DK142543B - Analogous process for the preparation of bis (benzamido) benzoic acid derivatives or pharmaceutically acceptable salts thereof. - Google Patents

Description

(11) PRESENTATION 1 42543 DENMARK <«'> In«. Cl. C 07 C 103/76 '(21) Application No 1 667/74 (22) Filed on the 26th HIST. 1974 (24) Race day 26 Mar 1974 (44) The application presented and the petition published on 17 · ΠΟΥ · 1 980

DIRECTORATE OF

PATENT AND TRADEMARKET SYSTEM 00) Priority requested from it

Mar 27 1973, 34152/73, JP

(71) CHUG AI SEIYAKU KABUSHIKI KAISHA, 5-1, 5-chorae, Ukima, Kita-ku, Tokyo, JP.

(72) Inventor: Takashi Mori, 2-8-302, Nagayama 4-chome, Tama-shi, Tokyo, JP: Sakæ Takaku, T-11-404, Nishiageo-Dainidanchi, 77-1, Oazakoshi = kiya, Ageo- shi, Saitama-ken, JP: Yoshiyuki Osugi, 373, Nakamachi, Ko = daira-shi, Tokyo, JP: Takashi Matsuno, 1-2- "408, Shimura 1-chotne, Ita = bashi-ku, Tokyo, JP: Shogo TotriTzawa, 3-3-402, Nagayama 3-chome, Tams-shi, Tokyo, JP.

(74) Plenipotentiary under the blessing:

International Patent Office. ____ (54) Analogous process for preparing bis- (benzamido) -benzoic acid derivatives or pharmaceutically acceptable salts thereof.

The invention relates to an analogous process for the preparation of novel bis (benzamido) benzoic acid derivatives of general formula I (see claim), wherein a hydroxyl group, a C 1-4 alkoxy group or an amino group, 2 hydrogen atom, a C 1-6 alkanoyl group, or a C 1-4 alkyl group, or pharmacologically acceptable salts thereof.

The process according to the invention is characterized by reacting a compound of formula II (see claim) wherein R 2 - has the meaning given above, with a carboxylic acid of formula III (see claim) wherein R has the above or, if desired, hydrolyzes ester groups in the product or acylates two phenolic hydroxyl groups in the product or, if the compound of formula I contains a carboxyl group, transfers the compound into a pharmaceutically acceptable salt.

Examples of compounds of formula II which can be used as starting materials are 3,5-diaminobenzoic acid, 3,4-diaminobenzoic acid, 2,4-diamino benzoic acid, 2,5-diamino benzoic acid and alkyl esters of diaminobenzoic acid (the number of carbon atoms in the alkyl group being between 1 and 4), e.g. methyl 2,4-diaminobenzoate, ethyl 2,4-diaminobenzoate, butyl 2,4-diaminobenzoate and methyl 3,5-diaminobenzoate, and 2,4-diaminobenzamide and 3,5-diaminobenzamide.

The compounds of formulas III and their reactive derivatives which can be used as starting materials include salicylic acid, 2-alkoxybenzoic acid, wherein numbers of carbon atoms in the alkyl moiety are between 1 and 4, e.g. 2-methoxybenzoic acid, 2-ethoxybenzoic acid and 2-n-butoxybenzoic acid, 2-alkanoyloxybenzoic acid wherein the number of carbon atoms in the alkyl moiety is between 1 and 4, e.g. 2-acetoxy-benzoic acid, and corresponding halides, esters, acid anhydrides and anhydrides of said acids with other acids such as other carboxylic acids, carbonic acids, sulfuric acids, sulfonic acids and phosphoric acids.

The reaction may, e.g. is carried out by subjecting a compound of formula II to a condensation reaction with a reactive derivative of a carboxylic acid of formula III at a temperature of usually between -10 and 50 ° C, preferably between 0 and 20 ° C for a period between 30 minutes and 4 hours.

Examples of solvents which can be used in this reaction include water, benzene, toluene, tetrahydrofuran, diethyl ether, dioxane, dimethylformamide, chloroform, methylene chloride, acetonitrile, acetone, tetrachloromethane, ethyl acetate and mixtures thereof.

