190s
SIDNEY
GOODWIN .4ND E.
serpiline and elliptinine were not detected, although a colorless alkaloid (90 mg.) not found in 0. elliptica was eluted after the yellow alkaloids. Suitable solvents for crystallizaticn could not be found and the alkaloid was converted to its hydriodide in acetone. The salt (which was quite soluble in acetone) was recrystallized from water,
/ C ( ~ S T R I I 1 U T I O NFROM T H E
c. HORNING
Yol. 81
m.p. 215' dec., [a]2368 +27" and [ a ] 2 3 4 6 ~ +58" ( c 0.45). The ultraviolet spectrum was examined: Amax 238 and 290 mp and A,:, 258 mp; infrared spectrum: A, (mull) 3.01 and 6.24 ,A.
BETHESDA 14, MD.
LABORATORY OF CHEMISTRY
O F S A T U R A L PRODUCTS, N A T I O U A L INSTITUTES OF H E A L T H ]
Alkaloids of Lunasia amar-a Blanco.
HEARTI N S T I T U T E ,
NATIONAL
Structure of Lunacrine
BY SIDNEY GOODWIN AND E. C. HORNING RECEIVED OCTOBER17, 1958 Lunacrine has been assigned the structure I on the basis of the chemical reactions and interpretations of spectra described i n this paper.
Lunacrine was first isolated in 1900 by Boorsmal scured by the presence of other b a ~ i d s . ~The , ~ abfrom the bark of Lzcnasia costzilata Miq. The al- sence of a methylenedioxy group was shown conkaloid was characterized by its melting point clusively by the absence of any signal in the appro(114O), solubility, precipitation reactions and color priate region of the n. m. r. s p e c t r u ~ n . ~ , ~ reactions. 'IVirth? carried out the first studies reThe infrared spectrumg of lunacrine was devoid lated to the structure of lunacrine in 1931, and re- of absorption in the 5 p region while the f i p region ported the empirical formula to be C16H2003N.was very rich in bands; structural assignments were The presence of one methoxyl and one methylimino not possible. The ultraviolet spectrum in alcohol group, and the forniation on zinc dust distillation was unaffected by the addition of alkali, but a of quinoline, skatole and ammonia were also re- marked change occurred on acidification (Fig. 1) ; ported.* -4few years later, Dieterle and Bey13cor- the long wave length bands (313 and 326 mp) exrected the obviously impossible formula and gave hibited a hypsochromic shift (300 mp). Thus the C16H1,OXS which was later confirmed by Steldt nitrogen atom is a part of the chromophore and inand Cheri The alkaloid described by the German volved in a structure which would give this beworkers, although agreeing in melting poitit havior in acid. This irnniediately eliminated from (,llii") with that reported by others,*,*was said to consideration the most prevalent nitrogen-contailibe opticall>-inactive whereas \-alues had been given iiig nucleus in the Rutaceae alkaloids, eiz., quinoline for [ N ] D of -3SO' and, later, -.iS0.3 Lunacririe whose long wave length ultraviolet absorptiori was stated to have a iiiethylenedioxy group by vir- maxima exhibit pronounced bathochromic shifts tue of the formation of the calculated amount of in acid solution. This behavior of lunacrine was i n Imcipitate on heating with phloroglucinol-sulfuric fact reminiscent of I - n i e t h ~ - l - 2 - p h e n y l - ~ - q u i n o l o ~ i ~ ~ , acid.3 Luiiacrim methiodide on treatment with a derirative prepared froni 4-rnethoxy-2-phenq-lsilver osirle followed by 40r; alkali was reported to quinoline, the first alkaloid isolated in the present give a 11roduct, m.p. S.i-8(i0, allegedly isomeric with study.1° In the spectrum of this 4-quinolone the lunacriiie.X The alkaloid was found to be stable typical bifurcated maxima (323 and 337 n ~ p were ) tciwvard perriiangniiate, chroiiiic oxide and other shifted to a single inaxiniuiii a t 304 nip in acid. osidiziiig agents and was riot affected by catalytic This is apparently a characteristic phenomenon of Iiq-tlrogciiaticiri ccin~litions.