JPH01313457A - Production of n-(3', 4'-dimethoxy-cinnamoyl)- anthranylic acid - Google Patents

Abstract

PURPOSE: To obtain with high purity and economically a compd. being useful for allergy such as asthma, rhinocatarrh and atypical dermatitis by performing decarboxylation of N-(3',4'-dimethoxy-2-carboxy-cynnamoyl)-anthranyl acid.

CONSTITUTION: An aimed product of formula II is obtd. by performing decarboxylation reaction of a new compd. for formula I in the presence of a basic catalyst such as a secondary amine with no solvent or in an org. solvent such as ethanol at 70-180°C. 0.05-2 mol base is used to the compd. of formula I. The compd. of formula I is obtd. by transforming (3,4dimethoxyphenyl)- methylene malonic acid monoalkyl ester or formula III (wherein R is a 1-4C alkyl) to an acid halide and then, reacting it with a compd. of formula IV and then, hydrolyzing the obtd. compd. of formula V.

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing N-(3',4'-dimethoxy-cinnamoyl)-anthranilic acid of the following formula (I) CH,0\/OOH.

The above-mentioned compound of formula (+), known under the name Tranilast, is particularly effective against allergic diseases, and therefore asthma, nasal catarrh,
Used to treat atypical dermatitis, etc.

[Prior Art] Numerous methods are described in the literature for the production of this compound.

These methods start with 3,4-dimethoxy-cinnamic acid and anthranilic acid (
Japanese Patent Publication No. 50-135047, No. 56-
40710 and 58-48545 and U.S. Pat. No. 3,940,442), anthranilic acid ester (1) this patent publication No. 57-36905 and U.S. Pat. No. 4,070,484) or 2H-3,1-benzoxazine -2,4 (l old-Sion (Japanese patent cylinder 60-5670
No. 1) can be used. The yield of all these methods is lower than 80%.

In other reaction methods for producing tranilast, 3.
4-4 dimethoxybenzaldehyde (i.e. veratrumaldehyde) is reacted with N-(2-carboxyphenyl)-malonic acid monoamide. Japanese Patent Publication Section 5
According to No. 8-17186, this reaction is carried out in penzol or doluol. Each reactant is boiled in the presence of an equivalent amount of piperidine, and the water formed during the reaction is continuously distilled off from the reaction mixture. The final product is obtained in the form of the piperidine salt, which is then treated with acid to give the compound in free form.

[Problems to be Solved by the Invention] However, many problems arise when this reaction system is transferred to the scale of industrial implementation. For example, upon quantitative expansion, the reaction times are not proportional, the separated piperidine salt is heavily contaminated, and large amounts of solvent are used for crystallization.

According to Japanese Patent Publication No. 60-19754, [(2-carboxyphenyl)-carbamoyl-methylene]-triphenylphosphorane is used as a reaction component. The disadvantage here is that the preparation of triphenylphosphorane is rather complex, and it is also toxic and therefore requires expensive protective measures.

Other technical means known from the literature are the preparation of veratrumaldehyde with 2-methyl-4H-benzoxazin-4-one (Japanese Patent Publication Nos. 59-70655 and 58-55).
138q) or with anthranil (Japanese Patent Publication No. 58-55139). At this time, a 3,4-methoxystyryl-benzoxazine derivative is produced as an intermediate product, which is hydrolyzed with an alkaline solution to form the final product. Make it into a product. A similar method is described in Japanese Patent Publication No. 59-1.
It is listed in issue 2244'l.

There, the intermediate product is a 3-hydroxy-4-methoxystyryl rust conductor. The yield of all these preparations is up to 48-51%.

Finally, several special methods are known for producing tranilast, for example hydrogenation of propioloyl anthranilic acid (Japanese Patent Publication No. 5!l-205351) or 2-(3,4 - treatment of dimethoxycinnamoyl-benzoic acid with highly explosive sodium azide (
Japanese Patent Publication No. 56-135454), but these methods are unsuitable for economical industrial scale production.

