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PL148212B1 - The method of manufacture of derivatives of 6-h-indol/2,3-b/-quinoline - Google Patents

The method of manufacture of derivatives of 6-h-indol/2,3-b/-quinoline Download PDF

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PL148212B1
PL148212B1 PL26301586A PL26301586A PL148212B1 PL 148212 B1 PL148212 B1 PL 148212B1 PL 26301586 A PL26301586 A PL 26301586A PL 26301586 A PL26301586 A PL 26301586A PL 148212 B1 PL148212 B1 PL 148212B1
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Przedmiotem wynalazku jest sposób wytwarzania pochodnych 6H-indolo /2,3-b7 chinoliny o wzorze 1, w którym R^, R^$ R^, R^, Rg, Rg, R^9 RQ i RQ sa takie same lub rózne i oznaczaja atom wodoru, grupe alkilowe lub alkoksylowe o 1-4 atomach wegla pierwszo-, drugo- lub trzeciorzedowe, grupe trifluorometylowe, grupe hydroksylowe lub atom fluorowca, ewentualnie w postaci soli czwartorzedowych o wzorze 2, w którym R± do Rg maje wyzej podane znaczenie, R^q oznacza grupe alkilowe o 1-4 atomach wegla pierwszo-, drugo- lub trzeciorzedowe, grupe trifluorometylowe, zas X" oznacza reszte kwasowe, korzystnie Cl", Br", J~. HS04, CH3S04.Te nowe zwiazki o charakterze potencjalnych interkalatorów DNA stanowie izomery strukturalne benzo f-O^karboliny, która wykazuje wysoke aktywnosc cytostatyczne w ba¬ daniach in vivo na mysim nowotworze Sa 180/80% zahamowania wzrostu nowotworu w dawce 100 mg/kg/ /L.Kaczmarek, P.Nantka-Namirski, Pol.3.Phamacol, Pharm.33, 121/1981^ W zwiazku z powyzszym zwiezki wytwarzane sposobem wedlug wynalazku posiadaje potencjalne wlasciwosci przeciwnowotworowe, a ponadto stanowie material wyjsciowy do otrzymywania pochodnych o wysokiej aktywnosci cytostatycznej, bakteriostatycznej i przeciwgrzybicznej /opis patentowy Polski nr 144539/.Sposób wytwarzania pochodnych wedlug wynalazku polega na tym, ze 2-fluorowco- pochodna chinoliny o wzorze 3, w którym R^, R2# R^» R4 i Rg Baje wyzej podane znaczenie, zas Y oznacza atom fluorowca, poddaje sie kondensacji z pochodne o-nitroaniliny o ogól¬ nym wzorze 4, w którym R , R , R i R maje wyzej podane znaczenie, po czym powstale pochodne o wzorze 5 redukuje sie do pochodnej o ogólnym wzorze 6, w którym R do Rg maje wyzej podane znaczenie* Nastepnie diazuje sie je do pochodnej benzotriazolu o wzorze 7, poddaje rozkladowi w podwyzszonej temperaturze, a po zaprzestaniu wydzielania sie azotu wyodrebnia sie produkt w znany sposób* Sole czwartorzedowe o wzorze 2 otrzymuje sie w wyniku reakcji zwiezków o wzorze 1 z pochodne o wzorze R^qX, w którym R10 oznacza grupe alkilowe o 1-4 atomach wegla 148 2122 148 212 pierwszo-, drugo- lub trzeciorzedowe, grupe trifluorometylowe, zas X oznacza reszte kwaso¬ we - korzystnie Cl", Br", 0", HSO4, CK^SO^ Wedlug wynalazku, termiczny rozklad triazolu o wzorze 7, w którym R^ - RQ maje podane wyzej znaczenie, najdogodniej jest prowadzic w kwasie polifosforowym lub oleju parafinowym w zakresie temperatur 120 - 350 