JPH0584313B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing a quinazolinone compound. The quinazolinone compound produced by the present invention has excellent antibacterial activity and is an extremely useful compound as an antibacterial agent. It is also useful as a raw material for the production of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid, a therapeutic agent for diseases caused by allergies. (Prior Art) Methods for producing 2-(β-arylethenyl)-3-arylquinazolinone compounds have already been described in several documents. For example: (1) Journal of Chemistry UAR
(J.Chem.UAR), 12 , 57 (1967), the following formula ()

It consists of directly reacting a styrylbenzooxysazone represented by the following formula with an arylamine. (2) Egyptian Journal of Chemistry (Egypt.J.Chem.) 19 , (20), 341 (1976)
The method described in 3-aryl-2-
It consists of reacting methylquinazolinone and aryl aldehyde in the presence of sodium ethoxide in dry ethanol for 24 hours. (3) Also, Parmazie, 34 , H.
11, 753 (1979), the method described in 3-
It consists of dehydrating condensation of aryl-2-methylquinazolinone and aryl aldehyde by heating. (Problems to be Solved by the Invention) However, in the method (1), the nucleophilic attack of the arylamine is hindered due to the steric hindrance of the β-arylethenyl group at the 2-position, resulting in a low yield. ,Also,
Requires a long reaction time. In method (2), since the reaction uses sodium ethoxide, which is a strong base, self-condensation of 3-aryl-2-methylquinazolinone occurs, resulting in the formation of by-products. Furthermore, in method (3), since the dehydration condensation is carried out only by heat, the reaction time is long, and thermal decomposition occurs due to high temperatures, resulting in the formation of by-products. The present invention solves the above problems and provides an industrial and economical method for producing 3-aryl-2(3',4'-dimethoxystyryl)quinazolinone. (Means and effects for solving the problem) In order to solve the above problem, as a result of intensive study, the general formula ()

2-methyl-3-aryl-(3H)- (wherein, X represents a halogen or lower alkoxy group, and n represents an integer of 0 to 3)
Quinazolinone and the following formula ()

By dehydrating and condensing 4-dimethoxybenzaldehyde represented by [Chemical formula] in the presence of an acidic catalyst,
General formula ()

2-(3',4'-dimethoxystyryl)- (wherein, X represents a halogen or lower alkoxy group, and n represents an integer of 0 to 3)
A 3-arylquinazolinone was successfully produced. In the formula, X represents a halogen or a lower alkoxy group, n represents an integer from 0 to 3, examples of the halogen include chlorine and bromine, and examples of the alkoxy group include a methoxy group and an ethoxy group. It is. Below, the method of implementing the present invention will be explained in more detail. The 2-methyl-3-aryl-(3H)-quinazolinone of the general formula (), which is the starting material of the present invention, is
The following formula ()

Isatoic anhydride represented by [Chemical formula] is condensed with an equivalent amount of arylamine under heating to form the general formula ()

[Formula, X is a halogen or lower alkoxy group,
n represents an integer from 0 to 3. ) After obtaining an anthranilide derivative represented by the formula (), it is acetylated with acetic anhydride and then dehydrated under heating, or by the following formula ()

