1214
nK.iKl3,
CRERCH, DRAPER,GARMAN, HAYWOOD, PECK, WALTON [CONTRIBUTION FROM
LABORATORIES OF THE UNIVERSITY OF
.1ND V A N
HOOK
vel. 68
MARnAND]
Synthetic Antimalarials. The Preparation and Properties of 7-Chlor0-4-(4-diethylamino-1-methy1butylamino)-quinoline(SN-7618) lt2 BY NATHI\N L. DRAKE,HUGHJ. CREECH,DANIELDRAPER, JOHN A. GARMAN, STUART HAYWOOD, RICHARD AT, PECK,EDWARD WALTON AND JOHN O’NEILLVAN HOOK When it became apparent that SN-7GlS, late) ; it melted a t 86.4-87.4°.6 The side chain 7 -chloro-4-(4-diethylamino-l-methylbutylamino) - was commercial “Noval diamine” (4-diethylquinoline, held considerable promise as a suppres- amino-1-aminopentane) which was purified before sive, we were called upon to produce considerable use by the method of Jones.’ The material was quantities of the drug for clinical use. The present assayed as better than 99.5% pure. I t is, of paper describes a satisfactory method of prepara- course, possible to prepare SN-7618 using less tion of the base and its solvent-free diphosphate, pure starting materials, but in order to eliminate with particular reference to the conditions neces- as many variables as possible, we chose to operate sary for a high yield of substantially solvent-free with pure DCQ and pure side chain. The reaction between DCQ and “Noval disalt. The drug has been described previously in the patent literature3 and more recently by,Surrey amine” (1 mole to 2 . 2 moles) takes place a t 160.170’ (temperature of reactants) with the evoluand I-faininer. -1good quality of 4,7-dichloroquinoline (herein- tion of considerable heat and is substantially comafter called DCQ’I is important in a satisfactory plete when the mixture has been heated for four to syrithesis of SN-761S.5 The DCQ used was purified five hours. Steam distillation of the mixture by distillation in vucuo followed by crystallization following the addition of excess concentrated sofrom methanol (1.5 ml. of methanol/g. of distil- dium hydroxide serves to remove unreacted DCQ and most of the excess side chain. The layers can then be separated and the product dissolved in 95% ethanol. Addition of 85% phosphoric acid dropwise to the refluxing ethanol solution precipitates the diphosphate of SN-7618. The crude product melts a t 213.8-215.7’ with preliminary softening a t 212’ and is obtained in about 827, yield. h recrystallization followed by reconversion of the salt to the base, extraction of the base with ether, removal of the solvent, and reprecipitation of the phosphate yields a product that melts a t 2 15.8-217’. 7-Chloro-4-(4-diethylamino1methylbutylamino) -quinoline distils cleanly under B pressure of a few millimeters as a light yellow oil. I t can be crystallized satisfactorily from benzenepetroleum ether. The pure product melts a t 88.789.5’. In early experiments low-melting phosphates were frequently obtained. A series of experiments was therefore carried out to elucidate the causes of the formation of these low-melting products from apparently pure base. In Fig. 1 is shown the variation of p H of a I O 1.2 1.1 1.6 1.8 2.0 2.2 solution of the base in water containing about one Moles HdP04/Molebase. mole of phosphoric acid (4 g. of water/g. of base) Fig. 1 .-Titration curve of SN-7618. as 85% phosphoric acid is added slowly up t o an amount slightly in excess of that required for a di( I ) This work was c:irried out under a contract recommended by phosphate. I t is apparent that a t PH’s below 4.0 the Committee o n Medical Research between the Office of Scientific the formation of diphosphate is complete. Research and Development and the University of Maryland. (2) The Sutvey Number, designated SN- identifies a drug in the Table I shows the effect of precipitating the difiles of the Survey of Antimalarial Drugs. The activities of these phosphate of SN-7618 with four different solvent will be tabulated in a forthcoming monograph. (3) Andersag, Ureitner and Jung, U . S. Patent 2,233,970,March 4, combinations a t different PH’s. As would be expected after a consideration of Fig. 1, the yield of 1941. ( 4 ) Surrey and Hammer, THIS J O U R N A L , 68, 113 (1946). product increases as the pH of the original aque( 5 ) The DCQ used was obtained principally from the Illinois and ous solution is lowered t o 4.0 and below. I t should Columbia groups; some was also obtained from Northwestern be noted that the yields are given as per cent. of the University. We should like t o express our thanks t o Dr. C. C. Price,
f
Dr. R . C . Elderfield, Dr. B . Riegel and their associates for their cooperation.
