CS200532B2 - Method of producing 5-amino-2-propargyloxy-n-n-butylbenzamide - Google Patents

Abstract

After 5-nitro-2-chlorobenzoic acid has been converted to 5-nitro-2-propargyloxy-N-n-butylbenzamide, the latter product is subjected to the action of a reducing agent to produce 5-amino-2-propargyloxy-N-n-butylbenzamide. This benzamide has antiinflammatory, analgesic and muscle-relaxing properties.

Description

The invention relates to a process for the preparation of 5-amino-2-propargyloxy-N-n-butylbenzamide as well as a process for the preparation of the intermediate used in the preparation of the above benzamide.

Swiss Patent 517 701 describes a process for the preparation of 2-hydroxy-5-aminobenzamide derivatives of the following general formula II:

in which

R represents an allyl or propargyl group,

R 1 represents a hydrogen atom or a lower alkyl group,

R 5 represents a lower alkyl group, a lower alkenyl group or a cycloalkyl group having a total number of carbon atoms of 3 to 6, wherein:

R 1 and R 5 can form, with the nitrogen atom to which they are attached, an N-heterocyclic group selected in particular from the group consisting of a pyrrolidine residue, a piperidine residue and a morpholine residue, and at least one of the general substituents,

R3 and R4 represent a hydrogen atom, the other of which may be a chlorine atom or a methyl group.

The above-mentioned products of the general formula II and in particular 5-amino-2-propargyloxy-N-n-butylbenzamide:

R = CH 2 —C = CH, R 1 = H, R 5 = n-butyl, and R 3 = R 4 = H, which has been internationally designated "parsalmide", have anti-inflammatory, analgesic and myo-relaxing activity (Bol. Chim. Farm. 115) 125, 1976).

According to the aforementioned method, mentioned in. Swiss Patent No. 517 701, 5-amino-2-propargyloxy-N-n-butylbenzamide is prepared by hydrolysis of the corresponding 5-acetamidobenzamides of formula III

CH.CONH

in which

R 1, R 1, R 2, R 3 and R 6 are as defined above in Chim. Ther. 1968 (3), 200.

The literature suggests that 5-amino-2-propargyloxy-N-n-butylbenzamide (Formula I) is in particular obtained from 2-acetoxy-5-acetamidobenzoic acid according to the following Reaction Scheme A.

It has the essence of being an acid

5-Nitro-2-chlorobenzoic acid is converted to 5-nitro-2-chloro-Nn-butylbenzamide by treatment with n-butylamine and the product thus obtained is treated with propargyl alcohol in the presence of a basic condensation agent, followed by 5-nitro-2-propargyloxy- N-butylbenzamide is subjected to the action of a reducing agent acting by an oxidation-reducing mechanism.

The reaction of propargyl alcohol with 5-nitro-2-chloro-N-n-butylbenzamide is preferably carried out in the presence of an excess of propargyl alcohol, which serves as both the solvent and the reagent.

Iron oxide powder in the presence of hydrochloric acid is preferably used as the reducing agent acting by the redox mechanism.

It should be noted that 5-nitro-2-propargyloxy-N-n-butylamide (IX) is a new chemical compound.

The process of the invention can be illustrated by the following Scheme B.

Scheme В

C O-NH- ** ** Qfty осилен (VI) coou

(VID (SOCtJ (Ct-COOC ^))

Cl ⁴³

CH 2 CONH

N0 / | CHEC-CH3H

C0-ND-n ~ C _for D ₃

O-CH3C-CD

l

CO-NH-n-Cl

OCH £ * CM

(IX)

It has now been found that 2-propargyloxy-5-amino-N-butylbenzamide can be prepared in three stages in excellent yield using 5-nitro-2-chlorobenzoic acid as a starting material, which is cheaper than the 2-acetoxy- 5-acetamidobenzoic acid; less expensive reagents and novel intermediates are also used in this new process.

The present invention provides a process for the preparation of 5-amino-2-propargyloxy-N-n-butylbenzamide,

5-Nitro-2-chlorobenzoic acid VII is converted to 5-nitro-2-chloro-N-n-butylbenzamide VIII by reaction with an n-butylamine amidation procedure using, for example, an acid chloride or mixed acid anhydride.

In acid chloride methodology, a suspension of 5-nitro-2-chlorobenzoic acid in thionyl chloride is heated, and after removal of excess thionyl chloride, the residue is dissolved in an inert organic solvent such as methylene chloride, chloroform, benzene, toluene or hexane. The solution thus obtained is added to a solution of n-butylamine and a mineral or organic base, such as sodium or potassium hydroxide, tertiary amine or an excess of n-butylamine, in the same solvent used for starting acid chloride, optionally in the presence of water.

