FI57103B - EXAMINATION OF ANTI-METAL ACTIVATION 5- (1-ALLYL-2-PYRROLIDINYLMETHYLCARBAMOYL) -6-METHOXY-1H-BENZOTRIAZOLE - Google Patents

Description

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_ · (44) Date of deflection and moon. -

Patent and registration authorities AnaMcan uttafd odiutUkrMtee published 29.02.80 (32) (33) (31) P) 74 «« y etuelltiut-jfeglrd prtortut H.oi.75

Federal Republic of Germany (DE) P 2500919.2 (71) Societe d'fitudes Scientifiques et Industrielles de 1'Ile-de-France, k6 boulevard de Latour-Maubourg, 75 Paris 7 °, France-Frankrike (FR) (72) Gerard Bulteau, Paris, Jacques Acher, Itteville, Claude Collignon,

Saint Remy-les-Chevreuses, Jean-Claude Honier, Lardy, France-Frankish (FR) (I1 *) Oy Kolster Ab (5U) Method for the antiemetic activity of 5- (1-allyl-2-pyrrolidinylmethylcarbamoyl) -6 -methoxy-1H-benzotriazole -Forfarande för framställning av antiemetiskt Aktiv 5- (1-allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole

The present invention relates to a process for the preparation of antiemetic 5- (1-allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole, its pharmaceutically acceptable acid addition salts and its quaternary ammonium salts.

It was found that the compound of the invention is superior in pharmacological properties to the corresponding compounds as well as to the still known and commercially available "metoclopramideM" compound.

The structure of a compound of the invention may be schematically represented by three tautomeric forms.

2 57103

CO - NH - CHg-X

JL ® CO - NH - CH2_I

Γ Γ °° Η3 CH2-CH-OH. L 'Y

Ί / | 3 ch2-ch = ch2 _ H H »N ---- N / f N ^ JO-HH-OH, - OCH 1 ULh3 CH2-CH = CH2 li

HN -N

The invention is characterized in that the compound of formula COX

] - 0CH3

V

NRR 'wherein X is a hydroxy group or an alkoxy group having 1 to 5 carbon atoms and R and R' represent a hydrogen atom or an acyl group, nitrated, the resulting 5-nitro compound is hydrated, the resulting 5-amino compound is diazotized, the resulting 1H-benzotriazole compound is amidated by direct reaction with 1- with allyl-2-aminomethylpyrrolidine or by a reaction between their reactive derivatives and that the compound obtained is, if necessary, converted into an acid addition salt with a pharmaceutically acceptable inorganic or organic acid or a quaternary ammonium salt.

3 57103

In the first step of the process according to the invention, methyl 2-methoxy-N-aminobenzoate is preferably used. However, other lower alkyl esters, such as ethyl, propyl, butyl or pentyl esters, may be used as well.

The hydrogenation of the nitro group according to the process of the invention can be carried out either with hydrogen in the presence of catalysts such as platinum, palladium or Raney nickel or with metals in the presence of strong acids such as Fe / HCl or Sn / HCl or Zn / HCl as well as other suitable hydrogens. -wool substances.

The 1 +, 5-diamino compound thus obtained can then be diazotized with a suitable diazotizing agent such as NaNQ 6 / HCl or isoamyl nitrite to give the corresponding 1,5'-azimido compound.

The azimido compound can be amidated with 1-allyl-2-aminomethylpyrrolidine.

This reaction can be carried out in the presence or absence of solvents. Such systems can be used as solvents 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 reactant amine as a solvent. It may be advantageous to heat the reaction mixture during amidation, e.g. to the boiling points of the above-mentioned solvents.

According to the above synthetic route, the reaction can be carried out starting from the lower alkyl ester of 2-methoxy-U-acylaminobenzoic acid. Instead of the acetyl group preferably used to replace the amino group of the i + position in the above starting material, other suitable cleavable groups such as formyl, propionyl, butyryl, alkoxycarbonyl, phthaloyl or benzoyl groups may be used, as well as other suitable cleavable groups. . The above reaction can also be carried out by cleaving the acyl group before hydrogenation of the nitro group. The U, 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 after amidation.

The process of the invention is further described by the following reaction scheme.

