DK156432B - 3-N-PYRROLO-5-SULFAMOYLBENZOIC ACID DERIVATIVES FOR USING INTERMEDIATES IN THE PREPARATION OF 3-N-PYRROLIDINO-5-SULFAMOYLBENZOIC ACID DERIVATIVES - Google Patents
3-N-PYRROLO-5-SULFAMOYLBENZOIC ACID DERIVATIVES FOR USING INTERMEDIATES IN THE PREPARATION OF 3-N-PYRROLIDINO-5-SULFAMOYLBENZOIC ACID DERIVATIVES Download PDFInfo
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iin
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Den foreliggende opfindelse angâr 3-N-pyrrolo-5-sulf-amoylbenzoesyre-derivater med den almene formelThe present invention relates to 3-N-pyrrolo-5-sulf-amoylbenzoic acid derivatives of the general formula
5 i / O5 I / O
R - N - C = COORR - N - C = COOR
R4R4
10 R10 R
hvor R1 og R1' betegner halogen, alkyl-, alkoxy- eller aralk- oxygrupper med 1-4 carbonatomer eller hydrogen i de forskel- lige stillinger i ringen eller tilsammen betyder en 3,4- -methylendioxygruppe, X betegner O, S eller NH, R er hydrogen 15 eller alkyl med 1-4 carbonatomer, og R3 og R4' hver isaer 3 4 betyder lavere alkylgrupper, eller R og R betyder cyclisk for-bundne lavere alkylgrupper.wherein R 1 and R 1 'are halogen, alkyl, alkoxy or aralkoxy groups of 1-4 carbon atoms or hydrogen at the various positions in the ring or together represent a 3,4-methylenedioxy group, X represents O, S or NH , R is hydrogen 15 or alkyl of 1-4 carbon atoms, and R 3 and R 4 'are each especially 4 4 are lower alkyl groups, or R and R are cyclic linked lower alkyl groups.
3-N-pyrrolo-5-sulfamoylbenzoesyre-derivaterne med den almene formel I kan fremstilles ved, at et 3-aminosubsti-20 tueret benzoesyrederivat af formlen - , "The 3-N-pyrrolo-5-sulfamoylbenzoic acid derivatives of the general formula I may be prepared by a 3-amino-substituted benzoic acid derivative of the formula -, "
R- N - C = N09S xCOORR- N - C = NO9S xCOOR
R4 4 hvori R-R og X har de ovenfor angivne betydninger, omsættes 30 med 2,5-dialkoxytetrahydrofuraner af formlenR4 4 wherein R-R and X have the meanings given above are reacted with 2,5-dialkoxytetrahydrofurans of the formula
Alk-0 O-Alk 35 hvori Alk betegner alkyl med 1-4 carbonatomer, fortrinsvis methyl, hvorefter de opnâede forbindelser eventuelt hydro-lyseres.Alk-OO-Alk 35 wherein Alk represents alkyl of 1-4 carbon atoms, preferably methyl, after which the compounds obtained are optionally hydrolyzed.
2 02 0
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Udgangsforbindelseme af formlen II er til dels kendt fra tysk offentligg0relsesskrift nr. 2.461.601 eller kan frem-stilles pâ tilsvarende mâde som beskrevet deri. Omsætningen af aminen II udf0res for det meste i svage organiske syrer, for-5 trinsvis i iseddike, ved kogetemperatur.The starting compounds of Formula II are known in part from German Publication No. 2,461,601 or may be prepared in a similar manner as described therein. The reaction of the amine II is mostly carried out in weak organic acids, preferably in glacial acetic acid, at boiling temperature.
Ved anvendelse af beskyttelsesgruppen ved sulfamoylfunk-tionen bliver overraskende udbyttet væsentligt for0get sammen-lignet med den analoge reaktion med tilstedeværelse af en fri sulfamoylfunktion, sâledes som den f.eks. er kendt fra belgisk 10 patentskrift nr. 828.441, og det er muligt at opnâ et næsten kvantitativt udbytte.Surprisingly, when using the protecting group at the sulfamoyl function, the yield is significantly increased compared to the analogous reaction in the presence of a free sulfamoyl function. is known from Belgian Patent Specification No. 828,441, and it is possible to obtain an almost quantitative yield.
Forbindelserne af formlen I er værdifulde mellempro-dukter til fremstilling af lægemidler, især diuretika, som beskrevet i belgisk patentskrift nr. 828.441. Disse forbin-15 delser, der i 3-stillingen bærer en tilsvarende pyrrolidin-ring, opnâs ved katalytisk hydrogenering, f.eks. ved hjælp af ædelmetalkatalysatorer som f.eks. Pd/aktivkul, Pt02,The compounds of formula I are valuable intermediates for the preparation of drugs, especially diuretics, as described in Belgian Patent Specification No. 828,441. These compounds, which carry a corresponding pyrrolidine ring at the 3-position, are obtained by catalytic hydrogenation, e.g. using precious metal catalysts such as Pd / active carbon, PtO2,
Rh/kul eller Pt/aktivkul, men reduktionen kan ogsâ udfores med andre til pyrroler kendte reduktionsmidler som f.eks.Rh / coal or Pt / activated carbon, but the reduction can also be carried out with other reducing agents known to pyrrole such as e.g.
20 zink/iseddike eller hydrogeniodidsyre og rodt phosphor.20 zinc / glacial acetic acid or hydrogen iodide acid and red phosphorus.
Efter reduktionen fraspaltes sulfonamid-beskyttelses-gruppen samt eventuelt esterresten R ved sur eller alkalisk hydrolyse.After the reduction, the sulfonamide protecting group and optionally the ester residue R are cleaved by acidic or alkaline hydrolysis.
At forbindelserne af formlen I skulle være anvendelige 25 til fremstilling af pyrrolidino-forbindelserne, var ikke til at forudse, da det var at befrygte, at beskyttelsesgruppen for sul-fonamidresten under de hydrogeneringsbetingelser, som er n0dven-dige til pyrrolresten, ligeledes ville blive angrebet.That the compounds of formula I should be useful in preparing the pyrrolidino compounds was not foreseeable, as it was to be feared that the protecting group for the sulfonamide residue under the hydrogenation conditions necessary for the pyrrole residue would also be attacked .
30 R1 og R1' kan ifolge definitionen være aralkoxygrup- per, hvilke ligeledes kan betragtes som værende OH-grupper, beskyttede med aralkylgrupper, f.eks. benzylgrupper.By definition, R1 and R1 'can be aralkoxy groups which can also be considered as OH groups protected by aralkyl groups, e.g. benzyl.
De folgende eksempler skal tjene til nærmere illustre-ring af fremgangsmâden til fremstilling af forbindelserne 35 ifolge opfindelsen.The following examples are intended to further illustrate the process of preparing the compounds 35 of the invention.
