PL170751B1 - 4H-carbazolone-4 PL - Google Patents
4H-carbazolone-4 PLInfo
- Publication number
- PL170751B1 PL170751B1 PL93298037A PL29803793A PL170751B1 PL 170751 B1 PL170751 B1 PL 170751B1 PL 93298037 A PL93298037 A PL 93298037A PL 29803793 A PL29803793 A PL 29803793A PL 170751 B1 PL170751 B1 PL 170751B1
- Authority
- PL
- Poland
- Prior art keywords
- methyl
- formula
- acid
- carbazolone
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 230000003213 activating effect Effects 0.000 claims abstract description 3
- 238000007171 acid catalysis Methods 0.000 claims abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 238000007363 ring formation reaction Methods 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 5
- 239000003377 acid catalyst Substances 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000012429 reaction media Substances 0.000 claims 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 abstract description 12
- 238000005727 Friedel-Crafts reaction Methods 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 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
- 239000000203 mixture Substances 0.000 description 8
- 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
- 239000007787 solid Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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
- 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
- 239000002253 acid Substances 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- NOOYFQLPKUQDNE-UHFFFAOYSA-N 2-(bromomethyl)prop-2-enoic acid Chemical compound OC(=O)C(=C)CBr NOOYFQLPKUQDNE-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-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
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 125000006519 CCH3 Chemical group 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 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
- 230000004913 activation Effects 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001448 anilines Chemical class 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
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Chemical group 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 125000004970 halomethyl group 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002955 isolation 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
- 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
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 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
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 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 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 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)
Abstract
1 . Sposób wytwarzania 1,2,3,9-tetra- hydro-9-metylo-3-[/2-metylo-1 H-imidazoli lo-l/metylo]-4H-karbazolonu-4 o wzorze 1, znamienny tym, ze cyklizuje sie kwas 2-[2- /2-/metylo- -1H-imidazolo-1/metylo]-4-/1 - metyloindolilo-2/-maslowy o wzorze 2, w warunkach reakcji acylowania Friedel-Craft- sa, aktywujac grupe karboksylowa za pomo- ca katalizy kwasow ej, w odpowiednim rozpuszczalniku i wyodrebnia sie pozadany produkt znanymi sposobami. Wzór 2 PL 1. A method of producing 1,2,3,9-tetrahydro-9-methyl-3-[/2-methyl-1H-imidazol-1-yl]methyl]-4H-carbazol-4-one of formula 1, characterized in that 2-[2-/2-/methyl-1H-imidazol-1-yl]-4-/1-methylindol-2-yl]butyric acid of formula 2 is cyclized under Friedel-Craft acylation reaction conditions, activating the carboxyl group by acid catalysis, in a suitable solvent, and the desired product is isolated by known methods. Formula 2 PL
Description
Przedmiotem wynalazku jest sposób wytwarzania 1,2,3,9-tetralh^y^hxoŁ9-^im^tt^d(^^3-[/2-metylo-1H-imii^kb^^(dil(o-1/metylo]-4^H^karhazolonu-4 o wzorze 1, związku syntetycznego, który selektywnie antagonizuje receptory 5-HT3 i wykazuje interesujące właściwości jako środek przeciwwymiotny w chemoterapii, jak również w leczeniu bólu głowy, schizofrenii, lęku, otyłości i stanu pobudzenia maniakalnego.The present invention relates to a process for the preparation of 1,2,3,9-tetralh ^ y ^ L hxo 9- ^ im ^ tt ^ d (^^ 3 - [/ 2-methyl-1 H-kb imii ^ ^^ (dil (o- 1 (Methyl] -4 ^H ^carhazolone-4 of the formula I, a synthetic compound that selectively antagonizes 5-HT3 receptors and has interesting properties as an antiemetic in chemotherapy as well as in the treatment of headache, schizophrenia, anxiety, obesity and manic agitation.