C.Nizej podane przyklady ilustruje sposób wedlug wynalazku* Przyklad I* Mieszanine 2-chlorolepidyny /10,6 g, 0,06 mola/ i 4-metylo- 2-nitroaniliny /9,2g, 0,06 mola/ stopiono 1 ogrzewano mieszajec w temperaturze 150 - 160°C przez 10 godzin* Po ochlodzeniu mieszanine rozpuszczono we wrzecym etanolu, dodano roztwór amoniaku i pozostawiono do ochlodzenia w lodówce* Wydzielone czerwone krysztaly 2-/4-metylo- 2-nitroanilino/lepidyny /wzór 5, Ry» Rg» CH^/ odseczono, wydajnosc 17,5 g /ilosciowa/* Czerwone krysztaly, temperatura topnienia 151 - 153°C /z etanolu/* IR /KBr, cm"1/: 3330, 1525* Analiza: dla C17H15N302 /293,3/; Obliczono: 69,61% Cj 5,15% Hj 14,32% N.Oznaczono: 69,41% C; 4,89% H? 14,33% N. - 2-/4-metylo-2-nitroanilino/lepidyne /14,7g, 0,05 mola/ dodano porcjami mieszajec i chlodzec 3 3 do roztworu 60g chlorku cynawego w mieszaninie 36% HCl /100 cm / i etanol /10 cm /, a nastep¬ nie calosc ogrzewano na lazni wodnej 1 godzine* Po ochlodzeniu mieszanine poreakcyjne pozosta¬ wiono przez noc w lodówce, odseczono wydzielony kompleks cynowy produktu i mieszano go z nad¬ miarem 20% Na OH* Wydzielony produkt odseczono i rekrystalizowano z wodnego etanolu* Otrzymano 11,0 g /78%/ - bezowych krysztalów 2-/3-amino-4-metyloanilino/lepidyny /wzór 6, R7» RQo CH3/.Po krystalizacji otrzymano kremowe krysztaly, temperatura topnienia 75 - 77 C /etanol-woda/* IR /KBr, cm"1/* 3360-3200, 1610, 1565, 1515, 1485, 1405, 1395, 750.Analiza: dla C17H17N3 * 1H2° /261,3/j Obliczono: 72,57% C; 6,81% H, 14,94% N.Oznaczono: 73,15% Cj 6,62% H; 15,11% N. - 2-/2-amino-4-raetyloanilino/lepidyne /8,4g, 0,03 mola/ rozpuszczono w mieszaninie 36% HCl-^O- etanol 1:1:1 /75 cm3/ i mieszajec w temperaturze 0-5°C wkraplano do roztworu NaN02 /2,3 g, 0,033 mola/ w wodzie /50 cm /• Calosc mieszano w temperaturze 0-5 C przez 30 min, po czym pozostawiono przez noc i odseczono produkt* Po rekrystalizacji z etanolu otrzymano bezbarwne krysztaly 2-/5-metylo-l-benzotriazolo/lepidyny /wzór 7, R7- Rg= CH3/ o temperaturze topnienia 150-152°C, wydajnosc 8,Ig /98%/» IR /KBr, cm"1/: 1600, 1425, 1050, 910.Analiza: dla CA H N /274,3/; 1/ 14 4 Obliczono: 74,43% Cj 5,14% H; 20,42% N, Oznaczono: 74,23% Cj 4,99% H; 20,45% N. - 2-/5-metylo-l-benzotriazolo/lepidyne /5,5 g, 0,02 mola/ dodano do kwasu polifosforowego /30 cm / i ogrzewano mieszanine w temperaturze 130-140°C w ciegu 30 min* oraz 200°C w ciegu 20 min* Po ochlodzeniu mieszanine rozpuszczono w etanolu /50 cm / i ogrzewano na lazni wodnej z roztworem kwasu pikrynowego /5g/ w 75% etanolu /150 cm3/. Wytworzony osad odseczono, prze¬ myto wode i ogrzewano w 8% NaOH /250 cm /. Po ochlodzeniu odseczono produkt, przemyto kolejno wode, 15% HCl i amoniakiem, po czym rekrystalizowano z pirydyny: kremowe krysztaly 9-11-dime- tylo-6H-indolo/2,3-b/ chinoliny /wzór 1, R7» Rga CH3/o temperaturze topnienia powyzej 300°C, wydajnosc 2,5 g /51%/* IR /KBr, cm"1/: 3150 - 2850, 1595, 750.XH NMR /100 MHz, CF3COOH, cT ppm/: 8,41 /d,lH,J»7/, 8,03-7,62 /m, 