NO300973B1 - Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3- [2- (2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one - Google Patents
Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3- [2- (2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one Download PDFInfo
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- NO300973B1 NO300973B1 NO930887A NO930887A NO300973B1 NO 300973 B1 NO300973 B1 NO 300973B1 NO 930887 A NO930887 A NO 930887A NO 930887 A NO930887 A NO 930887A NO 300973 B1 NO300973 B1 NO 300973B1
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- methyl
- imidazol
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- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title description 7
- -1 2-methyl-1H-imidazol-1-yl Chemical group 0.000 title description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 239000012429 reaction media Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- OTAOHVAQDLTDBP-UHFFFAOYSA-N 4-(3-ethoxycarbonyl-1-methylindol-2-yl)-2-methylidenebutanoic acid Chemical compound C=C(C(=O)O)CCC=1N(C2=CC=CC=C2C=1C(=O)OCC)C OTAOHVAQDLTDBP-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- AMLYRCOEFHJSFS-UHFFFAOYSA-N carbazol-1-one Chemical compound C1=CC=C2C3=CC=CC(=O)C3=NC2=C1 AMLYRCOEFHJSFS-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZFPUZZSDVPSGFJ-UHFFFAOYSA-N 2-(3-carboxybut-3-enyl)-1-methylindole-3-carboxylic acid Chemical compound C=C(C(=O)O)CCC=1N(C2=CC=CC=C2C=1C(=O)O)C ZFPUZZSDVPSGFJ-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- GUXGFEPITRBHDB-UHFFFAOYSA-N 2-[(2-methylimidazol-1-yl)methyl]-4-(1-methylindol-2-yl)butanoic acid Chemical compound CC=1N(C=CN=1)CC(C(=O)O)CCC=1N(C2=CC=CC=C2C=1)C GUXGFEPITRBHDB-UHFFFAOYSA-N 0.000 description 1
- 102000035037 5-HT3 receptors Human genes 0.000 description 1
- 108091005477 5-HT3 receptors Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- RQRUAENQOVZHNW-UHFFFAOYSA-N ethyl 1,2-dimethylindole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OCC)=C(C)N(C)C2=C1 RQRUAENQOVZHNW-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Chemical group 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av l,2,3,9-tetrahydro-9-metyl-3-[ (2-metyl-lH-imidazol-l-yl)metyl]-4H-karbazol-4-on med formelen I. The present invention relates to a method for the production of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one with the formula IN.
En syntetisk forbindelse som selektivt motvirker 5-HT3 reseptorene og har interessante egenskaper som antiemetikum i kjemoterapien, samt ved behandling av hodepine, schizofreni, angst, fedme og manier. A synthetic compound that selectively counteracts the 5-HT3 receptors and has interesting properties as an antiemetic in chemotherapy, as well as in the treatment of headaches, schizophrenia, anxiety, obesity and mania.
Patentet ES 548430 beskriver fremstillingen av 1,2,3,9-tetrahydro-9-metyl-3-[ (2-metyl-lH-imidazol-l-yl)metyl] -4H-karbazol-4-on ved omsetning av et karbazolon med formelen III med 2-metylimidazol. The patent ES 548430 describes the preparation of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one by reacting a carbazolone of the formula III with 2-methylimidazole.
hvor Y er et metylenradikal eller et halogenmetylradikal. where Y is a methylene radical or a halomethyl radical.
Patentet ES 556101 beskriver fremstillingen av 1,2,3,9-tetrahydro-9-metyl-3-[ (2-metyl-lH-imidazol-l-yl)metyl]-4H-karbazol-4-on ved oksidasjon av et karbazol med formelen IV. The patent ES 556101 describes the production of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one by oxidation of a carbazole of the formula IV.
hvor A er et hydrogenatom eller et hydroksyradikal. where A is a hydrogen atom or a hydroxy radical.
Patentet ES 539852 beskriver fremstillingen av 1,2,3,9-tetrahydro-9-metyl-3-[ (2-metyl-lH-imidazol-l-yl)metyl]-4H-karbazol-4-on ved alkylerinq av et karbazolon med formelen V. The patent ES 539852 describes the production of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one by alkylating a carbazolone of the formula V.
hvor R]_ og/eller R2 er et hydrogenatom. where R]_ and/or R 2 is a hydrogen atom.