~ the 4-quinolone system a s it has been found that the long wave length maxima (324 and 337 inp) of T i i tlic present study, lunacrine, m.p.111-118", [a --.i0.1", was isiilated frorn the Leaves of l-methyl-4-quinolo1ieare shifted hypsochroniically (plateau 3OH1.3 nip! in iV hydrochloric acid. Idioi(isL(zunzcirci Blanco of Philippine origin. The ciiipiricd formula and the presetice of one methosyl .liter examination of the litclrature,12it would apa i i t l oiic iiicthyliiniiio group were confirmed by ( 5 ) I.. I1 Briggs. L.D . C c l e b r u o k , I-I. >I. F a l e s a n d W. C. TTildmcin :iiialysis n i i t l , i i i adtlitiiiii, Kuhri-Iloth detcrxni~~atior~ .-Iii,ri Chian , 29, 904 ( I % i J D r . €I 31. FaIes f o r t h i s i n f o r m a t i o n . (b) lye a r e indcl,trd iiit1ic:itcti ciiie tcriiiiiinl iiicth!-l group (or gczt,iG o u d w i n J . N S l i c w l ~ ~ rrind y I - , I:. J o h n s u n , l'ms J o l . R V . \ r . , diincth>-l). The resistance of lunacririe toward 81,(7)In Spress (1859). catdytic lis-(lrogeiiatitiii was confirmed. S o evi( 8 ) 'i'he first n . m r . s p e c t r i i i n n f lunacriiie was olitnineii :Itirl iritcrt i c ~ i c ewas obtained for the presence of a methylene- p r e t t d b y I l r I1 C o u r o y of n r n n d r i s L'nivrrsity, t o w11-sis ( i f the 9..i--lO.ri p region was obti,
WL'
(2) T: H. l y i r r h , P h a i m H.Pikblnii. 68, 1011 (1931); C. A , 26, ,557 (19321 ( 3 ) I I . D i r t e r l e and H. B e y l , A r c h . Pharm , 276, 1 7 4 , 276 (1837). ( 4 ) F. A S t e l d t a n d K. K .Chen, J . A n i . Pharm. A s s o c . , Sci. E d . , 32,
s h i f t in t h e s p e c t r u m < i f .I--ril s?-stc.iii iiiethoxy-1-iiiethyl-l-quinoloiie,' ,i, ,A 231 and 3 k0 was presciit.15,16The fact that the maxima a t ' 3 4 n i p (log E 4.07 atid 4.05,resp.) and indefinite iiiand 294 iiip are a t considerably longer wave lengths flection a t 305 m y (log e 3 . S S ) , the shift in acid can tliaii the correspondiiig maxima in the the specbest be explained by this system. The infrared trum of 4-iriethosy-1 -iiietliylcarbostyril ("iiS and spectrum of lunacrine in the (i1-1 regicili is coinplctcly '77s n i p 1 can be attributed to further substitution. co:iipatible with a 4-quiiiolone structure. I t is kriowti that a 3-ethyl substituent causes a h n a c r i n e on refluxing with 1 5 5 aqueous alco- bathoclironiic shift of about 1.5 n i p in the 270 a i i t l holic potassium hydrosick solutioii was converted 280 inp masinin oi ~-liytlros>-carbost)-ril. in good yield t o an alkali-soluble sulistancc differSince the traiisfornintio:i of luiiacriiie having a -1ilig empirically from luriacrine by the athiition of quinolone systclii to liiriacridilie f(ir which ;i 4the elements of water. product, ClliH2104N, iiiethos!--:2-alkylc~irbostyrilsystciii 1i:is 1)c.m postu-- The 11i.p. l ( i O o , [ m ]j f q - I I .(io, had iin hands iii the 3 y lated occurred without loss of carlioii atonis, it is region of the, infrared and still coiitaiiietl one evident that lunwrine has either n furo- or a pyiiiethoxyl arid one niethyliniirio groiti), Treat- rano- system fuscd to the quinoloiie ring systetii. ment with ethereal diazoinethanc. qavc a non- By analog?r with the nietho~yfuroquiiioliiiealkacvstallizable oil which was coii\-c.rtctl i i i moderate loids which abouiid iii plants o f this fLliiiily, thc yield to a cr!-stallirie liyclro~jcrclil~irate.C17H23- oxygen-containing ring of luiracriiw was assuiiietl to O!N.HC104, 111.11. 1-18", [a]5y!I$22.:ln. The crys- be five-niein?ierecl and a dihydrofuran r:ithc.r thali talline base, C:;HJI,S, iii.11. hT0, I r u ] ~ , ! ) +%.lo, furan ir, acrordaiice with the alinlyticnl data, the obtained almost cjuaiititntivr.ly froi;i the hydro- proved absciice of an easily reducible cloublc 1x)iid perchlorate, was found to coiitain o ~ i ciiiethoxyl (furoquiiioliiie alkaloids arc converted to tliliydrii group more than luiiacritic aiid its al!;~.iliile trans- derivatives on hydrogenation over Pd-C ill alccihol I , formation product, a r i d it d s o coiitainctl oiie active and the ultraviolet spectrum. l 7 hydrogen atom. The sign o f speciiic rotation ( 1 4 ) R'e are i n d e b t e d to D r . J R . Price for t h i s sample. changed in the methylatioil of the alkaline trans(1.5) A[. F. G r u n d o n , S . J . LIcCorkindale a n d 11. N . R o d g e r , J . formation product, a reaction iii which inversion Chem. Soc., 4284 (1955); SI 1). G r u n d o n arid S J. I I c C o r k i n d a l e , i b i d . , 2177 (1957). certainly did not occur. (16) J. Berson, THISJ O U R N A L , 75, 3521 (1953). The empirical formula and physical constants (17) Compare iso-y-fagarine, Xmax 240, 304, 336 and 351 m p , as (13) R. D. Brown and F. N. Lahey, Ausl. Jour. Sci. R e s . , AS, 615