Examples of accelerators that can be used in the reaction include inorganic bases such as hydroxides, carbonates and acetates of alkali metals or alkaline earth metals, e.g. potassium acetate, sodium acetate, sodium carbonate, potassium carbonate, sodium hydroxide, calcium acetate and calcium carbonate, and organic tertiary amine bases, e.g. pyridine, triethylamine, dimethylaniline and picoline.

In addition, a compound of formula II, whose amino groups are activated using phosphorus trichloride or an ester of chlorophosphoric acid, can be reacted with a compound of formula III at a temperature between room temperature and the reflux temperature of the solvent used. It is preferred to carry out this reaction after the hydroxyl group of compound II is protected if R represents hydroxyl. The reaction is carried out in the presence of a solvent, e.g. a neutral solvent such as benzene, toluene, xylene, dioxane or tetrahydrofuran or in a basic solvent such as pyridine, triethylamine, dimethylaniline or picoline.

If the reaction is carried out in the presence of a neutral solvent, it is preferable to use a tertiary amine as an accelerator. The reaction time is between 30 minutes and 3 hours.

3 1425Λ3

In another embodiment of the process, a compound of formula II can be reacted with a compound of formula III in an inert organic solvent in the presence of an amide-accelerating compound such as dicyclohexylcarbodiimide at a temperature between room temperature and reflux temperature of the solvent used and below. using a reaction time of 1-5 hours. In case compound II has a hydroxyl group, it is preferred to protect this group prior to the reaction. Solvents which may be used in the reaction include benzene, toluene, tetrahydrofuran, chloroform, methylene chloride, acetonitrile and the like.

Said hydrolysis of a compound of formula I which has ester groups can e.g. is carried out by the action of a hydroxide or carbonate of alkali metal or alkaline earth metal in water or in an aqueous organic solvent at a temperature of from room temperature to 100 ° C for half to 30 hours. Acylation of the. phenolic hydroxyl groups may be effected by the action of an acid chloride or an acid anhydride of a lower fatty acid at 0-100 ° C for 1-10: hours. Use of a solvent is not necessary, but an inert solvent such as tetrahydrofuran, dioxane or acetone may be used. A basic accelerator such as pyridine, triethylamine or sodium acetate or an acidic accelerator such as sulfuric acid or p-toluenesulfonic acid may be suitably used.

If the product has a free carboxylic acid group, a pharmacologically acceptable salt thereof can be used for the same purpose as the product.

The compounds of formula I have characteristic biological effects, especially on antigen-antibody reactions. It is e.g. observed in in vitro experiments that the water-soluble compounds of formula I can inhibit even very small amounts of red blood cell haemolysis, which occurs by reaction between the red blood cells and anti (sheep red blood cells) in the presence of complement (immune hemolysis). In animal studies, the compounds of formula I greatly inhibit cutaneous anaphylactic reaction by oral administration at a dose up to 100 mg / kg.

The compounds of fomel I not only inhibit such immune responses as indicated above, but also have an antipyretic, sedative, anti-inflammatory and antiallergic effect. The compounds are particularly useful for treating diseases caused by immunological disorders, e.g. rheumatic arthritic, bronchial asthma and nephritis.

The invention is further illustrated by the following experiments and examples.

4 142543

Experiment 1 Inhibition of heat-induced hasholysis.

Red blood cells from a male Wister-Imamichi rat were suspended in 0.15 M phosphate buffer (pH 7.4) to obtain a 1% red blood cell suspension. Into a test tube was introduced 5 ml of the suspension and then 0.1 mm 10% solution of dimethyl sulfoxide in ethanol containing the compound to be tested and then incubated at 53 ° C for 20 minutes. The test tube was then cooled with water and the contents of the tube were centrifuged at 2000 rpm. minute for 10 minutes. The optical density of the Upper Liquid thus obtained was measured with a Hitachi-124 spectrophotometer at 540 ιαχύ. The inhibition of hemolysis was calculated from the equation below.

Hemolysis Inhibition (%) = (Absorption of Incubated Absorption of Unincubated \ Suspension Containing - Suspension without Sample Compound \ Sample Compound 1 ------- x 100 Absorption of Incubated Absorption of Unincubated Suspension without Sample Suspension without trial connection /

The results are shown in Table 1 below.

