NO141314B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THE THERAPEUTICALLY ACTIVE N- (1`-ALLYLPYRROLIDINYL-2`-METHYL) -2-METHOXY-4,5-AZIMIDOBENZAMIDE - Google Patents

Description

The present invention relates to the preparation of N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide and its hydrochloride.

It has been found that this compound with regard to its pharmacological properties is superior to similar compounds as well as the previously known and commercially available compound "Metoclopramide".

The compound's structure is indicated schematically by three tautomeric forms:

The compound is produced according to the invention by nitration of a compound of the formula:

in which X is a hydroxy or alkoxy radical, and

R and R' are hydrogen or an acyl radical,

followed by hydrogenation of the formed 5-nitrophorbinide and diazotization of the obtained 5-aminophorbinide, after which the amidation reaction is carried out by direct reaction of the thus obtained 4,5-azimidophorbinide with 1-allyl-2-aminomethylpyrrolidine or by reaction of their reactive derivatives .

According to the present method, the reaction can be carried out by nitration of a lower alkyl ester of 2-methoxy-4-aminobenzoic acid, by hydrogenation of the formed alkyl-2-methoxy-4-amino-5-nitrobenzoate, diazotization of the formed alkyl-2- methoxy-4,5-di-aminobezoate and amidation of the obtained alkyl-2-methoxy-4,5-azimidobenzoate with 1-allyl-2-aminomethylpyrrolidine.

In the first step of the above-mentioned method, methyl-2-methoxy-4-aminobenzoate is preferably used. However, other lower alkyl esters, such as ethyl, propyl, butyl or pentyl esters can also be used.

The hydrogenation of the nitro group according to the method can either be carried out using hydrogen in the presence of catalysts such as platinum, palladium or Raney nickel, or with active hydrogen with metals in the presence of strong acids such as Fe/HCl,

Sn/HCl or Zn/HCl, or with other suitable hydrogenating agents.

The 4,5-diaminoforbin ice thus obtained can then be diazotized with a suitable diazotizing agent such as NaNC/HCl or isoamyl nitrite, whereby the corresponding 4,5-azimidoforbin ice is obtained.

The azimidophoro compound can be amidated with 1-allyl-2-amino-methylpyrrolidine. The reaction can be carried out in the presence or absence of solvents. Such systems can be used as solvents which are inert to the amidation reaction, such as alcohols, polyols, benzene, toluene, dioxane, chloroform, diethylene glycol, dimethyl ether. It is also possible to use an excess of the amine used as a reaction partner as a solvent. It may be advantageous to heat the reaction mixture during the amidation, e.g. up to the boiling point of the solvents used.

According to the synthesis process indicated above, the reaction can be carried out by starting from a lower alkyl ester of 2-methoxy-4-acylaminobenzoic acid. Instead of the acetyl group which is preferably used for the substitution of the amino function in the 4-style in the above-mentioned starting material, other suitable, easily cleavable groups, such as formyl, propionyl, butyryl, alkoxycarbonyl, phthaloyl or benzoyl can also be used as well as other suitable cleavable groups.

The above-mentioned reaction can also be carried out in such a way that the acyl group is split off for hydrogenation of the nitro group. The 4,5-diamino compound thus obtained can then be further reacted as described above.

If the acyl group is not a phthaloyl group, it can also be cleaved off after the amidation.

The method according to the present invention is further illustrated by the following reaction scheme:

According to the present method, the reaction can be started from 2-methoxy-4-aminobenzoic acid which can be nitrated, after which the formed 2-methoxy-4-amino-5-nitrobenzoic acid is hydrogenated, the formed 2-methoxy-4,5-diaminobenzoic acid is diazotized, and the 2-methoxy-4,5-azimidobenzoic acid thus obtained is reacted either with a reactive derivative of l-allyl-2-aminomethylpyrrolidine or in the form of one of its reactive derivatives with l-allyl-2-aminomethylpyrrolidine. N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide is thus obtained.

The same synthesis procedure can be applied to a 2-methoxy-4-acylaminobenzoic acid as stated above.

The starting material can e.g. be 2-methoxy-4-acetyl-aminobenzoic acid. This compound can be nitrated, the 2-methoxy-4-acetylamino-5-nitrobenzoic acid thus obtained can be hydrogenated and diazotized as described above. Finally, the 1-acetyl-5-carbohydroxy-6-methoxybenzotriazole formed can be converted to the process compound, whereby either the above-mentioned acid is reacted with a reactive derivative of l-allyl-2-amino-methylpyrrolidine or the above-mentioned amine is reacted with a reactive derivative of the acid, and the reaction product is deacylated, possibly without prior isolation.