4H/, 7,37 /s, 2H/, 3,28 /s, 3H/, 2,53 /s, 3H/.MS /-70 eV, m/e/: 246 /100%/.Analiza: dla C H N /246,3/j 17 14 2 Obliczono :82,90% C; 5,73% Hj 11,37% N.Oznaczono: 82,71% C| 5,53% H; 11,32% N.148 212 3 - 9,ll-dimetylo-6H-indolo /2,3-t7 chinoline /2,5 g, Ot01 mola/, jodek netylu /4 cm / i etanol /25 cm3/ ogrzewano w zamknietej rurze w temperaturze 100-105°C w ciegu 12 godzin. Po ochlodzeniu do mieszaniny dodano eter, odseczono produkt, przemyto eterem i rekrystalizowano z mieszaniny metanol-eter» Otrzymano zólte krysztaly Jodku 5,9,ll-trimetylo-6H-indolo /2,3-b/ chinolinowego /wzór 2, R ¦ R « R«,nm CH / o temperaturze topnienia 275-285°C /rozklad/ z wydajnoscia 3f8g /98%/.Analiza: dla C H N J /388,2/i 18 1/ 2 Obliczono: 55,68% C; 4,41% Hi 7,22% N.Oznaczono: 55,10% Cj 4,20% H; 7,00% N.Przyklad II* Otrzymywano z 2-chlorolepidyny /10,6g, 0,06 mola/ i 4,meto- ksy-2-nitroaniliny /10,lg, 0,06 mola/ oraz wyodrebniono, jak w przykladzie I, ciemnoczerwone krysztaly 2-/4-metoksy-2-nitroanilino/lepidyny /wzór 5, R7=0CH3, Rg- CH3/, temperatura topnie¬ nia 148-150°C /etanol/, wydajnosci 13,3g /72%/.IR /KBr, cm"1/: 3400, 1505, Analiza: dla C H N O /309,3/; 17 Ib o J Obliczono: 66,01% C; 4,98% H; 13.58% N.Oznaczono: 65,74% Cr 4,74% Hj 13,46% N.- Otrzymywano z 2-/4-metoksy-2-nitroanilino/lepidyny /15,5 g, 0,05 mola/ oraz wyodrebniono, jak w przykladzie I 2-/2-amino-4-metoksyanilino/lepidyne /wzór 6, R = CHo» Rga CH3/'• wydajnosc 13,0g /99%/. Zwiezek uzyto dalej do nastepnego przeksztalcenia bez charakteryzacji.- Otrzymywano z 2-/2-amino-4-metoksyanilino/lepidyny /8,4g, 0,03 mola/ oraz wyodrebniono jak w przykladzie I kremowe krysztaly 2-/5-metoksy-l-benzotriazolo/lepidyny /wzór 7, R7» 0CH3, Rg» CH^/, temperatura topnienia 163-165°C /etanol/ wydajnosc 8,1 g /93%/.IR /KBr, cm" /: 1500, 1310.Analiza: dla C H NO /290,3/; 17 14 4 Obliczono: 70,33% Cj 4,86% Hf 19,29% N.Oznaczono: 70,13% C; 4,78% Hj 19,27% N. - 2-15-metoksy-l-benzotriazolo/lepidyne /5,8g, 0,02 mola/ dodano do kwasu polifosforowego 3 o o /30 cm / i ogrzewano w temperaturze 120-130 C w ciegu 30 min. i w temperaturze 180 C w ciegu 1 min, po czym wyodrebniono jak w przykladzie I zólte igly 9-metoksy-ll-metylo-6H-indolo /2,3-b/ chinoliny /wzór 1, R_= OCH , Rq= CH /, temperatura topnienia 283-285°C /pirydyna/, wydajnosc 1,2 g /23%/» IR /KBr, cm"1/: 3250-2700, 1670, 1490.XH NMR/100 MHz, CF3COOH, cfppm/: 8,45 /d, 1H, 3-9/f 7,75-8,03 /m, 4H/, 7,59 /d, 1H, 0=9/, 7,31/d, 1H, ^,05 /s, 3H/, 3,27 /s, 3H/.MS /-70 eV, m/e/: 262 /77%/, 247 /100%/.Analiza: dla C H N O /262,3/j 17 14 2 Obliczono: 77,85% C; 5,38% H; 10.68% N.Oznaczono: 77,97% Cj 5,23% Hj 10,71% N.