The synthesis of nitrogen mustard amides from 1-aminophenazine
and 8-aminoquinoline is described

D. Kolbah

J. Roy

R. C . Elderfield

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CR 0 AT I CA CHEM I CA ACT A 35 (1963) 35 CCA-287 547.865 : 547.831.6.01 Original Scientific Papet Synthesis of Potential Anti-Cancer Agents. XVI. Nitrogen Mustards from 1-Aminophenazine and 8-Aminoquinoline* R. C. Elderfield, D. Kolbah**, and J. Roy D epartment of Chemistry, University of Michigan, Ann Arbor, Michigan Re9eived February 2, 1963 The synthesis of nitrogen mustard amides from 1-aminophe-nazine and 8-aminoquinoline is described. In a'n ear.lier communicat1on 1 ·the syinthesis of a number of derivatives of 8-[3-bis-(2'-chloroethylamino)-propionamido]-quinoline (I, n = 2) as potential anti-cancer compounds was described. Preliminary evailua<tion of these sub-stances against exiperimenital animal ,tumors indicated a high degree of ac1Jivi1ty2• It 1therefore seem ed .desirable '1lo prepare further substances of ,this general type 'in which the 1side ·chain 11n the 8-position of the qu1no1'iine 11ing was varied 1since it is 'common knowledge, based largely on stud1ies o,f 1the 8-aminoquinoli~ne antimalarfals,3 1tha t the ipharmacological action of this group of compounds va1ries qiuiite widely both quahtatively and quantifatively as the nature ·of ·the s1de chain 1i1s ·altered. R R Q CICO(CH2)nCl I I I -----·----+-R- / '/ "\, NH2 I II I II / "\, /~N/ Q I HN(CH2CH20HL I Q ! NHCO (CH2) 11Cl III NHCO (CH2),.N (CH2CH2CJ) 2 NH(CHJ,.N(CH2CH20HL I t SOCl2 t IV ------------~------~ Q = the substituted qu1noline However, the 1preferred -syint1h e'tic route to these substances as shown m II-IV-I severely 'limits rthe choice in vania:tions of n. 'Thus, when n = 1, possilble cyclization .of 1the 1i1nterimediate (III) onto the quinoline ring nitrogen becomes a factor to be ,taken linto account aind when n = 3 cycliza'hon of III onto the amide nitrogen also must be considered. In order to obtain some ev1idence regarding the effect ·of 1increasing the length of the s1de chain in * The work here reported was done under Research Grant Cy-2961 from the National Cancer Institute to the University of Michigan. For the preceding paper ib. this series, see R. C. E 1 de r fie 1 d and J . R. Wood, J. Org. Chem. 27 (1962) 2463. ** Present Address : Faculty of Pharmacy, University Zagreb. CH O-"f',/N\:../\._ X(CH2)nCOCl CH 0_/"-./N~\/\._ HN(CH2CHpH)2 3 I 11 I I . 3 I 11 I I '\/"-. NAf'When n = 2, X = Cl V"-.wf'V · I When n = 4 or 6, X = Br / NH2 NHCO(CH 2)nX v N CH3 0-(Y ~~ '\/"-.N~ I . . SOCl 2 NH(CH 2) 3N(CH 2CH2Cl) 2 XII VI !JiAlH, (When n = 2) N CH3 0-('r{ Y~ V"-.N/'"-.? I NH(CH 2) 3N(CH 2CH20H) 2 XI N CH30-/"/ '\/'-I II I I '\/">N/"-./' I Nl HCO(CH2 ~:(CH2 CH2 0H)2 80012 N . CH3 0-(l( y~ '\("-.N/"-./ NHCO(CH 2)nN(CH2CH2C[) 2 VIII I CH3I (When n = 2) t CH 0-,,f''-{N~/Cl 3 \~NA) N CHo-A/ \/\._ s I II I I I V"-.N/V I + NHCOCH2CH2N{CH 2CH2Cl) 2 NHCO(CH 2) 2N(CH 2CH2Cl) 2 1-I CH3 IX x co 0) ~ fl ltj t" ti ltj ::0 "'1 ...... ltj t" ti ti ~ 0 t" o:J > _::i:: > z t:I !"-+ ::c 0 ~ SYNTHESIS OF POTENTIAL ANTI-CANCER AGENTS 87 substances of the ltyipe iof I, we ha:ve prepared 6-methoxy-8-[7-'bis-(2-ch1oro-ethylamino-heptanamido]-quinoline (I, n = 6) from the readily available 7-bwmohepitamoy·l chloride. Several quaternary 1Sa1'ts of phenazine ideri:vatives have shown eviidence of activity a1gainst expeI'ilmentaJl a1nimal ne0\plasms4 • However, the :only unquaternized phenazine which has displayed activity in this regard is 3-methoxy-1-(3-diethy.lam~napropyilamino)-phenazine prevfously .descr:ilbed by one of us.s The synthesis of 111itro:g.en mustard derivaitives of selected phenazines thus aippeaired