11. SURREY, :I. J. OLIVET,S.0.~VIKTHROPAND [ COXTRIBU'I'IOX
FROM THE
G.1'. L E ~ H E K
Vol. 7s
STERLISG-~~-INTHROP RESEARCH ISSTITLJ'I'B]
New Amebacides. V.I The Preparation of Some N- Alkoxyalkyl-N-b enzyldichloroacet amides H Y ALEXANDER K. SURREY, ARTHURJ. OLIVET,STANLEY 0. WINTHROPAND GEORGEY. LESHER RECEIVED MARCH14, 1956
A series of S-(2-alkoxyethyl)-,V-beiizyldicl1loroacetamidesand N-(3-alkoxypropyl)-S-benzylclichloroacetainideswere prepared by dichloroacylation of the appropriate aminoethers. T h e latter were prepared by alkylation of t h e alkoxyalkylatnine with a substituted benzyl chloride or by reductive alkl-lation of t h e alkoxyalkylamine with a substituted benzaldehyde. The reaction of ethoxyethyl chloride with substituted benzylamines was employed in t h e preparation of the S-(2ethoxyethy1)-betizylarnines. Some of the compounds in the present nmrk represent the most active antiamebic agents of all t h e compounds reported thus far which are derived from t h e general structure I.
The results of our previous investigations of potential aniebacides derived from the general for-
in the 3-alkoxyalkyl series most of the dichloroacetamides were obtained as high boiling viscous oils. /---.\(CH2) Y-Rl All of the compounds listed in Tables 111 and IV R X d n-I were screened in hamsters for aniebacidal activity COR. according t o the method of Dennis, Berberian and I Hansen. In many respects the results obtained iiiula I have indicated t h a t the most effective in the present series parallel those found for the agents were those in which jz = 1, R = 2,4-di- N-benz yl-N-hydroxyalkyldichloroacetamides. chloro, 4-butoxy and 4-isopropyl, and RS= CHC12. T h e unsubstituted benzyl derivatives showed relaThese observations were made in the series where tively lower therapeutic activity. T h e alkoxyIil is hydroxyalkyl, alkyl, acyloxyalkyl, cyano- ethyl series was considerably more effective than alkyl and carbamylalkyl. It appeared, therefore, the alkoxypropyl series. T h e most active cornt h a t the direction which offered the greatest pos- pounds again were those in which R is 2,klichloro sibilities for obtaining even more active anti- and 4-isopropyl. The peak in activity with variaamebic agents was in the variation of R1. I n the tions in R1 appeared to be associated with the present communication we are reporting the syn- ethoxyethyl group. Replacement of the alkoxy theses of derivatives of I in which K l is alkoxy- group b y a phenoxy group resulted in a marked deethyl, alkoxypropyl and aryloxyethyl. crease in amebacidal activity. Of all the coinMost of the N-(2-alkoxyethy1)- and N-(3-alkoxy- pounds reported thus far, N-(?-ethoxyethylj-;Npropyl)-benzylamines described in Tables I and I1 (4-isopropylbenzyl)-dichloroacetamide,with an apwere prepared either by the reaction of a substituted proximate ED5" value of 1 mg. 'kg., appears to be 3,4-C1?, 4-NO2) the most potent antiamebic agent. benzyl chloride (R = 2-Q 2>4-Cl2> with an excess of the appropriate alkoxyalkylAcknowledgment.