Table 1

Compound Hemolysis inhibition

Compound of Example 1 +++ II II "2 +++ II II II 3 ++.

tt n n 4 + 4- II II II 5 -HH *

II il ti 6 -f + T

11 II II 7 -H- ii ii "8 +++ µ ir ii 9 +" II 1 '10 ++ II ii n il + ii it ii 12 + ii ti ii 13 + ii ii ii 14 ++ ii ii " 17 ++ t 5 142543

Table 1 (continued)

Connection Haano bright haggling

Compound of Example 18 ++ T

ti π ii 19 +++ ii '' "20 +" "" 22 + "" "23 ++

Benzidamine +

phenylbutazone

Salicylic acid N- (2,3-xylyl) -anthranilic acid + +++: Over 80% inhibition at 1 x 10 -½-H-T: Ga. 50% hamstring at 1 x 10-½

("Less than 20% inhibition at 1 x 10-½ or (. Over 80% inhibition at 1 x 1 (T4M

-4

+: Go. 50% inhibition at 1 x 10 M

-4

Less than 20% inhibition at 1 x 10 M

Experiment 2 Inhibition of hemolysis induced by immune response.

The following four solutions were prepared.

A. Antiserum solution.

Commercially available sheep blood was washed 3 times with a physiological saline solution and centrifuged at 2000 rpm. minute for 5 minutes. One ml of precipitated blood cells was resuspended in 10 ml of physiological saline solution. The resulting solution was injected intravenously into mice (IV cs 5W) at a dose of 0.2 ml, and 4 days after injection a blood sample was taken from the mice. From this sample, serum containing anti (sheep blood cell) antibody was recovered and to obtain an anti-serum solution diluted to 40 times * · ++ the original volume with a solution hereinafter referred to as GVB, which is a buffer solution having a pH of 7.5 and containing gelatin, Ca and Mg. This buffer solution is prepared from the following ingredients: 5,5-diethylbarbituric acid 0.575 g.

sodium - 5.5 diethyl barbiturate 0.375 g

CaCl 2, 2H 2 O 0.022 g

MgCl2, 6H2O 0.1017 g gelatin 1 g

NaCl 8.5 g of 6 U2543 distilled water in 1 liter.

B. Complement solution.

As a source of complement, guinea pig serum was used. Guinea pig serum became

I I

diluted to 40 times its original volume with (GVB) to obtain a complement solution. All processes of preparing the solution were carried out under cooling.

C. Blood cell suspension.

-hI ·

Blood cells were suspended in GVB. 0.25 ml of the suspension was completely hemolysed with water to a volume of 3.3 ml. Then, the resulting suspension was prepared such that the optical density became 0.455 at 541n 2 at the end of hemolysis.

D. Sample Solution.

-H-

The compound to be tested was dissolved in GVB to obtain a concentration 1.5 times greater than the predetermined final concentration.

To 2 ml of the sample solution was added 0.5 ml of the antiserum solution, 0.25 ml of blood cell suspension and 0.25 ml of the complement solution, and the mixture was incubated at 27 ° C for 40 minutes. Then 0.3 ml of 3.8% aqueous trisodium citrate solution was added to the reaction mixture to complete the reaction. Non-hemolysed blood cells were separated from the mixture by centrifugation for 5 minutes at 2000 rpm. minute. The absorption of the upper fluid was measured at 541 mfi ·.

Separately, a control experiment was performed in a similar manner as stated above

j J

with the exception that 2 ml of non-test compound GVB was used.

In addition, a blank test was performed on each experiment following the same method + 4 method as stated above with the exception that 0.25 ml GVB was used instead of 0.25 ml of the complement solution and test errors caused by staining the sample solution were corrected. .

The hemolysis inhibition (%) was calculated according to the following equation: Hemolysis inhibition (%) = / Absorption of sample Absorption of equivalent- containing sample-containing blank sample \ binding \ I -----—- x 100

absorption of control- absorption of control- I

the sample - the sample at blank test time

The results obtained are listed in Table 2 below.