ito ibe wavrnnted. We have ·therefore prepared derivatives of 1-amino-3-methoxyiphenazine of •the •type 1shown d.n VIII in which n = 2,4 ·or 6 by the sequence V - VIII as well as •one derivative {IX) of 1-amin•o-3--methoxy-6-chlorlQlphenazilne. In view 1of the ac.tiV1~ty .reported for 1the quaternary :phenaziniium compo-unds, the methiodide (X) was prepared from VIII, n = 2. On treatment of X with methanolic hydrogen chlbride, the side chain was cleaved at the amido grouip. Basification of rtJhe irea01Jion miXJture •resu1ted in recovery •of 83 rper cent bf <the calcu.la;ted amount of 3-'melthoxy-1-amiinO!phena.zrne. Mc Ilwain6 .reports that N-methylpls.enazonium hydroxide disproportionates to phenazine and N-methyl-dihydrophenazine in equal amounts with formation of one equi-valent each iof forma~dehyde iand water. Fr.om .thiis we conclude tha:t iin all probabi.li!ty, the more basic .side-chain (mustard) :nii1trogen of VIII, n = 2, UJndergoes quatevniza·tion. Reductiion of VII, n = 2, igave XI, characte:rized as ·the pier.ate, which in turn apparently gave 1the mustard (XII) on •reaction with ithfonyl rchloride. The hydrochlior~de of XII was an ex1tremely hygrosc01pic SU1bstance for which no saiti.sfac.tory method of ipurification could ibe found. ResuHs of the evaluation o.f these compouinds .against experimentaJ animal tumors will ibe 1pr·esenrted elsewhere. EXPERIMENTAL All melting points are uncorrected. Microanalyses by Spang Microanalytical Laboratory, Ann Arbor, Michigan. 7-Bromoheptanoyl chloride To a cooled solution of 26.6 g. (0.127 mole) of 7-bromoheptanoic acid' was added gradually 30.3 g. (0.254 mole) of thionyl chloride. After stirring at 38-40° for 3 hours, the excess of thionyl chloride was removed at the water pump and the residue was distilled to give 26.6 g. (910/o) of the colorless acid chloride, b.p. 90° (0.3 mm.). 6-M ethoxy-8-(7 -bromoheptanamido )-quinoline This was prepared in 76-0/o yield by the general method previously described.1 It melted at 121-122° after recrystallization from 2-propanol. Anal. C17H21BrN20i (365.28) calc'd.: C 55.90; H 5.78; Br 21.88; N 7.670/o found: C 56.01; H 5.91; Br 21.80; N 7.640/o 6-Methoxy-8-[7 -bis-(2-hydroxyethy lamina )-heptanamido ]-quinoline dihydrochloride This was prepared by the procedure previously described1. The yield of yellow crystalline material, m.p. 140-143°, was 690/o. AnaL C21Hs1N304·2HC1 (472.41) calc'd.: C 54.55; H 7.20; N 9.09°/o found: C 54.48; H 7.27; N 9.11°/o R. C. ELDERFIELb, D. KOLBAH, AND J. ROY 6-M ethoxy-8-[7 -bis-(2-chloroethy lamino )-heptanamido ]-qui no line dihydrochloride (I, n = 6) To a cooled solution of 2.3 g. (0.0046 mole) of the above diol in 75 ml. of chloro-form (previously dried over calcium chloride) was added 3 ml. of purified thionyl chloride in one portion with vigorous stirring. A brown oily mass separated. After allowing it to come to room temperature was stirred for 3 hr. The chloroform was removed at 40° and the residue was concentrated twice with 20 ml. portions of benzene leaving 2.8 g. of yellow powder, m.p. 85-87°, after crystallization from a large volume of acetone with an amount of decolorizing carbon. The yield was 700/o. When the crude product was heated or allowed to stand with alcoholic hydrogen chloride, the dihydrochloride of 6-methoxy-8-aminoquinoline, m .p. 235-237°, was formed. Anal C21H29Cl2Na02 · 2HC1 (499.30) calc'd.: C 50.50; H 6.26; Cl 28.41; N 8.42°/o found: C 50.28; H 6.46; Cl 28.19; N 8.210/o The Phenazine Derivatives With a few exceptions these were prepared by the general procedure described in an earlier publication for the 8-aminoquinoline analogs ' . Deviations from this procedure will be noted. Yields, m .p. 