-The authors are indebted to amine2 or b y reductive alkylation of the amino- M r . 11. E. Auerbach and Xlr. I(.D. Fleischer and ether with a substituted benzaldehyde (R = staffs for the analytical data and corrected melting 4-OC4H9)3-CH(CHa)*or 3,4-02CH2). For the prep- points and t o Dr. D . -4. Berberian and X r . R. C . aration of the X-(2-ethoxyethyl)-benzylamines, Slighter for the screening data. alkylation of the benzylamine was first carried out Experimental5 with 2-ethoxyethyl chloride. Later, a better proPreparation of N-(3-Alkoxypropyl)-benzylamines (Table cedure was developed which involved alkylation of Ij,-Procedure A was employed in the prep;tratioii o f tile the benzylamine with the tosyl ester of ?-ethoxy- S-(3-alkox~~propyl)-chlorobenzylamines and K-(3-methox!-ethanol. SeL-era1 of the crude S-alkoxyalkyl- propy1)-4-nitrobenz>-lamine. Procedure B was employed benzylamines were converted directly to the hydro- in the preparation of the 4-butoxybenzylamines. ( A ) 3,4-Dichlorobenzyl chloride (19.5 8.) was added dropchloride salts which were used as such in the acyla- wise with stirring t o 311.9 g. of 3-ethoxypropylamine without tion step. a n y external cooling. The temperature rose to about 0 5 O Dichloroacetylation of the benzylaminoethers during the addition. Stirring was continued for 2 hr. and was effected by treatment with dichloroacetyl the mixture mas allowed to stand overnight at rooni teriiT h e solution was made strongly basic with 35% chloride in the presence of dilute sodium hydroxide perature. sodium hydroxide and the organic layer w a s taken up it! solution. For the preparation of N-(2-methoxy- ethL-lene dichloride. After drying with anhydrous pot:tsethyl)-4-isopropylbmzylaniine and the correspond- siurn carbonate the solvent was removed by distillation ing ~,.~-nieth!-lenetliosS;ben~~laiiiinc, the hydro- untler reduced pressure and the residue I11 sex-era1 cases the reiitiue wcis chloride salt of the benzylaminoether was heated distilled. propyl alcohol and the calculated ainount of alcoholic h>-with dichloroaretyl chloride in benzene until the drogen chloride W;IZ added. The li>drochloride salt wits reaction mixture hecanie homogeneous. I n the filtered off and recryitallized froin ethyl alcohol. ( B ) A mixture of 4-butoxS-beilzaldell?-de (17.9 g.) a t l d 2-alkoxyethyl series all the dichloroacetaniides 13.2 g. of 3-butox~-prop)-lan~irle was heated i 7 z zsacun 011 LL were obtained as crystalline solids with the excep- steam-bath for a few minutes, dissolved in 150 ml. of absotion of N- (:%methoxyethyl)-N-(3,4-methyIenedi- lute ethyl alcohol and then reduced catalyticall>-with pallaoxybenzyl) -dichloroacetamide. On the other hand, diuin-on-clinrcoal a t ;I hydrogen pressure < i f about two a t ,
I , Paprr I\.,
,\
K . S u r r r j .tiid ( i w
