CH624094A5 - Process for the preparation of 5-amino-2-propargyloxy-N-n-butylbenzamide - Google Patents

Description

The subject of the present invention is a process for the preparation of 5-amino-2-propargyloxy-N-n-butylbenzamide (I) as well as a

(IV)

wherein R is an allyl or propargyl group, Ri a hydrogen atom or a lower alkyl group, R2 a lower alkyl group, a lower alkenyl group or a cycloalkyl group having 3 to 6 carbon atoms, Ri and R2, taken together , being capable of forming, with the nitrogen atom to which they are linked, an N-heterocyclic group chosen in particular from the pyrrolidino, piperidino and morpholino groups, and at least one of the symbols R3 and R4 represents a hydrogen atom, the other being capable of representing a chlorine atom or a methyl group.

ço-nh- c h 11 4 9

ch2c = .ch

3

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According to a method described in German patent No. 2335439, 2-alkoxy-4-aminobenzoic acids can be prepared by the action of alcohols on 2-halo-4-amino-benzoic acids. Said patent does not however describe any etherification which is carried out on a compound carrying a free amine. In fact, attempts to prepare 5-amino-2-propargyloxy-benzoic acid according to the technique described in the above patent have failed and have given rise to mixtures of products which are difficult to separate and identify.

It has now been found that 2-propargyloxy-5-amino-Nn-butylbenzamide can be prepared in three stages with excellent yields using a raw material, 5-nitro-2-chlorobenzoic acid which is cheaper than 2-acetoxy-5-acetamidobenzoic acid of the prior art, and also using less expensive reagents and new intermediates.

The present invention therefore relates to a process for the preparation of 5-amino-2-propargyloxy-N-n-butylbenzamide, characterized in that:

a) the 5-nitro-2-chlorobenzoic acid is transformed into 5-nitro-

2-chloro-Nn-butylbenzamide by the action of n-butylamine and the product thus obtained is treated with propargyl alcohol in the presence of a basic condensing agent, and b) 5-nitro-2 is subjected -propargyloxy-Nn-butylbenzamide 5 thus obtained by the action of a reducing agent resulting in a redox mechanism.

Alternatively:

a) treating 5-nitro-2-chlorobenzoic acid with propargylic alcohol in the presence of a basic condensing agent and io transforming 5-nitro-2-propargyloxybenzoic acid thus obtained into 5-nitro- 2-propargyloxy-Nn-butylbenzamide by the action of n-butylamine, and b) the 5-nitro-2-propargyloxy-Nn-butylbenzamide thus obtained is subjected to the action of a reducing agent causing a

15 redox mechanism.

A further object of the present invention is 5-nitro-2-pro-pargyloxy-N-n-butylbenzamide (IX) as a new industrial product.

The process of the present invention is illustrated by Scheme B.

Diagram B:

(cl-c00c2h5)

COCH

: 0-nh-n.C4Hg n.C4HgNH2

(s0c19)

(below c2h5)

ch = c-ch2oh o-nh-n.c ^ hg o-ch2-c = ch

CÛ-NH-nC4Hg

0-CH2-CfCH

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4

The starting 5-nitro-2-chlorobenzoic acid (VII) is transformed into 5-nitro-2-chloro-Nn-butylbenzamide Vili) by reaction with n-butylamine according to the usual amidation techniques, for example by the acid chloride technique or that of mixed anhydrides.

According to the acid chloride technique, a suspension of the starting 5-nitro-2-chlorobenzoic acid in thionyl chloride is heated and, after removal of the excess of thionyl chloride, the residue is dissolved in a inert organic solvent, such as methylene chloride, chloroform, benzene, toluene, hexane or the like. The solution thus obtained is added, at a temperature of -10 to + 20 ° C, to a solution of n-butylamine and an inorganic or organic base, such as sodium or potassium hydroxide, an amine tertiary or an excess of n-butylamine, in the same solvent as that used for the starting acid chloride, optionally in the presence of water. The 5-nitro-2-chloro-N-n-butylbenzamide (VIII) thus obtained is isolated by neutralizing the alkaline medium with a strong mineral or organic acid, for example hydrochloric acid, and by evaporating the solvent.

