NO132098B - - Google Patents
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- NO132098B NO132098B NO154771A NO154771A NO132098B NO 132098 B NO132098 B NO 132098B NO 154771 A NO154771 A NO 154771A NO 154771 A NO154771 A NO 154771A NO 132098 B NO132098 B NO 132098B
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- Prior art keywords
- formula
- hydroxy
- acid
- phenyl
- chlorophenyl
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- -1 tri(C 4 )alkylamine Chemical class 0.000 description 4
- WUSKUMDOLSBRHW-UHFFFAOYSA-N 2-(4-chlorobenzoyl)benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1C(=O)C1=CC=C(Cl)C=C1 WUSKUMDOLSBRHW-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- JATMCAQQSXISOR-UHFFFAOYSA-N n-(2-aminoethyl)-4-methylbenzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)NCCN)C=C1 JATMCAQQSXISOR-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- UVNXNSUKKOLFBM-UHFFFAOYSA-N imidazo[2,1-b][1,3,4]thiadiazole Chemical compound N1=CSC2=NC=CN21 UVNXNSUKKOLFBM-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GJJVTLOHDLKVFS-UHFFFAOYSA-N 2-benzoylbenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 GJJVTLOHDLKVFS-UHFFFAOYSA-N 0.000 description 1
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- BJTHOLRDMKDSNE-UHFFFAOYSA-N FC=1C=C(C(=O)C2=C(C(=O)Cl)C=CC=C2)C=CC=1 Chemical compound FC=1C=C(C(=O)C2=C(C(=O)Cl)C=CC=C2)C=CC=1 BJTHOLRDMKDSNE-UHFFFAOYSA-N 0.000 description 1
- ZPXSCAKFGYXMGA-UHFFFAOYSA-N Mazindol Chemical compound N12CCN=C2C2=CC=CC=C2C1(O)C1=CC=C(Cl)C=C1 ZPXSCAKFGYXMGA-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002518 isoindoles Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VMIKHXOZRYCZSG-UHFFFAOYSA-N n-(2-aminoethyl)-3,4-dimethylbenzenesulfonamide Chemical compound CC1=CC=C(S(=O)(=O)NCCN)C=C1C VMIKHXOZRYCZSG-UHFFFAOYSA-N 0.000 description 1
- MWEBCGQFQBAAJP-UHFFFAOYSA-N n-(2-aminoethyl)-4-chlorobenzenesulfonamide Chemical compound NCCNS(=O)(=O)C1=CC=C(Cl)C=C1 MWEBCGQFQBAAJP-UHFFFAOYSA-N 0.000 description 1
- JVFJSUCEQDCCAH-UHFFFAOYSA-N n-(2-aminoethyl)benzenesulfonamide Chemical compound NCCNS(=O)(=O)C1=CC=CC=C1 JVFJSUCEQDCCAH-UHFFFAOYSA-N 0.000 description 1
- GCDZDXVTDCMNMN-UHFFFAOYSA-N n-(2-aminoethyl)methanesulfonamide Chemical compound CS(=O)(=O)NCCN GCDZDXVTDCMNMN-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229960001407 sodium bicarbonate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000015961 tonic Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960000716 tonics Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrorer en ny fremgangsmåte for fremstilling av 2,3-dihydro-5-hydroksy-5-fenyl-5H-imidazo-E,l-a]isoindoler med formel hvori R og R^, som er like eller forskjellige, i det enkelte tilfelle betyr hydrogen, klor eller fluor. The present invention relates to a new method for the preparation of 2,3-dihydro-5-hydroxy-5-phenyl-5H-imidazo-E,1-a]isoindoles of formula in which R and R^, which are the same or different, in the individual case means hydrogen, chlorine or fluorine.
Forbindelsene med formel I er kjente, jfr. norsk patent nr. 130826 Forbindelsene The compounds of formula I are known, cf. Norwegian patent no. 130826 The connections
kan foreligge i forskjellige tautomere og ioniske former. can exist in various tautomeric and ionic forms.