The thus isolated 5-nitro-2-chloro-N-n-butylbenzamide of formula VIII is isolated by neutralizing the alkaline medium with a mineral or organic acid, such as hydrochloric acid, and evaporating the solvent.

When mixed anhydride is used, n-butylamine is treated with a mixture of 5-nitro-2-chlorobenzoic acid starting material, triethylamine and ethyl chloroformate in an inert organic solvent such as methylene chloride at a temperature of from -10 ° C to a temperature of Surroundings.

The reaction is complete after 1 to 5 hours and 5-nitro-2-chloro-N-n-butylbenzamide of formula VIII can be isolated by evaporation of the solvent and recrystallization of the residue. The product of formula VIII has not been previously described in the literature.

The thus obtained 5-nitro-2-chloro-N-h-butylbenzamide, either raw or purified, is treated with propargyl alcohol in the presence of a condensing agent such as sodium hydride, sodium amide or sodium metal. The reaction is carried out at 15 to 70 ° C in an organic solvent such as benzene, toluene tetrahydrofuran and dioxane.

The 5-nitro-2-propargyloxy-N-n-butylbenzamide of formula IX, which is obtained after completion of the reaction, is isolated in a conventional manner.

In a preferred embodiment of the process of the invention, the reaction is between 5-nitro-2-chloro-N-. The n-butylbenzamide of formula VIII and propargyl alcohol are carried out using an excess of propargyl alcohol, which then plays both the solvent and the reactants.

5-Nitro-2-propargyloxy-N-butylbenzamide of formula (IX) is a novel compound which is a novel intermediate which underlies the novel reaction scheme of the process of the invention. This compound has the advantage over the starting compound used in the process described in Swiss Patent Specification No. 517,701 (a compound of formula VI) that it can be prepared in virtually quantitative yield from 5-nitro-2- acid. chlorobenzoic. It is therefore a very inexpensive product which makes it possible to significantly reduce the production costs of the production of 5-amino-2-propargyloxy-N-n-butylbenzamide of the formula I.

In addition, 5-nitro-2-propargyloxy-N-n-butylbenzamide is a product that crystallizes very easily and can thus be easily purified. In addition, it is not toxic (its lethal dose of DLo in mice is greater than 750 mg / kg when administered orally) and does not have the hypothesized hypnotic effect that it possesses to barbiturates, as the aforementioned known product of formula VI.

The 5-nitro-2-propargyloxy-N-n-butylbenzamide IX thus obtained is then reduced using reducing agents to determine the oxidation-reducing mechanism, which is usually used to convert aromatic nitro and aromatic amino groups.

As the reducing agents determining the redox mechanism, transition elements or derivatives of elements capable of switching from lower to higher valency in the presence of a nitro group may be used.

Examples of said reducing agents include:

zinc, cuprous chloride, aluminum amalgam, thallium chloride, stannous chloride, titanium tetrachloride, ammonia, hydrazine or substituted hydrazine, especially phenylhydrazine, phosphine, arsine, hydrogen sulfide and its salts, sulphite or acid sulphite, especially sodium sulphite, dithionite, especially dithionite sodium, iron or divalent salts thereof, in particular ferrous hydroxide, ferrous chloride and ferrous sulphate.

The reducing agents are used in the presence of an activating agent. In particular, the metals and their salts are activated by the action of mineral or organic acids, preferably using hydrochloric acid and sulfuric acid, while the non-metallic elements and their derivatives are activated by the action of metals or the alkalinity of the environment.

According to a preferred embodiment of the process according to the invention which is simple, rapid and inexpensive, the reduction is carried out using iron in the presence of hydrochloric acid as reducing agent.

In this embodiment, dilute hydrochloric acid and iron powder in an organic solvent, such as preferably ethanol, are slowly added to the slurry heated to reflux.

The reduction is complete after 30 to 90 minutes of heating. Excess iron and formed ferrous chloride and ferric chloride are removed by addition of alkali metal hydroxide or carbonate and filtration. Thereafter, the pH of the filtrate is adjusted to 2-3 by addition of concentrated hydrochloric acid, whereupon 5-amino-2-propargyloxy-N-n-butylbenzamide of formula I is eliminated by adding 10-20% alkali metal hydroxide flux until a pH of 5-6 is reached.

