1220
CARMACK, BULLITT,
[ CONTKIBUTION FROM
HANDRICK, KISSINGER AND VON
Vol. 68
THE DEPARTMENT OF CHEMISTRY AND CHEMICAL ENGINBERING OF TftE UNIVERSITY OF PBNNSYL-
VANIA]
The Synthesis of 4-(4'-hho-X '-methylbutylamino)-7-chloroquinoline and Some 4- (4'-Monoalkylamino- 1 '-methylbutylamino)-7-chloroquinolines B Y ~ ~ A R V ICARMACK, N ORVILLE H.
BULLITT, J R . , ~G. RICHARD HANDRICK,' L. ISAIAHV O N ~
The high antimalarial activity and relatively low toxicity of 4-(4'-diethylamino-1 '-methylbutylamino)-7-chloroquinoline (1, R = -N(CzH&; also known as SN-7618) prompted the synthesis of related compounds. The present paper describes the synthesis of a group of compounds which differ from SN-761s only in having the terminal tertiary amino group in the side chain replaced by a primary amino group or by various simple aliphatic secondary amino groups. CH,
I
NH-CHCHzCHzCHz-R I
I I1 I11 IV V
R = -N(CzHJr R = --OH R = LBr R = -C1 R = -NHq
X R = -NHCHzCH(CHa)z XI R = -NHCH(CHa)CzHr
The drugs were prepared from an intermediate compound having the same carbon skeleton but with a hydroxyl group in the terminal position (11, R = --OH). The hydroxyl group in I1 was replaced with halogen, preferably bromine, and the resulting halide (I11 hydrobromide) was then converted into the final drugs by reaction with an excess of anhydrous ammonia or the appropriate primary amine. The intermediate, 11, with the terminal alcohol group in the side chain was prepared by the heating of two moles of 4-amino-1-pentanol with one mole of 4,7-dichloroquinoline, About half of the extra mole of 4-amino-1-pentanol could be recovered in pure condition. The synthesis of 4-amino-1-pentanol from acetobutyrolactone through the intermediate stages of acetopropyl (1) The work described in this paper was done under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the University of Pennsylvania. (2) Present address: Experimental Station, E . I. du Pont de Nemours and Company, Wilmington, Delaware. (3) Present address: A. D. Little, Inc., Cambridge, Massachusetts. (4) Present address: Naval Ordnance Laboratory, Washington, n. C. (.5) Present address: Calco Chemical Division, American Cyanam i d Company, Bound Brook, New Jersey.
w. KISSINGER* AND
alcohol and 1-hydroxy-4-pentanone oxime was worked out in detail; the procedure offers a considerable improvement in yield and quality over the directions of Glynn and Linnelle and of Marshall and Perkin.' The conversion of the alcohol, 11, to the hydrobromide of 111, was accomplished by brief heating with 48% hydrobromic acid containing sulfuric acid. The insoluble liquid product was extracted with chloroform from the reaction mixture. A convenient and satisfactory simplification of the procedure was to use the crude liquid mixture of salts directly without purification in the next step, since the isolation of the pure crystalline hydrobromide of I11 is wasteful of material and, moreover, the crystalline free base, 111, is unstable and readily undergoes ring closure to form the solid hydrobromide of the pyrrolidine derivative, X I I . CHz-CHz
I
I
CHa-CH CH2 \N/ I
09 \"
XI1
The intermediate bromo cmpound, 111, was characterized as the crystalline monopicrate. The liquid salt of I11 (probably a mixture of hydrobromide and sulfate salts) was allowed to react with an excess of anhydrous liquid ammonia or the appropriate primary aliphatic amine t o produce the desired drugs. The side reaction involving cyclization to the pyrrolidine derivative, X I I , occurred in every case. The main reaction to form the drug was favored, however, by use of a considerable excess of ammonia or amine without other solvent and by running the reaction a t room rather than elevated temperatures. When higher temperatures were employed (autoclave) the conversion to drug was completed in a much shorter time, but the yields were lower than a t room temperature. In the case of the preparation of the methylamino drug (VI), one run carried out a t 125' with a large excess of methylamine gave some 4-methylamino-7-chloroquinoline.It therefore appears that under drastic reaction conditions the 4-amino side chain can be replaced by the methylamino group. Such a side ( 6 ) Glynn and Linnell. Quatr. J. Pharm. PharmaCOl., 6 , 496 (1932). (7) hlnr5hall and Perkin, J . Chem. S O L ,69, 867 (1891).