The deacylation can be carried out for hydrogenation or diazotization. This operating method is necessary e.g. in the case of 4-phthaloylamino substitutions. In the above-mentioned synthesis process, the following products can be used as reactive derivatives of amines: Reaction products of the amine with phosphorus chloride, phosphorus oxychloride, dialkyl or diaryl or orthophenylene phosphites, chlorinated alkyl or aryldichlorinated phosphites or l-allylpyrrolidinyl-2-methylisothiocyanate. The above-mentioned derivatives can be reacted in situ or after prior isolation with the acid.

The compound obtained according to the present method

may, if desired, be transferred to its hydrochloride.

For therapeutic purposes, the compound can be used in form. of the hydrochloride together with commonly used pharmaceutical excipients and/or diluents in the form of tablets, dragees, solutions for injection, syrups, or in any other suitable form.

Pharmacological investigations have shown that the process compound, hereinafter referred to as compound A, exhibits superior properties with regard to antiemetic and cataleptic action and relatively low toxicity compared to several partially commercially available benzamides which are known to have good properties. The following compounds were used as comparative material: N,N-diethylaminoethyl-2-methoxy-4-amino-5-chlorobenzamide (compound B) commercially known under the name "Metoclopramide"

N-(1-ethylpyrrolidinyl-2-methyl)-2-methoxy-4,5-azimido-benzamide

(compound C) known from French patent document 1 572 168, example 2„

The following results were obtained:

A. Toxicity (DL^, mg/kg i.v., 5 days, mice) B. Antiemetic activity (DE^q, s.c., dogs) C. Therapeutic index

The process compound thus exhibits a substantially improved therapeutic index compared to the comparison compounds, with a reduced cataleptic activity.

The above results have been confirmed in human therapy as the new compound has been shown to be an effective antiemetic agent for treatment

of children and adults, especially in the treatment of vomiting symptoms of toxic or infectious syndromes, in pneumencephalography and in brain surgery, for the treatment of mental illness and the treatment of post-chemotherapy-, post-radiotherapy- and post-surgery emetic symptoms.

The following examples illustrate the invention.

Example 1

Step I: Methyl 2-methoxy-4-amino-5-nitrobenzoate

72.5 g (0.4 mol) methyl-2-methoxy-4-aminobenzoate, 140 ml acetic acid and 126 g acetic anhydride were placed in a 2 liter flask equipped with tubes, thermometer and dropping funnel. The mixture was heated to approx. 40°C in the course of 30 minutes. 48 ml of nitric acid (d = 1.49) was added dropwise using the dropping funnel. After the addition of the nitric acid was finished, the stirring was continued for 2 hours at 40°C. The mixture was then poured into 600 ml of a methanolic solution of sulfuric acid (0.4 mol). The mixture was then stirred. 1600 ml of water and ice were then added. The formed crystals were filtered off. 55.2 g of methyl-2-methoxy-4-amino-5-nitro-benzoate with m.p. 214°C. Yield: 61%.

Step II: Methyl 2-methoxy-4,5-diaminobenzoate

555 g methyl-2-methoxy-4-amino-5-nitrobenzoate 2500 ml methanol, 300 g Raney nickel were introduced into a 5 liter autoclave.

Hydrogen was added at a pressure of 50 kg. The temperature rose to 50°C and was maintained throughout the absorption. After cooling, the nickel was removed by filtration and washed with methanol. The solvent was removed under reduced pressure. The formed crystals were washed twice with 600 ml of water and dried at 50°C.

305 g methyl-2-methoxy-4,5-diaminobenzoate with m.p. 139 - 140°C was obtained. Yield: 63.5%.

Step III: Methy1-2-methoxy-4,5-azimidobenzoate

294 g (1.5 mol) methyl 1-2-methoxy-4,5-diaminobenzoate 2500 ml water, 550 ml hydrochloric acid (d = 1.18) were introduced into a 5 liter flask equipped with stirrers, thermometer and dropping funnel. The mixture was cooled to 0-5°C, and a solution of 108 g of sodium nitrite in 500 ml of water was added dropwise. The mixture was heated to 35°C over 30 minutes and then cooled. The crystals obtained were filtered off, washed three times with 300 ml of methylene chloride and with water. After drying at 30°C, 256 g of methyl-2-methoxy-4,5-azimidobenzoate with m.p. 190 - 192°C. Yield: 82.4%.