Oppfinnelsen er folgelig ikke begrenset til fremstilling av bare de forbindelser hvis strukturformel er gjengitt ved formel I eller den tilsvarende kjemiske betegnelse. The invention is therefore not limited to the production of only those compounds whose structural formula is given by formula I or the corresponding chemical designation.
Det særegne ved fremgangsmåta!i henhold til oppfinnelsen er at et 3-hydroksy-3-fenyl-2-(2-sulfonylaminoetyl)-ftalimidin The distinctive feature of the method according to the invention is that a 3-hydroxy-3-phenyl-2-(2-sulfonylaminoethyl)-phthalimidine
med formel with formula
hvori R og R^ har den ovennevnte betydning og R2 står for alkyl med 1-5 karbonatomer eller en fenylrest med formel in which R and R^ have the above meaning and R 2 stands for alkyl with 1-5 carbon atoms or a phenyl radical of formula
hvori R. og R , som er like eller forskjellige, i det enkelte in which R. and R , which are the same or different, in the individual
3 4 3 4
tilfelle betyr hydrogen, klor, brom eller rettkjedet alkyl med 1-3 karbonatomer, idet hbyst,en av substituentene R^ og R4 befinner seg i orto-stilling på fenylringen, hvis R^ og R^case means hydrogen, chlorine, bromine or straight-chain alkyl with 1-3 carbon atoms, with at least one of the substituents R^ and R^ being in the ortho position on the phenyl ring, if R^ and R^
i det enkelte tilfelle har en annen betydning enn hydrogen, behandles med 85 til 100 vektprosent svovelsyre eller fosforsyre. in the individual case has a different meaning than hydrogen, is treated with 85 to 100 percent by weight sulfuric or phosphoric acid.
De nye forbindelser med formel II kan også foreligge i den tautomere form med formel The new compounds of formula II can also exist in the tautomeric form of formula
hvori R, R^ og R^ har den ovennevnte betydning. wherein R, R^ and R^ have the above meaning.
For enkelhets skyld anvendes i det fblgencte bare formel II For the sake of simplicity, only formula II is used in the fblgencte
eller den tilsvarende kjemiske betegnelse. or the corresponding chemical designation.
Fremgangsmåten i henhold til oppfinnelsen gjennomfores hensiktsmessig ved temperaturer mellom 15 og 75°C, foretrukket mellom 30 og 65°c, og spesielt mellom 50 og 65°C. Man kan arbeide uten ldsningsmiddel med omtrent ekvimolare mengder av reaksjonskomponentene, men anvender foretrukket et overskudd av svovelsyre eller fosforsyre som losningsmiddel. Som syre anvendes foretrukket svovelsyre med konsentrasjon foretrukket 90 til 98 vektprosent. Reaksjonstiden varierer og kan f.eks. utgjore 2 til 6 timer. The method according to the invention is conveniently carried out at temperatures between 15 and 75°C, preferably between 30 and 65°C, and especially between 50 and 65°C. One can work without a solvent with approximately equimolar amounts of the reaction components, but an excess of sulfuric acid or phosphoric acid is preferably used as a solvent. The acid used is preferably sulfuric acid with a concentration of preferably 90 to 98 percent by weight. The reaction time varies and can e.g. make 2 to 6 hours.
De forst som syreaddisjonssalter med svovelsyre henhv. fosforsyre erholdte forbindelser med formel I kan på i og for seg kjent måte isoleres og renses i form av de fri baser I. They understood as acid addition salts with sulfuric acid or compounds with formula I obtained from phosphoric acid can be isolated and purified in the form of the free bases I in a manner known per se.
De nye 2-(2-sulfonylaminoetyl)-3-hydroksy-3-fenylftalimidiner med formel II kan fremstilles ved at 1-(2-benzoylbenzosyre-klorid eller -bromid med formel hvori R og R^ har den ovennevnte betydning og X står for klor eller brom, i et inært organisk lbsningsmiddel omsettes med et N-(2-aminoetyl)-alkyl henhv. benzen-sulfonamid.med formel The new 2-(2-sulfonylaminoethyl)-3-hydroxy-3-phenylphthalimidines of formula II can be prepared by 1-(2-benzoylbenzoic acid chloride or bromide of formula in which R and R^ have the above meaning and X stands for chlorine or bromine, in an inert organic solvent, is reacted with an N-(2-aminoethyl)-alkyl or benzene-sulfonamide with the formula
hvori R2 har den ovennevnte betydning. wherein R 2 has the above meaning.
