CS219314B2 - Method of making the n-/1-allyl-2-pyrrolidinylmethyl/-2-methoxy-4,5-azi,idobenzamide - Google Patents

Abstract

1475234 N - [(1 - Allyl - 2 - pyrrolidinyl)- methyl] - 2 - methoxy - 4,5 - azimidobenzamide SOC D'ETUDES SCIENTIFIQUES ET INDUSTBIELLES DE L'ILE DE FRANCE 24 Feb 1975 [11 Jan 1975] 7674/75 Heading C2C The invention comprises the title compound and acid addition and quaternary ammonium salts thereof and its preparation by nitrating a compound of the formula wherein X is OH or C 1-5 alkoxy and R and R<SP>1</SP> each or H or carboxylic acyl or R and R<SP>1</SP> together from a phthaloyl radical, hydrogenating and, if necessary, deacylating the corresponding 5-amino compound, diazotizing the latter to produce a 4,5-azimido compound of the formula wherein R<SP>11</SP> is H or carboxylic acyl, and reacting this compound or a reactive derivative thereof with l-allyl-2-aminomethylpyrrolidine, or a reactive derivative thereof. Methyl 2 - methoxy - 4 - amino - 5 - nitrobenzoate, methyl 2 - methoxy - 4 - acetamido - 5- nitrobenzoate, and 2-methoxy-4-amino-5-nitrobenzoic acid are obtained by nitrating methyl 2- methoxy-4-aminobenzoate, methyl 2-methoxy- 4-acetamidobenzoate and 2-methoxy-4-aminobenzoic acid respectively. Pharmaceutical compositions, suitable for oral or parenteral administration, contain the above compound or pharmaceutically acceptable acid addition or quaternary ammonium salts thereof together with pharmaceutically acceptable diluents or carriers.

Description

Accordingly, the present invention provides a process for the preparation of N (11'-allyl-2'-pyridinyl) -2-methoxy-4,5-azimidobenzamide and its salts with pharmaceutically acceptable acids, characterized in that: the compound of formula (I)

wherein X is hydroxyl or C 1 -C 5 alkoxy and R is hydrogen or acetyl, nitrates to form a compound of formula II cox

and i) wherein X and R are as defined above, which. is hydrogenated to form a compound of formula III:

wherein X and R are as defined above, which is then diazotized to form a compound of formula IV cox

(IV) wherein X and R are as defined above, which is hydrolyzed when R is other than hydrogen, and the resulting compound is reacted with N-α-H-4-aminomeilhypyrrolidine or reactive thereof. and optionally forming the compound with a pharmaceutically acceptable acid to form a salt.

Thus, according to the invention, the lower alkyl ester of 2-methoxy-4-aminobenzoic acid is nitrated, hydrogenates the resulting 2-methoxy-4-amino-5-nitro-benzoic acid alkyl ester, further diazotizes the 2-methoxy-4,5-alkyl ester thus prepared. and the latter is converted to the amide by treatment with N-allyl-2-aminomethylpyrrolidide.

In the first reaction, methyl 2-methioxy-.alpha.-aminobenzoate is preferably used, but other lower alkyl esters such as ethyl, propyl, butyl or amyl esters may also be used.

The hydrogenation of the nitro group according to the invention can be carried out with hydrogen in the presence of a catalyst such as platinum, palladium or palladium. Raney nickel. or. The reduction can be carried out with hydrogen in the bottom state, i.e. by reacting the coiv with an acid, such as a combination of iron, tin or zinc, with a strong acid, for example hydrochloric acid, and with other suitable hydrogenating agents.

The obtained 4,5-diamine derivative can be diazotized with suitable diazotizing agents such as sodium nitrite and hydrochloric acid or isoamyl nitrite to give the corresponding

4.5-α-imide derivative.

The azimide derivative can be converted to the amide by reaction with N, N-llyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-hydroxy-2-methyl-2-hydroxy-2-methyl-2-hydroxy-2-methyl-2-hydroxy-2-hydroxy. this reaction may be carried out without solvent or in the presence of a solvent. Among the solvents, substances which are inert under the reaction conditions used, such as alcohols, polyols, benzene, toluene, dioxane, chloroform and dimethyl ether of diethylene glycol, can be used. .. Also. it is possible to use an excess of the amine which is used as the reactant instead of the solvent. It may be advantageous to heat the reaction mixture during the amide preparation, for example until the solvent is boiled.

