DE1966212B - Process for the preparation of 5 chlorine 4 amino 2 methoxybenzoic acid and its derivatives excreted from 1960130 - Google Patents

Description

ui the R the OH, OCH ₃ - or

NHCH ₂ CH ₂ N group

to

IO means, characterized in that the corresponding compound of the formula

OCH ₃

NH ₇

in an organic solvent with phenyl iodide chloride chlorinated.

2. The method according to claim 1, characterized in that by slowly adding Phenyl iodide chloride under cooling, especially at Temperatures from 0 to 5 ° C are chlorinated.

3. The method according to claim 1 or 2, characterized in that the chlorination in Presence of a basic agent such as pyridine, quinoline or triethylamine carried out.

The present invention relates to a new process for the preparation of 5-chloro-4-amino-2-methoxybenzoic acid and its derivatives in general
formula

corresponding compound with the formula
CO-R

OCH ₃

35

in which R the OH, OCH ₃ - or

C ₂ H ₅

NHCH ₂ CH ₂ N group
C ₂ H ₅

means that is characterized by the fact that the

40

45

COOH

A-OCH,

(D

COOCH ₃
/ V0CH ₃

NH,

NH,

chlorinated in an organic solvent with phenyl chloride.

According to the process of the present invention, 4-amino-5-chloro-2-methoxybenzoic acid, methyl -A- amino - 5 - chloro - 2 - methoxybenzoate and N- (2-diethylaminoethyl) -4-amino-5-chloro- 2-methoxybenzamide can be produced.

The following reaction scheme shows the preparation according to the invention of + -amino-S-chloro-2-methoxybenzoic acid as reaction I - »II, the preparation of methyl- ^ amino-S-chloro ^ -methoxybenzoate as reaction III - ^v IV and the preparation of N- (2-diethylaminoethyl) -4-amino-5-chloro-2-methoxybenzamide entered as reaction V - »VI.

C ₂ H ₅

CONHCH ₂ CH ₂ N

C ₂ H ₅

(V)

NH ₂

OCH ₃

(Π)

OCH ₃

NH ₂

CONHCH ₂ CH ₂ N

OCH,

C ₂ H ₅

C ₂ H ₅

(VI)

The N - (diethylaminoethyl) - 4 - amino - 5 - chloro-2-methoxybenzamide (VI) is a well-known compound, which is an excellent drug for treatment of functional diseases of the digestive organs, such as vomiting, loss of appetite or Heartburn, is used. The compounds I to V are valuable intermediates from which the compound VI can also be produced.

In the six-step manufacturing process described in French patent specification 1 407 055 of N - (diethylaminoethyl) - 4 - amino - 5 - chloro-2-methoxybenzamide becomes p-amino-salicylic acid too esterified to the methyl ester and then acetylated, methylated and finally to methyl 4-acetamino-5-chloro-2-methoxybenzoate chlorinated. This is then reacted with Ν, Ν-diethylethylenediamine to form N- (diethylaminoethyl) -4 - acetamino - 5 - chloro - 2 - meihoxybenzamide reacted, of which then the acetyl group Will get removed. In the process described there it is necessary to use the amino group during the To protect chlorination. The overall yield after the six process steps according to the process of the French patent is 35.2 ° o.

It is the aim of the present invention. avoid the disadvantages of previous methods.

Thus, it is the object of the invention to provide a better chemically unique process for the preparation of 4-amino-5-chloro-2-methoxybenzoic acid and the derivatives mentioned available, which in a simple We ^; se can be carried out and gives high yields.

According to the information inhouben-Weyl, Methoder der Organischen Chemie, 4th edition, Vol. V 3. 1962. p. 958, occasionally finds phenyl iodide chloride as Chlorinating agent use. However, it is from German 11 investigations by R. N e u (Ber. Vol. 72. 1939. Pp. 1505 to 1512) as well as from (Bei Ist ei η s manual of organic chemistry, 4th edition, second supplementary value, Vol. 5, Berlin, Springer Verlag 1943, p. 167. Paragraph 1) known that side reactions occur in the chlorination of aromatic amines, so that z. B. the formation of dyes takes place in the chlorination of aniline with phenyl iodide chloride. According to the investigations by R. Neu (p. 1512), it is evident in the chlorination of organic amines necessary to protect the amino group by introducing the acetyl group. It must therefore be surprising be considered that in the present case in the chlorination of 4-amino-2-methoxybenzoesäurc and their derivatives with phenyl iodide chloride convert them to 4-amino-5-chloro-2-methoxybenzoic acid or their derivatives run without side reactions and the chlorinated product can be obtained in great purity and high yield can, although the amino group is unprotected during the reaction.