- Otrzymano z 9,metoksy-ll-metylo-6H-indolo /2,3-b7 chinoliny /2,6g, 0,01 mola/ i Jodku mety- 3 lu /4 cm /, oraz wyodrebniono jak w przykladzie I, zólte krysztaly jodku 9-raetoksy-5,ll-dime- tylo-6H-indolo /2,3-b7chinoliniowego /wzór 2, R * OCH , R ¦ R =CH /,temperatura topnienia / O 9 10 w 235-245 C /rozklad/, /metanol-eter/, wydajnosc 3,5 g/87%/.Analiza: dla C18H17N20;D Z^4*2/* Obliczono: 53,48% C* 4,24% Hj 6,93% N.Oznaczono: 52,99% Cj 4,16% Hj 7,11% N.4 148 212 Zastrzezenia patentowe 1« Sposób wytwarzania pochodnych 6H-indolo /2,3-b7chinoliny o ogólnym wzorze 1, w którym R , R-, R3, R , R , R , R , R_, Rg sa takie same lub rózne i oznaczaja atom wodoru, grupe alkilowe lub alkoksylowe o 1-4 atomach wegla pierwszo-, drugo- lub trzeciorzedowe, grupe trifluorometylowe, hydroksylowe lub atom fluorowca, ewentualnie w postaci soli czwarto rzedowych, znamienny tym, ze 2-fluorowcopochodne chinoliny o wzorze 3, w którym R2, R_, R. i Rg maje wyzej podane znaczenie, zas Y oznacza atom fluorowca poddaje sie konden sacji z pochodne o-nitroaniliny o ogólnym wzorze 4, w którym R5, Rg, Ry i Rg maje wyzej pod znaczenie, po czym powstale pochodne o wzorze 5, w którym R^ do Rg maje wyzej podane znaczen redukuje sie do pochodnej o ogólnym wzorze 6, w którym R. do Rg maje wyzej podane znaczenie, nastepnie diazuje sie roztworem NaN02» zas otrzymane pochodne triazolu o wzorze 7, w którym Ri do R9 maJ$ wyzej podane znaczenie poddaje sie rozkladowi w podwyzszonej temperaturze, a p zakonczeniu wydzialania sie azotu wyodrebnia sie produkt w znany sposób i ewentualnie przepr wadza go w sól czwartorzedowe* 2. Sposób wedlug zastrz.l, znamienny tym, ze pochodne triazolu o wzorze 7, w którym R^ do Rg maje wyzej podane znaczenie poddaje sie rozkladowi w kwasie poliofosfo- rowym lub oleju parafinowym, korzystnie w temperaturze powyzej 100 C» R10 H X' WZÓR 1 N' Y WZÓR i.WZÓR 6 WZÓR 7 Pracownia Poligraficzna UP RP. Naklad 100 egz.Cena 1500 zl PLThe present invention relates to a process for the preparation of 6H-indole / 2,3-b7 quinoline derivatives of the formula 1, wherein R 1, R 1, R 1, R 2, R 6, R g, R 9, RQ and RQ are the same or different and denote a hydrogen atom, an alkyl or alkoxy group with 1-4 primary, secondary or tertiary carbon atoms, a trifluoromethyl group, a hydroxyl group or a halogen atom, optionally in the form of a quaternary salt of formula II, where R ± to Rg has the meaning given above , R5q represents a 1-4 carbon primary, secondary or tertiary alkyl group, a trifluoromethyl group, and X "represents an acid residue, preferably Cl", Br ", J ~. HS04, CH3SO4. These new compounds are Potential DNA intercalators are the structural isomers of benzo-carboline, which shows high cytostatic activity in in vivo tests on mouse Sa tumor 180/80% tumor growth inhibition at a dose of 100 mg / kg / L. Kaczmarek, P. Nantka-Namirski , Pol. 3. Phamacol, Pharm. 