IL29627A - Process for the preparation of 2-alkoxy-5-n(substituted or unsubstituted)sulphamidobenzoic acids and benzonitrile intermediates - Google Patents

Description

preparation of or acids and new in BE 2 The present invention concerns a process for the preparation of substituted or acids the corresponding having the in A is an alkyl radical of low molecular weight 1 to 5 carbon B is an or dialkylamino radical of low molecular weight in which the alkyl groups may be Joined together by a a nitrogen or oxygen and where this atom is a nitrogen atom may be linked to ah alkyl group of low molecular to form a pyrrolidine piperazino or The substituted or of formula I above in which X io a group are new compounds and form part of the present The substituted or acids are obtained from the new nitrile intermediates in good yields and at a higher degree of purity than could be achieved until now by known This constitutes a great advantage in view of the utility of these acids as synthesis intermediates for the tion of substituted or benzamides having important pharmacological properties such local Interesting 2a compounds to be cited are and The process comprises treating a sulphonyl nitrobenzene with ammonia or with an reducing the resulting substituted or unsubs u to the corresponding amino derivative iz the latter and converting into a nitrile by the substituted or sulphamido benzoic acid is obtained by hydrolysis of the 1 Preparation of the base material The nitrobenzene which constitutes the base material of this synthesis may be prepared in two different 1 by nitration of a alkoxybenzene which is itself obtained by chlorosulphonation of an alkoxy Nitration is effected by the action either of fuming concentrated nitric acid or of a sulphonitric mixture or of sodium nitrate and sulphuric Chlcrosulfonation is effected by the action of sulphuric 2 by of sulphonic is effected for example by the combined action of phosphorus and phosphorus The sulphonic acid be prepared in two a by sulphonation of an nitrobenzene using sulphuric The nitrobenzenes are obtained by alkylation of The alkylating agent is either galley1 halogenide such as ethyl propyl or an alkyl sulphate such as dimethyl diethyl or a substituted or alkyl arylsulphonate such as benzene butyl b by alkylation of nzene sulphonic acid using an alkylating agent selected from those described The sulphonic acid is prepared by nitration of sulphonic acid using a nitrating agent from those described in paragraph The sulphonic acid is prepared by the action of sulphuric acid on The process being the object of the invention Replacement of the chlorine atom on nitrobenzene is effected by the action of ammonium carbonate or an amine such as It is also possible to use the salts of these taking care previously to free the amine free from its salt by the action of an alkaline The reduction of the nitro group may be effected catalytically by hydrog the nitro compound by hydrogen under pressure in the presence of a catalyst such as reduced nickel or else iron and hydrochloric stannous tin or zinc and hydrochloric Hydrolysis of the nitrile in acid can be effected in an acid medium such as hydrochloric or sulphuric or in a slightly alkaline reduction diazotization reaction CN The following examples illustrate the invention without limiting A L I acid A Preparation of First possibility starting from STAGE Into a 2 litre balloon flask provided with a mechanical a thermometer and a dropping are g 900 ml Be soda lye 200 ml The mixture is dissolved by agitation and heating at and 252 g of dimethyl sulphate is introduced in drops in 15 mixture is put under After 10 minutes of reflux it is cooled to of the solution is and 100 ml of Be soda and 126 g of sulphate are The is put under reflux one It is verified that the pH is higher than 7 cooling to ambient temperature is Two layers are The organic layer is decanted and the aqueous ith T effected with 300 ml of Drying is effected on anhydrous sodium sulphate and the ether and then the product is distilled under 213 g of is S AGS Into a 500 balloon flask provided with a mechanical a and a dropping are βθ g of The mixture is agitated and with the temperature being maintained at co g of sulphuric chlorohydrin is introduction is agitation is continued for some minutes more and then solidification The mixture is left at rest in darkness for one then is reheated so as to liquify the mixture in is then passed a stream of dry nitrogen so as to drive out all the hydrochloric The liquid is poured into 1000 ml of The resulting solution is evaporated and drying is terminated in a drying oven at g ammonium sulphonate is The sulphonate is dissolved in ml of phosphorus oxychloride and g of phosphorus pentachloride is and is put under reflux for 2 The phosphorus oxychloride is then distilled under vacuum until a thick paste is obtained which is poured on to g of The product It is dried without heating and washed in ice cold water and then dried at In this way is Second starting from phenol I sodium Into a 2 litre balloon flask provided with a mechanical agitator and a thermometer are Phenol g Sulphuric g The mixture is heated under agitation for 6 hours at is slowly added while the temperature is allowed to The temperature reaches The solution produced in this way is run into a litre beaker provided with a mechanical agitator and containing a solution of g of sodium nitrate in 1C00 of The temperature reaches There is a eginning of then everything dissolves and the solution turns The temperature is of itself maintained at for 2 hours and then begins to go down The red solution is cooled at for A brick red crystallised product is which is dried without heating and washed with the