NO151825B - INTERMEDIATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 5-SULFAMOYL-BENZO ACID DERIVATIVES - Google Patents
INTERMEDIATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 5-SULFAMOYL-BENZO ACID DERIVATIVES Download PDFInfo
- Publication number
- NO151825B NO151825B NO784198A NO784198A NO151825B NO 151825 B NO151825 B NO 151825B NO 784198 A NO784198 A NO 784198A NO 784198 A NO784198 A NO 784198A NO 151825 B NO151825 B NO 151825B
- Authority
- NO
- Norway
- Prior art keywords
- sulfamoyl
- atoms
- benzoic acid
- pyrrolo
- acid
- Prior art date
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- 239000002253 acid Substances 0.000 title description 4
- 230000001225 therapeutic effect Effects 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- NAETXYOXMDYNLE-UHFFFAOYSA-N 3-sulfamoylbenzoic acid Chemical class NS(=O)(=O)C1=CC=CC(C(O)=O)=C1 NAETXYOXMDYNLE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 230000008018 melting Effects 0.000 description 15
- 238000002844 melting Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 229910001868 water Inorganic materials 0.000 description 13
- 239000013078 crystal Substances 0.000 description 11
- 239000005457 ice water Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 239000012362 glacial acetic acid Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000020477 pH reduction Effects 0.000 description 5
- 201000004624 Dermatitis Diseases 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000010668 atopic eczema Diseases 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- BJMFJGFUTBUPBX-UHFFFAOYSA-N 4-anilino-3-pyrrolidin-1-yl-5-sulfamoylbenzoic acid Chemical compound N(C1=CC=CC=C1)C1=C(C=C(C(=O)O)C=C1S(N)(=O)=O)N1CCCC1 BJMFJGFUTBUPBX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- ASNXJGMTRPTJON-UHFFFAOYSA-N 4-(4-methylanilino)-3-pyrrolidin-1-yl-5-sulfamoylbenzoic acid Chemical compound C1=CC(C)=CC=C1NC1=C(N2CCCC2)C=C(C(O)=O)C=C1S(N)(=O)=O ASNXJGMTRPTJON-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- VGKUIQWRNJBNJC-UHFFFAOYSA-N methyl 3-amino-4-phenoxy-5-sulfamoylbenzoate Chemical compound NS(=O)(=O)C1=CC(C(=O)OC)=CC(N)=C1OC1=CC=CC=C1 VGKUIQWRNJBNJC-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- -1 3-amino-4-phenoxy-5-n-butylsulfamoyl-benzoic acid methyl ester Chemical compound 0.000 description 1
- NNZQIZYLXISQCS-UHFFFAOYSA-N 3-amino-5-(methylsulfamoyl)-4-phenoxybenzoic acid Chemical compound CNS(=O)(=O)C1=CC(C(O)=O)=CC(N)=C1OC1=CC=CC=C1 NNZQIZYLXISQCS-UHFFFAOYSA-N 0.000 description 1
- ZFQWZHGDRRHUBY-UHFFFAOYSA-N 3-amino-5-sulfamoylbenzoic acid Chemical class NC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1 ZFQWZHGDRRHUBY-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PVTRUXDNYDEGHN-UHFFFAOYSA-N CN(C)C.CCCC(Cl)=O Chemical compound CN(C)C.CCCC(Cl)=O PVTRUXDNYDEGHN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- UJEWTUDSLQGTOA-UHFFFAOYSA-N Piretanide Chemical compound C=1C=CC=CC=1OC=1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1N1CCCC1 UJEWTUDSLQGTOA-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 238000010411 cooking Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- KFPDOOCSCWGFSK-UHFFFAOYSA-N methyl 3-amino-4-(4-methoxyphenoxy)-5-sulfamoylbenzoate Chemical compound NS(=O)(=O)C1=CC(C(=O)OC)=CC(N)=C1OC1=CC=C(OC)C=C1 KFPDOOCSCWGFSK-UHFFFAOYSA-N 0.000 description 1
- XCXVWYGETMDKCJ-UHFFFAOYSA-N methyl 3-amino-4-(4-methylanilino)-5-sulfamoylbenzoate Chemical compound COC(C1=CC(=C(C(=C1)S(N)(=O)=O)NC1=CC=C(C=C1)C)N)=O XCXVWYGETMDKCJ-UHFFFAOYSA-N 0.000 description 1
- KYKLDEZXRLXLAY-UHFFFAOYSA-N methyl 3-amino-4-anilino-5-sulfamoylbenzoate Chemical compound COC(C1=CC(=C(C(=C1)S(N)(=O)=O)NC1=CC=CC=C1)N)=O KYKLDEZXRLXLAY-UHFFFAOYSA-N 0.000 description 1
- GMXSPMKYAOAVCU-UHFFFAOYSA-N methyl 3-amino-4-phenylsulfanyl-5-sulfamoylbenzoate Chemical compound NS(=O)(=O)C1=CC(C(=O)OC)=CC(N)=C1SC1=CC=CC=C1 GMXSPMKYAOAVCU-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- APVPOHHVBBYQAV-UHFFFAOYSA-N n-(4-aminophenyl)sulfonyloctadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 APVPOHHVBBYQAV-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Description
Oppfinnelsen vedrører mellomprodukter for fremstilling av terapeutisk aktive 5-sulfamoyl-benzosyrederivater med den qenerelle formel I The invention relates to intermediates for the production of therapeutically active 5-sulfamoyl-benzoic acid derivatives with the general formula I
hvor where
R betyr hydrogen, halogen, alkyl eller alkoksy med 1-4 C-atomer, OH eller en eventuelt mono- eller dialkylert aminogruppe, R means hydrogen, halogen, alkyl or alkoxy with 1-4 C atoms, OH or an optionally mono- or dialkylated amino group,
R 1 og R 2 betyr hydrogenatomer eller like eller forskjellige alkylgrupper med 1-4 C-atomer, R 1 and R 2 mean hydrogen atoms or the same or different alkyl groups with 1-4 C atoms,
R"^ betyr hydrogen eller alkyl med 1-4 C-atomer, R"^ means hydrogen or alkyl with 1-4 C atoms,
A betyr en alkylengruppe med 2 C-atomer som eventuelt A means an alkylene group with 2 C atoms as optional
er substituert med alkylgrupper med 1-4 C-atomer, og X betyr 0, S eller NH, idet mellomproduktene er karakterisert ved at de har den generelle formel II is substituted by alkyl groups with 1-4 C atoms, and X means 0, S or NH, the intermediate products being characterized by having the general formula II
hvori in which
3 1 2 3 1 2
X, R og R , R og R har ovennevnte betydning, og X, R and R , R and R have the above meaning, and
7 8 7 8 7 8 7 8
Y betyr pyrrologruppen R -r jtR hvor R og R betyr hydrogen eller metyl, eller Y betyr -NH-CO-A-CH2L, hvor A har ovennevnte betydning, og L betyr en avspaltbar beskyttelsesgruppe. Y means the pyrrolo group R -r jtR where R and R mean hydrogen or methyl, or Y means -NH-CO-A-CH 2 L, where A has the above meaning, and L means a cleavable protecting group.