• · · ϊ; '* 57103 COOCHj COOCH ^ °° Η3 r ^^ V-ocH ^ + fl] jo3 -> 02νΟ ^ Ι1

NH I

NH2 · '»COOCH ,, I S COOCH ^ ff' +, us ^ ev) y ° 2H HglT% / ™ s ms COOCHj COOOHj f ^ r00" 5 \ pr *

Vv ~ rY

H -NH

COOCtij co _ NH _ ΐ'γ0 ”5 J 1 s Ργο ™, 1h2 Kaj + ^ - ° ¾4 ^ ^ IF ί» II I CH -CH = CH CH2

N -N-H j I

N-NH

57103 5

According to the process of the invention, the reaction can be started from 2-methoxy-N-aminobenzoic acid, which can be nitrated, the 2-methoxy-U-amino-5-nitrobenzoic acid hydrate formed, the 2-methoxy-U, 5-diaminobenzoic acid formed, diazotized to give the 6-carboxy- 6-Methoxy-1H-benzotriazole may react either with a reactive derivative of 1-allyl-2 "aminomethylpyrrolidine or in the form of one of its reactive derivatives with 1-allyl-2-aminomethylpyrrolidine. 5- (1-Allyl-2-pyrrolidinylmethyl) carbamyl methoxy-1H-benzotriazole.

The same synthetic route can be applied to 2-methoxy-U-acylaminobenzoic acid, as specified above.

The starting material may be, for example, 2'-ethoxy-k-acetylaminobenzoic acid. This compound can be nitrated, so that the 2-methoxy-1 + -acetylamino-5-nitrobenzoic acid thus obtained can be hydrogenated and diazotized as described above. The finally formed 1-acetyl-5-carbohydroxy-6 * -methoxybenzotriazole can be reacted into a compound of the invention, either by reacting the above acid with a reactive derivative of 1-allyl-2-aminomethylpyrrolidine or by reacting the above amine with a reactive derivative of the acid and reacting possibly deacylated without prior isolation. Deacylation can be performed before hydrogenation or diazotization. This procedure is necessary, for example, in the case of U-phthaloylamino substitutions. In the above synthetic route, the following products can be used as reactive derivatives of the amine;

Reaction products of amine with phosphorus chloride, phosphorus oxychloride, chlorinated dialkyl or diaryl or orthophenylene phosphites, dichlorinated alkyl or aryl phosphites or 1-allylpyrrolidinyl-2-methyl isothiocyanate.

The above derivatives can be reacted with the acid as such or after isolation. However, the above-mentioned reactive derivatives do not limit the invention.

The following compounds can be used as reactive derivatives of the acid: reactive acid esters, e.g. cyanomethyl ester, methoxymethyl ester, substituted or unsubstituted phenyl esters, acid halides such as chlorides and bromides; acid azides; symmetrical anhydrides; mixed anhydrides, e.g. formed with lower alkyl chloroformates; hydrazides; azolides such as triazoles, tetrazolides especially imidazolides; acidic isocyanates. However, the above-mentioned derivatives do not limit the invention.

Furthermore, it is also possible to react the free acid and the free amine in the presence of a condensing agent, e.g. a carbodiimide such as dicyclohexyl-carboxylimide, silicon tetrachloride, phosphoric anhydride. The compound obtained by the process of the invention can, if necessary, be reacted into an acid addition salt with pharmaceutically acceptable inorganic or organic acids, such as hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, oxalic acid, acetic acid,

Tartaric acid, citric acid, methanesulfonic acid.

For therapeutic purposes, the compound of the invention may be used in the form of a pharmaceutically acceptable acid addition salt together with pharmaceutically acceptable excipients and / or diluents in the form of tablets, beads, injectable solutions, syrups or any other suitable form.

Experiments according to pharmacological tests show that the compound of the invention, hereinafter referred to as Compound A, has superior properties in terms of antiemetic and cataleptic potency at relatively low toxicity values compared to several partially commercial benzamides, which are known to be very effective. The following compounds are used as reference substances: 1-N, N-diethylaminoethyl-2-methoxy-4-amino-5-chlorobenzimide (Compound B) commercially available compound "Metoclopramide" 5- (1-ethyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy ( compound C) 2-N- (1-ethylpyrrolidinyl-2-methyl) -2-methoxy-1,5-azimidobenzamide-1H-benzotriazole (known from FR Patent 1,572,168, Example 2).