Step IV: N-(1'-allylpyrrolidinyl-2-methyl)-2-methoxy-4,5-azimido-benzamide hydrochloride

621 g of methyl-2-methoxy-4,5-azimido-benzoate, 3 liters of anhydrous toluene and 425 g of 1-allyl-2-aminomethylpyrrolidine were introduced into a 6 liter three-necked flask equipped with a sealed mechanical stirrer, thermometer and ascending reflux condenser. The mixture was kept under reflux conditions for 5 hours.

The mixture was cooled to 50°C after which 600 ml of a solution of 350 g of hydrogen chloride in 1 liter of ethanol was added. The temperature rose to 70 - 80°C. The mixture was cooled to 50°C, after which the toluene layer was separated from an oily residue.

The latter was taken up in 3 liters of methanol. The mixture was heated until dissolution was achieved. This solution was filtered at the boiling temperature with 150 g of charcoal (3 S). 6 liters of methyl ethyl ketone were added to the filtrate, after which the mixture was cooled to 0°C. The benzamide crystallized slowly. It was filtered and washed with 500 ml of methyl ethyl ketone in two portions. It was then dried at 50°C in a ventilation dryer.

687 g of N{1'-allylpyrrolidinyl-2T<->methyl)-2-methoxy-4,5-azimidobenzamide hydrochloride were obtained (yield 65%). Sm.p. = 206 - 208°C. HC1 % : theoretical: 10.38; found: 10.18; purity in non-aqueous medium by HCl^: 99.5%.

Example 2

Step I: Methyl 2-methoxy-4-acetylamino-5-nitrobenzoate

223 g (1 mol) of methyl-2-methoxy-4-acetylaminobenzoate, 350 ml of acetic acid and 337 g of acetic anhydride were introduced into a 2 liter flask equipped with stirrers, thermometer and dropping funnel. The mixture was heated to 40°C, whereby a clear solution was obtained. This was then cooled to 15 - 20°C, after which 106 g (1.5 mol) nitric acid (d = 1.49) was added dropwise using the dropping funnel. After the addition of nitric acid was finished, the stirring was continued for 1/2 hour at 40°C. The mixture was then cooled and poured into 5 liters of water.

182 g (yield 68%) methyl-2-methoxy-4-acetylamino-5-nitrobenzoate with m.p. 163 - 165°C was obtained.

Step II: Methy1-2-methoxy-4-acetamino-5-aminobenzoate hydrochloride 1 kg of methyl-2-methoxy-4-acetamino-5-nitrobenzoate, 3 liters of ethyl acetate and 3 spoons of Raney nickel were placed in a 5 liter autoclave . This mixture was heated to 75°C with stirring. Hydrogen gas was then added at a pressure of 50 kg. The reduction reaction started quickly. For safety reasons, the reaction vessel was ventilated. The temperature rose to 95°C. This temperature was maintained throughout the absorption. The total absorption took 10 minutes. The hydrogen gas was reintroduced four to five times in the same way until absorption stopped.

The reaction was completed within 1 1/4 hours. After cooling, the nickel was removed by filtration and washed with 100 ml ethyl acetate. The filtrate was acidified with 500 ml of a solution containing 350 g of hydrogen chloride in 100 ml of ethanol. The hydrochloride crystallized out. This was filtered at 15°C and washed with 500 ml of ethyl acetate. 905 g of product (88%) with a m.p. at 202 - 205°C.

Step III: 1-acetyl-5-carbomethoxy-6-methoxybenzotriazole

14 liters of water and 1920 g of hydrochloride of 2-methoxy-4-acetamino-5-aminobenzoate were introduced into a 20 liter reaction vessel equipped with a mechanical stirrer, thermometer and dropping funnel, and which was suitably placed on a water bath to enable cooling.

The rydrochloride was completely dissolved by stirring.

700 ml of hydrochloric acid was added at once. Then a solution of 490 g of sodium nitrite in 1 liter of water was added dropwise within one hour at a temperature between 25 and 30°C. The azimido compound crystallized as it was formed.