reaction was not observctl iii any of the reactions atrs of the type of 11 or 111. Procedures using at room tem1)erature. 'The synthesis of tlie cthyl- the halide intcrmediatcs are especially suited, on amino drug (,VII)is described in detail in the Es- the other hand, for the rapid preparation of a variperimental and is typical of the best conclitiions ety of different homologs with a minimum of separate stcps. for the other members of the scries also. The chloro comp(mnc1, I\-, w a s i)rcparctl ;is :L The side chain was prepared in the form of a stable, crystalline free base by the action of thi- mono-N-acetyl derivative, 1-(X-acetyl)-ethylacinyl chloridc U ~ O I I I I , and was successfully c m - mino-4-aminopentane, in order that the condensa-. verted into the ethylamino drug, Y I I , but the tion with -I.,/-dichloroquinoline would not give the over-all yield of IV irom I1 w i s rather low a n d the undesired isomeric compound having the ethylpurification time-consuming, so that the alterna- amino grouping attached to the quinoline nutive procedure involving the bromide hytlrohro- cleus. Xcetopropyl chloride was allowed to react with aqueous ethylamine solution, then without mide proved to be thc most convenient. The crude drugs were iscilatcd as highly viscctus, isoliition of the intermediate condensation product ; treat9cIIow liqiiitl I)ascs col1tainillg varyiiix pro~:m- i proba1)ly I -cthyl-4-methyl-A?-pyrroliiie8,g) ticIris o f the pyn-oli(linc tlcrivativc, XI 1 . 'I'lic \:is- ment ( i f the mixture with hydroxylamine gave 1 -ctIiyla~niiio-~~--l,clltanone osime. Tlic oxime was cosity cvcii ;it high tcrnpcr;itures pr clcm scparatioii of the by-product by distillation isolittcd as a crystilline solid, then acetylated on under reclucttl pressure, arid it was therefore the aminr group and hydrogenated over Kaney necessary to utilize otlicr mc;iiis of purification. nickel tc) 1 - ( S-acetyl)-ethylamino-4-aminopentane. Advantage w;is taheii oi the iact that in both the 'I'hc side cliaiii W:LS condensed with 4-,7-dichloroi i i the usual way and the N-acetyl group drugs arid tlic pyrr(ilic1iric 1q-l)roduct thc pKp, oi c~ui~~ciliiic the quiiioline iiucleus is in the railgc i.2--7.i itiitl rcmovetl from the coiidensation product with hot the 4-;mino group is nearly ncutrril i l l cliaract.cr, coriccritratcd hydrocliloric acid, yielding VII. The catalytic hydrogenation of l-ethylaminowhile the tcrniiti:tl :tlil)hatic ainiiio groups in tlic drugs are stroiigl>-basic, with [ I K ,valuc~s ~ in t11c -1 -peritanone oxime was studied. The product apneighborhoot1 of !).S. ,\t ; i i i ;i1qxirciit />€I ( i f ~ic:ired to consist of a mixture of l-ethylamino-4ant1 l-ethyl-2-methyl-pyrroliciine, 8-S.4 i n alcohcil ~natcr solutici~i,tlic i)yrrolitliiic ~iniiiici~~e~itane compou~i(lis c:stractat)lc wit11 ctlicr, while tlic which could bc scparatcd by iractioiial distilladrugs rcniaiii i l l soluticiii ;is tlic inolio-acid s;tlts; tioii. N o :tttcinl)t w:is made to conderisc l-ethyl~ ~ I ~ ~ ~with ~ ~ ~4,7-dichloroI I ~ ~ ~ I I ~ the drug bases are rccovcrablc up(i~iacltlitioll ( i f ~ I I I ~ ~ I I O - ~ - : L I ~ directly quirioliiic. It Iias beeii reported from another an cxccss of stIci~igalkdi. I t was advaiitngeous also t o form tlic crys- laboratory I o tliat diamines of this typc condense talline oxalate snlts iollowilig thc 1)relimiiiary scp- preferentially 0 1 1 the primary amino group and aration ticscribcd above, aiid to digest the c l i f i - that drugs of the type of VI-XI can be convenicultly soluble !solids with hot absolute ~tl~(ih01 to ently prepared by such a procedure. dissolve out a small amount of impurity, includExperimental ing some colored material. The oxalates are not Oxime.