In the process of the present invention, the 2-methoxy-4-acetylamino-benzoic acid alkyl ester is used as the starting compound.

The reaction described above can also be carried out by cleaving the acetyl group before reducing the nitro group, whereupon the obtained

The 4.5'-diaminoderivative can be used for the following reactions as described above.

The process according to the invention is further illustrated in the reaction scheme:

with

HNO $ β

(Лапеу / nickel j

CH-CH-CH3

The process according to the invention starts from 2-methoxy-4-amino-benzoic acid, which can be mined, and then the 2-methoxy-4-amino-5-nitrobenzoic acid thus obtained is reduced to the resulting 2-methoxy-4-acid. The 5-diaminobenzoic acid is diazotized, the resulting 2-methoxy-4,5-azimidobenzoic acid is converted to the amide either by reaction with a reactive N-α-methyl-2-aminoethylpyrrolidone derivative, or by reacting the reactive derivative of said acid with N- adyld-aminomethylpyrrolidine. There was thus obtained N - '(1'-α-Hyl-2‘-pyrrolidinylmethyl) -2-methyl-4,5-azimidobenzamide.

The same procedure can be used starting from 2-methoxy-4-acetyla ^, minobenzoic acid, which is nitrated, the resulting 2-methoxy-.alpha.-acetylamino-S-nitrobenizoic acid is reduced and diazotized as described above. . Thereafter, the 1-acetyl-5-carboxy-6-methoxybenzotriazole thus prepared is converted to a compound of the invention by treating it with a reactive derivative of N-allyl-2-aminomethyl-pyrrolidolyl or by treating the amine with a reactive acid derivative. and the reaction product is dealcetylated, preferably without isolation.

In this synthesis, the following can be used as reactive amine derivatives: the product of the reaction of an amine with phosphorus pentachloride, phosphorus oxychloride, dialkyl phosphite, diaryphosphite or o-phenylene phosphite chloro derivatives, alkyl phosphite or arylphosphite dichloro derivatives or N-alilylpyerolidinyl-2-methylisothiocyanate. The above derivatives can be used to react with the acid in situ, i.e. immediately after preparation or prior isolation. However, the scope of the invention is not limited to these reactive derivatives.

The following compounds can be used as reactive acid derivatives: reactive esters, for example cyanomethylbstbr, methoxybutyl ester, phenyl ester, optionally substituted phenyl esters, halides of said acid such as corresponding chlorides or bromides, azide, symmetrical anhydride, mixed anhydrides, for example prepared by reaction with lower alkyl esters chloroformic acids, furthermore hydrazide, azolides such as triazolides, tetrazolides, especially imidazolides and isocyanates. However, the scope of the invention is not limited to these substances.

Furthermore, it is possible to carry out the reaction of the free acid with a free amine in the presence of a condensing agent such as a carbodiimide group, for example dicyclohexylcarbodiimide, silicon tetrachloride and phosphorus pentoxide.

The compounds prepared by the process of the invention may optionally be converted into salts with pharmaceutically acceptable inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, acetic, tartaric, citric, methanesulfonic acid.

For therapeutic purposes, the compounds of the invention may be used in the form of pharmaceutically acceptable acid salts together with pharmaceutically acceptable excipients and / or diluents, in the form of tablets, dragees, injectable solutions, syrups or any other form. forms.

Experimental pharmacological tests have shown that the compound of the invention, hereinafter referred to as &quot; Substance A &quot;

B. Anti-emetic activity (DE 50, subcutaneously, _p si) of efficacy at comparatively low -toxicities when compared to 3 some commercially available benzamide derivatives known to be superior in efficacy. The following compounds were used for the comparative tests:

1. N, N-Diethylamino-methyl-2-methoxy-4-amino-5-chlorobenzamide (substance B), used under the designation 'Metoclopramide',

2. N- (N-ethyl-4-pyrrolidinylmethyl) -2-methoxy-4,5-azimidiobenzamide (compound C), see Example 2 of French Patent No. 1,572,168.

