Synthetic studies on pyrroloquinolines. Part III. Improved synthesis of 7-chloro-2,3-dihydro-4-methoxy-1H-pyrrolo2,3-bquinoline and its conversion into 3a,10b-diazacyclopentajkphenanthrene derivatives

摘要

1974 1593Synthetic Studies on Pyrroloquinolines. Part 111.l Improved Synthesis of7-Chloro-2,3-dihydro-4-methoxy-lH-pyrrolo2,3-bquinoline and its Con-version into 3a,I Ob-Diazacyclopentajkphenanthrene DerivativesBy Tadasu Tanaka,' lkuo lijima, Michihiko Miyazaki, and Takeo Iwakuma. Organic Chemistry ResearchLaboratory, Tanabe Seiyaku Co. Ltd., Toda, Saitama, Japan3-(2-Aminoethyl) -7-chloro-4-methoxy-2-quinolone (7) was prepared by methylation of 7-chloro-4-hydroxy-3-(2-phthalimidoethyl)-2-quinolone and removal of the phthaloyl group. Cyclization of the 3-(2-acetamidoethyl)derivative (9) gave, after hydrolysis, the pyrrolo2,3-bquinoline (1 2). An addition reaction with ethyl acrylatefollowed by reduction with aluminium hydride led to the pyrroloquinolin-1 -ylpropanol (1 4).which was cyclizedto the diazacyclopentajkphenanthrene (1 6 ) via the quaternary salt (1 5). Hydrolysis of compound (1 6) gave the6-ketone (1 7), whose structure was confirmed by its n.m.r. spectrum.A SERIES of pyrrolo2,3-bquinoline derivatives 1,2 hasbeen found to possess promising antiphlogistic activityin the rat. We report here an improved method forsynthesizing 7-chloro-2,3-dihydro-4-methoxy- 1H-pyrrolo-2,3-bquinoline (12), the most active compound of theseries, and the preparation from it of 3a,l0b-diazacyclo-pentarjk phenanthrenes.Diethyl (2-phthalimidoethy1)malonate (1), readilyobtainable from 2-phthalimidoethyl bromide and diethylsodiomalonate,3 was condensed with m-chloroaniline indiphenyl ether at 240-250' to give 7-chloro-4-hydroxy-3-(2-phthalimidoethyl)-2-quinolone (2) in 94 yield.Methylation of compound (2) with methyl toluene+-sulphonate in anhydrous medium at room temperaturegave the 4-methoxy-derivative (3) (93) ; the 4-meth-oxy-l-methyl compound (6) was the predominantproduct of methylation at 50-40".Use of dimethylsulphate gave compound (3) in poorer yield. Methyla-tion with methyl iodide gave mainly the 3-methylderivative (4), whereas diazomethane gave compound (3)and the 2,4-dimethoxy-derivative (5) in the ratio 3 : 1.These methylation products were identified on the basisof analytical figures and i.r. spectroscopy (McCorkindale'sgeneralization on the carbonyl stretching bands of2- and 4-quinolones was adopted, though some excep-tions have been pointed out by Ishii 6).The phthaloyl group of the quinolone (3) was readilyremoved 'furnishing the amine (7) (96).For compari-son compound (6) was similarly converted into the aminePart 11, T. Tanaka, T. Iwakuma, M. Miyazaki, M. Wagat-suma, and I. Iijima, Chem. and Pharm. Bull. (Japan), 1972, 20,109. * T. Tanaka, T. Iwakuma, 11. Wagatsunia, and I. Iijima,J . Heterocyclic Chem., 1972,9, 1356. * R. Riemschneider, K. Brendel, and K. Preuss, Monalsh.,1961, 92, 1240.