W hiszpańskim opisie patentowym nr ES 548430 ujawniono wytwarzanie 1.2,3,9-tetrahydro-9-metylo-3-[/2-metylo-1H-imidaΌlilo-1-/metylo]-4H-karbazolonu-4 przez reakcję karbazolonu o wzorze 3, w którym Y oznacza grupę metylenową lub chlorowcometylową, z 2-metyloimidazolem.Spanish Patent Specification No. ES 548 430 discloses the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidalyl-1- (methyl] -4H-carbazolone-4) by reacting a carbazolone of formula 3 where Y is methylene or halomethyl, with 2-methylimidazole.
W hiszpańskim opisie patentowym nr ES 556101 ujawniono wytwarzanie 1,2,3,9-tetrahydro-9-metylo-3-[/2-metylo-1H-imidazoli]o-1/-metylo]-4H-karhazolonu-4 przez utlenianie karbazolu o wzorze 4, w którym A oznacza atom wodoru lub grupę hydroksylową.Spanish Patent Specification No. ES 556101 discloses the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazole] o-1H-methyl] -4H-4H-carhazolone-4 by oxidation carbazole of formula IV, wherein A is hydrogen or hydroxy.
W hiszpańskim opisie patentowym nr ES 539852 ujawniono wytwarzanie 1,2,3,9-tetrahydro-9-meίylo-3-[/2-metylo-1H-imidazolilo-1/-metylo]-4H-ka!'hazoionu-4 przez alkilowanie karbazolonu o wzorze 5, w którym R1 i/lub R2 oznacza atom wodoru.Spanish Patent No. ES 539852 discloses the preparation of 1,2,3,9-tetrahydro-9-meίyl-3 - [(2-methyl-1H-imidazolyl-1H-methyl] -4H-ka! 'Hazoion-4 by alkylation of a carbazolone of formula 5 wherein R1 and / or R2 is hydrogen.
W hiszpańskim opisie patentowym nr ES 2000935 ujawniono wytwarzanie 1,2,3,9-tetrahydro-9-metylo-3-[/2-metylo-1H-imidazolilo-1-/-metylo]-4H-karbazolonu-4 przez cyklizację pochodnej fenylohydrazynowej o wzorze 6.Spanish Patent Specification No. ES 2000 935 discloses the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazolyl-1 - N - methyl] -4H-4-carbazolone by cyclization of the derivative phenylhydrazine of formula 6.
W hiszpańskim opisie patentowym nr ES 2000936 ujawniono wytwarzanie 1,2,3,9-tetrahydro-9-In£tylo-3-[/2-metylo-1H-imid&zolilo-1/metyio]-4H-karbazolonu-4 przez cyklizację pochodnej aniliny o wzorze 7, w którym X oznacza atom wodoru lub chlorowca.Spanish Patent Specification No. ES 2000 936 discloses the preparation of 1,2,3,9-tetrahydro-9-N-ethyl-3 - [(2-methyl-1H-imide & zolyl-1 / methyl] -4H-4-carbazolone by cyclization of the derivative anilines of formula 7 wherein X is hydrogen or halogen.
Wynalazek ujawnia i zastrzega nowy sposób wytwarzania 1 ©©©-tetrahydro-b-metylo-o[/2-metylo-1 H-imidazolilo- 1/-metylo]-4H-k£rbazolonu-4 o wzorze 1, który obejmuje cyklizację kwasu 2-[/2-metylo-1H-imidazolilo-1/metylo]-4-/1-metyloindolilo-2/masłowego o wzorze 2 w warunkach reakcji acylowania Friedel-Craftsa, przez aktywowanie grupy karboksylowej za pomocą katalizatora kwasowego, w środowisku odpowiedniego rozpuszczalnika, a następnie wyodrębnienie pożądanego produktu znanym sposobem.The invention discloses and claims a new process for the preparation of 1 ©©© -tetrahydro-b-methyl-o [(2-methyl-1H-imidazolyl-1 / -methyl] -4H-k? Rbazolone-4 of the formula 1, which comprises cyclization 2 - [(2-methyl-1H-imidazolyl-1) methyl] -4- (1-methylindolyl-2) butyric acid of formula 2 under Friedel-Crafts acylation conditions, by activating the carboxyl group with an acid catalyst in a medium a suitable solvent followed by isolation of the desired product in a known manner.
