FI105098B - Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(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-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one Download PDFInfo
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- 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
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Description
105098105098
Menetelmä l,2,3,9-tetrahydro-9-metyyli-3-[(2-metyyli-lH-imidat-sol-l-yyli)metyyli]-4H-karbatsol-4-onin valmistamiseksi. -Förfarande för framställning av l,2,3,9-tetrahydro-9-metyl-3-[(2-metyl-lH-imidazol-l-yl)metyl]-4H-karbazol-4-on.Process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one. -1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one.
Tämä keksintö koskee menetelmää kaavan I mukaisen 1,2,3,9-tet-rahydro-9-metyyli-3-[ (2-metyyli-lH-imidatsol-l-yyli)metyyli] -4H-karbatsol-4-onin valmistamiseksi, 0 ch3 U7X> wThis invention relates to a process for the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one of the formula I , 0 ch3 U7X> w
— N- N
CH3 synteettisen yhdisteen, joka antagonisoi selektiivisesti 5-HT3-reseptoreja, ja jolla on kiinnostavia ominaisuuksia oksetusta estävänä aineena kemoterapiassa, samoin kuin päänsäryn, skitsofrenian, ahdistuneisuuden, lihavuuden ja kiihkomielisyyden hoidossa.CH3 is a synthetic compound that selectively antagonizes 5-HT3 receptors and has interesting properties as an anti-emetic agent in chemotherapy as well as in the treatment of headaches, schizophrenia, anxiety, obesity and arthritis.
ES-patenttijulkaisussa 548430 kuvataan 1,2,3,9-tetrahydro-9-metyyli-3-[(2-metyyli-lH-imidatsol-l-yyli)metyyli]-4H-karbat-sol-4-onin valmistus saattamalla kaavan III mukaisen karbat-solin reagoimaan 2-metyyli-imidatsolin kanssa,ES-A-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 Carbat-Sol of formula III with 2-methylimidazole
OrtVOrtV
CH3 2 105098 jossa Y on metyleeniradikaali tai halogeenimetyyliradikaali.CH3 2 105098 wherein Y is a methylene radical or a halomethyl radical.
ES-patenttijulkaisussa 556101 kuvataan 1,2, 3,9-tetrahydro-9-metyyli-3-[ (2-metyyli-lH-imidatsol-l-yyli)metyyli]-4H-karbat-sol-4-onin valmistus hapettamalla kaavan IV mukaista karbat-solia, A CH3 «'"N-iv li J1 . h w Γ jossa A on vetyatomi tai hydroksiradikaali.ES patent publication 556101 describes the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one by oxidation of the formula Carbatol of formula IV, A CH3 '' N-iv li J1. Hw Γ where A is a hydrogen atom or a hydroxy radical.
ES-patenttijulkaisussa 539852 kuvataan l,2,3,9-tetrahydro-9-metyyli-3- [ ( 2-metyyli-lH-imidatsol-l-yyli)metyyli ]-4H-karbat-sol-4-onin valmistus alkyloimalla kaavan V mukaista karbatsolo-nia, 3 R2 ίτ"%-ΑΓ'ν^ν l!. JL J H \=/ R1 jossa Ri ja/tai R2 on vetyatomi.ES-A-539852 describes the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one by alkylation of formula Carbazolone of formula V, 3 R 2 "% - ΑΓ ν ν ν l l l..
3 105098 ES-patenttijulkaisussa 2000935 kuvataan l,2,3,9-tetrahydro-9-metyyli-3-[(2-metyyli-lH-imidatsol-l-yyli)metyyli]-4H-karbat-sol-4-onin valmistus syklisoimalla kaavan VI mukaista fenyyli-hydratsiinijohdannaista, 9 CH3 CX. 0 "3,105098 EU-A-2000935 describes the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one. cyclizing the phenyl hydrazine derivative of formula VI, 9 CH 3 CX. 0 "
I I ch3 HI I ch3 H
ES-patenttijulkaisussa 2000936 kuvataan 1,2,3,9-tetrahydro-9-metyyli-3-[(2-metyyli-lH-imidatsol-l-yyli)metyyli]-4H-karbat-sol-4-onin valmistus syklisoimalla kaavan VII mukaista anilii-nijohdannaista, 0 CHo rv rV-A» PJ II I H w vhES-A-2000936 describes the preparation of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one by cyclizing the formula VII aniline derivative, 0 CHo rv rV-A »PJ II IH w vh
NTNT
• · ch3 jossa X on vetyatomi tai halogeeni.· · Ch3 where X is a hydrogen atom or a halogen.