The aim of the present invention is to find a process for producing highly pure N-(3',4'-dimethoxy-cinnamoyl)-anthranilic acid (tranilast) economically and on an industrial scale.

[Means for Solving the Problems] The present invention provides that N-(3',4'-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid of the following formula (V)/OOH is prepared in the presence of a basic catalyst. This is based on the knowledge that the decarboxylation of tranilast results in a virtually quantitative transfer to tranilast and therefore the product is produced in a very pure form.

The subject of the present invention is therefore a process for the preparation of N-(3',4'-dimethoxy-cinnamoyl)-anthranilic acid of the following formula (1)% formula %.

The feature of this method is that in producing N-(3',4-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid of formula (V), the presence of a basic catalyst, especially a secondary amine, is used. and optionally in the presence of a solvent, N-(3',4'-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid of the following formula (■) / OOH is decarboxylated.

[Function] As the basic catalyst, secondary and tertiary amines can be conveniently used. Secondary amines are particularly suitable as they reduce the reaction time and the temperature required for the decarboxylation reaction and lead to particularly good yields and very pure final products.

According to one particularly preferred embodiment of the process according to the invention, piperidine is used as basic catalyst in an amount of 0.05-2 mol, based on the starting compound of formula (V). In this case, the reaction proceeds practically quantitatively. Similar results are obtained using morpholine as catalyst. If the arsenic of the catalyst is increased within the ranges listed above, this results in an increase in the reaction rate.

The decarboxylation reaction can be carried out in an organic solvent, but it can also be carried out without a solvent. Examples of solvents include ethanol, n-butanol, ethylene glycol, anisole, doluol, quidylol, and dimethylformamide.

The decarboxylation reaction proceeds at temperatures of about 70°C to 180°C. It should be noted that as the reaction temperature increases, the reaction rate increases, but side reactions and therefore yield losses and impurities become more prevalent. The optimum temperature range is from 100°C to 125°C. It is therefore advantageous to choose a solvent which, together with its pond components, provides a reaction mixture that boils within this temperature range.

Basic catalysts can also be used as reaction media.

The compounds of the formula (V), for example, form a well-stirrable melt at 115-120 DEG C. with 1 to 2 molar amounts of piperidine, the reaction proceeding within 30-60 minutes.

The reaction mixture is worked up in a known manner. It is advantageous if the final product is produced in such a form that it can be precipitated out in the form of its sodium salt, filtered and subsequently converted to the free acid with a mineral acid. When using water-immiscible organic solvents as reaction medium, the final product can be extracted from the still warm reaction mixture with caustic soda.

The product crystallizes from the extract in the form of its sodium salt on cooling, which is filtered and then converted to the free acid in the manner described above.

The starting compound of formula (V) is a new compound. However, this compound has the following general formula (IV)/C0OR' (in this formula, R is an alkyl group having 1 to 4 carbon atoms, and R1 is a hydrogen atom or
means an alkyl group having 1i carbon atoms, where R
When 1 is hydrogen, it is a free acid, and when R1 is an alkyl group, it is an alkyl ester) N-(3',4'-
dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid or its ester is boiled in an alcoholic caustic solution, the compound having the formula (
V) is hydrolyzed to the desired N-(3',4'-dimethoxy-2-alkoxycarbonyl-cinnamoyl)-anthranilic acid.

The compound of general formula (rV) is also a new compound.

This compound is a (3,4-dimethoxyphenyl)-methylene-malonic acid monoalkyl ester (3,4-dimethoxyphenyl)-methylene-malonic acid monoalkyl ester of the following general formula (II) (in which R represents an alkyl group having 1 to 4 carbon atoms).
This converts 3,4-dimethoxyhenzal-malonic acid monoalkyl ester) into an acid halide, especially an acid chloride, which has the general formula (Ill
) COOR' / (where R1 represents hydrogen or an alkyl group having 1 to 4 carbon atoms, that is, when R1 is hydrogen, it is anthranilic acid, and when R1 is an alkyl group, it is anthranilic acid alkyl ester) ) can be obtained easily and in good yield.