00
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Eksempel 1 3-N-Pyrrolo-4-phenoxy-5-N,N-dimethylaminoniethylenaitiinosulfonyl-benzoesyremethylester.Example 1 3-N-Pyrrolo-4-phenoxy-5-N, N-dimethylaminonethylethyleneithinosulfonyl-benzoic acid methyl ester.
I 100 g iseddike opvarmes 100 g 3-amino-4-phenoxy-5-5 -N,N-dimethylaminomethylenaminosulfonylbenzoesyremethylester og 53 g 2,5-dimethoxytetrahydrofuran i 15 minutter under til-bagesvaling, hvorefter der afk01es til 10°C, og de udskilte krystaller suges fra, vaskes med 20 ml kold iseddike og t0rres i vakuum. Der fâs herved 96 g farvel0se til brunlige krystaller 10 med smp. 173-175°C. Til yderligere rensning kan der om n0dven-digt omkrystallisérés fra isopropanol eller eddikesyreethyl-ester.In 100 g of glacial acetic acid, 100 g of 3-amino-4-phenoxy-5-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester and 53 g of 2,5-dimethoxytetrahydrofuran are heated under reflux for 15 minutes, then cooled to 10 ° C. separated crystals are sucked off, washed with 20 ml of cold glacial acetic acid and dried in vacuo. 96 g of colorless to brownish crystals 10 with m.p. 173-175 ° C. For further purification, if necessary, recrystallization from isopropanol or acetic acid ethyl ester can be made.
Overf0ring til 4-phenoxy-3(l-pyrrolidinyl)-5-sulfamoylbenzoe-15 syre.Transfer to 4-phenoxy-3 (1-pyrrolidinyl) -5-sulfamoylbenzoic acid.
I 100 ml methanol og under tilsætning af 1 g 10%'s pal-ladium/aktivkul hydrogeneres 10 g 3-N-pyrrolo-4-phenoxy-5-N,N--dimethylaminomethylenaminosulfonylbenzoesyremethylester i 5 timer ved 100°C og 100 atm, hvorefter katalysatoren frafil-20 treres varmt. Ved afk01ing udkrystalliserer der fra opl0snin-gen 8 g 4-phenoxy-3-(1-pyrrolidinyl)-5-N,N-dimethylaminomethy-lenaminosulfonylbenzoesyremethylester med smp. 187-189°C.In 100 ml of methanol and with the addition of 1 g of 10% palladium / activated charcoal, 10 g of 3-N-pyrrolo-4-phenoxy-5-N, N - dimethylaminomethylenaminosulfonylbenzoic acid methyl ester is hydrogenated for 5 hours at 100 ° C and 100 atm. , after which the catalyst is filtered off hot. Upon cooling, 8 g of 4-phenoxy-3- (1-pyrrolidinyl) -5-N, N-dimethylaminomethyl-methylaminosulfonylbenzoic acid methyl ester crystallize from the solution, m.p. 187-189 ° C.
Det opnâede produkt suspenderes i 100 ml 2 N NaOH og opvarmes under tilbagesvaling, til der er dannet en klar opl0s-25 ning. Ved syrning med 2 N HCl til en pH-værdi pâ 3-4 udfældes den frie syre 4-phenoxy-3-(1-pyrrolidinyl)-5-sulfamoylbenzoe-syre. Efter omkrystallisation fra CH^OH/^O fâs lysegule krystaller med smp. 226-228°C.The obtained product is suspended in 100 ml of 2 N NaOH and heated at reflux until a clear solution is formed. When acidified with 2 N HCl to a pH of 3-4, the free acid precipitates 4-phenoxy-3- (1-pyrrolidinyl) -5-sulfamoylbenzoic acid. After recrystallization from CH2 OH / O, pale yellow crystals were obtained, m.p. 226-228 ° C.
3030
Eksempel 2 3-N-Pyrrolo-4-(41-methylphenoxy)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.Example 2 3-N-Pyrrolo-4- (41-methylphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethylen-35 aminosulfonylbenzoesyremethylester.a) 3-Nitro-4- (4'-methylphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
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En opl0sning af 235 g (0,67 mol) 3-nitro-4-chlor-N,N-di-methylamino-methylenaminosulfonylbenzoesyremethylester og 140 g (0,96 mol) kalium-4-methylphenolat i 1 liter absolut dimethyl-formamid (DMF) omr0res i 2 timer ved 90-100°C, hvorefter den 5 afk01ede opl0sning langsomt og under kraftig omr0ring dryppes ud i 4-5 liter isvand. Det herved udfældede produkt suges fra, vaskes med vand og omkrystalliseres af CHgOH, hvorved der fâs lysegule krystaller med smp. 200-201°C.A solution of 235 g (0.67 mol) of 3-nitro-4-chloro-N, N-dimethylamino-methylenaminosulfonylbenzoic acid methyl ester and 140 g (0.96 mol) of potassium 4-methylphenolate in 1 liter of absolute dimethylformamide ( The DMF) is stirred for 2 hours at 90-100 ° C, after which the 5 decolorized solution is slowly and rapidly stirred in 4-5 liters of ice water. The thus precipitated product is suctioned off, washed with water and recrystallized from CHgOH to give pale yellow crystals with m.p. 200-201 ° C.
10 b) 3-Amino-4-(4'-methylphenoxy)-5-N,N-dimethylaminomethylenami-nosulfonylbenzoesyremethylester.B) 3-Amino-4- (4'-methylphenoxy) -5-N, N-dimethylaminomethyleneamosulfonylbenzoic acid methyl ester.
171 g 3-Nitro-4-(4'-methylphenoxy)-5-N,N-dimethylamino-methylenaminosulfonylbenzoesyremethylester hydrogeneres med Ra-ney-nikkel som katalysator i dimethylformamid ved 50°C og 50 atm 15 i 8 timer i en autoklav, hvorefter der filtreres, filtratet ind-dampes, og remanensen omkrystalliseres fra CH^OH. Der fâs farve-I0se krystaller med smp. 172-173°C.171 g of 3-Nitro-4- (4'-methylphenoxy) -5-N, N-dimethylamino-methylenaminosulfonylbenzoic acid methyl ester is hydrogenated with Rene-nickel as a catalyst in dimethylformamide at 50 ° C and 50 atm 15 for 8 hours in an autoclave, and then the filtrate is evaporated and the residue is recrystallized from CH 2 OH. Color-free crystals with m.p. 172-173 ° C.
c) 3-N-Pyrrolo-4-(41-methylphenoxy)-5-N,N-dimethylaminomethy-20 lenaminosuifonylbenzoesyremethylester.c) 3-N-Pyrrolo-4- (41-methylphenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.