--A solution of 1072 g. as a rule too well defined in composition; conse- of 1-Hydroxy-4-pentanone acetobutyrolactone" in three liters of 5'5 hydrochloric quently, the free bases were recovered from the acid was stirred aiid heated under reflux in a &liter roundoxalates and distilled a t low pressure. The pale bottomed flask for three hours; the temperature was yellow distillates slowly cry-stallized spontaneously raised cautiously to avoid excessive frothing. The solution theii cooled a i d treated with 700 g. of hydroxylamine and were in nlost cascs submitted for tests without \vas hydrochloride and 870 g. of sodium carbonate nionofurther treatmcnt. Iiydrate. Solid potassium hydroxide (400 g , ) was added The properties of the drug bases submitted for with stirring aiid cooling t o maintaiii the temperature tests of antimalarial activity arc shown in Tablc bclo\r. f i ( l o . Afttr the mixture had stood a t room ternfor t\vciity hours thc PH was adjusted to i - 8 I. The properties of several salts which were pctature ith conrciitratcd hydrochloric acid and the crude l-hysubmitted for testing are giveii in Table 11. l'he droxy-~-I)ttitaiiolleoxime was extracted with ether for twenty-four hours i l l a liquid-liquid extractioii apparatus. results of the tests will be reported elsewhere. One of the drugs of this series ( V I I , It = Thc oxinit recovered from the ether waq distilled as a liquid, b. p. 122-124" (0.6 mtn.); yield, -KHC*Hb) was prepared by an alternatiive 72-74rc from ous acetobutyrolactone. The oxime crystallized method invol\-irig the presynthesis of the dia- spoiitaiirouslv upoil standiiig, atid \vas pure enough for mino side chain and its subsequent contler~satiot~ I~ytlrogc~iiatinti .% saiiilile r t c t y ~ t a l l i m lfroiii rthyl accl a t e fornictl ~olorlt.~.: crystals, 111. 11 fbl.>62*. Glynn and with ~,;-dichloroquinoline. The product of t hi:; Lititiel16 and iilarshall and Perkin' reported t h a t t h e series of reactions was identical with the base cth- oxime was liquid and could not be distilled because of detained in the manner described above. This in- hydration to a cyclic compound. S o decomposition was dependent synthesis serves as a confirmation of noted under the conditions described above. the correctness of tlie assigned structures. It was ( 8 ) Fischrr a n d O r t h . "Die Chemie des Pyrrols," Akademische considered desirable t o develop a method fnr the ~rrlaR,fie'rllsrhaft, l.eipzifi, I t l 3 I . Val. I . p 319 17 .\ atill A r t l i i i r C'. . C U I X ~'1'111s , ent means of preparing large quantities of indi- J O I I R S A I . . 68, 1225 lI!)4(!), vidual drugs t.han methods in\-nlving iiitcrnidi1 I I 1 S ~ ~ ~ ~ I,y ~ , AlcrrL. l i r ~ l; a ~ t , l C ~ ~ r i i ~ u i ~ y , :tiiHs
NO
VI VI1 1'111
IX
x
XI Carbon Calcd.
Found
Calcd.
M p.bOC 104-107 5 100 I02 100-1 02 60-63 67-71 6569
Surveyo number
SN 11,958 SIV 13,tilFI ss 11,0;9 SIV 14,078 SN 15,067 S S 15,062 Anal p e s , Hydrogpri Found
I
&Ha
Yield
%
48 5 44 30 17h 40 33
-_____
Oh--
Calrd
Formula
CijHmClNa CisHnClNI C,,HvCIN, Ci8Hze,ClNS CiaHd2Nz CI&z&lKia Neut. eqiiiv 0 Calcd. Found
Xitrogen Found
61.85 64.75' 7.2ti 7 ,5;ie 15.13 15.61" 139 142 65.85 65.56' 65 66 7 . 5 ~ i' , U 7.60 116 148 66.76 66.82' 66.79 7.52' 7 . 6 7 7.91 153 155 67.59 67.19' 67.11 8.19 8.02'' 7 . 8 5 1AU 163 67 59 67.97" 67 64 8.19 S.08d 8 . 0 5 13.1.1 13.3gd 13 25 1t i 0 161 67.59 0 8 . 1 0 d 67.83 s.19 8.19,' 8.32 13.14 1.3. 04" 13.02 16U 160 a The Survey Number identifies the drug in the files of the Survey of Antimalarial Drugs. The activities of these will be tabulated in a forthcoming monograph. M. p. values for solidified distillates. No b. p. values are given; vapor temperatures varied with apparatus and rate of heating but were tisually within the range of 170-200" a t approximately Analysis by Dr. Carl Tiedcke, 366 Fifth 0.05 min. c Values are over-all yields of purified drugs from the carbinol, 11. Analysis by Mr. B. H. Adclson, Northwestern University. Avenue, S e w York. Analysis by Mr. William Saschek, Colunibia University, College of Physicians and Surgeons. 0 Titration to quinoline endpoint with standard hydrochloric acid (PH meter). III.HBr reflused two hours with an excess of n-butylamine; later experience suggests that the yield could be improved by use of lower reaction temperature and longer reaction time.
