DE2357595A1 - PROCESS FOR THE PREPARATION OF 2,5 DISUBSTITUTED BENZAMIDES - Google Patents

Description

A.

Societe d'Etudes Scientifiques et Industrielles

de 1'Ile-de-France Paris / France

Process for the preparation of 2,5-disubstituted benzamides

The invention "relates to a process for the production of 2,5-disubstituted benzamides (VI) and their addition salts with pharmaceutically acceptable mineral acids or organic acids and through the conversion of benzamides (VI) quaternary ammonium salts obtainable with an aliphatic or aromatic alkylating agent.

409822/1195

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The benzamides (Yl) have the following general formula on,

CO-AH

^ ' ., - OZ
XO ₂ S

in which A a group containing at least two amine functions, wherein one amine function can form a bond with the acyl function and another is at least tertiary, Z one An alkyl or alkenyl group having 1 to 5 carbon atoms and X is an alkyl, amino or aminoalkyl group.

The benzamides (VI) can be obtained according to the invention, by using an amine compound of the general formula AHp (I)> in which A is as defined above, with a halophosphite of the general formula (II),

> PE ₃ (II)

R ₂

in which R _{1 is} an alkoxy or phenyl oxy group and Rp ^e ^ - ⁿ halogen atom and R ~ can be either a halogen atom or a hydroxy, alkoxy or phenyloxy group, in which case the. G-ruppen R. and R ^ with formation of a

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409822/1195

Alkylenedioxy or O-Pheny.lenäioxygruppe connected to one another leg can be converted and one "the phosphorus compounds of the general formulas (III) and (IV) thus obtained,

AH (III)

-, P = A ■ -. '■■ _s (IV)

in which E. and A are as defined above and R in the formula (III) either an alkoxy or phenyloxy group or a _{G group linked to the group E 1 to form} an alkylenedioxy or o-phenylenedioxy group or the amine radical AH can, with a 2,5-disubstituted benzoic acid of the general formula (V),

j ° 2 ^H

in which X and Z are as defined above.

The benzoic acids to be used as starting compounds (V) are from US-PS 3,342,826 dated September 19, 1967, knows. . '

409822/1195

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BAD Qffl & NÄL-

The benzamides prepared according to the invention have interesting pharmacological properties, which in the French patents Kr. 72 CAM, Hr. 4 879 M and ITr. 5,916 M, filed October 15, 1963. April 1, 1965 and on January 21, 1966, respectively.

The phosphorus compounds of the general formulas. (III) and (IV), which are used according to the invention as intermediates, can in the form of their additive salts with acids or in Form of the free bases can be isolated. You can also "in situ" used as soon as they are trained.

The phosphorus compounds are obtained by adding either a solution of the amine AH ₂ in a solvent to a solution of the phosphite of the formula (II) or the solution of the phosphate to the solution of the amine used.

The solvents used can be amines such as pyridine or triethylamine, or inert solvents, e.g. toluene, benzene or methylethylke, clay.

The process of the invention can be carried out by the following reaction scheme be reproduced:

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409822/1 195

P-R

(D

(H)

R.

P -
--- AH (in) V ■ ^ or R-, - P = A. (IV)

GO ₂ H

(V)

CO-AH

(VI)

The groups A, E .., R ₂ , R ^, E., Z and X are as defined above.

The following examples are provided for a better understanding the technical features as well as the advantages of the invention. -, _ "· ■

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409822/1195

Example 1 : U- (1-Ethyl-2-pyrrolidiny! Methyl) -2-metho-xy-5-sulf amoy Ibenz arci d

In a 500 ml flask are placed 12.8 g of Ef-Ätiiyl- .- ^ - methy! .pyrrolidine, 200 ml of pyridine and a solution of 7.4 g, Dichloroethylpiiosph.it in 60 ml pyridine.

The mixture is stirred for 45 minutes at ambient temperature and added 11.6 g of 2-methoxy-5-sulfamic benzoic acid were added. One heats up the reaction mixture under reflux for 4 1/2 hours.

Each time it cools, the solvent is evaporated off in vacuo and 100 ml of water are then added. The solution is made with hydrochloric acid Ms acidified to pH 1. The mixture is heated to reflux, filtered in the heat and treated the boiling Filtrate with 33% ammonia.

Subject to cooling, the precipitate is filtered off, washed with water and dried in a drying cabinet at 50 g. 14.1 g of H- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide are obtained (yield: 82.7 ° β). M.p .: 178-178.5 ° C
S: $ 9.38 (calculated), 9.34 # (found)

- β - 409822/1195

Example 2 : H- (1.-Ethyl - 2-pyjroIidiny! Methyl) -S-sul f amo y Ib enz ami d

Put? .7 g ft-Ä 'into a 500 ml-eol ¥ en metlr / lpyrrolidihj 200 ml of pyridine and a solution of 10.4. G üiäthylchlorphösphit in 60 ml pyriaine.

