JPH01110655A - Production of n-(3',4'-dimethoxycinnamoyl)-anthranylic acid using novel quinazolinone as intermediate - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a novel method for producing N-(5',4'-dimethoxycinnamoyl)-anthranilic acid using an IJT-type quinazolinone compound as an intermediate. . An object of the present invention is to industrially produce N-(3',4'-dimethoxycinnamoyl)-anthranilic acid and its salts, which are useful as therapeutic agents for diseases caused by allergies.

Moreover, it is to be produced at high yield.

(Prior Art) The method for producing N-(5',4'-dimethoxycinnamoyl)-anthranilic acid has always been carried out by the method of Akihiro. An example is as follows.

(I) The method described in Japanese Patent Publication No. 56-40710 uses a reactive functional derivative of y,4'-dimethoxycinnamic acid represented by the zero-order formula (v) and a linear formula (Vl"1). It consists of reacting with the indicated anthranilic acid.

(2) The method described in Japanese Patent Publication No. 58-48545 uses 5/, 4/-dimethoxycinnamic acid represented by ablation (V), -formula (■) (wherein R is Represents a hydrogen atom or a lower alkyl group.

) with anthranilic acid or its esterification in the presence of a condensing agent, if desired.

It consists of hydrolyzing the ester group by conventional methods.

(3) The method described in JP-A No. 57-38759 involves reacting 3,4-dimethoxybenzaldehyde with a malonanyl rR9 conductor represented by the linear formula (■) 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 (IX) with 3,4-dimethoxybenzaldehyde in the presence of a dehydration condensing agent. The process consists of forming an azlactone derivative represented by the linear formula (X), followed by hydrolysis treatment and ring opening.

(5) The method described in Japanese Patent Publication No. 58-55139 involves reacting a reactive functional derivative of 3/, 4/-dimethoxycinnamic acid (V) with anthranyl represented by the linear formula (xl). to form an azlactone derivative represented by deletion (X).

This is then subjected to hydrolysis treatment to open the ring.

(Problems to be Solved by the Invention) However, in the methods (I) and (5), there are problems such as side reactions occurring, reduction in product purity, and toxic gas generated during production. Also, in method (2).

Since 5Z4/-dimethoxycinnamic acid, which is a raw material, and N-(5',4'-dimethoxycinnamoyl)anthranilic acid, which is a target compound, are acidic substances, cleavage is difficult. In method (3), the raw material malonanthranyl derivative (■) is unstable to heat, and special care is required in its handling.

Although it is an industrial implementation process, it is cumbersome. Furthermore, in the method (4), benzoxazinone (IX) and 3.4
-Azlactone derivative (X), which is an intermediate compound, is produced by a dehydration condensation agent with dimethoxybenzaldehyde (■), but a dehydration condensation agent is required for one reaction, and it is not economical, such as the formation of rice and saccharine organisms. This is not satisfactory as a commercial and industrial manufacturing method.

The present invention solves the above-mentioned problems of the prior art.

The present invention provides an industrial and economical method for producing N-(3',4'-dimethoxycinnamoyl)anthranilic acid.

(Means and actions for solving the problems) We have conducted extensive studies to solve the above problems.

- Formula (I) (wherein, X represents Ct and OCH, and n is 0 to 3
represents an integer. ) By dehydrating and condensing 2-methyl-5-aryl-<5H)-quinazolinone represented by the formula with 3,4-dimethoxybenzaldehyde represented by the primary formula (I[), the general formula (ul) is obtained. (In the formula, X is Ct
or OCH, and n represents an integer from 0 to 3.

) 2-(3',4'-dimethoxystyryl)-
3-7 aryl quinazolinone is then formed.

This was hydrolyzed in the presence of a basic aqueous solution to obtain K.

Furthermore, by directly adding acid and hydrolyzing,
N-(ri,4'-dimethoxycinnamoyl) represented by the following formula (IV)
- A friend who discovered a method for producing anthranilic acid.

In the above formulas (I) and (ill), X represents Ct or OCH, and n represents an integer from 0 to 3.

In this case, instead of the general formula (Ill) as an intermediate, the general formula (■) (in the formula, R represents an alkyl group), where the 3rd position is H and the 3rd position is substituted with an alkyl group. Even when the quinazolinone compound was incorporated, the reaction did not proceed.

Target substance (IV) cannot be obtained. However, the present inventors found that the desired product (I
It was discovered that V) could be obtained with high yield straw, leading to the completion of the present invention.

2-methyl- of the above (I) which is the starting material for the method of the present invention
5-Aryl-(3H)-quinazolinone has the linear formula (X[
Isatoic anhydride represented by [I] is condensed with an equivalent amount of arylamine under heating to obtain the formula α■) (wherein, X represents Ct and represents OCH, 1, and n represents 0 to
Represents an integer of 3. ) After obtaining the anthranylanilide derivative shown.

