IL31799A - Processes for the preparation of 1-sulphanilyl-2-imino-imidazolidine derivatives - Google Patents

Description

Processes for the preparation of derivatives 2 The present invention relates to the preparation of novel sulfanilamide compounds of the general formula in which is an alkyl group of at most 5 a or group of not mors than 7 carbon and acid addition salts thereof with or organic These new compounds are claimed in Israel Patent They show valuable pharmaceutical properties particularly the and the sho caemlc effect if given orally or parenterally Therefore the new compounds are most suitable for the treatment of The hypoglycaemic effect has been tested with standard methods using warm blooded animals rabbits and In the compounds of general formula can be a lower alkyl group the In addition can be or group such as the or the or a or group such as the h lTmeth the or the 3 or or the The present invention consists in new methods for the preparation of the compounds of formula I By a first method according to the invention compounds of formula I are prepared by cyclization of a compound of general formula 4 in which the same meaning as in formula is hydro an or a the methyl or allyl and X is a radical which can be converted by hydrolysis or by reduction to a free amino group if is hydrogen X is the free with a reactive derivative of cyanic if X is other than the amino group the reaction product is hydrolyzed or reduced to convert the group X into the free amino group if the compound obtained can be converted with an inorganic or organic acid into an acid addition is an or the or trityl group Suitable reactive derivatives of cyanic acid are cyanogen halldes such as cyanogen chloride or cyanogen bromide or cyanic acid in particular cyanic acid phenyl The reaction is preferably carried out in the presence of an inert water miscible or immiscible organic in the presence or absence of Suitable inert organic solvents hydrocarbons such as toluene or lower such as methanol or solvents such as 5 dioxane or chlorinated hydrocarbons such as lower ketones such as acetone or methyl ethyl carboxylic such as ethyl carboxylic acid nltriles such as or sulfones such as The reaction can be performed in the presence or absence of an acid binding Suitable acid binding agents are inorganic or salts alkali metal hydrogen carbonates or as well as the corresponding or Also calcium carbonata calcium phosphates and magnesium carbonate can be The subsequent conversion of the group X into the free amino which converts the reaction product into a compound of general formula depends upon the kind of the group It can be carried out by reduction or reductive Examples of radicals X which can be by hydrolysis into the free amino group are acylamino radicals such as the acetamido Also lower carbonylamino radicals such as the ethoxycarbonylamino radical radicals such as the or arylmethoxycarbonylamino radicals such as the benzyloxycarbonylamino radical or radicals of corresponding thiocarboxylic acid Other examples are stituted radicals such as the benzylideneamino or the The hydrolysis to liberate the amino group can carried out in an acid in methanolic hydrochloric acid solution or in dilute aqueous hydrochloric acid or sulfuric acid if X is an it can also be performed under mild alkaline conditions with or sodium hydroxide An example of a radical X which can be converted into the amino group by reduction is the nitro group and examples of those radicals which can be converted to the amino group by reductive cleavage are the or The reduction of these radicals can be done catalytically with hydrogen in the presence of palladium or platinum on in an inert solvent such as There may also be used other known reduction methods for example the reduction of nitro groups or the reductive cleavage of azo groups by means of iron in acetic acid or hydrochloric 7 The starting materials of formula II are substituted in the para position of the phenyl ring with the group X and in the amino group by and These compounds can be prepared by reacting a substituted by X with a primary or secondary amine which contains the groups and Representatives o these aziridines are described in the literature the 4 anilide et 5475 f Other aziridines of this type can be prepared in a similar By a method according to the invention compounds of general formula I are prepared by condensation and cyclization of a compound of general formula in which X is the amino group or a radical which can be converted by hydrolysis or reduction into the amino with a compound of the general formula IV C Z ff in which has the same meaning as in formula I or with an or metal derivative of such if compounds and X ia other than the amino group the reaction product is thereafter hydrolyzed or reduced to convert the group X into the free amino group if the obtained can be converted with a inorganic or organic acid into an acid addition Suitable alkali metal or alkali earth metal derivatives