Forbindelsene med formel IV kan også foreligge som tautomere med formel The compounds of formula IV can also exist as tautomers of formula
hvori R, R^ og X har den ovennevnte betydning. wherein R, R^ and X have the above meaning.
For enkelhets skyld gås dazi.det fdlgende bare ut fra formel IV eller den tilsvarende kjemiske Betegnelse., Fremgangsmåten skal imidlertid ikke være begrenset til anvendelse av bare de forbindelser som angis med formel IV eller som defineres med den tilsvarende kjemiske betegnelse. For the sake of simplicity, the following is only based on formula IV or the corresponding chemical designation. However, the method shall not be limited to the use of only the compounds indicated by formula IV or which are defined by the corresponding chemical designation.
Fremgangsmåten gjennomfdres foretrukket ved temperaturer mellom 20 og 60°C, spesielt mellom 40 og 50°C. Hensiktsmessig arbeider man i nærvær av et syrebindende middel, nemlig et organisk amin, som tri(C^_4)alkylamin, f.eks. trimetyl- eller trietylamin, pyridin eller (C^ ^)alkylpyridin, f.eks. metyl-eller etylpyridin, eller et alkalikarbonat eller -bikarbonat', f.eks. natriumkarbonat henhv. -bikarbonat eller kaliumkarbonat. Som losningsmidler egner seg f.eks. aromatiske hydrokarboner, som benzen, toluen eller xylen, halogenerte hydrokarboner som metandiklorid eller kloroform, eller etere, som tetrahydrofuran eller dioksan. Reaksjonstiden kan variere men ligger f.eks. mellom 3 og 24 timer. The method is preferably carried out at temperatures between 20 and 60°C, especially between 40 and 50°C. It is expedient to work in the presence of an acid-binding agent, namely an organic amine, such as tri(C 4 )alkylamine, e.g. trimethyl- or triethylamine, pyridine or (C₁₋)alkylpyridine, e.g. methyl or ethyl pyridine, or an alkali carbonate or bicarbonate', e.g. sodium carbonate or -bicarbonate or potassium carbonate. Suitable solvents are e.g. aromatic hydrocarbons, such as benzene, toluene or xylene, halogenated hydrocarbons such as methane dichloride or chloroform, or ethers, such as tetrahydrofuran or dioxane. The reaction time can vary but is e.g. between 3 and 24 hours.
De erholdte forbindelser med formel II kan isoleres og renses på i og for seg kpnt måte. Forbindelsene med formel II kan foreligge i to forskjellige krystallformer, og den i det enkelte tilfelle erholdte form avhenger av krystallisasjons-betingelsene f.eks. losningsmidlet. The obtained compounds of formula II can be isolated and purified in the manner described in and of itself. The compounds of formula II can exist in two different crystal forms, and the form obtained in each case depends on the crystallization conditions, e.g. the solvent.
Forbindelsene med formel IV og V er kjente eller kan fremstilles på i og for seg kpnt måte. The compounds of formula IV and V are known or can be prepared in the manner described in and of itself.
Forbindelsene med formel I kan anvendes som legemidler og de virker spesielt apetitthemmende og stimulerer sentralnerve-systemet, slik at de kan finne anvendelse som anoreksia og psykiske styrkemidler. The compounds of formula I can be used as pharmaceuticals and they have a particularly appetite-suppressing effect and stimulate the central nervous system, so that they can find use as anorexia and psychological tonics.