(6) All melting points are corrected. (7) R . G . Jones, I n d . Eng. Chcm., Anal. E d . , ‘7, 431 (1944).
July, 1946
TABLE I Precipitating agents in ml./g. of base Yield,) M. p., CHIOH C:HrOH (CHdrCHOH % QC.
9H"
5.0 5.0 5.0
1215
7-CHLORO-4- (4-DIETHYLAMINO- 1-METHYLBUTYLAMmO)-QUINOLINE
11
2.75 13.75
P
C
Analysqc % H
Methoxyl
-
Moisture
68 60 66 72
214-218 11.95 12.01 192-194 11.25 11.34 13.75 214-217 11.96 12.08 5.0 13.75 211-213 12.00 12.05 11 83 194-213 11.25 11.09 4.5 2.75 4.5 33.75 90 192-194 11.30 11.40 4.5 13.75 79 212-215 11.80 11.85 13.75 87 193-195 11.09 10.95 4 .5 4.0 2.75 11 96 192-193 11.28 4.0 13.75 82 192-193 11.15 80 190-194 11.45 11.37 4.0 13.75 95 194-197 11.15 11.23 4.0 13.75 3.5 2.75 11 97 192-193 11.11 11.05 2.17 3.87 3 . 5 13.75 98 191-192 11.21 11.10 41.4 41.9 6.44 6 . 6 1 5.19 5 . 3 5 5.14 3.5 13.75 89 194-196 11.35 11.42 3 9 . 7 40.4 6 . 1 6 . 2 0.19 3.54 3 .5 13.75 97 194-196 11.67 11.76 0.20 3.87 216 12.01 0 The $13 values are for aqueous solutions containing 4 g. HlO/g. of base before addition of precipitating agents. h Calculated on the basis of solvent-free diphosphate. Calculated values for mono-methanol solvate: C, 41.6; H, 6.63; P, 1 1 . 3 1 ~ ~ methoxyl, ; 5.66; for dihydrate, I-', 111.22; for solvent-free diphosphate, C, 41.9; H, G.25; P, 12.01.