(1950).
given b y V. Deulofeu and D. Basi, A n d e s asoc. q u i m A r g f ? i l i ? i a ,40, 249 (1952).
1910
SIDNEY GOODWIN AND E. C. HORNING
In an investigation of the properties of (+)lunacridine (derived from (-)-lunacrine), it was found that treatment of (+)-lunacridine with atoluenesulfonyl chloride in pyridine gave, in low yield, a crystalliiie substance, m.p. 118-120°, which was identical with lunacrine in infrared and ultraviolet spectra, and in paper chromatographic behavior. However, on admixture with natural (-)-lunacrine the m.p. was elevated. A cornparison of the more easily handled hydroperchlorates indicated that the reaction product was (+)-lunacrine; specific rotations of -35.9" and +35.1° were found for the hydroperchlorates of natural (-)-lunacrine and of the reaction product, respectively. The rise in m.p. after mixture of the two bases was evidently due to racemate formation. These results indicated that (-)-lunacrine was converted to (+)-lunacridine by a sequence involving an alkali-induced ring opening reaction, and that (+)-lunacridine was in turn convertible to (+)-lunacrine in a cyclization reaction. The resultant formation of the enantiomorph of lunacrine required, in view of the reactions involved, t h a t lunacrine have only a single asymmetric center which must be the a-carbon atom of the dihydrofuran ring; thus the three unassigned carbon atoms of lunacrine must be placed a t this position. The suggested mechanism for the alkaline hydrolysis of lunacrine may be represented by
Vol. 81
temperature (about 194') on reheating. When the fusion was carried out on a larger scale, a nicely crystalline product, C1,H2203N(f)C10&-), m.p. 196', [CY 11189 +33.9", containing two methoxyl groups, was obtained. The ultraviolet spectrum of this substance was almost identical with that of lunacrine in acid solution. The structure of the product was evidently that of the (+)-quinolinium perchlorate resulting from the acid-catalyzed cyclization with inversion of configuration of (+)lunacridine hydroperchlorate as represented by OCH3
OCH3
Again i t is interesting to note t h a t the direction of rotation does not change during the postulated inversion. The quinolinium perchlorate was recovered unchanged after treatment with 30% perchloric acid a t 100' for 3 hours, indicating that acidic hydrolytic conditionslg were not responsible for the formation of lunacrine in the a-toluenesulfonyl chloride-pyridine reaction. When the (+)-quinolinium perchlorate was heated in acetonitrile in the presence of a large excess of lithium bromide, the product formed was (+)-lunacrine. The mechanism of this reaction may be shown as CH3" Br /-I
'
'0 CH3
and the cyclization may be represented as
I CH3
The hydrolysis is viewed as proceeding without inversion and the cyclization with inversion. The participation of an amide group in the displacement of tosylate and the stereochemical course of the reaction have been demonstrated by Winstein and Boschan. The conversion of the postulated quinolinium ion intermediate to (+)-lunacrine could conceivably occur either by S N ~displacement by chloride ion on the methyl carbon of the 4-methoxyl group or hydrolytically during the work-up of the reaction mixture. That the first possibility was probably correct was shown in the following manner. I t had been observed that lunacridine hydroperchlorate (m.p. 148") melted a t a much higher (18) S . Winstein and R . Boschan. THIS JOURNAL, 73, 4669 (1950).
