HU200996B - Process for producing n-(3', 4'-dimethoxycinnamoyl)-anthranilic acid (tranilast) - Google Patents

Abstract

The present invention relates to a process for the preparation of an N- (3 ', 4'-dimethoxy-cinnamoyl) -antranylic acid (tranylast) of the formula I, wherein Rése has the meaning of C 3,4-C alkyl. to form an acid chloride from a phenylmethylene monomeric acid monoalkyl moiety, and reacting a compound of formula III wherein R 1 is hydrogen or C 1-4 alkyl, followed by the formula IV wherein R and R 1 are as defined above. - N- (3''-dinylcarbonylcinnamoyl) -anthanylic acid ester is hydrolyzed alkalinically and the resulting N- (3 ', 4'-dieto-2-carboxycinnamoyl) anthranilic acid is a basic catalyst, preferably in the presence of a secondary amine without the use of an organic solvent, decaboxylsilyl · CH = CH-CONH COOH (1) ROO1; R100C CH = C-C0HNCOOH CH = C-C10RR-Ct-4 alkyl (IV) (H) Scope of the disclosure: 5 pages, Figure 1 R1 = C1-4alkylH CH30, HOOC (III) 1Online CH3O- # 2VCH = <-_ (V) HOOC COHN HU 200 996 B -1-

Description

The present invention relates to a process for the economical preparation of N- (3 ', 4'-dimethoxycinnamoyl) anthranilic acid (tranylast) of formula I. The process is characterized in that, from a 3,4-dimethoxyphenylmethylenemalonic acid monoalkyl ester of formula II wherein R is a C 1-4 alkyl group, it is known to form an acid chloride with a compound of formula III wherein R 1 is hydrogen or (C 1 -C 4) -alkyl. The resulting N- (3 ', 4'-dimethoxy-2-alkoxycarbonylcinnamoyl) anthranilsa v ester of Formula IV, wherein R and R 1 are hydrolyzed alkaline as above, and the resulting N- (3') of Formula V is obtained. (4'-dimethoxy-2-carboxy-cm-3moyl) -anthranilic acid is decarboxylated in the presence of a basic catalyst, preferably secondary amine.

Tranylast has significant antiallergic properties, such as asthma, hay fever, atopic dermatitis, etc. drug.

Several pathways for the preparation of tranilast are reported in the literature.

One possible solution is to manufacture

3,4-dimethoxycinnamic acid and anthranilic acid (Japanese Patent Nos. 50-135047, 56-40710, 58-48545 and U.S. Patent 3,940,442), anthranilic acid ester (Japanese Patent Nos. 57-36905 and 4,070). 484) or 2H-3,1-benzoxazine-2,4 (1H) -dione (Japanese Patent No. 60-56701) are used as reaction partners. The main disadvantage of the above-mentioned processes is that the yields do not exceed 80%.

Another route for the preparation of tranilast is based on 3,4-dimethoxybenzaldehyde (veratraldehyde) which is reacted with N- (2-carboxyphenyl) malonic acid monoamide according to Japanese Patent Application No. 58-17186 by reacting the reaction partners. and an equimolar amount of piperidine in benzene or toluene, while continuously distilling off the reaction water from the reaction mixture. The target product is isolated in the form of the piperidine salt and the free acid is prepared by acidic decomposition.

The industrial realization of the reaction raises a number of problems, for example, the reaction time is disproportionately increased during the scale-up, the product isolated in the form of the piperidine salt is highly contaminated and recrystallization requires solvent.

Japanese Patent No. 60-19754 discloses [(2-carboxyphenyl) carbamoylmethylene] triphenylphosphorane as a reaction partner. The disadvantage of the reaction is that the production of triphenylphosphorane, due to its very complex and toxic nature, makes the manufacture extremely hazardous.

Other methods known in the art include reacting averatraldehyde with 2-methyl-4H-benzoxazin-4-one (Japanese Patent Nos. 59-70655 and 58-55138) and anthranil (Japanese Patent No. 58-55139) as intermediates.