Foretrukne forbindelser med formel II i henhold til oppfinn-eisen er slike hvori R 3betyr hydrogen, X betyr oksygen, R betyr hydrogen eller metyl og Y har ovenfor angitte betydning, idet A fortrinnsvis betyr en eventuelt metylsubstituert etylen-7 8 Preferred compounds of formula II according to the invention are those in which R 3 means hydrogen, X means oxygen, R means hydrogen or methyl and Y has the above meaning, with A preferably meaning an optionally methyl-substituted ethylene-7 8
gruppe, og R og R betyr hydrogen eller metyl, group, and R and R are hydrogen or methyl,
Forbindelser med forme.l II, hvor Y betyr en pyrrologruppe, Compounds of form II, where Y means a pyrrolo group,
får man fra 3-amino-5-sulfamoyl-benzosyrederivater med is obtained from 3-amino-5-sulfamoyl-benzoic acid derivatives with
formel III formula III
hvori in which
R til R<3> og X har ovenfor angitte betydning, ved at man om-setter de på vanlig måte med 2,5-dimetoksytetrahydro- R to R<3> and X have the meaning indicated above, by reacting them in the usual way with 2,5-dimethoxytetrahydro-
furanene med formel the furans of formula
hvori in which
7 8 7 8
R og R har den angitte betydning. R and R have the indicated meaning.
Reduksjonen av de dannede pyrroloforbindelser foregår fortrinnsvis ved katalytisk hydrogenering med de for dette formål vanlige katalysatorer, idet forbindelsene med formel I fåes. The reduction of the pyrrolo compounds formed preferably takes place by catalytic hydrogenation with the catalysts usual for this purpose, the compounds of formula I being obtained.
Forbindelsene med formel II, hvor Y betyr gruppen The compounds of formula II, where Y represents the group
-NH-CO-A-CI^L, kan fåes fra aminoforbindelsene med ovennevnte formel III ved omsetning med w-substituerte karboksylsyrederivater med formel IV -NH-CO-A-CI^L, can be obtained from the amino compounds of the above formula III by reaction with w-substituted carboxylic acid derivatives of the formula IV
i henhold til betingelsene for Schotten-Baumann-reaksjonen. Som "leaving-group" L kommer det fortrinnsvis på tale halogen, OH, aktive estergrupper som o-tosyl, trialkylammonium-résp. pyrridiniumgrupper. Som karboksylsyrederivater kommer det på tale u-klorsmørsyreklorid, (D-bromsmørsyreklorid eller -fenylester, klorid av trimetylammoniumsmørsyreklorid. according to the conditions of the Schotten-Baumann reaction. The "leaving group" L preferably refers to halogen, OH, active ester groups such as o-tosyl, trialkylammonium-resp. pyrridinium groups. Carboxylic acid derivatives include u-chlorobutyric acid chloride, (D-bromobutyric acid chloride or -phenyl ester, chloride of trimethylammonium butyric acid chloride.
Utgangsmaterialet med formel III er kjent fra litteraturen. The starting material of formula III is known from the literature.
For å overføle de således dannede forbindelser med formel II til diuretika med formel I reduseres i henhold til formel-skjemaet To react the thus formed compounds of formula II to diuretics of formula I is reduced according to the formula scheme
først amidgrupper med borhydrogen eller komplekse borhydrider i nærvær av Lewis-syrer, idet det dannes forbindelser med formel V. Ved denne reduksjon er det overraskende at amid-gruppen reduseres uten at "leaving-group" L påvirkes. first amide groups with boron hydrogen or complex borohydrides in the presence of Lewis acids, forming compounds of formula V. In this reduction, it is surprising that the amide group is reduced without the "leaving group" L being affected.
Forbindelsene med formel I dannes fra forbindelsene V ved cyklisering under avspalting av HL under sure eller basiske betingelser. The compounds of formula I are formed from the compounds V by cyclization during cleavage of HL under acidic or basic conditions.