7 142543

Table 2

Compound Hamolysis Inhibition

Compound of Example 1 +++ »» "2 +++" "" 8 +++ N- (2,3-xylyl) -anthranilic acid +

Disodium Chromoglycate +

salicylic acid

Phenylbutazone ++

Above 50% inhibition at 3.5 x 10 ~ ^ M or over 80% inhibition at 8.8 x 10-½ ++: 50-80% inhibition at 8.8 x 10_Sl -4

+: 20-50% inhibition at 8.8 x 10 M

-4

Below 20% inhibition at 8.8 x 10 M

Example1 1

A solution of 17.5 g of 2-acetoxybenzoyl chloride in 20 ml of dioxane was added at once to a mixture of 4.6 g of 3,5-diaminobenzoic acid, 15.3 g of potassium acetate and 80 ml of water while stirring at a temperature of between 0 and 5 ° C. Stirring was continued at this temperature for 1 hour, then at room temperature for 30 minutes and at 50 ° C for 30 minutes. The resulting reaction mixture was added to 20 ml of cold dilute hydrochloric acid and no solute was separated. This dust was dissolved in ca. 100 ml of 1N aqueous NaOH solution, and then the solution was treated with activated charcoal and acidified with hydrochloric acid to give a pH of 3-4, thereby separating crystals. The crystals were removed and washed with water. Recrystallization from methanol-water gave 7.2 g of 3,5-bis (salicylamido) benzoic acid, m.p. between 305 and 308 ° C (dec.).

Analysis:

Calculated: C 64.3, H 4.1, N 7.1 (%)

Found: C 64.5, H 4.1, N 7.1 (%)

Example 2

A solution of 17.2 g of 2-acetoxybenzoyl chloride in 20 ml of dioxane was added at once to a mixture of 4.6 g of 3,4-diaminobenzoic acid, 15.3 g of potassium acetate and 70 ml of water under stirring at a temperature of between 0 and 5 ° C, followed by stirring at this temperature for 30 minutes. To the mixture was added a solution of 1 g of 2-acetoxybenzoyl chloride in 3 ml of dioxane. The resulting mixture was stirred at room temperature for 30 minutes and then at 50 ° C for 30 minutes.

U 2543 8

The reaction mixture was added to 200 ml of cold dilute hydrochloric acid, and the undissolved mixture of oil and powdered solid was isolated. The mixture was dissolved in ca. 100 ml of aqueous 1 N sodium hydroxide solution, and the solution is treated with activated charcoal and then acidified to separate crystals. The crystals were recovered by filtration and washed with water. Recrystallization from a mixture of dioxane and water gave 6.9 g of 3,4-bis (salicylamido) benzoic acid, m.p. 305-307 ° C (dec.).

Analysis:

Calculated: G 64.3, H 4.1, N 7.1 (7 =)

Found: C 64.4, H 4.1, N 6.8 (%)

Example 3

A mixture of 3.32 g of methyl 2,5-diaminobenzoate, 5.8 ml of triethylamine and 20 ml of tetrahydrofuran was added dropwise to a solution of 8.7 g of 2-acetoxybenzoyl chloride in 150 ml of tetrahydrofuran over 30 minutes. stirring at 5-10 ° C. After completion of the addition, the mixture was stirred at room temperature for 1 hour and then poured into 500 ml of ice water to separate crystals. The crystals were recovered by filtration, washed with water and dried in air. Recrystallization from ethyl acetate gave 8.1 g of methyl 2,5-bis (2 * -acetoxybenzamido) benzoate with a m.p. 170-171 ° G.

Analysis:

Calculated: G 63.7, H 4.5, N 5.7 (7.)

Found: C 63.5, H 4.6, N 5.7 (%)

Example 4 In 150 ml of methanol was dissolved 5.3 g of methyl 2,5-bis (2'-acetoxybenzamido) benzoate prepared as described in Example 3. To the solution was added 2.5 g of sodium carbonate dissolved in 40 ml of water, and then the mixture was stirred at room temperature for 30 minutes. The mixture was poured into 500 ml of water containing 10 ml of acetic acid to separate crystals. The crystals were recovered by filtration, washed with water, dried and recrystallized from ethyl acetate to give 3.8 g of methyl 2,5-bis (salicylamido) benzoate, m.p. between 243-244 ° G.

