Journal of illeclicinal Chernistry, 1970, Vol. 13, .Yo.
4
599
those used to produce the HOCH2 analog of VIa8 The Skraup'O reaction on 4-chloro-o-toluidine using mnitrobenzenesulfonic acid as the oxidant" proceeded smoothly, and nitration produced XI11 in an average overall yield (from XI) of 50%. 8-lUethyl-5-nitroCH quinoline has been oxidized to 5-nitro-8-quinolineIX carboxylic acidI2 and a modification of this procedure gave XIVa. Catalytic reduction of the X e ester (preon an aromatic ring. Investigations carried out in this pared by BFs-catalyzed esterification) followed by laboratory7,*have demonstrated that conversion of the chloroacetylation and subsequent treatment of the aromatic Ale into HOCH2 results in a marked increase chloroacetamide with NHEtz produced XVII in good in activity. The HOCH2 derivatives have been shown overall yield. Attempted reduction of this amido ester for several of the above examples to be the active metabLAH-AlC1, as previously describeds resulted in olites responsible for the observed biological a c t i ~ i t y . ~ , with ~ overreduction to IX. Although we were aware of only Hycanthone (X), as an example, is a well-tolerated, a single example13 of the reduction with diborane of a highly effective parenteral agent against schistosomiasis secondary amide of an aromatic amine, we attempted in mangawhile poor human tolerance and lack of parthe use of this reagent in the hope of obtaining a selecenteral activity of lucanthone (11) make it a lehs detive reduction to give XIX. The results, however. sirable drug for use against Schistosoma haematobiuin were disappointing, as the ester function was reduced and S . mansoni infectiomgb faster than the amide. 0 NHCH2CH,K(C,H,), II I I
vHCH,CH,N( C2H5jL
I
CH,OH
x Chemistry.-With this body of evidence in hand, \\e set out to synthesize XVIII, the hydroxymethyl analog and anticipated active metabolite of compound IX. The sequence of reactions originally proposed is outlined in Scheme I, the final steps being analogous to SCHEME I
I
CH XI
CH, XI1
- "@
,o:L
\
CHI XI11
+ [HI
"
COOR XIVa, R = H h.R=CH .?JHCOCH,CI
I
COOCH XVI
COOCH XV NHCOCH,N( C,H5
"@ ' N'
NHCH,CH,N(C,H,), + [HI
bOOCHJ XVII
N'
CH,OH XVIII
.. . -
( 8 ) L). Kosi, T. It. Lewis, K. Lorenz,
11. Freele, D. 1.Berberian, a n d
S.Archer, J . .\fed. Chem., 10, 877 (1967). (9) (a) V. D e V. Clarke, D. M. Blair, a n d h1. C. Weber, Centr. Afr. J . M e d . , 15, 1 (1969); (b) D. bl. Blair, Bull. W .H . O., 18, 989 (1958).
COOCH XIX
An alternative route to XIX was the direct alliylatioii of XV with diethylaminoethyl chloride. The alkylation of 5-amino-6-methoxyquinoline with diethylaminopropyl chloride using KaKH2 in liquid SHB has been described,14 but application of these conditions to XV gave none of the desired material. However, XaHinduced alkylation in DAIF gave an 80% conversion into XIX (glpc analysis). The product was separated from unreacted starting material by extraction from EtOAc with pH 3 buffer and was isolated as a viscous oil in 68y0 yield. Reduction of XIX in ether with LAH a t -22" gave a mixture which contained (glpc) a major fraction comprising 60% of the total, starting material (lo%), IX (20%), and two unknown materials (total loyo). The major component was separated by preparative thin-layer chromatography on alumina using 99: 1 CHC13-AIeOH as the eluant. The product could not be induced to crystallize. It was characterized by elemental analysis and by solution ir, pmr, glpc, and tlc comparisons with material obtained by fermentation of IX. Microbiological Transformations.-Incubation of IX2 nith Aspergillus sclerotiorum for 5 days resulted in its transformation to a t least 5 more polar producth. The major component was purified by a combinatioti of solvent extractions and preparative thin-la? er chromatography on silica gel plates. Its pmr spectrum showed that the 8-Me signal in the spectrum of IX was replaced by :L +glial for C H a next to oxygen, and the elemental analysis of the free base and dihj.dro(IO) K. H. ,!I hIanske a n d .\I. Kulka. O w . I?u g the following 2 hr ocvasioil;il cwoliiig %vasnece5sary t o keep the temperature t)elo\y 50". . i f t i'r -Ih r the niistiire \vas poiireti oii ire. anti the organic inatei.ia1 wa> takeii r i p i i i ClCH2CII,Cl. Ttie desired acid was extracted froin the orgaiiir ,5ii -'th tliliuc. K&Oa (the N a + :tiid XH4Lsaltroniparat i oI\It)lei. Acidificvttion rif the 1 i o i i gave 1.4:i i ( i f pri)diiri, mp 173-176'. 1: t i c i t i froin fro ti c ptirt' rriaierial, rnp 173.3--1 ((~"~,H>~IX'O,''11, ('1, s. 0 1 her r11t1s gave ~ I c l l y m o r p h ~till' j le?4--I36' : i t i < l l%4-1%6': ('HCl,