As in performing the method of this invention in contrast to previous methods (see French patent specification 1407 055, p. 1, right column below, example 1 to p. 2, below right, or in British patent specification 1 019 781 there attached formula drawing) the amino group is never protected, by simplification and Substantial improvements were achieved by making manufacturing plants cheaper. In addition, the Surprisingly proceeding reaction obtained the process products in excellent yields. So results in the implementation of the process according to the invention on a laboratory scale yields of 64.8 to 80%, on a factory scale even higher yields were found

Yet another advantage of the process of this invention is that the iodobenzoL which serves as the starting material for the production of the phenyl iodide chloride in the technical implementation of the process is practically completely recovered, so that the chlorination is not very expensive is

The chlorination reaction is carried out using phenyl iodide chloride as a chlorinating agent. The chlorination takes place selectively only in the 5-position, despite the presence of a free one Amino group in the vicinal 4-position.

in one embodiment of reactions I - ♦ II, III - »IV as well as V - * VI of the procedure of the present Invention is the chlorination with phenyl iodide chloride by its dropwise addition to one Solution of I or III or V in a common organic solvent such as acetone or chloroform or tetrahydrofuran with cooling, preferably in the temperature range from 0 to 5 ° C. Phenyl iodine chloride is added slowly, usually over the course of 2 to 4 hours. The addition a basic agent, such as pyridine, quinoline or triethylamine, to the reaction mixture is advantageous, to speed up the chlorination reaction.

The examples illustrate the process of the invention.

example 1
a) Production of phenyl iodide chloride

7u of a mixture of 28 g of iodobenzene and 87 ml of anhydrous tetrahydrofuran are added with stirring at -30 to -40 "C, 9.5 g of liquefied chlorine were added dropwise and the mixture was stirred at -30 ° C. for 2 hours, during which Phenyl iodide chloride separates immediately in the form of yellow crystals and the reaction mixture a sludge-like suspension results.

b) Preparation of 4-methyl-4-amino-5-chloro-2-methoxybenzoate (III - »IV)

To a solution of 3.62 g of methyl 4-amino-2-methoxybenzoate 1.62 g of pyridine were added in 100 ml of anhydrous tetrahydrofuran. To the solution 5.5 g of phenyl iodide chloride was added dropwise over 4 hours with stirring and cooling. Subsequently was stirred for two more hours. After standing in the cold overnight the reaction mixture was concentrated. The residue obtained was then mixed with a mixture of 150 ml of ethyl acetate and 50 ml of distilled water extracted. The ethyl acetate layer was made twice each with 50 ml of 1 normal aqueous hydrochloric acid, 50 ml of 5% aqueous sodium carbonate solution and 50 ml of distilled water and washed dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure.

After adding 50 ml of petroleum ether, the crystalline residue was finely triturated, filtered off and washed with Washed petroleum ether. Recrystallization from methanol gave 3.2 g (75%) IV with a melting point of 135 ° C. 35 g (87%) of phenyl iodide could be recovered from the petroleum ether mixture.

Example 2

Preparation of N- (2-diethylaminoethyl) -4-aramo-5-chloro-2-methoxybenzamide (V - ♦ VI)

To a solution of 450 mg of N- (2-diethyIaminoethyI) -4-ainino-2-methoxybenzamide in 10 ml of acetone, 470 mg of phenyl iodide chloride were added dropwise Stir and ice cooling added over 3 hours. After stirring for a further 30 minutes, the acetone was released from the reaction mixture Evaporation under reduced pressure removes excess Phenyliodide chloride was removed from the residue by steam distillation obtained aqueous solution was made basic by adding 300 mg of sodium bicarbonate and with a small amount of chloroform. The extract was extracted with 5% aqueous sodium carbonate solution and water, then dried over anhydrous magnesium sulfate and reduced under reduced pressure Pressure restricted. The crystalline crude product resulted after recrystallization from ethyl acetate and petroleum ether 370 mg (73%) VI with a melting point of 143 to 144.5 ° C.

Example 3

Preparation of N- (2-diethylaminoethyl) -4-amino-5-chloro-2-methoxybenzamide (V -> VI)

To a solution of 0.77 g of N, N-diethylaminoutyl-4-amino-2-methoxybenzamide in 20 ml of chloroform, 0.81 g of phenyliodine chloride was added dropwise over 4 hours while cooling with ice. The reaction mixture was washed with 5 ml of 5% aqueous sodium bicarbonate solution and 5 ml of water and dried over anhydrous magnesium sulfate. The reaction mixture was then passed under reduced pressure. ¹ Ck concentrated to a crystalline crude product. Recrystallization from ethyl acetate gave 0.65 g (75%) VI with a melting point of 143 to 144.5 ° C.