Hvis L eksempelvis betyr et halogenatom, fortrinnsvis klor eller brom så foregår cykliseringen f.eks. ved behandling med alkali. I surt medium lar cykliseringen seg gjennomføre i henhold til Ber. dtsch. chem. Ges. 42, 3427 (1907) (Overblikk Chem. Rev. 63, 55 (1963)). Derved dannes saltene av karbok-sylsyrene med formel I (R<3> = H). Som baser som kan anvendes ved avspalting kan nevnes trietylamin, alkalihydroksyder, N,N-dimetylanilin eller også alkaliacetat. If L, for example, means a halogen atom, preferably chlorine or bromine, then the cyclization takes place e.g. by treatment with alkali. In an acidic medium, the cyclization can be carried out according to Ber. dtsch. chem. Ges. 42, 3427 (1907) (Overview Chem. Rev. 63, 55 (1963)). Thereby, the salts of the carboxylic acids of formula I (R<3> = H) are formed. As bases that can be used for cleavage, mention may be made of triethylamine, alkali hydroxides, N,N-dimethylaniline or also alkali acetate.
Eksemp_el_l Example_el_l
8 g 3-amino-4-fenoksy-5-sulfamoyl-benzosyremetylester oppvarmes under tilbakeløp med 5 g 2,5-dimetoksytetrahydrofuran i 100 ml iseddik. Etter 1,5-2 timer innrøres blandingen i isvann. Det derved utfelte råprodukt oppvarmes på dampbad med 1-normal NaOH til det er dannet en klar oppløsning. Ved surgjøring med 2-normal HC1 faller det ut 3-N-pyrrolo-4-fenoksy-5-sulfamoylbenzosyre. Den kan omkrystalliseres fra metanol eller iseddik/vann. 8 g of 3-amino-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester are heated under reflux with 5 g of 2,5-dimethoxytetrahydrofuran in 100 ml of glacial acetic acid. After 1.5-2 hours, stir the mixture into ice water. The thus precipitated crude product is heated on a steam bath with 1-normal NaOH until a clear solution is formed. On acidification with 2-normal HCl, 3-N-pyrrolo-4-phenoxy-5-sulfamoylbenzoic acid precipitates. It can be recrystallized from methanol or glacial acetic acid/water.
Hvitgråe krystaller med smeltepunkt 214°C. White-grey crystals with a melting point of 214°C.
2Y§^f2Ei22_iii_il^§D2lS5Yl2iIlEY££2ii§iSYill<5>l§<yl>£§<m>2Yi22<n>?2§YE2 8,8 g 3-N-pyrrolo-4-fenoksy-5-sulfamoyl-benzosyremetylester (råprodukt) oppløses i iseddik og hydrogeneres med 1 g Pd-kull ved normalt trykk. Reaksjonen avsluttes etter ca. 30 timer. Hvis hydrogeneringen gjennomføres i autoklav ved 40-50°C og 100 atm er reaksjonen avsluttet allerede etter 5 timer. 2Y§^f2Ei22_iii_il^§D2lS5Yl2iIlEY££2ii§iSYill<5>l§<yl>£§<m>2Yi22<n>?2§YE2 8.8 g 3-N-pyrrolo-4-phenoxy-5-sulfamoyl -benzoic acid methyl ester (crude product) is dissolved in glacial acetic acid and hydrogenated with 1 g of Pd charcoal at normal pressure. The reaction ends after approx. 30 hours. If the hydrogenation is carried out in an autoclave at 40-50°C and 100 atm, the reaction is already finished after 5 hours.
Oppløsningen filtreres og inndampes og det faste residum forsåpes ved 1-normal NaOH på dampbad. Den klare oppløsning av-kjøles og surgjøres med 2-normal HC1. Den utfelte 4-fenoksy-3(1-pyrrolidinyl)-5-sulfamoylbenzosyren omkrystalliseres fra metanol/vann. Smeltepunkt 226-227°C. The solution is filtered and evaporated and the solid residue is saponified with 1-normal NaOH on a steam bath. The clear solution is cooled and acidified with 2-normal HCl. The precipitated 4-phenoxy-3(1-pyrrolidinyl)-5-sulfamoylbenzoic acid is recrystallized from methanol/water. Melting point 226-227°C.
Eksemp.el_2 Example.el_2
<4-anilino-3>N<-p_Y£E2l2l§I§yi£§m2Yll22D52§>Y<E?n>}2£<Yi>2§<t§£><4-anilino-3>N<-p_Y£E2l2l§I§yi£§m2Yll22D52§>Y<E?n>}2£<Yi>2§<t§£>
12,8 g 3-amino-4-anilino-5-sulfamoyl-benzosyremetylester suspenderes i iseddik og oppvarmes under tilbakeløp. Der- 12.8 g of 3-amino-4-anilino-5-sulfamoyl-benzoic acid methyl ester are suspended in glacial acetic acid and heated under reflux. There-
etter tildrypper man til dette 5,6 ml 2,5-dimetoksytetrahydrofuran oppløst i litt iseddik. Etter en reaksjonstid på 0,5 time rører man blandingen inn i isvann og utskiller det utfelte produkt. then 5.6 ml of 2,5-dimethoxytetrahydrofuran dissolved in a little glacial acetic acid is added dropwise to this. After a reaction time of 0.5 hour, the mixture is stirred into ice water and the precipitated product is separated.
2Y?£É 2£i22_tii_ilÉGiiiD2l3il;;gy.r^o^ 4-anilino-3-N-pyrrolo-5-sulfamoyl-benzosyremetylester- oppløses som råprodukt i metanol og hydrogeneres 16 timer ved 100°C og 100 atm i nærvær av Pd/kull (^-1 g). Deretter filtrerer man og inndamper filtratet. Residuet tas opp med 2-n NaOH og oppvarmes til en klar oppløsning. Ved tilsetning av 2-n HC1 til pH 4 utfelles 4-anilino-3(1-pyrrolidinyl)-5-sulfamoyl-benzosyre. 2Y?£É 2£i22_tii_ilÉGiiiD2l3il;;gy.r^o^ 4-anilino-3-N-pyrrolo-5-sulfamoyl-benzoic acid methyl ester- is dissolved as crude product in methanol and hydrogenated for 16 hours at 100°C and 100 atm in the presence of Pd/coal (^-1 g). The filtrate is then filtered and evaporated. The residue is taken up with 2-n NaOH and heated to a clear solution. When 2-n HCl is added to pH 4, 4-anilino-3(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid is precipitated.