EKSEMPEL 1: 5-(4-klorfenyl)-2,3-dihydro-5-hydroksy-5H- - EXAMPLE 1: 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H- -
imidazo j2, l-ajisoindol. imidazo j2, l-ajisoindole.
a) 3-(4-klorfenyl-3-hydroksy-2-(2-p-toluensulfonylaminoetyl- ftalimidin. En blanding av 43 g N-(2-aminoetyl)-4-metylbenzensulfonamid med formel 51 g trietylamin og 250 ml vannfri toluen bmrbres og tilsettes dråpevis ved rom-temperatur en lbsning av 62 g 2-(4-klorbenzoyl) benzosyreklorid i 100 ml vannfri toluen på en slik måte at den indre temperatur ikke overstiger 35°C. Reaksjonsblåndingen omrbres videre i 6 timer ved romtemperatur, hvoretter det erholdte faststoff frafiltreres og filtratet inndampes i vakuum. Den halvfaste rest behandles med 150 ml 2N saltsyre (ved en temperatur under 30°C), og etter frafiltrering av faststoffet kommer man frem til den i overskriften nevnte forbindels e i en krystallform A med smeltepunkt 81 - 83°C. Ved omkrystalli-sedng av dette material fra toluen erholdes det samme produkt i en krystallform B med smeltepunkt 101 - 102°C. utbyttet 90%. b) 5- (4-klorf enyl) -2, 3-dihydro-5-hydroksy-5H-imidazo [2,1-aJisoindol. (1) 50 g 3-(4-klorfenyl)-3-hydroksy-2-(2-p-toluensulfonyl-aminoetyl)ftalimidin tilsettes til 150 ml 85 vektprosent svovelsyre, idet temperaturen holdes på 15 -25°C. Blandingen omrbres videre i 3 timer ved romtemperatur og fortynnes så med 250 ml vann på en slik måte at temperaturen ikke sdger over 25°C. Den erholdte lbsning ekstraheres med 150 ml metylenklorid, hvoretter de to faser skilles og den vandige fase nøytraliseres med 45% kåliumhydroksydlbsning, idet den indre temperatur holdes på 15 -25°C. Det erholdte faststoff frafiltreres og vaskes to ganger med vann ( hver gang 100 ml ) hvorved den i overskriften nevnte forbindelse erholdes, som etter omkrystallisering fra metanol/metylenklorid (1:1) smelter ved 202 203°C. Utbyttet 85%. a) 3-(4-chlorophenyl-3-hydroxy-2-(2-p-toluenesulfonylaminoethyl- phthalimidine. A mixture of 43 g of N-(2-aminoethyl)-4-methylbenzenesulfonamide with the formula 51 g of triethylamine and 250 ml of anhydrous toluene is stirred and added dropwise at room temperature to a solution of 62 g of 2-(4-chlorobenzoyl)benzoic acid chloride in 100 ml anhydrous toluene in such a way that the internal temperature does not exceed 35°C. The reaction mixture is further stirred for 6 hours at room temperature, after which the solid obtained is filtered off and the filtrate is evaporated in vacuo. The semi-solid residue is treated with 150 ml of 2N hydrochloric acid (at a temperature below 30°C), and after filtering off the solid, the compound mentioned in the title is obtained in a crystal form A with a melting point of 81 - 83°C. By recrystallization of this material from toluene, the same product is obtained in a crystal form B with a melting point of 101 - 102°C. yield 90%. b) 5-(4-Chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-α]isoindole. (1) 50 g of 3-(4-chlorophenyl)-3-hydroxy-2-(2-p-toluenesulfonyl-aminoethyl)phthalimidine is added to 150 ml of 85% by weight sulfuric acid, keeping the temperature at 15-25°C. The mixture is further stirred for 3 hours at room temperature and then diluted with 250 ml of water in such a way that the temperature does not exceed 25°C. The solution obtained is extracted with 150 ml of methylene chloride, after which the two phases are separated and the aqueous phase is neutralized with a 45% potassium hydroxide solution, the internal temperature being kept at 15-25°C. The solid obtained is filtered off and washed twice with water (each time 100 ml), whereby the compound mentioned in the title is obtained, which after recrystallization from methanol/methylene chloride (1:1) melts at 202-203°C. Yield 85%.
(2) Til det samme produkt kommer man ved anvendelse av (2) The same product is obtained by applying
85 vektprosent fosforsyre i stedet for 85 vektprcænt svovelsyre for fremgangsmåten b) (1). 85% by weight phosphoric acid instead of 85% by weight sulfuric acid for method b) (1).