(8). Although attempted cyclization of the ainine (7)with acidic reagents proved fruitless, treatment of itsacetyl derivative (9) with phosphoryl chloride containinga few drops of pyridine gave the acetyl compound (10)in 71 yield. Alkaline hydrolysis then led to thepyrroloquinoline (12) in almost quantitative yield.When the pyridine was omitted from the reactionmedium, the yield was much lower.Use of morevigorous reaction conditions gave rise to the 4-chloro-compound ( l l ) , formed in competition with compoundCondensation of compound (12) with ethyl acrylate inthe presence of Triton B yielded the adduct (13) in 70yield, which was reduced with lithium aluminium hydridein tetrahydrofuran at 5-10deg;, affording the alcohol (14)in 72 yield v,, 3330 cm-l (OH). The alcohol (14)was treated with thionyl chloride in the presence oftriethylamine, and the crude product was heatedunder reflux in benzene to afford the quaternarysalt (15). Without purification, the salt was reducedwith sodium borohydride in methanol to give thediazacyclopentaphenanthrene (16) in 64 overall yieldfrom the alcohol (14).Its U.V. spectrum indicated thatrupture of the quinoline chromophore had occurred andits i.r. spectrum exhibited two sharp Bohlmann bands(2760 and 2720 cm-l) and a band due to C=C stretchingconjugated with the benzene ring. Its mass (M+ 262)(10).4 ( a ) N. J. McCorkindale, Tetrahedron, 1961, 14, 223; (b)M. F. Grundon, N. J. McCorkindale, andM. N. Rodger, J . Chem.Soc., 1955,4284; (c) B. Witkop, J . P. Patrick, andM. Rosenblum,J . Amer. Chem. Soc., 1961, 73, 2641.a H. R. Ing and R. F. H. Rlanske, J . Chem. Soc.. 2348, 1926.7 N. Ito, K. Irie, Y. Sato, and M. Wada, presented in part atthe 93rd Annual Meeting of Pharmaceutical Society of Japan,Tokyo, April 1973.H.Tshii, Yagugaku Zassiii, 1961, 81, 2481594 J.C.S. Perkin IAcO M e+OMeH H( 1 1 1 (7)CL a- bsol; Phth = p h t h a l o y lAc H(10 1 ( 1 2 1OMeC l a T L bsol; NP h t hMe( 6 )OMc( 8 1SCHEME 1' U 3( 1 7 ) 2SCHEME 1974 1595and n.m.r. spectra T 6-27 (s, OMe) and 6.14 (s, 10c-H)supported the structure (16).Finally, the methoxy-derivative (16) was convertedinto the ketone (17) almost quantitatively by treatmentwith methanolic 10 hydrogen chloride. The n.m.r.spectrum showed a characteristic downfield shift of the7-proton signal T 2.12 (d, J 9 Hz) in comparison withcompound (16), due to the magnetic anisotropy of thenewly formed carbonyl group. The 6a,lOc-H couplingconstant (7 Hz) suggested a cis ring junction; additionof deuterium oxide turned the 10c-H signal into asinglet.EXPERIMENTAL1.r. spectra were recorded with a JASCO 1R-E spectro-meter for Kujol mulls, U.V.spectra with a Hitachi EPS-2Uspectrometer, n.m.r. spectra with a JEOL JNM-MH-60spectrometer (tetramethylsilane as internal standard), andmass spectra with a Hitachi RMS-4 spectrometer.7-Chloro-4- hydroxy-3-( 2-phthalimidoethyl)-2( 1H)-quinolone(2) .-A solution of diethyl (2-phthalimidoethy1)malonate(40.0 g, 0.12 mol) and m-chloroaniline (16.6 g, 0.12 mol) indiphenyl ether (240 ml) was heated at 250-260" for 3 hwhile the ethanol produced was distilled off. The solutionwas cooled and the product was filtered off and washed withether t o give the quinolone (2) (41.6 g, 94), m.p.270deg;, asrhombs (Found: C, 61.75; H , 3.65; C1, 9.7; N , 7.65.C,,H,,ClN,O, requires C , 61-9; euro;3, 3-55; C1, 9.6; N , 7-6),vmX. 3280 ( N H ) , 1755, and 1690 cm-l, 7 (CF,*CO,D) 1.77( l H , d, J 9 H z , H-5), 2.26 ( l H , d, J 2 H z , H-8), and 2-40(lH, q, J 2 and 9 H z , H-6).Methylation of the Quinolone (2) .