JPH0536432B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention has an inhibitory effect on histamine release from leukocytes during antigen-antibody reactions, Prausnitz-Ku¨stner reaction, allergen intradermal reaction, allergen inhalation-induced reaction, etc. N-(3,4-dimethoxycinnamoyl), which is known as a therapeutic agent for allergic diseases, etc.
The following general formula (4) such as alanthranilic acid (However, in the formula, R ¹ is a lower alkoxy group and R ² is a hydrogen atom or a lower alkoxy group. The same applies hereinafter.) BACKGROUND ART Conventionally, as a method for producing the aromatic carboxylic acid amide derivative represented by the above formula (4) or a salt thereof, the following methods have been proposed. The method described in JP-A No. 49-93335 The following general formula (5) The reactive functional derivative of aromatic carboxylic acid represented by and the following formula (3') A method of reacting with anthranilic acid shown in Method described in JP-A-50-135046 A method of reacting the reactive functional derivative of the aromatic carboxylic acid of formula (5) with an anthranilic acid ester and hydrolyzing the ester group of the resulting reaction product. The method described in JP-A-50-140413, in which the aromatic carboxylic acid of the formula (5) and the anthranilic acid or anthranilic acid ester of the formula (3') are reacted in the presence of a condensing agent, and then the anthranilic ester is used. In this case, the ester group of the reaction product is hydrolyzed. Method described in JP-A No. 52-65279 The following formula (6) Aromatic aldehyde and 2-methyl-
By reacting with 3,1-benzoxazin-4-one at high temperature, the following general formula (7) is obtained. A method of synthesizing a benzoxazinone derivative represented by formula (7) and then hydrolyzing this compound of formula (7). The method described in JP-A-52-83428, in which an aromatic aldehyde of formula (6) and 2-methyl-3,
A method of synthesizing a benzoxazinone derivative of formula (7) by reacting 1-benzoxazin-4-one in the presence of a dehydration condensation agent, and then hydrolyzing the compound of formula (7). The method described in JP-A No. 52-83429, in which a reactive functional derivative of aromatic carboxylic acid of formula (5) is reacted with anthranilic acid of formula (3').
A method of synthesizing a benzoxazinone derivative of formula (7) and then hydrolyzing this compound of formula (7). The method described in JP-A-52-83473, in which an aromatic carboxylic acid of formula (5) and anthranilic acid of formula (3') are reacted in a pyridine solvent in the presence of an excess amount of a condensing agent (7) A method of synthesizing a benzoxazinone derivative of the formula and then hydrolyzing this compound of formula (7). The method described in JP-A-56-135454 The following general formula (8) A method of reacting a chalcone derivative represented by the formula with hydrazidic acid or a salt thereof in the presence of water and an acid. The method described in JP-A-57-38759 Aromatic aldehyde of formula (6) and the following formula (9) A method of reacting malonic anthranilic acid represented by the formula in a pyridine solvent in the presence of a basic substance. A method described in JP-A-58-38244, in which an aromatic aldehyde of formula (6) and malonic anthranilic acid of formula (9) are reacted in an inert organic solvent in the presence of an equimolar amount of a cyclic amine. The method described in JP-A-60-19754 The following general formula (10) (However, in the formula, R ⁵ is a lower alkyl group and Hal is a halogen atom. The same applies hereinafter.) From the N-halogenoacetylanthranilate ester represented by the following general formula (11) [However, in the formula, Y is

[Formula] or

[Formula] (In the formula, X ¹ is an alkyl group having 1 to 10 carbon atoms, a phenyl group, or a substituted phenyl group,
X ² represents an alkoxyl group having 1 to 10 carbon atoms, and Hal' represents a chlorine atom, a bromine atom, or an iodine atom. )
It is. Same below. ] After synthesizing the phosphorus compound represented by, this compound is treated with a basic substance to form the following general formula (12). [However, in the formula, Y′ is (X ¹ ) ₃ P − or

[Formula] (B represents a cation derived from a basic substance). ] A method of obtaining a phosphorus ylide derivative represented by the above formula (12), then reacting the phosphorus ylide derivative of the above formula (12) with an aromatic aldehyde of the above formula (6), and further hydrolyzing the ester group of the reaction product. Problems to be solved by the invention However, among the above methods,
The method has a very low reaction yield of 21 to 46%, it is difficult to purify the target compound of formula (4), and the starting material, aromatic carboxylic acid of formula (5), is expensive. Economically disadvantageous. In addition, in all methods ~, after synthesizing the benzoxazinone derivative of formula (7), hydrolysis is performed.