Patentet ES 2 000 935 beskriver fremstillingen av 1,2,3,9-t e t r ahy dr o - 9-mety1-3-[(2-mety1-1H-imida z o1-1-y1)mety1]-4 H - karbazol-4-on ved syklisering av et fenylhydrasinderivat med formelen VI. The patent ES 2 000 935 describes the production of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazo1-1-y1)methyl]-4H-carbazole -4-one by cyclization of a phenylhydrazine derivative of the formula VI.
Patentet ES 2000936 beskriver fremstillingen av 1,2,3,9-tetrahydro-9-metyl-3- [ (2-metyl-lH-imidazol-l-yl) metyl] -4H-karbazol-4-on ved syklisering av et anilinderivat med formelen The patent ES 2000936 describes the production of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one by cyclization of a aniline derivative with the formula
VII. VII.
hvor X er et hydrogenatom eller et halogen. where X is a hydrogen atom or a halogen.
Den foreliggende oppfinnelse beskriver og krever en ny fremgangsmåte for fremstilling av 1,2,3,9-tetrahydro-9-metyl-3-[(2-metyl-lH-imidazol-l-yl)metyl]-4H-karbazol-4-on med formelen The present invention describes and requires a new process for the production of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazole-4 -on with the formula
I. IN.
som omfatter syklisering av 2-[(2-metyl-lH-imidazol-l-yl)metyl] -4-(l-metylindol-2-yl]smørsyre med formelen II. which comprises the cyclization of 2-[(2-methyl-1H-imidazol-1-yl)methyl]-4-(1-methylindol-2-yl)butyric acid of the formula II.
under Friedel Crafts<1> acyleringsreaksjonsbetingelser ved aktivering av karboksylgruppen ved hjelp av sur katalyse i et egnet løsningsmiddelmedium og videre isolering av det ønskede produkt på konvensjonell måte. under Friedel Crafts<1> acylation reaction conditions by activation of the carboxyl group by means of acid catalysis in a suitable solvent medium and further isolation of the desired product in a conventional manner.
Aktiveringen av karboksylsyren utføres ved omdanning av den til et acylhalogenid eller til et blandet trifluoreddiksyre-, metansulfonsyre- eller "triflic"anhydrid, fortrinnsvis til et blandet triflureddiksyreanhydrid. The activation of the carboxylic acid is carried out by converting it to an acyl halide or to a mixed trifluoroacetic acid, methanesulfonic acid or "triflic" anhydride, preferably to a mixed trifluoroacetic anhydride.
Den sure katalysator kan være en uorganisk syre såsom saltsyre, svovelsyre eller fosforsyre, eller en Lewissyre, såsom bor trifluorid, sinkklorid eller aluminiumtriklorid, fortrinnsvis fosforsyre. The acid catalyst can be an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or a Lewis acid, such as boron trifluoride, zinc chloride or aluminum trichloride, preferably phosphoric acid.
Reaksjonen gjennomføres i et aprotisk organisk løsningsmiddel såsom kloroform, diklormetan, dikloretan, eter, tetrahydrofuran eller acetonitril, fortrinnsvis acetonitril. The reaction is carried out in an aprotic organic solvent such as chloroform, dichloromethane, dichloroethane, ether, tetrahydrofuran or acetonitrile, preferably acetonitrile.
Sykliseringsreaksjonen kan passende gjennomføres ved temperaturer i området fra -60°C til +50°C, fortrinnsvis ved 0°C. The cyclization reaction can conveniently be carried out at temperatures in the range from -60°C to +50°C, preferably at 0°C.
Etter fullstendig omsetning blir det ønskede produkt isolert på konvensjonell måte og omkrystallisert fra et organisk løsnings-middel, fortrinnsvis metanol, og gir kjemisk rent 1,2,3,9-tetrahydro-9-metyl-3-[(2-metyl-lH-imidazol-l-yl)metyl]-4H-karbazol-4-on. After complete reaction, the desired product is isolated in a conventional manner and recrystallized from an organic solvent, preferably methanol, giving chemically pure 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H -imidazol-1-yl)methyl]-4H-carbazol-4-one.
Forbindelsen med formelen II kan fremstilles ved en omsetning av 2-metylen-4-(3-karboksy-l-metylindol-2-yl) smørsyre med formelen VIII med 2-metylimidazol. The compound of formula II can be prepared by reacting 2-methylene-4-(3-carboxyl-1-methylindol-2-yl)butyric acid of formula VIII with 2-methylimidazole.
