JPH01110656A - Production of n-(3',4'-dimethoxycinnamoyl)-anthranylic acid - Google Patents

Abstract

PURPOSE:To economically obtain a compound useful as a remedy for allergic disorder in high yield without causing problem of air pollution or by-product, by hydrolyzing 2-(3',4'-dimethylstyryl)-3-phenylquinazolinone. CONSTITUTION:A compound expressed by formula I (X is halogen or lower alkoxy; n is 0-3) in a solvent such as ethanol using a base (e.g. NaOH) at 50 deg.C- reflux temperature for 1-10hr. Then, the reaction solution is cooled to 30-50 deg.C and an acid (e.g., hydrochloric acid) is added thereto and the mixture is hydrolyzed for 1-10hr to provide the aimed product expressed by formula II. The base and acid used are each added at amounts of 1-20 times mol and 2-40 times mol based on the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel method for producing N-(S',4'-dimethoxycinnamoyl)anthranilic acid.

The purpose of the present invention is to industrially produce N-(3',4'-dimethoxycinnamoyl)anthranilic acid and its salts in high yield, which are useful as therapeutic agents for diseases caused by allergies. be.

(Prior Art) Various methods have already been used to produce N-(3',4'-dimethoxycinnamoyl)-anthranilic acid. For example, the first order is as follows.

(I) Japanese Patent Publication No. 56-4 (I71) The method described in Publication I is based on the linear formula (In). (IV) It consists of a compound that is reacted with anthranilic acid represented by (IV).

(2) The method described in Japanese Patent Publication No. 5B-48545 uses 5', 4'-dimethoxycinnamic acid represented by the cutting allowance (III) and the formula M (wherein R is a hydrogen atom or Represents a lower alkyl group.

) with anthranilic acid or an ester thereof in the presence of a condensing agent, if desired.

It consists of hydrolyzing the ester group in a conventional manner.

(3) Method u described in JP-A No. 57-58759, in which 5,4-dimethoxybenzaldehyde and a malonic acid derivative represented by the following formula (VI) are reacted in the presence of a basic substance. Consists of things.

(4) The method described in Japanese Patent Publication No. 58-55138 involves reacting a benzoxazinone derivative represented by the linear formula (■) with 3,4-dimethoxybenzaldehyde in the presence of a dehydration condensation agent. The azlactone derivative of the following formula (■) is formed, and then.

This consists of hydrolysis treatment and ring opening.

(5) The method described in Japanese Patent Publication No. 58-55139 involves combining a reactive functional derivative of 3',4'-dimethoxycinnamic acid (■■) and anthranyl represented by the primary formula (IX). The process consists of reacting to form an azlactone derivative indicated by a cutting margin (■), and then hydrolyzing this to open the ring.

(Problems to be Solved by the Invention) However, 1) In the method of (5), side reactions occur, resulting in a decrease in the purity of the product and the generation of toxic gases during production. Also, in method (2).

Since the raw material 3:41-dimethoxycinnamic acid and the target compound N-(5',4'-dimethoxycinnamoyl)anthranilic acid are acidic substances, purification is difficult. In method (3), the raw material malonanthranyl derivative (VI) is unstable to heat;
It requires special care in its handling and cannot be called an industrial implementation process. Furthermore, in method (4), an intermediate compound, an azlactone derivative (Vllll), is produced using a dehydration condensation agent of benzoxazinone (■) and 5,4-dimethoxybenzaldehyde, but one reaction involves dehydration condensation. This method is not satisfactory as an economical and industrial production method because it requires a chemical agent and the production of by-products.

The present invention solves the above problems of the prior art and provides an industrial and economical method for producing N-(3',4'-dimethoxycinnamoyl)anthranilic acid.

(Means and effects for solving the problems) The results of intensive studies to solve the above problems.

- 2 -(3
N -(3',4'
A method for producing -dimethoxycinnamoyl)anthranilic acid has been discovered.