I 150 ml iseddike opvarmes under tilbagesvaling 19,5 g (0,05 mol) 3-amino-4-(4'-methylphenoxy)-5-N,N-dimethylaminome-thylenaminosulfonylbenzoesyremethylester og 7 ml Ov 0,075 mol) 2,5-dimethoxytetrahydrofuran, og efter 1 times omsætning dryp-25 pes blandingen ud i isvand. Det herved udfældede, lysebrune produkt suges fra og omkrystalliseres fra en blanding af CH^OH og lidt acetone. Der fâs herved 17,5-18 g med smp. 178-179°C.In reflux 150 ml of glacial acetic acid, 19.5 g (0.05 mol) of 3-amino-4- (4'-methylphenoxy) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester and 7 ml of Ov (0.075 mol) are heated. dimethoxytetrahydrofuran, and after 1 hour reaction the mixture is dripped into ice water. The precipitated light brown product is suctioned off and recrystallized from a mixture of CH 2 OH and a little acetone. 17.5-18 g with m.p. 178-179 ° C.
30 Eksempel 3 3-N-Pyrrolo-4-(41-methoxyphenoxy)-5-N,N-dimethyl-aminomethy-lenaminosulfonylbenzoesyremethylester.Example 3 3-N-Pyrrolo-4- (41-methoxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-(4'-methoxyphenoxy)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.a) 3-Nitro-4- (4'-methoxyphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
35 I 600 ml abs. DMF opvarmes i 2 timer og under tilbage svaling 0,4 mol (126 g) 3-nitro-4-chlor-5-N,N-dimethylamino-methy lenamino suif onylbenzoesyremethyles ter og 72,5 g (/v0,535 In 600 ml abs. DMF is heated for 2 hours and under reflux 0.4 mol (126 g) of 3-nitro-4-chloro-5-N, N-dimethylamino-methylamino sulfonylbenzoic acid methyl ester and 72.5 g (/ v0.5
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5 Ο mol) natrium-4-methoxyphenolat, hvorefter reaktionsblandin-gen udr0res i 4 liter isvand, og det udfældede produkt suges . fra. Fra CH^OH fâs lysegule krystaller med smp. 199-201°C.5 µmol) of sodium 4-methoxyphenolate, after which the reaction mixture is stirred in 4 liters of ice water and the precipitated product is suctioned. from. From CH 2 OH, pale yellow crystals with m.p. 199-201 ° C.
5 b) 3-Amino-4-(41-methoxyphenoxy)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.B) 3-Amino-4- (41-methoxyphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
Reaktionen udf0res som beskrevet i eksempel 2b, og ved omkrystallisation fra CH^OH fâs farvel0se krystaller med smp.The reaction is carried out as described in Example 2b, and by recrystallization from CH2 OH, colorless crystals of m.p.
141-143°C.141-143 ° C.
10 c) 3-N-Pyrrolo-4-(4'-methoxyphenoxy)-5-N,N-dimethylaminomethy-lenaminosulfonylbenzoesyremethylester.C) 3-N-Pyrrolo-4- (4'-methoxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
I 150 ml iseddike opvarmes i ca. 1 time under tilbage-svaling 20,37 g (0,05 mol) 3-amino-4-(4'-methoxyphenoxy)-5-15 -N,N-dimethylaminomethylenaminosulfonylbenzoesyremethylester og 7 ml 2,5-dimethoxytetrahydrofuran, og den afk0lede blan-ding r0res ud i isvand, hvorpâ det udfældede produkt suges fra og vaskes med vand. Der fâs herved 20,8 g af et râprodukt, som uden yderligere rensning kan anvendes som mellemprodukt, 20 dvs. hydrogeneres katalytisk og hydrolyseres som tidligere beskrevet .In 150 ml glacial acetic acid, heat for approx. Reflux 20.37 g (0.05 mol) of 3-amino-4- (4'-methoxyphenoxy) -5-15-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester and 7 ml of 2,5-dimethoxytetrahydrofuran and cooled for 1 hour. The mixture is stirred into ice water, whereupon the precipitated product is sucked off and washed with water. There is thus obtained 20.8 g of a raw product which can be used as an intermediate without further purification, ie. is catalytically hydrogenated and hydrolyzed as previously described.
Eksempel 4 25 3-N-Pyrrolo-4-(3'-methoxyphenoxy)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.Example 4 3-N-Pyrrolo-4- (3'-methoxyphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-(31-methoxyphenoxy)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.a) 3-Nitro-4- (31-methoxyphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
Pâ samme mâde som i eksempel 3a, men med natrium-3-30 -methoxyphenolat og en reaktionstid pâ 3 timer fâs der fra gly-colmonomethylether lysegule krystaller med smp. 201°C.In the same manner as in Example 3a, but with sodium 3-30-methoxyphenolate and a reaction time of 3 hours, pale yellow crystals of m.p. 201 ° C.
b) 3-Amino-4-(31-methoxyphenoxy)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.b) 3-Amino-4- (31-methoxyphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
35 Pâ samme mâde som beskrevet i eksempel 2b og ved omkry stallisation fra glycolmonomethylether fâs der farvel0se kry-In the same manner as described in Example 2b and by recrystallization from glycol monomethyl ether, colorless crystals are obtained.
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0 6 staller med smp. 176-178°C.0 6 stables with m.p. 176-178 ° C.
c) 3-N-Pyrrolo-4-(3'-methoxyphenoxy)-5-N,N-dimethylaminomethy-lenaminosulfonylbenzoesyremethylester.c) 3-N-Pyrrolo-4- (3'-methoxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
5 I 150 ml iseddike opvarmes i 30 minutter under tilbage- svaling 12,7 g (0,03 mol) 3-amino-4-(3,-methoxyphenoxy)-5-N,N--dimethylaminomethylenaminosulfonylbenzoesyremethylester og 4,6 ml 2,5-dimethoxytetrahydrofuran, hvorefter produktet udfæl-des ved udr0ring af reaktionsblandingen i 1,5 liter isvand og 10 omkrystalliseres fra CH^OH/I^O. Der fâs herved beige krystal-ler med smp. 165-166°C.In 150 ml glacial acetic acid, reflux 12.7 g (0.03 mol) of 3-amino-4- (3, -methoxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester and 4.6 ml of reflux for 30 minutes. 5-Dimethoxytetrahydrofuran, after which the product is precipitated by stirring the reaction mixture in 1.5 liters of ice water and recrystallized from CH Thereby beige crystals with m.p. 165-166 ° C.
Eksempel 5 3-N-Pyrrolo-4-(41-chlorphenoxy)-5-N,N-dimethylaminomethylenami-15 nosulfonylbenzoesyremethylester.Example 5 3-N-Pyrrolo-4- (41-chlorophenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-(41-chlorphenoxy)-5-N,N-dimethylaminomethylenami-nosulfonylbenzoesyremethylester.a) 3-Nitro-4- (41-chlorophenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.