"
TABLE I1 QUINOLINE BASES
SALTS OF
c
R -OH -NHx -NHCZH,
d
Survey number S N 15.063 S N 13,817 SN 13,616
M. p . , OC. 108-116 234-236 (dec.) 220--221 (dec.)
Carbon Formula Calcd. Found Ci4Hi~ClN:O.HCl.HzO 5 2 . 6 7 52 29' ,52.14 C I ~ H I ~ C ~ N I ~ H Z S O4~2~. 2~6H X 42.72' O 42.76 (CiaHrtClNl)t(HzCzOl)i' 5 3 . 4 6 53 01' 5 3 . 0 7 5 2 . 74d
a Oxalic acid salt recrystallized from 70% methanol. Analysis by Mr. B. H, Adelson.
Analyses, % Hydrogen Calcd. Found 6.32 6.39' 6.35 6.08 6.20a 6.08 5.90 6.04' 5 . 8 6 5.71d
Analysis by Dr. L. Cavalieri.
Irr itrogen Calcd. Found 8.78 8.8OC 8 . 8 6 10.56 11.2OC 11.42 9.84 9.94d
Analysis by Dr. Carl Tiedcke.
A n d . Calcd. for CsHllNOl: C, 51.23; H, 9.47. with stirring in a large round-bottomed flask equipped with a thermometer dipping into the liquid and protected Foundll: C, 51.28; H, 9.44. 4-Amino-l-pentanol.-Distilled, but not recrystallized, by a soda-lime tube. By means of an oil-bath the temperature was brought gradually t o 145 * 2' and held there 1-hydroxy-4-pentanone oxime ( 110 g.) was hydrogenated over 3-4 g. of Raney nickel catalyst a t a n iiiitial pres- for four hours (constant stirring). Unless the temperature was carefully controlled the strongly exothermic sure of 1800 lb. per sq. in. The temperature was raised cautiously during thirty minutes to 60" and eventually to reaction showed a tendency to become violent. The mix75"; uptake of hydrogen stopped after two mole equiva- ture was cooled t o loo'', poured into water, and stirred t o lents had been absorbed. The product was purified by dis- induce crystallization. It was washed with water, filtered, tillation, b. p. 117-119' (25 mm.); yield, 7 4 4 0 % . A and the slightly moist solid recrystallized from 95y0 alcohol (Darco and Celite). The yield of first crop material was small amount of yellow by-product, b. p. 144-150" (1mm.), 70-75% of t h e theoretical, but additional quantities rewas always formed. The freshly prepared material did not usually crystallize spontaneously, but unreacted 4-amino- covered from the first washings (by addition of potassium I -pentanol recovered from the next step sometimes solidi- hydroxide) and from the alcohol filtrates brought the yield of product melting a t 178-180" t o 85-95% based upon dified t o a colorless solid with setting point of 32". chloroquinoline. The material so obtained was satisBecause of the hygroscopic nature of the amino alcohol i t was not analyzed, but was characterized as the diben- factory for use in the next step; several recrystallizations zoate, prepared by the Schotten-Baumann method and from 9570. alcohol gave an analytically pure sample of recrystallized from dilute alcohol, m. p. 99-100" (reported colorless crystalline material, m. p. 179-181 m. p. 87.5'8). Anal. Calcd. for ClrHl,CINtO: C, 63.51; H, 6.47; N, Anpl. Calcd. for C I Y H ~ l N OC ~ : 73.29; H, 6.80. 10.58; neut. equiv., 265. Found14: C, 63.17; H, 6.41; N, 10.37; neut. equiv., 273. Found12: C, i3.31, 73.02; H, 6.27, 7.10. 4-(4'-Hydroxy-1 '-rnethylbutylamino)-7-~~oroquindine The mono-hydrochloride mono-hydrate was prepared (II),-A mixture of 1.6 moles of 4,7-di~hloroqvinoline~~ and from the base by mixing 1.5 equivalents of concentrated 3.2 moles of 4-amino-1-pentanol was cautiously heated hydrochloric acid with one molecular equivalent of base
'.
(12) Analyses by Dr. L. Cavalieri.
(13) Supplied by the National Aniline Company.
(14) Analyses b y Dr. Carl Tiedcke, 366 Fifth Avenue, New York.
N. Y.
July, 1946
SYNTHESIS OF SOME METHYLBUTYLAMINO-7-CHLOROQUINOLINES
1223
in an equal volume of water and recrystallizing the re- lidyl)-7-chloroquinoline, This compourld was subiriittecl sulting solid from absolute alcohol-ether; needles, m. p. fur antimalarial tests as SN-14,959. 108-115"; the salt is further described in Table 11.