It is produced by acetylating this with acetic anhydride, followed by intramolecular dehydration condensation under heating, or by dehydration condensation of a benzoxazinone derivative shown by deletion (■) with 7-aryl amine under heating. can do.

The first step of the method of the invention, namely -2 of formula (I)
The dehydration condensation reaction between methyl-5-7-lyru(3H)-quinazolinone and 3,4-dimethoxybenzaldehyde with a cutting allowance of
This can be carried out by reacting at 50C for 1 to 10 hours, preferably 1 to 5 hours. Further, at this time, if one reaction is carried out in the presence of an acidic catalyst, one reaction time can be shortened.

Moreover, it is possible to improve the yield. At this time, examples of acidic catalysts that can be used include sulfuric acid and
It is desirable to use mineral acids such as hydrochloric acid, phosphoric acids such as phosphoric anhydride and pyrophosphoric acid, and especially sulfonic acid compounds such as para-toluenesulfonic acid and methanesulfonic acid.

The amount of the acidic catalyst used at this time is -0.01 to 1 times the equivalent of formula (I), particularly preferably 0.01 to 0
．． This is twice the equivalent. Next, the inert solution used in one reaction, TeIri, Neff1, Hensen. Toluene, xylene.

Aromatic solvents such as cumene, or THF, 1.4-
Examples include ether solvents such as dioxane and diglyme, DMF, and 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. Next, the second step of the method of the present invention, that is, the 2-
The solvent used in the hydrolysis reaction of (3',4'-dimethoxystyryl)-3-arylquinazolinone is as follows:
methanol, ethanol.

Alcohol solvents such as propatool and improptool, 1,2-dimethoxyethane, THF, dioxane,
Ether solvents such as diglyme.

Examples include nitrile solvents such as acetonitrile and propionitrile, amide solvents such as DAM, 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. Bases that can be used for peeling, such as lithium hydroxide and sodium hydroxide.

Alkali metal hydroxides such as potassium hydroxide.

Hydroxic acid [hydroxides of alkaline earth metals such as magnesium hismagnesium, water hycalcium, especially hydroxide) I
Jumquat or potassium hydroxide kumquat is preferred.

An example of the acid used in the above step is 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-(3',4'-dimethoxystyryl)-3-
Add 7-aryl quinazolinone ([11) and base to all solvents in an aqueous bath solution for 1 to 10 hours, preferably 6 to 5 hours, 5 hours.
The reaction is carried out at a temperature ranging from 0C to reflux, preferably under reflux. The amount of base is 2-(3',4'-dimethoxystyryl)-
1 to 20 for 3-arylquinazolinone ([11)
It is twice the molar amount, preferably 10 to 15 times the molar amount. continue,
Add acid to the solution cooled to 30-50C,
This is carried out by stirring for 10 to 15 minutes, preferably 10 to 15 minutes. The amount of acid is 2 to 40 times the molar amount of 2-(5',4'-dimethoxystyryl)-3-arylquinazolinone (ILI).

Desirably it is 15 to 20 times the molar amount.

Target N-(3',4'-dimethoxycinnamoyl)-
Anthranilic acid is an acidic substance and can be easily isolated by known purification procedures.

(Effect of the invention) The present invention provides 2-(3',4'-dimethoxystyryl)- represented by the linear formula (XV).
By introducing an aromatic substituent at the 3-position of the quinazolinone, the stability of the quinazolinone term can be eliminated.

By hydrolyzing and ring-opening this, N-(5',4'-dimethoxystyryl)anthranilic acid, which is useful as a therapeutic agent for diseases caused by allergies and is represented by the above formula (IV), is produced. This is a new manufacturing method that has been extremely successful. In addition, the 2-(3',4'-dimethoxystyryl)-3-arylquinazolinone (III) obtained by the first step of the method of the present invention is the 2-methyl-3-aryl-( From 3H)-quinazolinone and 3,4-dimethoxybenzaldehyde with cutting allowance 〇.

The present invention solves the problems of air pollution and by-products in conventional methods, which can be obtained quantitatively without producing by-products. It can be said to be an industrial and economical process.

(Example) Next, the present invention will be explained in more detail using an "i6 example," but the present invention is not limited to this example.

Note that the melting points of the products in the examples are all uncorrected.

Example 1 2-Methyl-3-phinyl(3H)-quinazolinone 2
．． 37f (I0mmot) and 3,4-dimethoxybenzaldehyde 1.859 (I1mmot) i, 190
The mixture was stirred at C for 4 hours. After cooling the reaction solution, it was recrystallized from ethanol to yield 3.7 r of 2-(3',4'-dimethoxystyryl)-3-phenylquinazolinone as yellow needle-like crystals.
(95%).

mp 167-168C NMR (CDC1,): δ 5.74 (5H, s
)3.81 (3H,S) 6.1~8.5 (I4H,m) IR(KBr): 1670 crrI-' l/
C01260cIr1-' C-0-C Elemental analysis values C, 4H,, N, O.