EKSEMPEL 2: 5-(4-klorfenyl)-2,3-dihydro-5-hydroksy-5H- EXAMPLE 2: 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-
imidazo (2,l-ajisoindol.. imidazo (2,l-ajisoindole..
a) 3-(4-klorfenyl)-3-hydroksy-2-(2-p-toluensulfonylamino-etyl)ftalimidin. a) 3-(4-chlorophenyl)-3-hydroxy-2-(2-p-toluenesulfonylamino-ethyl)phthalimidine.
En blanding av 33,3 g 2—(4-klorbenzoyl)benzosyreklorid og A mixture of 33.3 g of 2-(4-chlorobenzoyl)benzoic acid chloride and
100 ml toluen tilsettes i lbpet av 3 minutter under kraftig rbring en blanding av 24,7 g N-(2-amino-etyl)-4-metylbenzen-sulfonamid og 14,-4 g trietylamin i 160 ml toluen. Temperaturen holdes på 50°C. Blandingen omrbres så videre i 20 minutter, fortynnes med 160 ml toluen og oppvarmes på nytt til 50°C. Lbsningen vaskes tre ganger med vann ( hver gang 50 ml), fire ganger med 5% ammoniumhydroksydlbsning (hver gang 50 ml) og på nytt tre ganger med vann (hver gang 50 ml), idet temperaturen holdes på 50°C. Den erholdte toluenlbsning avkjbles til 32°C og filtreres. Filtratet avkjbles til 0°c og filtreres på nytt. De i de enkelte tilfeller erholdte faststoffer forenes, omkrystalliseres fra toluen/kloroform (7:1) og således erholdes den i overskriften nevnte forbindelse med smeltepunkt 81 - 83°C (form A). Utbytte 90%. b) 5-(4-klorfenyl)-2,3-dihydro-5-hydroksy-5H-imidazo-(2, l-a]isoindol. 100 ml of toluene is added over the course of 3 minutes with vigorous stirring to a mixture of 24.7 g of N-(2-amino-ethyl)-4-methylbenzene-sulfonamide and 14.4 g of triethylamine in 160 ml of toluene. The temperature is kept at 50°C. The mixture is then stirred further for 20 minutes, diluted with 160 ml of toluene and reheated to 50°C. The solution is washed three times with water (each time 50 ml), four times with 5% ammonium hydroxide solution (each time 50 ml) and again three times with water (each time 50 ml), keeping the temperature at 50°C. The toluene solution obtained is cooled to 32°C and filtered. The filtrate is cooled to 0°c and filtered again. The solids obtained in the individual cases are combined, recrystallized from toluene/chloroform (7:1) and thus the compound mentioned in the title with melting point 81 - 83°C (form A) is obtained. Yield 90%. b) 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo-(2,1-a]isoindole.
50 g 3-(4-klorfenyl)-3-hydroksy-2-(p-toluensulfonyl-animoetyl)-ftalimidin tilsettes under omrbring i lbpet av 2 minutter til 135 g 96 vektprosent svovelsyre. Temperaturen stiger til omtrent 50°C og holdes i 1,5 time på denne verdi. Den erholdte lbsning avkjbles til 30°C og tilsettes dråpevis under blanding og avkjbling til 250 ml vann. Under denne fortynning utgjor temperaturen omtrent 40°C. Den erholdte vandige lbsning omrbres så i 30 minutter ved 10°C og tilsettes deretter dråpevis 220 50 g of 3-(4-chlorophenyl)-3-hydroxy-2-(p-toluenesulfonyl-animoethyl)-phthalimidine are added with stirring over a period of 2 minutes to 135 g of 96% by weight sulfuric acid. The temperature rises to approximately 50°C and is held at this value for 1.5 hours. The resulting solution is cooled to 30°C and added dropwise while mixing and cooling to 250 ml of water. During this dilution, the temperature is approximately 40°C. The obtained aqueous solution is then stirred for 30 minutes at 10°C and then added dropwise 220
ml 28 - 30% ammoniakk, idet temperaturen holdes på 25°C. Den erholdte blanding omrbres i en halv time og filtreres så under vakuum. Filterkaken vaskes med vann og deretter med aceton og ml 28 - 30% ammonia, keeping the temperature at 25°C. The resulting mixture is stirred for half an hour and then filtered under vacuum. The filter cake is washed with water and then with acetone and
etter orrikrystallisering fra dimetylformomid kommer man frem til den i overskriften nevnte forbindelse med smeltepunkt 201 - 203°C. Utbytte 85%. after oricrystallization from dimethylformomide, the compound mentioned in the title is obtained with a melting point of 201 - 203°C. Yield 85%.