of general formula IV are or calcium The condensation preferably carried out in an ether type solvent such as anisole or ethylene glycol dimethyl The group X has the same meaning as in the preparation method and its conversion into the free amino group to form a compound of general formula can be done in the same way as described in the first Suitable starting materials of general formula III are those in which the symbol X has the same meaning as the groups named in connection with formula A method for preparation of such compounds has already been described By a third method according to the invention compounds of general formula I are prepared by condensation and of a compound of general formula in which X is the amino group or a radical which can be converted by hydrolysis or reduction into the amino with a reactive ester of a hydroxy compound of formula in which has the same meaning as in formula 1 if X is other than the amino group the reaction product is thereafter hydrolyzed or reduced to convert the group X into the free amino group if the compound obtained can be converted with an inorganic or organic acid into an addition Suitable reactive esters of hydroxy compounds of general formula VI are particularly chlorides or bromides also sulfonic acid the or acid ester or the methane sulfonic acid The condensation is preferably carried out in a solvent which is miscible or immiscible with the absence or presence of Suitable solvents are alkanols such as such as carboxylic acid amides such as or sulfoxides such as dimethyl Preferably the condensation is carried out in the presence of an acid bindin As such there can be used those compounds named in the first preparation In addition there can also be used tertiary organic bases such as The group X has the same meaning as in the first preparation method and its conversion into the free amino group to form a compound of general formula I can be carried out as described As starting materials of formula VI there can be used all the reactive of a hydroxy compound of general formula VI which have been named in which the symbol the same meaning as in formula One group of bromides of general formula VI can be prepared by reaction of an or aziridine Heterocyclic Compounds with Three and Part John Wiley Sons London with in By a fourth method according to the invention compounds of general formula I are prepared by condensation and cyclization of an ester of a compound of general formula which is a residue which can be converted by hydrolysis or reduction into the free amino with an amine of general formula VIII in which has the same meaning as in formula after the reaction product is hydrolyzed or reduced to convert the group into the free amino group if the compound obtained can be converted with an inorganic organic acid into an acid addition Suitable reactive esters of hydroxy compounds of general formula VII are halides particularly chlorides or or sulfonic acid esters particularly acid esters substituted in para position by the group The condensation is preferably carried out in a There are used the same solvents as in the third preparation The reaction is preferably carried out in the presence of an acid binding As acid binding agents there are preferably used excesses of bases of general formula As a radical which can be converted by hydrolysis or reduction into the free amino group has the same meaning as the radical X of the first preparation The into the free amino group to form a compound of general formula I can also be effected in the same manner as described in the first preparation Suitable starting materials for this method of preparation are the reactive esters of hydroxy compounds of general formula VII named the symbol of which has the same meaning as those named formula Such compounds are prepared as Aziridine is reacted with bromfcyanogen in ether to yield the this is condensed in acetone with a sulfonylchloride substituted in with the radical X in the presence of dilute sodium this reaction hydrochloric acid is split off and the corresponding benzenesulfonamlde is By a fifth method according to the invention compounds of general formula I are prepared by cyclization under heating of an addition salt of general formula in which has the same meaning as in formula is a radical which can be converted to the free amino group by hydrolysis or by reduction and 14 Y the reaction product is hydrolyzed or reduced to convert the group into the free amino group if the compound obtained can be converted with an inorganic or organic acid into an acid addition I can as halogen mean bromine or The condensation can be achieved by heating in a solvent or without a Suitable solvents are high boiling such as glycol dimeth lether or carboxylic acid amides such as As a radical which can be converted by hydrolysis or by reduction into the free amino group has the same meaning as the radical X of the first preparation The conversion of into the free amino group to