NO135092B

NO135092B -

Info

Publication number: NO135092B
Application number: NO2498/73A
Authority: NO
Inventors: G Bulteau; J Acher; J-C Monier
Original assignee: Ile De France
Priority date: 1972-06-20
Filing date: 1973-06-15
Publication date: 1976-11-01
Also published as: JPS553340B2; YU36691B; DD107441A5; FR2277815B1; RO64465A; JPS5070334A; CS167389B2; BE801038A; JPS5070333A; HU166936B; SE7607356L; ATA531673A; AU5699473A; JPS4985039A; CA1001170A; BG22073A3; SE7602735L; FI56677C; AU468921B2; IE37800L

Description

Foreliggende oppfinnelse angår en ny fremgangsmåte ved fremstilling av N-(diethylaminoethyl)-2-methoxy-4-amino-5-klorbenzamid (IV), dets syreaddisjonssalter med farmasøytisk aksep- The present invention relates to a new process for the production of N-(diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide (IV), its acid addition salts with pharmaceutical acceptance

table uorganiske eller organiske syrer, og kvartære ammonium- table inorganic or organic acids, and quaternary ammonium

salter derav fremstilt ved omsetning av benzamidet med et alkyl-eringsmiddel. salts thereof prepared by reacting the benzamide with an alkylating agent.

Benzamidet av formel (IV) fremstilles ved at en ester av 2-methoxy-4-acetamino-5-klorbenzosyre (I) behandles med et ethanolamin under dannelse av N-(2-hydroxyethyl)-2-methoxy-4-acetamino-5-klorbenzamid (II). Når denne forbindelse behandles med thionylklorid, erholdes det N-(2-klorethyl)-2-methoxy-4-amino-5-klorbenzamid (III) som omsettes med diethylamin under dannelse av det ønskede N-(diethylaminoethyl)-2-methoxy-4-amino-5-klorbenzamid (IV) . The benzamide of formula (IV) is prepared by treating an ester of 2-methoxy-4-acetamino-5-chlorobenzoic acid (I) with an ethanolamine to form N-(2-hydroxyethyl)-2-methoxy-4-acetamino-5 -chlorobenzamide (II). When this compound is treated with thionyl chloride, N-(2-chloroethyl)-2-methoxy-4-amino-5-chlorobenzamide (III) is obtained, which is reacted with diethylamine to form the desired N-(diethylaminoethyl)-2-methoxy- 4-amino-5-chlorobenzamide (IV) .

Dette kjente benzamid har gode farmakologiske egenskaper This known benzamide has good pharmacological properties

som antiemetisk middel og som et modifiserende middel ved fordøy-elsesprosessen. as an antiemetic agent and as a modifying agent in the digestive process.

Reaksjonsdiagrammet er som følger: The reaction diagram is as follows:

Det følgende eksempel illustrerer oppfinnelsen. The following example illustrates the invention.

N-( diethylaminoethyl)- 2- methoxy- 4- amino- 5- klorbenzamid N-(diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide

Trinn I: N-(2-hydroxyethyl)-2-methoxy-4-acetamino-5-klorbenzamid Step I: N-(2-hydroxyethyl)-2-methoxy-4-acetamino-5-chlorobenzamide

200 g (0,78 mol) methyl-2-methoxy-4-acetamino-5-klorbenzoat, 57 g (0,93 mol) ethanolamin, 460 ml xylen og 20 g aluminium iso-propylat ble innført i en 2 liters kolbe utstyrt med rører, 200 g (0.78 mol) methyl-2-methoxy-4-acetamino-5-chlorobenzoate, 57 g (0.93 mol) ethanolamine, 460 ml xylene and 20 g aluminum isopropylate were introduced into a 2 liter flask equipped with pipes,

kjøler, termometer og destillasjonsanordning. cooler, thermometer and distillation device.

Blandingen ble oppvarmet i 3 timer under tilbakeløpskjøl-ing, avkjølt, og den øvre fase ble dekantert fra, oljen ble løst i 500 ml dioxan, og de uløselige bestanddeler ble filtrert fra og løsningsmidlet fordampet. The mixture was heated for 3 hours under reflux, cooled, and the upper phase was decanted, the oil was dissolved in 500 ml of dioxane, and the insolubles were filtered off and the solvent was evaporated.

Residuet ble delvis løst i'acetonitril. Løsningen fikk stå over natten i et kjøleskap og ble derefter filtrert og løsnings-midlet fordampet. Det ble erholdt 89 g N-(2-hydroxyethyl)-2- The residue was partially dissolved in acetonitrile. The solution was allowed to stand overnight in a refrigerator and was then filtered and the solvent evaporated. 89 g of N-(2-hydroxyethyl)-2-

methoxy-4-acetamino-5-klorbenzamid med smeltepunkt 170°C. methoxy-4-acetamino-5-chlorobenzamide with melting point 170°C.