EKSEMPEL 3: 5-(4-klorfenyl)-2,3-dihydro-5-hydroksy-5H-imidazo [2, l-ajisoindol. EXAMPLE 3: 5-(4-Chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-azisoindole.
a) På analog måte som i eksempel la) eller 2a), men hvor man i stedet for N-(2-aminoetyl)-4-metylbenzensulfonamid anvender a) In an analogous way as in example la) or 2a), but where instead of N-(2-aminoethyl)-4-methylbenzenesulfonamide is used
omtrent ekvivalente mengder av henhv. approximately equivalent amounts of
N-(2-aminoetyl)metylsulfonamid, N-(2-aminoetyl)benzensulfonamid, N-(2-aminoetyl)-3,4-dimetylbenzensulfonamid, N-(2-aminoetyl)-2,5-dimetylbenzensulfonamid eller N-(2-aminoethyl)methylsulfonamide, N-(2-aminoethyl)benzenesulfonamide, N-(2-aminoethyl)-3,4-dimethylbenzenesulfonamide, N-(2-aminoethyl)-2,5-dimethylbenzenesulfonamide or
N-(2-aminoetyl)-4-klorbenzensulfonamid, N-(2-aminoethyl)-4-chlorobenzenesulfonamide,
erholdes henhv. obtained respectively
A 3-(4-klorfenyl)-3-hydroksy-2-(2-metylsulfohylaminoetyl)-ftalimidin, A 3-(4-chlorophenyl)-3-hydroxy-2-(2-methylsulfohylaminoethyl)-phthalimidine,
B 2-(2-benzensulfonylaminoetyl)-3-(4-klorfenyl)-3-hydroksy-ftalimidin, smeltepunkt 156 - 157°C. (omkrystallisering fra kloroform), B 2-(2-benzenesulfonylaminoethyl)-3-(4-chlorophenyl)-3-hydroxyphthalimidine, melting point 156 - 157°C. (recrystallization from chloroform),
C 3- (4-klorf enyl) -3-hydroksy-2- [ l-(3, 4-dimetylbenzen)' C 3-(4-chlorophenyl)-3-hydroxy-2-[1-(3,4-dimethylbenzene)'
sulfonylaminoetylj ftalimidin, sulfonylaminoethyl phthalimidine,
D 3-(4-klorfenyl)-3-hydroksy-2-[ 2-(2,5-dimetylbenzen) sulfonylaminoetyljftalimidin, smeltepunkt 86 -90°c D 3-(4-chlorophenyl)-3-hydroxy-2-[ 2-(2,5-dimethylbenzene) sulfonylaminoethylphthalimidine, melting point 86 -90°c
(omkrystallisering fra toluen), eller (recrystallization from toluene), or
E 2-(4-klorbenzensulfonylaminoetyl)-3-(4-klorfenyl)-3-hydroksyftalimidin,smeltepunkt 147 - 148°C(omkrystallisering fra toluen). E 2-(4-chlorobenzenesulfonylaminoethyl)-3-(4-chlorophenyl)-3-hydroxyphthalimidine, melting point 147 - 148°C (recrystallization from toluene).
b) På analog måte som eks. lb (1), lb (2) eller 2b, men under anvendelse av omtrent ekvivalente mengder av forbindelsene b) In an analogous way as e.g. lb (1), lb (2) or 2b, but using approximately equivalent amounts of the compounds
A, B, C, D eller E fra den ovenstående fremgangsmåte a) istedet for 3- (4-klorf enyl)-3-hydroksy-2- (2-p-toluensulfonyl-aminoetyl)ftalimidin, erhddes 5-(4-klorfenyl)-2,3-dihydro-5-hydroksy-5H-imidazo^2,l-ajisoindol med et smeltepunkt 201 - 203°C. A, B, C, D or E from the above method a) instead of 3-(4-chlorophenyl)-3-hydroxy-2-(2-p-toluenesulfonyl-aminoethyl)phthalimidine, 5-(4-chlorophenyl) is obtained )-2,3-dihydro-5-hydroxy-5H-imidazo^2,1-azisoindole with a melting point of 201 - 203°C.