By using the mixed anhydrides procedure, n-butylamine is made to act on a mixture of the starting 5-nitro-2-chlo-robenzoic acid, triethylamine and ethyl chloroformate in an inert organic solvent, preferably methylene chloride at a temperature of -10 ° C to room temperature. After a period of 1 to 5 h, the reaction is complete and the 5-nitro-2-chloro-N-n-butylbenzamide (VIII) can be isolated by evaporation of the solvent and recrystallization of the residue. Product VIII is not described in the literature.

Propargyl alcohol is reacted on the 5-nitro-2-chloro-Nn-butylbenzamide thus obtained, in the raw or purified state, in the presence of a condensing agent such as sodium hydride, sodioamide. or metallic sodium. The reaction is carried out at a temperature of 15 to 70 ° C in an organic solvent such as, for example, benzene, toluene, dioxane, tetrahydrofuran and the like.

The 5-nitro-2-propargyloxy-N-n-butylbenzamide (IX) which is obtained at the end of the reaction is isolated according to the usual technique.

According to a preferred operating technique, the reaction between 5-nitro-2-chloro-Nn-butylbenzamide (VIII) and propargyl alcohol is carried out using an excess of propargyl alcohol, which thus acts simultaneously as solvent and as reagent .

The conversion of 5-nitro-2-chlorobenzoic acid (VII) into 5-nitro-2-chloro-Nn-butylbenzamide (IX) can be carried out by applying the amidation reactions with n-butylamine and etherification with propargyl alcohol described above,

but in reverse order, while using the same operating techniques.

Thus, on 5-nitro-2-chlorobenzoic acid (VII), propargyl alcohol is made to act in the presence of a basic condensing agent and the 5-nitro-2-propargyloxybenzoic acid (X) thus obtained, which is not described in the literature, is transformed into 5-nitro-2-propargyloxy-Nn-butylbenzamide (IX) by reaction with n-butylamine according to the usual amidation techniques, for example by the chloride technique acid or that of the mixed anhydrides described above.

5-nitro-2-propargyloxy-N-n-butylbenzamide (IX) is a new product which constitutes the key intermediate in the process of the present invention. This product, compared to the starting product (VI) of the process described in Swiss patent No. 517701, has the advantage of being obtained with a practically quantitative yield from 5-nitro-2-chlorobenzoic acid. It is therefore a very inexpensive product which makes it possible to significantly lower the industrial cost of 5-amino-2-propargyloxy-N-n-butylbenzamide (I).

In addition, 5-nitro-2-propargyloxy-N-n-butylbenzamide is a product which very easily crystallizes and which can be easily purified. It is not toxic (its LDo in the oral mouse is greater than 750 mg / kg) and it is devoid of the potentia-reading action of the hypnotic effect of the barbiturates proper to the product (VI) of the art. prior.

The 5-nitro-2-propargyloxy-N-n-butylbenzamide (IX) thus obtained is subjected to a reduction using the reducing agents causing a redox mechanism usually used to transform the aromatic nitro groups into corresponding amino groups.

As reducing agents causing a redox mechanism, use may be made of transition elements or derivatives of elements capable of passing from the lower valence to the higher in the presence of the nitro group.

Representative reducing agents are Zn, HgCl, aluminum amalgam, TlCl, SnCb, TiCU, NH2-NH2 or a substituted hydrazine, particularly phenylhydrazine, phosphine, arsine, H2S and its salts, sulfite or bisulfite, in particular NaHSOs, a dithionite, in particular Na2S204, Fe or one of its valence two derivatives, in particular Fe (OH) 2, FeCfe, FeS04.

Said 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, hydrochloric and sulfuric acids preferably, while the derivatives of non-metallic elements are activated by the action of the metals or the alkalinity of the medium.