r i i ~ , ~ I t l vi/,i,/., r, 6 1 , l:(il; ? c r l ~ n >11 , .\. t3eriw(i.,!i i i t l d >, I j ' i r l - r ~ t . . 4 f 1 # .I ' / Y U / J l / r , i , 29, h83 (liJ491. 1 4 1 A K. S u r r r g , 'I'HIS J < ~ : N N A I . , 76, 2214 (1924). (-1) ,411 m r l t i n g p o i i i l k i i r r u r r r r t r i l i i t i I e i \ o t h r ~ ~ l i nwi i i c : i i r i l
3835 PREPARATION OF N - A L ~ ; O X Y A L ~ ; Y L - ~ J - B E N Z Y L D I ~ ~ ~ L O R ~ ~ ~CETA~~I~~S TABLE I h'-(3-ALKoXYPROPYL)-BESZYLAMINES
R 2,4-C12
R3
CH3 2,4-C1z CHiCHa 2,4-C1n CH(CH3)z 2,4-C12 (CH2)CHa 3,4-Cln CHj 3,4-C1z CHZCHI 3,4-C1z CH(CHa)? 3,1-C12 (CHz)aCHa 4-OC4Hs CHa 4-OCdHs (CHdjCHa 4-NOz CH3 a
Yield,
B.P., "C. Mm. 132-134 0 . 5 132-134 .5 140-142 .3 146-148 .3
~ Z Z ~ D
%
1.5312 1.5203 1.5170 1.5100
86 77 89 76
134-137 162-165
1.5178 1.5152
G7 76
.2 .7
R+ ~ H z X H C H ~ C H ~ C H Z O R ~
Nitrogen, Yo Formula Calcd.Found CiiHidXzNO 5 . 6 4 5 . 6 2 CizHi7ClzNO 5 . 3 4 5 . 3 2 CiiHipCltNO 5 . 0 7 5 . 1 2 CirHziChiTO 4 . 8 3 4 . 9 8 Ci1HisClzX0 CizHiiCInSO CL~HLOCI~N 5 .O 0 7 5.11 C1rHziClzN0 4 . 8 3 4 . 8 4 CisH?sKOr ClsHz~S0z C~iHieNzOa
M.p., OC. 128.5-130.5 127.8-133.8 141.6-142.2 115.2-117.6 214.1-215.7 217.1-219.2 208.Ck209.2 184.4-185.8 164-16Y 125-12V 188-190a
C 46.40 48.26, 49.92 51.47 46.40 48.26 49.92 51.47 H2.58 65.53
Hydrochlorides, analyses, % Calcd. Found H C1C H 5 . 6 6 12.45 46.61 5 . 9 9 6 . 0 7 11.89 48.60 6 . 1 8 6 . 4 5 1 1 . 3 4 50.05 6 . 4 1 6 . 7 9 10.85 51.71 0 . 6 7 5.DG 1 2 . 4 5 4 6 . 6 3 5 . 8 3 6 . 0 7 1 1 . 8 9 4 8 . 2 2 G.07 6 . 4 5 11.34 1 0 . 7 2 6 . 6 4 6 . 7 9 10.83 5 1 . 3 f i 6 . 7 9 9 . 1 1 12.32 62.17 8 . 9 8 9.78 9.78 65.11 9.74 13.60
c112.57 11.91 11.42 10 83 12 50 12 13 11 30 10 83 12 32 10 82 13 49
Uncorrected Ineltiiig point.
TABLE I1 CH2SHCHzCH20K3
N-(~-ALKOXYETHYL)-BENZYLAMINES R \"/ B.P.. 'C. Mm. 75 0.4 H CHzCHa 142-144 11 4-CH(CHa)z CH3 95-100 0 . 3 4-CH(CHa)? CHzCHi 4-CH(CHs)z (CHd3CH3 170-174 7 . 0 CHnCHg 106-111 1 . 3 2.c1 CH; 1ocb105 0.4 2,4-C1z 100-104 .5 2,4-C1z CHzCHi (CHz)CHa 135-140 .4 2,4-C1z 119-125 .5 3,4-C1n CHzCHa (CHn)aCH3 114-148 .4 3,4-C12 CaHa 150-156 .02 3,4-C1z CHa 134-137 .ti 4-OCdHp 118122 .02 4-OCdHs CHnCH3 R
a
Yield,
K3
7 1 2 5 ~
1.4985 1.4995 1.4914 1.4898 1,5089 1.5302 1,5209 1.5147 1.5230 1,5150 1.5755 1.5005 1,5015
%
Formula 15 CiiHiiKO 54 C13HziKO 47 CiaHzaKO 58 Ci6Hz7NO 6 8 CiiHi6C1NO 64 CiaHiiClzNO 52 CiiHiiClnNO 50 Ci~HisCIzh-0 54 CiiHisClzNO 40 CiaHieClnNO 64 CisHisClzSO 67 Ci4HZaN02 5b C I I H Z ~ N O ?
Sitrogen, %, Calcd. Found 7.81 7.78 6.75 6.67 6.33 5 . 9 8 5.62 5.58 6.56 5.98 5.98 5.61 5.64 5.33 5.07 4 . 8 2 5.64 5.43 5.07 4 . 8 9 4 . 7 3 4.61 5.89 5 . 6 1 5.57 4.92
R l . p , OC.
C
Hydrochlorides, analyses, %, Calcd. Found H C1C H
46.61
j.95
12.0li
46.42 5 . 6 6 19.94 0.45 54.31 4 . 8 6
12.46 4 6 . 7 7 11.34 3 0 . 3 2 10.68 54 20
5,15 6.63 4.90
12.28 11.23 10.59
02.59
12.32
8.89
12.10
131-131a
4G.42
183.5-186.1 158.6-160.1 201-205.2 1CO-160.8
5.66
9.11
12 4lj
C1-
62.45
Uncorrected melting point.
TABLE 111
ACH~KCH~CH~CH~O
6-(3-ALKOXYPROPYL)-~-BENZYLDICHLOROACETAMIDES R
K
Ra
OC.
B.P.,
hIm.