Omsetningen gjennomføres beleilig ved temperaturer i området fra 100°C til 200°C, fortrinnsvis ved 150°C. The reaction is conveniently carried out at temperatures in the range from 100°C to 200°C, preferably at 150°C.
Omsetningen utføres i et høytkokende løsningsmiddel såsom toluen, xylen eller brombenzen, eller blandinger derav, eller uten løsningsmiddel, fortrinnsvis uten løsningsmiddel. The reaction is carried out in a high-boiling solvent such as toluene, xylene or bromobenzene, or mixtures thereof, or without solvent, preferably without solvent.
Etter fullstendig omsetning blir det ønskede produkt isolert på konvensjonell måte og omkrystallisert fra et organisk løsnings-middel såsom metanol, toluen, dimetoksyetan eller metoksy-etanol, fortrinnsvis dimetoksyetan. After complete reaction, the desired product is isolated in a conventional manner and recrystallized from an organic solvent such as methanol, toluene, dimethoxyethane or methoxyethanol, preferably dimethoxyethane.
Disyren med formel VIII fremstilles ved hydrolyse av 2-metylen-4-(3-etoksykarbonyl-l-metylindol-2-yl) smørsyre med formelen IX. The diacid with formula VIII is prepared by hydrolysis of 2-methylene-4-(3-ethoxycarbonyl-1-methylindol-2-yl) butyric acid with formula IX.
som i sin tur kan fremstilles ved omsetning av etyl 1,2-dimetylindol-3-karboksylat-anionet med formelen X fremstilt ifølge John E. Macor, Kewin Ryan, Michael E. Newman i J. Org. Chem. 54. 4785 (1989) fra a-(brommetylakrylsyre) med formelen XI. which in turn can be prepared by reacting the ethyl 1,2-dimethylindole-3-carboxylate anion with the formula X prepared according to John E. Macor, Kewin Ryan, Michael E. Newman in J. Org. Chem. 54. 4785 (1989) from α-(bromomethylacrylic acid) of the formula XI.
Fremgangsmåten beskrevet i den foreliggende beskrivelse skal ytterligere detaljeres gjennom de følgende eksempler. The procedure described in the present description shall be further detailed through the following examples.
EKSEMPEL 1 EXAMPLE 1
2- metylen- 4-( 3- etoksykarbonyl- l- metylindol- 2- vl) smørsyre Til en løsning av litiumsaltet fremstilt fra 4,34 g (20 mmol) av etyl 1,2-dimetylindol-3-karboksylat i 150 ml tetrahydrofuran, holdt ved -60°C, blir tilsatt i løpet av 10 s en løsning av 4,98 g (30 mmol) av a-(brommetylakrylsyre) i 20 ml tetrahydrofuran. Temperaturen bør ikke overskride -50°C. Etter 2 h omrøring ved -60°C helles løsningen over i en blanding omfattende 400 g is, 15 ml konsentrert saltsyre, og 2 00 ml etylacetat. Etter fordeling blir fasene adskilt, og det vandige sjikt ekstraheres med etylacetat (2 x 2 00 ml). De samlede 2- methylene- 4-( 3- ethoxycarbonyl- 1- methylindole- 2- vl) butyric acid To a solution of the lithium salt prepared from 4.34 g (20 mmol) of ethyl 1,2-dimethylindole-3-carboxylate in 150 ml of tetrahydrofuran , kept at -60°C, a solution of 4.98 g (30 mmol) of α-(bromomethylacrylic acid) in 20 ml of tetrahydrofuran is added over 10 s. The temperature should not exceed -50°C. After stirring for 2 hours at -60°C, the solution is poured into a mixture comprising 400 g of ice, 15 ml of concentrated hydrochloric acid and 200 ml of ethyl acetate. After partitioning, the phases are separated, and the aqueous layer is extracted with ethyl acetate (2 x 200 ml). They collected
organiske ekstrakter tørkes over MgS04 og inndampes deretter. Det resulterende faste stoff omkrystalliseres fra toluen og deretter fra metanol, hvorved det oppnås 3,0 g (50 %) av den analyttisk rene tittelforbindelse i form av et hvitt fast stoff. organic extracts are dried over MgSO4 and then evaporated. The resulting solid is recrystallized from toluene and then from methanol, whereby 3.0 g (50%) of the analytically pure title compound is obtained as a white solid.