170 751170 751
Aktywowanie kwasu karboksylowego przeprowadza się przez przekształcenie go w halogenek acylu lub w mieszany bezwodnik trójfluorooctowy, metanosulfonowy lub trójfluorometylosulfonowy, korzystnie mieszany bezwodnik tiOjjluorooctoww.Activation of the carboxylic acid is carried out by converting it to an acyl halide or to mixed trifluoroacetic, methanesulfonic or trifluoromethylsulfonic anhydride, preferably mixed thiOjluoroacetic anhydride.
Jako katalizator kwasowy można stosować kwas nieorganiczny taki jak chlorowodorowy, siarkowy lub fosforowy lub kwas Lewisa taki jak trójfluorek boru, chlorek cynku lub trójchlorek glinu, korzystnie kwas fosforowy.As acid catalyst, an inorganic acid such as hydrochloric, sulfuric or phosphoric acid, or a Lewis acid such as boron trifluoride, zinc chloride or aluminum trichloride, preferably phosphoric acid, can be used.
Reakcję prowadzi się w aprotonowym rozpuszczalniku organicznym takim jak chloroform, dwuchlorometan, dwuchloroetan, eter, tetrahydrofuran lub acetonitryl, korzystnie acetonitryl.The reaction is carried out in an aprotic organic solvent such as chloroform, dichloromethane, dichloroethane, ether, tetrahydrofuran or acetonitrile, preferably acetonitrile.
Reakcję cyklizacji dogodnie prowadzi się w zakresie temperatur od -60° do +50°C, korzystnie 0°C.The cyclization reaction is conveniently carried out in a temperature range of from -60 ° to + 50 ° C, preferably 0 ° C.
Po doprowadzeniu reakcji do końca, pożądany produkt wyodrębnia się znanym sposobem i rekrystalizuje z rozpuszczalnika organicznego, korzystnie metanolu, otrzymując chemicznie czysty 1.2,3,9-tet^^^lh^y^hr)-()-Tm+\d<o^;3-[/2-met;^d(^-1U-imn^^ro^^zdil(y-1/mctylol-4^H-karbazolon-4.After completion of the reaction, the desired product is isolated in a known manner and recrystallized from an organic solvent, preferably methanol, to give a chemically pure 1,2,3,9-tet ^^^ lh ^ y ^ hr) - ( ) -Tm + \ d <o ^ ; 3 - [/ 2-meth; ^ d (^ - 1U-imn ^^ r ^^ zdil (y-1 / mctylol-4 ^ H-carbazolone-4.
Związek o wzorze 2 można sporządzić poddając reakcji kwas 2-metyleno-4-/3-^k^a^rboksy1-metyloindoiilo-2/ masłowy o wzorze 8, z 2-metyloimidazolem.A compound of formula II can be prepared by reacting 2-methylene-4- (3, 4, 4, 6, 2-hydroxy-1-methylindoyl-2) butyric acid of formula 8 with 2-methylimidazole.
Reakcję dogodnie prowadzi się w temperaturze 100-200°C, korzystnie 150°C.The reaction is conveniently carried out at a temperature of 100-200 ° C, preferably 150 ° C.
Reakcję prowadzi się w wysokowrzącym rozpuszczalniku takim jak toluen, ksylen lub bromobenzen lub ich mieszaniny, bądź bez rozpuszczalnika, korzystnie bez rozpuszczalnika.The reaction is carried out in a high-boiling solvent such as toluene, xylene or bromobenzene or mixtures thereof, or in the absence of a solvent, preferably without a solvent.