Tämä keksintö kuvaa ja vaatii uuden menetelmän kaavan I mukaisen 1,2,3,9-tetrahydro-9-metyyli-3-[(2-metyyli-lH-imidatsol-l-yyli)metyyli]-4H-karbatsol-4-onin valmistamiseksi, 4 105098This invention describes and requires a new process of 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one of formula I for making, 4 105098
O C HO C H
Ca A> CH3 jossa menetelmässä syklisoidaan kaavan II mukaista 2-[(2-metyy- li-lH-imidatsol-l-yyli)metyyli]-4-(l-metyyli-indol-2-yyli)voi-happoa r· ch3Ca A> CH 3 wherein the 2 - [(2-methyl-1H-imidazol-1-yl) methyl] -4- (1-methylindol-2-yl) butyric acid of formula II is cyclized
Friedel-Crafts-asylointireaktio-olosuhteissa aktivoimalla kar-* boksyyliryhmän happokatalyysillä sopivassa liuotinväliaineessa, ja eristämällä halutun tuotteen edelleen tavanomaisella tavalla.Under Friedel-Crafts acylation reaction conditions, by activating the carboxyl group by acid catalysis in a suitable solvent medium, and further isolating the desired product in a conventional manner.
Karboksyylihapon aktivointi suoritetaan muuttamalla sen asyyli-halogenidiksi tai seka-trifluorietikka-, -metaanisulfoni-, tai -trifluorimetyylisulfonihappoanhydridiksi, edullisesti seka-trif luorietikkahappoanhydridiksi.Activation of the carboxylic acid is accomplished by converting it into an acyl halide or mixed trifluoroacetic, methanesulfonic, or trifluoromethylsulfonic anhydride, preferably mixed trifluoroacetic anhydride.
Hapan katalysaattori voi olla epäorgaanista happoa kuten suola-, rikki- tai fosforihappo, tai Lewis-happoa kuten booritri- 5 105098 fluoridi, sinkkikloridi tai aluminiumtrikloridi, edullisesti fosforihappoa.The acid catalyst may be an inorganic acid such as hydrochloric, sulfuric or phosphoric acid, or a Lewis acid such as boron trichloride, zinc chloride or aluminum trichloride, preferably phosphoric acid.
Reaktio suoritetaan aproottisessa orgaanisessa liuottimessa kuten kloroformi, dikloorimetaani, dikloorietaani, eetteri, tetrahydrofuraani tai asetonitriili, edullisesti asetonitrii-lissä.The reaction is carried out in an aprotic organic solvent such as chloroform, dichloromethane, dichloroethane, ether, tetrahydrofuran or acetonitrile, preferably acetonitrile.
Syklisointireaktio voidaan suorittaa mukavasti lämpötiloissa alueella -60 - +50°C, edullisesti 0°C:ssa.The cyclization reaction may conveniently be carried out at temperatures of -60 to + 50 ° C, preferably 0 ° C.
Reaktion edettyä loppuun haluttu tuote eristetään tavanomai-. sella tavalla ja uudelleenkiteytetään orgaanisesta liuotti-mesta, edullisesti metanolista, jollon saadaan kemiallisesti puhdasta 1,2,3,9-tetrahydro-9-metyyli-3-[(2-metyyli-lH-imidatsol-l-yyli)metyyli]-4H-karbatsol-4-onia.Upon completion of the reaction, the desired product is isolated by conventional means. and recrystallizing from an organic solvent, preferably methanol, to give chemically pure 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H carbazol-4-one.
Kaavan II mukainen yhdiste voidaan valmistaa saattamalla kaavan VIII mukaisen 2-metyleeni-4-(3-karboksi-l-metyyli-indol-2-yyli)voihapon reagoimaan 2-metyyli-imidatsolin kanssa.The compound of formula II may be prepared by reacting 2-methylene-4- (3-carboxy-1-methylindol-2-yl) butyric acid of formula VIII with 2-methylimidazole.
