J. F. MEAD,hl. M. RAPPORT AND J. B. KOEPFLI
2703 [CONTRIBUTION FROM THE
GATESAND
CRELLIN
LABORATORIES O F CHEMISTRY, No. 10461
Vol. 68
CALIFORNIA INSTITUTE Ofi TECHNOLOGY,
The Synthesis of Potential Antimalarials. The Reaction of Organic Lithium Compounds with Quinolinemethanolsl BY J. F. MEAD,M. M. RAPPORT AND J. B. KOEPFLI
n
The reaction of organic lithium compounds with certain quinolinemethanols was undertaken in the hope of obtaining, without recourse to total syntheses, compounds related to cinchonine (Ia) but featuring a quinoline-2 substituent. Such compounds were desired for testing as antimalarials for reasons elaborated upon in another paper.2 CHzCH, I
CHOH-CH
CH-R1
I CH, C H ~ I
IIb. When, however, the reaction of phenyllithium with 6-methoxy-a- (2-piperidyl)-4-quino ~ carried out a t 80°,the linemethanol ( I I C )was principal product was apparently ti-methoxy-4quinolinemethanol (111) accompanied by only a small amount of the desired 6-methoxy-%phenyla- (2-piperidy1)-4-quinolinemethanol (11d) . CHzOH I
The first attempts were made with cinchonine (Ia) using biityllithium and phenyllithium, reI11 spectively. In both instances products were formed which gave satisfactory elementary analyThe above product I11 of m. p. 135-136' was ses. However, in the case of the so-called butyl- probably a result of hydrogenolysis a t the bond cinchonine, a. quantitative hydrogenation with between the piperidyl ring and the quinoline platinic oxide indicated a hydrogen uptake of methanol group in IIc. A similar hydrogenolysis only about one-third of the theoretical. Further- was postulated by Ainley and King,5 who remore, neither the butyl nor phenyl derivative of ported obtaining a compound of the same struccinchonine gave a precipitate with c~prichloride~ture and like properties, but of m. p. 83-84') durand it therefore seemed probable that the vinyl ing ring closure and catalytic reduction of +bromogroup had been partially reduced in each instance €-( 6-methoxycinchoninyl)-n-amylamine. Their to yield a mixture. These attempts were there- compound analyzed for two moles of water of fore abandoned in favor of the reaction of phenyl- crystallization and thus may not be identical with lithium with dihydrocinchonine ; this was success- that reported here. fully carried out and the structure of the resulting Experimental' dextrorotatory 2'-phenyl-3-ethylruban-9-01(Ib) was confirmed by oxidation to 2-phenylcinchoDextrorotatory 2'-Phenyl-3-ethylruban-9-01 (Ib), (SN 10,285).8-From 30 g. of cinchonine (Ia), 27.8 g. (93%) ninic acid by the method of John.4 Previous to the synthesis of 2-phenyl-a-(2- of dihydrocinchonine was prepared9 and after recrystallization from 650 ml. of benzene (using a Soxhlet piperidyl)-4-quinolinemethanol (IIb) from 2- extractor) the compound was obtained as colorless needles, phenylcinchordnic ester, the feasibility of obtain- m. p. 270.5-273 (dec.). A solution of 0.02 mole of pheriyllithium in 30 ml. of ether ing such a 2-substituted Ainley and King type of quinolinemethanol directly from the unsubsti- was preparedlo and added to a suspension of 5.9 g. (0.02 mole) of dihydrocinchonine in 40 ml. of dry ether in an icetuted analog IIa5,6by means of phenyllithium was water-bath. The mixture was stirred and after five minutes explored. the temperature was allowed to rise to room temperature The reacti0.n of phenyllithium with IIa a t room over a period of thirty minutes. Most of the solid having temperature gave the desired 2-phenyl analog, dissolved, the dark yellow-green reaction mixture was O
( I ) T h e work described in this paper was done under a contract, recommended b y t h e Committee o n Medical Research, between t h e Office of Scientific Research a n d Development a n d t h e California Institute of Techncllogy. (2) R a p p o r t , Senear, Xlead a n d Koepfli, THIS J O U R N A L , 68, 2697 (1946). (3) Cohen, J . C i e m . Sor., 999 (1933). (4) John, Ber., 63, 2657 (1930). ( 5 ) Ainley and King, Proc. Roy.Soc. (London), 121B. 60 (1938). (6) Senear. Sargent, Mead a n d Koepfli, THIS J O U R N A L , 68, 2695 (1948).
poured into 500 ml. of ice water and the ether removed by warming. The insoluble solid which separated was collected, washed with water, dried and extracted with 500 (7) All melting points are corrected. T h e micrnanalyses were performed by Dr. Gertrude Oppenheimer and M r . Alan Swinhart. (8) T h e Survey number. designated S S . identifies a drug in t h e Records of t h e Survey of Antimalarial Drugs. The antimalarial activities of those compounds t o which Survey numbers have been assigned will be tabulated in a forthcoming monograph. (9) Skita and Franck, Ber., 44, 2866 (1911). (10) Gilman, Zoellner and Selhy, T H I S J O U R N A I . . 54, 1957 (1932).