En opl0sning af 164 g 3-nitro-4-chlor-5-N,N-dimethylami-nomethylenaminosulfonylbenzoesyremethylester og 117 g kalium-20 -p-chlorphenolat opvarmes i 800 ml frisk destilleret DMF i 2-3 timer under tilbagesvaling, hvorefter reaktionsblandingen under kraftig omr0ring dryppes ud i den 4-dobbelte mængde isvand. Det herved udfældede produkt skilles fra og udkoges med CH30H/acetone og har da smp. 227-228°C.A solution of 164 g of 3-nitro-4-chloro-5-N, N-dimethylaminoethylenaminosulfonylbenzoic acid methyl ester and 117 g of potassium 20-p-chlorophenolate is heated in 800 ml of freshly distilled DMF for 2-3 hours under reflux, then the reaction mixture is heated under reflux. vigorous stirring is dropped into the 4-fold amount of ice water. The precipitated product is then separated and boiled with CH30H / acetone and then has m.p. 227-228 ° C.
25 b) 3-Amino-4-(41-chlorphenoxy)-5-N,N-dimethylaminomethylenami-nosulfonylbenzoesyremethylester.B) 3-Amino-4- (41-chlorophenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.
130 g Af nitroforbindelsen fra trin a hydrogeneres i 1 liter DMF med Raney-nikkel i 9 timer ved 50 atm og 50°C. Ef-30 ter frasugning af Raney-nikkelet inddampes opl0sningen, og re-manensen udkoges med CH^OH. Der fâs herved et farvel0st stof med smp. 207-208°C.130 g of the nitro compound from step a is hydrogenated in 1 liter of DMF with Raney nickel for 9 hours at 50 atm and 50 ° C. After suction of the Raney nickel, the solution is evaporated and the residue is boiled with CH 2 OH. This gives a colorless substance with m.p. 207-208 ° C.
c) 3-N-Pyrrolo-4-(4'-chlorphenoxy)-5-N,N-dimethylaminomethylen- 35 - aminosulfonylbenzoesyremethylester.c) 3-N-Pyrrolo-4- (4'-chlorophenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
0 70 7
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I 150 ml iseddike opvarmes i 1 time under tilbagesva-ling 20,6 g af aminoforbindelsen fra trin b med 7 ml 2,5-di-methoxytetrahydrofuran, hvorefter produktet udfældes ved ud-hældning af reaktionsblandingen i 1,5 liter isvand. Efter fra-5 sugning og omkrystallisation fra CHgOH fâs lysebrune krystal-ler med smp. 165°C.In 150 ml of glacial acetic acid, for one hour under reflux, 20.6 g of the amino compound from step b is heated with 7 ml of 2,5-dimethoxytetrahydrofuran, after which the product is precipitated by pouring the reaction mixture into 1.5 liters of ice water. After extraction and recrystallization from CHgOH, light brown crystals were obtained with m.p. 165 ° C.
Eksempel 6 3-N-Pyrrolo-4-(41-fluorphenoxy)-5-N,N-dimethylaminomethylen-10 aminosulfonylbenzoesyremethylester.Example 6 3-N-Pyrrolo-4- (41-fluorophenoxy) -5-N, N-dimethylaminomethylene-10-aminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-(4'-fluorphenoxy)-5-N,N-dimethylaminomethylenami-nosulfonylbenzoesyremethylester.a) 3-Nitro-4- (4'-fluorophenoxy) -5-N, N-dimethylaminomethyleneamosulfonylbenzoic acid methyl ester.
En opl0sning af 210 g (0,6 mol) 3-nitro-4-chlor-5-N,N--dimethylaminomethylenaminosulfonylbenzoesyremethylester og 15 120 g natrium-4-fluorphenolat i 800 ml abs. DMF omr0res i 3-4 timer ved 120-130°C, og efter afk0ling dryppes den kolde op-l0sning langsomt under kraftig omr0ring ud i 4-5 liter isvand. Det herved udfældede produkt suges fra, vaskes godt med vand, digereres med acetone i varmen og omkrystalliseres derefter 20 fra glycolmonomethylether. Der fâs herved lysegule krystaller med smp. 224-225°C.A solution of 210 g (0.6 mol) of 3-nitro-4-chloro-5-N, N - dimethylaminomethylenaminosulfonylbenzoic acid methyl ester and 120 g of sodium 4-fluorophenolate in 800 ml of abs. The DMF is stirred for 3-4 hours at 120-130 ° C and after cooling, the cold solution is slowly dripped out with vigorous stirring into 4-5 liters of ice water. The thus precipitated product is sucked off, washed well with water, digested with acetone in the heat and then recrystallized from glycol monomethyl ether. This gives pale yellow crystals with m.p. 224-225 ° C.
b) 3-Amino-4-(41-fluorphenoxy)-5-N,N-dimethylaminomethylenami- 25 nosulfonylbenzoesyremethylester.b) 3-Amino-4- (41-fluorophenoxy) -5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.
140 g Af nitroforbindelsen fra trin a opl0ses i DMF og hydrogeneres med Raney-nikkel ved 50°C og 50 atm i 8 timer, hvorefter katalysatoren suges fra, og opl0sningen dryppes ud i isvand. Det herved udfældede produkt skilles fra og vaskes 30 med CH^OH og derefter med ether. Det praktisk taget rene produkt kan omkrystalliseres fra glycolmonomethylether. Der fâs farvel0se krystaller med smp. 234-236°C.140 g of the nitro compound from step a is dissolved in DMF and hydrogenated with Raney nickel at 50 ° C and 50 atm for 8 hours, after which the catalyst is suctioned off and the solution is dropped into ice water. The thus precipitated product is separated and washed with CH 2 OH and then with ether. The practically pure product can be recrystallized from glycol monomethyl ether. There are colorless crystals with m.p. 234-236 ° C.
c) 3-N-Pyrrolo-4-(4'-fluorphenoxy)-5-N,N-dimethylaminomethy- lenaminosulfonylbenzoesyremethylester.c) 3-N-Pyrrolo-4- (4'-fluorophenoxy) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
17,5 g Af "aminesteren" fra trin b og 6,5 ml 2,5-di- 35 8 ο17.5 g of the "amine ester" from step b and 6.5 ml of 2,5-di-8 ο
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methoxytetrahydrofuran opvarmes i 150 ml iseddike i ca. 1 ti-me under tilbagesvaling, hvorefter blandingen dryppes ud i 1,5 liter isvand, og det udfældede produkt filtreres fra og omkrystalliseres fra CH^OH. Der fâs lysebrune krystaller med 5 smp. 180°C.methoxytetrahydrofuran is heated in 150 ml glacial acetic acid for approx. At reflux, the mixture is then poured into 1.5 liters of ice water and the precipitated product is filtered off and recrystallized from CH 2 OH. There are light brown crystals with 5 m.p. 180 ° C.