In the above formula (I), X is a nitrogen or a lower alkoxy group, and, for example, the nitrogen is preferably Br or Ct. Further, when X is a lower alkoxy group, for example, methoxy group, ethoxy group, etc. are preferable. Furthermore, in the formula 0, X represents an integer from 0 to 5.

At this time, even if a quinazolinone compound represented by general formula (X) (in 6, R represents H or an alkyl group) is substituted with H or an alkyl group as a starting material, the reaction does not proceed. .

Target substance (n) cannot be obtained. However, the inventors
Only when the substituent at position 5 is an aryl group.

It was discovered that the target (II) could be obtained in high yield.

The present invention has now been completed.

The compound represented by the formula 〇) used in the present invention is produced as follows.

2-(5',4'-dimethoxystyryl)-3-arylquinazolinone represented by the formula σ) is a 2-(5',4'-dimethoxystyryl)-3-arylquinazolinone represented by the formula
represents an integer from 0 to 3. ) 2-methyl-3
-aryl-(3H)-quinazolinone and the following formula (Xll
) with 3,4-dimethoxypenzaldehyde,
It can be produced by reacting 1 with 1 for 10 hours, preferably 5 hours, at a temperature of 100 to 250 C without a solvent or in an inert solvent.

Moreover, at this time, if one reaction is carried out in the presence of an acidic catalyst,
It is possible to shorten reaction time and improve yield. Examples of acidic catalysts that can be used at this time include mineral acids such as sulfuric acid and hydrochloric acid, phosphoric acid a such as phosphoric anhydride and birophosphoric acid, and sulfonic acid catalysts such as C para-toluenesulfonic acid and methanesulfonic acid. Preferably, acid compounds are used. The equivalent of the acidic catalyst used at this time is 0.01 to 1 times equivalent to 1%, preferably 0.01 to 0.2 times equivalent relative to formula (■). Examples of inert solutions used in one reaction include aromatic solvents such as benzene, toluene, xylene, and cumene; ether solvents such as THF, 1,4-dioxane, and diglyme; and DMF.

Examples include DMSO. Particularly when using an acidic catalyst, it is desirable to use a solvent that forms an azeotropic mixture with the desorbed water and that can be separated from the water after azeotropic distillation.

Solvents used in the present invention include 1 alcoholic solvents such as methanol, ethanol, propatool, and isopropanol; 1 #2-dimethoxyethane, THF;
, ether solvents such as dioxane and diglyme, nitrile solvents such as acetonitrile and propionitrile, and DAM.

Examples include amide solvents such as DMF and N-methylpyrrolidone, and sulfoxide solvents such as DMSO and sulfolane. In particular, in order to suitably carry out the present invention, it is desirable to use ethanol, isopropanol, or the like.

Examples of bases that can be used in the present invention include 1. For example, hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, and hydroxides of alkaline earth metals such as magnesium hydroxide and calcium hydroxide. Preference is given to using hydroxides, in particular iumium hydroxide or potassium hydroxide.

Examples of acids used in the present invention include hydrochloric acid.

Nitric acid, sulfuric acid, perchloric acid, etc. can be mentioned.

In particular, it is preferable to use hydrochloric acid. The reaction is 2-(xl
, al-dimethoxystyryl)-3-arylquinazolinone (I) and a base were added to the solvent, and 1 to 10
time, preferably Fi 3 to 5 hours, 50C to reflux temperature,
The reaction is preferably carried out under reflux. At this time, the amount of base is
The amount is 1 to 20 times mole, preferably 10 to 15 times mole, relative to 2-(3',4'-dimethoxystyryl)-3-arylquinazolinone σ).

Subsequently, the reaction solution is cooled to 30 to 50C, and then an acid is added thereto, followed by stirring for 1 to 30 minutes, preferably 10 to 15 minutes. The amount of base used at this time is 2-(3',4'-dimethoxystyryl)-3-
The amount is 2A-40 times, preferably 15A-20 times, based on luquinazolinone (I). Purpose N
< sJ, al-dimethoxycinnamoyl)-anthranilic acid is an acidic substance and can be easily isolated by published purification procedures.