The results of the experiments are as follows:

Toxicity: (DL 50, mg / kg, intravenously, 5 days, mouse):

LátkaDL50

A92.7

B38

C69.2

Apesis caused by A apomorphine5,4 hydergine63 copper sulphate0,99 lanatoside133

26 ', 8 14 (CI / kg

207 - jug / kg

0.92 mg / kg

4.5 mg / kg

C. Therapeutic index __DL50, intravenous, mouse ~ DE50, subcutaneous, -psi

Compound J

A 100-ΙΟ ²

B 14. Ю ²

C 49.102

D. Cataleptic efficacy (DE50, subcutaneous, mg / kg)

Compound DE50

And 10% to -200mg / kg

B30.8

C84.8

Thus, the compound of the present invention is characterized by a substantially improved therapeutic index when compared to other agents, with reduced cataleptic activity.

The above results were potvťzeny in medicine where it was shown that the compound of this invention is an effective antiemetic during the treatment of both -Children and the -dospělých particularly -in case of treating emesis symptoms of toxic or infectious syndromes, and while ^one or pneumocefalografii - brain disease, in naupathia, or in the treatment of emetic syndromes of postchemical, post-radiotherapy and post-operative origin.

The invention is further illustrated by the following non-limiting examples.

Example 1

Stage 1

2-m-Ethoxy-4-amino-5-nitrobenzoic acid methyl ester

A mixture of 72.5 g (0.4 mol) of 2-methoxy-4-aminobenzoic acid methyl ester, 140 ml of acetic acid and 126 g of benzoic anhydride is heated to 40 DEG C. in a 2-liter flask with stirrer, thermometer and dropper. and 48 ml of nitric acid (1.49) is added dropwise over about 30 minutes. After the addition of nitric acid was complete, the reaction mixture was stirred at 40 ° C for 2 hours, then the reaction mixture was poured into a 600 ml solution of 0.4 mole of sulfuric acid in methanol. The reaction mixture was further stirred, 1600 ml of ice and ice were added, and the resulting crystals were filtered off with suction to give 2-methoxy-4-amino-5-nitrobenzoic acid methyl ester in 55.2 g (61%), mp 214 Noc: 2 ° C.

Stage 2

2-Methoxy-4,5-diamino-benzoic acid methyl ester

A mixture of 555 g of 2-methoxx-4-amino-5-nitrobenzoic acid methyl ester, 2500 ml of methanol and 300 g of Raney nickel is placed in a 5-liter autoclave, pressurized with hydrogen into the autoclave, then raising the temperature to 50 ° C and is maintained at this level throughout the absorption. After cooling, the nickel is filtered off, distilled off under reduced pressure and the crystals formed are washed twice with 600 ml of water each time and then dried at 50 ° C.

Yield: 305 g (63.5%); 2-methoxy-4,5-diaminobenzoic acid methyl ester, m.p. 139-140 ° C.

Stage 3

2-Methoxy-4,5-alzimidobenzoic acid methyl ester

Mixture. 294 g (1.5 mol) of methyl 2-methoxy-4,5-diaminobenzoyl ester, 2500 ml of water and 550 ml of hydrochloric acid (1,18) are placed in a five-liter flask equipped with stirrer, thermometer and dropper, mixture Cool to. A solution of 108 g of sodium nitrite in 500 ml of water is added dropwise. Next, the reaction mixture is added. The mixture is heated to 35 DEG C. over 30 minutes, cooled, the crystals obtained are filtered off with suction, washed three times with 300 ml of methylene chloride each time, followed by water and the like. drying at 30 ° C yielded 256 g of 2-methoxy-4,5-azimidimidobenzoic acid methyl ester (i.e., 82.4% yield), mp 190-192 ° C.

Stage 4

N- (1-Allyl-2H-pyrrolidinyimethyl) -2-methoxy-4,5-azimidobeosamide hydrochloride

A mixture of 621 g of 2-methoxy-4,5-α ^, zimidobenzoic acid methyl ester, 3 liters of anhydrous toluene and 425 g of the corresponding amine is charged to a 3-neck, 6-liter flask equipped with sealed mechanical stirring, thermometer and reflux condenser. The reaction mixture is kept under reflux for 5 hours, then cooled to 50 ° C, 600 ml of a solution of 350 g of hydrogen chloride in 1 liter of ethanol are added, the temperature is raised to 70-80 ° C and the reaction mixture is cooled to 50 ° C. and the toluene layer is separated from the oily residue.