Po doprowadzeniu reakcji do końca, pożądany produkt wyodrębnia się znanym sposobem i rekrystalizuje z rozpuszczalnika organicznego takiego jak metanol, toluen, dwumetoksyetan lub metoksyetanol, korzystnie dwumetoksyetan.After completion of the reaction, the desired product is isolated in a known manner and recrystallized from an organic solvent such as methanol, toluene, dimethoxyethane or methoxyethanol, preferably dimethoxyethane.
Kwas dwukarboksylowy o wzorze 8 otrzymuje się przez hydrolizę kwasu 2-metyleno-4/3-etoksykarbonylo-1 -metyloindolilo-2/masłowego o wzorze 9, który z kolei sporządza się przez reakcję anionu hd-dwumetyloindolo-b-karboksylanu etylu o wzorze 10 /sporządzony według Johna E. Macora, Kewina Ryana, Michaela E. Newmana w J.Org.Chem. 54,4785 /1989//z kwasu a-/bromometylo-akrylowego/ o wzorze 11.The dicarboxylic acid of formula 8 is obtained by hydrolysis of the ethyl 2-methylene-4- (3-ethoxycarbonyl-1-methylindolyl-2) butyric acid of formula 9, which in turn is prepared by reacting the ethyl hd-dimethylindole-b-carboxylate anion of formula 10 / Prepared according to John E. Macor, Kewin Ryan, Michael E. Newman in J.Org.Chem. 54, 4785 (1989) from α- (bromomethyl-acrylic acid) of formula 11.
Sposób ujawniony w niniejszym opisie będzie dalej szczegółowo opisany za pomocą przykładów, których zadaniem jest zilustrowanie wynalazku, a nie ograniczenie jego zakresu.The method disclosed in this specification will be further described in detail by means of examples which are intended to illustrate the invention and not to limit its scope.
Przykład I. Wytwarzanie kwasu 2-metyleno-4-/3-etoksykarbonylo-1-metyloindolilo2/masłowego.Example 1 Preparation of 2-methylene-4- (3-ethoxycarbonyl-1-methylindolyl-2) butyric acid.
Do roztworu soli litowej sporządzonej z 4,34 g /20 mmoli/ 1,2-dwumetyloindolokarboksylanu-3 etylu w 150 ml tetrahydrofuranu, utrzymywanego w temperaturze -60°C dodano w przeciągu 10 sekund roztwór 4,98 g /30 mmoli/ kwasu a-/bromometyloakrylowego/ w 20 ml tetrahydrofuranu. Temperatura nie powinna przekroczyć -50°C. Po 2 godzinach mieszania w temperaturze -60°C, roztwór przelano do mieszaniny zawierającej 400 g lodu, 15 ml stężonego kwasu solnego i 200 ml octanu etylu. Po rozdzieleniu na fazy, warstwy rozdzielono i warstwę wodną wyekstrahowano octanem etylu /2 x 200 ml/. Połączone ekstrakty organiczne osuszono nad MgSO.4 a następnie odparowano. Otrzymane ciało stałe rekrystalizowano z toluenu a następnie z metanolu, otrzymując tym sposobem 3,0 g / wydajność 50%/ analitycznie czystego tytułowego związku w postaci białego ciała stałego.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 acid was added within 10 seconds. - (bromomethylacrylic) in 20 ml of tetrahydrofuran. The temperature should not exceed -50 ° C. After 2 hours of stirring at -60 ° C, the solution was poured into a mixture of 400 g of ice, 15 ml of concentrated hydrochloric acid and 200 ml of ethyl acetate. After separation into the phases, the layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were dried over MgSO 4 then evaporated. The obtained solid was recrystallized from toluene and then from methanol, thus obtaining 3.0 g (50% yield) of the analytically pure title compound as a white solid.
Temperatura topnienia 138°C - 140°C.Melting point 138 ° C - 140 ° C.