” The compound of formula (V) produced by the method described in 1 is 2
It exists as a mixture of two geometric isomers in a ratio of 2:1. These isomers can be separated from each other by fractional crystallization. However, this is unnecessary for the purposes of the present invention, since both isomers give the desired tranilast in equal yields. The melting point of one isomer is 210°C, while that of the more abundant one is 180°C.

General formula used as starting material for each of the above intermediate products
Compounds (II) and (III) are known compounds.

〔Example〕

The present invention will be explained in more detail below using some examples.
These examples are not intended to limit the invention in any way.

Example - Ichiyo N-(3',4'-dimethoxy-2-methoxycarbonyl-cinnamoyl)-anthranilic acid methyl ester
[Compound of formula IV in which R and R' are methyl groups] 1υD mI of henzol, 26.5 g i[1,
I [1 mol) of (3,4-dimethoxyphenyl)-methylene-malonic acid monomethyl ester (melting point: 176
-177° C.), 357 g [0.30 mol) of thionyl chloride and 3 drops of dimethylformamide are kept at low boiling for 3 hours. The henzol and excess thionyl chloride are then distilled off in vacuo. The residue was dissolved in 50 ml of tetrahydrofuran and the solution was heated at a temperature below 25°C.
A solution of 16.6 g (0.11 mol) of anthranilic acid methyl ester and 9.5 g (0.12 mol) of pyridine in 50 ml of tetrahydrofuran is added within minutes. The reaction mixture is stirred at 50° C. for 3 hours and then the solvent is removed in vacuo. The residue is suspended in methanol, filtered, then washed first with water and then with methanol and finally dried in vacuo at 50"C. 36.4 g of the title compound (
91.1%) is obtained, but the melting point of this is 13
It is 45-135.590.

If((KBr): 1730.1700.1675
cm-'(CO)'H-NMR [DMSO): 3
．． 81 (s, 3H,0CH3), 3, 85
(s, 3H, 0CII!l), 3, 94 (s,
611. 0CHa), 7, 05-8.51 (m,
7H, arom heat, 7, 76 (s, l H
, -Ct (=), 11.20 (s, IN i,
N11 Example - Once N-(3',4'°-dimethoxy-2-methoxycarbonyl-cinnamoyl)-anthranilic acid [R of formula TV
= methyl, R' = hydrogen compound] 2 [i, fig (0,10 mol) of (3,4-dimethoxyphenyl)-methylene-malonic acid monomethyl ester and 15.1 g (0,11 mol) of anthranilic acid are reacted with each other in the manner described in Example 1.

16.1 g (41.7%) of the title compound are obtained, the melting point of which is 213-214<0>C.

rR(KBr): 1755.1730 am-'
(CO)'H-NMR (CDCI, ]): 3.96
(s, 3t(, 0C11,l, 3.99 (s, 3H
,0CHs), 4.04 (S, 3H,0CH5), 6.93-
8.25 (m, 7H, aroma,), 7, 85
Is, IN, -CH=) Example 3 N-(3',4'-cy,methoxy-2-ethyl-oxycarbonyl-cinnamoyl)-anthranilic acid medyl ester [R-ethyl of formula IV, R' = CH , l compound] 28.0
g (0,10 mol) of (3,4-dimethoxyphenyl)-methylene-malonic acid monoethyl ester (melted;
1. , j, 154-155 °C) and 16.6 g
(0.11 mol) of anthranilic acid methyl ester are reacted with each other in the manner described in Example 1.

37 g (89.5%) of the title compound are obtained, the melting point of which is 144-145°C.