33, 121/1981 ^ In connection with the above, the compounds produced by sp the person according to the invention has potential antitumor properties, and is also a starting material for the preparation of derivatives with high cytostatic, bacteriostatic and antifungal activity (Polish Patent No. 144,539). The method of producing derivatives according to the invention consists in that 3, in which R 1, R 2, R 4, R 4 and R 6 are as defined above, and Y is a halogen atom, are condensed with the o-nitroaniline derivatives of the general formula 4, wherein R, R, R and R has the meaning given above, and the resulting derivatives of formula 5 are reduced to the derivative of general formula 6, in which R to Rg has the same meaning as above * They are then diazotized to the benzotriazole derivative of formula 7, decomposed at elevated temperature, and then cessation of nitrogen evolution, the product is isolated in a known manner * Quaternary salts of formula 2 are obtained by reacting compounds of formula 1 with derivatives of formula R qX, where R10 is an alkyl group with 1-4 carbon atoms 148 2122 148 212 primary, secondary or tertiary, trifluoromethyl, and X is an acid residue - preferably Cl ", Br", O ", HSO4, CK According to the invention, the thermal decomposition of the triazole of formula 7, in which R 1 - RQ has the meaning given above, is most conveniently carried out in polyphosphoric acid or paraffin oil in the temperature range 120-350 ° C. The following examples illustrate the process according to the invention * Example I * A mixture of 2-chlorolepidine / 10.6 g, 0.06 mol / and 4-methyl-2-nitroaniline / 9.2 g, 0.06 mol / melted and heated with a stirrer at 150 - 160 ° C for 10 hours * After cooling, the mixture was dissolved in ethanol, an ammonia solution was added and allowed to cool in the refrigerator * Separated red crystals of 2- (4-methyl-2-nitroaniline / lepidin / formula 5, Rg »CH2) / drained, yield 17.5 g / quantitative / * Red crystals, melting point 151 - 153 ° C / from ethanol / * IR / KBr, cm "1 /: 333 0.1525 * Analysis: for C17H15N302 (293.3); Calculated: 69.61% Cj 5.15% Hj 14.32% N Found: 69.41% C; 4.89% H 14.33% N. - 2- (4-methyl-2-nitroanilino / lepidine / 14.7 g, 0.05 mol) was added in portions with a stirrer and a cooler 3 3 to a solution of 60 g of stannous chloride in a mixture of 36% HCl / 100 cm / and ethanol (10 cm), and then the whole thing is heated in a water bath for 1 hour. After cooling, the reaction mixture is left overnight in the refrigerator, the separated tin complex of the product is filtered off and mixed with an excess of 20% NaOH. The separated product drained and recrystallized from aqueous ethanol. Obtained 11.0 g (78%) - meringue 2- (3-amino-4-methylaniline) crystals (lepidin (formula 6, R7, RQo CH3). After crystallization, cream crystals were obtained, m.p. 75 - 77 C (ethanol-water) * IR / KBr, cm "1 / * 3360-3200, 1610, 1565, 1515, 1485, 1405, 1395, 750. Analysis: for C17H17N3 * 1H2 ° / 261.3 / j Calculated : 72.57% C; 6.81% H, 14.94% N Found: 73.15% Cj 6.62% H; 15.11% N - 2- (2-amino-4-raethylanilino) lepidine (8.4 g, 0.03 mol) was dissolved in the mixture of 36% HCl- 4 O-ethanol 1: 1: 1/75 cm3 / and stirred at the temperature 0-5 ° C was added dropwise to the NaNO 2 solution / 2.3 g, 0.033 mol / in water / 50 cm / • The whole was stirred at 0-5 C for 30 min, then left overnight and the product was