The following experimental results are obtained: A. Toxicity (DL, -0, mg / kg, i.v., 5 days, mice)

Compound DL ^ q A 92.7 B 38 C 69.2 B. Antiemetic activity (DE ^ q, s.c., dogs)

Emesis causative agent A B C

apomorphine 5 Λ 2β, 8 μg / kg hydergine 63 207 - jilkg copper sulphate 0.99 0.92 - mg / kg lanatoside 1.3 it, 5 - mg / kg 7 57103 C. Therapeutic index DL iv, mice J ^ DE ^ 0> 8.C., dogs

Compound J

A 160 x 102 B Ik x 102 C 1 + 9 x 102 D. Cataleptic activity (DE ^ 0, * .c., Ag / kg)

Compound DEC.

-> A 10% at 200 ag / kg B 30.8 C 81 », 8

Thus, the compound of the invention has a substantially improved therapeutic index compared to the reference substances, with a reduced level of cataleptic activity.

The above results have been confirmed in human therapy, whereby the compound of the invention proved to be an effective antieaetic agent in infants and adults, especially in the treatment of emesis symptoms of toxic or infectious syndromes, pneumocencephalography and reading. The invention is further illustrated by the following examples.

Example 1

Step I:

Methyl 2-acetoxy-1'-adno-5-nitrobenzoate 72.5 g (0.1 »mol) of ethyl 2-ethoxy-1-aminobenzoate are treated with 0 ml of acetic acid and 126 g of acetic anhydride. with a stirrer with a thermometer and dropping into a flask fitted with a funnel. The mixture is heated to about 40 ° C for 30 minutes. Using a dropping funnel, add 4β * 1 nitric acid (d «1, 1 * 9) dropwise. after the addition of nitric acid is complete, stirring is continued for 2 hours at 1 ° C.

8 57103

The mixture is then poured into 600 ml of a methanolic solution of sulfuric acid (0.1 U mol).

The mixture is then stirred. Then add 1600 ml of water and ice. The crystals formed are filtered off with suction. 55-2 g are obtained (yield 61% of methyl 2-methoxy-1 + -amino-5-nitrobenzoate - m.p. 21 [deg.] C.).

Phase II

Methyl 2-methoxy-1,3-diaminobenzoate 555 g of methyl 2-methoxy-U-amino-5'-nitrobenzoate, 2500 ml of methanol, 300 g of Raney nickel are placed in a 5 l autoclave. Hydrogen is used at a pressure of 50 kp. The temperature rises to 50 ° C and is maintained there throughout the absorption. After cooling, the nickel is removed by filtration and washed with methanol. The solvent is removed under reduced pressure. The formed crystals are washed twice with 600 ml of water and dried at 50 ° C.

305 g of methyl 2-methoxy-1,5-diaminobenzoate are obtained (yield 63.5% of mp, = 139-140).

Phase III

5-Carbamethoxy-6-methoxy-1H-benzotriazole 29k g (1.5 moles) of methyl 4-methoxy-1 *, 5-diaminobenzoate, 2500 ml of water, 550 ml of hydrochloric acid (d = 1.18) are placed 5 to a flask equipped with a 1 l stirrer, thermometer and dropping funnel. The mixture is cooled to 0-5 ° C and a solution of 108 g of sodium nitrite in 500 ml of water is added dropwise. The mixture is heated to 35 ° C over 30 minutes and then cooled. The crystals obtained are filtered off, washed three times with 300 ml of methylene chloride and with water. After drying at 30 ° C, 256 g of 5-carbamethoxy-6-methoxy-1H-benzotriazole are obtained (yield 82.4 m.p. 190-192 ° C).

Phase IV

5- (1-Allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole hydrochloride 621 g of 5-carbomethoxy-6-methoxy-1H-benzotriazole, 3 l of anhydrous toluene and U25 g of amine are placed in a 6 l three-necked flask, equipped with a water-tight mechanical stirrer, a thermometer and a vertical condenser. The mixture is refluxed for 5 hours. The mixture is cooled to 50 [deg.] C., then 600 ml of a solution containing 350 g of hydrogen chloride in 1 l of ethanol are added. The temperature rises between 70-80 ° C. The mixture is cooled to 50 ° C, after which the toluene layer is separated from the oily residue.

The latter is dissolved in 3 l of methanol. The mixture is heated until complete dissolution is achieved. This solution is filtered at its boiling point with 150 g of activated carbon (3 S).