Calculated value C: 74.913% H: 5.24 cm N: 7.29 cm Actual value C: 74.72% H: 5.09 cm Nia, 11% Next, the obtained -ft2-(5' , 0.517 (I
, 3 mmot) in 30 mj of t-ethanol, and add 0.66 t of sodium hydroxide (I7 mm
ot) was added to the mixture, and the mixture was stirred under reflux for 5 hours. After cooling to 40-50C, 2.3 di of concentrated hydrochloric acid was gradually added dropwise.

Stirred for 10 minutes. After the reaction was completed, 30- of water was added, and the mixture was extracted three times with 30- of chloroform. Sara K.

The chloroform layer was dissolved in a saturated aqueous sodium carbonate solution 3
Extracted as monocarboxylic acid salt at 0+d. The water layer 11
The pH was adjusted to 2 with N-hydrochloric acid, and the precipitated crystals kP turned out to be N-(
0.32 f of 3',4'-dimethoxycinnamoyl)-anthranilic acid (yield: 73 g) was obtained.

mp 209-210C NMR (d+5-CDC15): δ 5.87 (3
H, s) 3.92 (3H, s) 6.0-9.0 (I0H, m) IR (KBr): 2900Crn-'&1C
OOH1670(yl-” WCO 1255cW1-' VC-OC Elemental analysis value 01aH1?05N Calculation 1st shift C: 6 6.0 5 %H: 5
．． 24% N: 4.2 8% Actual value C: 66.01≠)1: 5,19% N: 4.23% Example 2 2-Methyl-3-(p-chlorophenyl)-(3H)-
Quinazoline 2.71? (I0mmot) and 5.4-
Dimethoxybenzaldehyde 1,839 (I1mmot
) The mixture was stirred under reflux at 210C for 4 hours.

After cooling the reaction solution, reconsolidate using inproper tool.

2-(5',4'-dimethoxystyryl)-3-(p-
chlorophenyl) quinazolinone s, 43 t (a 2
q6) was obtained.

mp 200-201C NMR (CDC1,): δ 3.69 (3H,
s) 3.7 5 (3H,S) 6.0~8.2 (I3H,m) IRCKBr'): 1685 (I'B-' VCO1
270crn-I C-0-C elemental analysis value C2
a HIa Nt Os C1 calculated value C: 68.82
% H: 4.57 % H: 4.29 % N: 6.45 % C4: 8.7 5 ≠ Then, the obtained 7'j 2- (3', 4'-dimethoxystyryl)-3-( Dissolve 0.54 ft (C5 mmol) of p-chlorophenyl)quinasolinon in 3 mmol of ingropanol, and add 1.3 mmol of an aqueous solution of 0.661 mmol (I7 mmol) of sodium hydroxide to the solution of -f:.

The mixture was stirred under reflux for 5 hours. After cooling to 40-50C, #hydrochloric acid 2
．． 3d was gradually added dropwise and stirred for 10 minutes.

After the reaction is completed, by performing the same post-treatment as in Example 1, ? , N-(3',4'-dimethoxycinnamoyl)-77 tranyl acid 0.50 f (88 t) was obtained.

Example 5 2-Methyl-3-(p-methoxyphenyl)-(3H)
- quinazolinone 2.66 t (I0mmot) and 3.
4-dimethoxybenzaldehyde 1.85F (I1mm
ot)f, and stirred at 200 C for 4 hours under reflux. After cooling the reaction solution, it was reconsolidated from ingropanol to give 2-(3',
5.60 f (87%) of 4'-dimethoxystyryl)-3-(p-methoxyphenyl)quinazolinone was obtained.

mp 193-194C NMR (CDCt,): δ3,67 (3H,s)5
．． 70 (3H,s) 5.85 (3H,s) 6,Q ~8.2 (I3H,m) IR (KBr): 167ocrn-lyc.

1255crn-'! /C-0-C1265crn
-" VC-0-C Elemental analysis value C,, HHN, 04 Calculated value C: 72.45 cm H2 5.35% N: 6.76% Actual value C: 72.29 cm) (: 5,19 ThiN: 6.70% Next, 0.0% of the obtained 22-(3',4'-dimethoxystyryl)-3-(p-methoxyphenyl)quinazolinone.
54? (I,3mmot) to isoprono(nol3
0- and hydroxide in the solution) IJum0.
66? Add 1.31 nti of water bath solution (I7mmot).

Stir under reflux for 5 hours. After cooling to 40-50C, add a salt powder 2
．． 5 ml was gradually added dropwise and stirred for 10 minutes.