After the addition was finished, stirring was continued for one hour at 25°C.

The azimido compound was filtered and washed several times with water. It was dried in a ventilation dryer at 30°C.

1485 g (85% yield) with m.p. 114 - 115°C was obtained.

Step IV: Methyl 2-methoxy-4,5-azimidobenzoate

7.4 L of methanol and 1485 g of 1-acetyl-5-carbomethoxy-6-meth-oxybenzotriazole were introduced into a 20 liter reaction vessel equipped with a sealed mechanical stirrer, a rising backwash skirt and dropping funnel.

The mixture was heated with stirring to the reflux temperature. Then 460 ml of hydrochloric acid was added. Complete dissolution was observed. Then 100 g of bone charcoal (3 S) was added and the reflux conditions were maintained for 20 minutes.

The bone char was filtered from the hot mixture. The latter was cooled to 0°C, whereby the azimidoester crystallized out. This was filtered, washed several times with water and dried in a ventilation dryer at 50°C.

780 g (63% yield) of product was obtained.

The product was purified by dissolving 780 g of azimido ester in a solution of 1 liter of concentrated ammonia in 3.9 liters of water, followed by the addition of 100 g of bone charcoal. The mixture was then allowed to stand for 10 minutes, after which it was filtered.

The filtrate was acidified with hydrochloric acid up to pH = 1. The azimidoester crystallized out. It was filtered and washed several times with water.

The impure product was again dissolved in a solution of

1 liter of ammonia in 3.9 liters of water and filtered with lOO g of charcoal.

The azimido compound was precipitated at a pH = 1 with hydrochloric acid. It was filtered, washed with water and dried in a vent dryer at 50°C.

742 g of a colorless product with m.p. 192°C. Total yield 60%.

Step V: N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide hydrochloride

621 g of methyl-2-methoxy-4'5-azimidobenzoate, 3 liters of anhydrous toluene and 425 9 l-allyl-2-aminomethylpyrrolidine were introduced into a 6 liter three-necked flask equipped with a sealed mechanical stirrer, thermometer and ascending reflux condenser. The mixture was kept under reflux conditions for 5 hours.

The mixture was cooled to 50°C, after which 600 ml of a solution of 350 g of hydrogen chloride in 1 liter of ethanol was added. The temperature rose to 70 - 80°C. The mixture was cooled to 50°C, after which the toluene layer was separated from an oily residue. The latter was taken up in 3 liters of methanol. The mixture was heated until complete dissolution was achieved. This solution was filtered at the boiling temperature with 150 g of charcoal (3 S). 6 liters of methyl ethyl ketone were added to the filtrate, after which the mixture was cooled to 0°C. The benzamide crystallized slowly. It was filtered and washed with 500 ml of methyl ethyl ketone in two portions. It was then dried at 50°C in a ventilation dryer.

687 g of N-(1'-allylpyrrolidiny1-2'-meth-yl)-2-methoxy-4,5-azimidobenzamide hydrochloride were obtained (yield 65%). Melting point: 206 - 208°C.

HC1 %: theoretical 10.38

found 10.13

purity in non-aqueous medium with HC1 04: 99.5.

Example 3

Step I: 2-methoxy-4-amino-5-nitrobenzoic acid

In the same way, 16.7 g (0.1 mol) of 2-methoxy-4-amino-benzoic acid was nitrated.

13.8 g of 2-methoxy-4-amino-5-nitrobenzoic acid were obtained with m.p. 254°C. Yield: 64.9%.

Step II: 2-methoxy-4,5-diaminobenzoic acid

As described above, 28 g (0.13 mol) of 2-methoxy-4-amino-5-nitrobenzoic acid were hydrogenated, and 19.8 g of 2-methoxy-4,5-di-aminobenzoic acid were obtained (yield 83.6%).

Step III: 2-methoxy-4,5-azimidobenzoic acid

36.4 g (0.2 mol) of 2-methoxy-4,5-diaminobenzoic acid was treated as described above with sodium nitrite in the presence of hydrochloric acid. 31 g of 2-methoxy-4,5-azimidobenzoic acid was obtained (yield: 80.3%). Sm.p. 245°C.