For rensing oppløser man produktet i litt aceton, tilsetter For cleaning, dissolve the product in a little acetone, add
et overskudd av mettet eterisk HCl-oppløsning og innrører blandingen i den dobbelte mengde eter. Hydrokloridet av 4-anilino-3(1-pyrrolidinyl)-5-sulfamoyl-benzosyre faller ut. an excess of saturated ethereal HCl solution and stir the mixture into twice the amount of ether. The hydrochloride of 4-anilino-3(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid precipitates.
Den fraskilles, vaskes med aceton, oppløses i 2-n NaOH og inn-stilles på pH 4 med 2-n HC1. Den utfelte 4-anilino-3(1-pyrro-lidinyl )-5-sulfamoyl-benzosyren omkrystalliseres fra CH3OH/H20. It is separated, washed with acetone, dissolved in 2-n NaOH and adjusted to pH 4 with 2-n HCl. The precipitated 4-anilino-3(1-pyrrolidinyl)-5-sulfamoyl-benzoic acid is recrystallized from CH 3 OH/H 2 O.
Gule krystaller med smeltepunkt 214-216°C. Yellow crystals with melting point 214-216°C.
Eksemgel_3 Eczema gel_3
iliilzmS£Yi§Diii22il5l5lEYEE2i2l5l§Hifa2!0YiDeD50sYre 3-amino-4-(4'-metylanilino)-5-sulfamoyl-benzosyremetylester omsettes analogt eksempel 2 med 2,5-dimetoksytetrahydrofuran og deretter forsåpes det utfelte råprodukt med 2-n NaOH. iliilzmS£Yi§Diii22il5l5lEYEE2i2l5l§Hifa2!0YiDeD50sYre 3-amino-4-(4'-methylanilino)-5-sulfamoyl-benzoic acid methyl ester is reacted analogously to example 2 with 2,5-dimethoxytetrahydrofuran and then the precipitated crude product is saponified with 2-n NaOH.
Man får etter surgjøring med 2-n HC1 til pH 3-4 4-(4'-metyl-anilino) -3-N-pyrrolo-5-sulfamoyl-benzosyre med smeltepunkt 226-228°C (fra CH3OG/H20). After acidification with 2-n HCl to pH 3-4, 4-(4'-methyl-anilino)-3-N-pyrrolo-5-sulfamoyl-benzoic acid with melting point 226-228°C (from CH3OG/H20) is obtained.
QY§Ef?£i09_!:ii_ililllm§<t>Yi&D^ §HifÉ<m>2Yi22D22§YE2 QY§Ef?£i09_!:ii_ililllm§<t>Yi&D^ §HifÉ<m>2Yi22D22§YE2
Syren oppløses i etylacetat og hydrogeneres 16 timer ved The acid is dissolved in ethyl acetate and hydrogenated for 16 hours at
100°C og 150 atm i nærvær av rodium/karbon. Filtratet inndampes, residuet tas opp med litt aceton (abolutt) og eter- 100°C and 150 atm in the presence of rhodium/carbon. The filtrate is evaporated, the residue is taken up with a little acetone (abolut) and ether
isk HC1 tilsettes. Ved fortsatt tilsetning faller det ut hydroklorid av 4-(4'-metylanilino)-3(1-pyrrolidinyl)-5-sulfamoylbenzosyre. Den fraskilles, vaskes med litt aceton/ eterisk HC1 og oppløses deretter i 2-n NaOH. Ved surgjøring til pH 3-4 faller det ut 4-(4'-metylanilino)-3(1-pyrrolidinyl)-5-sulfamoylbenzosyre. ice HC1 is added. On continued addition, hydrochloride of 4-(4'-methylanilino)-3(1-pyrrolidinyl)-5-sulfamoylbenzoic acid precipitates. It is separated, washed with a little acetone/ ethereal HCl and then dissolved in 2-n NaOH. When acidified to pH 3-4, 4-(4'-methylanilino)-3(1-pyrrolidinyl)-5-sulfamoylbenzoic acid precipitates.
Omkrystallisering fra CH.JOH/H2O, gule krystaller med smeltepunkt 188-191°C. Recrystallization from CH.JOH/H2O, yellow crystals with melting point 188-191°C.
