68.64 5.14 2.86 Actual value 68.42 5.11 2.68 Reference example 2 Correspondence The following compound was obtained by performing substantially the same operation as in Reference Example 1 using the starting material.

[Table] Reference example 3 16.0 g of triethyl phosphite and 9.0 g of methyl N-chloroacetylanthranilate at 140 to 150
The reaction was carried out at ℃ for 3 hours. After the reaction was completed, excess triethyl phosphite was distilled off under reduced pressure to obtain 13.0 g of diethyl [(2-methoxycarbonylphenyl)carbamoylmethyl]phosphonate. Infrared absorption spectrum (liquid film) νCO: 1685cm ^-1 nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 1.33 (6H, t, J = 7Hz), 3.03 (2H,
d, J=20Hz), 3.89 (3H, s), 4.13 (2H,
q, J = 7Hz), 4.22 (2H, q, J = 7
Hz), 6.9-8.8 (4H, m), 11.22 (1H, s) Reference Example 4 Using the corresponding raw materials, substantially the same operation as in Reference Example 3 was performed to obtain the following compound.

[Table] Example 1 Add 150 ml of water and 100 ml of benzene to 5.16 g of [(2-methoxycarbonylphenyl)carbamoylmethyl]triphenylphosphonium chloride, and add 0.48 g of sodium hydroxide to the water while stirring under ice cooling.
A solution dissolved in 20 ml was added dropwise. After the addition, the mixture was stirred for another 15 minutes, and the benzene layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from benzene-diethyl ether to give [(2-methoxycarbonylphenyl)
Carbamoylmethylene]triphenylphosphorane
4.7g was obtained. Melting point 160-163℃ Infrared absorption spectrum (KBr) νCO: 1670cm ^-1 nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 3.82 (3H, s), 6.6-8.8 (20H, m),
10.43 (1H, s) Elemental analysis value (as C ₂₈ H ₂₄ NO ₃ P) C% H% N% Calculated value 74.16 5.33 3.09 Actual value 74.19 5.14 3.86 [(2-methoxycarbonylphenyl)carbamoylmethylene] triphenylphospho Ran 500mg
and 183 mg of 3,4-dimethoxybenzaldehyde were dissolved in 20 ml of methanol and stirred at room temperature for 2.5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: benzene: ethyl acetate = 5:1) and recrystallized from benzene-n-hexane to obtain N-
265 mg of methyl (3,4-dimethoxycinnamoyl)anthranilate was obtained. Melting point 141-143℃ Infrared absorption spectrum (KBr) νCO: 1700, 1680cm ^-1 nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 3.83 (3H, s), 3.86 (6H, s), 6.40
(1H, d, J=15Hz), 6.7-8.9 (8H, m),
11.27 (1H, s) Elemental analysis value C ₁₉ H ₁₉ NO ₅ C% H% N% Calculated value 66.85 5.61 4.10 Actual value 67.00 5.58 3.85 Example 2 [(2-methoxycarbonylphenyl)carbamoylmethyl]triphenylphosphonium 1.0 g of chloride was added to 40 ml of methanol, and 0.11 g of sodium methoxide was added while stirring under ice cooling.
After stirring for a while, 0.34 g of 3,4-dimethoxybenzaldehyde was added, and the mixture was stirred at room temperature for 17 hours.
After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was made acidic by adding aqueous hydrochloric acid solution, and then extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene:ethyl acetate = 5:1) and recrystallized from benzene-n-hexane to obtain N-(3,4
-dimethoxycinnamoyl) methyl anthranilate 0.5 g was obtained. The physical properties of this product were shown to be the same as the compound obtained in Example 1. Example 3 [(2-methoxycarbonylphenyl)carbamoylmethylene]triphenylphosphorane 453mg
and 152 mg of vanillin were added to 20 ml of methanol and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: benzene: ethyl acetate =
5:1) and then recrystallized from methylene chloride-diethyl ether-n-hexane to obtain N-
(4-hydroxy-3-methoxycinnamoyl)
263 mg of methyl anthranilate was obtained. Melting point 127-128℃ Infrared absorption spectrum (KBr) νOH: 3470cm ^-1 νCO: 1670, 1620cm ^-1 Nuclear magnetic resonance spectrum (90MHz, d ₆ -DMSO) δ: 3.82 (3H, s), 3.86 (3H, s) ,6.6~8.6
(9H, m), 9.42 (1H, s) 10.71 (1H, s) Elemental analysis value (as C ₁₈ H ₁₇ NO ₅ ) C% H% N% Calculated value 66.04 5.24 4.28 Actual value 66.16 5.03 4.12 N-(4 -Hydroxy-3-methoxycinnamoyl) 200 mg of methyl anthranilate was added to a mixture of 5 ml of ethanol and 5 ml of water, 100 mg of sodium hydroxide was added thereto, and the mixture was stirred at 50°C for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, the residue was made acidic by adding dilute hydrochloric acid, the precipitated crystals were collected by filtration, and then recrystallized from acetone to obtain N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid. Obtained 150mg. Melting point 231-235℃ Infrared absorption spectrum (KBr) νOH: 3500cm ^-1 νCO: 1670, 1650cm ^-1 Nuclear magnetic resonance spectrum (90MHz, _d6 -DMSO) δ: 3.82 (3H, s), 6.5-8.8 (9H, m), 9.2
~9.7 (1H, br), 11.22 (1H, s) Elemental analysis value (as C ₁₇ H ₁₅ NO ₅ ) C% H% N% Calculated value 65.17 4.82 4.47 Actual value 65.28 4.79 4.45 Example 4 [(3-methoxy Dissolve 500 mg of diethyl (carbonylphenyl)carbamoylmethyl phosphonate in 20 ml of methanol and stir under ice cooling until 50%
146 mg of sodium hydride was added and stirred for an additional hour. To this was added 252 mg of 3,4-dimethoxybenzaldehyde, and the mixture was stirred at room temperature for 6 hours.
