CS200533B2 - Method of producing 5-amino-2-propargyloxy-n-n-butylbenzamide - Google Patents

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,

R1 represents a hydrogen atom or a lower alkyl group,

R '2 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:

R1 and R1 may 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 abovementioned products of the general formula II and in particular 5-amino-2-propargyloxy-N-n-butylbenzamide:

R = CH 2 - C = CH,

R1 = 'H,

R 2 = n-butyl,

R5 = R4 = ± H, which has received the international designation "parsalmide", have anti-inflammatory, analgesic and myo-relaxing efficacy (Boli. Chim. Farm. 115, 125; 1976).

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

2U0533

in which

R, R 1, R 2, R 5 and R d are as defined above in Chim. Ther. 1968 (3), 200.

The literature suggests that 5-amino-2-propargyloxy-N-n-butylbenzamide is mainly obtained from 2-acetoxy-5-acetamidobenzoic acid according to the following reaction scheme

AND.

S c h e m A

5-amino-2-propargyloxy-N-butylbenzamide, which comprises treating the starting 5-nitro-2-chlorobenzoic acid with propargyl alcohol in the presence of a basic condensing agent and converting the 5-nitro-2-propargyloxybenzoic acid thus obtained to 5-nitro-2-propargyloxy-N-tert-butylbenzamide by treatment with n-butylamine, and the thus obtained 5-nitro-2-propargyloxy-N-butylbehzamide is subjected to the action of a reducing agent acting by an oxidation-reduction mechanism.

The reaction of propargyl alcohol with 5-nitro-2-chlorobenzoic acid is preferably carried out in the presence of an excess of propargyl alcohol.

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

5-Nitro-2-propargyl-N-n-butylbenzamide (IX) is a new chemical compound.

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

Scheme B

COOH (Vin

NO.

CO-NH-n-CF 6 CH = C-CN _from OH (V)

CO-NH-n-Cfá CH (VI)

CO-NH-h-C 1 H 2 OC 1 C 2 CH 2

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 the starting material, which is cheaper than the 2-acetoxy- S-acetamidobenzoic acid; less expensive reagents and novel intermediates are also used in this new process.

The subject of the invention is a method of preparation

COOH

Thus, 5-nitro-2-chlorobenzoic acid of formula VII is treated with propargyl alcohol in the presence of a condensation base and the thus obtained 5-nitro-2-propargyloxy acid of formula X, not previously described in the literature, is converted to 5-nitro-2- For pargyloxy-N-butylbenzamide of formula IX by reaction with n-butylamine using a conventional amidation procedure such as using acid chloride or mixed acid anhydride.

The reaction of 5-nitro-2-chlorobenzoic acid with propargyl alcohol is carried out in the presence of a condensing agent such as sodium hydride, sodium amide or sodium metal. This reaction is carried out at a temperature of 15 to 70 ^Q C in an organic solvent such as benzene, toluene, dioxane or tetrahydrofuran.

The product obtained is then reacted with n-butylamine using, for example, acid chloride or mixed acid anhydride.

In acid chloride methodology, a suspension of 5-nitro-2-propargyloxybenzoic 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 at -10 to 20 ^Q C was added a solution of n-butylamine and an inorganic or organic base such as sodium hydroxide or potassium hydroxide, tertiary amine or an excess of n-butylamine in the same solvent as is used for starting acid chloride, optionally in the presence of water.

The thus obtained 5-nitro-2-propargyloxy-N-benzylbenzamide of formula IX is isolated by neutralizing the alkaline medium with a strong acid, such as hydrochloric acid, and evaporating the solvent.

When mixed anhydride is used, n-butylamine is treated with a mixture of product X, triethylamine and ethyl chloroformate in an inert organic solvent, such as methylene chloride, at a temperature of -10 ° C to ambient temperature.

The reaction is complete after 1 to 5 hours and the product obtained can be isolated by evaporation of the solvent and recrystallization of the residue.

The 5-nitro-2-propargyloxy-N-n-butylbenzamide of formula IX is a novel compound which represents a novel intermediate which underlies the novel reaction scheme employed in 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 (compound of formula VI) that it can be prepared in virtually quantitative yield from 5-nitro-2 acid. 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-butylbenzamide of the formula I.