Analysis:

Calculated: G 65.0, H 4.5, N 6.9 (7.)

Found: G 65.1, H 4.6, N 7.0 (7.) 9

Example1 5

An aqueous solution of 4 g of sodium hydroxide in 10 ml of water was added to a mixture of 5.3 g of methyl 2,5-bis (2, -acetoxybenzamido) benzoate, prepared as described in Example 13, and 100 ml of methanol. The resulting mixture was stirred at room temperature for 20-30 hours and then poured into 500 ml of water containing 10 ml of acetic acid to separate crystals. The crystals were recovered by filtration, washed with water and rank crystallized from a mixture of dioxane and water to give 3.5 g of 2,5-bis (salicylamido) benzoic acid, m.p. between 280 and 283 ° C (dec.).

Analysis:

Calculated: C 64.3, H 4.1, N 7.1 (%)

Found: C 64.3, H 4.0, N 6.9 (%)

Example 6

A mixture of 6.64 g of methyl 2,4-diaminobenzoate, 11.5 ml of diethylamine and 50 ml of tetrahydrofuran was added dropwise to a solution of 17.4 g of 2-acetoxybenzoyl chloride in 300 ml of tetrahydrofuran over 1/2 -1 hour, with stirring at 5-10 ° C. Stirring was then continued at room temperature for 2 hours. The resulting reaction mixture was poured into 10.5 liters of dilute hydrochloric acid to separate crystals. The crystals were recovered by filtration, washed with water, dried and rank crystallized from ethyl acetate to give 10 g of methyl 2,4-bis (2'-acetoxybenzamido) benzoate with m.p. 143-145 ° C.

Analysis:

Calculated: G 63.7, H 4.5, N 5.7 (%)

Found: C 63.5, H 4.3, N 5.6 (%)

Example 7 In a similar manner to Example 4, methyl 2,4-bis (2'-acetoxybenzamido) benzoate was hydrolyzed by sodium carbonate to give crystals. Recrystallization of the crystals from a mixture of acetone, dioxane and water gave methyl 2,4-bis- (salicylamido) benzoate, mp 259-260 ° C (Yield 82%) ·

Analysis:

Calculated: G 65.0, H 4.5, N 6.9 (%)

Found: C 65.1, H 4.4, N 6.8 (%) in 142543

Example 8 In a similar manner as described in Example 5, 2,4-bis (2'-acetoxybenzamido) benzoate, prepared as described in Example 6, was hydrolyzed by sodium hydroxide. Recrystallization of the hydrolyzed product from a mixture of dioxane and water gave 2,4-bis (salicylamido) benzoic acid, m.p. between 250-252 ° C (dec.). (Yield 85%).

Analysis:

Calculated: C 64.3, H 4.1, N 7.1 (%)

Found: G 64.1, H 4.2, N 6.9 (%)

Example 9

A solution of 3.86 ml of phosphorus oxychloride in 20 ml of tetrahydrofuran was added dropwise to a mixture of 3.3 g of methyl 2,4-diaminobenzoate, 6.7 g of 2-methoxybenzoic acid, 1.8 g of triethylamine and 100 ml of tetrahydrofuran. over 1-2 hours with stirring at -10 to -5 ° C followed by stirring at room temperature for 1 hour. The resulting mixture was then poured into 1 liter of ice water to precipitate crystals. The crystals were recovered by filtration, washed with water, dried and recrystallized from ethyl acetate to give 7.2 g of methyl 2,4-bis (2, -methoxybenzamido) benzoate, m.p. 166-167 ° C.

Analysis:

Calculated: C 66.4, H 5.1, N 6.5 (%)

Found: C 66.6, H 5.1, N 6.5 (%)

Example 10 5 g of methyl 2,4-bis (2'-methoxybenzamido) benzoate, prepared as described in Example 9, were mixed with 250 ml of dioxane, 3 g of potassium hydroxide and 50 ml of water, and the mixture was stirred at room temperature for 20 minutes. -30 hours. The mixture was then poured into 1.5 ml of ice water containing 20 ml of acetic acid to separate crystals. The crystals were recovered by filtration, washed with water and recrystallized from ethanol-water to give 3.6 g of 2,4-bis (2'-methoxy-benzamido) -benzoic acid, m.p. 232-233 ° C.