Dec., 1946
2705
a-(2-PIPERIDYL)-2-ARYL.-4-QUINOLINEMETHANOLS
ml. of ether. The ether solution was taken to dryness and The Reaction of B-Methoxy-a-( 2-piperidyl)-4-quinolinethe residue crystallized from 9570 ethanol. Two crops, methanol ( I I C ) ~ ,with ~ * Pheny1lithium.-The reaction beobtained by concentration of the solutionLLand mother tween phenyllithium and I I c was carried out as described liquors, weighed 2.7 g. (367,). Recrystallization from in the last experiment except that dry benzene was used as ethanol gave colorless needles, m. p. 260-261" (dec.), a solvent and the reaction mixture was warmed a t 80" for [ o 1 I z 5 ~+129" (15%solution of the base in water containone-half hour before pouring it into water. Long lighting four equivalents of hydrochloric acid). colored needles appeared on the oily phase, some of which A n d . Calcd. for C25H2bON\j2:C, 80.6; H, 7.6; N, 7.5. (0.35 g . ) were collected, crystallized twice from water, washed and dried to give colorless needles of m. p. 135Found: C, 80.5; H, 7.7; S,7.7. 136'. The compound was soluble in hot water and dilute The above base (1.0 8.) was oxidized by the method of acids but insoluble in base; it formed a methiodide with John4 and 0.31 g. (46%) of colorless needles, m. p. 214215", was isolated from the reaction mixture. A mixed methyl iodide and did not give any test for a carbonyl melting point with an authentic sample of 2-phenylcin- group. Anal. Calcd. for CllHllO2N: C, 69.8; H, 5.9; S, choninic acid was 214-216 '. The Reaction of ~-(2-Piperidyl)-4-quinolinemethanol 7.4; MeO, 16.4. Found: C, 69.6; H, 5.9; N, 7.7; MeO, (IIaY with Phenvl1ithium.-To 0.06 mole of Dhenvllith- 16.3. ium; prepared by 'the method of Evans and Alien,Li from The remaining solid and oil, obtained by evaporation 1.1 g. of lithium and 12 g. of bromobenzene, was added of the benzene phase, was dissolved in ethanol and treated with stirring a t O", 4.8 g. (0.02 mole) of IIa suspended in with hydrochloric acid gas. The resulting light brown pre100 ml. of dry ether. The temperature was allowed to rise cipitate (2 g.), m. p. 245" (dec.), was collected and cona.nd the stirring continued for one-half hour a t room tem- verted to a free base, m. p. 134-136', identical with the perature; the reaction mixture was then poured into compound isolated above and is probably 6-methoxy-4water and rapid1.y stirred for an additional half hour. quinolinemethanol (111). The ether phase was separated, dried and evaporated to From the mother liquors of the hydrochloride (m. p. dryness, the resic.ue dissolved in a little absolute ethanol 245") obtained above, there was isolated 0.25 g. of crystals and treated with dry hydrochloric acid gas. The crystal- of m. p. 234-236" (dec.) which did not depress the melting line hydrochloride which precipitated was collected, point when mixed with a sample of the dihydrochloride washed with ethanol and dried to give 0.5 g. of a com- hemihydrate of C, - methoxy - 2 -phenyl - a-(Z-piperjdyl)-4pound, 111. p. 22:1-227' (dec.); the melting point of the quinolinemethanol (IId)2. dihydrochloridc of 2-phenyl-cr-(2-piperidyl)-4-quinolinemethanol (IIb)2is 235" (dec.). Summary The abovr salt was converted to the free base which was The preparation of.dextrorotatory 3'-phenyl-3obtained as colorless needles of m. p. 96-97" from absolute methanol. The free base showed no depression in melting ethylruban-9-01 from dihydrocinchonine by means point when mixed with an authentic sample of IIb.2 of phenyllithium is reported. The reaction of t6
(11) The product when crude is much more soluble t h a n after Piiti _I p .rificiti,n. mikin: it necessary t o concentrate t h e first eth.in > I s')I i i o n ti, s m a l l vol,ime (13) E,. I T ' - in4 L l e n . "Or,anic Syntheses," Coll. Vol. 11, 1943, p. 317.
phenyllithium with two Ainley and King type quinolinemethanols is described. (13) Sargent, THIS J O U R N A L , 68, 2688 (1946)
PASADENA, CALIFORNIA
RECEIVED APRIL 5 , 1946
DEPARTMENTS O F THE UNIVERSITY OF CALIFORNIA, L O S ANGELES, AND THE UNIVERSITYOF SOUTHERN CALIFORNIA]
[CONTRIBUTION FROM THE CHEMISTRY
CY-
(2-Piperidyl)-2-aryl-4-quinolineme thanols
BY RONALD F. BROWN,THOMAS L. JACOBS,S. WINSTEIN,MILTONC. KLOETZEL, EARLC. SPAETH, JOHN H. ROBSON, EDWARD F. LEVY,GEORGEM. BRYAN, ALANB. ~ I A G N U S WARNERH. FLORSHEIM, SON, STANLEY J. MILLER, MELVINL. OTT 4 N D JOSEPH A. TEREK The discovery that a-(2-piperidyl)-2-phenyl-4- These compounds were prepared in 10-30% quino1in:methanol was much more effective over-all yield by a slight modification of the proagainst avian malaria than the corresponding cedure described by Koepfli and co-workers2 compound without the 2-phenyl group2 suggested (I -+ VI) except in the case of a-(2-piperidyl)-2the synthesis of a number of analogous compounds (p-hydroxyphenyl)-4-quinolinemethanol(VI, R containing substituted 2-aryl groups of different = p-hydroxyphenyl) which was obtained from types. I t was found that p-chlorophe'nyl was especially effective in increasing the quinine equivalent of these quinolinemethanols. (1) This work was done under a contract, recommended by the Committee o n Medical Research, between t h e Office of Sclentific Research a n d Development and t h e University of California, Los angeles, and t h e Lniversity of Southern California. T h e survey number. designated SN,identifies a drug in the records of t h e Survey of Antimalarial Drugs. T h e antimalarial activity of those compounds t o which such numbers have been assigned will be tabulated in a forthcoming monograph. (3) R a p p o r t , Senmear, .?Ie;rd a n d Koeplli, Tms J O V R K A L , 68, 2697 (1940).