form a compound of general formula I can be achieved in the same manner as described in the first preparation Suitable starting material for this method of preparation are compounds of general formula IX in which the symbols and Y have the same meanings as the groups that are named after formula II and IX A group of such starting materials can be prepared by reacting benzene sulfonyl chlorides substituted with the radical in the with disodiumcyanamide in water to obtain the sodium derivative of the corresponding benzenesulfonamides these condensation products are thereafter reacted with chlorides which are substituted on the nitrogen with a group By a sixth method according to the inventio compounds of general formula I are prepared by reduction of a compound of general formula in s a cycloalkenyl group with 5 to 7 carbon X is the amino group or a radical which can be converted into the free amino group by hydrolysis or reduction if X is other than the amino group the reaction product is hydrolyzed or reduced to convert the group X into an amino group if the compound obtained can be converted with an inorganic or organic acid into an acid addition The reduction is preferably carried out with hydrogen in the presence of a catalyst in a Suitable catalysts are noble metal catalysts such for palladium which can be suspended on carbon and also Raney 16 Suitable solvents for alkanols such as methanol or and also It is preferable to carry out the reduction at normal pressure and room The group X has the same meaning as in the first preparation Its conversion into the free amino group which converts the reaction product into a compound of general formula I can also be done as described in the first preparation Starting materials of general formula X may be prepared according to first preparation method by reacting sulfonyl substituted by the radical X with an or to form the corresponding or substituted by the radical This reaction product is condensed with bromocyanogen and By a seventh method according to the invention compounds of general formula are prepared by reacting a compound of general formula 17 in has the same meaning as in formula I and is a radical which can be converted b hydrolysis or reduction into the free amino with a reactive diester of the reaction product is thereafter hydrolyzed or reduced to convert the group into the free amino group if the compound obtained can be converted with inorganic or organic acid into an acid addition s Suitable reactive diesters of ethyleneglycol are in particular dichlorides or also fonic acid or acid esters or sulfonic acid The reaction is preferably carried out in an inert Suitable inert solvents are aromatic such as toluene or halogenated hydrocarbons such as chloroform or carbon ethers such as dioxane or diethyleneglycol monomethyl carboxylic acid amides such as or 18 acid amide or also sulfoxides such as dimethyl The reaction can be carried out in tie presence or absence of an additional acid binding Suitable acid binding agents are inorganic bases or salts alkali metal hydrogen carbonates or phosphates as well as the corresponding or assium Calcium calcium phosphates and magnesium carbonate can also be As acid binding agents there may also be used suitable organic tertiary nitrogen bases such as As a radical which can be converted by hydrolysis or reduction into the free amino has the same meaning as the radical X of the first preparation The conversion of into the free amino group to form a compound of general formula I can also be done as described in the first preparation A starting material of general formula the described by Boggiano et and Other starting materials of the general formula XI can be prepared By an eighth method according to the invention compounds of the general formula I are prepared by reaction of a compound of the general formula in which is a radical which can be converted by hydrolysis or reduction into the free amino group with a reactive of a hydroxy compound of the general formula OH in which is an alkyl group with not more than 7 carbon the reaction product is hydrolysed or reduced to convert the group into the free amino group if the compound obtained can be converted with an inorganic or organic acid into an acid addition Suitable reactive derivatives of hydroxy compounds of the general formula XIII are particularly chlorides or also sulfonic acid the or sulfonic esters or the methane sulfonic acid The reaction is preferably carried out in an inert Suitable inert solvents are aromatic such as toluene or the halogenated such as chloroform or carbon such as dioxane or diethyleneglycol carboxylic acid such as or and also sulfoxides such as the The reaction can be carried out or absence of an additional acid binding Suitable acid binding agents are inorganic bases or salts such as alkali metal hydrogen carbonates or like the corresponding or potassium Calcium calcium phosphates and magnesium carbonates can also be As acid binding agent