Eksemp_el_4 Example_el_4
3lN-^w-kiorbutYrYlamino).-4-f enokgY-5-sulf amgYlbenzosyre-met<y>lester 3lN-[w-kiorbutyrylamino).-4-f enokgy-5-sulfa amgylbenzoic acid methyl ester
24 g 3-amino-4-fenoksy-5-sulfamoyl-benzosyremetylester og 7,5 ml pyrridin i 100 ml absolutt dioksan og 21,2 g w-klor-smørsyreklorid i 100 ml absolutt aceton settes i løpet av 2 timer langsomt og jevnt dråpevis til 100 ml kokende absolutt dioksan. Etter 1 time fortsatt omrøring inndampes opp-løsningen. Den gjenblivende olje opptas med en liten mengde aceton og inndryppes i isvann under kraftig omrøring. 3-N-(w-klorbutyrylamino)-4-fenoksy-5-sulfamoyl-benzosyre-metylesteren faller ut og omkrystalliseres fra metanol. Smeltepunkt 151-153°C. QY§l£<®>£iQ2_tii_5lN-^w-klorbutYlamino)-4-fenoksy-5-sulfamoYl-benzosYremetylester 12 g 3-N-(w<->klorbutyrylamino)-4-fenoksy-5-sulfamoyl-benzosyremetylester suspenderes i 150 ml diglym. Deretter tilsettes 7 ml BF3~eterat. JEn oppløsning av 2,2 g NaBH^ i 150 ml diglym tildryppes langsomt ved værelsestemperatur. Etter noen minutters etteromrøring utfelles produktet forsiktig med vann. 24 g of 3-amino-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester and 7.5 ml of pyridine in 100 ml of absolute dioxane and 21.2 g of w-chlorobutyric acid chloride in 100 ml of absolute acetone are placed slowly and evenly over the course of 2 hours dropwise into 100 ml of boiling absolute dioxane. After 1 hour of continued stirring, the solution is evaporated. The remaining oil is taken up with a small amount of acetone and dropped into ice water with vigorous stirring. The 3-N-(w-chlorobutyrylamino)-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester precipitates and is recrystallized from methanol. Melting point 151-153°C. QY§l£<®>£iQ2_tii_5lN-^w-chlorobutylamino)-4-phenoxy-5-sulfamoyl-benzosYremethyl ester 12 g of 3-N-(w<->chlorobutyrylamino)-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester are suspended in 150 ml diglyme. 7 ml of BF3~etherate are then added. A solution of 2.2 g of NaBH^ in 150 ml of diglyme is slowly added dropwise at room temperature. After a few minutes of stirring, the product is carefully precipitated with water.
Etter omkrystallisering fra metanol har produktet smeltepunkt 125°C. After recrystallization from methanol, the product has a melting point of 125°C.
benzosyre benzoic acid
3-N- (co -klorbutylamino) -4-f enok sy-5-sul f amoyl-benzosyremetylester suspenderes i 1-normal NaOH og oppvarmes på dampbad til det er dannet en klar oppløsning. Fra den kalde oppløsning utfelles 3-N-pyrrolidino-4-fenoksy-5-sulfamoylbenzosyren med 1-normal HC1. 3-N-(co-chlorobutylamino)-4-phenoxy-5-sulfamoyl-benzoic acid methyl ester is suspended in 1-normal NaOH and heated on a steam bath until a clear solution is formed. From the cold solution, the 3-N-pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid is precipitated with 1-normal HCl.
Eksemp_el_5 Example_el_5
2l5lEY££2i2~il£§2Yi£i2l§I§<u>i£5<m>2Yi22D<z>2<s>YE2_ 2l5lEY££2i2~il£§2Yi£i2l§I§<u>i£5<m>2Yi22D<z>2<s>YE2_
13,5 g (0,04 mol) 3-amino-4-fenyltio-5-sulfamoyl-benzosyremetylester og 9,2 g (0,07 mol) 2,5-dimetoksytetrahydrofuran omrøres i 150 ml iseddik i en halvtime ved 90°C. Deretter innføres reaksjonsoppløsningen i isvann, og det utfelte råprodukt hydrolyseres med ln NaOH i 1 time på dampbad. Ved surgjøring med 2n HC1 faller det ut 3-N-pyrrolo-4-fenyltio-5-sulfamoylbenzosyre. Den omkrystalliserer i første rekke av 1,2;—dikloretan og deretter av metanol/vann. Krystaller av smeltepunkt 198-200°C. 13.5 g (0.04 mol) of 3-amino-4-phenylthio-5-sulfamoyl-benzoic acid methyl ester and 9.2 g (0.07 mol) of 2,5-dimethoxytetrahydrofuran are stirred in 150 ml of glacial acetic acid for half an hour at 90° C. The reaction solution is then introduced into ice water, and the precipitated crude product is hydrolysed with ln NaOH for 1 hour on a steam bath. On acidification with 2n HCl, 3-N-pyrrolo-4-phenylthio-5-sulfamoylbenzoic acid precipitates. It recrystallizes first from 1,2;-dichloroethane and then from methanol/water. Crystals of melting point 198-200°C.
Eksemp_el_6 Example_el_6
5lN-pYrrolo^4-^4^-benzyloksyf enoksy/z5;sulf amoy_lbenzosYre_ 5lN-pYrrolo^4-^4^-benzyloxyphenoxy/z5;sulf amoy_lbenzosYre_
Til en oppløsning av 38,6 g (0,09 mol) 3-amino-4-^4'-benzyl-oksyfenoksY?-5-sulfamoyl-benzosyremetylester i 350 ml iseddik dryppes ved 90°C under omrøring 16,3 g (0,12 mol) 2,5-dimet-oksytetrahydrof uran . Etter en times omrøring ved 90°C inn-føres reaksjonsproduktet i isvann. Det utfelte råprodukt omkrystalliseres etter klaring med kull fra metanol og hydrolyseres deretter med ln NaOH til dannelse av en klar oppløs-ning ved 80°C. 3-N-pyrrolo-4-^4'-benzyloksyfenoksY/-5-sulfa-moylbenzosyre utfelles med 2n HC1 ved pH 3-4 og omkrystalliseres fra metanol/^O. Krystaller av smesltepunkt 285-300°C. 16.3 g ( 0.12 mol) 2,5-dimethoxytetrahydrofuran. After one hour of stirring at 90°C, the reaction product is introduced into ice water. The precipitated crude product is recrystallized after clarification with charcoal from methanol and then hydrolyzed with 1N NaOH to form a clear solution at 80°C. 3-N-pyrrolo-4-^4'-benzyloxyphenoxy/-5-sulfa-moylbenzoic acid is precipitated with 2n HCl at pH 3-4 and recrystallized from methanol/^O. Crystals of melting point 285-300°C.