filtered off * After recrystallization from ethanol colorless crystals of 2- (5-methyl-1-benzotriazole) lepidin (formula 7, R7-Rg = CH3) were obtained with a melting point of 150-152 ° C, yield 8, Ig / 98% / »IR / KBr, cm" 1 /: 1600, 1425, 1050, 910. Analysis: for CA HN / 274.3 /; 1/14 4 Calculated: 74.43% Cj 5.14% H; 20.42% N, Found: 74.23% Cj 4.99% H; 20.45% N. - 2- (5-methyl-1-benzotriazole (lepidine) (5.5 g, 0.02 mol) was added to polyphosphoric acid (30 cm) and the mixture was heated at 130-140 ° C in a 30 min * and 200 ° C in 20 min * After cooling, the mixture was dissolved in ethanol (50 cm 3) and heated in a water bath with a picric acid solution (5 g) in 75% ethanol (150 cm 3). The resulting precipitate was filtered off, washed with water and heated in 8% NaOH (250 cm). After cooling, the product was desalted, washed successively with water, 15% HCl and ammonia, then recrystallized from pyridine: cream crystals 9-11-dimethyl-6H-indole (2,3-b) quinoline / formula 1, R7 »Rga CH3 (melting point above 300 ° C, yield 2.5 g (51%) * IR / KBr, cm "1): 3150 - 2850, 1595, 750.XH NMR / 100 MHz, CF3COOH, cT ppm /: 8, 41 (d, 1H, J, 7), 8.03-7.62 (m, 4H), 7.37 (s, 2H), 3.28 (s, 3H), 2.53 (s, 3H) .MS (-70 eV, m / e): 246 (100%). Analysis: CHN (246.3) 17 14 2 Calculated: 82.90% C; 5.73% Hj 11.37% N. Determined: 82.71% C | 5.53% H; 11.32% N. 148 212 3-9.11-dimethyl-6H-indole / 2.3-t7 quinoline / 2.5 g, Ot01 mole /, Netyl iodide (4 cm) and ethanol (25 cm 3) were heated in a closed tube at 100-105 ° C for 12 hours. After cooling, ether was added to the mixture, the product was suction filtered, washed with ether and recrystallized from a methanol-ether mixture. 5.9,11-trimethyl-6H-indole (2,3-b) quinoline iodide crystals (formula 2, R "R" R ", nm CH) melting point 27 5-285 ° C (decomposition) in a yield of 3 [mu] g (98%). Analysis: for CHN J (388.2) and 18 1/2. Calculated: 55.68% C; 4.41% Hi 7.22% N Found: 55.10% Cj 4.20% H; 7.00% N. Example II * Prepared from 2-chlorolepidine (10.6 g, 0.06 mol) and 4, methoxy-2-nitroaniline (10.1 g, 0.06 mol) and isolated as in the example I, dark red crystals of 2- (4-methoxy-2-nitroanilino) lepidin (formula 5, R7 = OCH3, Rg-CH3), mp 148-150 ° C (ethanol), yield 13.3 g (72%) .IR (KBr, cm "1): 3400,1505, Analysis: for CHNO (309.3); 17 Ib o J Calculated: 66.01% C; 4.98% H; 13.58% N Found: 65, 74% Cr 4.74% Hj 13.46% N - Prepared from 2- (4-methoxy-2-nitroanilino) lepidin (15.5 g, 0.05 mol) and isolated as in example I 2- / 2-amino-4-methoxyanilino / lepidine / formula 6, R = CHo »Rga CH3 / '• yield 13.0 g (99%). The animal was further used for the next conversion without characterization. - Obtained from 2- (2-amino-) 4-methoxyanilino (lepidins) (8.4 g, 0.03 mol) and cream crystals of 2- (5-methoxy-1-benzotriazole) lepidins (formula 7, R7, OCH3, Rg, CH2), were isolated as in example I mp 163-165 ° C / ethanol / Yield 8.1 g (93% IR / KBr, c m "/: 1500, 1310. Analysis: for CH NO / 290.3 /; 17 14 4 