CHB
CH3
The stability of the quinolinium ion to perchlorate ion but not to halide ion may be explained by the poor nucleophilic character of the perchlorate ion." The lability of the quinolinium ion to attack by halide ion was further demonstrated by the fact that lunacrine methiodide reverted to lunacrine on being boiled vigorously in aqueous solution, as well as on sublimation in vacuo a t its m.p. and on refluxing in acetonitrile with lithium bromide. The quinolinium perchlorate may be assigned the name ( + ) - h a s i n e perchlorate in accord with the demonstration bv J. R. Pricelg that the alkaloid lunasine is the methyllunacrinium ion. The infrared and ultraviolet spectra of (-)-lunacrine methiodide (( - ) -1unasine iodide) and the (+)quinolinium perchlorate were essentially identical. The remaining problems of structure for lunacrine concerned the position of the methoxyl group and the nature of the side chain. An assignment of the position of the methoxyl group in the alkaloid and its transformation products by the comparison (19) Alkaline hydrolysis of quinolinium ions of this type takes a different course affording carbostyril derivatives according to J. R . Price (private communication; see also "Current Trends in Heterocyclic Chemistry," Academic Press, Inc., N e w York, N. Y.,1958, P. 92). (20) This reaction is analogous to the easy formation of 2-phenyl-4hydrochloride on heating quinolone from 4-methoxyl-2-phenylquinoline a t its melting point; the corresponding hydroperchlorate melted without demethylation.
STRUCTURE OF LUNACRINB
April 20, 1959
1911
of their ultraviolet spectra with less substituted by Mr. W. Manser. Zurich, and Mr. J. F. Alicino, MeN. J. The paper chromatographic systems1@used model compounds could not be made with cer- tuchen, were the following: A, isoamyl alcohol saturated with water tainty. The 7-position was definitely eliminated and paper impregnated with PH 2.4 MacIlvaine buffer by comparison of the ultraviolet spectra of the 4- (citrate-phosphate); and B, benzene-hexane (1: 1) and hydroxycarbostyril derived from lunacrine and 3- paper impregnated with a 1: 1 mixture of ethylene glycol p H 2.2 MacIlvaine buffer. ethyl - 4 - hydroxy - 7 - methoxy - 1 - methyl- and( -)-Lunacrine.-The alkaloids of Lunasia a m i u leaves carbostyril,21a derivative of evolitrine22; major dif- were separated by chromatography on acid-washed alumina ferences in both alcohol and alkaline solution were (Merck); lunacrine was eluted with chloroform and crysfound. Analysis of the nuclear magnetic reso- tallized from ethyl acetate-hexane. Wet ether was also to be a good crystallization med'um; t h e hydrate nance spectrum of lunacrine revealed comlusively found crystallized in good recovery as fine chorless needles of t h a t the methoxyl group was in the 8-positi0n.