there can also be used suitable organic tertiary nitrogen like ethyl As a radical which can be converted by hydrolysis or reduction into the free has the same meaning as the radical X of the first preparation The conversion of into the amino group to form a of the general formula I can also be done as described in the first preparation Starting materials of the general formula XII are for example obtained by reaction of a benzene sulfonyl chloride substituted by in the chloride with the in the presence of sodium The compounds of the general formula I prepared by the methods according to the invention are if into the salts with Inorganic or organic by reaction of compounds of the general formula Ϊ with an equivalent amount of acid in a suitable aqueous organic or inorganic solvent such as diethylether chloroform or For use as drugs instead of the free compounds salts of the general formula their pharmaceutical salts are salts with hydrochloric sulfuric phoric onic ethanesulfonic ethan sulfonic acetic acidfl lactic oxalic succinic hydroxy succinic tartaric citric benzoic phenylacetic acid and She new are preferable administered oralo The daily doses are between 100 and 500 for an adult patient with weigh Suitable doses forms like contain preferable 50 to 500 of the e usually 20 to of a coEipound of general formula For their preparation the active compound is combined with a solid powder like carrier like sorbi like corn starch or also laiainaria powder or cellulose derivatives or if desired under addition of sliding agents like or calcium or glycols of suitable molecular weights to form tablets or She last named coated with concentrated solutions of sugar which may also contain talc or titan or with a volatile organic solvents o mixtures of solvents which contain dissolved It is possible to add to these coatings pigments to mark different doses of the active As other oral doses forms there are suitable capsule of gelatine or soft closed capsules of gelatine and so ening agent like Plugged capsules contain the active ingredient preferable as granulate in mixture with fillers like corn starch sliding talc or magnesium stearat and if desired like or In the soft capsules the active ingredient is preferable dissolved or suspended in suitable liquid polyethylenglycols whereby if desired a stabiliser can be addedo The ollowing methods preparation are describing the preparation o tablets and in more details 1000 are mixed together with 500 g lactose and 270 g The mixture is with an aqueous solution of g and granulated through a After drying it mixed together with g potatoe g talc g stearat and g colloidal silic After this the is pressed to 24 each of which has a weight of 200 and contains ingredien if desired the tablets can get part notches to adjust finer From g 345 g lactose and the aqueous solution of g gelatine there is a granulate which a er drying is mixed with g colloidal g g potatoe starch and g and pressed to These are coated afterwards with a concentrated syrup of 533 g cristalline g g 250 g 20 g colloidale and g dye and driedo She tained weig each 240 mg and contain each mg active ollowing examples describe the preparation of the new compounds of ormula I and of intermediates which are not so far but they are not the only way to prepare temperatures are given in 1 31 g are dissolved in hydroxide and to this solution is added while cooling to 20 g bromcyan0 crude product precipitates After 30 it is filtered off and from dimethyl 4 y obtained at g of acetanilide obtained after method and 100 acid are heated for 1 hour at the reaction is cooled to and alkaline with base is filtered of 9 washed with water and from i obtained melts at 179 She starting material of is obtained according to the following procedures 2 g et 5475 f are dissolved in 100 ml and 15 ml water in the cold and this solution is dropped to ml After this the reaction is refluxed for one hour and then the excess of and is of the crystalline residue from actio acid ethyl ester yields the puree point According 1 one g and melting point of the de obtained after and 200 ml acid 48 at is to dryness in crystalline residue is dissolved in and the solution is alkaline free crude base it is filtered off and pure at starting used under the with a melting point of acetic is prepared according 1 from 24 g and 00 aqueous According one g of point acetic acid ethyl and the e daz id of melting point which according 1 with acid to the endp l of point The material of is obtained according 1 g acetanilide and ethyl A According example 1 one obtains starting with g melting point acetic acid ethyl with g bromcyan the l acetanilide melting point of 32 g according 2 are ic hydrochloric acid to yield the melting point 0 starting material of is obtained according example i 2 and According example one obtains starting with g of melting point acetic acid ethyl with g chlorcyan the d of point g of which are according 2 with 200 ethanolic hydrochloric acid to the end product