After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dissolved in a small amount of ethanol, poured into ice water, and made acidic by adding dilute hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and recrystallized with aqueous alcohol to obtain 360 mg of methyl 3-(3,4-dimethoxycinnamoylamino)benzoate. Melting point 128-130℃ Infrared absorption spectrum (KBr) νCO: 1705, 1650cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 3.78 (3H, s), 3.85 (6H, s), 6.3-8.3
(10H, m) Elemental analysis value (as C ₁₉ H ₁₉ NO ₅ ) C% H% N% Calculated value 66.85 5.61 4.10 Actual value 67.09 5.79 3.89 Example 5 [(2-methoxycarbonylphenyl)carbamoylmethyl]phosphonic acid 500 mg of diethyl was dissolved in 20 ml of dry dioxane, and while stirring under ice cooling, 70 mg of lithium amide was gradually added, followed by stirring at room temperature for 1 hour. To this was added 252 mg of 3,4-dimethoxybenzaldehyde, and the mixture was stirred at room temperature for 18 hours.
After the reaction was completed, dilute hydrochloric acid was added to the reaction solution to make it acidic, and the mixture was extracted with methylene chloride. Wash the extract with water, dry it,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: benzene:
After purification with ethyl acetate = 7:1), benzene-n
-Methyl N-(3,4-dimethoxycinnamoyl)anthranilate 350 mg after recrystallization from hexane
I got it. The physical properties of this product were shown to be the same as the compound obtained in Example 1. Example 6 [(2-methoxycarbonylphenyl)carbamoylmethyl]diisopropylphosphonate 500mg
Dissolve in 30 ml of dry acetonitrile, add 64 mg of lithium amide while stirring under ice cooling, and dissolve at room temperature for 1 hour.
I stirred the time. 232 mg of 3,4-dimethoxybenzaldehyde was added to this, and the mixture was reacted at room temperature for 17 hours. After the reaction was completed, the same operation as in Example 5 was carried out,
320 mg of methyl N-(3,4-dimethoxycinnamoyl)anthranilate was obtained. The physical properties of this product were shown to be the same as the compound obtained in Example 1. Example 7 {1-[(2-methoxycarbonylphenyl)carbamoyl]ethyl}diethylphosphonate 500 mg
was dissolved in 20 ml of methanol, 140 mg of 50% sodium hydride was added while stirring under ice cooling, and the mixture was further stirred at room temperature for 1 hour. 232 mg of 3,4-dimethoxybenzaldehyde was added to this, and the mixture was reacted at room temperature for 18 hours. After the reaction is complete, the solvent is distilled off under reduced pressure.