-(a) With methyl toluene-p-sulphonate and with dimethyl sulphate. To a stirred mix-ture of the quinolone (2) (180.0 g, 0.488 mol) and an-hydrous potassium carbonate (67.2 g, 0.488 mol) in di-methylformamide (2.5 1), methyl toluene-p-sulphonate(197.2 g, 1.07 mol) was added dropwise at 20-25" andstirring was continued for 17 h. After addition of glacialacetic acid (100 g) the mixture was poured into ice-water(ca.1 kg) and the solid was collected, washed with water andbenzene, and dried to give 7-chloro-4-methoxy-3-(2-~hthaZim-idoethyZ-2( 1H)-quinolone (3) (173 g, 93), m.p. 268-260"(from methanokhloroform) (Found: C, 63.05; H, 3.96;C1, 9.35; X, 7.35. C,H,,ClN,O, requires C, 63-75; H ,3.95; C1, 9-5; N, 7.3), Y- 1640 cm-l, T (CD,),SO 6-15(3H, s). When a large excess of this methylating agent wasused and the reaction mixture was kept at 50-60", 7-chlovo-4-mcthoxy- 1 -methyl- 3- (2-phthalimidoethyl) -2 ( 1 H) -quinoZone( 6 ) was obtained as the major product (31-7), accompaniedb y 7-chlo~o-2,4-dimethoxy-3- (2-Phthalimidoethyl) quinoline (5)(10.9) and the quinolone ( 3 ) (26.1), separated b ycolumn chromatography on alumina with chloroform aseluant.Compound (5) had m.p. 137-139" (from meth-anol) (Found: C, 63.8; H , 4.45; C1, 8.7; N , 7.0. C,,H,,-ClN,O, requires C, 63-55; H, 4.3; C1, 8.95; N , 7.050,/,),vmX. 1620 cm'l (C=N), T (CD,),SO 6-25 (3H, s, 4-OMe) and6-10 (3H, s, 2-OMe). Compound (6) had m.p. 212-213'(from acetic acid) (Found: C, 63.65; H , 4.4; C1, 9.1; N ,7.25. C,,H,,ClN,O, requires C , 63.55; H , 4.3; C1, 8-95;N , 7.05), vmX 1634 cm-', T (CD,),SO 6-18 (3H, s, ONe)and 6.42 (3H, s, NMe). When methyl toluene-9-sulphonatewas replaced by dimethyl sulphate under the same reactionconditions, compound (3) (53.7 yield) was the onlyseparable product.(b) With methyl iodide. A mixture of compound (2)(3.68 g, 0.01 mol), anhydrous potassium carbonate (1.38 g,0.01 mol), and methyl iodide (1.70 g, 0.012 mol) in dimethyl-formamide (50 ml) was stirred a t room temperature for 18 h,then poured into ice-water.The product was filtered off,washed with water, dried, dissolved in chloroform, andpurified by column chromatography on alumina (chloro-form as eluant). Compound (3) (0.72 g, 18.8) was elutedfirst, followed by 7-chloro- 3-methyl-3- (2-phthalimidoethyZ)-quinoline-2( lH),4(3H)-dione (4) (2.56 g, 67.0y0), m.p. 222-224' (from chloroform) (Found: C, 62-6; H , 3-8; C1, 9.66;N , 7.26. C,H,,ClN,O, requires C, 62.75; H , 3-95; C1,9.25; N , 7*3), vmak 1780, 1708, 1680, and 1644 cm'l,7 (CDCl,) 8.65 (3H, s, Me).(c) With diazomethane. To a suspension of compound(2) (0.92 g, 0.0026 mol) in anhydrous methanol (14 ml) andchloroform (40 ml), a large excess of ethereal diazomethane(ca.0.025 mol) was added, and the mixture was left at roomtemperature. After 3 days, insoluble material was filteredoff and the filtrate was evaporated in vacuo. The residuewas purified by fractional recrystallization from chloro-form-methanol to give compound (3) (0.21 g, 22.1), m.p.260-262" and compound (5) (0.05 g, 5.06), m.p. 137-139'.3-( 2-Aminoethyl)-7-chlo~o-4methoxy-2( 1H)-quinolone (7).-To a boiling solution of compound (3) (160.0 g, 0.418 mol)in dioxan (4.80 1) and methanol (2.40 1). 90 hydrazinehydrate (150.0 g, 2.70 mol) was added all at once, andrefluxing was continued for 1.5 h. The solvent was evapo-rated off in vacuo and the residue was dissolved in aceticacid (4.0 1) at 80-90".To the solution was added 10hydrochloric acid (530 ml) in one portion and the resultingsolution was kept at 30" for 16 h. The separated solid wascollected, washed with acetone, and dried in air to give thecrude hydrochloride of compound (7) (116 g , 95.1), m.p.264-266" (decomp.) (from methanol) (Found: C, 49.4; H ,4-8; C1, 24-55; N, 9.56. C,,H,,Cl,N,O, requires C, 49-85;H, 4.9; C1, 24.5; N, 9-7), v,, 1645 cm-l; the free basc(7) had m.p. 164-165" (from methanol) (Found: C, 57.3;H, 6.25; C1, 14.0; N , 11.2. Cl,Hl,CIN,O, requires C,3- (2-A minoethyl) -7-chloro-4-methoxy- l-met hyl-2 ( 1 H ) - p i n -olone (euro;9.