(Effects of the Invention) According to the present invention, by hydrolyzing 2-(3',4'-dimethylstyryl)-6-phenylquinazolinone (I), problems of air pollution and by-products caused by conventional methods can be solved. By solving this problem, it became possible to produce the target product N-(s',41-dimethoxycinnamoyl)-anthranilic acid (II) in high yield.

In general, the raw material 2-(5',4'-dimethylstyryl)-3-ruquinazolinone (I) is a compound (
X]) can be obtained in higher yields, the present invention can be said to be an industrial and economical process.

(Example) Example 1 2-(3',4'-dimethoxystyryl)-6-phenylquinazolinone o,s 1t (I,s mmot)
(30% ethanol solution, hydroxide) IJum 0.
Add 1.3- of an aqueous solution of 66 S' (I7mmot),
The mixture was stirred under reflux for 5 hours. After cooling to 40-50C, add concentrated hydrochloric acid 2
．． 31R1 was gradually added dropwise and stirred for 10 minutes. After the reaction was completed, 3 lx/ of water was added and extracted with chloroform.
7t. Furthermore, the chloroform layer was extracted as a carboxylate salt with 30 ntt of a saturated aqueous sodium bicarbonate solution. The aqueous layer was adjusted to pH 2 with 1N hydrochloric acid, the precipitated crystals were removed, and N-(3',4'-dimethoxycinnamoyl)-anthranyl pO, 52? (yield 73%).

mp 209 A-210C NMR (da-DMSO): δ 3.87 (3H
,s).

5.92 (5H, S).

6.0 to 9.0 (tOH, m) IR (KBr): 2900o+s-'(νcOOH)1
6700 Tsu l-Otori (ν C0) 12550 m' (Si c-0-C) Elemental analysis value C,, H,, Calculated value as OSN C: 66.05% H: 5.24 Chi N: 4.28 Chi Actual value C: 66.01 h H: 5.19 h N: 4.23% Example 2 2-(3',4'-dimethoxystyryl)-5-phenylquinazolino y O,51f (I,5mmot ) in DMS O20− solution, sodium hydroxide 0.66
? Add 1.3- of an aqueous solution of (I7 mm o L),
The mixture was stirred under reflux for 5 hours. After cooling to 40-50C, add 1 m of hydrochloric acid 2
．． 3- was gradually added dropwise and stirred for 10 minutes. By performing the same post-processing as in Example 1, N-(sl, 41
-dimethoxycinnamoyl)-anthranyl (Iio,
15? (50 chi) was obtained.

Example 3 2-(3',4'-dimethoxystyryl)-5-(p
-chlorophenyl)quinazolinone 0.549 (I,3
mmot) Improper Tool 30-solution, sodium hydroxide o, 66 t (I7mmot) aqueous solution 1.
3- was added, and the mixture was stirred under reflux for 5 hours. After cooling to 40-50C, concentrated hydrochloric acid 2.3- was gradually added dropwise and stirred for 10 minutes. After completion of the reaction, by performing the same post-treatment as in Example 1, N <3', al-dimethoxycinnamoyl)
-anthranyl@0.50 f (88 h) was obtained.

Example 4 2-(3',4'-dimethoxystyryl)-3-(p
-methoxyphenyl)quinazolinone 0,54 t(I,
3 mmot) of isopropanol 50-solution.

Added 1.3 d of an aqueous solution of sodium hydroxide A O, 66t (I7mmot) and stirred under reflux for 5 hours.
After cooling to C., 2.3 d of 1# hydrochloric acid was gradually added dropwise and stirred for 10 minutes. After completion of the reaction, the same post-treatment as in Example 1 was performed to obtain fi, N-(3',4'-dimethoxycinnamoyl)-anthranyl fio, 37 f (6
5%).