calculated yield of solvent-free diphosphate. I t is apparent from the phosphorus contents of these products that they are more or less solvated; they contain both water and alcohol of solvation. Our initial production of diphosphate was carried out under the conditions described in the bottom line in Table I , using 2.08 moles of 85% phosphoric acid per mole of base. I t seems t h a t the causes of formation of the low-melting products which were frequently obtained for no obvious reason were inadvertent changes of compcrsi-
tion of the solutions which brought them into the region where partially solvated products separated. I t is interesting to note t h a t the product which separates from methanol-water is a solvate of the composition C I ~ H ~ ~ N ~ C I * ~ H ~ P O IThis .CH~~H. compound separates in heavy, well-formed, compact crystals and differs markedly in crystalline form from the diphosphates obtained from the other solvents studied. The latter are extremely finely divided, micro-crystalline precipitates
El .5
."s 4d
2 4
-E I.(' .-
I
8
0
200
10
20
30
7027580 90 300 10 2032530 40 350 60 70375 Wave length. Fig. 2.-Absorption spectra of SN-7618 and its diphosphate: molality = 3.88 X 10-5; salt in 0.01 N hydrochloric acid; base in dioxane; SN-7618 (diphosphate), free base of SN-7618. 40
250
60
----
-
which are lilteretl very slowly arid sucked dry with difficulty ; they have :t relatively broad melting range. 'The solvate from methanol-water has a much sharpcr melting raiigc a i i t l possesses tlie composition required by the :tbovc formula when thrown out of solutions having a n y of the pH's studied. Thv ultraviolet absorption spectra oi SS-TO1 S ;IS fret: base m t l as diphosphate are shown in Fig. 2. 'Thc peak a t 345 mp can be used to determine the per cent. of base in a specimen of drug. The absorption of the base was measured in purified dioxane, t h a t oi the diphosphate in 0.01 A' hytlrochloric acid. X Beckmarin spectrophotometcr was ustd. 'I'w) absorptioii inasima iii tlic, regioii b e t w c ~ i :(?.-I aiitl 39W mp arc chnractcristic of thr ahsorpt i o i i spectra of the salts of d l of the 4-arninoquilioliiicas which we have examined. I t seems likely that this absorptioii is caused by the introduction [ii ;I iicw resoii;itor through sult forinatioii, a i i t l i t should I ~ cnoted that (ti-ncitl s:tlts o f the 4-miiiioquiiitiliiics i 11 qiicstioli may lie coiisitlcretl ;IS rcsoiixiicc hyl)ritls, ilivolvi1ig tlic ions ?I1
--
;I --k1lK2
and was the11 filtered. T l ~ efilter-cake was twice heated with ethanol for about three hours and filtered hot. The product wcighctl 215 g. (82.57;) and i2elted a t 213.8213.i" with prcliiiiiiiary softetiiiig a t 212 . A portion (197 g.) of this iiiaterial was dissolved iii 400 1111. of hot water, a i d heatcd with Llarco. An additional 100 1111. of Eater \vas added aiid the diphosphate precipitated by atldiiig 250 i d . of inethaiiol and 1 liter of 2])ropaiiol. After the Inisturc had been cooled overnight, t h e product was filtered; it weighed 177 g. (747; over-all yield) and iii'dted a t 190-191 ". Analysis showed that the sulistaiice coiitaiiicd soiiic nioisturc aiid methanol. Anal. Calcti. for (:,,Il~~S.lCI.3H,PO~: C, 41.9; 14, 8.24; P, 13.02. Found: C , 40.ti3; H, (;.04; P, 11.52; moisture, 2 , 0 3 ; alkoxyl sho\vii to be present. Forty grams of this product was recoiivcrted to base, takcii u p i i i ctthcr aiid the ether removed iit L ' ~ C ? L O . The colorless residue weighed about 25 g. I t waq dissolved iii cthaiiol aiiti licatctl with stirring uiitler rcflux while 17.9 g. of XS', phosphoric acid was added droj)wisc>. ileatirig iiiider reflux was cuiitiiiuctl lor oiie hour after the atlditioii of the acid was coiiiplctc aiid thc iiiixtiire i v a - thcii allowed tostaiid overiiight. After tiltratioii aiid dryiiig the product wcighcd 37.r; g.; its iiicltiiig range was 213.X-217O. The yield \vas W'~c, for this step aiid (i9.(if,iit \'uciIIItn. 11 \'dCltllln i s applied C I I I Fclr) I ! LLII: ~ ~;it l l l O o . LIw p h < * q ) l i ; ~ tleu s e s w.rter ;ip]':irently lruni lc,lj
I I I P l ~ t i c ~ ~ . l ~ t ii i, r vi q~l c ~ 1 , ~ 1 ~ ~ , 1 'I'hi, t t r ~ l ) r < > p w l \ 1. jihntc, 01 t,thcr f - . i i u t i i i ~ i ~ i ~ i n n 5tudied liici
ihnreil I,v plm-