A 3,4-dimethoxy-stryl-benzoxazine derivative is prepared which is hydrolyzed to give the target product. An analogous procedure is described in Japanese Patent Application No. 59-122449, where the intermediate is a 3-hydroxy-4-methoxy-styryl-benzoxazine derivative. However, these solutions can only be realized with a yield of 4851%.

Other special processes known for the preparation of tranylast include the hydrogenation of the corresponding propioloyl anthranilic acid according to Japanese Patent Application Nos. 59-205351 or 2- (3,4-dimethoxycinnamoyl) benzoic acid with sodium azide according to Japanese Patent Application Nos. 56-135454. is hazardous and unsuitable for economical industrial production.

SUMMARY OF THE INVENTION It is an object of the present invention to provide an economically feasible industrial scale process of high purity N- (3 ', 4'-dimethoxycinnamoyl) anthranilic acid (tranylast).

The present invention is based on the discovery that by decarboxylation of N- (3 ', 4'-dimethoxy-2-carboxy-cmnamoyl) -anthranilic acid of formula V in the presence of a basic catalyst, virtually quantitative tranylate is obtained and the product thus obtained can be obtained in very pure form. reaction.

Secondary and tertiary amines can be used as basic catalysts. It has been found that, particularly in the presence of secondary amines, the reaction time and temperature required for decarboxylation are significantly reduced, and the product quality and yield are greatly improved.

According to a preferred embodiment of the invention, decarboxylation is practically quantitative in the presence of 0.05 to 2.0 moles of piperidine per mole of the compound of formula V.

Morpholine can be used with similar good results instead of piperidine. Increasing the amount of catalyst within the above range increases the reaction rate.

Decarboxylation can be carried out in an organic solvent medium and without the use of a solvent. Suitable solvents are, for example, ethanol, n-butanol, ethylene glycol, anisole, toluene, xylene, dimethylformamide. An important aspect of solvent selection is the solubility of the starting material and its amine salt.

In our experience, the decarboxylation reaction is carried out at 78-180 ° C. As the temperature rises, the reaction rate increases, but at the same time product quality and yield deteriorate. The optimum temperature for the reaction was found to be between 100 ° C and 125 ° C. Therefore, it is advisable to select the solvent used so that its boiling point is within the optimum temperature range.

The catalyst may also be used as a medium for carrying out the reaction. The compound of formula V gives a melt that can be stirred at 1.0-1.0.0 molar equivalents of piperidine at 115-120 ° C and the reaction is complete within 0.5-1 hour.

The catalyst may also be used as a medium for carrying out the reaction. The compound of formula V gives a melt that can be stirred at 1.0-1.0.0 molar equivalents of piperidine at 115-120 ° C and the reaction is complete within 0.5-1 hour.

The tranylast is preferably isolated from the reaction mixture in the form of its sodium salt, filtered and subsequently converted to the free acid with a mineral acid. By this method, a very pure final product is obtained.

In the case of reaction with water not

As a medium, the tranylast is extracted warm from the reaction mixture with an aqueous solution of sodium hydroxide. After cooling the extract, the crystallized sodium salt is converted to the tranyl salt as described above.

It is also within the scope of the present invention to provide the compound of formula V in a simple and high yield manner by reaction of the 3,4-dimethoxyphenylmethylenemalonic acid monoalkyl ester of formula sav in a known manner to form the acid chloride. with the anthranilic acid or ester of the formula: The reaction is carried out in particularly good yield when using methyl or ethyl anthranilic acid. The resulting N- (3 ', 4'-dimethoxy-2-alkoxycarbonylcymamoyl) anthranilic acid or ester of formula IV is boiled in an alcoholic aqueous solution of N (3', 4'-dimethoxy) It is hydrolyzed to -2-alk (2-carbonylcinnamoyl) -antranilic acid to give a 2: 1 mixture of two geometric isomers which can be separated by fractional crystallization, the major isomer melting at 180 ° C and the other at 210 ° C. Tranylast can be obtained from both isomers in the same yield by decarboxylation in the presence of secondary or tertiary amine.