In addition, 5-nitro-2-propargyloxy-N-butylbenzamide is a product that crystallizes very easily and can thus be easily purified. Moreover, it is not toxic (its lethal dose of 3 β

Ka Dho is more than 750 mg / kg in porosity mice and does not have the hypothesized hypnotic effect inherent in the harbiturates, as the aforementioned known product of formula VI.

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

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

Examples of such reducing agents include: zinc, copper (I) chloride, aluminum amalgam, thallium chloride, stannous chloride, titanium (III) chloride, ammonia, hydrazine or substituted hydrazine, especially phenyl · hydrazine, phosphine, arstine, hydrogen sulfide and its salts, sulfite or acid a sulphite, in particular sodium bisulphite, a dithionite, in particular sodium dithionite, iron or its divalent salts, 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, quick and inexpensive, the reduction is carried out using iron 7 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 refluxing slurry. 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 solution to pH 5-6.

In order to further elucidate the method of the invention, an exemplary embodiment of the method of the invention is described in the following.

Example

a.) 5-nitro-2-propargyloxybenzoic acid

To a suspension of 27 g of sodium hydride (55-60 percent in mineral oil) in 300 ml of tetrahydrofuran is added under stirring and at ambient temperature 60.6 g of 5-nitro-2-chloro-benzoic acid. A solution of 19.5 ml of propargyl alcohol in 200 ml of tetrahydrofuran is added dropwise and the suspension obtained is stirred at 45 to 50 ° C for 6 hours.

The reaction mixture was then poured into ice water and extracted with ether. The pH of the aqueous phase was adjusted to 4 by addition of 6 N hydrochloric acid to give a solid product which, after filtration and crystallization from isopropanol, yielded 153 g of 5-nitro-2-propargyloxybenzoic acid.

The melting point of this product is 157-160 degrees Celsius.

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

To a solution of 50 g of 5-nitro-2-propargyloxybenzoic acid and 25 g of triethylamine in 500 ml of methylene chloride was added 27.15 g of ethyl chloroformate under stirring at -10 ° C. 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 1 hour and then for 3 hours at ambient temperature.

The solvent is removed under reduced pressure, the residue is taken up in 300 ml of water, filtered, the solid is washed with water and dried.

5-Nitro-2-propargyloxy-N-n-butylbenzamide is obtained in a yield of 92% of theory.

cj 5-amino-2-propargyloxy-N-n-butylbenzamide

A suspension of 8.94 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide in 200 ml of an aqueous solution of titanium tetrachloride is heated to reflux for 30 minutes. The reaction mixture was then cooled and extracted with ethyl acetate. After evaporation of the organic solvent to dryness, 200 ml of water are added to the residue and the pH of the resulting suspension is adjusted to 2.5 N with 6 N hydrochloric acid. The suspension is decolorised with activated charcoal. The mixture was stirred for 30 minutes and then filtered. The filtrate is poured into 200 ml of water containing 3 g of sodium hydroxide. The mixture was filtered, the solid washed with water and dried in vacuo.

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

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

Yield: 62.7% of theory.

Claims (3)

Process for the preparation of 5-amino-2-propargyloxy-N-butylbenzamide, characterized in that 5-nitro-2-chlorobenzoic acid is treated with propargyl alcohol in the presence of a basic condensing agent and the thus obtained 5-nitro-2-propargyloxybenzoic acid is converted to The 5-nitro-2-propargyloxy-Nn-butylbenzamide is treated with n-butylamine and the 5-nitro-2-propargyloxy-Nn-butylbenzamide thus obtained is subjected to the action of a reductive agent acting by an oxidative reduction mechanism. 2. A process according to claim 1, wherein the reaction of propargyl alcohol with 5-nitro-2-chlorobenzoic acid is carried out in the presence of an excess of propargyl alcohol. 3. Process according to claim 1, characterized in that iron oxide in the presence of hydrochloric acid is used as the reducing agent acting by the redox mechanism.