EKSEMPEL 4; EXAMPLE 4;
a) På analog måte med eksempel la eller 2a, men hvor man istedet for 2-(4-klorbenzoyl)benzosyreklorid anvender omtrent a) In an analogous manner to example la or 2a, but where instead of 2-(4-chlorobenzoyl)benzoic acid chloride approximately
ekvivalente mengder av equivalent amounts of
2-(3, 4-diklorbenzoyl)benzosyreklorid, 2-(3,4-dichlorobenzoyl)benzoic acid chloride,
2-(benzoyl)benzosyreklorid eller 2-(benzoyl)benzoic acid chloride or
2-(3-fluorbenzoyl)benzosyrexlorid, 2-(3-fluorobenzoyl)benzoic acid chloride,
erholdes henhv. obtained respectively
F 3- (3>-4-diklorf enyl) -3-hydroksy-2- (2-p-toluensulf onylamino-etyl) f talimidin, smeltepunkt 96 - 98°C, utbytte 75%. F 3-(3>-4-dichlorophenyl)-3-hydroxy-2-(2-p-toluenesulfonylamino-ethyl)phthalimidine, melting point 96 - 98°C, yield 75%.
G 3-hydroKsy-3-fenyl-2-(2-p-toluensulfonylaminoetyl)-ftalimidin, smeltepunkt 155 - 157°C, utbytte 96%. G 3-hydroxy-3-phenyl-2-(2-p-toluenesulfonylaminoethyl)-phthalimidine, melting point 155 - 157°C, yield 96%.
H 3-(3-fluorfenyl)-3-hydroksy-2-(2-p-toluensulfonylaminoetyl)-ftalimidin, smeltepunkt 116 - 119°C, utbytte 68%. H 3-(3-fluorophenyl)-3-hydroxy-2-(2-p-toluenesulfonylaminoethyl)-phthalimidine, melting point 116 - 119°C, yield 68%.
b) På analog måte som eks. lb (1), lb (2) eller 2b, men under anvendelse av omtrent ekvivalente mengder av forbindelsene b) In an analogous way as e.g. lb (1), lb (2) or 2b, but using approximately equivalent amounts of the compounds
F, G eller H fra den foregående fremgangsmåte a) istedet for 3-(4-klorfenyl)-3-hydroksy-2-(2-p-toluensulfonylaminoetyl)-ftalimidin, erholdes henhv. F, G or H from the preceding method a) instead of 3-(4-chlorophenyl)-3-hydroxy-2-(2-p-toluenesulfonylaminoethyl)-phthalimidine, is obtained respectively.
5-(3,4-diklorfenyl)-2,3-dihydro-5-hydroksy-5H- 5-(3,4-dichlorophenyl)-2,3-dihydro-5-hydroxy-5H-
imidazo { 2, l-ajisoindol, smeltepunkt .200 - 201°C. imidazo { 2, l-ajisoindole, melting point .200 - 201°C.
(Omkrystallisering fra metanol/tetrahydrofuran (1:1)). Utbytte 30%. (Recrystallization from methanol/tetrahydrofuran (1:1)). Dividend 30%.
2, 3-dihydro-5-hydroksy-5-f enyl-5H-imidazo [2,1-aJJ-isoindol, smeltepunkt 197 - 199°C, utbytte 40%. 2, 3-dihydro-5-hydroxy-5-phenyl-5H-imidazo [2,1-aJJ-isoindole, melting point 197 - 199°C, yield 40%.