This. the residue is dissolved in 3 liters of methanol, heated until complete dissolution, the solution is filtered while boiling using 150 g of activated carbon (3S).

6 liters of methyl ethyl ketone are added to the filtrate, the reaction mixture is cooled to 0 ^DEG C. The benzamide is crystallized slowly, filtered off with suction and washed with 500 ml of methyl ethyl ketone in two portions and dried at 50 DEG C. in a ventilated oven.

687 g (65%) of N - (.alpha.-allyl-2- (pyrimidinylmethyl) -2-methoxy-4,5-azimidobenzamide hydrochloride, m.p. 206 DEG-208 DEG C., are obtained.

Analysis:

Hydrochloride, Found: 10.38% o, Calculated: 10.18%.

Purity by titration with perchloric acid in a non-aqueous medium: 99.5%.

Example 2

Stage 1

2-Methoxy-4-acetylamino-5-nitrobenzoic acid methyl ester

A mixture of 223 g (1 mole) of 2-methoxy-4-acetylamino-benzoic acid methyl ester, 350 ml of acetic acid and 337 g of acetic anhydride is placed in a 2-liter flask with soda. with a stirrer, a thermometer and a dropper, the reaction mixture is heated to about 40 ° C to give a clear dissolution. The reaction mixture was then added. After cooling to 15 DEG -20 DEG C., 106 g (1.5 mol) of nitric acid (1.49) are added dropwise. The addition of nitric acid is complete, the reaction mixture is stirred for a further 30 minutes at 40 ° C and, after cooling, poured into 5 liters of water.

Yield: 182 g (68%) of 2-methoxy-4-methyl-amino-5-nitrobenzoic acid methyl ester, m.p. 163-165 ° C.

Stage 2

2-Methoxy-4-acetamido-5-aminobenzoic acid methyl ester hydrochloride

A 5 liter autoclave is charged with a mixture of 1 kg of 2-methoxy-4-acetamido-5-nitrobenzoic acid methyl ester, 5 liters of ethyl acetate and 3 teaspoons of Raney nickel, heated to 75 ° C with stirring, pressurized with hydrogen and then rapidly deploys the reduction reactions. With respect to cooling, the reaction vessel is vented, thereby raising the temperature to 95 ° C, and this temperature is maintained during the entire absorption flow, which lasts 10 minutes. Hydrogen is replaced four to five times in the same way until absorption ceases.

The reaction is carried out during. hours and 15 minutes, and after cooling, the nickel is filtered off and then washed with 100 ml of ethyl acetate. The filtrate is acidified by the addition of 500 ml of a solution of 350 g of hydrogen chloride in 1000 ml of ethanol, thereby crystallizing the hydrochloride which is filtered off with suction at 15 DEG C. and washed with 500 ml of ethyl acetate. The product is dried in a ventilated oven at 50 ° C.

905 g (88%) of the product are obtained.

Stage 3

Tacetyl-5-methoxyicarbonyl-6-methoxybenzotriazole

A mixture of 14 liters of water and 1920 g of 2-methoxy-4-acetamido-5-aminobenzoic acid hydrochloride is placed in a 20-liter reaction vessel equipped with a mechanical stirrer, thermometer and dropper suitably connected to allow cooling using a cooling bath. The hydrochloride dissolves completely during stirring.

700 ml of hydrochloric acid are added in one portion, followed by the dropwise addition of a solution of 490 g of sodium nitrite per liter of water at a temperature between about 25-30 ° C over an hour. The azimido compound crystallizes as it is formed.

Once the above addition is complete, stirring is continued at 25 ° C for one hour.

The azimido compound is aspirated and washed several times with water; it is then dried in a ventilated oven at 30 ° C.

This gave 1485 g (85%) of the product, m.p. 114-115 ° C.