Step IV: N-(1-allyl-2-pyrrolidylmethyl)-2-methoxy-4,5-azimidobenzamide

38.6 g (0.2 mol) of 2-methoxy-4,5-azimidobenzoic acid was dissolved in anhydrous toluene, and 56 g (0.4 mol) of 1-allyl-2-amino-methylpyrrolidine was added. The mixture was heated to 50°C, after which 42 g (0.3 mol) of phosphoric anhydride was added. The mixture was heated to reflux for 3 hours and then cooled to 80°C. After addition of water, the aqueous layer was made alkaline. The crystals were filtered off, washed with water and then dissolved in 450 ml of acetone. After crystallization, the product was filtered, washed and dried.

40.4 g of N-(1-allyl-2-pyrrolidylmethyl)-2-methoxy-4,5-azimidobenzamide were obtained (yield: 65%, m.p. 139°C).

Example 4

Step I: 2-methoxy-4-acetylamino-5-nitrobenzoic acid

In the same way, 20.9 g (0.1 mol) of 2-methoxy-4-acetyl-aminobenzoic acid was nitrated. 16.5 g of 2-methoxy-4-acetylamino-5-nitro-benzoic acid were obtained (m.p. 186 - 188°C; yield: 64.9%).

Step II: 2-methoxy-4-acetylamino-5-aminobenzoic acid

As described above, 32 g (0.13 mol) of 2-methoxy-4-acetylamino-5-nitrobenzoic acid was hydrogenated, and 24.5 g of 2-methoxy-4-acetylamino-5-aminobenzoic acid was obtained (yield: 84%).

Step III: 1-acetyl-5-hydroxycarbonyl-6-methoxybenzotriazole

8.7 g (0.039 mol) of 2-methoxy-4-acetylamino-5-aminobenzoic acid was treated as described above with sodium nitrite in the presence of hydrochloric acid. 7.3 g of 1-acetyl-5-hydroxycarbonyl-6-methoxy-benzotriazole were obtained (m.p. 208-212°C; yield: 79.6%).

Step IV: 1-acety1-5-chlorocarbonyl1-6-methoxybenzotriazole

4.7 g of 1-acetyl-5-hydroxycarbonyl-6-methoxy-benzotriazole, 16.5 ml of thionyl chloride, 11 ml of chloroform were placed in a 250 ml flask. The mixture was heated to the reflux temperature for 30 minutes. After cooling, the solvents were removed under reduced pressure.

4.7 g of 1-acetyl-5-chlorocarbonyl-6-methoxy-benzotriazole were obtained (yield: 92.7%, m.p. 170°C).

Step V: N-(1-allyl-2-pyrrolidylmethyl)-2-methoxy-4,5-azimidobenzamide hydrochloride

2.2 g (0.016 mol) of 1-allyl-2-aminomethyl-pyrrolidine, 28 ml of methyl ethyl ketone was introduced into a 250 ml flask. After that was

3.8 g (0.015 mol) of 1-acetyl-5-chlorocarbonyl-6-methoxy-benzotriazole added. The mixture was allowed to stand overnight, the solvent was removed under reduced pressure. 5 ml of hydrochloric acid (d = 1.18) and 28 ml of ethyl alcohol were added and the mixture was heated to reflux for 30 minutes. After cooling, the solvent was removed under reduced pressure, and the residue was dissolved in boiling dimethylformamide. The mixture was filtered, and after cooling the benzamide crystallized. The crystals were filtered, washed with some dimethylformamide, then with tetrahydrofuran,

and dried at 50°C. 3.2 g of N-(1-allyl-2-pyrrolidylmethyl)-2-meth-oxy-4,5-azimidobenzamide hydrochloride was obtained (yield: 60.7%). Sm.p. 206 °C. HC1 % : theoretical 10.38

found 10.27.

Claims (1)

Analogous process for the preparation of the therapeutically active N-(1'-allylpyrrolidinyl-2'-methy])-2-methoxy-4,5-azimido-benzamide of the formula as well as its tautomeric forms and its hydrochloride, characterized in that a compound of the formula where X is hydroxyl or an alkoxy radical with 1-5 carbon atoms, and R and R' are hydrogen or an acyl radical, preferably the acetyl radical, is nitrated, the 5-nitro compound is hydrogenated, and the 5-amino compound thus obtained is diazotized, after which the amidation is carried out by direct reaction of the obtained 4,5-azimidophorbindeise with 1-allyl-2-aminomethylpyrrolidine, or by reaction of their reactive derivatives, and the obtained N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4 ,5-azimidobenzamide is optionally transferred to its hydrochloride.