^ COOH^ COOH
i ] j A JL _ cooh \/\ As/w viii ch3i] j A JL _ cooh \ / \ As / w viii ch3
Reaktio suoritetaan mukavasti lämpötiloissa alueella 100 - 200°C, edullisesti 150°C:ssa.The reaction is conveniently carried out at temperatures of 100 to 200 ° C, preferably 150 ° C.
Reaktio suoritetaan korkeassa lämpötilassa kiehuvassa liuottimessa kuten tolueeni, ksyleeni tai bromibentseeni, tai näiden seoksessa, tai ilman liuotinta, edullisesti ilman liuotinta.The reaction is carried out in a high boiling solvent such as toluene, xylene or bromobenzene, or a mixture thereof, with or without a solvent, preferably without a solvent.
6 1050986 105098
Reaktion edettyä loppuun haluttu tuote eristetään tavanomaisella tavalla ja uudelleenkiteytetään orgaanisesta liuottimesta kuten metanoli, tolueeni, dimetoksietaani tai metoksietanoli, edullisesti dimetoksietaanista.After completion of the reaction, the desired product is isolated in conventional manner and recrystallized from an organic solvent such as methanol, toluene, dimethoxyethane or methoxyethanol, preferably dimethoxyethane.
Kaavan Vili mukainen dihappo saadaan hydrolysoimalla kaavan IX mukaista 2-metyleeni-4-(3-etoksikarbonyyli-l-metyyli-indol-2-yyli)voihappoa, ^ COOEtThe diacid of formula VIII is obtained by hydrolysis of 2-methylene-4- (3-ethoxycarbonyl-1-methylindol-2-yl) -butyric acid of formula IX,
OnTONT
t i ch3 joka puolestaan voidaan valmistaa saattamalla kaavan X mukaisen etyyli-1,2-dimetyyli-indoli-3-karboksylaattianionin ___ / C O O Et i J~~f CH3 ch3 (valmistettu menetelmällä, joka kuvataan julkaisussa: John E. Macor, Kewin Ryan, Michael E. Newman; J. Org. Chem. 54 (1989) 4785) reagoimaan kaavan XI mukaisen a-(bromimetakryyli)hapon kanssa.ti ch3, which in turn can be prepared by reacting the ethyl 1,2-dimethylindole-3-carboxylate anion of formula X with CH3 ch3 (prepared by the method described by John E. Macor, Kewin Ryan). Michael E. Newman; J. Org. Chem. 54 (4785) (1989)) with an α- (bromomethacrylic) acid of formula XI.
7 1050987 105098
ΒΓ COOH XIΒΓ COOH XI
Menetelmää kuvataan tässä julkaisussa vielä yksityiskohtaisemmin tämän jälkeen seuraavilla esimerkeillä, jotka on tarkoitettu kuvaaviksi, eivätkä millään lailla rajoita keksinnön suoja-alaa.The process is described in more detail in this publication by the following examples, which are intended to be illustrative and in no way limit the scope of the invention.
Esimerkki 1 2 -Mety 1 eeni - 4 - (3 - e tok s ikar bonw 1 i -1 -metvvl i - indol - 2 - wl i) -voihappoExample 1 2 -Methyl 1 ene-4 - (3-e tok s Icar bonw 1 i -1 -methyl i -indole-2-w i l) butyric acid
Liuokseen, jossa on litiumsuolaa, joka on valmistettu 4,34 g:sta (20 mmol) etyyli-1,2-dimetyyli-indoli-3-karbok-sylaattia 150 ml:ssa tetrahydrofuraania, pidetään -60°C:ssa, lisätään yli 10 sekunnin ajan liuos, jossa on 4,98 g (30 mmol) a-(bromimetyyliakryyli)happoa 20 ml:ssa tetrahydrofuraania. Lämpötila ei saa ylittää -50°C:tta. Sekoitetaan 2 tuntia -60°C:ssa, minkä jälkeen liuos kaadetaan seokseen, joka sisältää 400 g jäätä, 15 ml väkevöityä suolahappoa ja 200 ml etyyliasetaattia. Jakamisen jälkeen faasit erotetaan ja vesikerros uutetaan etyyliasetaatilla (2 x 200 ml). Yhdistetyt orgaaniset uutteet kuivataan MgSCUrlla ja sitten haihdutetaan. Saatu kiinteä aine uudelleenkiteytetään tolueenista ja sitten metano-lista, jolloin saadaan 3,0 g (50 %) analyyttisesti puhdasta otsikkoyhdistettä valkoisena kiinteänä aineena, sp.: 138-140°CTo 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 is maintained at -60 ° C, For 10 seconds, a solution of 4.98 g (30 mmol) of α- (bromomethyl acrylic) acid in 20 ml of tetrahydrofuran. The temperature must not exceed -50 ° C. After stirring for 2 hours at -60 ° C, the solution is poured into a mixture of 400 g of ice, 15 ml of concentrated hydrochloric acid and 200 ml of ethyl acetate. After separation, the phases are separated and the aqueous layer is extracted with ethyl acetate (2 x 200 mL). The combined organic extracts are dried over MgSO 4 and then evaporated. The resulting solid is recrystallized from toluene and then methanol to give 3.0 g (50%) of the analytically pure title compound as a white solid, m.p. 138-140 ° C.