Comparative Example 1 To a solution of z + (61,al-dimethoxystyryl)quinazoline y 0.40 f (L5 mmot) in ethanol 50, was added sodium hydroxide o, 6,6 t (t
y mmot) was added thereto, and the mixture was stirred under reflux for 5 hours. After cooling to 40-50C, -hydrochloric acid 2.3- was gradually added dropwise.

Stirred for 10 minutes. After the reaction was completed, the same post-treatment as in Example 1 was carried out, but the desired N-(5',4'-dimethoxycinnamoyl)-anthranilic acid was not obtained. As a result of distilling off the solvent from the extracted chloroform layer, 2-
(5',4'-dimethoxystyryl)quinazolinone 0.
399 (recovery rate 97%) was obtained.

2-(5',4'-dimethoxystyryl)quinazolinone mp 269 to 27Q7: NMR(d6-DMSO): δ 4. o 7 (
3H, s) 4.10 (3H, s) 7.0-8.7 (9H, m) IR (KBr): 3180m-"yN-H16
70 scratches 1 νC0 1270 scratches-1C-0-C Elemental analysis value cts I(ta N, o.

Calculated value C: 70.13% H: 5.19 Coordination N: 9.09% Actual value C: 70.20C H: 5.21 Coordination N: s, qs Coordination comparative example 2 2- (3', 4 A solution of 0.46 t (I, 3 mmot) of 0.46 t of '-dimethoxystyryl)-3-propylquinazolinone in 5 Otttl of ethanol was added with 0.46 t of sodium hydroxide.
66t (I7mmot) of an aqueous solution of 1.3% was added, and the mixture was stirred under reflux for 5 hours. After cooling to 40-50C, add concentrated hydrochloric acid 2.3
- was gradually added dropwise and stirred for 10 minutes. After the reaction is complete.

The same post-treatment as in Example 1 was carried out, but the target N-
(5',4'-dimethoxycinnamoyl)-anthranilic acid was not obtained. As a result of solvent distillation from the extracted chloroform layer, 2-(5',4'-dimethoxystyryl)
-3-Propylquinazolinone 0.449 (recovery rate 93) was obtained.

2-(5',4'-dimethoxystyryl)-3-propylquinazoline mp 138A-140C NMR (CD CAm): δ o, ya (3u
, t).

1.70 (2H, t, q), 183 (3H, s), 5
．． 86 (3H, s), 4.29 (3H, t)
.

6, q -8,2 (tpH, m) IR (KBr): 2850m-1y-CH2-1670
GB” WCO 1270 Plow C-0-C Elemental analysis value C,, H,, N, o.

Calculated value C: 71.98% H: 6.55% N: 8.00 Actual value C: 71.72% H: 6.17% N: 8.01% Reference example Compound of general formula (I) An example is 2-(3', 4'-
An example of the production of dimethoxystyryl-5-phenylquinazolinone is shown below.

2-Methyl-3-phenyl-(3H)-quinashiri/7
2.679 (I0 mmoj) and 5.4-dimethoxybenzaldehyde 1.83 f (I1 mmOt), 190
The mixture was stirred at C for 4 hours. After cooling the reaction solution, it was recrystallized from ethanol to give yellow needle-shaped crystals of 2-(5',4'-dimethoxystyryl)-3-phenylquinazolinone (3.79 (9
Section 5) was obtained.

168C NMR (CDCt, ) to mp 167: δ s, 74 (3H, t), 3
．． 81 (3H, SL 6.1-8.5 (I4H%m) IR (KBr): 1670cIR-"yc.

1260 bias-1 C-0-C Elemental analysis value C24H. N, 0° Calculated value C: 74.98 壬 H: 5.24% N:　　7.29 Section Actual value C: 74,72 壬 H: 5,09ch Nia, 11 regrets

Claims (1)

[Claims] General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents a halogen or a lower alkoxy group, and n represents an integer from 0 to 3.) 2-(3',4'-dimethoxystyryl)-
N-(2', Method for producing 4'-dimethoxycinnamoyl)anthranilic acid.