571 03 9 6 L of methyl ethyl ketone are added to the filtrate, after which the mixture is cooled to 0 ° C. Benzamide crystallizes slowly. It is filtered off with suction and washed with 500 ml of methyl ethyl ketone in two portions. It is then dried at 50 ° C in a ventilated dryer.

5- (1-allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole hydrochloride (65% yield). Mp, 206 ~ 208 ° C.

HC1% ·. in theory: 10.38 obtained; 10.18 purity in anhydrous medium with HClO 2+: 99.5% ·

Example 2

Step I: Methyl 2-methoxy-acetylamino-5-nitrobenzoate 223 g (1 mol) of methyl 2-methoxy-acetylamino-benzoate, 350 ml of acetic acid and 337 g of acetic anhydride are placed in a 2 l mixer, to a flask fitted with a thermometer and a dropping funnel. The mixture is heated to about U0 ° C to give a clear solution. It is then cooled to between 15 and 20 ° C, after which 106 g (1.5 mol) of nitric acid (d = 1, U9) are added dropwise via addition funnel. At the end of the nitric acid addition, stirring is continued for one half hour at + 0 ° C. The mixture is then cooled and poured into 5 liters of water.

182 g (68% yield) of methyl '2-methoxy-U-acetylamino-5-nitrobenzoate (m.p. 163-165 ° C) are obtained.

Phase II:

Methyl 2-methoxy-U-acetamino-5-aminobenzoate hydrochloride 1 kg of methyl 2-methoxy-1-acetamino-5-nitrobenzoate, 3 l of ethyl acetate and 3 tablespoons of Raney nickel are placed in a 5 liter autoclave. The mixture is heated to 75 ° C with stirring. Hydrogen gas is used at a pressure of 50 kp. The reduction reaction begins rapidly. The reaction vessel is vented for cooling. The temperature rises to 95 ° C. This temperature is maintained throughout the absorption. The entire absorption takes ten minutes. Hydrogen gas is replenished four to five times in the same manner until absorption is complete.

The reaction is carried out for one hour and fifteen minutes. After cooling, the nickel is removed by filtration and washed with 100 ml of ethyl acetate. The filtrate is acidified with 500 ml of a solution containing 350 g of hydrogen chloride in 1000 ml of ethanol. The hydrochloride crystallizes. It is filtered off with suction at 15 [deg.] C. and washed with 500 ml of ethyl acetate. It is dried in a ventilated dryer at 50 ° C.

10 57103

905 g of product (88%) with a melting point of 202-205 ° C are obtained.

Phase III; 1-Acetyl-5-carbomethoxy-6-methoxybenzotrates are dissolved in 1 * + 1 water and 1920 g of 2-methoxy-U-acetamino-5-aminobenzoate hydrochloride are placed in a 20 l reaction vessel equipped with a mechanical stirrer and a thermometer. and a dropping funnel, and suitably positioned so that it can be cooled by a cooling bath. The hydrochloride is completely dissolved with stirring.

700 ml of hydrochloric acid are added immediately. A solution of 1 + 90 g of sodium nitrite in 1 l of water is then added dropwise over a period of about one hour at a temperature between 25 and 30 ° C. The azimido compound crystallizes upon formation.

After completion of the above reaction, stirring is continued for one hour at 25 ° C. The azimido compound is filtered off with suction and washed several times with water. It is dried in a ventilated dryer at 30 ° C.

11 + 85 g (85%) of product with a melting point of 111 + - 115 ° C are obtained.

Phase IV; 5-Carbomethoxy-6-methoxy-1H-benzotriazole 7.1 + 1 methanol and 1 85 g of 1-acetyl-5-carbomethoxy-6-methoxybenzotriazole are placed in a 20 l reaction vessel equipped with a water-tight mechanical stirrer, a condenser and a dropping funnel. The mixture is heated to boiling with stirring. U60 ml of hydrochloric acid are then added. Achieve complete dissolution. 100 g of activated carbon (3S) are then added and refluxing is continued for 20 minutes. The activated carbon is filtered off from the hot mixture. The latter is cooled to 0 ° C whereupon the title compound crystallizes. It is filtered off with suction, washed several times with water and dried in a ventilated dryer at 50 ° C. 70 g (63%) of product are obtained.