According to a preferred embodiment which has the advantage of being simple, rapid and inexpensive, the reduction is carried out by using iron as reducing agent in the presence of hydrochloric acid.

For this purpose, hydrochloric acid diluted in a suspension, heated at reflux, of iron powder in an organic solvent, preferably ethanol, is slowly added. After 30-90 minutes of heating, the reduction is complete. The excess iron and the ferrous and ferric chlorides which have formed are removed by addition of an alkali metal hydroxide or carbonate and filtration, the pH of the solution is adjusted to 2-3 with concentrated hydrochloric acid and the 5 -amino-2-propargyloxy-Nn-butylbenzamide (I) precipitates by adding a solution of an alkali hydroxide at 10-20% until pH 5 to 6.

The following nonlimiting examples illustrate the invention.

Example 1:

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

A mixture of 100 g of 5-nitro-2-chlorobenzoic acid in 80 g of thionyl chloride is heated with stirring for 3 h and then the excess of thionyl chloride is removed under reduced pressure. The residue is taken up in 100 ml of chloroform and 250 mg of 2N sodium hydroxide is added to the solution thus obtained. The mixture is cooled to 5 ° C. and the mixture thus obtained is added dropwise at the same temperature to a mixture of 40.15 g of n-butylamine, 200 ml of water and 200 ml of chloroform. The reaction mixture is kept under stirring until it has reached room temperature, then the pH is adjusted to 7 with concentrated hydrochloric acid and the solvent is evaporated off under reduced pressure. The residue is taken up in 11 of water, the solid is filtered, washed with water, then with 5% sodium bicarbonate, again with water and finally with petroleum ether. After drying over P2O5, 119 g of 5-nitro-2-chloro-N-n-butyl-benzamide are obtained; Mp 134-136 ° 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 under nitrogen, 3.5 ml of dissolved propargyl alcohol is added at room temperature in 20 ml of anhydrous tetrahydrofuran. At the end of the evolution of hydrogen, a solution of 13.8 g of 5-nitro-2-chloro-N-n-butylbenzamide in 80 ml of anhydrous tetrahydrofuran is slowly added to the mixture, then the mixture is kept

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reaction for 3 h at room temperature and the solvent is evaporated. The residue is taken up in water, filtered, washed with water and crystallized from isopropanol. 13.2 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide are thus obtained; Mp 115-117 ° C.

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

To a solution of 9 g of 5-nitro-2-propargyloxy-N-n-butyl-benzamide in 35 ml of 70% ethanol, 5.45 g of iron powder is added. To the suspension heated to reflux, 19 ml of 2.5N hydrochloric acid are added dropwise, then the reflux is continued for 1 h. It is made alkaline with a 15% alcoholic solution of potassium hydroxide, filtered hot, the pH of the solution is adjusted to 2.5 with concentrated hydrochloric acid and concentrated under reduced pressure. The residue is taken up in water, the suspension is discolored with charcoal and filtered. The pH of the solution is adjusted to 5-6 with a 15% sodium hydroxide solution, filtered and the solid washed with water. 6.2 g of 5-amino-2-propargyloxy-N-n-butylbenzamide are obtained; Mp 83-85 ° C.

Example 2:

a) 5-Nitro-2-chloro-N-n-butylbenzamide (Vili).

Is heated to reflux with stirring for 3 h a suspension of 100 g of 5-nitro-2-chlorobenzoic acid in 80 ml of thionyl chloride. The excess thionyl chloride is removed under reduced pressure, the residue is taken up in benzene, the solvent is completely evaporated in vacuo and the residue is dissolved in 100 ml of chloroform. To the solution thus obtained, a solution of 80 g of n-butylamine in 600 ml of chloroform is added at the temperature of -10 ° C., then the suspension is allowed to return to ambient temperature, while stirring, it is neutralized by adding 120 ml of N hydrochloric acid and the solvent is removed under reduced pressure. The residue is taken up at. water, filter, wash with water, then with 5% sodium bicarbonate, again with water and dry over P2O5. 120 g of 5-nitro-2-chloro-N-n-butylbenzamide are obtained; M 134-136 ° C.