The reaction mixture is left to stir for 3/4 hour stand at ambient temperature and. then adds 11.6 g of 2-ethoxy-5-sulfamoylbenzoic acid ninzu. The mixture is heated under reflux for 4 1/2 hours. After grinding, the solvent is evaporated in Yaliuum ..

100 ml of water are added and the solution is acidified with hydrochloric acid up to. a pH of 1. The UiederSGlilag is sucked off and then dissolved in the heat with 100 ml of water. The solution is treated with 33% ammonia at the boiling point ... '".... .. ■" ■ "■ ;.

laughing cooling the precipitate is filtered off, with iaschen What gev-ser \ and dried in an oven at 5O ⁰ C. 10.2 g of K- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoylbenzamide are obtained (yield: 59.8 fo). , M.p .; 177 to 178 ⁰ C
S: 9.38 fo (calculated), 9 »6.0 $> (found)

BAD OBKSirslAL

Example 3 · ^ - (1-Ethyl-2-pyrrolidinylmethyl) -2-metho: K: y-5 · sulfam ayIbenzami Ä

7.7 g of F-ethyl - <^ L-methy! Pyrrolidine are placed in a 500 ml flask, 200 ml of pyridine and a solution of 10.5 g of o-phenylene chlorophosphite in 60 ml of pyridine.

The reaction mixture is left in for 45 minutes Ambient temperature. 11.6 g of 2-methoxy-5-sulfamoylbenzoic acid are added add and. then keeps the reaction mixture at reflux for 4 1/2 hours.

Compartment, cool, evaporate the solvent in vacuo and add 50 ml of water. The solution is acidified with hydrochloric acid up to a pH of Ί. Each time it cools, the precipitate is filtered off and dissolved in boiling water. The solution is filtered and washed with 33 conclude ammonia treated.

Uach cooling, the precipitate is abf-iltriert, washed with water and dried at 5O ⁰ C im'Trockenschrank. 9.5 g of IT- (i-jitliyl-2-pyrrolidinylmet] ayl) -2-metlioxy-5-sulfamoylbenzamide are obtained (yield: 55> 7 ^). Smp.i 178 -.178,5 ⁰ C
S: 9.38 ^ (calculated), 9.50 <f ° (found)

409822/1195

Beis pie l 4 ϊ -Ii- ("1 -Ethyl-2-pyrrolidiny! Methyl) -2-methoxy-5 · - athy-Isulfonylbenzamid-Chlorhyxlrat ',

In a 500 ml flask are placed 12.8 g of! F-ethyl-crt.-aminomethy! Pyrrolidine, 200 ml of pyridine and a solution of 7.35 g Dichlorathylphosph.it in 60 ml of pyridine.

The mixture is then stirred for 45 minutes at ambient temperature and 12.2 g of 2-methoxy-5-ethylsulfonylbenzoic acid are added. That The mixture is refluxed for 4 1/2 hours.

After cooling, the solvent is evaporated in a vacuum and add 100 ml of water. The solution is made with caustic soda Made alkaline and extracted with chloroform, laughing at it The organic solution is dried over calcium chloride and filtered, and the solvent is evaporated off in vacuo. One solves the Residue in 50 ml of absolute ethanol and the benzamide precipitates out by adding 20? Iger ethanolic hydrochloric acid.

The precipitate wird.filtriert, washed with ethanol and drying oven at 5O ⁰ C dried. After recrystallization from ethanol, 5> 5 g of N- (1-ethyl-2-pyrrolidinylmethyl) -2-methox3 '-5-ethylsulfonylbenzamide chlorohydrate are obtained.

Mp .: 189 to 190 ⁰ C

S: 8.19 ° / ° (calculated), $ 8.23 (found) ■

HCl; 9.34 fo (calculated), 9.28 ° ß> (found)

2 ~ 2 / Yi95; BAD.OFBG ₁ NAL

Example 5: K- (i-Ethyl - ^ - pyrrolidiriy! Methyl) -2-methoxy-5-ethy lsulfony roenzaiaid chlorohydrate

7.7 g of M-ethyl-oC-aminoßie are placed in a 500 ml flask thy! pyrrolidine, 200 ml of pyridine and a solution of 10.4 g of chlorodiathylphosph.it in 60 ml of pyridine.

The reaction mixture is stirred for 45 minutes at ambient temperature and adds 12.2 g of 2-methoxy-5-ethylsulfonylbenzoic acid. The mixture is refluxed for 4 1/2 hours.