‘H-NMR ó/CDCl3/: 1,46/t, J=7,1, 3H, -CH2-CH3/, 2,62-2,71 /m, 2H, -CH2-C=C/, 3,363,48//,2H, indolo-CH!, 3,78/s, 3H, N-CHj/, 4,41 /q, J=7,1, 2H, -CH2-CH3/, 5,81/d, J=-1,2, 1H, -C=CH/, 6,37 /d, J=1,2, 1H, -C=CH/, 7,15-7.40/m. 3H, aromatyczny/, 8,10-8,20 /m, 1H, aromatyczny/.1 H-NMR 6 (CDCl 3 ): 1.46 (t, J = 7.1,3H, -CH 2 -CH 3), 2.62-2.71 (m, 2H, -CH 2 -C = C), 3.363.48), 2H, indole-CH !, 3.78 (s, 3H, N-CH3), 4.41 (q, J = 7.1, 2H, -CH2-CH3), 5.81) d, J = -1.2,1H, -C = CH), 6.37 (d, J = 1.2, 1H, -C = CH), 7.15-7.40 (m). 3H, aromatic (8.10-8.20 (m, 1H, aromatic).
Przykład II. Wytwarzanie kwasu 2-metyleno-(4-/3-karboksy-1(metylomdolilo-2/ma( słowego.Example II. Preparation of 2-methylene- (4- (3-carboxy-1 (methylmdolyl-2 / ma) acid (word.
Do zawiesiny 5,7 g /18,9 mmola/ związku z przykładu I w 15 ml metanolu i 15 ml wody, dodano 19 g wodorotlenku potasu i uzyskaną mieszaninę ogrzewano we wrzeniu w warunkach powrotu skroplin przez 30 minut. Następnie przelano ją na mieszaninę 200 g lodu i 200 ml wody i zakwaszono 30 ml stężonego kwasu solnego. Produkt odsączono i zawieszono w 250 ml toluenu, następnie oddestylowano z tego 100 ml i, po ochłodzeniu w temperaturze 20°C i dalszymTo a suspension of 5.7 g (18.9 mmol) of the compound of Example 1 in 15 ml of methanol and 15 ml of water, 19 g of potassium hydroxide was added and the resulting mixture was heated under reflux for 30 minutes. It was then poured onto a mixture of 200 g of ice and 200 ml of water and acidified with 30 ml of concentrated hydrochloric acid. The product was filtered off and suspended in 250 ml of toluene, then 100 ml of this was distilled off and, after cooling at 20 ° C and further
170 751 odsączeniu uzyskano 4,5 g /wydajność 87%/ analitycznie czystego związku tytułowego w postaci białego ciała stałego.Filtration gave 4.5 g (87% yield) of the analytically pure title compound as a white solid.
Temperatura topnienia: 194-196°C.Melting point: 194-196 ° C.
1H-NMR ó/CDCfe/: 2,40-2,60/m, 2H, indolo-CH2CH2-/, 3,20-3,50 /m, 2H, indolo-CH2CHi/, 3,77/s, 3H, N-CH2/, 5,59 /d, J=1,5, 1H, -C=C-H, 6,07/d, J=1,5, 1H, -C=C-H/, 7,10-7,25 /m,2H, aromatyczny/, 7,46-7,54/m, 1H, aromatyczny/, 7,96-8,05/m, 1H, aromatyczny/. 1 H-NMR 6 (CDCl 2): 2.40-2.60 (m, 2H, indole-CH 2 CH 2 -), 3.20-3.50 (m, 2H, indole-CH 2 CH 1), 3.77 (s, 3H, N-CH2 /, 5.59 (d, J = 1.5, 1H, -C = CH, 6.07 (d, J = 1.5, 1H, -C = CH), 7.10- 7.25 (m, 2H, aromatic), 7.46-7.54 (m, 1H, aromatic), 7.96-8.05 (m, 1H, aromatic).