Analysis: for C ₁₄ H ₂₂ NjO ₂ Cl will

Calculated ... C 56.09, H 7.40, N 14.02%;
found .... C 56.11, H 7.32, N 13.88%.

Example 4

production of 4-amino-5-chloro-2-methoxybenzoic acid (I - ► II)

To a solution of 167 mg of 4-amino-2-ynethoxybenzoic acid in 5 ml of anhydrous acetone, 138 mg of phenyliodine chloride were added dropwise with stirring and ice-cooling over a period of 4 hours. After standing in the cold overnight, 89 mg of 4-amino-2-methoxybenzoic acid hydrochloride had precipitated and were filtered off. The filtrate was concentrated under reduced pressure to give a crystalline residue. After adding 5 ml of distilled water, the crystalline residue was triturated, filtered and washed with water. The obtained white crystals were dissolved in 30 ml of ethyl acetate, washed xt / once with 10 ml each of 1 normal aqueous hydrochloric acid and 10 ml of distilled water, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure. 71 mg (71%) II were obtained as white crystals with a melting point of 208 ° C.

Analysis: For C ₈ H ₈ NO ₃ Cl will

· Calculated ... C 47.66, H 4.00, N 6.95%;
found .... C 47.65, H 3.85, N 6.78%.

Example 5

Production of Φ-2-methoxybenzoic acid (I - * II)

In a solution of 167 mg + -amino - ^ - methoxybenzoic acid in 5 ml of anhydrous acetone was 138 mg of phenyliodine chloride dropwise with stirring and

Ice cooling added within 4 hours. After standing in the cold overnight, it was 87 mg 4-Amino-2-methoxybenzoic acid hydrochloride precipitated and were filtered off. The filtrate was concentrated under reduced pressure and a crystalline one Obtain residue. After adding 5 ml of water, the crystalline residue was triturated and filtered and washed with water. The white crystals obtained were dissolved in 30 ml of ethyl acetate, twice with 10 ml of 1 normal aqueous chlorine

hydrochloric acid and 10 ml of water, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and 70 mg (70%) III as white crystals with a melting point of 208 to 209 "C obtained.

Analysis: For C ₈ H ₈ NO ₃ Cl will

Calculated ... C 47.66, H 4.00, N 6.95%;
Found ... C 47.65, H 3.85, N 6.78%.

B e i s ρ i e 1 6

Preparation of 4-amino-5-CiiIor-2-methoxybenzoic acid (I - ♦ II)

In a solution of 2.76 g of 4-amino-2-methoxybenzoic acid in 100 ml of anhydrous tetrahydrofuran there were 1.62 g of pyridine and 5.5 g of phenyliodine chloride added dropwise with stirring and ice cooling over 4 hours and then for a further 2 hours additionally stirred. After standing in the cold overnight, the reaction mixture was concentrated; the residue was then extracted with a mixture of 950 ml of ethyl acetate and 50 ml of water. the Äthylacetatr-chicht was twice with 50 ml 1 normal aqueous hydrochloric acid and 50 ml of water. Then it was poured over anhydrous sodium sulfate dried. The solution was concentrated under reduced pressure and the crude product obtained in crystal form. After adding 50 ml of petroleum ether, the crude product was finely ground, filtered off and washed with petroleum ether. It was recrystallized from methanol. 2.40 g (72%) II obtained as white crystals with a melting point of 208 to 209 "C.

Example 7

Production of 4-amino-5-chloro-2-methoxybenzoic acid (I - * II)

To a solution of 2.76 g of 4-amino-2-methoxybenzoic acid and 1.62 g of pyridine in 100 ml of anhydrous tetrahydrofuran was added dropwise 4.6 g of phenyliodine chloride over the course of 2 hours with stirring and cooling at temperatures between 3 to 5 "C

added. Stirring was continued for another 3 hours at the same temperature. Then the reaction mixture was concentrated under reduced pressure. The residue obtained was extracted with a mixture of 15 ml of petroleum ether and 40 ml of 1 normal aqueous sodium hydroxide solution. The obtained aqueous layer was separated and treated with activated charcoal. The pH of the resulting adverse solution was adjusted to 2 by adding 18% aqueous hydrochloric acid. The crystal precipitated was separated by filtration and dried under reduced pressure. 2.4 g of 4-amino-5-chloro-2-methoxybenzoic acid with a melting point of 200 to 207 ^° C. were obtained, corresponding to a yield of 71.5%.

Example 8

Production of 4-amino-5-chloro-2-methoxybenzoic acid (I - »II)

The procedure was as indicated in Example 7, but acetone was used instead of tetrahydrofuran used as a solvent. It became 4-amino-5-chloro-2-methoxybenzoic acid with a melting point of 190 to 192 ° C in a yield of 65.5% receive.