sm.p. 138°C-140°C sm.p. 138°C-140°C
1- H-NMRS (CDCI3) : 1,46 (t, J=7,l, 3H, -CH2) , 2,63- 1- H-NMRS (CDCl 3 ) : 1.46 (t, J=7.1, 3H, -CH 2 ), 2.63-
2,71 (m, 2H, -CH2-C=C), 3,36-3,48 (m, 2.71 (m, 2H, -CH2-C=C), 3.36-3.48 (m,
2H, indole-CH2) 3,78 (s, 3H, N-CH3), 2H, indole-CH2) 3.78 (s, 3H, N-CH3),
4,41 (q, J = 7,1, 2H, -CH2-CH3), 5,81 4.41 (q, J = 7.1, 2H, -CH2-CH3), 5.81
(d, J = 1,2, 1H, -C=CH), 6,37 (d, J = (d, J = 1.2, 1H, -C=CH), 6.37 (d, J =
1,2, 1H, -C=CH), 7,15-7,40 (m, 3H, aromatisk), 8,10-8,20 (m, 1H, aromatisk). 1.2, 1H, -C=CH), 7.15-7.40 (m, 3H, aromatic), 8.10-8.20 (m, 1H, aromatic).
EKSEMPEL 2 EXAMPLE 2
2- Metylen- 4-( 3- karboksv- l- metvlindol- 2- yl)- smørsyre Til en oppslemming av 5,7 g (18,9 mmol) av forbindelsen fra eksempel 1 i 15 ml metanol og 15 ml vann tilsettes 19 g kaliumhydroksid, og den resulterende blanding oppvarmes til tilbakeløp i 30 min. Deretter helles den over i en blanding av 200 g is og 200 ml vann, og surgjøres med 30 ml konsentrert saltsyre. Produktet gjenvinnes ved filtrering og slemmes opp i 250 ml toluen, 100 ml derav blir avdestillert, og etter avkjøling ved 20°C og ytterligere filtrering oppnås 4,5 g (87 %) av den analyttisk rene tittelf orbindelse som et hvitt fast stoff. 2- Methylene- 4-(3-carboxyl-1-methyllindol-2-yl)-butyric acid To a slurry of 5.7 g (18.9 mmol) of the compound from example 1 in 15 ml of methanol and 15 ml of water is added 19 g of potassium hydroxide, and the resulting mixture is heated to reflux for 30 min. It is then poured into a mixture of 200 g of ice and 200 ml of water, and acidified with 30 ml of concentrated hydrochloric acid. The product is recovered by filtration and slurried in 250 ml of toluene, 100 ml of which is distilled off, and after cooling at 20°C and further filtration, 4.5 g (87%) of the analytically pure title compound is obtained as a white solid.
sm.p. 194°C-196°C sm.p. 194°C-196°C
^■H-NMRiS (CDCI3) : 2,40-2,60 (m, 2H, indol-CH2-CH2~) , ^■H-NMRiS (CDCl3) : 2.40-2.60 (m, 2H, indole-CH2-CH2~) ,
3,20-3,50 (m, 2H, indol-CH2-CH2-), 3.20-3.50 (m, 2H, indole-CH2-CH2-),
3,77 (s, N-CH3), 5,59 (d, J = 1,5, 3.77 (s, N-CH3), 5.59 (d, J = 1.5,
1H, -C=C-H), 6,07 (d, J = 1,5, 1H, 1H, -C=C-H), 6.07 (d, J = 1.5, 1H,
-C=C-H), 7,10-7,25 (m, 2H, aromatisk), 7,46-7,54 (m, 1H, aromatisk), 7,96-8,05 -C=C-H), 7.10-7.25 (m, 2H, aromatic), 7.46-7.54 (m, 1H, aromatic), 7.96-8.05
(m, 1H, aromatisk). (m, 1H, aromatic).