Przykład III. Wytwarzanie kwasu 2-[/2-metylo-1H-imida:olilo-1]-4-1-metyloindolilo-2/masłowego.Example III. Preparation of 2 - [(2-methyl-1H-imide: olyl-1] -4-1-methylindolyl-2) butyric acid.
Mieszaninę 2,73 g /10 mmoli/ związku z przykładu II i 2,46 g /30 mmoli/ 2-metyloimidazolu ogrzewano w temperaturze 160°C przez 2 minuty. Po ochłodzeniu do temperatury pokojowej, mieszaninę rozpuszczono w chloroformie, naniesiono na kolumnę chromatograficzną z krzemionką i eluowano mieszaninę 70:30 chlorku metylenu/metanolu. Tym sposobem otrzymano 2,21 /wydajność 71%/ tytułowego związku w postaci analitycznie czystego żółtawego ciała stałego.A mixture of 2.73 g (10 mmol) of the compound of Example 2 and 2.46 g (30 mmol) of 2-methylimidazole was heated at 160 ° C for 2 minutes. After cooling to room temperature, the mixture was dissolved in chloroform, applied to a silica chromatography column and eluted with a 70:30 mixture of methylene chloride / methanol. In this way, 2.21 (71% yield) of the title compound was obtained as an analytically pure yellowish solid.
Temperatura topnienia: 198°C- 199°C.Melting point: 198 ° C- 199 ° C.
‘H-NMR δ /DMSO/: 1,65-2,05/m, 2H, indolo-CH2-CH2-/, 2,27 /s, 3H, C-CH3/, 2,652,95/m, 3H, indolo-CH2- i -HC-COOH/, 3,63 /s, 3H, N-CH3/, 3,95-4,25/m, 2H, imidazolo-CH2-/, 6,15/s, 1H, indolo-H/, 6,79/d, J=1,6, 1H, imidazolo-H/, 6,90-7,10/m, 3H/ łącznie z 7,06 /d, J=1,6, 1H, imidazolo-H/, 7,30-7,45 /m, 2H, aromatyczne/.1 H-NMR δ (DMSO): 1.65-2.05 (m, 2H, indole-CH2-CH2-), 2.27 (s, 3H, C-CH3), 2.652.95 (m, 3H, indole-CH2- and -HC-COOH), 3.63 (s, 3H, N-CH3), 3.95-4.25 (m, 2H, imidazole-CH2-), 6.15 (s, 1H, indole-H), 6.79 (d, J = 1.6, 1H, imidazole-H), 6.90-7.10 (m, 3H) totaling 7.06 (d, J = 1.6, 1H, imidazole-H), 7.30-7.45 (m, 2H, aromatic).
Przykład IV. Wytwarzanie 1,2,3,9-tetrt^liyyiro-^-imt\'lm.3-[/ź^-me't^vlm-1H-imidazolilo-1/metylo]-4H-karbazolonu-4.Example IV. Preparation of 1,2,3,9-tetramethyl-lyyl-1m-3 - [(1H-imidazolyl-1 / methyl] -4H-carbazolone-4.
Do zawiesiny 311 mg/l mmol/związku z przykładu III w 10ml acetonitrylu dodano 28 μl /0,28 mmola/85% kwasu fosforowego. Mieszaninę reakcyjną oziębiono do temperatury 0°C i wkroplono 353 μl /2,5 mmola/ bezwodnika trójfluorooctowego. Po 15 minutach, całość przelano na mieszaninę 50 g lodu i 50 ml nasyconego roztworu wodorowęglanu sodu i wyekstrahowano chlorkiem metylenu /3 x 10 ml/. Połączone ekstrakty organiczne osuszono /MgSOz4 i odparowano. Stałą pozostałość rekiystalizowano z metanolu otrzymując 160 mg /wydajność 55%/ tytułowego związku w postaci analitycznie czystego ciała stałego.To a suspension of 311 mg / L mmol / of the compound of Example 3 in 10 ml of acetonitrile was added 28 µl / 0.28 mmol / 85% phosphoric acid. The reaction mixture was cooled to 0 ° C and 353 µL (2.5 mmol) of trifluoroacetic anhydride was added dropwise. After 15 minutes, it was poured onto 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 were dried / MgSO 4 and evaporated. The solid residue was recrystallized from methanol to give 160 mg (55% yield) of the title compound as an analytically pure solid.