The product is purified by dissolving it in a solution of 70 g containing 1 l of concentrated ammonia in 3.9 l of water and adding 100 g of activated carbon. The solution is then allowed to stand for 10 minutes, after which it is filtered.

The filtrate is acidified with hydrochloric acid to pH 1. The title compound crystallizes. It is filtered off with suction and washed several times with water. The wet product is redissolved in a solution of 1 L of ammonia in 3.9 L of water and filtered with 100 g of carbon.

The title compound precipitates at pH 1 with hydrochloric acid. It is filtered off with suction, washed with water and dried in a ventilated dryer at 50 ° C.

11 571 03

7 kg (60% overall yield) of a colorless product with a melting point of 192 [deg.] C. are obtained.

Step V; 5 '(1-allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole hydrochloride 621 g of 5''-carbomethoxy-6'-netoxy- <1H-benzotriazole, 3 l of anhydrous toluene and 1 * 25 g of amine 1 to a three-necked flask equipped with a water-locked mechanical stirrer, a thermometer and a vertical condenser. The mixture is boiled at reflux for 5 hours. The mixture is cooled to 50 [deg.] C., then 600 ml of a solution containing 350 g of hydrogen chloride in 1 l of ethanol are added. The temperature rises between 70-80 ° C. The mixture is cooled to 50 ° C, after which the toluene layer is separated from the oily residue.

The latter is dissolved in 3 liters of methanol. The mixture is heated until complete dissolution. This solution is filtered at its boiling point with 150 g of activated carbon (3S).

6 L of methyl ethyl ketone are added to the filtrate, after which the mixture is cooled to 0 ° C. Benzamide crystallizes slowly. It is filtered off with suction and washed with 500 ml of methyl ethyl ketone in two portions. It is then dried at 50 ° C in a ventilated dryer.

687 g of 5- (1-allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole are obtained (yield 65%), m.p. 206-208 ° C.

HCl%: in theory 10.38 10.13 purity obtained in anhydrous medium with HClO 2 R 9995 ·

Example 3

Step I »2-Methoxy-1 * -amino-5-nitrobenzoic acid

In the same manner, 16.7 g (0.1 mol of 2-methoxy-1-aminobenzoic acid) are nitrated. 13.8 g of 2-methoxy-1-amino-5-nitrobenzoic acid are obtained (m.p. 254 ° C, yield 6k, 9%). .

Step II1 2-Methoxy-U, 5 "diaminobenzoic acid

28 g (0.13 mol) of 2-methoxy-4-amino-5-nitrobenzoic acid are hydrogenated as described above to give 19.8 g of 2-methoxy - * +, 5-diaminobenzoic acid (yield 83.6%).

12 57103

Step III: 6-Carboxy-6-methoxy-1H-benzotriazol sol 36, hg (0.2 mol.) 2-Methoxy-1 +, 5-diaminobenzoic acid is treated as described above with sodium nitrite in the presence of hydrochloric acid. 31 g of 6-carboxy-6 -methoxy-1H-benzotriazole (yield 80.3% - m.p. 2 + 5 ° C).

Step IV: 5- (1-Allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole 30.6 g (0.2 mol) of 6-carboxy-6-methoxy-1H-benzotriazole are dissolved in anhydrous toluene and 56 g of g (0.1 U moles) of 1-allyl-2-aminomethylpyrrolidine are added. The mixture is heated to 50 [deg.] C. and then k2 g (0.3 mol) of phosphoric anhydride are added. The mixture is heated to reflux for three hours and then cooled to 80 ° C. After the addition of water, the aqueous layer is made basic. The crystals are filtered, washed with water and then dissolved in 1 * 50 ml of acetone. After crystallization, the product is filtered, washed, dried.

100 g of 5- (1-allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole are obtained (yield 65% - m.p. 139 ° C).

Example U

Step I: 2-Methoxy-1 + -acetylamino-5-nitrobenzoic acid

In the same manner, 20.9 g (0.1 mol) of 2-methoxy-U-acetylamino-benzoic acid are nitrated.

16.5 g of 2-methoxy-U-acetylamino-5-nitrobenzoic acid are obtained (m.p. 186-188 ° C - yield 6U, 9%) ·

Phase II; 2-methoxy-U-acetylamino-5-aminobenzoic acid

32 g (0.13 moles) of 2-methoxy-U-acetylamino-5-nitrobenzoic acid are hydrogenated as described above and 2.5 g of 2-methoxy-U-acetylamino-5-aminobenzoic acid are formed (yield 8U%).