minimum of It is dried at and g of sodium sulphonate is S Calculated 9 STAG5 II sulphonate Into a 2 litre balloon flask provided with a mechanical a thermometer and a reflux are sodium sulphonate l g Be soda lye ml water ml Agitation at ambient temperature is effected for minutes until the components 126 g of dimethyl sulphate is added and the mixture is put under reflux for Cooling is ef and the following is added e soda lye dimethyl sulphate 63 g The mixture is put under reflux for minutes and then cooled and the following is again e soda lye dimethyl sulphate g The mixture is put under reflux for is The product is completely dried without without washing and is dried at δθ of benzene sulphonate is Calculated Actual Into a balloon flask are put sulphonate S phosphorus oxychloride 80 g of phosphorus is then reaction begins immediately and the mass becomes The mixture is to slight boiling for 2 The greatest part of the product is The phosphorus oxychloride is distilled under and the residue is poured on to 500 g of The product which is at first viscous crystallises after approximately It is dried without washed to 5 times in ice cold water and is dried at The product is then dissolved hot in of g of animal black is added and the solution is 120 ml of petroleum ether is added to the filtered This is left to The resulting precipitate of nitrobenzene is dried without heating and is dried at Melting B Preparation of acid g of crushed ammonium carbonate and 2C0 g of are put into a 2 litre balloon flasko The mixture is homogenised with an agitator and the balloon flask is placed in a boiling It is left for 2 hours and then the mixture is poured on to 2 kg of water and is effected for 15 minutes and then drying without The pieces of ammonium carbonate have not dissolved are removed by repeatedly caking the product into a paste foams are no longer 2 g of and oOO ml of absolute alcohol are introduced into litre balloon flask provided with a mechanical thermometer and a reflux mixture is heated under agitation to to dissolve it and 800 ml of water and 20o g of powdered iron are The temperature is raised to under strong agitation so as to put the powdered iron into suspension and the reaction is started a few of the following hydrochloric acid 20 ml water 80 ml The reaction is fairly violent and the flask must be cooled by a bath of ice cold water to prevent the temperature rising above the reaction has slowed the remainder of the diluted hydrochloric acid is introduced and the temperature is maintained at from 80 to for The pH is brought to without cooling by the addition of a few millilitres of the following mixture potash 20 g alcohol ml The brown residue is hot dried without heating and is twice made into a paste each time with of boiling The 2 filtrates are added to the main solution and the whole is cooled by an ice bath for 1 It is dried without heating and then dried and g of is The mother liquors are then concentrated under vacuum until the alcohol is An abundant crystallisation is The mixture is cooled for 12 hours by means of an ice bath and is dried without washed in water and then dried at altogether 119 g of is point l III mechanical a thermometer and a dropping are 8l g ml hydrochloric 77 ml mixture is The mixture is cooled to and with the temperature being maintained at from g of sodium nitrite dissolved in ml of water is The agitation is continued for minutes at from 0 to In a separate into a 2 litre balloon flask provided with a mechanical agitator and a are water 5 ml crystallised copper sulphate g The mixture is agitated to dissolve the reagents and g of sodium cyanide is added in small temperature reaches at the close of this here first occurs the formation of a brovm precipitate and then Finally a dark brown solution is obtained which is raised to By means of a dropping funnel the diazo solution obtained above is then introduced into this solution in a fine A temperature of from 8 to is maintained this operation of introducing the diaso solution which lasts about 15 There occurs abundant liberation of gas and a beginning of crystallisation toward the end of the Agitation is continued for 20 minutes more at from to and then cooling is the temperature being maintained from 0 to for 2 he mixture is dried without twice washed in water and dried at The crude product is set to boil with 1650 ml of absolute The insoluble is filtered and g of animal black is added to the filtrate and the mixture is boiled for half an the black is filtered and the filtrate is concentrated at ordinary pressure to a volume of OO Cooling is effected with ice for 1 hour and the crystallise STAGE IV acid of is introduced into a balloon flask provided a mechanical agitator and a following mixture is then added under agitation sulphuric acid ml is raised to from to and is maintained for the reagents dissolve completely at Cooling to from 0 to is effected and this temperature is maintained 2 The mixture is completely dried without heating and is made into a paste four times with the sufficient quantity of being completely dried without heating after each time it is made into a Drying is effected at The product is dissolved cold with caution in ml of a saturated sodium bicarbonate A cloudy rosy solution is obtained to which g of animal black is Contact filtered is maintained for half an the black is without heating and is rinsed with a raillilitres of water and the acid is precipitated by ml of hydrochloric acid suspension has a pH of It is dried without heating and washed in water until the ions disappear in the washing water and drying is effected at 11 g of acid is obtained point S X A P L OF ACID I Into a 2 litre balloon flask provided with a mechanical a and a