The compound of formula (4) is obtained, and the method of and uses anthranilic acid as a starting material and 2-methyl-
via 3,1-benzoxazin-4-one (7)
Several steps are required to synthesize the benzoxazinone derivative of the formula, and the synthesis yield is also low.On the other hand, methods (1) and (2) use an expensive aromatic carboxylic acid as a starting material, similar to the above methods. ,
The drawback is that the synthesis cost of the benzoxazinone derivative of formula (7) is high, and in addition, these methods have a low overall synthetic yield of the target substance. Furthermore, in the above method, the starting material hydrazoic acid is toxic, explosive, and dangerous, and the synthesis of the chalcone derivative of formula (8) requires several steps, making the production cumbersome. In addition, there is a problem that the overall synthesis yield of the target substance is low. Furthermore, in the above method, after the reaction is completed, the target substance is crystallized with hydrochloric acid in water or aqueous alcohol as the final step, but at this time, the starting materials remaining in the reaction solution and by-products that are poorly soluble in the acidic aqueous solution are substances may precipitate or get mixed in, hindering the purification of the target substance, and
There is a problem that pyridine, which is a reaction solvent, has a bad odor and is toxic, which adversely affects the human body. Therefore,
In this method, the same reaction as in the presence of equimolar amounts of cyclic amines is carried out in an inert solvent, and most of the problems of the above methods are solved. However, both methods and method use malonic anthranilic acid of formula (9) as a starting material, and both methods require several steps to synthesize malonic anthranilic acid as shown in the reaction formula below. The overall synthesis yield of the target substance is low for both methods. Furthermore, the method uses anthranilic acid as a starting material to obtain N-halogenoacetylanthranilic acid ester of formula (10), and then converts it to a phosphorus compound of formula (11) to obtain (12).
After obtaining the phosphorus ylide derivative of the formula, this is reacted with the aromatic aldehyde of the formula (6), and then hydrolyzed to obtain the target compound of the formula (4), but the overall synthesis yield is low due to the large number of reaction stages. This method is not preferred as an industrial synthesis method because it has a low yield and involves an unstable phosphorus compound as an intermediate. Therefore, all of the above methods are industrially disadvantageous, and for this reason, there has been a demand for the development of a method for producing the compound of formula (4) or a salt thereof that is satisfactory on an industrial scale. The present invention has been made in view of the above circumstances, and enables the compound of formula (4) to be synthesized in a high yield, safely and economically with a small number of reaction stages, and furthermore, the target substance, which is a reaction product, can be synthesized from the reaction mixture. An object of the present invention is to provide an industrially advantageous method for producing the compound of formula (4) or a salt thereof, which can be easily isolated and purified. Means and Effects for Solving the Problems In order to achieve the above object, the present inventors have made extensive studies and found that the following general formula (1) (However, in the formula, R ¹ is a lower alkoxy group, and R ² is a hydrogen atom or a lower alkoxy group. The same applies hereinafter.) An alkoxybenzene compound represented by the following formula and
(2) (However, in the formula, R ³ and R ⁴ are lower alkyl groups or aryl groups. The same applies hereinafter.) After reacting with the formamide compound represented by the formula in the presence of phosphoryl chloride, thionyl chloride, or phosgene, The reaction product and the following formula (3) (However, in the formula, X is a hydrogen atom or an acetyl group. The same applies hereinafter.) Reacting the anthranilic acid or N-acetylanthranilic acid represented by the formula in the presence of acetic anhydride, especially the above formula (1). After reacting an alkoxybenzene compound with N-methylformanilide as the compound of formula (2) above in the presence of phosphoryl chloride,
Furthermore, by reacting this reaction product with anthranilic acid as the compound of the above formula (3) in the presence of acetic anhydride, the following general formula (4) is obtained. The aromatic carboxylic acid amide derivative or its salt represented by can be easily synthesized in high yield by continuous two-step reaction in a reaction vessel using safe, relatively inexpensive and easily available starting materials and reagents, and The inventors found that the final reaction product, the compound of formula (4), can be easily isolated and purified from the reaction mixture after completion of this two-step reaction, leading to the present invention. Therefore, the present invention involves reacting an alkoxybenzene compound represented by the above formula (1) with a formamide compound represented by the above formula (2) in the presence of phosphoryl chloride, thionyl chloride, or phosgene, and then reacting the alkoxybenzene compound represented by the above formula (1) with the formamide compound represented by the above formula (2). An aromatic carboxylic acid amide derivative represented by the above formula (4), or an aromatic carboxylic acid amide derivative represented by the above formula (4), characterized in that the reaction product is reacted with anthranilic acid or N-acetylanthranilic acid represented by the above formula (3) in the presence of acetic anhydride. A method for producing the salt is provided. The present invention will be explained in more detail below. In the production method of the present invention, as a first step reaction, an alkoxybenzene compound of formula (1) and a formamide compound of formula (2) are reacted in the presence of phosphoryl chloride, thionyl chloride, or phosgene. In this case, specific examples of the alkoxybenzene compound of formula (1) include methoxybenzene, ethoxybenzene, propioxybenzene, butoxybenzene, etc. in which substituent R ¹ is a lower alkoxy group and R ² is a hydrogen atom, and R ¹ and 1,2-dimethoxybenzene, 1,2-diethoxybenzene, 1,2-dipropoxybenzene, in which R ² is the same lower alkoxy group,
Examples include 1,2-dibutoxybenzene. Furthermore, the formamide compound represented by the above formula (2) may be a lower alkyl group or an aryl group in which the substituents R ³ and R ⁴ are the same or different, such as a lower alkyl group such as a methyl group or an ethyl group, or a phenyl group, etc. A formamide compound having an aryl group is used, and specifically N,N-dimethylformamide and N-methylformanilide, particularly N-methylformanilide, are preferably used. Further, as phosphoryl chloride, thionyl chloride, or phosgene used in this first step reaction, any may be used, but it is particularly preferable to use phosphoryl chloride from the viewpoints of reaction yield, toxicity, and operability. Here, 1,2-dimethoxybenzene (generic name: veratrol) used as the compound of formula (1) above, N-methylformanilide and N,N-dimethylformamide used as the compound of formula (2), and chloride Both phosphoryl and thionyl chloride are known compounds and can be easily obtained as commercial products. Note that the alkoxybenzene compound of formula (1) and N-methylformanilide of formula (2) can be easily produced by methods described in various literatures, and in particular, N-methylformanilide can be effectively recycled after recovery and reprocessing. Available. In the first step reaction of the production method of the present invention, as described above, when the alkoxybenzene compound of formula (1) and the formamide compound of formula (2) are reacted in the presence of phosphoryl chloride, thionyl chloride, or phosgene, the following formula (13) The immonium salt shown by is produced, and by further performing the following second step reaction using this immonium salt as an intermediate, the target compound of formula (4) can be easily obtained in good yield. . In particular, in this first step reaction, it is preferable to react the alkoxybenzene compound of formula (1) with N-methylformanilide as the formamide compound of formula (2) in the presence of phosphoryl chloride. When the first step reaction is carried out using the compound, the intermediate immonium salt represented by formula (13) can be obtained in high yield, and this intermediate immonium salt can be obtained without isolation or purification. A second stage reaction can then be carried out. Next, in the second stage reaction of the production method of the present invention,
Acetic anhydride and anthranilic acid or N-acetylanthranilic acid of the above formula (3) are added to the immonium salt of the intermediate obtained in the first step reaction or a reaction mixture containing this intermediate to react, and the desired reaction is achieved. Do(4)
A compound of formula is prepared. Here, anthranilic acid or N-acetylanthranilic acid of the formula (3) is a known compound and can be easily obtained as a commercial product, particularly anthranilic acid can be obtained at low cost, and acetic anhydride is also a known compound. It is inexpensive and easily available as a commercial product. In this second step reaction, it is preferable to use anthranilic acid as the compound of formula (3), and in particular, as mentioned above, in the first step reaction, an alkoxybenzene compound of formula (1) and a compound of formula (2) are used. as N-
After reacting with methylformanilide in the presence of phosphoryl chloride to obtain the immonium salt of the intermediate, the intermediate is not isolated and purified, but acetic anhydride is added to the reaction mixture containing this intermediate as a second step reaction. and(3)
When anthranilic acid is added as a compound of the formula and reacted, the target compound of the formula (4) can be obtained in good yield, safely, inexpensively, and economically by simple reaction operations. In the present invention, the molar blending ratio of the starting materials and reagents is variously selected and is not particularly limited, but preferably 1 mole of the compound of formula (1) is mixed with 1 mole of the compound of formula (3).