1H-NMR 6 (CDCla): 1,46 (t, J=7,l, 3H, -CHa-CH3), 2,62-2,71 (m, 2H, -CH2-C=C), 3,36-3,48 (m, 2H, indoli-CH2), 3,78 (s, 3H, N-CH3), 4,41 (q, J=7,l, 2H, -CH2-CH3), 5,81 (d, J=l,2, 1H, -C=CH), 6,37 (d, J=1,2, 1H, -OCH), 7,15-7,40 (m, 3H, aromaattinen), 8,10-8,20 (m, 1H, aromaattinen) 8 1050981 H-NMR δ (CDCl 3): 1.46 (t, J = 7.1, 3H, -CH 2 -CH 3), 2.62-2.71 (m, 2H, -CH 2 -C = C), 3, 36-3.48 (m, 2H, indole-CH2), 3.78 (s, 3H, N-CH3), 4.41 (q, J = 7.1, 2H, -CH2-CH3), δ, 81 (d, J = 1.2, 1H, -C = CH), 6.37 (d, J = 1.2, 1H, -OCH), 7.15-7.40 (m, 3H, aromatic). , 8.10-8.20 (m, 1H, aromatic) 8105098
Esimerkki 2 2-Metyleeni-4-(3-karboksi-l-metvyli-indol-2-vyli)voihappoExample 2 2-Methylene-4- (3-carboxy-1-methyl-indol-2-yl) -butyric acid
Suspensioon, jossa on 5,7 g (18,9 mmol) esimerkin 1 yhdistettä 15 ml:ssa metanolia ja 15 mlrssa vettä, lisätään 19 g kalium-hydroksidia ja saatua seosta kuumennetaan refluksoiden 30 minuuttia. Sitten se kaadetaan seokseen, jossa on 200 g jäätä ja 200 ml vettä ja tehdään happameksi 30 ml :11a väkevöityä suolahappoa. Tuote saadaan takaisin suodattamalla ja sus-pendoidaan 250 mlrssa tolueenia, sitten siitä suodatetaan pois 100 ml, minkä jälkeen jäähdytetään 20°C:ssa ja edelleen suodatetaan, jolloin saadaan 4,5 g (87 %) analyyttisesti puhdasta otsikkoyhdistettä valkoisena kiinteänä aineena, sp.: 194-196°CTo 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 are added 19 g of potassium hydroxide and the resulting mixture is heated under reflux for 30 minutes. 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 suspended in 250 ml of toluene, then filtered off with 100 ml, then cooled at 20 ° C and further filtered to give 4.5 g (87%) of the analytically pure title compound as a white solid, m.p. 194-196 ° C
XH-NMR 6 (CDCla): 2,40-2,60 (m, 2H, indoli-CH2-CH2-), 3,20-3,50 (m, 2H, indoli-CH2-CH2-), 3,77 (s, 3H, N-CHa), 5,59 (d, J=l,5, 1H, -C=C-H), 6,07 (d, J=1,5, 1H, -C=C-H), 7,10-7,25 (m, 2H, aromaattinen), 7,46-7,54 (m, 1H, aromaattinen), 7,96-8,05 (m, 1H, aromaattinen)1 H-NMR δ (CDCl 3): 2.40-2.60 (m, 2H, indole-CH 2 -CH 2 -), 3.20-3.50 (m, 2H, indole-CH 2 -CH 2 -), 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)
Esimerkki 3 2-Γ (2-Metwli-lH-imidatsol-l-wli1-4- (l-metwli-indol-2-wli)-voihappoExample 3 2-Γ (2-Methyl-1H-imidazol-1-yl] -4- (1-methyl-indol-2-yl) -butyric acid
Seosta, jossa on 2,73 g (10 mmol) esimerkin 2 yhdistettä ja 2,46 g (30 mmol) 2-metyyli-imidatsolia kuumennetaan 160°C:ssa 2 minuuttia. Jäähdytetään huoneenlämpötilaan, minkä jälkeen seos liuotetaan kloroformiin, laitetaan silikonidioksidikro- «A mixture of 2.73 g (10 mmol) of the compound of Example 2 and 2.46 g (30 mmol) of 2-methylimidazole is heated at 160 ° C for 2 minutes. After cooling to room temperature, the mixture is dissolved in chloroform, placed in silicon dioxide
matografiseen pylvääseen ja eluoidaan 70:30 metyleenikloridi/-metanolilla. Täten 2,21 g (71 %) otsikkoyhdistettä saadaan analyyttisesti puhtaana keltaisena kiinteänä aineena, sp.: 198-199°Ccolumn and eluted with 70:30 methylene chloride / methanol. Thus 2.21 g (71%) of the title compound are obtained as an analytically pure yellow solid, m.p. 198-199 ° C.