5-(3-fluorfenyl)-2, 3-dihydro-5-hydroksy-5H-imidazo-( 2, l-ajisoindol, smeittepunkt 200 - 203°C, (omkrystallisering fra metanol/tetrahydrofuran (1:1)). 5-(3-Fluorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo-(2,1-azisoindole, melting point 200 - 203°C, (recrystallization from methanol/tetrahydrofuran (1:1)).
Claims (3)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US3277270A | 1970-04-28 | 1970-04-28 | |
US9250370A | 1970-11-24 | 1970-11-24 | |
US11588471A | 1971-02-16 | 1971-02-16 |
Publications (2)
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NO132098B true NO132098B (en) | 1975-06-09 |
NO132098C NO132098C (en) | 1975-09-17 |
Family
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Application Number | Title | Priority Date | Filing Date |
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NO154771A NO132098C (en) | 1970-04-28 | 1971-04-26 |
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AT (1) | AT323729B (en) |
BE (1) | BE766294A (en) |
CA (1) | CA952114A (en) |
CH (1) | CH548406A (en) |
CS (1) | CS181208B2 (en) |
DD (1) | DD96944A5 (en) |
DE (1) | DE2120263A1 (en) |
ES (2) | ES390610A1 (en) |
FI (1) | FI52727C (en) |
FR (2) | FR2086411B1 (en) |
GB (1) | GB1355074A (en) |
NL (1) | NL7105665A (en) |
NO (1) | NO132098C (en) |
SU (1) | SU442598A3 (en) |
YU (1) | YU34697B (en) |
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US3454592A (en) * | 1963-12-18 | 1969-07-08 | Sandoz Ag | 2-(omega-hydroxyalkyl)-3-hydroxy-3-phenylisoindolones |
-
1971
- 1971-03-26 YU YU103671A patent/YU34697B/en unknown
- 1971-04-16 CH CH556071A patent/CH548406A/en not_active IP Right Cessation
- 1971-04-26 FR FR7114732A patent/FR2086411B1/fr not_active Expired
- 1971-04-26 NO NO154771A patent/NO132098C/no unknown
- 1971-04-26 GB GB1133471A patent/GB1355074A/en not_active Expired
- 1971-04-26 ES ES390610A patent/ES390610A1/en not_active Expired
- 1971-04-26 CA CA111,339A patent/CA952114A/en not_active Expired
- 1971-04-26 DE DE19712120263 patent/DE2120263A1/en active Pending
- 1971-04-26 BE BE766294A patent/BE766294A/en unknown
- 1971-04-27 NL NL7105665A patent/NL7105665A/xx unknown
- 1971-04-27 SU SU1651060A patent/SU442598A3/en active
- 1971-04-27 CS CS303571A patent/CS181208B2/en unknown
- 1971-04-27 DD DD16168971A patent/DD96944A5/xx unknown
- 1971-04-27 FI FI116671A patent/FI52727C/en active
- 1971-04-27 AT AT362571A patent/AT323729B/en not_active IP Right Cessation
-
1972
- 1972-01-28 FR FR7202872A patent/FR2120188B1/fr not_active Expired
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1973
- 1973-05-25 ES ES415167A patent/ES415167A1/en not_active Expired
Also Published As
Publication number | Publication date |
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DE2120263A1 (en) | 1971-11-18 |
CS181208B2 (en) | 1978-03-31 |
FR2086411A1 (en) | 1971-12-31 |
FR2086411B1 (en) | 1973-06-08 |
CH548406A (en) | 1974-04-30 |
NO132098C (en) | 1975-09-17 |
NL7105665A (en) | 1971-11-01 |
SU442598A3 (en) | 1974-09-05 |
YU103671A (en) | 1979-07-10 |
FI52727B (en) | 1977-08-01 |
AT323729B (en) | 1975-07-25 |
DD96944A5 (en) | 1973-04-12 |
FR2120188A1 (en) | 1972-08-11 |
CA952114A (en) | 1974-07-30 |
ES390610A1 (en) | 1974-06-16 |
ES415167A1 (en) | 1976-05-16 |
YU34697B (en) | 1979-12-31 |
FI52727C (en) | 1977-11-10 |
BE766294A (en) | 1971-10-26 |
FR2120188B1 (en) | 1977-12-23 |
GB1355074A (en) | 1974-06-05 |
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