Eksemgel_7 Eczema gel_7
3-N-gYrrolo-4-H^-hydroksYfsnokgY^-5-sulfamoylbenzosyre 12,9 g (0,027 mol) 3-N-pyrrolo-4-(4'-benzyloksyfenoksy)-5-sulfamoylbenzosyre oppløses i 600 ml av en KOH-oppløsning 3-N-gYrrolo-4-H^-hydroxyYfsnokgY^-5-sulfamoylbenzoic acid 12.9 g (0.027 mol) of 3-N-pyrrolo-4-(4'-benzyloxyphenoxy)-5-sulfamoylbenzoic acid are dissolved in 600 ml of a KOH -resolution
(2 g KOH/600 ml ) og hydrogeneres med Raney-nikkel ved 50°/to atm H.,/8 timer. Etter adskillelse av katalysatoren felles 3-N-pyrrolo-4-(4'-hydroksyfenoksy)-5-sulfamoyl-benzosyre ved pH 3-4 med ln HC1 og omkrystalliseres fra metanol/H20. Krystaller av smeltepunkt 239-241°C. (2 g KOH/600 ml ) and hydrogenated with Raney nickel at 50°/two atm H.,/8 hours. After separation of the catalyst, 3-N-pyrrolo-4-(4'-hydroxyphenoxy)-5-sulfamoyl-benzoic acid is precipitated at pH 3-4 with 1N HCl and recrystallized from methanol/H 2 O. Crystals of melting point 239-241°C.
Eksemgel_8 Eczema gel_8
5~N-gyrrolo;;42 H^-klgrf enoksy2;5-sulf amoylbenzosyre Til en oppløsning av 17 g (0,05 mol) 3-amino-4-(4<1->klor-fenoksy)-5-sulfamoyl-benzosyremetylester i 200 ml iseddik dryppes ved 9 0°C under omrøring 9,2 g (0,07 mol) 2,5-dimetoksytetrahydrofuran. Etter en times omrøring ved 90°C inn-føres reaksjonsproduktet i isvann, og det utfelte råprodukt oppvarmes ln NaOH for dannelse av en klar oppløsning på dampbad. 3-N-pyrrolo-4-(4'-klorfenoksy)-5-sulfamoyl-benzosyre felles ved pH 4 med 2n HC1. For rensing opp- 5~N-gyrrolo;;42 H^-klgrf enoxy2;5-sulfamoylbenzoic acid To a solution of 17 g (0.05 mol) 3-amino-4-(4<1->chloro-phenoxy)-5-sulfamoyl -benzoic acid methyl ester in 200 ml of glacial acetic acid is added dropwise at 90°C with stirring 9.2 g (0.07 mol) of 2,5-dimethoxytetrahydrofuran. After stirring for one hour at 90°C, the reaction product is introduced into ice water, and the precipitated crude product is heated in NaOH to form a clear solution on a steam bath. 3-N-pyrrolo-4-(4'-chlorophenoxy)-5-sulfamoyl-benzoic acid combined at pH 4 with 2n HCl. For cleaning up
løses forbindelsen i metanol, klares med kull og felles ved tilsetning av vann. Krystaller av smeltepunkt 212-214°C. the compound is dissolved in methanol, clarified with charcoal and separated by adding water. Crystals of melting point 212-214°C.
Eksemgel_9 Eczema gel_9
2zN-gyrrolo-4_2f enoksy-5-metyl sul f amoylbenzosyre 18,5 g (0,055 mol) 3-amino-4-fenoksy-5-metylsulfamoyl-benzosyre og 9 ml (0,066 mol) 2,5-dimetoksytetrahydrofuran oppvarmes i 200 ml iseddik til koking. Etter 10 minutters koking under tilbakeløp utfelles produktet ved innhelling i isvann og utfellingen suspenderes i 2n NaOH og oppvarmes til klar oppløsning på vannbad. Ved surgjøring med 2n HC1 faller det ved pH 3-4 ut 3-N-pyrrolo-4-fenoksy-5-metylsulfa-moylbenzosyre som krystalliseres fraksjonert fra metanol/vann. Krystaller av smeltepunkt 208-209°C. 2zN-gyrrolo-4_2f enoxy-5-methyl sulfamoylbenzoic acid 18.5 g (0.055 mol) of 3-amino-4-phenoxy-5-methylsulfamoylbenzoic acid and 9 ml (0.066 mol) of 2,5-dimethoxytetrahydrofuran are heated in 200 ml glacial acetic acid for cooking. After 10 minutes of boiling under reflux, the product is precipitated by pouring into ice water and the precipitate is suspended in 2N NaOH and heated to a clear solution in a water bath. On acidification with 2n HC1, 3-N-pyrrolo-4-phenoxy-5-methylsulfamoylbenzoic acid precipitates at pH 3-4, which is fractionally crystallized from methanol/water. Crystals of melting point 208-209°C.