's. and analytical data are given in Table I. Unless otherwise noted, all compounds were recrystallized from absolute ethanol. In general, they formed yellow or brownish yellow crystals. 1-[3-bis-(2-chloroethylamino)-propionamido]-3-methoxyphenazine (VIII, n = 2) Ice-cold purified thionyl chloride (10 ml.) was added all at once to 9.6 g. of VII,n = 2, chilled in ice and the mixture was kept in the ice bath an hour with occasional swirling. Within a few minutes most of the diol had dissolved with the formation of a deep red solution. After allowing the mass to come to room tempera-ture overnight, the thionyl chloride was removed at reduced pressure leaving 11.1 g . of the mustard hydrochloride as a red solid, m .p. 181-183° (dee.). An ice-cold suspension of the hydrochloride in 50 ml. of water w as basified and stirred for 30 min. Collection of the precipitate and recrystallization from absolute ethanol gave 8 g. (760/o) of the free base as golden yellow needles, m .p . 134- 135°. 1-[3-bis-(2-hydroxyethylamino)-propylamino]-3-methoxyphenazine (XI) To a well-stirred suspension of 1.5 g. of lithium aluminum hydride in 150 ml. of dry tetrahydrofuran was gradualy added 3 g. of VII,n = 2. After addition of 50 ml. of solvent, the mixture was refluxed gently for 9 hr. To the cooled stirred reaction mixture ethanol was cautiously added followed by 100 ml. of water and finally, 200 ml. of a 100/o potassium hydroxide solution. After thorough stirring the organic layer was separated and alkaline solution was extracted with ether. Removal of the solvent from the combined washed and dried organic extracts left 2.8 g. of red viscous material. For isolation 1.4 g. of the crude product w as converted to the hydrochloride in warm absolute ethanol. The yield of the light blue salt, m.p. 198-200° (dee.) was 1.5 g. (950/o). The pi crate, prepared in absolute ethapnl and recrystallized from the same solvent, formed small chocolate-colored needles, m .p. 172.5- 173°. Anal. C20H29N70 10 (599 .55) calc'd.: C 52.06 ; H 4.88; N 16.360/o found: C 52.13 ; H 4.89; N 16.180/o 1-[3-bis-(2-chloroethylamino)-propylamino]-3-methoxyphenazine {XII) To 1.5 g. of XI purified through the hydrochloride and cooled in an ice bath was added 3 ml. of cold purified thionyl chloride. After one hour in the ice bath the mixture was allowed to stand overnight and the excess thionyl chloride was r emoved under reduced pressure. The free base w as liberated with sodium hy-droxide and extracted into chloroform. Conversion to the hydrochloride gave a tacky, hygroscopic material which could not be purified. / n I Ri I R2 2 H Cl 2 H N(CH2CH20H)2 2 H N(CH2CH2Cl)2 4 H Br 4 H N(CH2CH20H)2 4 H N(CH2CH2Cl)2 6 H Br 6 H N(CH2CH20H)2 6 H N(CH2CH2Cl)2 2 Cl Cl 2 Cl N(CH2CH20H)2 2 Cl N(CH2CH2Cl)2 {a) Calcd. and found for bromine (b) Recrystallized from methanol m.p., oc 172-173 145-146 134-135 173.5 139-140 96-98b 180 104-105 71_73• 210.5 147.5-148 172-173 TABLE I Derivatives of 1-Aminophenazine ,A/N~/~ R CHa0-1 II I 1-1 '\/"-N,1"-~ I NHCO(CH2)nR2 Analysis 11 Calculated 11 Yield l!I c (O/o) H I N I Cl 'II c 85 60 79 62 .83 4.47 13.32 11.23 60.841 .46 6.29 14.58 62.53 76 56 .99 5.27 13.30 16.84 56.74 90 55 .68 4.67 10.82 20.58• 55.90 85 64 .06 6.84 13.58 63.96 55 58 .80 5.83 12.47 15.78 58.98 90 57 .68 5.33 10.09 19.21• 57.85 96 65 .43 7.32 12.72 65.34 31 60 .37 6.33 11.74 14.85 60.21 77 54 .87 3.74 12.00 20.25 54.79 76 57 .34 5.53 13.38 8.46 57.10 71 52 .70 4.64 12.29 23.34 52.66 I Found H I N 4.72 13.35 6.08 14.75 5.54 13.20 4.77 10.92 6.86 13.68 5.98 12.52 5.38 9.96 7.24 12.59 6.22 11.85 3.87 12.02 5.43 13.25 4.77 12.15 Cl 11.60 17.01 20.69. 15.98 19.06. 