~ indefinite melting point. The analytical sample was crysThe n.m.r. spectrum also indicated t h a t the side tallized from ethyl acetate, m.p. 117-119', [ a ] * h -50.4', ~ chain hydrogen atoms were present in a n isopropyl [ C Z ] * ~ ~ S-113' (c 0.806) (reported' m.p. 115O, [ a I r a-58O group. This is in accord with biogenetic considera- (95% alcohol)); infrared spectra: XmSx 6.18(s), 6.29(s), 6.64(s), 6.84(m), 6.96(w), 9.37(s), 9.88(v.w), tions since it affords an isoprene unit attached to 6.45(s), 10.61(s) (compare, 1-methyl-4-quinolone: .A., 6.15(s), the 3-position of a 4-hydroxycarbostyril derivative, 6.30(s), 6.44(m), 6.70(s); 3-p region (Beckman IR-3) 3.24(v.w.), sh3.31(m), 3.36(s), 3.46(m), 3.51(m); a situation known to occur in the alkaloid flinder- :':::1 ultraviolet spectra: A , 220, 242, 300, 313 and 326 mp sine.23 (log e 4.34, 4.61, 4.00, 4.01 and 3.99, resp.); Xmin 225, All features of the structure I assigned to luna- 269, 306 and 319 mp (log E 4.32, 3.45, 3.95 and 3.93, resp.); crine are in complete agreement with the n.m.r. in 0.1 N HCI, Am, 216, 253sh, 257, 300 and 330sh (log c spectrum.' The structure ?I1 has been derived 4.54, 4.57, 4.59, 3.89 and 3.58, resp.); Amin 284 and 2 i l for lunacridine and the significant transformations mp (log e 4.21 and 3.62, resp.). Anal. Calcd. for ClsHloOaN: C , 70.31; H, 7.01; N , are summarized below. OH
0
I
OCH3
v Acknowledgment.-We
are very grateful to Dr.
J. R. Price, C.S.I.R.O., Melbourne, for a stimulating exchange of information and for compounds pertaining to the Lunasia alkaloids. The relationship between lunasine and lunacridine has been established in Melbourne. We are also indebted to Miss A. F. Smith for assistance in the isolation of the lunacrine used in this study. Experimental Melting points were taken on a Rofler block. Rotations and ultraviolet spectra were determined in absolute ethanol, and infrared spectra were taken in chloroform, unless otherwise specified. Only a selected number of infrared absorption bands, principally in the 6 p region, are given as characterization features of the substances (s = strong, m = medium and w = weak). Instrumental measurements were made by Mr. H. F. Byers, Misses P. A. Wagner and C. Monaghan, and Mrs. I(. Warren. Analyses were made (21) We are grateful to Dr. R. G. Cookc, Melbourne, for this sample. (22) R . G. Cooke, Ausfral. J . Chem., 7, 273 (1954). (23) R . F. C. Brown,J. J. Hobbs, G . K . Hughes and E. Ritchie, ibid., 7, 348 (1954).
5.13; OCH,, 11.35; (N)CH,, 5.50; (C)CH: 5.50. Found: C , 69.91: H , 7.12:. N.. 5.08; OCHa, 10.23; (NIGH:, 6.13; (C)CH:, .3.44. Hydroperchlorate .-Lunacrine hydroperchlorate was prepared in ethanol-ether. The analytical sample was crystallized from the same solvent pair; m.p. 178-180°, [ a ) * ' ~ -35.9', [a]14t~a-78.5' ( c 0.720); ;:A: 6.08(m), 6.21(m), 6.51(s) and 6.70(s) p . Anal. Calcd. for C1eHloOaN.HC10,: C, 51.41; H , 5.39; N,3.75. Found: C,51.62; H, 5.50; N,3.72. Picrate.-The picrate crystallized from acetone as bright yellow crystals, m.p. 213-214' (reported* 208"). Anal. Calcd. for CnHnOloN,: C, 52.59; H , 4.41; N, 11.15. Found: (2,5251; H,4.42; N, 11.16. Color Tests.-Lunacrine which had been rigorously purified formed a colorless solution in concd. sulfuric acid which on the addition of gallic acid (Labat test), accompanied by heating on the steam-bath, became rose in color. In t h e chromotropic acid test no color developed. Hydrogenation Conditions.-A solution of 0.3 g. of lunacrine in 10 ml. of ethanol was added to a mixture of prereduced platinum from 80 mg. of platinum oxide in 10 ml. of ethanol. There was no hydrogen absorption after stirring for 3 hours. The catalyst was tested by the addition of 1 ml. of cyclohexene and found to be quite active. Lunacrine was recovered unchanged. Alkaline Hydrolysis of Lunacrine.