Eksermoel_10 Exermoel_10
3zN~EYEE2l2zl~f 2D2lSsYz5zDzE<y>tYisu^f^moYlbe^z^sYr^3zN~EYEE2l2zl~f 2D2lSsYz5zDzE<y>tYisu^f^moYlbe^z^sYr^
20 g (0,053 mol) 3-amino-4-fenoksy-5-n-butylsulfamoyl-benzosyremetylester oppløses i 200 ml iseddik. Ved 90°C tildryppes 11,2 g (0,085 mol) 2,5-dimetoksytetrahydrofuran. Etter 15 minutters omrøring ved 90°C innføres blandingen i isvann. Det utfelte stoff frafiltreres, omkrystalliseres fra metanol/vann og hydrolyseres deretter med 2n NaOH på dampbad. Deretter filtreres den mørke oppløsning, fortynnes med isvann og 3-N-pyrrolo-4-fenoksy-5-n-butylsulfamoyl-benzosyre felles med 2n HC1. Det mørkebrune råprodukt opp-løses i aceton. Ved tilsetning av n-heksan felles forurensningene. Det lysegule filtrat inndampes og residuet omkrystalliseres fra metanol/vann. Lyse krystaller av smeltepunkt 177-178°C. 20 g (0.053 mol) of 3-amino-4-phenoxy-5-n-butylsulfamoyl-benzoic acid methyl ester are dissolved in 200 ml of glacial acetic acid. At 90°C, 11.2 g (0.085 mol) of 2,5-dimethoxytetrahydrofuran are added dropwise. After 15 minutes of stirring at 90°C, the mixture is introduced into ice water. The precipitated substance is filtered off, recrystallized from methanol/water and then hydrolysed with 2N NaOH on a steam bath. The dark solution is then filtered, diluted with ice water and 3-N-pyrrolo-4-phenoxy-5-n-butylsulfamoyl-benzoic acid together with 2n HCl. The dark brown crude product is dissolved in acetone. When n-hexane is added, the impurities are separated. The pale yellow filtrate is evaporated and the residue is recrystallized from methanol/water. Light crystals of melting point 177-178°C.
Eksemp_el_ll Example_el_ll
2z5zEYEE2l2zlzi 1 IzÉmiD2f SD2!S§Yiz§Z§HlÉ5m2Yl2?G52§YE?_ 2z5zEYEE2l2zlzi 1 IzÉmiD2f SD2!S§Yiz§Z§HlÉ5m2Yl2?G52§YE?_
Til en oppløsning av 19 g (0,05 mol) 3-amino-4-(4-acetadmido-fenoksy)^5rsmlfamoylbenzosyre i 200 ml iseddik tildryppes ved 90°C under omrøring 10,4 g (0,08 mol) 2,5-dimetoksy-tetrahydrof uran . Etter 20 minutters omrøring ved 90°C innføres blandingen i isvann. Det utfelte stoff omkrystalliseres fra metanol/vann og hydrolyseres deretter på dampbad med 2n NaOH. 3-N-pyrrolo-4-(4'-aminofenoksy)-5-sulfamoyl-benzosyre felles med 2n HC1. Det mørkebrune råprodukt oppløses i aceton. Ved tilsetning av n-heksan felles forurensningene. Filtratet inndampes og residuet omkrystalliseres fra metanol/vann. Krystaller av smeltepunkt 168-171°C. 10.4 g (0.08 mol) 2, 5-dimethoxy-tetrahydrofuran. After 20 minutes of stirring at 90°C, the mixture is introduced into ice water. The precipitated substance is recrystallized from methanol/water and then hydrolyzed on a steam bath with 2N NaOH. 3-N-pyrrolo-4-(4'-aminophenoxy)-5-sulfamoyl-benzoic acid combined with 2n HCl. The dark brown crude product is dissolved in acetone. When n-hexane is added, the impurities are separated. The filtrate is evaporated and the residue is recrystallized from methanol/water. Crystals of melting point 168-171°C.
<Eks>empel_12 <Ex>empel_12
2zNzEY£E2l2ziziilzm§£2lSs.Yf?D25S§Y!Z:2Zsyi£ §m2Yi2§052§YE2 2zNzEY£E2l2ziziilzm§£2lSs.Yf?D25S§Y!Z:2Zsyi£ §m2Yi2§052§YE2
8,5 g 3-amino-4-(4'-metoksyfenoksy)-5-sulfamoylbenzosyre-metylester oppvarmes med 5 g 2,5-dimetoksytetrahydrofuran i 100 ml iseddik under tilbakeløp. Etter 1,5-2 timer innrøres blandingen i isvann. Det derved utfelte råprodukt oppvarmes 8.5 g of 3-amino-4-(4'-methoxyphenoxy)-5-sulfamoylbenzoic acid methyl ester are heated with 5 g of 2,5-dimethoxytetrahydrofuran in 100 ml of glacial acetic acid under reflux. After 1.5-2 hours, stir the mixture into ice water. The thus precipitated raw product is heated
i ln NaOH til dannelse av en klar oppløsning på dampbad. Ved surgjøring med 2n HC1 faller det ut 3-N-pyrrolo-4-(41 - metoksyfenoksy)-5-sulfamoylbenzosyre. Det omkrystalliseres fra metanol. Krystaller av smeltepunkt 166-168°C. in ln NaOH to form a clear solution on a steam bath. On acidification with 2n HCl, 3-N-pyrrolo-4-(41-methoxyphenoxy)-5-sulfamoylbenzoic acid precipitates. It is recrystallized from methanol. Crystals of melting point 166-168°C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2419970A DE2419970C3 (en) | 1974-04-25 | 1974-04-25 | 3- <1-Pyrrolidinyl) -4-phenoxy-5sulfamoylbenzoic acid and process for its preparation |
| DE2461601A DE2461601C2 (en) | 1974-04-25 | 1974-12-27 | 3-Pyrrolidino-4-phenoxy-5-sulfamoylbenzoic acid ester and process for their preparation |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO784198L NO784198L (en) | 1975-10-28 |
| NO151825B true NO151825B (en) | 1985-03-04 |
| NO151825C NO151825C (en) | 1985-06-12 |
Family
ID=25767039
Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO751470A NO146745C (en) | 1974-04-25 | 1975-04-24 | PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE HETEROCYCLIC SUBSTITUTED 5-SULFAMOYLBENZOIC ACID DERIVATIVES |
| NO784198A NO151825C (en) | 1974-04-25 | 1978-12-13 | INTERMEDIATE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 5-SULFAMOYL-BENZO ACID DERIVATIVES |
| NO784196A NO149736C (en) | 1974-04-25 | 1978-12-13 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE HETEROCYCLIC SUBSTITUTED 5-SULPHAMOYLBENOS ACID DERIVATIVES |
| NO784197A NO150681C (en) | 1974-04-25 | 1978-12-13 | INTERMEDIATES FOR THE PREPARATION OF HETEROCYCLIC SUBSTITUTED 5-SULFAMOYLBENZO ACID DERIVATIVES |
| NO833116A NO152749C (en) | 1974-04-25 | 1983-08-30 | SUBSTITUTED BENZO ACID DERIVATIVES AS INTERMEDIATES FOR DIURETICS. |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO751470A NO146745C (en) | 1974-04-25 | 1975-04-24 | PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE HETEROCYCLIC SUBSTITUTED 5-SULFAMOYLBENZOIC ACID DERIVATIVES |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO784196A NO149736C (en) | 1974-04-25 | 1978-12-13 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE HETEROCYCLIC SUBSTITUTED 5-SULPHAMOYLBENOS ACID DERIVATIVES |
| NO784197A NO150681C (en) | 1974-04-25 | 1978-12-13 | INTERMEDIATES FOR THE PREPARATION OF HETEROCYCLIC SUBSTITUTED 5-SULFAMOYLBENZO ACID DERIVATIVES |
| NO833116A NO152749C (en) | 1974-04-25 | 1983-08-30 | SUBSTITUTED BENZO ACID DERIVATIVES AS INTERMEDIATES FOR DIURETICS. |
Country Status (22)
| Country | Link |
|---|---|
| AR (7) | AR215839A1 (en) |
| AU (1) | AU507614B2 (en) |
| BR (1) | BR7502487A (en) |
| CS (1) | CS188242B2 (en) |
| DD (2) | DD124230A5 (en) |
| DK (1) | DK158978C (en) |
| EG (1) | EG11682A (en) |
| ES (1) | ES453840A1 (en) |
| FI (1) | FI62075C (en) |
| HK (1) | HK51279A (en) |
| HU (1) | HU174751B (en) |
| IE (1) | IE42601B1 (en) |
| IL (2) | IL47128A (en) |
| IT (1) | IT1041753B (en) |
| KE (1) | KE2971A (en) |
| MT (1) | MTP779B (en) |
| MY (1) | MY8000060A (en) |
| NO (5) | NO146745C (en) |
| NZ (1) | NZ177095A (en) |
| RO (6) | RO66590A (en) |
| SE (2) | SE404796B (en) |
| ZM (1) | ZM4875A1 (en) |
-
1975
- 1975-01-25 RO RO7582089A patent/RO66590A/en unknown
- 1975-04-02 NZ NZ177095A patent/NZ177095A/en unknown
- 1975-04-21 IL IL47128A patent/IL47128A/en unknown
- 1975-04-22 ZM ZM48/75A patent/ZM4875A1/en unknown
- 1975-04-23 EG EG242/75A patent/EG11682A/en active
- 1975-04-23 DD DD193161A patent/DD124230A5/xx unknown
- 1975-04-23 IT IT22687/75A patent/IT1041753B/en active Protection Beyond IP Right Term
- 1975-04-23 FI FI751213A patent/FI62075C/en not_active IP Right Cessation
- 1975-04-23 AR AR258480A patent/AR215839A1/en active
- 1975-04-23 DD DD185644A patent/DD119589A5/xx unknown
- 1975-04-23 AU AU80474/75A patent/AU507614B2/en not_active Expired
- 1975-04-24 HU HU75HO1794A patent/HU174751B/en not_active IP Right Cessation
- 1975-04-24 CS CS765597A patent/CS188242B2/en unknown
- 1975-04-24 DK DK179875A patent/DK158978C/en active
- 1975-04-24 BR BR3159/75D patent/BR7502487A/en unknown
- 1975-04-24 NO NO751470A patent/NO146745C/en unknown
- 1975-04-24 IE IE921/75A patent/IE42601B1/en unknown
- 1975-04-25 RO RO7585289A patent/RO70346A/en unknown
- 1975-04-25 SE SE7504841A patent/SE404796B/en not_active IP Right Cessation
- 1975-04-25 RO RO7585292A patent/RO70426A/en unknown
- 1975-04-25 RO RO7585291A patent/RO70353A/en unknown
- 1975-04-25 RO RO7585290A patent/RO81781A/en unknown
- 1975-04-25 RO RO7585293A patent/RO70678A/en unknown
- 1975-05-02 MT MT779A patent/MTP779B/en unknown
-
1976
- 1976-06-25 AR AR263743A patent/AR217056A1/en active
- 1976-06-25 AR AR263742A patent/AR216633A1/en active
- 1976-06-25 AR AR263740A patent/AR217055A1/en active
- 1976-06-25 AR AR263741A patent/AR219057A1/en active
- 1976-06-25 AR AR263739A patent/AR218225A1/en active
- 1976-12-01 ES ES453840A patent/ES453840A1/en not_active Expired
-
1977
- 1977-10-27 SE SE7712097A patent/SE435379B/en not_active IP Right Cessation
-
1978
- 1978-12-13 NO NO784198A patent/NO151825C/en unknown
- 1978-12-13 NO NO784196A patent/NO149736C/en unknown
- 1978-12-13 NO NO784197A patent/NO150681C/en unknown
-
1979
- 1979-03-20 IL IL56919A patent/IL56919A0/en not_active IP Right Cessation
- 1979-06-20 KE KE2971A patent/KE2971A/en unknown
- 1979-07-02 AR AR277151A patent/AR231135A1/en active
- 1979-07-26 HK HK512/79A patent/HK51279A/en unknown
-
1980
- 1980-12-30 MY MY60/80A patent/MY8000060A/en unknown
-
1983
- 1983-08-30 NO NO833116A patent/NO152749C/en unknown
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