-By using the same procedure as described in thepreparation of compound (7), compound (6) was convertedinto the hydrochlovide of the quinolone (8) (87 yield), m.p.204-205' (Found: C, 51.35; H , 5.6; C1, 23.5; N , 9.3.C,,H,,Cl,N,O,requires C, 61.5; H , 5.3; C1,23.4; N , 9.25) ;the free base (8) had m.p.129-132" (from n-hexane)(Found: C, 58.4; H , 5.8; C1, 13.4; N , 10.6. Cl,Hl,C1N,02requires C, 68.55; H , 5-65; C1, 13.3; N, 10*5), vmx. 1640cm-'.3- (2-A cetamidoethyl) -7-chloro-4-methoxy-2( 1 H)-quinolone(9).-To a stirred solution of compound (7) (20.2 g, 0.08mol) in glacial acetic acid (50 ml) was added acetic anhydride(12.3 g, 0.12 mol) at 40". The mixture was stirred for 20min, the solvent was evaporated off in vacuo, and theresidue was triturated with methanol (100 ml). The solidwas filtered off and dried to give the product (9), m.p.283-285" (decomp.) (from acetic acid-methanol) (Found : C,56.9; H, 5.2; C1, 11.9; N , 9-55. Cl4H1,C1N20, requires C,(3H, s, OMe) and 7.72 (3H, s, Ac).l-Acetyl-7-chloro-2,3-dihydro-4-methoxy- lH-pyrrolo2,3-b-quinoline (10) .-A stirred suspension of compound ( 9 ) (60-057-05; H , 5.2; C1, 14.05; N, ll*lyo).57.05; H , 5-15; C1, 12.05; N , 9*5), T (CF,*CO,D) 5-80M. G. Karplus, J. Chem. Phys., 1959, SO, 111596 J.C.S. Perkin Ig, 0.203 mol) in phosphoryl chloride (180 ml) was kept atroom temperature for 46 h, and the excess of phosphorylchloride was then distilled off in vucuo below 30". Coldaqueous 10 sodium hydroxide (1 1) was added to theresidue and the mixture was extracted with chloroform.The extract was washed with water, dried (Na,SO,), andevaporated, and the residue in benzene (40 ml) was chroma-tographed on alumina (chloroform as eluant).1-Acetyl-4,7-dichZoro-2,3-dihydro-lH-pyrroZo2,3-bquinoZine (1 l),eluted first, was obtained as rhombs, m.p. 191-192"(from benzene) (Found: C, 55.5; H, 3-56; N, 9-85; C1,24.75. Cl,Hl,C1,N,O requires C, 55.55; H, 3.6; N, 9.95;C1, 25.2). Further elution gave compound (10) (1543 g,26.7), isolated as needles, m.p. 175-177" (from benzene)(Found: C, 61.0; H, 4.75; C1, 12.75; N, 10.05. C14H13-ClN,O, requires C, 60.75; H, 4.75; C1, 12-8; N, 10.2y0),vmx. 1655 and 1620 cm-l, 'c (CDCl,) 5-90 (3H, s, OMe) and7.25 (3H, s, Ac), followed by 4,7-dichloro-2,3-dihydro-4-methoxy- lH-pyrrolo2,3-bquinoline, and finally 7-chloro-2,3-dihydro-4-methoxy-1H-pyrrolo2,3-bquinoline (12), iso-lated as sandy crystals, m.p. 224" (decomp.) (from chloro-form) (Found: C, 61-1; H, 4.85; C1, 15.3; N, 11.85.Calc.for C1,HllClN20: C, 61.4; H, 4.7; C1, 15.1; N, 11.95),vmx. 1628 (C=N), T (CD,),SO 5.97 (3H, s, OMe), 2.33 (lH, d,J 9 Hz, 5-H), 3-05 (lH, q, J 2 and 9 Hz, 6-H), and 2.75(24,600), 251 (25,000), 335 (4100), and 343 nm (3900), m/e234 (M+), identical (i.r. spectrum) with authentic material.2Ethyl 3-( 7-ChZoro-2,3-dihydro-4-methoxy- lH-pyrroZo2,3-b-quinolin- 1-yZ)propionute (13) .-A mixture of compound (12)(50 g), ethyl acrylate (10 ml), and Triton B (1 drop) washeated in an oil-bath at 100" for 20 h, then cooled. Chloro-form (250 ml) was added and the resulting solution wasextracted with cold 1 sulphuric acid (4 times).Theaqueous layer was neutralized with 3 sodium hydrogencarbonate solution and the separated oil was extracted withchloroform. The extract was evaporated and the residuewas crystallized from di-isopropyl ether to give the product(13) (5.00 g, 70) as needles, n1.p. 95-97" (Found: C,60.85; H, 5.7; Cl, 10.65; N, 8-25. C,,H,,CIN,O, requiresC, 60.8; H, 5.7; C1, 10-6; N, 8.35), vmX. 1720 cm-l.3- ( 7-Ch~oro-2,3-dihydro-4-nzethoxy- 1 H-pyrrolo 2,3-b quino-Zin- 1-yZ)~opun-l-oZ (14) .