Calculated: 70.33% Cj 4.86% Hf 19.29% N Found: 70.13% C; 4.78% Hj 19.27% N - 2-15-methoxy-1-benzotriazole (lepidine) (5.8 g, 0.02 mol) was added to polyphosphoric acid 3 oo (30 cm) and heated at 120-130 C within 30 minutes. and at a temperature of 180 C during 1 min, after which the yellow needles of 9-methoxy-11-methyl-6H-indole (2,3-b) quinolines (formula 1, R_ = OCH, Rq = CH) were isolated as in example I, mp 283-285 ° C (pyridine), yield 1.2 g (23%) "IR (KBr, cm" 1): 3250-2700, 1670, 1490. XH NMR (100 MHz, CF3COOH, cfppm): 8 , 45 (d, 1H, 3-9 (f) 7.75-8.03 (m, 4H), 7.59 (d, 1H, 0 = 9), 7.31 (d, 1H, R-05) s, 3H), 3.27 (s, 3H) .MS (-70 eV, m / e): 262 (77%), 247 (100%). Analysis: for CHNO (262.3) j 17 14 2 Calculated: 77.85% C; 5.38% H; 10.68% N Found 77.97% Cj 5.23% Hj 10.71% N - Prepared from 9, methoxy-11-methyl-6H-indole (2,3-b7 quinoline / 2.6 g, 0.01 mole) and methyl iodide (4 cm), and yellow crystals of 9-raetoxy-5,1l-dimethyl iodide were isolated as in example 6H-indole / 2,3-b7quinoline / formula 2, R * OCH, R ¦ R = CH /, melting point / O 9 10 at 235-245 C / decomposition /, / methanol-ether /, yield 3.5 g (87%/. Analysis: for C18H17N2O; DZ ^ 4 * 2) * Calculated: 53.48% C * 4.24% Hj 6.93% N. Found: 52.99% Cj 4 , 16% Hj 7.11% N 4 148 212 Claims 1 "Process for the preparation of 6H-indole / 2,3-b7quinoline derivatives of the general formula 1, in which R, R-, R3, R, R, R, R , R, R 8 are the same or different and represent a hydrogen atom, a 1-4 alkyl or alkoxy group with 1-4 primary, secondary or tertiary carbon atoms, a trifluoromethyl, hydroxyl or halogen group, optionally in quaternary salt form, characterized by that 2-halogen derivatives of quinoline of formula III, wherein R2, R_, R. and Rg have the same meaning as defined above, and Y is a halogen atom is condensed with o-nitroaniline derivatives of formula IV, in which R5, Rg, Ry and Rg is as defined above, whereupon the resulting derivatives of formula 5, in which R5 to Rg have the above meaning, are reduced to the derivative of general formula 6, in which R. to Rg is as defined above, then diazotized with NaNO2 solution »And the obtained triazole derivatives of formula 7, in which Ri to R9 have the meaning given above, are subject to decomposition at an elevated temperature, the product is isolated in a known manner after the evolution of the nitrogen has ceased and, if necessary, it is quaternized * 2. The process according to claim 1, characterized in that the triazole derivatives of formula 7, wherein R 1 to R 8 have the above-mentioned meaning is decomposed in polyphosphoric acid or paraffin oil, preferably at a temperature above 100 ° C. R10 HX 'PATTERN 1 N' Y PATTERN and PATTERN 6 PATTERN 7 Printing Workshop of the Polish Patent Office. Mintage 100 copies Price PLN 1,500 PL

Claims (2)