Trinn II: N-( 2- klorethyl)- 2- methoxy- 4- amino- 5- klorbenzamid 3 g (0,01 mol) N-(2-hydroxyethyl)-2-methoxy-4--acetamino-5-klorbenzamid og 15 ml thionylklorid ble innført i en 100 ml kolbe utstyrt med rører, termometer og kjøler, og blandingen ble omrørt i 7 timer ved omgivende temperatur. Step II: N-(2-chloroethyl)-2-methoxy-4-amino-5-chlorobenzamide 3 g (0.01 mol) N-(2-hydroxyethyl)-2-methoxy-4--acetamino-5-chlorobenzamide and 15 ml of thionyl chloride were introduced into a 100 ml flask equipped with a stirrer, thermometer and condenser, and the mixture was stirred for 7 hours at ambient temperature.

Thionylkloridet ble fordampet under vakuum, residuet ble vasket med vann og filtrert, vasket med natriumhydroxyd, igjen filtrert og vasket med vann og derefter tørket, i en eksikator under vakuum i nærvær av kaliumhydroxyd. The thionyl chloride was evaporated under vacuum, the residue was washed with water and filtered, washed with sodium hydroxide, again filtered and washed with water and then dried, in a desiccator under vacuum in the presence of potassium hydroxide.

Det ble erholdt 2,80 g N-(2-klorethyl)-2-methoxy-4-amino-5-klorbenzamid med smeltepunkt l40°C. 2.80 g of N-(2-chloroethyl)-2-methoxy-4-amino-5-chlorobenzamide with a melting point of 140°C were obtained.

Trinn III: N-(diethylaminoethyl)-2-methoxy-4-amino-5-klorbenzamid - » Step III: N-(diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide - »

2,5 g (0,0095 mol) N-(2-klorethyl)-2-methoxy-4-amino-5-klorbenzamid og 35 ml diethylamin ble innført i en 50 ml kolbe utstyrt med kjøler og rører, og blandingen ble kokt under tilbakeløp i 3 dager. 2.5 g (0.0095 mol) of N-(2-chloroethyl)-2-methoxy-4-amino-5-chlorobenzamide and 35 mL of diethylamine were introduced into a 50 mL flask equipped with a condenser and stirrer, and the mixture was boiled under reflux for 3 days.

Blandingen ble avkjølt og filtrert, og filtratet ble fordampet. Residuet ble løst i 18 ml N saltsyre fulgt av filtrer-ing og vasking med vann, og løsningen ble gjort alkalisk med The mixture was cooled and filtered, and the filtrate was evaporated. The residue was dissolved in 18 ml of N hydrochloric acid followed by filtration and washing with water, and the solution was made alkaline with

20 ml 40%-ig natriumhydroxyd. 20 ml of 40% sodium hydroxide.

20 ml vann ble tilsatt, og løsningen ble kokt under til-bakeløp i 1,5 time. 20 ml of water was added and the solution was refluxed for 1.5 hours.

Reaksjonsblandingen ble avkjølt, filtrert, og produktet ble The reaction mixture was cooled, filtered, and the product was

omkrystallisert fra benzen. recrystallized from benzene.

Det ble erholdt 0,7 9 N-(diethylaminoethyl)-2-methoxy-4-amino-5-klorbenzamid med smeltepunkt l43°C. 0.79 N-(diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide with a melting point of 143°C was obtained.

Claims

1. Procedure for the production of N-(diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide with formula: and acid addition salts with pharmaceutically acceptable inorganic or organic acids, and quaternary ammonium salts thereof, characterized in that an ester of 2-methoxy-4-acetamino-5-chlorobenzoic acid of general formula: where R is an alkyl group with 1-3 carbon atoms, is reacted with ethanolamine, after which the resulting N-(2-hydroxyethyl)-2-methoxy-4-acetamino-5-chlorobenzamide is treated with thionyl chloride to form N-(2-chloroethyl) -2-methoxy-4-amino-5-chlorobenzamide, which is reacted with diethylamine to form N-(diethyl-aminoethyl)-2-methoxy-4-amino-5-chlorobenzamide, which is optionally converted into an acid addition salt or a quaternary ammonium salt.

2. Method according to claim 1, characterized in that methyl-2-methoxy-4-acetamino-5-chlorobenzoate is used as ester.