-A solution of 3.36 g. of lunacrine, 40 i d . of ethanol and 40 ml. of 3070 potassium hydroxide solution was refluxed for 10 hours. The pale yellow reaction mixture was diluted with water and washed with methylene chloride which removed a trace (0.06 9.) of material. The aqueous solution was adjusted to pH 5 with sulfuric acid and extracted with methylene chloride. Evaporation of the solvent afforded a crystalline residue (3.35 9.) which on crystallization from a small volume of ethyl acetate gave 3.15 g. of colorless rods melting at 159-160'. The product was soluble in aqueous sodium hydroxide solution and gave a negative ferric chloride test. The analytical sample. m.p. unchanged, was crystallized from ethyl acetate a d dried at; 80' (0.1 -187" (:c 0.990); [a1*4m chloroform); infrared specta: =A, 6.10(s), 6 . p ; ultraviolet spectra: Xmsx 237, sh e 4.48, 4 and 325 288 and resp.); resp.); Amax (0.1 N KOH) 307 (log E 4.03) (compare, 3ethyl-4-hydroxy-i-methoxy-1-methylcarbostyril:Amax is 226, sh 242, 252, sh 277, 286, 317 and 328 mp (log 4 . i 3 4.11, 4.06, 3 2 6 , 3.83, 4.15 and 4.14, resp.)); Xmin 248, 262, 295 and 324 mp (log e 3.80, 3.61, 3.73 and 4.06, resp.); in 0.1 N potassium hydroxide: Xmsx 316 mp (log e 4.28). Anal. Calcd. for C~~,H~IO,N: C, 65.95; H , 7.27; N, 4.81; OCHs, 10.65; (N)CH1, 5.18; (C)CHI, 5.16. Found:
1012
SIDNEY GOODWIN A N D E. C. HORNING
C , 66.08:11, 7.32; N , 4.82; OCH3, 10.48; (N)CHj, 5.22; (C)CHZ, 8.42. ( f )-Lunacridine. (A) From t h e Alkaline Hydrolysis Product.-A solution of 2.11 g. of the hydrolysis product in 10 ml. of methanol was treated with a large excess of diazomethane in ether (prepared from 18 g. of N-methyl-Xnitrosotoluene-p-sulfonamide). There was a n immediate decolorization of the diazomethane solution accompanied by gas evolution. T h e yellow solution was allowed t o stand in an ice-bath for several hours and then overnight at room temperature. Evaporation of the solvents afforded a pale yellow oil which could not be crystallized from a variety of solvents and it w:ts therefore converted t o a salt by treatment of :in ethereal solution of the oil with a solution of 2 ml. of perchloric acid and 2 ml. of methanol. The hydroperchlorate crystallized as shiny, colorless flakes, 1.49 g. (51%). The analytical sample was crystallized from methanolether and dried a t 80" (0.1 mm.) for 6 hours, m.p. 146148" (clear, colorless melt), re-melt 193-195", [ a ] 2 s ~ g +22.3", CY]?^,^^ +60.7" ( c 0.750); Amax (Xujol); 6.25 and 6.51 p . H?aOdS,HC104: C, 50.31; H, 5.96; ( N ) C H 3 , 3.71. Found: C, 50.39; €1, 5.98; S ,3.34; OCHA, 15.28; (N)CH3,3.92. Tlie free bast: \VLS prepared by treatment of a solution of 1.13 g. ( i f tlie i i ~ - t l r ~ i ~ ~ i ' r c h lin~ i5r aml. t e of methanol with 1 iiil. Of CiJliCd. : i i n r i i ( , n i a ; water wns added until cloudy ( 2 . 