b) S-Nìtro-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 toluene dried over sodium is added, at room temperature, 25.36 ml of propargyl alcohol dissolved in 100 ml of toluene. At the end of the evolution of hydrogen, the mixture is heated to the internal temperature of 45-50 ° C. and is added thereto in 1 h, in portions, 100 g of 5-nitro-2-chloro-N-n-butylbenzamide. The suspension is left to stand at the same temperature for 2 h, then it is neutralized by adding approximately 60 ml of a normal hydrochloric acid solution and the solvent is removed under reduced pressure. The residue is taken up in about 1 l of water, filtered, washed thoroughly with water and crystallized from 400 ml of isopropanol. 87 g of 5-nitro-2-pro-pargyloxy-N-n-butylbenzamide are obtained; F. 113-116r C.

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

The reduction is carried out under the operating conditions described in example le). From 82 g of 5-nitro-2-propargyl-oxy-N-n-butylbenzamide, 55.8 g of 5-amino-2-propar-gyloxy-N-n-butylbenzamide are 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 is added with stirring at the temperature of -10 ° C. ethyl chloroformate. The mixture is stirred for 15-30 min, 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 is stirred at -10 ° C for 1 h, then for 3 h at room temperature.

The solvent is removed under reduced pressure, the residue is taken up in 300 ml of water, filtered, washed with water and dried. The 5-nitro-2-chloro-N-n-butylbenzamide thus obtained melts at 134-136 ° C. Yield: 97% of theory.

b) S-Nitro-2-propargyloxy-N-n-butylbenzamide (IX).

To 100 ml of propargyl alcohol is added 3 g of sodium. After the evolution of hydrogen, 27.6 g of 5-nitro-2-chloro-Nn-butylbenzamide are added and the suspension thus obtained is heated for 3 h at 60 ° C. The solvent is removed, the residue is taken up in water, it is filtered, washed with water and crystallized from isopropanol. 26.5 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide are thus obtained; Mp 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-butyl-benzamide in 300 ml of methanol is added 2 ml of a suspension of Ni-Raney. The mixture is heated to 50 ° C. and 20.3 ml of 98% hydrazine hydrate and 1 ml of a Ni-Raney suspension are added dropwise. During the addition of the reagents, the reaction mixture reaches the temperature of 60 ° C. The mixture is kept at reflux for 1 h, filtered and the solution is poured into 2200 ml of water. The pH is adjusted to 2.5 with hydrochloric acid, the suspension is discolored with charcoal and filtered. The filtrate is adjusted to a pH of 5 to 6 with a 15% sodium hydroxide solution, filtered, washed with water and the product is crystallized from 600 ml of di-isopropyl ether. 20 g of 5-amino-2-propargyloxy-N-n-butylbenzamide are obtained; Mp 81-83 ° C.

Example 4:

A suspension of 50 g of 5-nitro-2-propargyloxy-Nn-butylbenzamide, prepared according to example 1 a) and b), is heated at reflux for 30 min in 300 ml of 70% ethanol, then there is add, in small portions, in about 30 minutes, 135 g of Na2S2O4. After the addition, the mixture is kept at reflux for 30 min, filtered hot and concentrated in vacuo. The residue is taken up in 600 ml of water, filtered, washed with water and dried over P2O5. 10 g of 5-amino-2-propargyloxy-N-n-butylbenz-amide are obtained; Mp 84-85 ° C.

Example 5:

a) 5-nitro-2-propargyloxybenzoic acid (X).