The invention is illustrated by the following examples, without limiting our claims.

Example 1

N- (3 ', 4'-Dimethoxy-2-methacarbonyl-cinnamoyl) -anthranilic acid methyl ester

26.6 g (0.10 mol) of 3,4-dimethoxyphenylmethylenemalonic acid monomethyl ester (m.p. 176-177 ° C), 35.7 g (0.30 mol) of thionyl chloride are charged in 100 ml of benzene. and three drops of dimethylformamide. The reaction mixture was gently boiled for 3 hours and then the benzene and excess thionyl chloride were distilled off in vacuo. The residue was dissolved in tetrahydrofuran (50 mL) and methyl anthranilate (16.6 g, 0.11 mol) was added over 20 min at a temperature below 25 ° C.

9.5 g (0.12 mol) of pyridine in 50 ml of tetrahydrofuran. The reaction mixture was stirred at 50 ° C for 3 hours. The tetrahydrofuran is then distilled off in vacuo. The distillation residue was suspended in methanol, filtered, washed with water and methanol and dried at 50 ° C in vacuo.

Yield: 36.4 g (91.1%)

Mp 134-1353 *

JR (KBr): 1730 ^{cm-2 * 4,} 1700 ⁴ cm, 1675 ^'1 (CO) ^X H NMR (DMSO): 3.81 (S3H, _OCH3)

3.86 (s, 3H, OCH ₃ )

3.94 (s, 6H, OCH ₃ )

7.05-8.51 (m, 7H, aromatic)

7.76 (s, 1H, -CH =)

11.20 (s, 1H, NH)

Example 2

N 3 \ 4 * Dimethyl »-2-methoxycarbonyl-cmnamoil)

anthranilic

26.6 g (0.10 mol) of 3,4-dimethoxyphenylmethylenemalonic acid monomethyl ester and 15.1 g (0.11 mol) of anthranilic acid are reacted as in Example 1.

Yield: 16.1 g (41.7%)

Mp: 213-214'C

IR (KBr): 1755 n ¹ 1730 ⁴ (CO)

NMR (CDCl 3): 3.96 (s ₃

4.04 (s3H, OCH2)

6.93-8.26 (m, 7H, aromatic)

7.85 (s, 1H, -CH =)

Example 3

N- (3 ', 4'-dimethoxy-2-ethoxycarbonyl-cmnamoil) anthranilic acid methyl ester

28.0 g (0.10 mol) of 3,4-dimethoxyphenylmethylenemalonic acid monoethyl ester (m.p. 154-155 ° C) and 16.6 g (0.11 mol) of methyl anthranilate are obtained in Example 1. The reaction was carried out as described in Example 1.

Yield: 37 g (893%)

144-145'C

IR (KBr): 1720 cm ⁴ , 1700 cm ⁴ , 1680 cm ⁴ (CO)

NMR (DMSO): 1.33 (t ₃ H, CH ₃ )

3.90 (S3H, _OCH3)

3.95 (s, 3H, OCH ₃ )

4.43 (q, 2H, CH ₂ )

3.98 (s, 3H, OCH ₃ )

6.86-8.80 (m, 7H, aromatic)

7.89 (s, H, CH ")

Example 4

N- (3', 4'-dimethoxy-2-ethoxycarbonyl-cinnamoyl) anthranilic

28.0 g (0.10 mol) of 3,4-dimethyl-phenyl-methylenemalonic acid monoethyl ester and 15.1 g (0.11 mol) of anthranilic acid are reacted as in Example 1.