The residue was acidified with dilute hydrochloric acid and extracted with methylene chloride. The extract was washed with water, dried, and the solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from methylene chloride-diethyl ether-n-hexane to give N-(3,
344 mg of methyl 4-dimethoxy-α-methylcinnamoyl)anthranilate was obtained. Melting point 153-155℃ Infrared absorption spectrum (KBr) νCO: 1690, 1665cm ^-1 nuclear magnetic resonance spectrum (90MHz, d ₆ -DMSO) δ: 2.17 (3H, s), 3.77 (6H, s), 3.86
(3H, s), 7.0~8.7 (9H, m), 11.20 (1H,
s) Elemental analysis value (as C ₂₀ H ₂₁ NO ₅ ) C% H% N% Calculated value 67.59 5.96 3.94 Actual value 67.78 6.13 3.86 Example 8 [(2-methoxycarbonylphenyl)carbamoylmethyl]diethyl phosphonate 1.0 g and 3,
570 mg of 4-dimethoxybenzaldehyde was dissolved in 30 ml of benzene, 100 mg of piperidine and 50 mg of acetic acid were added thereto, a dehydrator was attached, and the mixture was heated under reflux for 50 hours. After cooling, the solvent was distilled off under reduced pressure, the residue was dissolved in 30 ml of ethanol, 1 g of potassium hydroxide was added, and the mixture was heated at 60° C. for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, ice water and dilute hydrochloric acid were added to the residue, and the precipitated crystals were collected by filtration, washed with water, dried, and recrystallized from chloroform to give N-(3,4-dimethoxycinnamoyl)anthranyl. 634 mg of acid was obtained. Melting point 208-208.5℃ Infrared absorption spectrum (KBr) νCO: 1690, 1655cm ^-1 nuclear magnetic resonance spectrum (90MHz, d ₆ -DMSO) δ: 3.77 (3H, s), 3.79 (3H, s), 6.73
(1H, d, J=16Hz), 6.9~8.7 (8H, m),
11.33 (1H, s) Elemental analysis value (as C ₁₈ H ₁₇ NO ₅ ) C% H% N% Calculated value 66.04 5.24 4.28 Actual value 66.12 5.22 4.26 Example 9 N-(3,4-dimethoxycinnamoyl)anthranilic acid 40 ml of 10% aqueous sodium hydroxide solution was added to 1.7 g of methyl and heated for 1 hour. After cooling, the precipitated crystals were collected by filtration to obtain 1.4 g of sodium salt of N-(3,4-dimethoxycinnamoyl)anthranilic acid. This was heated and dissolved in an appropriate amount of water, and diluted hydrochloric acid was added to make it acidic. The precipitated crystals were collected by filtration, washed with water, dried, and recrystallized from chloroform to give N-(3,4-
Dimethoxycinnamoyl) anthranilic acid 1.0g
I got it. The physical properties of this product were shown to be the same as those obtained in Example 8. Example 10 The following compounds could be obtained by performing substantially the same operations as in each of the above Examples using the corresponding raw materials.

【table】

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, R ² is a lower alkyl group having 1 to 3 carbon atoms, and Z is the formula [formula] or [formula] ( However, X ¹ in each formula is an alkyl group having 1 to 10 carbon atoms, a phenyl group, or a substituted phenyl group, X ²
is an alkoxyl group having 1 to 10 carbon atoms, and Hal is a group represented by a chlorine atom, bromine atom, or iodine atom.] A phosphorus compound represented by the following is treated with a basic substance to form the general formula [R ¹ and R ² in the formula have the same meanings as above,
Z′ is the formula (X ¹ ) ₃ P− or [Formula] (However, X ¹ and X ² in each formula have the same meanings as above, and B ⁺ is a cation derived from a basic substance) A phosphorus ylide derivative represented by (Y in the formula may be the same or different, and each has a linear or branched lower alkoxyl group having 1 to 4 carbon atoms, a hydroxyl group, and a hydroxyl group having 2 carbon atoms.
-5 lower acyloxy groups, n is 2 or 3) A method for producing an aromatic carboxylic acid amide derivative represented by the formula (R ¹ , R ² , Y and n have the same meanings as above). 2 General formula [In the formula, R ¹ is a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, R ² is a lower alkyl group having 1 to 3 carbon atoms, and Z is the formula [formula] or [formula] ( However, X ¹ in each formula is an alkyl group having 1 to 10 carbon atoms, a phenyl group, or a substituted phenyl group, X ²
is an alkoxyl group having 1 to 10 carbon atoms, and Hal is a chlorine atom, bromine atom, or iodine atom.] The phosphorus compound represented by is treated with a basic substance to form the general formula (R ¹ and R ² in the formula have the same meanings as above,
Z' is the formula (X ¹ ) ₃ P- or [Formula] (However, X ¹ and X ² in each formula have the same meanings as above, and B ⁺ is a cation derived from a basic substance) A phosphorus ylide derivative represented by the following is prepared, and this and the general formula (Y in the formula may be the same or different, and each has a linear or branched lower alkoxyl group having 1 to 4 carbon atoms, a hydroxyl group, and a hydroxyl group having 2 carbon atoms.
~5 lower acyloxy groups, n is 2 or 3)), then the ester group is hydrolyzed by a conventional method, and if desired, the ester group is General formula, characterized by converting the product into a salt (R ¹ and n in the formula have the same meanings as above,
Y' may be the same or different, and each is a linear or branched lower alkoxyl group or hydroxyl group having 1 to 4 carbon atoms) and pharmacology of aromatic carboxylic acid amide derivatives represented by A method for producing salt that is acceptable to the public.