Eksempel 7 3-N-Pyrrolo-4-phenylthio-5-N,N-dimethylaminomethylenamlnosul- fonylbenzoesyremethylester.Example 7 3-N-Pyrrolo-4-phenylthio-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester.
10 I i5o ml iseddike opvarmes i 1/2 time under tilbagesva ling 15,8 g 3-amino-4-phenylthio-5-N,N-dimethylaminomethylen-aminosulfonyl-benzoesyremethylester og 9,2 g 2,5-dimethoxyte-trahydrofuran. Ved udhældning i isvand udfældes produktet, som endnu sugefugtigt kan digereres med varm CH^OH. Remanensen omis krystalliseres fra glycolmonomethylether, og der fâs lysegule krystaller med smp. 210-211°C.10 ml of glacial acetic acid are heated under reflux for 15 1/2 g of 3-amino-4-phenylthio-5-N, N-dimethylaminomethylene-aminosulfonyl-benzoic acid methyl ester and 9.2 g of 2,5-dimethoxy-tetrahydrofuran. When poured into ice water, the product is precipitated, which can still be digested with hot CH 2 OH. The residue is crystallized from glycol monomethyl ether to give pale yellow crystals with m.p. 210-211 ° C.
Eksempel 8 20 3-N-Pyrrolo-4-(41-methylphenylthio)-5-N,N-dimethylaminomethy-lenaminosulfonylbenzoesyremethylester.Example 8 3-N-Pyrrolo-4- (41-methylphenylthio) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-(4'-methylphenylthio)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.a) 3-Nitro-4- (4'-methylphenylthio) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
70 g 3-Nitro-4-chlor-5-N,N-dimethylaminomethylenaminosul-25 fonylbenzoesyremethylester suspenderes i 450 ml abs. DMF og opvarmes til 80°C, hvorefter der langsomt tildryppes en opl0sning af 40 g kalium-p-thiocresolat i 400 ml abs. DMF og efteromr0res i 2 timer ved 80°C. Derefter udr0res blandingen i 4 liter isvand, og det udfældede produkt suges fra, vaskes godt med vand og om-30 krystalliseres af iseddike. Der fâs gule krystaller med smp. 163-164°C.70 g of 3-Nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester are suspended in 450 ml of abs. DMF and heated to 80 ° C, then slowly dissolve a solution of 40 g of potassium β-thiocresolate in 400 ml of abs. DMF and stirred for 2 hours at 80 ° C. Then the mixture is stirred in 4 liters of ice water and the precipitated product is sucked off, washed well with water and recrystallized from glacial acetic acid. Yellow crystals are obtained with m.p. 163-164 ° C.
b) 3-Amino-4-(41-methylphenylthio)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.b) 3-Amino-4- (41-methylphenylthio) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
35 . En opl0sning af 67,7 g3-nitro-4-(4'-methylphenylthio)- -5-N,N-dimethylaminomethylenaminosulfonylbenzoesyremethylester i 800 ml abs. DMF tilsættes Raney-nikkel, og der indledes hy-35. A solution of 67.7 g of 3-nitro-4- (4'-methylphenylthio) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester in 800 ml of abs. DMF is added to Raney nickel and hy-
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9 Ο drogen i 8 timer ved 50°C og 50 atm. Efter fraskillelse af kata-lysatoren udr0res opl0sningen i 2 liter isvand, og det udfæl-dede produkt isoleres. Efter omkrystallisation fra CH^OH (un-der tilsætning af aktivkul) fâs farveI0se krystaller med smp.9 Ο the drug for 8 hours at 50 ° C and 50 atm. After separation of the catalyst, the solution is stirred in 2 liters of ice water and the precipitated product is isolated. After recrystallization from CH2 OH (without the addition of activated charcoal), colorless crystals with m.p.
5 179°C.5 179 ° C.
c) 3-N-Pyrrolo-4- (41 -methylphenylthi'O) -5-N,N-dimethylaminome-thylenaminosulfonylbenzoesyremethylester.c) 3-N-Pyrrolo-4- (41-methylphenylthio) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
18,3 g Af "Aminesteren" fra trin b opl0ses i 150 ml is-10 eddike og opvarmes til kogning, hvoreïter der tilsættes 7 ml .2,5-dimethoxytetrahydrofuran. Efter ca. 10 minutters for10b ud-krystalliserer produktet pludseligt, og der omr0res i yderli-gere 15 minutter under tilbagesvaling, hvorefter krystallerne suges fra i kulden og vaskes med iseddiike. Der fâs lysegule 15 krystaller med smp. 242-243°C.18.3 g of the "amine ester" from step b is dissolved in 150 ml of ice-10 vinegar and heated to boil, to which ether is added 7 ml of 2,5-dimethoxytetrahydrofuran. After approx. 10 minutes for 10b, the product suddenly crystallizes out and is stirred for a further 15 minutes under reflux, after which the crystals are sucked off in the cold and washed with glacial acetic acid. There are pale yellow 15 crystals with m.p. 242-243 ° C.
Eksempel 9 3-N-Pvrrolo-4-(41-benzyloxyphenoxy)-5-N,N-dimethylaminomethy-20 -lenaminosulfonylbenzoesyremethylester.Example 9 3-N-Pyrrolo-4- (41-benzyloxyphenoxy) -5-N, N-dimethylaminomethyl-20-lenaminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-(4'-benzyloxyphenoxy)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.a) 3-Nitro-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
Til en opl0sning af 87,5 g (0,25 mol) 3-nitro-4-chlor--5-N,N-dimethylaminomethylenaminosulfonylbenzoesyremethylester 25 i 500 ml vandfri dimethylformamid sættes 77,5 g (0,35 mol) na-trium-4-benzyloxyphenolat, og reaktionsblandingen opvarmes under grundig omr0ring og tilbagesvaling i 3-4 timer. Efter afk0-ling dryppes den uklare opl0sning ud i 3 liter isvand, og det herved udfældede gule bundfald suges fra, vaskes godt med vand 30 og omkrystalliseres fra methanol. Der fâs herved 94 g 3-nitro--4-(4'-benzyloxyphenoxy)-5-N,N-dimethylaminomethylenaminosulfo-nylbenzoesyremethylester i form af gule krystaller med smp. 132°C.To a solution of 87.5 g (0.25 mol) of 3-nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester 25 in 500 ml of anhydrous dimethylformamide is added 77.5 g (0.35 mol) of sodium -4-benzyloxyphenolate and the reaction mixture is heated under thorough stirring and reflux for 3-4 hours. After cooling, the cloudy solution is dropped into 3 liters of ice water, and the precipitated yellow precipitate is suctioned off, washed well with water 30 and recrystallized from methanol. There were thus obtained 94 g of 3-nitro-4- (4'-benzyloxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester in the form of yellow crystals, m.p. 132 ° C.