melting point starting compound of is obtained according example 1 from g acetanilide and ml 6 According example 1 one starting with of melting point acetic acid ethyl with g the melting point g of which are according example 2 with ethanolic hydrochloric acid to the end product melting point me starting material of is obtained according 1 from g amide and 100 ml According example 1 one obtains starting with of melting point with g the of melting point of which g example are with 200 ml nolic hydrochloric acid to the end product melting point The starting material of is obtained according example 1 g 50 acetanilide and Example 8 According example 1 one obtains starting with 31 g melting point acetic acid ethyl with g instead of the 3 t er of ing point g of which are according 1 with acid the e d product ne of melting point starting material of is obtained according 1 from g ony acetanilide and 00 According e 1 one obtains starting with g of melting point acetic acid ethyl g the melting point 51 So g of sulfuric acid is to are added while g obtained is 2 hours at and poured under stirring in 750 whereby the crude product precipitates She ac hydroxide to whereby f or minor ies the product adding 2 g active carbon on the reaction mixture is stirred for minutes and filtrated over She filtrate ia alkaline with sodium hydroxide crude product is filtered of dried at in vacuo and from methano a melting point of The starting material of is obtained according example 1 00 ml pentylaain 10 According example 1 obtains starting with 1 of melting point acetic acid ethyl with instead the of melting point g of which are according 2 200 hydrochloric acid to the product of melting point e starting of is obtained g 200 According 1 obtains starting h g point of the g the of point g of which are d 1 2 hydrochloric acid to end product 1 of point starting of obtained example from 24 g and 0 V According 1 one obtains of point g the of point g of which accordi g 2 with 200 hydrochloric acid to the end p oduct point starting of is obtained according example from g anilide and 100 ml C According ono obtains from g and bromcyan in 100 sodium hydroxide th dine of melting point 2 g of itro compound prepared according method are dissolved in 1 1 ethancl and in the presence of at pressure till io no sore uptake hydrogen this catalyst filtered washed filtrate evaporated in of residue the pure of melting point She starting of method ia prepared 1 ne and ml g are dissolved ia 500 So the solutio are added g then the reactio is stirred 3 at room residue treated hydroxide it are precipitating which are with water and pure obtained melts at According 5 the aee anilide is to yield the of melting point V 55 starting is produced according the following 2 g are dissolved 100 and 20 ml g while s the reaction mixture is obtained crystallises in acetic acid from acetic acid ethyl the melts at Example 15 To a solution of 25 5 sulfanilamide in 100 are added within 10 minutes while cooling to a solution of 1 phenylcyanat in 50 e suspension obtained ie for hours and after this in the residue are added iaethylenehloride and insoluble crude product is filtered 0 the organic phase separated from the dried over sulfate and evaporated in The is with the obtained crude product and the is after this the 1 melts at She starting is according g point obtained by catalytic reduction cny asiridine with Raney nickel in 52 are in 70 solution is within 1 hour to g boiling reaction is for 2 the of cyc is off and the eaction evaporated in is zed from acetic ethyl f one obtains the an melting point According example one g melting point and a solution of g phenylcyanat in ether the sul melting point starting obtained according the ollowing After an interval of some crystals are suspension at for and after this She residue is dissolved in little alkaline GO that has w it solution is extracted three with each with 200 She solution is with little dried over sulfate and She residue obtained is from acid ethyl ester whereafter the obtained y at According 5 o e obtains g the hydrochloride of which melts at solution of g in 50 ml ether the melting point is prepared 11 from g amide 500 et hydrochloric in this solution are added g reaction is stirred for 1 hour at e and this the crystals the the 1 melting point According 18 one obtains sta ting 20 ml sodium with and g the melting point and with and g the point So a solution of S absolute are added while at to 30 a solution of 50 ml absolute reaction mixture is stirred 30 additional minutes and the precipitated filtered of the in which the obtained ide is ia added while still a suspension of g sodium hydride in 40 ml absolute suspension which is cooled at the same temperature is stirred for minutes and thereafter one adds to the formed suspended sodium derivative of the 2 9 g 4 reaction mixture is warmed oom temperature and stirred at room the reaction mixture ia thereafter added slowly hydrochloric the two different phases She acid aqueous