In order to further elucidate the process of the invention, several examples are set forth below.

He did

and)

5-Nitro-2-chloro-N-n-butylbenzamide (VIII)

A mixture of 100 g of 5-nitro-2-chlorobenzoic acid and 80 g of thionyl chloride is heated with stirring for 3 hours, and then excess thionyl chloride is removed under reduced pressure. To the residue was added 100 ml of chloroform, and 250 mg of a 2 N sodium hydroxide solution was added. The reaction mixture is cooled to 5 DEG C. and a mixture of 40.15 g of n-butylamine, 200 ml of water and 200 ml of chloroform is added dropwise at the same temperature.

The reaction mixture is then stirred until it reaches ambient temperature and the pH is adjusted to 7 by the addition of concentrated hydrochloric acid. The solvent was evaporated under reduced pressure, 1 liter of water was added to the residue, and the mixture was filtered. and the solid is washed with water and then with 5% sodium bicarbonate solution and finally with water and finally with pethol ether.

After drying over phosphorus pentoxide, 119 g of 5-nitro-2-chloro-N-n-butylbenzamide are obtained.

M.p.

136 ° C.

(b)

5-Nitro-2-propargyloxy-N-n-butylbenzamide (IX)

To a suspension of 2.6 g of sodium hydride (55-60% in mineral oil) in 20 ml of anhydrous tetrahydrofuran was added at ambient temperature 3.5 ml of propargyl alcohol dissolved in 20 ml of anhydrous tetrahydrofuran. Once hydrogen evolution ceased, a solution of 13.8 g of 5-nitro-2-chloro-N-n-butylbenzamide in 80 ml of anhydrous tetrahydrofuran was added slowly to the reaction mixture. The reaction mixture is left at room temperature for 3 hours, then the solvent is evaporated. Water was added to the residue, the mixture was filtered and the solid was washed with water.

Recrystallization from isopropanol gave 13.2 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide.

Melting point 115-117 ° C.

cl

5-Amino-2-propargyloxy-N-n-butylbenzamide (I)

To a solution of 9 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide in 35 ml of ethanol (75%) was added 5.45 g of iron powder. 19 ml are added dropwise to the suspension heated to reflux

2.5 N hydrochloric acid is added and the reaction mixture is further refluxed for one hour.

The alcoholic solution was then basified with 15% potassium hydroxide solution, then the mixture was filtered hot and the pH of the filtrate adjusted to 2.5 N with concentrated hydrochloric acid. Then the acidified filtrate is concentrated under reduced pressure. '

Water was added to the residue, and the resulting suspension was decolorised with activated charcoal and filtered. The pH of the solution was then adjusted to 5-6 with a 15% sodium hydroxide solution. The mixture was filtered and the solid washed with water. 6.2 g of 5-amino-2-propargyloxy-N-n-butylbenzamide are obtained.

The melting point of this product is 83-85 degrees Celsius.

Example 1 a d 2

(a) 5-nitro-2-chloro-N-n-butylbenzamide (VIII)

A suspension of 100 g of 5-nitro-2-chlorobenzoic acid in 80 ml of thionyl chloride is heated to reflux with stirring for three hours. The excess thionyl chloride is then removed under reduced pressure and the residue is treated with benzene, then all the solvent is evaporated off under vacuum and the residue is dissolved in 100 ml of chloroform. A solution of 80 g of n-butylamine in 600 ml of chloroform is then added to the solution at -10 DEG C. and the suspension is allowed to cool to room temperature with stirring. The suspension is then neutralized by the addition of 120 ml of 1 N hydrochloric acid and the solvent is removed under reduced pressure. Water was added to the residue and the resulting mixture was filtered; the solid is washed with water, then with 5% sodium bicarbonate solution and finally with water, and the solid is dried over phosphorus pentoxide.

120 g of 5-nitro-2-chloro-N-n-butylbenzamide are obtained.

Mp 134-136 ° C.

b) 5-nitro-2-propargyloxy-N-n-butylbenzamide (IX)

To a suspension of 18.84 g of sodium hydride (55-60% in mineral oil) in 1400 ml of sodium-dried toluene, 25.36 ml of propargyl alcohol dissolved in 100 ml of toluene are added at ambient temperature. When the evolution of hydrogen ceased, the reaction mixture was heated to 45-50 ° C and 100 g of 5-nitro-2-chloro-N-n-butylbenzamide was added portionwise over one hour.