9 105098 ^H-NMR 6 (DMSO): 1,65-2,05 (m, 2H, indoli-CH2-CH2-), 2,27 (s, 3H, C-CHa), 2,65-2,95 (m, 3H, indoli-CH2- ja -HC-COOH), 3,63 (s, 3H, N-CHa), 3,95-4,25 (m, 2H, imidatsoli-CHa-), 6,15 (s, 1H, indoli-H), 6,79 (d, J=l,6, 1H, imidatsoli-H), 6,90-7,10 (m, 3H) mukaanlukien 7,06 (d, J=l,6, 1H, imidatsoli-H), 7,30- 7,45 (m, 2H, aromaattinen)Δ 105098 1 H-NMR δ (DMSO): 1.65-2.05 (m, 2H, indole-CH 2 -CH 2 -), 2.27 (s, 3H, C-CH 2), 2.65-2. 95 (m, 3H, indole-CH2- and -HC-COOH), 3.63 (s, 3H, N-CHa), 3.95-4.25 (m, 2H, imidazole-CHa), 6, 15 (s, 1H, indole-H), 6.79 (d, J = 1.6, 1H, imidazole-H), 6.90-7.10 (m, 3H), including 7.06 (d, J = 1.6, 1H, imidazole-H), 7.30-7.45 (m, 2H, aromatic)
Esimerkki 4 1,2,3,9-Tetrahvdro-9-metwli-3-r (2-metwli-lH-imidatsol-l-wli) metwli 1 -4H-karbatsol-4-oniExample 4 1,2,3,9-Tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one
Suspensioon, jossa on 311 mg (1 mmol) esimerkin 3 yhdistettä 10 ml:ssa asetonitriiliä lisätään 28 μΐ (0,28 mmol) 85 % fosfo-rihappoa. Reaktioseos jäähdytetään 0°C:een ja 353 μΐ (2,5 mmol) trifluorietikkahappoanhydridiä lisätään tipottain. 15 minuutin kuluttua se kaadetaan seokseen, jossa on 50 g jäätä ja 50 ml natriumvetykarbonaattilla kyllästettyä liuosta ja uutetaan metyleenikloridillä (3 X 10 ml). Yhdistetyt orgaaniset uutteet kuivataan (MgSO*) ja haihdutetaan. Kiinteä jäännös uudelleen-kiteytetään metanolista, jolloin saadaan 160 mg (55 %) otsikko-yhdistettä analyyttisesti puhtaana valkoisena kiinteänä aineena.To a suspension of 311 mg (1 mmol) of the compound of Example 3 in 10 ml of acetonitrile is added 28 μΐ (0.28 mmol) of 85% phosphoric acid. The reaction mixture is cooled to 0 ° C and 353 μΐ (2.5 mmol) of trifluoroacetic anhydride are added dropwise. After 15 minutes, it is poured into a mixture of 50 g of ice and 50 ml of a saturated solution of sodium hydrogen carbonate and extracted with methylene chloride (3 X 10 ml). The combined organic extracts are dried (MgSO 4) and evaporated. The solid residue is recrystallized from methanol to give 160 mg (55%) of the title compound as an analytically pure white solid.