phase is washed two times with purified with activated filtrated and made alkaline with concentrated sodium hydroxide at precipitated 4 is filtered off and from melting point The acetanilide obtained is according 1 to yield the point According 20 0210 s from g ether g the converted g sodium hydride in 40 ether into this yields with g the melting point which according 2 to the melting point g in ml e with g bro cyan th which converted with g sodium hydride in 40 ether into the sodium derivatives this yields g anilide the acetanilide of melting point which is according to the melting point from g propylamine in 100 ether with g the which is converted with g hydride in 4012I ether into the sodium this yields with g i the acGtaailide of is according to the point g 100 g the w g sodium in 40 sodium this 24 g 4 melting point vh eh is according example 8 to the 1 point from ia 100 ether wi g which is converted with g sodium hydride ia 40 ml into sodium this 24 acetaniXide the point 261 which ia according to yield the malting point 8 g in with g the is converted g sodium hydride in 40 into the sodium this with g the 4 point which is according 1 to yield the 1 β point wit g the which is converted hydride in 40 into the this yields with 0 g point 2 whic hydrolised 9 to yield the melting point 63 a solution g in 50 ml ether are added w stirring and at to a solution of in absolute some minutes the hydrochloride It is filtered the filtrate in which the butyl cyanamide added portionswiee sodium hydride in 40 ml A precipitate suspension ia diluted 200 absolute 200 ml and is for minutes at the reaction g suspension is stirred fo there are is It ia extracted with d aqueous phases are purified d is neutralised solid sodium carbonate a resin She resin is off ove the colorless clear ia is kept for hour at thereafter the precipitated crystals are filtered off One obtains the point According one from in ml ether g is w g sodium hydride ia ether into the sodium this g 1 in 00 ail ether h g the io with g hydride in 40 ether the this g the ra elting point g propylamine 100 ether with g the which is converted with sodium hydride in 40 ral ether into the sodium this yields with g ne the melting point g in ether with the which is converted with g sodium hydride 40 ml ether into the odium this with g the melting point from g in 100 ml ether with g the which is converted g hydride in 40 ml into the yields with the nel point g in ml ether g cyc with g hydride 40 ml ether into the sodium this yields g 1 point 24 er Hete cyclic hree and Ring Wiley Sons dissolved in ml this solution are added g an exothermic reaction a of is dropped while stirring to solution of g in 100 hydroxide S reaction mixture is hour and evaporated in vacuo to half of the separated crystals are filtered off with water and dried at in vacuo and from acetic ethyl One obtains the is e 3 yield the point According 2 one and g yields with g ia 100 ml 1 sodium the melting point this is according example 2 to jr the dine point from and g in the which yields g in 100 hydroxide the melting point this is hydrolised to yield the ing point y g g 60 the 2 hydroxide the salting point according 4 to the point g and g in 60 ml the which yields g in 100 sodium hydroxide the point this is according to the point from g and g 60 the which yields with g in 100 ml sodium the point this is hydroliaed according 6 to the melting point g 1 and g sal the which with g 4 100 hydroxide the 4 1 molting point is example 7 to yield the 5 g in 60 ml the g 4 in 00 hydroxide melting point this is according Xe 9 to yield the X f om g 1 and g in 60 iaX ane the which yields g in sodium hydroxide the 4 melting point this is according 10 to yield the point g g 60 yields sodium salting point this according 11 to yield molting g g 60 yields 4 g in 100 hydroxide 4 point is according 21 to yield 1 melting point 26 a solution of g in 60 d are added g In as reaction is added in the reaction solution ring to a of 17f2 g sulfanilamide in f 1 evaporated in the residue is precipitate is acetic obtained 1 obtains g t g in 60 ml the yields g ia 100 ml hydroxide the 9 melting point 1 wi g in 60 diosane the whic yields with sulfanilamide in hydroxide the poin 171 g with g in 60 ml the v g 1 point g with in 60 ml the which yields with in 100 sodium hydroxide the point g g ia ml the with g s 100 the melting from g with g ia 60 ml which g ia 100 ml 1 l melting poiat g with g ia 60 ml the which yields with g ia ml 52 hydroxide melting point g g omcyan in 60 ml yields g sulfanilamide in sodium hydroxide the 1 melting point g with g in 60 yields 1 g sulfanilamide in 100 ml the 1 molting point g with g 60 ml which yields g sulfanilamide in 00 hydroxide the Example 23 A e of g g potassium hydroxide and 2 g sulfanilamide in ml heated la a bat of for 30 the reaction is and suspension filtration is dissolved in discoloured activated charcoal filtered and sodium precipitated crystals are filtered and aXlised Oae point S are dissolved