After the reaction was completed, the same post-treatment as in Example 1 was performed to obtain 0.377 (65%) of N-(5',4'-dimethoxycinnamoyl)anthranilic acid.

Comparative Example 1 0.401 (I, 5 mmol) of 2-(3',4'-dimethoxystyryl)quinazolinone in ethanol! 10
Sodium hydroxide 0.66 ? (I7mm
1.3 d of an aqueous solution of ot) was added, and the mixture was stirred under reflux for 5 hours.

After cooling the noodles to 40-50C, 2.5 d of concentrated hydrochloric acid was gradually added dropwise and stirred for 10 minutes. After the reaction was completed, the same post-treatment as in Example 1 was carried out, but the desired N-(3',4'-dimethoxycinnamoyl)-anthranilic acid could not be obtained. As a result of solvent removal from the extracted chloroform layer, 2-(
3',4'-dimethoxystyryl)quinazolinone 0.3
9 S' (recovery rate of 97 inches) was obtained.

,,2-(3',4'-dimethoxystyryl)-quinazolinone mp 269-270 C NMR (d,-CDCLs): δ 4.0
7 (31 (, s) 4.1 0 (3H, S) 7.0 ~ 8.7 (9H, m) IR (KBr): 31806n-' l/N-H1
670cy-'! 'C=0 1270m-'I'C-0-C Elemental analysis value C1,H,1IN203 Calculated value C: 70.13 Chi) 1: 5.19 Chi N: 9.09 Chi Actual value C: 70.20 H: 5.21% N: 8.95 H Comparative Example 2 2-(3',4'-dimethoxystyryl)-3-propylquinazolinone 0.46? (I, smmot) in ethanol 30-solution, sodium hydroxide 0.669 (
1.3 d of a water bath solution of I7mmoA) was added, and the mixture was stirred under reflux for 5 hours. After cooling to 40~soc, a hydrochloric acid 2.5 td
Gradually add it dropwise and stir for 10 minutes. After the reaction was completed, the same post-treatment as in Example 1 was carried out to obtain the desired N-(3
/, 4/-dimethoxycinnamoyl)-anthranilic acid was not obtained. After extraction with chloroform, the solvent was distilled off and 0.442 of 2-(3',4'-dimethoxystyryl)-3-isoprobylquinazo IJnon was obtained (recovery rate 93%).

2-(3',4'-dimethoxystyryl)-3-propylquinazolinone mp 138-140C NMR (CDC): a O, 98 (3H, t)
1.70 (2H,t,q) 3.85 (!+H,s) 3.86 (AH,S) 4.29 (3H,t) 6.9~8.2 (9H,m) IR (KBr ):21350. -1 Sea CHI-1
670crn-' j/C0 1270cW1-1 C-0-C Elemental analysis value cttattl'Jtos calculated value C: 7
1.98% H: 6.55% N: 8,00% Actual value C: 71.72% 1(: 6.1% N: 8.01% Acid catalyst of compound represented by general formula (III) An example of a manufacturing method using the following is shown below.

Reference Example 2-Methyl-5-(p-chlorophenyl)-(5H)-
Quinazolinone 2.71 t (I0mmot) and 3.4
-dimethoxybenzaldehyde 1.66fc10mmo
t) and para-toluenesulfonic acid-hydrate 0.19
In addition to f(Immot)i and xylene 5d, a water condensation reaction was carried out for 2 hours by azeotropic distillation with xylene. After xylene was distilled off from the reaction solution under reduced pressure, it was reconsolidated from ethanol to obtain 2-(3',4'-dimethoxystyryl)-s-<p-chloro7enyl)quinashly, non-5,7
79 (90%) T-Toku 90mp 200-201
'C' NMR (CDC2,): δ5.69 (3H,s)3.
75 (3H, s) 3.68 (3H, s) 6.0~8.2 (I5H, m) IR (KBr): 1685tM-” yc01270C
rn-1νC-0-C Elemental analysis value C□Hr o Nt Os C1 calculated value C
: 68.82 H: 4.57 N: 6.69 CL: B, 4 6 Actual value C: 68,53 H: 4.29 N: 6.43 C4: 8.75 -. i:'9'

Claims (1)

[Claims] General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X represents Cl or OCH_3, and n is 0 to
Represents an integer of 3. ) is dehydrated and condensed with 3,4-dimethoxybenzaldehyde represented by the following formula (II) ▲ Numerical formula, chemical formula, table, etc. ▼ (II) , general formula (III) ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, X represents Cl or OCH_3, and n is 0 to
Represents an integer of 3. ) 2-(3',4'-dimethoxystyryl)-
It is characterized by forming a 5-arylquinazolinone, then hydrolyzing it with a base, and then further hydrolyzing it with an acid. A method for producing N-(3',4'-dimethoxycinnamoyl)-anthranilic acid.