5 nil. required). ( 7j-Lunacridiiie (0.80 g., 94yo) crystallized on scratching. The product was recrystallized from met hanol-ivat cr for lysis, m.p. 86-87", [a]*6yig $28.1; [ c y I Z 5 ; d 6 L;G..i" (C 0 ., The sample was dried at 56 (0.1 i i i n i . ) . Luriacr is not visibly soluble in 0.1 N or 2 .V hydruchloric acid a t room temperature or with warming :rnd the aqueous portions of these mixtures remained clear o n tlie addition of blayer reagent; infrared spectra: Xmax 3.0 (broad), 6.11(5), 6.19(m), 6.30(sj p ; ultraviolet spectra: ,< 239, 257, 28.7, 2il4 and 333 m p (log e 4.38, 4.41, 3.94, .!I1 a n d 3.55, resp.); A,,, 224, 246, 275, 291 and 310 mp Iiig c 4 3 1 , 4.31, 3.89, 3.90 and 8.36, resp.). The spectrum in S hytlrnclil~iric acid in alcohol i? identical with t h e specl r u i i i i i i iilrohol. Lunacridine does not form a picrate. Ancii. C,ilcd. for CI:Hz,O,S: C , 66.86; H , 7.59; S, -4.59; OCli;, 2 O X 3 ; ( X j C H a , 4.92. Found: C , 66.86,; I [ , 7.,52; S, 4.,54;OCII?, 20.04; ( X j C H a , 5.03. This materiJl \vas identical with ( - j-lunacridinr isolated friiin Lzinclsin b,irk b y the C.S.I.R.O. group. T h e hustritlian sample, 11i.p. 85", [ c ~ ] 2 5 ~ 8 9+30.1", [ a I Z 5 ~+80.4" e ( c o . % l ( J ) , s l i ~ ~ ~ vno e dticpression uf m.p. on admixture and tlic iiifr,iretl s p w t r a were identical. B . From Lunacrine Methiodide.--.l solution of 0.35 g. IIC luiiacririe in 10 ml. i l f methyl iodide was allowed t o stand f i r tlirer tl.iys; after 2 s a colorless crystalline precipiacetate (20 m l . ) was added t o and the product . '3s collected n.p. 130" dec., [ a I Z 4 s s g -26.3", -60,:j' ( c 0.873); A,,, 254, 302 and ca. 330(sh) and 3.45, resp.); 6.12(m), 6.23(m), Tlie methiodide reverted readily to nation a t 130-140° ( c a . 0.001 mm.), ( b i boiling in water and ( c ) refluxing in acetonitrile with lithium bromide. T h e i e reactions were studied b y means ( i f the ultraviolet spectra of the reaction mixtures and paper cliromatography using system B which readily distinguishes between lunacrine, Rfabout 0.5; lunacridine, at the solvent front; a n d lunacrine methiodide, at the origin. Coiiversion of the inethiodide t o lunacridine was effected according to Price'g by warming a solution of 30 mg. of the methiodide in 3 nil. of methanol with 1 ml. of 1 N sodium hydroxide solution. Crystallization of t h e product yielded 17 mgd ( 7 8 % ) of (+I-lunacridine, m.p. 85-87", [cyI2%89 -tS0.1 , +81.8" ( c 1.007). T n e infrared spectrum in chloroform \vas idmtical with t h a t of lunacridine prepared by the diazoiiiethane method. ( +j-Lunacrine. ( A ) Tosylate Method.-A solution of 0.455 g. of (+)-lunacridine in 5.5 ml. of pyridine was treated \vit!i 1 . O S g . of 0-tolumrsulfonyl chloride. T h e reaction
Yol. s1
mixture became red and Jr'arm. :liter standing for several days, most of t h e pyridine was evaporated in vacuo. T h e residue was treated with 80 ml. of 0.5 N sodium hydroxide solution and the mixture was extracted with ethcr. The combined ethereal extracts were extracted with 2 S sulfuric acid. The acid extract was made alkaline with potassium hydroxide and extracted with ether. -4discolored crystalline solid was obtained on treating the ether residue with about 5 ml. of ethyl acetate and 2 ml. of pentane. Four recrystallizations from the same solvent pair afforded 60 mg. of shiny, prismatic crystals, m.p. 119-120", [ a I Z 5 5 8 9 +66", [cY]25436 +loo" ( c 0.58). T h e infrared spectrum in chloroform, the ultraviolet spectrum in alcnhol and the Rr in system B were identical with (-)-lunacrine. The analytical sample was dried for 20 hours a t 80" (0.1 m m . ) . Anal. Calcd. for C l R t I , ~ 0 2 SC:. 