After cooling and evaporating the solution in vacuo 100 ml of water and then sodium hydroxide solution are added until the pH value is alkaline.

After the solution has been extracted with chloroform, the organic phase is dried over calcium chloride and evaporated in vacuo. The residue is dissolved in 50 ml of absolute ethanol.

The benzamide is obtained by adding 20% ethanol Hydrochloric acid precipitated. The precipitate is filtered off, washed with ethanol and dried at 50 ° C. in a drying cabinet.

After recrystallization from ethanol, 7? 4 g W- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-ethylsulfonyl-

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<^? KF ^ i 409822/1195
ORtGlNAL

benzamide chlorohydrate. "

Smp.i 188-189 ⁰ C ■

Sr 8.19 io (calculated), 8.26 fo (found) HCl: 9.34 Φ (calculated), 9.27 i (found)

Example 6 : H- (1-Ethyl ^^ pyrrolidinylmethyl) ^ - ethy1sulfqny Ib enz amide-Ghlorhydrat

7.7 g of H-ethyl ~ oC-aminoraethylpyrrolidine are placed in a 500 ml inch, 200 ml of pyridine and a solution of 10.5 g o-Pheiiylenchlorphosphit in 60 ml pyridine.

The mixture is stirred for 45 minutes at room temperature and adds 12.2 g of 2-methoxy-5-ethylsulfonylbenzoic acid. That ■ The mixture is refluxed for 4 1/2 hours.

Allow the solution to cool and evaporate in vacuo add 100 ml of water and then sodium hydroxide solution 'up to one alkaline pH is added.

After the solution has been extracted with chloroform, it is dried the organic phase, filtered through calcium chloride and evaporated in vacuo .. The residue is dissolved in 50 ml of absolute ethanol solved.

The benzamide is obtained by adding 20% ethanol 'Hydrochloric acid precipitated.

4098 ^22/1 I 195 BAD

The precipitate is filtered off and washed with ethanol

and dried in Brockenschranfc "at 50 ^{° C.}

! laughing obtained 5.8 g of IT dmfcristallisation from ethanol (t-ÄtlLyl-2-pyrrQlidizLylmethyl.) - 2-m.ethox3 / "- 5-ätli3 ^r lsulf onyl-

y drat *

M.p.t 1B9-19O ⁰ G

Si 8.19 # (calculated} »7 *, 9T f>

Example 7 • IT- (BiätJayXaEiinoätJiyl) -2-methLOxy-5-i! I.e'tiiiyl s

11> 6 g of SF _r H diamine, 20% of pyridine, and a solution of Iron 7.4 g of dichloroethylphosphate in 60 ml of pyridine are placed in a 50-100 ml flask.

The mixture is stirred for 45 minutes at ambient temperature and 11.5 g of 2- methoxy-5-methylsulfonylbenzoic acid are then added. The mixture is refluxed for 4 1/2 hours.

Cooling and evaporating the solvent in the compartment "Vacuum one adds 100 ml of water. The mixture is made with hydrochloric acid acidified to a pH value of 1 and then filtered »

The benzamide is obtained from the 3? Filtrate by adding 40% Caustic soda precipitated. After filtering and drying the

IL-L ; - '' ■ - 12 -

AO9822 / 1195

(] Diäthy lana.noäthyl) -2-meiaipscy -5-methylsulf amide onylbenz - one g] i the product in a drying cabinet "50 ^'0 C is 8.5.

Smp.s 120-122 ⁰ C. - '

S: 9.76 fi (calculated), $ 9.83 (found)

EXAMPLE 8 E- (Oiätiiylaminöätliyl) -2-iQe1; lioxj ^r -5-iüe1; li _<yl- sulf onyXbenzamid ■. ■

Put 7 g of H, E-Dläthyläthylenediamine into a 500 ml flask, 350 ml of pyridine and a solution of 10.35 g of diethyl chlorophosphile; in 60 ml of pyridine.

The mixture is stirred for 45 minutes at ambient temperature, and then add 11.5 g of 2-methoxy-5-methylsulfonylbenzoic acid added. The mixture is refluxed for 4 hours.

After cooling, the solvent is evaporated off in vacuo and add 200 ml of water. The mixture will be up to one Acidified pH value of 1 with 36% hydrochloric acid and then filtered.

The benzamide is made up by adding 40% sodium hydroxide solution precipitated by the Piltrat. -. ;

Uach filtration and drying of the product obtained in Trockenschrankt at 5O ⁰ C J, 8 g of H- (diethylaminoethyl) -2-methoxy-5-methylsulfoiiy "benzamide.