sp.: 227-228,5°Cmp: 227-228.5 ° C
. ^H-NMR 5 (CDCla): 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) ja 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, aromaattinen), 7,20- 7,40 (m, 3H, imidatsoli-H ja aromaattinen), 8,20-8,30 (m, 1H, aromaattinen). 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, CH 3), 2.75-3.15 (m, 3H, HC (1) and HC (3)), 3.72 (S, 3H, N-CH 3), 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)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES9200552 | 1992-03-13 | ||
| 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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| FI931104A0 FI931104A0 (en) | 1993-03-12 |
| FI931104A FI931104A (en) | 1993-09-14 |
| FI105098B true FI105098B (en) | 2000-06-15 |
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Country Status (15)
| Country | Link |
|---|---|
| KR (1) | KR100277414B1 (en) |
| AR (1) | AR248019A1 (en) |
| AT (1) | AT402730B (en) |
| 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) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR920003064B1 (en) * | 1984-01-25 | 1992-04-13 | 글락소 그룹 리미티드 | Process for preparing hetero cyclic compounds |
| GB8518741D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Process |
| GB8518743D0 (en) * | 1985-07-24 | 1985-08-29 | Glaxo Group Ltd | Heterocyclic compounds |
| GB8518742D0 (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
-
1993
- 1993-03-08 SK SK169-93A patent/SK278786B6/en not_active IP Right Cessation
- 1993-03-09 GR GR930100094A patent/GR930100094A/en not_active IP Right Cessation
- 1993-03-10 EG EG14493A patent/EG20262A/en active
- 1993-03-10 CZ CZ93396A patent/CZ281753B6/en not_active IP Right Cessation
- 1993-03-11 NO NO930887A patent/NO300973B1/en not_active IP Right Cessation
- 1993-03-11 IS IS3985A patent/IS1783B/en unknown
- 1993-03-11 PT PT101216A patent/PT101216B/en not_active IP Right Cessation
- 1993-03-11 KR KR1019930003609A patent/KR100277414B1/en not_active IP Right Cessation
- 1993-03-11 AR AR93324474A patent/AR248019A1/en active
- 1993-03-12 HU HU9300718A patent/HU210775B/en not_active IP Right Cessation
- 1993-03-12 AT AT0048793A patent/AT402730B/en not_active IP Right Cessation
- 1993-03-12 FI FI931104A patent/FI105098B/en not_active IP Right Cessation
- 1993-03-12 RU RU93004833/04A patent/RU2109741C1/en not_active IP Right Cessation
- 1993-03-12 PL PL93298037A patent/PL170751B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| SK16993A3 (en) | 1993-11-10 |
| CZ281753B6 (en) | 1997-01-15 |
| ES2043535B1 (en) | 1994-08-01 |
| ATA48793A (en) | 1996-12-15 |
| RU2109741C1 (en) | 1998-04-27 |
| PL170751B1 (en) | 1997-01-31 |
| FI931104A0 (en) | 1993-03-12 |
| IS1783B (en) | 2001-10-22 |
| KR100277414B1 (en) | 2001-01-15 |
| KR930019665A (en) | 1993-10-18 |
| PL298037A1 (en) | 1993-12-27 |
| HU9300718D0 (en) | 1993-05-28 |
| AR248019A1 (en) | 1995-05-31 |
| PT101216A (en) | 1994-03-31 |
| NO930887L (en) | 1993-09-14 |
| CZ39693A3 (en) | 1994-01-19 |
| GR930100094A (en) | 1993-11-30 |
| HU210775B (en) | 1995-07-28 |
| NO300973B1 (en) | 1997-08-25 |
| EG20262A (en) | 1998-05-31 |
| PT101216B (en) | 1999-10-29 |
| FI931104A (en) | 1993-09-14 |
| AT402730B (en) | 1997-08-25 |
| IS3985A (en) | 1993-09-14 |
| SK278786B6 (en) | 1998-02-04 |
| NO930887D0 (en) | 1993-03-11 |
| ES2043535A1 (en) | 1993-12-16 |
| HUT64537A (en) | 1994-01-28 |
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Owner name: VITA CIENTIFICA Free format text: VITA CIENTIFICA |
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| PC | Transfer of assignment of patent |
Owner name: INKE, S.A. Free format text: INKE, S.A. |
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| MM | Patent lapsed |