EKSEMPEL 3 EXAMPLE 3
2- r f2- metvl- lH- imidazol- l- yl1- 4- fl- metylindol- 2- yl) smørsyre En blanding av 2,73 g (10 mmol) av forbindelsen fra eksempel 2 og 2,46 g (30 mmol) av 2-metylimidazol blir oppvarmet ved 160°C i 2 min. Etter avkjøling til romtemperatur løses blandingen i kloroform, påsettes på en silisiumdioksid kromatografikolonne og elueres med 70:30 metylenklorid/metanol. På denne måte fremstilles 2,21 g (71 %) av tittelforbindelsen som et analyttisk rent gulaktig fast stoff. 2- r f2- metvl- 1H- imidazol- 1- yl1- 4- fl- methylindol- 2- yl) butyric acid A mixture of 2.73 g (10 mmol) of the compound from Example 2 and 2.46 g (30 mmol ) of 2-methylimidazole is heated at 160°C for 2 min. After cooling to room temperature, the mixture is dissolved in chloroform, applied to a silicon dioxide chromatography column and eluted with 70:30 methylene chloride/methanol. In this way, 2.21 g (71%) of the title compound are prepared as an analytically pure yellowish solid.
sm.p. 198°C-199°C sm.p. 198°C-199°C
<1>H-NMR5(DMS0): 1,65-2,05 (m, 2H, indol-CH2-CH2-), <1>H-NMR5(DMS0): 1.65-2.05 (m, 2H, indole-CH2-CH2-),
2,27 (S, 3H, C-CH3), 2,65-2,95 (m, 3H, indol-CH2- og -HC-COOH), 3,63 (s, 2.27 (S, 3H, C-CH3), 2.65-2.95 (m, 3H, indole-CH2- and -HC-COOH), 3.63 (s,
3H, N-CH3), 3,95-4,25 (m, 2H, imidazol-CH2-), 6,15 (s, 1H, indol-H), 3H, N-CH3), 3.95-4.25 (m, 2H, imidazole-CH2-), 6.15 (s, 1H, indole-H),
6,79 (d, J = 1,6, 1H, imidazol-H), 6.79 (d, J = 1.6, 1H, imidazole-H),
6,90-7,10 (m, 3H) inkludert ved 7,06 6.90-7.10 (m, 3H) included at 7.06
(d, J = 1,6, 1H, imidazol-H), 7,30- (d, J = 1.6, 1H, imidazole-H), 7.30-
7,45 (m, 2H, aromatisk). 7.45 (m, 2H, aromatic).
EKSEMPEL 4 EXAMPLE 4
1. 2. 3, 9- Tetrahvdro- 9- metvl- 3 f f2- metyl- lH- imidazol- l- yl)- metyl1-4H- karbazol- 4- on 1. 2. 3, 9- Tetrahydro- 9- methyl- 3 f f 2- methyl- 1H- imidazol- 1- yl)- methyl 1-4H- carbazol- 4- one
Til en oppslemming av 311 mg (1 mmol) av forbindelsen fra eksempel 3 i 10 ml acetonitril tilsettes 28 ul (0,28 mmol) 85 % fosforsyre. Reaksjonsblandingen kjøles ned til 0°C, og 353 /il (2,5 mmol) trifluoreddiksyreanhydrid tilsettes dråpevis. Etter 15 min helles den over i en blanding av 50 g is og 50 ml natriumhydrogenkarbonatmettet løsning, og ekstraheres med metylenklorid (3 x 10 ml). De samlede organiske ekstrakter tørkes (MgS04) og inndampes. Den faste rest omkrystalliseres fra metanol og gir 160 mg (55 %) av tittelforbindelsen som et analyttisk rent hvitt fast stoff. To a slurry of 311 mg (1 mmol) of the compound from example 3 in 10 ml of acetonitrile is added 28 ul (0.28 mmol) of 85% phosphoric acid. The reaction mixture is cooled to 0°C, and 353 µl (2.5 mmol) of trifluoroacetic anhydride is added dropwise. After 15 min, it is poured into a mixture of 50 g of ice and 50 ml of saturated sodium bicarbonate solution, and extracted with methylene chloride (3 x 10 ml). The combined organic extracts are dried (MgSO4) and evaporated. The solid residue is recrystallized from methanol to give 160 mg (55%) of the title compound as an analytically pure white solid.
sm.p. 227°C-228,5°C sm.p. 227°C-228.5°C
1-H-NMRcS (CDCI3) : 1,70-2,05 (m, 1H, H-C(2)), 2,10-2,30 1-H-NMR cS (CDCl 3 ) : 1.70-2.05 (m, 1H, H-C(2)), 2.10-2.30
(m, 1H, H-C(2)), 2,45 (s, 3H, CH3), 2,75-3,15 (m, 3H, H-C(l) ogH-C(3)), 3,72 (s, 3H, N-CH3), 4,10 (dd, J= 8,15, 1H, N-CH2), 4,70 (dd, J = 4,15, 1H, N-CH2), 6,85-7,05 (m, 2H, aromatisk), 7,20-7,40 (m, 3H, imidazol, H og aromatisk), 8,20-8,30 (m, 1H, aromatisk). (m, 1H, H-C(2)), 2.45 (s, 3H, CH3), 2.75-3.15 (m, 3H, H-C(1) and H-C(3)), 3.72 ( s, 3H, N-CH3), 4.10 (dd, J= 8.15, 1H, N-CH2), 4.70 (dd, J = 4.15, 1H, N-CH2), 6.85 -7.05 (m, 2H, aromatic), 7.20-7.40 (m, 3H, imidazole, H and aromatic), 8.20-8.30 (m, 1H, aromatic).