Stage 4

2-Methoxy-4,5-azimidobenzoic acid methyl ester

A mixture of 7.4 liters of methanol and 1485 g of 1-acetyl-5-methoxycarbonyl-6-methoxybeinzotriazole was charged to a 20 L reaction vessel equipped with a sealed mechanical stirrer, reflux condenser and dropper.

The reaction mixture is heated under stirring to reflux, then 460 ml of hydrochloric acid are added, complete dissolution is observed, 100 g of activated carbon (3S) are added, and the mixture is refluxed for 20 minutes.

The activated carbon is filtered off from the hot reaction mixture, then the reaction mixture is cooled to 0 ° C, after which the azimido ester crystallizes, which is filtered off with suction, washed several times with water and dried in a vacuum oven at 50 ° C.

Yield: 780 g (6.3%).

This is 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 activated carbon. The mixture was allowed to stand for 10 minutes and then filtered.

The filtrate was acidified by addition of hydrochloric acid to pH 1; The azimidoester crystallizes out and is filtered off with suction and washed several times with water.

The still wet product is redissolved in a solution of 1 liter of ammonia in 3.9 liters of water, and the filter is filtered after addition of 100 g of activated carbon.

The azimidos compound is precipitated with hydrochloric acid to acidify to pH 1, the precipitate is filtered off with suction, washed with water and dried in a ventilated oven at 50 ^° C.

A total of 742 g (60%) of a colorless product was obtained, mp 192 ° C.

Stage 5

N- (1'-allyl-2'-pyrrolldinylmethyl) -2-methoxy-4,5-azimidobertziamide hydrochloride

A mixture of 621 g of 2-methoxy-4,5-azimidobenzoic acid methyl ester, 3 liters of anhydrous toluene and 425 g of amine is placed in a 6-liter three-necked flask equipped with a mechanical stirrer, thermometer and reflux and maintained at reflux for 5 hours.

The reaction mixture is then cooled to 50 [deg.] C. and then diluted with 600 ml of a solution of 350 g of hydrogen chloride in 1 liter of ethanol. The temperature is thereby raised to 70-80 ° C, the reaction mixture is cooled to 50 ° C, and the toluene layer is separated from the oily residue.

The residue was dissolved in 3 L of methanol, heated to complete dissolution, and the solution was filtered while boiling after addition of 250 g of activated carbon (3S).

After adding 6 liters of methyl ethyl ketone to the filtrate, the reaction mixture was cooled to 0 ° C. The behzamide derivative slowly crystallized, was filtered off with suction and washed with two 500 ml portions of methyl ethyl ketone, and then dried at 50 ° C in a ventilated oven.

Yield: 687 g (65%) of N- (1'-allyl-2'-pyrrolidinylmethyl) -2-methoxy-4,5-azimidobenzamide hydrochloride, m.p. 206-208 ° C.

Analysis:

HCl calculated: 10.38%, found: 10.13%.

Purity by titration with non-aqueous perchloric acid: 99.5.

Example 3

Stage 1

2-Methoxy-4-amino-5-nitnobenzoic acid

16.7 g (0.1 mol) of 2-methoxy-4-aminobenzoic acid are nitrated in the same manner.

Yield: 13.8 g (64.9%) of 2-methyl-2-methoxyl-α-piperazonate, mp 254 ° C.

Stage 2

2-Methoxy-4,5-diaminobenzoic acid

As described above, a reduction of 28 g (0.13 mol) of 2-methoxy-4-amino-5-nitrobenzoic acid yielded 19.8 g of 2-methoxy-4,5-diaminobenzoic acid corresponding to the yield 83.6%.

Stage 3

2-Methoxy-4,5-azimidobenzoic acid

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

Stage 4

N- (1'-allyl-2 '' - pyrrolidinylmethylmethyl) -2-methoxy-4,5-azimidobenzamide

38.6 g (0.2 mol) of 2-methoxy-4,5-azimidobenzoic acid are dissolved in boiling toluene and 56 g (0.4 mol) of N-allyl-2-aminomethylpyrrolidine are added to the solution. The reaction mixture is heated to 50 ° C, 42 g (0.3 mol) of phosphorus pentoxide are added and the reaction mixture is heated under reflux for 3 hours, cooled to 80 ° C and, after the addition of water, The precipitated crystals are filtered off with suction, washed with water, then dissolved in 450 ml of acetone, and after crystallization the precipitated product is filtered off with suction, washed and dried.