Temperatura topnienia: 227°C - 228,5°C.Melting point: 227 ° C - 228.5 ° C.
'H-NMR δ /CDCls/: 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/1/ i 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, aromatyczny/, 7,20-7,40 /m, 3H, imidazolo-H i aromatyczny/, 8,20-8,30 /m, 1H, aromatyczny/1 H-NMR δ (CDCl 3): 1.70-2.05 (m, 1H, HC (2), 2.10-2.30 (m, 1H, HC (2), 2.45 / s) , 3H, CH3), 2.75-3.15 (m, 3H, HC (1) and HC (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)
170 751170 751
Ćh3 Ch 3
Wzór 5Formula 5
170 751170 751
COOHCOOH
COOH CH2 COOH CH 2
ch3 ch 3
Wzór 8Formula 8
r ch3 r ch 3
Wzór 10 cooc2h5 Formula 10 cooc 2 h 5
CH,CH,
BrvBrv
CH3 ch2 ^COOHCH 3 CH 2 4 COOH
Wzór 11Formula 11
COOC2H5COOC2H5
COOHCOOH
CH2 Wzór 9CH2 Formula 9
Departament Wydawnictw UP RP. Nakład 90 egz.Publishing Department of the UP RP. Circulation of 90 copies
Cena 2,00 zł 'Price PLN 2.00
Claims (6)
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| 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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| PL170751B1 true PL170751B1 (en) | 1997-01-31 |
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| EG (1) | EG20262A (en) |
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| FI (1) | FI105098B (en) |
| GR (1) | GR930100094A (en) |
| HU (1) | HU210775B (en) |
| IS (1) | IS1783B (en) |
| NO (1) | NO300973B1 (en) |
| PL (1) | PL170751B1 (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 |
| RU2207340C2 (en) * | 2001-08-10 | 2003-06-27 | Ципла Лтд. | Method for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]-4h-carbazole-4-one or its pharmaceutically acceptable salts |
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| GB8518742D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
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| GB8617994D0 (en) * | 1986-07-23 | 1986-08-28 | Glaxo Group Ltd | Heterocyclic compounds |
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| NO930887L (en) | 1993-09-14 |
| HU210775B (en) | 1995-07-28 |
| FI931104A0 (en) | 1993-03-12 |
| GR930100094A (en) | 1993-11-30 |
| NO300973B1 (en) | 1997-08-25 |
| AT402730B (en) | 1997-08-25 |
| RU2109741C1 (en) | 1998-04-27 |
| IS1783B (en) | 2001-10-22 |
| IS3985A (en) | 1993-09-14 |
| HUT64537A (en) | 1994-01-28 |
| PL298037A1 (en) | 1993-12-27 |
| SK278786B6 (en) | 1998-02-04 |
| PT101216B (en) | 1999-10-29 |
| ES2043535B1 (en) | 1994-08-01 |
| EG20262A (en) | 1998-05-31 |
| AR248019A1 (en) | 1995-05-31 |
| PT101216A (en) | 1994-03-31 |
| ES2043535A1 (en) | 1993-12-16 |
| FI931104L (en) | 1993-09-14 |
| FI105098B (en) | 2000-06-15 |
| HU9300718D0 (en) | 1993-05-28 |
| KR100277414B1 (en) | 2001-01-15 |
| KR930019665A (en) | 1993-10-18 |
| CZ39693A3 (en) | 1994-01-19 |
| CZ281753B6 (en) | 1997-01-15 |
| ATA48793A (en) | 1996-12-15 |
| SK16993A3 (en) | 1993-11-10 |
| NO930887D0 (en) | 1993-03-11 |
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