-To a stirring suspension of lithiumaluminium hydriamp; (4.90 g) in tetrahydrofuran (70 ml), asolution of compound (13) (4-90 g) in tetrahydrofuran (70ml) was added dropwise at 5-7". The mixture was kepta t room temperature for 1 h, then cooled in ice and decom-posed with water.The separated inorganic matter wasfiltered off and the filtrate dried (Na,SO,) and evaporated.The residue gave compound (14) (3.10 g, 72.0) as needles,(lH, d, J 2 Hz, 8-H), hx. (95 EtOH) 227 (E 16,800), 246m.p. 136-138" (from ethyl acetate) (Found: C, 61.45; H,5.9; C1, 12-15; N, 9.7. C15Hl,ClN,02 requires C, 61.55;H, 5.85; C1, 12-1; N, 9.5504,), vmaZ 3330 cm-l.9-ChZoro-2,3,4,5-tetruhydro-6-nzethoxy- lH, lOcH-Sa, lob-di-azucycZopentujkphenanthrene ( 16) .-TO a mixture of com-pound (14) (2.10 g), chloroform (15 ml), and triethylamine(3 ml), thionyl chloride (10.0 g) was added dropwise a t4-7". The mixture was allowed to warm to room tempera-ture and left for 16 h.The solvent and the excess of thionylchloride were removed in vacao and 3 sodium hydrogencarbonate solution was added t o the residue. The separatedoil was extracted with benzene (30 ml) and the extract wasdried (Na,SO,) and refluxed for 1 h, yielding a yellow gum(15) insoluble in the solution. The solvent was decantedand the gum was dissolvcd in methanol (50 ml). Sodiumborohydride (0.8 g) in methanol (20 ml) was added a t roomtemperature and the solution was set aside for 16 h. Thesolvent was evaporated off and the residue was extractedwith chloroform. Evaporation of the extract gave awhite solid which afforded compound (16) C0.28 g, 37.00,bfrom compound (la) as rhonibs, m.p. 144-146" (fromethyl acetate) (Found: C, 65-35; H, 6.25; C1, 12.55;N, 10-3.Cl,H1,CIN,O requires C, 65-1; H, 6-2; C1, 1243;N, 10.l~o), vmE (CHCl,) 2760 and 2720 (Bohlmann bands)and 1670 cm-l, T (CDCl,) 6.30-8.30 (lOH, m), 6-27 (3H, s,OMe), 6.14 (lH, s, 10c-H), 3-60 (lH, d, J 2-5 Hz, 10-H),3.52 (lH, q, J 8 and 2-5 Hz, 8-H), and (lH, d, J 8 Hz,7-H), m / e 276 (M+).9-Chloro-2,3,4,5,5a, 10c-I~en.ahydro- 1H-3s, lob-diazucyclo-pemtuu kp~zenuntlzren-6-one ( 17) .-A solution of compound(16) (0.1 g) in methanolic 10 hydrochloric acidrefluxed for 5 min then evaporated in vucuo. The residuewas neutralized with saturated sodium hydrogen carbonatesolution and the separated oil was extracted into chloro-form. Evaporation of the extract left a solid whichcrystallized from di-isopropyl ether to give conzpound (17)(0.09 g, 94.8) as rhombs, m.p. 135-137" (Found: C,64.05; H, 5-8; N, 10.95. Cl,Hl,CIN,O requires C, 64.0;H, 5.75; N, 10.65), ymx. (CCl,) 2780 and 2720 (Bohlmannbands) and 1660 cm-1, T (CDC1,) 6.13 (lH, d, J 7 Hz,10c-H), 3.26 (lH, q, J 9 and 1-5 Hz, 10-H), and 2-12 (lH, d,J 9 He, 7-H), m/e 262 (M+).We thank Professor Emeritus S. Sugasawa, TokyoUniversity, Professor H. Fujimura, Gifu University, andMr. M. Yamazaki, director of this laboratory, for discussionsand suggestions. We also thank Dr. K. Kotera and thestaff of the instrumental analysis room in this company forelemental analyses and spectral measurements.i4/200 Received, 1st February, 1974)0 Copyright 1974 by The Chemical Societ