Step III: 1-Acetyl-5-hydroxycarbonyl-δ-methoxybenzotriazole 8.7 g (0.039 mol) of 2-methoxy-β-acetylamino-5-aminobenzoic acid are treated as described above with sodium nitrite in the presence of hydrochloric acid.

57103 13

7.3 g of 1-acetyl-5 * -hydroxycarbonyl-6-methoxybenzotriazole are obtained (m.p. 208-212 ° C - yield 79.6%).

Step IV: 1-Acetyl-5-chlorocarbonyl-6-methoxybenzotriazole U, 7 g of 1-acetyl-5'-hydroxycarbonyl-6-bethoxybenzotriazole, 16.5 ml of thionyl chloride, 11 ml of chloroform are placed in a 250 ml flask. The mixture is heated to boiling point for 30 minutes. After cooling, the solvents are removed under reduced pressure.

1.7 g of 1-acetyl-5 "chlorocarbonyl-6-methoxybenzotriazole are obtained (yield 92.7% - m.p. 170 ° C).

Step V: 5- (1-Allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole hydrochloride 2.2 g (0.016 mol) of 1-allyl-2-aminomethylpyrrolidine, 28 ml of methyl ethyl ketone are placed in a 250 ml flask. . 3.8 g (0.015 mol) of 1-acetyl-5-chlorocarbonyl-6-methoxybenzotriazole are then added. The mixture is allowed to stand overnight, the solvent is removed under reduced pressure, 5 ml of hydrochloric acid (d = 1.18) and 28 ml of ethyl alcohol are added and the mixture is heated to reflux for 30 minutes. After cooling, the solvent is removed under reduced pressure and the residue is dissolved in boiling dimethylformamide. The mixture is filtered and, after cooling, the benzamide crystallizes. The crystals are filtered off with suction, washed with a small amount of dimethylformamide, then with tetrahydrofuran and dried at 50 ° C. 3.2 g of 5- (1-allyl-2-pyrrolidinylmethylcarbanioyl) -6-methoxy-1H-benzotriazole hydrochloride are obtained (yield 60.7%). Sp. 206 ° C.

HCl}: in theory 10.38 obtained 10.27.

Claims (2)

57103 1U Claim: A process for the preparation of an antiemetically active 5- (1-allyl-2-pyrrolidinylmethylcarbamoyl) -6-netoxy-1H-benzotriazole of the formula CO - NH - CHO-1. - OCH3 CH2-CH2 = CH2 QO-NH-CH2- OCH3 CH2-CH »CH2 I 'N-NH -: Jl. HN γ N—- - - N CO - NH - CH0-L. I ^ N— och3 ch2-ch = ch2 N for the preparation of acid addition salts with HN-N and its pharmaceutically acceptable inorganic or organic acids and its quaternary ammonium salts, characterized in that the compound of formula COX η-OCH3 V NRR '57103 15 wherein X is a hydroxy group or 1 An alkoxy group having 5 to 5 carbon atoms and R and R 'represent a hydrogen atom or an acyl group, nitrated, the resulting 5-nitro compound is hydrated, the resulting 5-amino compound is diazotized, the resulting 1H-benzotriazole compound is amidated by direct reaction with 1-allyl-2-aminomethylpyrrolidine by reaction between reactive derivatives, and that the obtained compound if necessary, the acid is converted into an acid addition salt with a pharmaceutically acceptable inorganic or organic acid or a quaternary ammonium salt. 57103 16 For the preparation of antiemetics Active 5 - (1'-allyl-2-pyrrolidinylmethylcarbamoyl) -6-methoxy-1H-benzotriazole with the formula CO - NH - CH2 ________ ^ -och3 ch2-ch2 »ch2 CO - HH - ^ * ιΥ °° η3 ch -ch = ch, 1. I. --®: - »N - -N% s CO - NH - CH -L. ^ -OCH3 CH2-CH = CH2 hJi_i och dess syrraadditionssalter med pharmaceutiskt godtagbara organic or organic syror ell or quaternary ammonium salt, kännetecknat därav, att man nitrerar en forening med formuleln COX '^> ^ Λ— och3 V NRR