Yield: 40.4 g (65%) of Ν- (Γ-allyl-2‘-pyrrolidinylmethyl) -2-methoxy-4,5-azimidobenzenamide, m.p. 139 ° C.

Example 4

Stage 1

2-Methoxy-4-acetylamino-5-nitrobenzoic acid

Similar. nitrated 20.9 g (0.1 mol) of 2-methoxy-4-acetylaminobenzoic acid to give 16.5 g of 2-methoxy-4-acetylamino-5-nitro-benzoic acid, m.p. 188 ° C (64.9% yield).

Step 2, 2-Methoxy-4-acetylamino-5-lmil-1-enoic acid

As mentioned above, by reducing 32 g (0.13 mmol) of 2-methoxy-4-acetylamino-5-nitrobenzoic acid, 24.5 g (84%) of 2-methoxy-4-acetylamin-5 is obtained. -ammobenzoové.

S bake 3 1-xetyl-5-carboxy-6-methoxybenzene

8.7 g (0.039 mol) of 2-methoxy-4-acetylamino-5-aminoincene are treated with sodium nitrite in the presence of hydrochloric acid to give 7.3 g of 1-acetyl-5-carboxy-6-methoxybenzoate. mp 208-212 ° C (yield 79.6%).

Step 4 1-Acetyl-5-chlorocarbonyl-6-methoxybenzotriazole

A mixture of 4.7 g of 1-carboxy-5-carboxy-6-methoxybenzazole, 16.5. ml of thionyl chloride and ml of chloroform are added to. 250 mL flask and reflux for 30 minutes. After cooling, the solvents were distilled off under reduced pressure. Yield 4.7 g. (92.7%) gave 1-acetyl-5-chlorocarbonyl-6-methoxybenzenotrianol, 11. 170 ° C.

Stage 5

N- (1'-allyl-2'-pyrrolidinyl • methyl) -2-methoxy-4,5-azimidobenzamide hydrochloride

2.2 g (0.016 mol) of N-allyl-2-aminomethylpyrrolidine, 29 ml. The m-thylethylketone was added to a 250 mL flask, 3.8 grams were added. (0.015 mol) of 1-acetyl-5-chlorocarbonyl-6-methoxybenzotriazole, the reaction mixture was allowed to stand overnight, after which the solvent was distilled off under reduced pressure. pressure. 5 ml of hydrochloric acid (1.18) and 28 ml of ethanol are added and the reaction mixture is again heated to reflux for 30 minutes. After cooling, the solvent was distilled off in vacuo, the residue was dissolved in boiling dimethylformamide, the reaction mixture was filtered and, after cooling, the benzamide derivative crystallized. The crystals are filtered off with suction, washed with a small amount of dimethylformamide, then with tetrahydrofuran and dried at 50 ° C.

Yield 3.2 g (60.7%) of N - (- allyl-2H-pyrrolidinylmethyl) -2-methoxy-4,5-azimidobenzamide hydrochloride, mp 206 ° C .

Analysis:

HCl, calc. 10.38%, found 10.27%.

Claims (1)

the subject of the invention A process for the preparation of N- (1'-allyl-2,4-trifluoromethylmethyl) -2-methoxy-4,5-azimidobenzamide and its salts with pharmaceutically acceptable acids, characterized in that the compound of formula (I) is x (1). where X is hydroxy or C 1 -C 5 alkoxy, and R is hydrogen or -acetyl, nitrates to form a compound of formula (II) wherein X and R are as defined above, which is then diazotized to form compounds of formula IV cox (IV) CQX (II) wherein X-and R are as defined above, which is hydrolyzed when R is other than hydrogen, and the resulting compound is reacted with or reactive with - N-α-methyl-2-aminomethylpyrrolidine, a derivative and optionally reacting the resulting compound with a pharmaceutically acceptable acid to form salts. wherein X and R are as defined above, which is hydrogenated to form a compound of formula III Severography, n. P., Plant 7 Most Price 2,40 Kčs