70.31: H. 7.01: X. 5.13; OCH3, 11.35; (%)CH3, 5.50. Found: C , 69.85, 69.92; H , 6 69, 6.88; N, 5.08; OCHS, 10 21, 10.26; (NjCH3,,6.6. The marginal analytical results are ascribed t o the difficulty in purifying a small sample of lunacrine, due t o its great solubility and t o its propensity to hydrate; the hydroperchlorate may be handled with greater ease. Hydroperchlorate.-The hydroperchlorate was prepared in methanol-ether. T h e analytical sample, crystallized from the same solvent pair, m.p. 176", WRS dried a t 80' (0.1 m m . ) for analysis; [ a I z 5 j ~ + 9 35.lC, [ a I z 3 ~ 3 6 f78.0" ( c 0.295). Anal. Calcd. for C 1 ~ H ~ 9 0 3 N ~ H C 1C, 0 421.41; : H , 5.39. Found: C, 51.32; H , 5.45. (dl)-Lmacrine.--.% mixture of 20 mg. of natural ( - jlunacrine and 20 mg. of (+)-lunacrine on crystallization from ethyl acetate-pentane afforded prismatic crystals, m.p. 146-148', [ ~ ] t 2 ~ . 3j " ,~ ~ ~ +1.2" ( c 0.864). T h e crystallization residue was converted t o the hydroperchlorate, [ a ] 2 5 ~ a 9+1.7", [a]25;36 0" (c 0.208). ( B ) V i a ( +j-Lunasine Perchlorate.-( )-Lunacridine hydroperchlorate (0.314 9.) was heated in an id-bath for two minutes a t a bath teniperature of %IO3. Crystallization of the residue from mctli.tnol afforded 0.202 g. of tan crystals, 1n.p. 18G190'. The analytical sample was recrystallized from methanol :ind dried a t ! O o (0.2 inin.) for 20 hours, m . p . 195-196', [ U ] * ~ ~+33.S Q , [ ( ~ ] ~ * , . ~ +70.7' fi ( c 0.1931; infrared spectra: h,,,,, fi.l-k(ni], 6.24(111), G.54(s), 6.72(sj p ; ultraviolet spectra: A,, 3 y 234, 303 :ind shoulder c n . 330 m p (lng c 4.56, 3.80 .itid 3.46, r e i p ) ; h ,,,. 237 and 273 m p (log e 3.93 and 3.43, resp.j. A n d . Calcd. for C I ; I ? ~ ~ O s S ' c ~ C I O ~C( ,- ~52.65; : €1, 5.72; S ,3.61; OCHa, 16.01. Found: C , .52.57; 11, 5.89; X , 3.75; OCHa, 16.30. On paper chromatography in system A , (+)-lunasinc perchlorate, Rr 0.61, appeared with bright blue fluorescence and gave an orange Dragendorff color; lunacrine and lunacridine travel with the solvent front in this system. (+)-Lunasine perchlorate (10 nig.) was recovered unchanged on heating a t 100' for 3 hours in 2 ml. of 357, perchloric acid. A solution containing 77 mg. of ( j-lunasine perchlorate and 0.8 g. of lithium bromide in 8 ml. of acetonitrile was refluxed f & 12 hours. Xfter removing most of tlie solvent in uacuo, water was added and the product was extr:rcted with methylene chloride. T h e residue was converted to the hydroperchlorate in methanol-ether and recrystallization from the same solvents afforded colorless crystals, m . p . 178B O 0 , [ a ] 2 3 w g +35.4', [ a ] 2 4 4 3 a +79.7" ( c O.%O), having ideiitical infrared spectra and paper c l i r o ~ r ~ u t ~ ~ g r a pbehaviur liic with ( - )-lunacrine hydroperchlorate. Anal. Cnlcd. for C15H100JS.HCIOI:N, 3.75. l ; o i i i i ( l : 3.88. Instrumental Measurements.-Infrared spectra wyere obtained with a Perkin-Elmer spectrophotometer niodel 21, ultraviolet spectra with a Cary recording spectrophotiirnetcr model 11, and rotations were measured in 2-dm. cells using a Rudolph photoelectric polarimeter niodel 80.
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BETHESDA, LID.