TR (Br): 1720.17 yen, 1680 cm
-'(COI'H-NMR(DMSO)・1.33
(t, 3H, CH!+1.3, 90 (s, 3H,
0CH3), 3.95 (s, 3H,0CH3), 3
, 98 (s, 3H,0CH3), 4.43 (q
, 2H, CH21, 6,86-8,80 (n+, 7H, aroma,),
7,89 (s, IN, -CH=) Example--4 N-(3',4'-cymeI xy-2-ethoxycarbonyl-cinnamoyl)-anthranilic acid [R of formula TV
=ethyl, R'=H] 28.0 g (0.10 mol) of (3,4-dimethoxyphenyl)-methylene-malonic acid monoethyl ester and 15.1 g (0.11 mol) of anthranyl The acids are reacted with each other in the manner described in Example 1.

16.0 g (40.1%) of the title compound are obtained, the melting point of which is +91-193°C.

IR(War): 1760.1725 cm-'
(CD)'H-NMR (CDC1,): 1.43 (
t, 3H,CH,), 3.90 (s, 3H,0C
Hs), 3, 93 (s, 3H,0CH3), 4, 4
8 (q, 2t(, CH21,6, 88-8,23(
m, 7H, arom, l, 7, 91 (s,
IH, -CH = 1 example - once N-(3',4'-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid [formula 1 formula % 6 in a mixture consisting of 130 ml methanol and 30 ml water g (0.15 mol) of sodium hydroxide are dissolved. 20 g (0.05 mol) of N-(3',4'-dimethoxy-2-methoxycarbonyl-cinnamoyl)-anthranilic acid methyl ester prepared according to Example 1 are added to this solution. After the mixture has been boiled under reflux for 3 hours, the methanol is distilled off in vacuo. The remaining solution is diluted with 30 ml of water and extracted twice with 30 ml each of chloroform.

The aqueous phase was stirred with Ig activated carbon for 30 minutes,
The activated carbon is then filtered off. The filtrate is acidified to put with semi-concentrated hydrochloric acid. After filtering the precipitate and washing with water,
Dry at 50'C in vacuum. 18.20
g (98%) of the title compound is obtained, which is a 2:l mixture of two geometric isomers. Thin layer chromatography (eluent: chloroform/methanol/water =
50/4015) gives values of 0.39 and 0.5. The isomers can be separated from each other by fractional crystallization from 90% strength aqueous methanol solutions.

The analytical values for each isomer are as follows: 1) R,=
0.39 Melting point = 178-180℃ (decomposition) IR (KBr): 1730.1695.1645 c
m-'(Co)'H-NMR (DMSO): 3.5
0 (s, 3H,0CHsl, 3, 76 (s, 3
H, 0CHsl, 6.96-8.71 (m, 7H,
arom, ), 7, 65 (s, IH, -CH=1,
Il, 50 (s, IN, NH)2) Rr
:0.50 Melting point = 208-210℃ (decomposition) IR (KBr): 1695.1670 cm-' (
Co)'H-NMR (DMSO): 3.78 (s,
3H1OCHa), 3.83 (S, 3H,0CR
-1,7,03-8,63(m, 7H,arom,
), 7.58 (s, group, -CH=1, It,
70 fs, IH, NH) Example - Once N-(3',4'°-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid [formula 1 formula %] of general formula (IV) in the manner described in Example 5 A compound of general formula (V) is produced from various compounds. The respective yields obtained are summarized in Table 1 below.

Table 1 The physical constants of the obtained compound of formula (V) correspond to those listed in Example 5.

N-(3",4-dimethoxycinnamoyl)-anthranilic acid [compound of formula I, i.e. tranilast] in a flask equipped with a stirrer and a top distiller, 7
．． 43 g (0.02 mol) of N-(3',4'-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid (2=1 mixture of both geometric isomers) and 3.41 g
A mixture of (0.04 mol, 4 ml) with piperidine is heated to 115-120° C. on an oil bath and stirred until gas evolution ceases (approximately 30-60 minutes). The reaction mixture was then cooled to below 100°C and warmed to 0.5°C.
Add 55 IIll of 4N caustic soda.