~1.5 mol, preferably 1 to 1.5 mol of the compound of formula (2), preferably 1 to 1.5 mol of phosphoryl chloride, thionyl chloride, or phosgene, and preferably 1 to 4.5 mol of acetic anhydride. Although the reaction according to the production method of the present invention does not require the use of a solvent, an inert solvent such as benzene or chlorobenzene may be used if desired. The reaction conditions are appropriately selected, but the first stage reaction is usually carried out at a temperature of 50 to 120°C for about 5 to 20 hours, and the second stage reaction is usually carried out at a temperature of 50 to 120°C.
It is preferable to carry out the reaction at a temperature of about 80°C for about 5 to 20 hours, and most preferably to carry out the first stage reaction for about 8 hours and the second stage reaction for about 6 hours at a temperature of about 80°C. After the second stage reaction is completed, the reaction mixture is transferred to ice water, sodium hydroxide etc. are added and treated with activated carbon under alkaline conditions, then the precipitate is filtered under acidic conditions and recrystallized with a solvent such as methanol/water. By doing so, the final reaction product, the compound of formula (4), can be easily isolated and purified from the reaction mixture. Note that the obtained compound of formula (4) can be converted into a salt thereof if necessary. Conversion to a salt can be carried out according to a conventional method, for example, by dissolving the compound of formula (4) in alcohol, adding an equimolar amount of an aqueous sodium hydroxide solution, and proceeding with the conversion at room temperature or heating. Thus, the sodium salt of the compound of formula (4) can be suitably obtained. Effects of the Invention As explained above, the production method of the present invention enables the aromatic carboxylic acid amide derivative represented by the above formula (4) or its salt to be produced easily, with a high yield, and safely with a small number of reaction stages. Furthermore, the final reaction product, the target substance, can be easily isolated and purified, which is very advantageous industrially. Furthermore, the starting materials and reagents of the present invention are relatively inexpensive and easily available, especially 1,2-dimethoxybenzene used as the alkoxybenzene compound of formula (1) and anthranilic acid of formula (3) are available at low cost. Since the N-methylformanilide used as the formamide compound in formula (2) above can be recovered and reused, it is very advantageous from an economic standpoint. EXAMPLES Hereinafter, the present invention will be specifically explained with reference to examples, but the present invention is not limited to the following examples. In addition, in the following examples, all melting points of products are uncorrected values. Example 1 2.07 g (0.015 mol) of 1,2-dimethoxybenzene represented by the above formula (1), N- represented by the above formula (2)
Mix 1.89 g (0.014 mol) of methylformanilide and 2.30 g (0.015 mol) of phosphoryl chloride,
After reacting at 80°C for 8 hours with stirring, 4.59 g (0.045 mol) of acetic anhydride and 1.37 g (0.01 mol) of anthranilic acid represented by the above formula (3) were added, and the mixture was heated at 80°C.
The mixture was stirred for 6 hours. After the reaction was completed, the reaction mixture was transferred to ice water.
Activated carbon treatment was performed using sodium hydroxide under alkaline conditions. Next, the precipitate was collected by filtration under hydrochloric acid, washed with water, and then recrystallized with methanol/water to obtain the above.