dropping are put g at ambient The solution is poured into 1200 g of crushed The chloroformic layer is decanted and is dried on sodium sulphate and is 200 g of ethoxybenzene is obtained point STAGE II 700 ml of nitric acid put in a balloon flask provided with a mechanical agitator and a It is cooled to and 1 g of is added in 2 Agitation is continued for 1 The solution obtained is poured on to 1 kg of The formed precipitate of is dried without heating and washed on a filter with ml of g of is obtained STAGS III itrobenzene is dissolved in Q ml of acetone and with cooling to 6Sg of anhydrous dimethylamine is added in small The mixture is poured on to 1 kg of crushed The precipitate of is filtered and washed on a filter in 133 g of product is obtained N Calculated Actual STAGS IV Into a litre balloon flask provided with a mechanical a thermometer and a reflux condenser are introduced g absolute alcohol ml The mixture is heated under agitation to to dissolve the reagents and of water and 100 g of powdered iron are The temperature is raised to under strong agitation so as to put the powdered iron in suspension and the reaction is started with a few hydrochloric acid 10 ml water ml The reaction is fairly violent and the mixture must be cooled by a bath of ice cold water to prevent the exceeding When the reaction has slowed the remainder of the diluted hydrochloric acid is introduced and the temperature is maintained at from for 3 is brought to without cooling by the addition of a few millilitres of the following mixture Potash 20 g water ml alcohol ml The brown residue is dried hot without heating and is twice made into a paste each time with ml of boiling The 2 filtrates are added to the main solution and the whole is cooled by an ice bath for 1 The mixture is dried without and dried and g of point is N Calculated Actual V Into a 1 litre balloon flask provided with a mechanical a thermometer and a dropping funnel are aniline g water 72 ml hydrochloric acid 10 ml The mixture is The reagents The mixture is cooled to and with the temperature being maintained at 0 to g of sodium nitrite dissolved in 10 ml of water is Agitation is continued for another minutes at from 0 to In a separate into a 2 litre balloon flask provided with a mechanical agitator and a are water mixture is agitated to dissolve the reagents and of sodium cyanide is added in snail The reaches at the end of the There is first of all formation of a brown precipitate and then a dark brown solution obtained which is raised to 3y means of a dropping the diazo solution obtained above is then introduced into this solution in a thin A temperature of from 85 to is maintained throughout this operation which lasts approximately 15 There occurs abundant liberation of gas and a beginning of crystallisation toward the end of the Agitation is continued for another 20 minutes at from 85 to and then cooling is effected and a temperature of from 0 is maintained for 2 The mixture is dried without washed in water twice and dried at The crude product is set to boil ml of absolute The insoluble is filtered and g animal black is added to the filtrate and the whole is boiled for half an the black is filtered and the filtrate is concentrated at ordinary pressure to a volume of 100 Cooling with ice is effected for one the crystallised product is dried without heating and then dried at 12 g of is obtained point 103 STAGE VI acid 12g of is introduced into a 250 ml balloon flask provided with a mechanical and then with agitation the following mixture is water 70 ml Sulphuric acid 65 ml The temperature is raised to from and is maintained for 30 reagents dissolve completely at The mixture is cooled to from 0 to and this temperature is maintained The mixture is completely dried without heating and 4 times made into a paste with the sufficient quantity of being completely dried without heating after each time it is made into a dried at product is dissolved cold with in 100 ml of saturated sodium bicarbonate A cloudy rosy solution is obtained to which g of black is Contact is maintained half an the black is dried without heating and is rinsed with a few millilitres of water and the acid is precipitated by 15 ml of hydrochloric acid d suspension has a of It is dried without washed in water until the ions disappear in the washing water and is filtered at 6 g of acid is obtained point EXAMPLE 5 2 benzoic acid An equimolar amount of pyrrolidine in aqueous tion and of nitrobenzene by the proceesjiascribed in Stage III A of Example is reacted under continuous cooling at d the reaction temperature is maintained below by of an ice The pyrrolidine solution is introduced gradually and the temperature is then allowed to rise to precipitate is washed with chloric acid and then with water in Example and the duct obtained is hydrogenated Stage II B of Example Conversion into the is then Garried out as in Example Hydrolysis to the corresponding benzoic acid is achieved aeid lation with hydrochloric The final product is separated by filtration and washed with water on the filter until free of It is then dried in an aerated drier at The acid melts at 86 EXAMPLE 4 Into a one liter provided with a mechanical a and a dropping 100 g of lnitrobenzene are dissolved with 300 of and then cooled to By the way of the dropping funnel 100 g of morpholine are The mixture is poured on The obtained precipitate is filtered and washed with water to i 88 g of This compound is reduced exactly as in Example 2 hydrogenating it into absolute to obtain The corresponding nitrile is prepared as in Example 2 and and has a melting point of The nitrile is then hydrolysed with sulfuric There are obtained 70 g of benzoic acid which melt a 17 insufficientOCRQuality

