FI59087C - FOERFARANDE FOER FRAMSTAELLNING AV 2,5-DISUBSTITUERADE BENSAMIDER - Google Patents

Description

ΓΒΊ nil κυ ulutusj ulkaisu 5 9087 UTLÄGGN I NGSSKRIFT 0 ~ U 0 'C and Patoni ti uyjnr.ctty 10 C6 1731 Patent aeddelat ^' r ^ (51) Kv.ik.3 / Int.ci.3 C 07 D 207 / 09, C 07 o 143/78 FINLAND — FINLAND (21) * M «ttitak.> Iw.-i *« «« * knii »« 2762/714 (22) Hikamliptlvt - Amttknincidag 23.09-7 ^ (23) Alkuptivt— Gllti | * i * ad «(23-09-71 * (41) Tullut Julkteak ·! - Bltvlt offuntlig 29-03 · 75

National Board of Patents and Registration · NU.tivUc.ip * ™ i. Kuutiuiiohun ~ m.-

Patent · och reglsterttyrelaen '' Antöktn udtjTxh uti.tkrHtm pubikand 27 - 02.81 (32) (33) (31) Pyy4 «tty privilege — Begird priorltet 28-09-73

France-France (FR) 73/35095 (71) Societe d'fitudes Scientifiques et Industrielles de 1'Ile-de-France, h6, Boulevard de Latour-Maubourg, 75 Paris 7 »France-France (FR) (72) Gerard Bulteau, Paris, Jacques Acher, Itteville, Jean-Claude Monier, Lardy, France-France (FR) (7U) Oy Kolster Ab (5U) Method for the preparation of 2,5-disubstituted benzamides -Förfarande för framställning av 2,5-disubstituerade benzensamider

The invention relates to a new process for the preparation of 2,5-disubstituted benzamides of the formula

CONH (CH.) A

Λ "^ V 0B (I)

TO2s ~ vj

wherein A is a dialkylamino or 1-alkylpyrrolidin-2-yl group, B and Y represent an alkyl group and n is 1 or 2, and for the preparation of acid addition salts and quaternary ammonium salts thereof with pharmaceutically acceptable inorganic or organic acids.

2 59087

The invention is characterized in that the 2,5-substituted benzoic acid of formula

COOH

/ J [0B

TO2S

wherein B and Y are as defined above, are reacted with an amine of formula

H 2 N (CH 2) n

wherein A is as defined above, in the presence of phosphoric anhydride, and that the compound obtained is, if desired, converted into an acid addition salt or a quaternary ammonium salt.

Methods for the preparation of 2,5-disubstituted benzamides of the formula I are known from FI patent applications 1 + 0/65, 3553/73 and 563/7 * +; the advantage of the present invention over these known methods is that the yield is considerably better; in the preparation of N- (1-ethylpyrrolidin-2-ylmethyl) -2-methoxy-5-ethylsulfonylbenzamide according to the invention the yield is 69% t while in the known processes the yield is 60% t 28-38% and 31% respectively (Diacylaminoethyl) -2-methoxy-5-methylsulfonylbenzamide according to the invention is a yield of 67% * while the yield of the process according to FI patent application 3553/73 is * + 8 ~ 51% and the yield of the process according to FI patent application 563/7 * + is 51% · of the FI patent applications 56l / 7 * i, 562/7 * + and 1076/7 * + in known processes for the preparation of compounds of formula I the yield is almost the same as in the process according to the invention, but the process according to the invention has the advantage that it can be performed in one step; In the process according to FI patent application 562/7 * +, it is necessary to prepare a reactive derivative of an acid before the reaction with an amine, which makes the known process a slow two-step process which is more complicated to implement than the process according to the invention. Compared to the processes known from FI patent applications 561/7 * + and 1076/7 * + for the preparation of compounds of formula I, the process according to the invention has the advantage of speed, since the reaction of the process according to the invention ends in 15 to 20 minutes. known methods have several hours.

The following examples illustrate the invention.

59087

Example I

N- (diethylaminoethyl) -2-methoxy-5-methylsulfonylbenzamide 6.9 g (0.03 mol) of 2-methoxy-5-methylsulfonylbenzoic acid and 7 g (0.06 mol) of Ν, Ν-diethylethylenediamine are charged to a 250 ml round-bottomed flask. equipped with a stirrer and a thermometer.

The mixture is raised to 100 [deg.] C. and 6.5 g (0.0 * + 5 mol) of phosphoric anhydride are added. After a few minutes the temperature rises to 135 ° C · Heating is continued and the reaction is maintained at 150 ° C for 20 minutes. The whole mixture is cooled to about 100 [deg.] C., 80 ml of water are added and, when completely dissolved, the solution is made alkaline with 20 ml of sodium hydroxide. The solution is left to cool and then extracted three times with 50 ml of methylene chloride. The organic phase is dried over magnesium sulfate, followed by filtration and evaporation of the solvent in vacuo. The residue is dissolved in 20 ml of water and 2 ml of sodium hydroxide. The solution is filtered, the product is washed with water and then dried in a drying oven at 50 ° C.

6.6 g (yield 6%) of N-diethylaminoethyl-2-methoxy-5-methylsulphonylbenzamide (melting point 18 DEG C.) are obtained.

Example II

N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-ethylsulfonylbenzamide 7.3 g (0.03 mol) of 2-methoxy-5-ethylsulfonylbenzoic acid and 6.8 g (0.053 mol) of N-ethyl-2-aminoethylpyrrolidine place in a 250 ml spherical flask equipped with a stirrer and a thermometer.

The mixture is heated to 100 ° C and 6.3 g (0 → 0UU mol) of phosphoric anhydride are added. The reaction is very exothermic. Heating is continued and the temperature reaches 160 ° C. The components are left to react for about 15 minutes, followed by cooling to 100 ° C. 50 ml of water are added and the solution is made alkaline with sodium hydroxide. The aqueous solution is left to cool to normal temperature and extracted three times with 50 ml of methylene chloride. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness. The residue is dissolved in ethanol and the solution is acidified with hydrochloric acid. The solution is left to crystallize on ice and filtered and the product is washed with a small amount of alcohol and then dried in a drying oven at 50 ° C.

8.1 g (69% yield) of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-5-ethylsulphonylbenzamide (melting point 186 ° C) are obtained.

Claims (2)

11,59087 Claim: A new process for the preparation of 2,5-disubstituted benzamides of the formula CONH (CH_) A. 2 n 1 OB (I)! Π YO 2s wherein A is a dialkylamino or 1-alkylpyrrolidin-2-yl group, B and Y represent an alkyl group and n is 1 or 2, and for the preparation of their acid addition salts and their quaternary ammonium salts with pharmaceutically acceptable inorganic or organic acids, characterized in that A 2,5-substituted benzoic acid of the formula COOH "v 05 I (II) yo0s _L>! Wherein B and Y are as defined above is reacted with an amine of the formula H_N (CHJ A (III) 2. n wherein A means the same as above, in the presence of phosphoric anhydride, and that the compound obtained is, if desired, converted into an acid addition salt or a quaternary ammonium salt.