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES09200552A ES2043535B1 (en) | 1992-03-13 | 1992-03-13 | PROCEDURE FOR OBTAINING 1,2,3,9-TETRAHYDRO-9-METHYL-3- (2-METHYL-1H-IMIDAZOL-1-IL) METHYL * -4H-CARBAZOL-4-ONA. |
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| NO930887D0 NO930887D0 (en) | 1993-03-11 |
| NO930887L NO930887L (en) | 1993-09-14 |
| NO300973B1 true NO300973B1 (en) | 1997-08-25 |
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| NO930887A NO300973B1 (en) | 1992-03-13 | 1993-03-11 | Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3- [2- (2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one |
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| KR (1) | KR100277414B1 (en) |
| AR (1) | AR248019A1 (en) |
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| CZ (1) | CZ281753B6 (en) |
| EG (1) | EG20262A (en) |
| ES (1) | ES2043535B1 (en) |
| FI (1) | FI105098B (en) |
| GR (1) | GR930100094A (en) |
| HU (1) | HU210775B (en) |
| IS (1) | IS1783B (en) |
| NO (1) | NO300973B1 (en) |
| PL (1) | PL170751B1 (en) |
| PT (1) | PT101216B (en) |
| RU (1) | RU2109741C1 (en) |
| SK (1) | SK278786B6 (en) |
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| KR100368895B1 (en) * | 2000-03-30 | 2003-01-24 | 하나제약 주식회사 | A process for preparing 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one |
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| NL190373C (en) * | 1984-01-25 | 1994-02-01 | Glaxo Group Ltd | A 3-SUBSTITUTED AMINOMETHYL-2,3-DIHYDRO-4 (1H) -CARBAZOLONE, PROCESS FOR ITS PREPARATION, AND A PHARMACEUTICAL PREPARATION. |
| GB8518742D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
| GB8518743D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Heterocyclic compounds |
| GB8518741D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
| GB8617994D0 (en) * | 1986-07-23 | 1986-08-28 | Glaxo Group Ltd | Heterocyclic compounds |
-
1992
- 1992-03-13 ES ES09200552A patent/ES2043535B1/en not_active Expired - Fee Related
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- 1993-03-10 EG EG14493A patent/EG20262A/en active
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| RU2109741C1 (en) | 1998-04-27 |
| FI105098B (en) | 2000-06-15 |
| SK16993A3 (en) | 1993-11-10 |
| CZ281753B6 (en) | 1997-01-15 |
| EG20262A (en) | 1998-05-31 |
| IS3985A (en) | 1993-09-14 |
| NO930887L (en) | 1993-09-14 |
| AR248019A1 (en) | 1995-05-31 |
| PT101216A (en) | 1994-03-31 |
| ATA48793A (en) | 1996-12-15 |
| KR100277414B1 (en) | 2001-01-15 |
| KR930019665A (en) | 1993-10-18 |
| NO930887D0 (en) | 1993-03-11 |
| SK278786B6 (en) | 1998-02-04 |
| IS1783B (en) | 2001-10-22 |
| FI931104A (en) | 1993-09-14 |
| AT402730B (en) | 1997-08-25 |
| PT101216B (en) | 1999-10-29 |
| CZ39693A3 (en) | 1994-01-19 |
| HU210775B (en) | 1995-07-28 |
| ES2043535B1 (en) | 1994-08-01 |
| HUT64537A (en) | 1994-01-28 |
| HU9300718D0 (en) | 1993-05-28 |
| ES2043535A1 (en) | 1993-12-16 |
| PL170751B1 (en) | 1997-01-31 |
| FI931104A0 (en) | 1993-03-12 |
| PL298037A1 (en) | 1993-12-27 |
| GR930100094A (en) | 1993-11-30 |
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