Claims (7)

1. 2-Alkoxy-5-N( substituted or unsubstituted )sulphamido benzonitriles, having the general fcrntula in which A is an alkyl radical of low molecular weight (from 1 to 5 carbon atoms); is an amino, mono- or dialkylamino radical of low molecular weight in which the alkyl groups may be joined together by a -CHg- group, a nitrogen or oxygen atom, and where this atom is a nitrogen atom it may be linked to an alkyl group of low molecular weight, to form a pyrrolidine, piperidino, piperazino, 4-alkyl piperazino or morph-olino radical.

2, 2-Met iOxy-5-sulphamido-benzonitrile.

3. ' 2-Etboxy-5-H,N-diaiethylsulphamido-benzonitrile.

4· 2-Alkoxy-5-H(substituted or unsubstituted)sulphamido benzonitriles according to Claim 1> substantially as described herein with reference to the Examples.

5„ A process for the preparation of benzonitriles of formula I in Claim 1 which comprises treating a 2-alkoxy-5-chlorosulphonyl-nitrobensene with ammonia or with a mono- or dialkyl amine or a heterocyclic amine of the formula BMH, reducing the thereby formed 2-alkoxy-5-N( substituted or unsubstituted )-sulphamido«»nitrobenzene and convering the so obtained 2-alkoxy-5-M(substituted or unsubstituted)sulphamido-aniline into the corresponding nitrile by the Sandmeyer method. - 18 - 29627/2

6. A process according to Claim 5» substantially as described herein with reference to the Examples.

7. A process for the preparation of 2-alkoxy-5--N( substituted or unaubstituted) sulphamido benzoic acids of the formula in which A and B have the same meaning as in Claim 1, wherein a benzonitrile of formula 1 in Claim 1 is hydrolyzed. PC/rb