in 500 ml ethanol and and for 17 S is evaporated and the residue taken up in chloroform ydrochloride is mde alkaline with sodium crude product it is iltered off and ed by from etbanol and She obtained melts at is according example 1 to yield the mel point She sulfanilamide which is the starting can be prepared according the following 30 minutes one drop a a solution azirldine in 20 ml ether at to a solution of g in 50 ml is evaporated in a temperature residue is slurried in nil to this suspension t ere is added a solution of 25 g chloride in ml minutes 5 g sodium hydroxide in 10 ml water to the reaction mixture and the resulting fo cooling the crude product It is filtered off She ltrate yields after diluting water another amount of crude product which is separated and combined with the irst fractions are from whereafter the de melts at According 29 one starting with in 500 ml with 31 g the z d sul etani e melting nt which hydrolised according 2 to yield the point g e ol anili d melting point is according to yield the melting point with propylamine the malting which is according 4 to yield the 1 melting point Q the 4 point which is hyd according 5 to yield the melting point with g the 4 point which is according to yield the point with g the point is 7 to yield melting point g point 8 to yield the melting point w is 9 to yield molting point with 85 point according 11 to yield the molting and g point to the point 5 addition of and in a of 1 whereby the salt mixture is cooled hydrochloric and the solution is the ioa is with sodium hydroxide crude product is filtered washed from One the poiat is 8 to j of poiat the So a fit g ia 100 there added g a slight solution is at whereby the sodium is 15 g to salt of salt filtered washed and whereafter it has a point of 4 Ac one the the addition salt of amid and t the which 2 to yield the of addition which is is prepared according 31 and addition salt of amide and the p point which is 1 to 1 point salt used has prepared 31 from addition salt of and the ael is 21 to yield the d melting point addition oalt used has prepared according example 31 and och from the addition salt of amide and the point which is according to yield the point addition used prepared according 31 sodium and and the addition salt of amide and the point is according 9 to yield the melting point addition salt used is according 31 and g melting point are dissolved in 350 ml and hydrogenated with g percent pallad um on charcoal at room and After the uptake of hydrogen the catalyst is filtered off and the filtrate obtains the melting point 61 starting is prepared to starting t and molting point According obtains starting g melting point melting point there a also the 1 mel ing point the point and the mel point Example A reaction mixture containing g melting point d ide and 900 is reflated for 30 hours and evaporated to dryness After adding ml sodium hydroxide to the residue it is She chloro orm extract is on a silica gel The fractions solvent orm checked by thin layer compound desired has an Rf value of 056 methanols chloroform fractions which contain the desired compounds in sufficien purity are combined and freed of the obtained crude is from melting point g of the compound obtained after method are sad according example 1 to the melting point According example 35 one obtains starting with g et and g onyl melting point et melting which is accordin 2 yield 1 mel ing point and 3 g guanidine the melting point which is according example to yield melting point and g the ng point which is according 21 to yield the melting point A reaction containing g g butyl bromide and 900 is 30 hours and thereafter evaporated to the residue are added 60 sodium hydroxide and thereafter it is extracted She chloroform extract is ied a silica gel She fractions with a of are checked by thin She compound has a Value methano chloroform Ί She fractions which contain the desired compound in sufficient purity are combined and freed of the solven She crude anil de obtained is melting point saponi of the acetanilide tained after method are warmed with ml chloric acid 1 hour at She reaction x cooled to and alkaline with sodium She precipitated crude base is filtered of washed with water and recrystallised from She obtained is dried in point She starting material used for method can be pared according the following So a solution of g f chloride in 250 ml acetone there are added a solution of g hydrochloride in 100 Shereafter is added to the reaction a solution of 8 g sodium hydroxide in ml whereby a thick slurry precipita reaction mixture is warmed 1 hour at The cipitated are treated 3000 hot water and filtered off from the anil de melting point which is insoluble in wate Cooling the filtrate yields the desired onyl e are filtered off and melting point 2 8 According example 37 one obtains from g 4 and 7 g p yl bromide the 4 ylsul melting point saponi cation of the obtained acetanilide according method are with 200 etbanolic chloric acid for 