Yield,
159-1 62 0.01 63 CH3 2,4-C1? 2,44212 CH2CH8 162-164 .01 75 2,4-C12 CH(CH3)? 170-172 .02 84 2,4-C1z (CH2)3CHs 174-176 .05 41 3,4-C12 CH3 98.0-103.0b 86 3,4-C1? CHzCH3 6 0 , 1 4 1 ,8h 63 3,4-C1z CH(CH3)z 178-180 0.03 57 :3,4-Cln (CHa)aCH3 185188 .01 50 4-OC4Hg CH3 188-189 .04 63 4-OC4Hs (CH2)aCHa 188-189 .01 69 4-NO2 CHI 93,2-95.l b 73 a Determination of readily hydrolyzable chlorine. 4.18. Found N (NOZ):4.15.
Formula
COCHClz I
Chlorine,5 o/o Found Calcd.
Carbon, % Found Calcd.
Hydrogen, 0'0 Calcd. Found
1Y.iY 43.48 43.55 4.21 4.70 C l a H l a C l a S 0 2 19.75 18.78 45.07 44.92 4.59 4.7'8 C I ~ H I ~ C ~ ~ 19.01 XO~ CisH1gCldSOz 18.32 18.14 46.53 47.11 4.95 5.26 C18HZ1Cl4SO2 17.68 17.81 47.91 48.29 5.28 5.71 Ci,H,,Cl,KO-. 19.75 19.67 43.48 43.26 4.59 4.39 C14H17C14SOa 19.01 18.81 45.07 45.53 4.59 5.01 CisH1gC14SOa 18.32 18.75 46.53 46.22 4.95 5 04 C16H~1C14~0-. 17.68 17.57 17.91 48.09 5.28 F . 4 6 C17HzjClaS08 19.56 19.18 56.35 56.31 6.96 7 23 CtaH31ClsSOs 17.54 17.45 59.40 59.12 7.73 7.51 Ci3HlaC12Sz04 21.16" 21.00 Corrected melting point. e Total chlorine. Calcd. N (NOz):
rnospheres. The catalyst was removed by filtration, the solvent distilled, arid the residue was dissolved in ethyl acetate and treated with a n equivalent amount of alcoholic hydrogen chloride. T h e product was recrystallized from ethl-l alcohol-ether. Preparation of N-(2-Alkoxyethy1)-benzylamines (Table II).-The following examples illustrate the procedures employed in the preparation of the S-(2-ethoxyethyl)-benzylamines. The remaining hT-(2-alkoxyethyl)-benzylamines were prepared according t o methods A and B described above.
T J
( C ) A mixture o f 57 g. of 2,4-dichlorobenzyla~~ii1ie atid 17.r; g. o f ~-Ch1Oroeth~1 et1lYl ether was heated with stirring for 7 hr. : i t 1 4 0 150'. 1rthc.r W : I \ :Itl(letl t o coinpletely prr-
cipitate the 2,4-dichlorobenzylamine hydrochloride which was removed by filtration. The filtrate was freed of ether by distillation and the residue distilled t o give unreacted 2,4-dichlorobenzylamine a n d N - (2 - ethoxyethyl) - 2,4- dichlorobenzylamine. Alternatively, after removing unreacted materials, the residue was dissolved in absolute ether and the solution was saturated with d r y hydrogen chloride. T h e crystalline hydrochloride was collected, washed with a little dry ether and dried a t 50'. Recrystallization from d r y acetone gave a n analytically pure product. ( D ) 6 A mixture of 14.2 g. of 2-chloroberizyla111irie,26.8 ((i) The initial work un thi, m e l h < d W : L \ cnrrirll o u t I>).
X1:tvrr i n tiii.: 1,:it>oriitory
I3r I . R .
3836
-4.li. SURREY, A. J. OLIY’ET,S.0.\YISTHROP
AND
G.Y. LESI-IER
TABLE IY J~~CH~?CH,CHIOR~ P\~-(2-ALKOXUETHYL)-h’-BESZYLDICHLOROACETAMIDESR
COCHClz I
-l)-ben- RESSSELAER,XEW Y O R K g. of the tosyl ester of 2-ethoxyethanol and 12.1 g. of triethylamine was heated with stirring for 24 hr. on a steanibath. After cooling, the reaction mixture was taken up in ethylene dichloride and the solution was washed several times with water. The solvent was removed by distillation and the product mas fractionated under reduced pressure; yield