The resulting suspension is left at this temperature for two hours, then neutralized by the addition of about 60 ml of a normal hydrochloric acid solution, after which the solvent is stripped off under reduced pressure. About 1 liter of water is added to the residue, and the solid is washed thoroughly with water and then crystallized from 400 ml of isopropanol.

87 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide are obtained.

The melting point of this product is 113-116 degrees Celsius.

c) 5-amino-2-propargyloxy-N-n-butylbenzamide (Ij

The reduction is carried out under the operating conditions already described in Example 1c. From 82 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide, 55.8 g of 5-amino-2-propargyloxy-N-n-butylbenzamide is obtained.

Mp 81-83 ° C.

Example 3

(a) 5-nitro-2-chloro-N-n-butylbenzamide (VIII)

To a solution of 50.5 g of 5-nitro-2-chlorobenzoic acid and 25.30 g of triethylamine in 500 ml of methylene chloride, 27.15 g of ethyl chloroformate was added at -10 ° C with stirring. The reaction mixture is stirred for 15 to 30 minutes and then a solution of 19.2 g of n-butylamine in 75 ml of methylene chloride is added at the same temperature.

The reaction mixture was stirred at -10 ° C for one hour and then at ambient temperature for three hours.

The solvent is removed under reduced pressure and 300 ml of water are added to the residue. The mixture was filtered, washed with water and dried. The 5-nitro-2-chloro-N-n-butylbenzamide thus obtained melted at 134-136 ° C.

Yield: 97% of theory.

b) 5-nitro-2-propargyloxy-N-n-butylbenzamide (IX)

To 100 ml of propargyl alcohol is added 3 grams of sodium. When hydrogen evolution ceased, 27.6 g of 5-nitro-2-chloro-N-n-butylbenzamide was added and the resulting suspension was heated at 60 ° C for three hours. The solvent was stripped off and water was added to the residue. After filtering the mixture and washing the solid with water, the product is crystallized from isopropanol.

26.5 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide are obtained.

Melting point: 115-117 ° C.

(c) 5-amino-2-propargyloxy-N-n-butylbenzamide (I)

To a solution of 53 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide in 300 ml of methanol was added 2 ml of a Raney nickel suspension. The reaction mixture was heated to 50 ° C and added dropwise. 20.3 ml hydrazine hydrate (98%) and 1 ml Raney nickel suspension. The temperature of the reaction mixture reaches 60 ° C during the addition of said reactants. *

The reaction mixture was heated at reflux for 1 hour, filtered, and the filtrate was poured into 2200 ml of water. The pH of the mixture was adjusted to pH by addition of hydrochloric acid. The suspension obtained is decolorised with activated carbon. After filtration, the pH of the filtrate was adjusted to 6-15% sodium hydroxide solution. After filtration, the solid is washed with water and the product is crystallized from 600 ml of diisopropyl ether.

20 g of 5-amino-2-propargyloxy-N-n-butylbenzamide are obtained.

The melting point of this product is 81-83 degrees Celsius.

Example 4

A suspension of 50 g of 5-nitro-2-propargyloxy-N-butylbenzamide, prepared according to Examples 1a and 1b, in 300 ml of 70% ethanol is heated to reflux for 30 minutes and then added to the reaction mixture in small amounts. 135 g of Na2SO4. After the addition was complete, the reaction mixture was heated to reflux for 30 minutes, filtered hot and the filtrate concentrated in vacuo.

600 ml of water are added to the residue, the mixture is filtered and the solid is washed with water and dried over phosphorus pentoxide. 10 g of 5-amino-2-propargyloxy-N-n-butylbenzamide are obtained.

The melting point of this product is 84 to 85 degrees Celsius.

Claims (3)

SUBJECT OF THE INVENTION Process for the preparation of 5-amino-2-propargyloxy-N-butylbenzamide, characterized in that 5-nitro-2-chlorobenzoic acid is converted to 5-nitro-2-chloro-Nn-butylbenzamide by treatment with n-butylamine and the thus obtained the product is treated with propargyl alcohol in the presence of a basic condensing agent, and then the thus obtained 5-nitro-2-propargyloxy-N-butylbenzamide is subjected to the action of a reducing agent acting by an oxidation-reducing mechanism. 2. The process of claim 1 wherein the reaction of propargyl alcohol with 5-nitro-2-chloro-N-n-butylbenzamide is carried out in the presence of an excess of propargyl alcohol. 3. The method of claim 1, wherein:. For example, iron powder in the presence of hydrochloric acid is used as the reducing agent acting by the redox mechanism.