Analysis:

Calculated: C 65.7, H 4.8, N 6.7 (%)

Found: C 65.4, H 4.9, N 6.7 (%)

Example 11 In 250 ml of tetrahydrofuran were dissolved 2 g of 2,4-diaminobenzamide and 3.7 ml of triethylamine, and to the solution was added dropwise a solution of 4.5 g of 2-methoxybenzoyl chloride in 20 ml of tetrahydrofuran over 1 hour. and then stirred at room temperature for 1 hour. The reaction mixture was then poured into 1.5 liters of dilute hydrochloric acid to separate crystals. The crystals were recovered by filtration, washed with water and recrystallized from a mixture of dimethylformamide and water to give 4.1 g of 2,4-bis (2, -methoxybenzamido) benzamide with m.p. 270-272 ° C (dec.).

Analysis:

Calculated: C 65.9, H 5.1, N 10.0 (%)

Found: C 65.7, H 5.3, N 10.1 (7.)

Example 12 In 40 ml of tetrahydrofuran was dissolved 4.35 g of 2-acetoxybenzoyl chloride and 1.5 g of 3,5-diaminobenzamide was added to the solution. A solution of 3.08 ml of triethylamine in 10 ml of tetrahydrofuran was added dropwise to the reaction mixture over 1.5 hours with stirring at room temperature followed by stirring at room temperature for 2 hours. The reaction mixture thus obtained was poured into 300 ml of cold dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallization of the residue from hot benzene gave 2.1 g of 3,5-bis (2'-acetoxybenzamido) benzamide with a m.p. above 105 ° C (dec.).

Analysis:

Calculated: C 63.2, H 4.5, N 8.8 (%)

Found: C 63.0, H 4.4, N 8.6 (%)

Example 13 In a similar manner as described in Example 4, 3,5-bis (2'-acetoxybenzamido) benzamide prepared as described in Example 12 was hydrolyzed with sodium carbonate. Recrystallization of the hydrolyzed product from a mixture of ethanol and water gave 3.8-bis (salicylamido) benzamide, m.p. 276-277 ° C.

(Yield 83%).

Analysis:

Calculated: C 64.4, H 4.4, N 10.7 (%)

Found: C 64.1, H 4.7, N 10.7 (%)

Example 14

A solution of 16.2 g of 2-methoxybenzoyl chloride in 40 ml of dioxane was added dropwise to a mixture of 4.6 g of 3,5-diaminobenzoic acid, 15.3 g of potassium acetate and 70 ml of water over 30 minutes with stirring at 0 ° C. 5 ° G, followed by stirring at room temperature for 1 hour and then at 50 ° G for 1 additional hour. The reaction mixture was cooled and poured into 100 ml of dilute hydrochloric acid to separate crystals. The crystals were recovered by filtration, washed with water and recrystallized from ethanol to give 6 g of 3,5-bis (2'-methoxybenzamido) benzoic acid, m.p. 253-254 ° C.

Analysis:

Calculated: C 65.7, H 4.8, N 6.7 (%)

Found: C 65.5, H 4.9, N 6.5 (%)

Example 15 In 200 ml of pyridine was dissolved 8.3 methyl-2,4-diaminobenzoate and to the solution was added a solution of 4.4 ml of phosphorus trichloride in 30 ml of pyridine under ice-cooling and stirred at 50-70 ° C for 1 hour. To the mixture was added 21 g of salicylic acid and then heated to 90 ° C for 3 hours. After cooling the mixture upon standing, solutes were filtered off and the filtrate concentrated under reduced pressure. To the concentrate was added cold dilute hydrochloric acid to separate crystals. The crystals were recovered by filtration, washed with water and recrystallized from an acetone-dioxane-water mixture to give 11.1 g of methyl 2,4-bis (salicylamido) benzoate, m.p. 259-260 ° C.

It was confirmed that the product was identical to the product of Example 7.