Yield: 16.0 g (40.1%)

M.p .: 191-193'C

IR (KBr): 1760 cm ^4, 1725 (cm ⁴ (CO)

NMR (CDCl 3): 1.43 (t ₃ H, CH ₃ )

3.90 (S3H, _OCH3)

3.93 (S3H, _OCH3)

4.48 (q, 2H, CH ₂ )

6.88-8.23 (m, 7H, aromatic)

7.91 (s, 1H, -CH =)

Example 7

N- (3 ', 4'-Dimethoxy-2-carboxycinnamoyl) -anthranilic acid

Sodium hydroxide (6 g, 0.15 mol) was dissolved in a mixture of methanol (130 ml) and water (30 ml). To the solution was added 20 g (0.05 mol) of N- (3 ', 4'-dimethyl-2-methoxycarbonylcinnamoyl) anthramyl methyl ester. The reaction mixture was refluxed for 3 hours. The methanol was removed in vacuo. The resulting solution was diluted with water (30 mL) and extracted with chloroform (2 x 30 mL). The aqueous phase was stirred with 1 g of decolorizing carbon for 0.5 h and the decolorizing carbon was filtered off. The filtrate was cooled to pH 1 with 1: 1 hydrochloric acid. The precipitate was filtered off, washed with water and dried in vacuo at 50 ° C.

Yield: 18.20 g (98%)

The product is a 2: 1 mixture of geometric isomers. Thin layer chromatography (eluent: chloroform: methanol: water = 50: 40: 5) Rf values of the two spots were 0.39 and 03 ·

The geometric isomers can be separated from the 90% methanol by fractional crystallization.

R f = 039

-3HU 20Ö996 Β

178-180 'C (dec.)

IR (KBr): 1730 cm ^-1 , 1695 cm ^-1 , 1645 ⁴ (CO)) NMR (DMSO): 3.50 (s, 3H, OCH ₃ )

3.76 (s, 3H, OCH ₃ )

6.96-8.71 (m, 7H, aromatic)

7.65 (s, 1H, -CH =)

11.50 (s, 1H, NH)

Rf = 0.50

208-210'C (decomposes)

IR (KBr): 1695 cm ^-1 , 1670 cm ^-1 (CO)

NMR (DMSO): 3.78 (s, 3H, OCH ₃ )

3.83 (s, 3H, OCH ₃ )

7.03-8.63 (m, 7H, aromatic)

7.58 (s, 1H, -CH =)

11.70 (s, 1H, NH)

Example 6

N- (3 ', 4'-Dimethoxy-2-carboxycinnamoyl) -anthranilic acid

19.3 g (0.05 mol) of N- (3 ', 4'-dimethoxy-2-methoxycarbonylcinnamoyl) anthranilic acid are obtained as in Example 5.

Yield: 17.9 g (96.4%)

The assay results for the final product identification are in agreement with the values given in Example 5.

Example 7

N- (3 ', 4'-Dimethoxy-2-carboxycinnamoyl) -anthranilic acid is obtained from N- (3', 4'-dimethoxy-2-ethoxycarbonylcinnamoyl) -anthranilic acid (0.05 mol). Example 5.

Yield: 18.0 g (96.9%)

The test results for the final product identification are the same as in Example 5.

& example

N- (3 ', 4'-Dimethoxy-2-carboxycinnamoyl) -anthranilic acid

20.7 g (0.05 mol) of N- (3 ', 4'-dimethoxy-2-ethoxycarbonylcinnamoyl) anthranilic acid methyl ester are obtained according to Example 5.

Yield: 17.8 g (95.8%)

The assay results for the final product identification are in agreement with the values given in Example 5.

Example 9

N- (3 ', 4'-Dimethoxy-cinnamoyl) -anthranilic acid 7.43 g (0.02 mol) of N- (3', 4'-dimethoxy-25-carbamoyl-cinnamoyl) -anthranil are charged into a flask with a stirring flask. acid (2: 1 mixture of geometric isomers) and 3.41 g (0.04 mol, 4 ml) of piperidine. The reaction mixture was heated in an oil bath and reacted at 115-120 ° C until gas evolution ceased (0.5-1 hour). The reaction mixture was cooled to below 100 ° C and 55 ml of 0.4 N warm sodium hydroxide solution was added.