35 b) 3-Amino-4-(4'-benzyloxyphenoxy)-5-N,N-d±methylaminomethylen-aminosulfonylbenz oesyremethylester.B) 3-Amino-4- (4'-benzyloxyphenoxy) -5-N, N-d ± methylaminomethylene-aminosulfonylbenzoic acid methyl ester.
94 g 3-Nitro-4-(4'-benzyloxyphenoxy)-S-N/N-dimethylami- 1094 g of 3-Nitro-4- (4'-benzyloxyphenoxy) -S-N / N-dimethylamino
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ο nomethylenaminosulfonylbenzoesyremethylester opl0ses i 1,5 li-ter dimethylformamid og hydrogeneres med Raney-nikkel ved stue-temperatur og normaltryk i 6-7 timer, hvorefter der filtreres, og den klare opl0sning dryppes ud i isvand. Produktet omkrystal-5 lisérés fra methanol, og der fâs 70 g hvide krystaller med smp. 170°C.ο nomethylenaminosulfonylbenzoic acid methyl ester is dissolved in 1.5 liters of dimethylformamide and hydrogenated with Raney nickel at room temperature and normal pressure for 6-7 hours, then filtered and the clear solution is dropped into ice water. The product was recrystallized from methanol and 70 g of white crystals were obtained with m.p. 170 ° C.
c) 3-N-Pyrrolo-4-(4,-benzyloxyphenoxy)-5-NfN-dimethylaminome-thylenaminosulfonylbenzoesyremethylester.c) 3-N-Pyrrolo-4- (4, -benzyloxyphenoxy) -5-NfN-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
10 43,5 g Af "aminesteren" fra trin b og 13 ml 2,5-dimeth- oxytetrahydrofuran opvarmes i 1 time i 250 ml iseddike under tilbagesvaling, hvorefter reaktionsblandingen hældes ud i isvand, og det herved udfældede produkt suges fra, vaskes med vand og omkrystalliseres fra CH^OH (under tilsætning af aktiv-15 kul). Produktet sintrer fra 80°C og omdannes derefter til en h0jviskos olie, som I0ber ud ved 105-110°C.43.5 g of the "amine ester" from step b and 13 ml of 2,5-dimethoxytetrahydrofuran are heated for 1 hour in 250 ml of glacial acetic acid under reflux, after which the reaction mixture is poured into ice-water and the product precipitated is suction washed with water and recrystallized from CH 2 OH (with the addition of activated carbon). The product sinters from 80 ° C and then converts to a high viscous oil, which discharges at 105-110 ° C.
Eksempel 10 3-N-Pyrrolo-4-anilino-5-N,N-dimethylaminomethylenaminosulfonyl- 20 benzoesyremethylester.Example 10 3-N-Pyrrolo-4-anilino-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-anilino-5-N,N-dimethylaminomethylenaminosulfonylbenzoesyremethy lester.a) 3-Nitro-4-anilino-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
En opl0sning af 52,5 g 3-nitro-4-chlor-5-N,N-dimethyl- aminomethylenaminosulfonylbenzoesyremethylester i 360 ml abs.A solution of 52.5 g of 3-nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester in 360 ml of abs.
25 O25 O
DMF opvarmes til 100 C, hvorefter der under omr0ring tildryp-pes 18 ml anilin, og reaktionsblandingen holdes i 3 timer pâ 100°C. Derefter udhældes opl0sningen i 2 liter isvand, og det herved udfældede produkt isoleres og vaskes godt med vand, hvorefter det renses ved udkogning med 250 ml CH-,OH og lidt acetone. Der fâs krystaller med smp. 182-183°C.DMF is heated to 100 ° C, then 18 ml of aniline is added dropwise with stirring and the reaction mixture is maintained at 100 ° C for 3 hours. Then, the solution is poured into 2 liters of ice water and the precipitated product is isolated and washed well with water, after which it is purified by boiling with 250 ml of CH, OH and a little acetone. Crystals with m.p. 182-183 ° C.
b) 3-Amino-4-anilino-5-N,N-dimethylaminomethylenaminosulfonyl-benzoesyremethylester.b) 3-Amino-4-anilino-5-N, N-dimethylaminomethylenaminosulfonyl benzoic acid methyl ester.
40,7 g Af "nitroesteren" fra trin a opl0ses i 600 ml 35 DMF og hydrogeneres med Raney-nikkel som katalysator i 8 timer ved 50°C og 50 atm. Den filtrerede opl0sning udr0res i 040.7 g of the "nitro ester" from step a is dissolved in 600 ml of DMF and hydrogenated with Raney nickel as catalyst for 8 hours at 50 ° C and 50 atm. The filtered solution is stirred in 0
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11 2 liter isvand, og det udfældede produkt isoleres og omkrystal-liseres fra glycolmonomethylether. Der fâs £arvel0se krystal-1er med smp. 227-228°C.11 2 liters of ice water and the precipitated product is isolated and recrystallized from glycol monomethyl ether. Hereditary crystal-1s with m.p. 227-228 ° C.
5 c) 3-N-Pyrrolo-4-anilino-5-N,N-dimethylaminomethylenaminosul-fonylbenzoesyremethylester.C) 3-N-Pyrrolo-4-anilino-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
11,3 g Af "aminesteren" fra trin b opl0ses i 130 ml is-eddike og tilsættes 4,5 ml 1,2-dimethoxytetrahydrofuran. Efter 15 minutter under tilbagesvaling udr0res blandingen i 500 ml 10 isvand, og det udfældede produkt iseûieres og vaskes flere gan-ge med vand. Qmkrystallisation fra CH^OHA^HgOH giver et produkt med smp. 185°C.11.3 g of the "amine ester" from step b is dissolved in 130 ml of ice-vinegar and 4.5 ml of 1,2-dimethoxytetrahydrofuran is added. After refluxing for 15 minutes, the mixture is stirred in 500 ml of 10 ice water and the precipitated product is isolated and washed several times with water. Crystallization from CH2 OHA ^ HgOH gives a product, m.p. 185 ° C.
15 Eksempel 11 3-N-Pyrrolo-3-(3',41-methylendioxyphenoxy)-5-N,N-dimethylamino-methylenaminosulfonylbenzoesyremethylester.Example 11 3-N-Pyrrolo-3- (3 ', 41-methylenedioxyphenoxy) -5-N, N-dimethylamino-methylenaminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-3- (31,4 ' -methy lendioxyphen.oxy) -5-N,N-dimethylamino-.methylenaminosulfonylbenzoesyremethylester.a) 3-Nitro-3- (31,4'-methylenedioxyphenoxy) -5-N, N-dimethylamino-methylenaminosulfonylbenzoic acid methyl ester.