To a suspension of 27 g of sodium hydride (55-60% in mineral oil) in 300 ml of tetrahydrofuran under nitrogen is added, with stirring, at room temperature, 60.6 g of 5-nitro acid -2-chlorobenzoic acid. A solution of 19.5 ml of propargyl alcohol in 200 ml of tetrahydrofuran is added dropwise at 30-40 ° C and the suspension obtained is stirred at 45-50 ° C for 6 h. The reaction mixture is poured into ice water and extracted with ether. The pH of the aqueous phase is adjusted to 4 with 6N hydrochloric acid and a solid is obtained which, after filtration and crystallization from isopropanol, gives 153 g of 5-nitro-2-propargyloxybenzoic acid; Mp 157-160 ° C.

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

By subjecting the product thus obtained to the action of triethylamine and ethyl chloroformate and then of n-butylamine according to the indications in Example 3a), 5-nitro-2-propargyloxy-Nn-butylbenzamide is obtained. . Yield: 92% of theory.

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

A suspension of 8.94 g of 5-nitro-2-propargyloxy-N-n-butylbenzamide in 200 ml of an aqueous solution of TÌCl3 is maintained at reflux for 30 min. The mixture is cooled and extracted with ethyl acetate. After evaporation to dryness of the organic solvent, the residue is taken up in 200 ml of water and the pH of the suspension is adjusted to 2.5 with chlorine acid.

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water 6N. The suspension is discolored with charcoal, the mixture is stirred for 30 min and filtered. The solution is poured into 200 ml of water containing 3 g of sodium hydroxide, the solid is filtered, washed with water and dried under vacuum. 5 g of 5-amino-2-propargyloxy-N-n-butylben7amide are obtained; Mp 83-85 ° C. Yield: 62.7% of theory.

R

Claims (4)

624,094 2 1. Process for the preparation of 5-amino-2-propargyloxy-N-n-butylbenzamide, characterized in that: a) the 5-nitro-2-chlorobenzoic acid is transformed into 5-nitro-2-chloro-Nn-butylbenzamide by the action of n-butylamine and the product thus obtained is treated with propargyl alcohol in the presence a basic condensing agent; b) the 5-nitro-2-propargyloxy-N-n-butylbenzamide thus obtained is subjected to the action of a reducing agent causing a redox mechanism. 2. Process for the preparation of 5-amino-2-propargyloxy-N-n-butylbenzamide, characterized in that: a) 5-nitro-2-chlorobenzoic acid is treated with propargylic alcohol in the presence of a basic condensing agent and the 5-nitro-2-propargyloxybenzoic acid thus obtained is transformed into 5-nitro-2 -propargyloxy-Nn-butylbenzamide by the action of n-butylamine, and the 5-nitro-2-propargyloxy-Nn-butylbenzamide thus obtained is subjected to the action of a reducing agent resulting in a redox mechanism. 3. Method according to claim 1, characterized in that the reaction of propargylic alcohol on 5-nitro-2-chloro-benzoic acid or on 5-nitro-2-chloro-Nn-butylbenzamide is carried out in the presence an excess of propargyl alcohol acting both as a solvent and as a reagent. 4. Method according to claim 1, characterized in that, as reducing agent causing an oxidation-reduction mechanism, iron powder is used in the presence of hydrochloric acid. The products of formula II above and, in particular, 5-amino-2-propargyloxy-Nn-butylbenzamide (R = CH2 —C = CH; Ri = H, R2 = n-butyl, R3 = R4 = H) , which received the international common name of parsalmide, have a good anti-inflammatory, analgesic and muscle relaxant activity ("Boll. Chim. Farm.", 115,125; 1976). According to the method of Swiss patent No. 517701, the compounds of formula I above are obtained by hydrolysis of the corresponding 5-acetamido-benzamides of formula: • R1 (iii) b) ch3conh in which R, Ri, R2, R3 and R4 are as defined above, described in "Chim. Ther. ", 1968 (3), 200. In particular, according to the literature, 5-amino-2-propargyl-25 oxy-N-n-butylbenzamide is therefore obtained from 2-acetoxy-5-acetamidobenzoic acid according to scheme A. Diagram A: cooh 30 35 ch3c0nh 0 ~ c0ch „