14.27 20.24 8.64 23.46 Ul ~ z >-3 ::i:: M Ul ...... Ul 0 "'1 "Cl 0 >-3 M z >-3 :; t-< > z >-3 ...... I (} > z (} gj > Q M z >-3 Ul co co 90 R. C. ELDERFIELD, D. KOLBAH, AND J . ROY M ethiodicle of 1-[3-bis-(2-chloroethylamino)-propionamido ]-3-methoxyphenazine (X) The free base (1.5 g.) was r efluxed with methyl iodide (5 ml.) in ethanol for 5 hr. The methiodide (80°/o) separated as golden yellow plates, m.p. 118.5°. Anal. C21H25ChJN40 2 (563.26) calc'd.: C 44.75 ; H 4.48; N 9.950/o found: C 44.69; H 4.38; N 10.210/o Preparation of the m ethiodide was particularly sensitive to variation of reaction conditions and solv ent. When the reaction time was changed, lower yields resulted. With benzene. as solvent, unreacted starting material was r ecovered. When 300 m g. of the m ethiodide was h eated with 50 ml. of a saturated solution of hydrogen chloride in m ethanol, the initial r ed color of the solution changed to greenish blue within 20 min. After cooling, the solution was diluted and made basic with sodium hydroxide. A r ed solid (100 mg., 830/o) precipitated. This was identified by m.p., mixture m .p. and infrar ed spectrum as 1-amino-3-methoxyphenazine. 5-Bromovaleryl chloride 5-Bromovaleric acid was prepared by h ydrolysis of 5-bromovaleronitrile (Co-lumbia Organic Chemicals, Inc.) with 48-0/o hydrobromic acid and purified by distillation under reduced pressure, b.p. 121-125° (3 mm.). The acid chloride, b.p. 80° (3.5 mm.) was prepar ed with thionyl chloride. 1-[5-bis-(2-chloroethyl.ami.no)-valeramido]-3-methoxyphenazine (VIII,n = 4) The sem i-solid mass obtained by the standard procedure w as dissolved in water, the solution was basified and extracted with chloroform. Removal of the solvent from the washed and dried extracts left a red viscous m ass which, after r ecrystal-liza tion from m ethanol, gave brownish yellow crystals (550/o yield), m.p. 96-98°. 1-Amino-3-methoxy-7-chlorophenazine This w as prepa red according to Elderfield, et al". This compound has now been found to m elt at 204- -205° a fter recrystalliza tion from a large volume of absolute ethanol. Reported m.p. 187-1900. Anal. C1aH 10ClN30 (259.69) calc'd.: C 60.12 ; H 3.88; Cl 13.65; N 16.180/o found: C 60.23; H 4.03 ; Cl 13.72 ; N 16.080/o Acknowiedgm ent. We acknowledge the valuable assistance of J . Hud<aon in the pr epara tion of certain intermediates. REFERENCES 1. R. C. E 1 de r f i e 1 d and E. F. L e von, J . Org. Chem. 25 (1960) 1576. 2. Private communicati.on from Dr. Ra 1 p h L. J one s, Jr., Univ. of Miami, Flo-rida. 3. F . Y. Wis e 1og1 e, Survey of Antimaiariai Drugs, Edwards Brothers, Ann Arbor, Michigan, 1946, Vol. 1, p. 106. 4. Private communication from Dr. R. B. Ro ss, Cancer Chemotherapy National Service Center, Bethesda, Maryland. 5. R. C. E 1 de r fie d, W. J . Gens 1 e r, and 0. Bir s t e in, J. Org. Chem . 11 (1946) 812. 6. H . Mc I 1 wain, J . Chem. Soc. 1937, 1704. 7. D. E . Ames, R. C. Bown en, and R. G. M asso n , J . Chem. Soc. 1950; 174. A. F . Sa 1 vat ore, K. W. Green 1 e e, and< J , B. B r o w n , J. Am. OH. Chem. Soc. i?S (1951) 416, SYNTHESIS OF POTENTIAL ANTI-CANCER AGENTS 91 IZVOD Sinteza potencijalnih antikancerogenih supstancija. XVI. Derivati bis-(2-kloretil)-amina od 1-aminofenazina i 8-aminokinolina R. C. Elderfield, D. Kolbah i J. Roy Derivati diklor-dietilamina su jos uvijek u centru pafoje na podrucju prona-lazenja sredstava za sprefavanje rasta tumora. Kao prilog tim istrazivanjima pri-reden je niz novih spojeva iz toga reda polazeci od 1-aminofenazina i 8-aminoki-nolina. KEMIJSKI ODJEL UNIVERZITET MICmGAN ANN ARBOR, MICHIGAN, U.S.A. Prlmljeno 2. veljal!e 1963. 

Synthesis of Potential Anti-Cancer Agents. XVI. Nitrogen Mustards from 1-Aminophenazine and 8-Aminoquinoline

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