20 96 g 3-Nitro-4-chlor-5-N,,N-dimethylaminomethylenaminosul- fonylbenzoesyremethylester og 58 g natrium-3,4-methylendioxy-phenolat blandes med 500 ml abs. DMF og omr0res i 2 timer ved 120°C, hvorefter blandingen under omr0ring hældes ud i 4 liter isvand. Det herved udfældede, lysegule produkt skilles fra og 25 omkrystalliseres fra n-butanol eller CHgOH/acetone, hvorefter det smelter ved 216-217°C.20 g of 3-Nitro-4-chloro-5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester and 58 g of sodium 3,4-methylenedioxyphenolate are mixed with 500 ml of abs. DMF and stir for 2 hours at 120 ° C, then pour the mixture under stirring into 4 liters of ice water. The precipitated pale yellow product is separated and recrystallized from n-butanol or CHgOH / acetone, whereupon it melts at 216-217 ° C.
b) 3-Amino-4-(3',4'-methylendioxyphenoxy)-5-N,N-dimethylamino-methylenaminosulfonylbenzoesyremethylester.b) 3-Amino-4- (3 ', 4'-methylenedioxyphenoxy) -5-N, N-dimethylamino-methylenaminosulfonylbenzoic acid methyl ester.
30 76 g Af nitroforbindelsen fra trin a opl0ses i ca. 500 ml abs. DMF og hydrogeneres med Raney-nikkel som katalysator i 8 timer ved stuetemperatur og 5.0 atm. Den filtrerede opl0sning dryppes ud i isvand, og det udfæildede produkt skilles fra og omkrystalliseres fra CH^OH. Der fâs farvel0se krystaller med 35 smp. 190-191°C.30 g of the nitro compound from step a are dissolved in ca. 500 ml abs. DMF and hydrogenated with Raney nickel as catalyst for 8 hours at room temperature and 5.0 atm. The filtered solution is dropped into ice water and the precipitated product is separated and recrystallized from CH2 OH. There are colorless crystals with 35 m.p. 190-191 ° C.
00
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12 c) 3-N-Pyrrolo-4-(3*,4'-methylendioxyphenoxy)-5-N,N-dimethyl-aminomethylenaminosulfonylbenzoesyremethylester.C) 3-N-Pyrrolo-4- (3 *, 4'-methylenedioxyphenoxy) -5-N, N-dimethylaminomethylenaminosulfonylbenzoic acid methyl ester.
11,5 g Af "aminesteren" fra trin b opvarmes sammen med 4 ml 2,5-dimethoxytetrahydrofuran i 150 ml iseddike i 1 time 5 til tilbagesvalingstemperatur, hvorefter produktet udfældes ved tildrypning af reaktionsblandingen til 1,5 liter isvand. Omkrystallisation fra glycolmonomethylester giver et produkt med smp. 206°C.11.5 g of the "amine ester" from step b is heated together with 4 ml of 2,5-dimethoxytetrahydrofuran in 150 ml of glacial acetic acid for 1 hour 5 to reflux temperature, after which the product is precipitated by adding the reaction mixture to 1.5 liters of ice water. Recrystallization from glycol monomethyl ester gives a product of m.p. 206 ° C.
1010
Eksempel 12 3-N-Pyrrolo-4-(4'-methylanilino)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.Example 12 3-N-Pyrrolo-4- (4'-methylanilino) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
a) 3-Nitro-4-(4'-methylanilino)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.a) 3-Nitro-4- (4'-methylanilino) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
10 0,2 Mol 3-nitro-4-chlor-5-N,N-dimethylaminomethylenami-nosulfonylbenzoesyremethylester opl0ses i 500 ml dimethylform-amid ved 100°C, og derefter tildryppes en opl0sning af 0,33 mol p-toluidin i 200 ml abs. DMF. Efter 4 timers for10b udr0res 20 blandingen i isvand, og det udfældede produkt skilles fra. Omkrystallisation fra CH^ÛH giver gule krystaller med smp. 210°C.Dissolve 0.2 mol of 3-nitro-4-chloro-5-N, N-dimethylaminomethyleneaminosulfonylbenzoic acid methyl ester in 500 ml of dimethylformamide at 100 ° C and then drop a solution of 0.33 mol of p-toluidine in 200 ml. abs. DMF. After 4 hours for 10b, the mixture is stirred in ice water and the precipitated product is separated. Recrystallization from CH 2 H gives yellow crystals, m.p. 210 ° C.
b) 3-Amino-4- (4 * -methylanilino) -5-N ,N-dimethy laminomethylenami-nosulf onylbenzoesyremethylester .b) 3-Amino-4- (4 * -methylanilino) -5-N, N-dimethylaminomethyleneamino sulfonylbenzoic acid methyl ester.
25 63,4 g 3-nitro-4-(4'-methylanilino)-5-N,N-dimethylamino- methylenaminosulfonylbenzoesyremethylester opl0ses i 1,5 liter dimethylformamid og hydrogeneres i nærværelse af Raney-nikkel i 8 timer ved 50°C og 50 atm, hvorefter katalysatoren skilles fra, og filtratet udr0res i isvand. Der fâs herved den 0nskede for-30 bindelse med smp. 186-188°C.63.4 g of 3-nitro-4- (4'-methylanilino) -5-N, N-dimethylaminoethylenaminosulfonylbenzoic acid methyl ester are dissolved in 1.5 liters of dimethylformamide and hydrogenated in the presence of Raney nickel for 8 hours at 50 ° C and 50 atm, after which the catalyst is separated and the filtrate is stirred in ice water. There is thus obtained the desired compound with m.p. 186-188 ° C.
c) 3-N-Pyrrolo-4-(4'-methylanilino)-5-N,N-dimethylaminomethylen-aminosulfonylbenzoesyremethylester.c) 3-N-Pyrrolo-4- (4'-methylanilino) -5-N, N-dimethylaminomethylene-aminosulfonylbenzoic acid methyl ester.
0,1 Mol 3-amino-4-(4'-methylanilino)-5-N,N-dimethylami-35 nomethylenaminosulfonylbenzoesyremethylester opl0ses i 400 ml iseddike og opvarmes til tilbagesvaling. Efter tilsætning af 13 Ο0.1 Mole of 3-amino-4- (4'-methylanilino) -5-N, N-dimethylaminoethylenaminosulfonylbenzoic acid methyl ester is dissolved in 400 ml glacial acetic acid and heated to reflux. After the addition of 13 Ο
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15 ml 2,5-dimethoxytetrahydrofuran opvarmes der i yderligere 30 minutter, hvorefter blandingen udr0res i 3 liter isvand. Det herved udfældede produkt kan omkrystalliseres af CH^OH og smel-ter ved 169-173°C.15 ml of 2,5-dimethoxytetrahydrofuran are heated for an additional 30 minutes, after which the mixture is stirred in 3 liters of ice water. The precipitated product can be recrystallized from CH 2 OH and melt at 169-173 ° C.