1. Zastrzezenia patentowe 1« Sposób wytwarzania pochodnych 6H-indolo /2,3-b7chinoliny o ogólnym wzorze 1, w którym R , R-, R3, R , R , R , R , R_, Rg sa takie same lub rózne i oznaczaja atom wodoru, grupe alkilowe lub alkoksylowe o 1-4 atomach wegla pierwszo-, drugo- lub trzeciorzedowe, grupe trifluorometylowe, hydroksylowe lub atom fluorowca, ewentualnie w postaci soli czwarto rzedowych, znamienny tym, ze 2-fluorowcopochodne chinoliny o wzorze 3, w którym R2, R_, R. i Rg maje wyzej podane znaczenie, zas Y oznacza atom fluorowca poddaje sie konden sacji z pochodne o-nitroaniliny o ogólnym wzorze 4, w którym R5, Rg, Ry i Rg maje wyzej pod znaczenie, po czym powstale pochodne o wzorze 5, w którym R^ do Rg maje wyzej podane znaczen redukuje sie do pochodnej o ogólnym wzorze 6, w którym R. do Rg maje wyzej podane znaczenie, nastepnie diazuje sie roztworem NaN02» zas otrzymane pochodne triazolu o wzorze 7, w którym Ri do R9 maJ$ wyzej podane znaczenie poddaje sie rozkladowi w podwyzszonej temperaturze, a p zakonczeniu wydzialania sie azotu wyodrebnia sie produkt w znany sposób i ewentualnie przepr wadza go w sól czwartorzedowe*1. Claims 1 "Process for the preparation of 6H-indole / 2,3-b7quinoline derivatives of the general formula 1, wherein R, R-, R3, R, R, R, R, R_, Rg are the same or different and are hydrogen atom, alkyl or alkoxy groups with 1-4 primary, secondary or tertiary carbon atoms, trifluoromethyl, hydroxyl or halogen, optionally in the form of quaternary salts, characterized in that the 2-halogen quinoline compounds of formula III are R2, R_, R. and Rg have the meaning given above, and Y is a halogen atom is condensed with the o-nitroaniline derivatives of the general formula where R5, Rg, Ry and Rg are as defined above, and then the resulting derivatives are of formula 5 in which R5 to Rg has the above meaning is reduced to the derivative of general formula 6 in which R to Rg has the above meaning, then diazotized with NaNO2 solution and the resulting triazole derivatives of formula 7 in which Ri to R9 have the meaning given above decomposes in increased t temperature, and after the nitrogen evolution has ended, the product is isolated in a known manner and possibly converted into quaternary salt * 2. Sposób wedlug zastrz.l, znamienny tym, ze pochodne triazolu o wzorze 7, w którym R^ do Rg maje wyzej podane znaczenie poddaje sie rozkladowi w kwasie poliofosfo- rowym lub oleju parafinowym, korzystnie w temperaturze powyzej 100 C» R10 H X' WZÓR 1 N' Y WZÓR i. WZÓR 6 WZÓR 7 Pracownia Poligraficzna UP RP. Naklad 100 egz. Cena 1500 zl PL2. A method according to claim 1, characterized in that the triazole derivatives of formula 7, in which R 1 to R g has the meaning given above, are decomposed in polyophosphoric acid or paraffin oil, preferably at a temperature above 100 ° C. R10 HX ' PATTERN 1 N 'Y PATTERN i. PATTERN 6 PATTERN 7 Printing workshop of the Polish Patent Office. Mintage 100 copies Price PLN 1500 PL
PL26301586A 1986-12-16 1986-12-16 The method of manufacture of derivatives of 6-h-indol/2,3-b/-quinoline PL148212B1 (en)

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