Example 9

Preparation of methyl ^ amino-S-chloro-2-methoxybenzoate (III - + IV)

21.7 g of methyl 4-amino-2-methoxybenzoate were dissolved in 600 ml of anhydrous tetrahydrofuran at 30 ° C. with stirring, and 9.7 ml of anhydrous pyridine were added to the solution. While this solution was stirred and cooled to -20 ° C., a slurry-like suspension of phenyl iodide chloride in tetrahydrofuran was slowly added, the mixture was stirred for a further 3 hours at -20 ° C., then slowly warmed to room temperature and left to stand overnight at room temperature. The tetrahydrofuran was distilled off with stirring at 60 to 70 ° C. and under reduced pressure from the light yellow-brown solution obtained as a mixture with white crystals and a light brown, clear, viscous mass was obtained as a residue isolate, this residue is first extracted with a mixture of ethyl acetate and water and worked up further as indicated in Example 1. IV was obtained in a yield of 75% with a melting point of 135 ° C.

Example 10

Production of methyl- ^ amino-S-chlorine-
2-methoxybenzoate (III - IV)

To a solution of 83 g of methyl 4-amino-2-methoxybenzoate in 180 ml of anhydrous acetonitrile was added 4.5 ml of pyridine. To the solution, 12.6 g of phenyl iodide chloride were added in one portion with stirring at room temperature. The mixture was stirred for a further 2 hours. After standing overnight at room temperature, the reaction mixture was concentrated. The residue obtained was then extracted with a mixture of 350 ml of ethyl acetate and 100 ml of distilled water. The ethyl acetate layer was washed twice each with

100 ml of 1 normal aqueous hydrochloric acid, then with 100 ml of 5% aqueous sodium carbonate solution washed and finally washed with 100 ml of distilled water. ' Then the ethyl acetate solution dried over anhydrous sodium sulfate. The solution was made under reduced pressure constricted. After adding 100 ml of petroleum ether, the crystalline residue was finely triturated and nitrated and washed with petroleum ether. A crystalline product was obtained. After recrystallization 7.9 g (yield: 80%) IV with a melting point of 134 ° C. were obtained from methanol.

Example 11

Production of
2-methoxybenzoic acid (I.

♦ II)

To a solution of 500 mg of 4-amino-2-methoxybenzoic acid in 10 ml of anhydrous tetrahydrofuran, 0.12 ml of triethylamine and 205 mg of phenyl iodide chloride were added while cooling with ice. The mixture was stirred at the same temperature for 40 minutes. 0.1 ml of triethylamine and 205 mg of phenyl iodide chloride were added to the reaction mixture and stirring was continued for 40 minutes . This addition of 0.1 ml of triethylamine, 205 mg of phenyl iodide chloride and the stirring for 40 minutes were then repeated twice (three times in total). The reaction mixture was then stirred for a further 1 hour at room temperature.

The reaction mixture thus obtained was concentrated under reduced pressure. The residue obtained was dissolved in 7 ml of 1N aqueous sodium hydroxide solution. The aqueous solution was washed with 15 ml of ether and treated with activated charcoal. The pH of the aqueous solution was adjusted to 2 by adding 1N hydrochloric acid. The precipitated crystals were separated by filtration and dried. 390.8 mg (yield: 64.8%) of 4-amino-5-chloro-2-methoxybenzoic acid with a melting point of 189 to 194 ° C. were obtained.

Example 12

Production of 4-amino-5-chloro-2-methoxybenzoic acid (I - » II)

To a solution of 2.76 g of 4-amino-1- methoxybenzoic acid and 1.62 g of pyridine in 100 ml of anhydrous acetonitrile , 4.6 g of phenyliodide chloride were added dropwise over the course of 2 levels of outer tubes and the temperature was maintained between 3 and 3 by cooling 5 ° C, added. The mixture was continued overnight in the specified temperature range.

SS stirred. Then the reaction mixture was concentrated under reduced pressure. The residue obtained was extracted with a mixture of 15 ml of petroleum ether and 40 ml of 1 normal aqueous sodium hydroxide solution. The aqueous layer was separated and treated with activated charcoal. The pH of the resulting aqueous solution was adjusted to 2 by adding 1.5% aqueous hydrochloric acid. The precipitated crystals were separated by filtration and dried under reduced pressure was 23 g (yield: 68%) of 4-amino-5-chloro-2-methoxybenzoesäare fed a melting point VOA I9S to 200 ⁰ C obtained.

209553532

Claims (1)

Patent claims: 1. Process for the preparation of 5-chloro-4-amino-2-methoxybenzoic acid and their derivatives of the general formula CO-R OCH ₃