" ¹³ -409822/1195

M.p .: 121-122 ⁰ O

S: 9.76 9b (calculated), 9.39 <& (found)

Example 9 J N- (Diethylaminoethyl) -2-i2iethoxy-5-methylsulfonylbenzamide

7 g of IT, IT dietary hydrolysis are placed in a 500 ml flask diamine, 200 ml of pyridine and a solution of 10.5 g of o-pnenylene chlorophosphite in 60 ml of pyridine.

The mixture is stirred for 45 minutes at room temperature * 11.5 g of 2-methoxy-5-methylsulfonylbenzoic acid are then added. The mixture is refluxed for 4 1/2 hours.

After cooling, the solvent is evaporated off in vacuo and 200 ml of water are added. The mixture is acidified with 36% hydrochloric acid to a pH of 1 and then filtered. The benzamide is precipitated from the piltrate by adding 40% sodium hydroxide solution. 8 g of M- (diethylaminoethyl) -2-methoxy-5-methylsulfonylbenzamide are obtained. M.p .: 120-122 ⁰ C.
S: 9.76 <fo (calculated), 9.95 ^ (found)

SAD ORK3SNAL

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Claims (1)

Pat ent a η s u rü che ¹ ί "Γ * Process for the preparation of 2, S-substituted ones B ens; ami of the general formula. COE-ER in which A is a group containing at least two amine functions, where one amine function can form a bond with the acyl function and another is at least tertiary: Z is an alkyl or alkenyl group with 1 to 5 carbon atoms and X is an alkyl j mean amino or aminöaikylgruppe, as well as their addition salts with phafmäaeütisöh compatible mineral acids or organic acids and by reacting them with an aliphatic or aromatic alleylating agent cjuartäfen.Ammoniumsalzen, characterized geke η η ■ - distinguishes that.man an amino compound of the general formula AH ₉ (I), where A is defined as "above, with a halophosphite of the general Loriiiel (II)>. . (H) - 1.5.-22/1 T95 '.,;_; BAD DfttGlNÄL in which R ₁ represents an alkoxy or phenyloxy group and Rp.ein halogen atom and R ^ can be either a halogen atom or a hydroxy, alkoxy or phenyloxy _r in which case the groups R ₁ and R ₇ to form a Alkyleiidioxy- or o-Phenylenedioxy groups can be linked to one another, and one. the so obtained. Phosphorus compounds of the general formulas (ill) and (IV) _r P-AH (III) - P = A (IV) in which R ₁ and A are as defined above and R. in the form 1 (III) either an alkoxy or phenyloxy group or a group _{connected to the group R 1} - with the formation of an alkylenedioxy or o-phenylenedioxy group or the amine radical AH can be with a 2,5-disubstituted benzoic acid of the general formula (V), QO ₉ H. in which X and Z are as defined above 82 ~ 2 / ΊΪ9 BATH ORIGINAL - " 2 »The method according to claim 1, characterized in that: n η records, -that iaan as halophosphite 131 chloroethylpihoephite one e ± z ± . . . 3 · ¥ erf-clij-en iiacli Claims 1, dadurcli g .e- k · e η η ζ ei unites that inari ols Halogenpliosphii; Chlorine diet hylpliospliit 4 - ¥ erf akren according to claim 1. "thereby g e k e η η ζe i c h η e t that the halogen phosphite used is q-phenylene chlorophosphite begins. 5. The method according to claim 2 for the preparation of li- (1-ethyl-2-p; yTrO, lidinylmethyl) _r 2-methqry-5-sulf amoylpenz.amid. ■ 6. V-experience according to Ansprucli 3 for. Manufacturing γοη ¥ - (1-Ethyl-2 ^ pyrroliüinylmethyl) -2- 7. Process according to claim 4 for / production γ on IT— C1-Ethyl ^ -pyrr.olidinylme.thy ^ ^
■ benzamide. 8. The method according to claim for producing γόη 1- (1-Ethyl-2-pyrro ^ idinylmethyi) -2-iiiethoxy-5-ethylsulfonyl- ■ benzamide. ■ - π - 409822/1195 BATH 9. Yerfoüiren according to claim 3 for the production of 17- (1-Ethyl-2-pyrrolidinylmethyl) -2-methoxy-5-ethylsulfonylbenzamide. 10. The method according to claim 4 for the production of N- (1-ethyl-2-pyrrolidine _t yliuethyl) -2-methoxy-5-äthylsulfonylucnzainid. 11. The method according to claim 2 for the production of Ii- (diethylamino ether 1) -2-methoxy-5-ethylsulfonylbenzamide. 12. The method according to claim J for the production of If- (diethylaminoethy 1) -2-methoxy-5-methy isulphonylbenz amide .. 13. The method according to claim 4 for the production of E- (diethylaminoethyl) -2-ine thoxy-5-methy isulfony! Benzamide. BADORfGfMAL - 18 - 4 0 9 8 2 2/1195