48 hours at The reaction mixture is evaporated in the crystalline residue dissolved in water and the water solution made alkaline with The precipitating crude base is filtered off and from me obtained at βδ 39 According 57 there are obtained from 28 2 g 4 and 5 5 g the 4 melting point So 125 g 50 percent acid at are added g after The warmed 2 hours at and thereafter stirring poured in 750 ml The crude product cipitates as reaction mixture is adjusted with on whereby except for small ies a solution is After adding 2 g active charcoal the reaction mixture is stirred for 15 minutes and filtered over o The filtrate is made with hydroxide The crude product it filtered of 9 washed with wate dried at in vacuo and from The obtained imidajsolidine has a melting point of prepared according example 37 is alkylated with butyl bromide according example 37 The crude product obtained after the on a silica is crystallised obtained pure has a melting point of 390 g nitro compound prepared according are solved in 15 1 and with of pla percent at and catalyst filtered off and with She in to the residue are added 1 1 ydrochloric acid and the insoluble par s are filtered S filtrat is alkaline with sodium precipitated is filtered of washed with and dried in vacuo at obtained melts at According exajsple 57 one prepares starting with 28y2 g 4 and g the melting point which is according 2 to yield the melt lag point 1 obtains starting A melting aoetio acid ethyl g the point g 21 to yield tho point iaX of is obtained 1 g anil de 00 ml 69 insufficientOCRQuality

Claims (1)

1. Method for the preparation of derivatives of the sulfanilamide of general formula in which R^ is an alkyl group of at most 5 carbon atoms, a cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, cycloalkenyl alkyl-cycloalkenyl or cycloalkenyl-alkyl group of not more than 7 carbon atoms, and acid addition salts thereof with inorganic or organic acids which comprises: a) reaction and cyclization of a compound of the general formula in which R^ has the same meaning as in formula I, Rg is hydrogen, an aryImethyl, diaryImethyl or triarylmethyl group, the methyl or allyl group, and X is a residue which can be converted by hydrolysis or reduction into the free amino group or, if Rg is hydrogen it can be the free amino group, with a reactive derivative of cyanic acid; or b) condensation and cyclization of a compound of the general formula III 31799/3 - 70 In which X Is the amino group or a radical which can be converted by hydrolysis or reduction into the amino group wit a compound of general formula IV H - N - R. t ] IV 0 Ξ in which ^ has the same meaning, as in formula I or fith an alkali metal or alLSalLife earth metal derivative of such a compound j or c) condensation and cyclization of compound of the general formula in which X has the same meaning as in formula III with a reactive ester of a hydroxy compound of the general formula in which ^ has the same meaning as fcwaulalj or d) condensation and cyclization of a reactive ester of a compound of the general formula in which X'! is a radical which can be converted by hydrolysis or reduction into the free amino group with an amine of formula ■ R1 * W2 VIII 31799/3 - 71 - reaction product is hydrolyzed or reduced to convert X· into the free amino group; or e) cyclization under heating of an addition salt of the general formula in formula I, X' has the same meaning as in which R^ has the same meaning as/in formula VII and Y is halogeri, and, thereafter the reaction product is hydrolyzed or reduced to convert the group X' into the free amino group; or f) reduction of a compound of the general formula in which ^' is an alkenyl group with 3 to 5 carbon atoms or a cycloalkenyl group with 5 to 7 carbon atoms and X has the same meaning as in formula III; or g) reacting a compound of the general formul in formula I and X* has the same meaning as in which ^ has the same meaning ae in formula VII, with a reactive diester of ethylene glycol, thereafter the reaction product is hydrolyzed or reduced to convert the group X' into the free amino group; or 31799/3 - 72 - reacting a compound of the general formula in which X' has the same, meaning as in formula VII with a reactive ester of a hydroxy compound of the formula OH - R, XIII in which R^ is an alkyl group with not more than 7 carbon atoms, thereafter the reaction product is hydrolyzed or reduced to convert the group X' into the free amino group; and, if desired, wherein the compounds of formula II, III, V or X the substituent X is other than the amino group, the reaction product is hydrolyzed or reduced to convert the group X into the free amino group and, if desired, the compound of formula I obtained is converted with an inorganic or organic acid into an acid addition salt.; 2, Processes for the preparation of l-sulphanilyl- 2-imino^imidazolidine derivatives of formula I in Claim 1, substantially as described herein with reference to the Examples . For the Applicants J?C:CB