2.34 g of the target compound N-(3,4-dimethoxycinnamoyl)anthranilic acid represented by formula (4) was obtained (yield 71.6%, melting point 209-211°C). The results of nuclear magnetic resonance spectrum, mass spectrum, and elemental analysis of the obtained compound are shown below. Nuclear magnetic resonance spectrum ( _d6 -DMSO) δ3.81 (s, 3H), δ3.84 (s, 3H), δ6.61-8.71
(m, 9H), δ11.27 (s, 1H) Mass spectrum M/e = 327, 309 Elemental analysis value (as C ₁₈ H ₁₇ NO ₅ ) C H N Calculated value 66.05% 5.24% 4.28% Actual value 65.90% 5.16% 4.36% Example 2 2.07 g (0.015 mol) of 1,2-dimethoxybenzene, 1.89 g (0.014 mol) of N-methylformanilide, and 2.30 g (0.015 mol) of phosphoryl chloride were reacted at 80°C for 8 hours with stirring. After that, acetic anhydride
Add 4.59 g (0.45 mol) and 1.79 g (0.01 mol) of N-acetylanthranilic acid of formula (3) above, and heat at 80°C.
The mixture was stirred for 6 hours. After the reaction was completed, 1.84 g of the target compound N-(3,4-dimethoxycinnamoyl)anthranilic acid was obtained in the same manner as in Example 1 (yield 56.2%). In addition, when the melting point, infrared absorption spectrum, nuclear magnetic resonance spectrum, and mass spectrum of the obtained compound were measured, it was confirmed that it was the same as the compound obtained in Example 1. Example 3 2.07 g (0.015 mol) of 1,2-dimethoxybenzene, 1.10 g (0.015 mol) of N,N-dimethylformamide represented by the above formula (2), and 2.30 g (0.015 mol) of phosphoryl chloride were mixed with stirring at 80% The reaction was carried out at ℃ for 8 hours. Hereinafter, the target compound N-(3,4-dimethoxycinnamoyl) was prepared in the same manner as in Example 1.
1.28 g of anthranilic acid was obtained (yield 39.1%). The obtained compound was found to be the same as the compound obtained in Example 1 from the measurement results of melting point, infrared absorption spectrum, nuclear magnetic resonance spectrum, and mass spectrum. Example 4 1.62g of methoxybenzene shown in (1) above
(0.015 mol), N-methylformanilide 1.89 g
(0.014 mol) and 2.30 g (0.015 mol) of phosphoryl chloride were reacted at 80° C. for 8 hours with stirring. below,
1.94 g of the target compound N-(4-methoxycinnamoyl)anthranilic acid was obtained in the same manner as in Example 1 (yield 65.2%, melting point 195-197°C).

Claims (1)

[Claims] 1 The following general formula (1) (However, in the formula, R ¹ is a lower alkoxy group, and R ² is a hydrogen atom or a lower alkoxy group.) An alkoxybenzene compound represented by the following formula (2) (However, in the formula, R ³ and R ⁴ are lower alkyl groups or aryl groups.) After reacting the formamide compound represented by the formula in the presence of phosphoryl chloride, thionyl chloride or phosgene, this reaction product is further reacted with General formula (3) below (However, in the formula, X is a hydrogen atom or an acetyl group.) The following general formula (4) is characterized by reacting anthranilic acid or N-acetylanthranilic acid represented by the following in the presence of acetic anhydride. (However, in the formula, R ¹ and R ² have the same meanings as above.) A method for producing an aromatic carboxylic acid amide derivative or a salt thereof. 2. The manufacturing method according to claim 1, wherein the alkoxybenzene compound represented by the above formula (1) is 1,2-dimethoxybenzene. 3 The formamide compound represented by formula (2) above is N
-Methylformanilide The manufacturing method according to claim 1 or 2, which is methylformanilide. 4. According to any one of claims 1 to 3, the alkoxybenzene compound represented by the above formula (1) and the formamide compound represented by the above formula (2) are reacted in the presence of phosphoryl chloride. Manufacturing method described. 5. The manufacturing method according to any one of claims 1 to 4, wherein the compound represented by the above formula (3) is anthranilic acid.