Example1 16

By a method similar to that described in Example 15, methyl 2,5-diaminobenzoate was condensed with salicylic acid by phosphorus trichloride to give methyl 2,5-bis (salicylamido) benzoate (yield 54%). The product was found to be identical to that obtained in Example 4.

Example 17 1 g of 3,5-bis (salicylamido) benzoic acid, prepared as described in Example 1, was treated with 30 ml of acetic anhydride and 3 ml of pyridine followed by stirring at room temperature for 3 hours. To the reaction mixture was added 100 ml of ice water to separate crystals which were recovered by filtration. Recrystallization from a dioxane-water mixture gave 0.8 g of 3,5-bis (2 * -acetoxy-benzamido) benzoic acid, m.p. 211-212 ° C (dec.).

13 142543

Analysis:

Calculated: C 63.0, H 4.2, N 5.9 (%)

Found: C 62.8, H 4.4, N 5.7 (%)

Example 18

To a mixture of 4.9 g of 2,4-diaminobenzoic acid, 12 g of sodium acetate, 90 ml of methylene chloride and 90 ml of water was added 19.2 g of 2-acetoxybenzoyl chloride with stirring at 5-10 ° C, followed by continued stirring at 5- 15 ° C for 4 hours.

The separated crystals were recovered by filtration, washed with water and then with methylene chloride and carefully mixed with 70 ml of methanol. To the mixture was added 30 ml of water, and it was left to separate crystals. The crystals were recovered by filtration and recrystallized from 90% aqueous methanol to give 7.5 g of 2,4-bis (2'-acetoxybenzamido) benzoic acid, m.p. 194-195 ° C.

Analysis:

Calculated: C 63.0, H 4.2, N 5.9 (¾)

Found: C 62.7, H 4.1, N 6.0 (%)

Example 19 In a similar manner as described in Example 1, 2,4-diaminobenzoic acid was condensed with 2-ethoxybenzoyl chloride to give 2,4-bis (2'-ethoxybenzamido) -benzoic acid, m.p. 225-226 ° C.

Analysis:

Calculated: C 67.0%, H 5.4, N 6.3 (%)

Found: C 66.7, H 5.5, N 6.0 (%)

Example 20 In a similar manner as described in Example 12, 3,5-diaminobenzamide was condensed with 2-methoxybenzoyl chloride to give 3,5-bis (2'-methoxybenzamido) benzamide with a m.p. 226-227 ° C.

Analysis:

Calculated: C 65.9, H 5.1, N 10.0 (%)

Found: C 65.5, H 5.3, N 10.1 (%)

Example 21 In a similar manner as described in Example 6, ethyl 2,4-diaminobenzoate was condensed with 2-acetoxybenzoyl chloride to give ethyl 2,4-bis (2'-acetoxybenzamido) benzoate with a m.p. 154-155 ° C.

14 142543

Analyset

Calculated: G 64.3, H 4.8, N 5.6 (%)

Found: G 64.4, H 4.9, N 5.5 (%)

Example 22 In a similar manner as described in Example 6, ethyl 2,4-diaminobenzoate was condensed with 2-n-butoxybenzoyl chloride to give ethyl 2,4-bis (2'-n-butoxybenzamido) benzoate with a mp. 134-136 ° C.

Analysis:

Calculated: G 69.9, H 6.8, N 5.3 (%)

Found: G 70.0, H 6.8, N 5.3 (%)

Example 23 In a similar manner to Example 6, n-butyl-2,4-diamino-benzoate was condensed with 2-acetoxybenzoyl chloride to give n-butyl-2,4-bis (21-acetoxybenzamido) benzoate, m.p. 149-152 ° C.

Analysis:

Calculated: C 65.4, H 5.3, N 5.3 (%)

Found: C 65.7, H 5.2, N 5.3 (%)

Example 24 In a similar manner as described in Example 6, ethyl 2,4-diamino benzoate was condensed with 2-ethoxybenzoyl chloride to give methyl 2,4-bis (2'-ethoxybenzamido) benzoate, m.p. 199-200 ° C.

Analysis:

Calculated: C 67.5, H 5.7, N 6.1 (%)

Found: C 67.5, H 5.5, N 6.0 (%)