5 Ved forsæbning med 2 N NaOH til dannelse af en klar op- 10sning kan produktet overf0res til 3-pyrrolo-4-(4'-methylani-lino) -5-sulfamoylbenzoesyre, soin fra CH^OH/^O danner lysegule krystaller med smp. 226-228°C.By saponification with 2N NaOH to give a clear solution, the product can be transferred to 3-pyrrolo-4- (4'-methylanilino) -5-sulfamoylbenzoic acid, soin from CH2 OH / O forms light yellow crystals with mp. 226-228 ° C.
no d) Hydrering til 4-(41-methylanilino)-3(1-pyrrolidinyl)-5--sulfamoylbenzoesyre.no d) Hydration to 4- (41-methylanilino) -3 (1-pyrrolidinyl) -5-sulfamoylbenzoic acid.
Den i trin c opnâede 3-N^pya3rolo-4-(4 ' -methylanilino) -—5-N, N- dimethy 1 aminomethy lenaminosulfony lben z oe sy r emethy le s ter <£5 ssuspenderes som râprodukt i methanol og hydrogeneres i nærvæ-nzelse af Pd/C som kafcalysator ved !ΊΉ0°0 og 150 atm i 16 timer. Jliiliiæaiet inddampes Jt±l t0rhed og .qpvarmes med 2 N NaOH til en Klar iop!0sning, hvorefter pH-værdien indstilles pâ 4 med 2 N ?NaC0Hf/ <-ag -det herved uidfældede produkt omkrystalliseres fra 20 COH^QH/vand. Der fâs herved giile krystaller med smp. 188-191°C.The 3-N 3 -pyrrolo-4- (4'-methylanilino) -5-N, N-dimethyl-1-aminomethylenaminosulfonylbenzene, which is obtained in step c, is obtained as a crude product in methanol and hydrogenated. in the presence of Pd / C as a caffeine catalyst at ΊΉ0 ° 0 and 150 atm for 16 hours. The mixture is evaporated to dryness and heated with 2N NaOH to a clear solution, then the pH is adjusted to 4 with 2N? NaCOhf / <ag> thereby recrystallizing crude product from 20 COH / QH / water. This gives yellow crystals with m.p. 188-191 ° C.
Eksempel 13 25 4-Phenoxy-3-pyrrolyl-5-pyrrolidinylmethylenaminosulfonylben-zoesyremethylesterExample 13 4-Phenoxy-3-pyrrolyl-5-pyrrolidinylmethylenaminosulfonylbenzoic acid methyl ester
Til en suspension af 12,1 g (0,03 mol) amino-4-phen-oxy-5-pyrrolidinylmethylenaminosulfonylbenzoesyremethylester i 100 ml af en blanding af iseddike/methylenchlorid (1:1) sættes 30 der ved tilbagesvalingstemperatur 13 ml dimethoxytetrahydrofu-ran. Temperaturen fâr lov at stige til 65°C, og der efterr0res i 2-3 timer. Den afk0lede opl0sning fortvndes med methylenchlo-rid og ekstraheres tre gange med vand. Den over natriumsulfat t0rrede organiske opl0sning inddampes, og remanensen omkrystal-35 lisérés fra methanol/DMF, Der fâs krystaller med et smeltepunkt pâ~206-208°C.To a suspension of 12.1 g (0.03 mol) of amino-4-phenoxy-5-pyrrolidinylmethyleneaminosulfonylbenzoic acid methyl ester in 100 ml of a glacial acetic acid / methylene chloride (1: 1) mixture is added at reflux temperature 13 ml of dimethoxytetrahydrofuran. . The temperature is allowed to rise to 65 ° C and required for 2-3 hours. The cooled solution is diluted with methylene chloride and extracted three times with water. The organic solution dried over sodium sulfate is evaporated and the residue recrystallized from methanol / DMF, crystals having a melting point of ~ 206-208 ° C are obtained.
DK 156432 BDK 156432 B
14 o 4-Phenoxy-3-pyrrolyl-5-sulfamoylbenzoesyre 9 g (0,02 mol) 4-Phenoxy-3-pyrrolyl-5-pvrrolidinyl-methylenaminosulfonylbenzoesyremethylester suspenderes i 75 ml 2 N NaOH og forsæbes under god omr0ring ved 80-90°C. Sâ snart 5 der er fremkommet en klar opl0sning, efterr0res der i yderli-gere 1 time ved den samme temperatur. Den a£k0lede opl0sning sættes til 100 ml 2 N HCl. Det krystallinske bundfald skilles fra ved sugning og omkrystalliseres fra iseddike/^O. Der fâs krystaller med et smeltepunkt pâ 214°C.14 o 4-Phenoxy-3-pyrrolyl-5-sulfamoylbenzoic acid 9 g (0.02 mole) of 4-Phenoxy-3-pyrrolyl-5-pyrrolidinyl-methylenaminosulfonylbenzoic acid methyl ester are suspended in 75 ml of 2 N NaOH and saponified under good stirring at 80-90 ° C. As soon as a clear solution has been obtained, an additional 1 hour is required at the same temperature. The cooled solution is added to 100 ml of 2 N HCl. The crystalline precipitate is separated by suction and recrystallized from glacial acetic acid. Crystals with a melting point of 214 ° C are obtained.
10 15 20 25 30 3510 15 20 25 30 35
Claims (1)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2658766A DE2658766C2 (en) | 1976-12-24 | 1976-12-24 | 3-N-Pyrrolo-5-sulfamoylbenzoic acid derivatives and process for their preparation |
| DE2658766 | 1976-12-24 | ||
| DE2718494 | 1977-04-26 | ||
| DE19772718494 DE2718494A1 (en) | 1977-04-26 | 1977-04-26 | PROCESS FOR THE PREPARATION OF PYRROLO-BENZOIC ACID DERIVATIVES |
| DK577477A DK162088C (en) | 1976-12-24 | 1977-12-23 | METHOD FOR PREPARING 3-N-PYRROLO-5-SULFAMOYLBENZOIC ACID DERIVATIVES |
| DK577477 | 1977-12-23 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK237782A DK237782A (en) | 1982-05-26 |
| DK156432B true DK156432B (en) | 1989-08-21 |
| DK156432C DK156432C (en) | 1990-01-15 |
Family
ID=27187070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK237782A DK156432C (en) | 1976-12-24 | 1982-05-26 | 3-N-PYRROLO-5-SULFAMOYLBENZOIC ACID DERIVATIVES FOR USING INTERMEDIATES IN THE PREPARATION OF 3-N-PYRROLIDINO-5-SULFAMOYLBENZOIC ACID DERIVATIVES |
Country Status (1)
| Country | Link |
|---|---|
| DK (1) | DK156432C (en) |
-
1982
- 1982-05-26 DK DK237782A patent/DK156432C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK156432C (en) | 1990-01-15 |
| DK237782A (en) | 1982-05-26 |
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| PBP | Patent lapsed |