Piperidine in the form of an azeotrope formed with water 1
Distill off until a steam temperature of 00°C is reached.

This mixture of water and piperidine can be used for the next batch.

The remaining mixture is cooled, and the precipitated crystals are separated by filtration and washed with water. Tranilast is liberated from this sodium salt with hydrochloric acid. After drying in vacuo at 95° C., 6.3 g of tranilast are obtained.

The solution remaining after filtration of the sodium salt is combined with the washing solution and acidified to pH 1 with hydrochloric acid. Separate the precipitate by filtration
Crystallize after dissolving in 0.4N caustic soda under heating. The final product is liberated from the sodium salt as described above. A further 0.006 g (971%) of product are obtained.

Melting point: 211-213°C IRI to Br): 1690.1655 cm-' (
COI'H-NMR (DMSO): 3.80 (s,
3H, OCH*).

3.84 (s, 3H,0CHs), 6.80 (d
, IH,J=17H2,-CH-1,6,98-8,
66(m, 8H, arom,, -CH-)kai-1 N-(3',4-dimethoxycinnamoyl)-anthranilic acid [compound of formula I] 7.43 g (0.02 mol) of N- (3', 4'-
dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid, 100 ml anisole and 0.10
A mixture of ml (0,001 mol) of piperidine is boiled under reflux for 2 hours. This reaction mixture
Cool to below 100°C and add 55ml of 0.4N warm caustic soda. The phases are separated from each other at warm temperatures. The aqueous phase is cooled and worked up in the manner described in Example 7. 5.9 g (90.1%) of the title compound are obtained, the physical data of which correspond to those given in Example 7.

The yield, solvent, etc. under various reaction conditions are summarized in Figure 2 below.

Hereinafter, the present invention will be described in detail with reference to Examples, and the gist thereof is as described in the claims. However, the following embodiments of the present invention are particularly mentioned.

2. The process according to claim 1, wherein: (1) the decarboxylation is carried out at a temperature of 70-18[][deg.]C, in particular +00-125[deg.]C.

(2) The method according to claim 1, wherein piperidine or morpholine is used as the basic catalyst.

(3) The method according to claim 1, wherein an excess amount of basic catalyst is used as the reaction medium.

Claims (1)

[Scope of Claims] (1) In producing N-(3',4'-dimethoxy-cinnamoyl)-anthranilic acid of the following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I), In the presence of a basic catalyst, especially a secondary amine, and optionally a solvent, N-(3' of the following formula (V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ , 4'-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid is decarboxylated. (2) N-(3',4'-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid of the following formula (V) ▲Mathematical formulas, chemical formulas, tables, etc.▼(V). (3) In producing N-(3',4'-dimethoxy-2-carboxy-cinnamoyl)-anthranilic acid of the above formula (V), the following general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(IV) (In this formula, R represents an alkyl group having 1 to 4 carbon atoms, and R^1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.) −
A manufacturing method characterized by hydrolyzing (3',4'-dimethoxy-2-alkoxycarbonyl-cinnamoyl)-anthranilic acid or its ester in an alcoholic caustic solution at a high temperature. (4) Formula (IV) below ▲Mathematical formulas, chemical formulas, tables, etc.▼(IV) (In this formula, R is an alkyl group having 1 to 4 carbon atoms, and R^1 is a hydrogen atom or N- (meaning an alkyl group having 1 to 4 carbon atoms)
(3',4'-dimethoxy-2-alkoxycarbonyl-cinnamoyl)-anthranilic acid or its ester. (5) N-(3',4'-dimethoxy- of formula (IV) above)
In producing 2-alkoxycarbonyl-cinnamoyl)-anthranilic acid, the following formula (II) ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (II) (However, in this formula, R has the above-mentioned meaning) (3
, 4-dimethoxyphenyl)-methylene-malonic acid monoalkyl ester is converted into an acid halide, especially an acid chloride, and this is converted into the following formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (However, R^ 1 has the above-mentioned meaning).