The piperidine is distilled from the reaction mixture as its aqueous azeotropic to a vapor temperature of 100 ° C. The piperidine-water mixture was used in the next batch. The reaction mixture is cooled, the precipitated crystals are collected and washed with cold water. The sodium salt of the product was dissolved in warm water (30 ml) and poured into a mixture of water (20 ml) and 37% hydrochloric acid (2 ml) with stirring. The precipitated product was filtered off, washed with water and dried at 95 ° C in vacuo. We obtain 63 g of tranil.

The mother liquor and washings obtained after filtration of the sodium salt are acidified to pH 1 with hydrochloric acid, filtered, dissolved in 0.4N sodium hydroxide solution, crystallized and the final product is isolated with hydrochloric acid as described above. 0.06 g of product is obtained.

Yield: 6.36 g (97.1%)

Mp 211-213 'C

IR (KBr): 1690 cm ^-1, 1655 cm ^-1 (CO) ^X H NMR (DMSO): 3.80 (S3H, _OCH3)

3.84 (s, 3H, OCH ₃ )

6.80 (d, 1H, J = 16Hz, -CH =)

6.98-8.66 (m, 8H, aromatic, -CH =)

Example 10

N- (3 ', 4'-Dimethoxy-cinnamoyl) -anthranilic acid 7.43 g (0.02 mol) of N- (3', 4'-dimethoxy-2-carboxycinnamoyl) -anthranilic acid, 100 ml of anisole and 0.10 of piperidine (0.001 mol) was refluxed for 2 hours. To the reaction mixture cooled to 100 ° C was added 55 ml of 0.4 N warm sodium hydroxide solution. The phases were separated separately while warm. The aqueous phase is cooled and proceeded as in Example 9 below.

Yield: 5.9 g (90.1%)

The test results for the final product identification are the same as in Example 9.

11-19. example

N- (3 ', 4'-dimethoxy-cinnamoyl) -antramlsav

Example number Starting material Catalyst molar ratio Catalyst Medium Temperature Time yield g % 'C hour 11th 1: 2 piperidine - 115-120 0,5-1 6.22 95.0 12th - - piperidine 115 4.5 5.90 90.1 13th 1: 1 morpholine n-butanol 118 lólOp 6.20 94.7 14th 1: 1 piperidine ethanol 78 20 5.56 84.9 15th 1: 1 diethylamine - 160-170 1.5 4.88 743 16th 1: 1 morpholine toluene 111 3 5.50 84.0 17 - - dimethylformamide 110 13 4.20 64.2 18th 1: 1 piperidine dimethylformamide 110 1.5 4.76 72.7 19th 1: 1 piperidine diphenyl ether 180 20p 4.72 72.1

-4HU 200996 Β

Claims (4)

PATENT CLAIMS A process for the preparation of N- (3 ', 4'-dimethoxycinninoyl) anthranilic acid (tranylast) of the formula I, wherein 3,4-dimethoxyphenyl of the formula Π in which 5 R is a C 1-4 alkyl group of the methylene-malonic acid monoalkyl ester is reacted in a manner known per se with 10 compounds of the general formula III wherein R ¹ is hydrogen or C 1-4 alkyl and the resultant compound of the general formula IV where R ¹ is as defined above. The N- (3 ', 4'-dimethoxycarbonylcinnamoyl) anthranilic acid ester is basically hydrolyzed and the resulting N- (3', 4'8-dimethoxy-2-carboxycinnamoyl) anthranilic acid of formula V is a basic catalyst, preferably and decarboxylated in the presence of secondary amine without the use of an organic solvent. Process according to claim 1, characterized in that a mixture of geometric isomers of the compound of formula V is used for the decarixxylation. Process according to claim 1 or 2, characterized in that the decarboxylation is carried out at a temperature of from 78 to 180 ° C, preferably from 100 to 125 ° C. 4. Process according to any one of claims 1 to 3, characterized in that 0.05 to 2.0, preferably 1.0 mol, of piperidine is used as the basic catalyst for the compound of formula V.