It can be produced by dehydration condensation of anthranyl represented by the following formula with an arylamine under heating. Examples of acidic catalysts that can be used in the present invention include mineral acids such as sulfuric acid and hydrochloric acid, phosphoric acids such as phosphoric anhydride and pyrophosphoric acid, and especially sulfonic acid compounds such as para-toluenesulfonic acid and methanesulfonic acid. It is desirable to use The equivalent of the acidic catalyst used in this case is 0.01 to 1 equivalent, particularly preferably 0.01 to 0.2 equivalent, relative to the general formula (). Next, examples of the solvent used in this reaction include aromatic solvents such as benzene, toluene, xylene, and cumene, or THF, 1,4
- Examples include ether solvents such as dioxane and diglyme, DMF, and DMSO. Particularly preferably, it is desirable to use a solvent that forms an azeotrope with the desorbed water during this reaction and can be separated from the water after azeotropic distillation. The dehydration condensation reaction of the present invention involves combining 3-aryl-2-methyl-quinazolinone of the general formula () and 3,4-dimethoxybenzaldehyde of the formula () in a solvent.
This is carried out by azeotropic distillation with water in the presence of an acidic catalyst from 50 DEG C. to the azeotropic temperature of the water and solvent, preferably at the azeotropic temperature, for 1 to 10 hours, preferably 1 to 5 hours. (Effect of the invention) 2-(3',4'-dimethoxystyryl)- of the present invention
The method for producing a 3-arylquinazolinone compound is as follows:
2-(3′,
4'-dimethoxystyryl)-3-arylquinazolinone. In addition, 2-(3',4'-dimethoxystyryl)-3- obtained in the present invention
Arylquinazolinone compounds are useful as raw materials for the production of N-(3',4'-dimethoxycinnamoyl)anthranilic acid, a therapeutic agent for diseases caused by allergies. (Example) Example 1 2-methyl-3-phenyl-(3H)-quinazolinone 2.37 g (10 mmol), 3,4-dimethoxybenzaldehyde 1.66 g (10 mmol) and para-toluenesulfonic acid monohydrate 0.19 g ( 1 mmol)
was added to 5 ml of xylene and azeotropically distilled off with the xylene to carry out a dehydration condensation reaction for 2 hours. After removing xylene from the reaction solution under reduced pressure, it was reconsolidated from ethanol to obtain 2-(3',4'-dimethoxystyryl).
3.72 g (97%) of -3-phenylquinazolinone was obtained. mp 167-168℃ NMR (CDCl ₃ ): δ3.74 (3H, s), 3.81 (3H, s),
6.1-8.5 (14H, m) IR (KBr): 1670cm ^-1 νCO 1260cm ^-1 νC-O-C Elemental analysis value C ₂₄ H ₂₀ N ₂ O ₃ Calculated value C: 74.98% H: 5.24% N: 7.29% Actual values C: 74.72% H: 5.09% N: 7.11% Example 2 2.37 g (10 mmol) of 2-methyl-3-phenyl-(3H)-quinazolinone, 1.66 g (10 mmol) of 3,4-dimethoxybenzaldehyde, and methanesulfone 0.10 g (1 mmol) of acid was added to 5 ml of xylene, and the mixture was azeotropically distilled off with xylene to carry out a dehydration condensation reaction for 2 hours. After removing xylene from the reaction solution under reduced pressure, it was reconsolidated from ethanol to obtain 2-
3.65 g (95%) of (3',4'-dimethoxystyryl)-3-phenylquinazolinone was obtained. Example 3 2-Methyl-3-(p-chlorophenyl)-
(3H)-quinazolinone 2.71g (10mmol), 3,4
- Dimethoxybenzaldehyde 1.66g (10m
mol) and paratoluenesulfonic acid monohydrate
0.19 g (1 mmol) was added to 5 ml of xylene, and azeotropic distillation with xylene was carried out to carry out a dehydration condensation reaction for 2 hours. After removing xylene from the reaction solution under reduced pressure, it was reconsolidated from isopropanol to give 2-(3',
3.77 g (90%) of 4'-dimethoxystyryl)-3-(p-chlorophenyl)quinazolinone was obtained. mp 200−201℃ NMR (CDCl ₃ ): δ3.69 (3H, s), 3.73 (3H, s),
6.0−8.2 (13H, m) IR (KBr): 1685cm ^-1 νCO 1270cm ^-1 νC−O−C Elemental analysis value C ₂₄ H ₂₀ N ₂ O ₃ Cl Calculated value C: 68.82% H: 4.57% N: 6.69 % Cl: 8.46% Actual value C: 68.53% H: 4.29% N: 6.43% Cl: 8.75% Example 4 2-Methyl-3-(p-methoxyphenyl)-
(3H)-quinazolinone 2.66g (10mmol), 3,4
- Dimethoxybenzaldehyde 1.66g (10m
mol) and methanesulfonic acid 0.10 g (1 mmol)
was added to 5 ml of xylene and azeotropically distilled off with the xylene to carry out a dehydration condensation reaction for 2 hours. After xylene was distilled off from the reaction solution under reduced pressure, it was reconsolidated from isopropanol to obtain 3.85 g (93%) of 2-(3',4'-dimethoxystyryl)-3-(p-methoxyphenyl)quinazolinone. mp 193-194℃ NMR (CDCl ₃ ): δ3.67 (3H.s), 3.70 (3H, s),
3.83 (3H, s), 6.0−8.2 (13H, m) IR (KBr): 1670cm ^-1 νCO 1255cm ^-1 νC−O−C 1265cm ⁻¹ νC−O−C Elemental analysis value C ₂₅ N ₂₂ N ₂ O ₄ Calculated values C: 72.45% H: 5.35% N: 6.76% Actual values C: 72.29% H: 5.19% N: 6.70% Test example An antibacterial activity test was conducted on the compounds obtained in Examples 1, 3, and 4. Ta. The antibacterial test was conducted in accordance with the Veterinary Antibiotic Preparation Certification Standards (June 1972). Use a cup with an outer diameter of 9 mm,
The strength of antibacterial activity was expressed as the diameter of the inhibition circle (mm). The test results are shown in Table 1.

【table】

[Table] Reference Example An example of synthesizing N-(3',4'-dimethoxycinnamoyl)-anthranilic acid from the compound of the present invention is shown below. 2.89 g of sodium hydroxide in a solution of 2.22 g (5.8 mmol) of 2-(3',4'-dimethoxystyryl)-3-phenylquinazolinone in 18 ml of isopropanol.
(72.1 mmol) was added, and the mixture was stirred under reflux for 4 hours. After cooling to 40-50°C, 10 ml of concentrated hydrochloric acid was gradually added dropwise and stirred for 10 minutes. After the reaction was completed, water was added and the precipitated crystals were dried separately. Furthermore, by recrystallizing this crystal from chloroform, N-
1.42 g (yield 75%) of (3',4'-dimethoxycinnamoyl)-anthranilic acid was obtained. mp 209-210℃ NMR (CDCl ₃ ): δ3.87 (3H, s), 3.92 (3H, s),
6.0−9.0 (13H, m) IR (KBr): 2900cm ^-1 (νCOOH) : 1670cm ^-1 (νCO) : 1255cm ^-1 (νC-O-C) Elemental analysis value C ₁₈ H ₁₇ NO ₅ Calculated value C: 66.05% H: 5.24% N: 4.28% Actual value C: 66.21% H: 5.17% N: 4.25%

Claims (1)

[Claims] 1 2-methyl-3-aryl represented by the general formula () 3H)-quinadolinone and 3,4-dimethoxybenzaldehyde represented by the following formula () [Chemical formula] are dehydrated and condensed in the presence of an acidic catalyst. represents a halogen or a lower alkoxy group, and n represents an integer of 0 to 3.) A method for producing a 3-aryl-2(3',4'-dimethoxystyryl)-quinazolinone compound. 2. The manufacturing method according to claim 1, wherein the acidic catalyst is p-toluenesulfonic acid or methanesulfonic acid.