720
\ 01. h
A \ KaOH. The oil wliicli scpar:ttcd taken up in ether, and the ether solution was dried ( l I g S 0 4 j . The solution wits t,reated with dry HCI to precipitate the hydroc,hloride s:ilt. i b).--Equivalent :imouiits of %,'2-diphenyl-2-c}ilori~aret yl rh111ride (0.043 mole) mid the appropriate 4-amino-2-butynol were inised and heated a t 100-105" for 25 niin., then a t TOo for inin., :tiid the resultant Ixowii viscous oil was washed thoroughly with anhydrous et her and dissolved in 100 ml. of :inhydrous ethanol. The ethanolic solution was allowed t o reflux for 25 111,. with 5 g. of Na2CIO:I. The reaction mixture was cooled, filtered, :ind neutralized with 2 S SaOH, and most of the ethanol w i ~ removed under reduced pressure. The remaining aqueous mixture wits estract3ed with et,her m d the extract was dried (hIgKO4). Hydrogen chloride was passed into the ether solution t,o precipitat e the hydroc.hloride salt. D. Ester-Ester Interchange.---~;yuivaleiit :iriiounts ((1.25 iiiole) of 4-diethyl:tiiiino-~-bntyn~-l wet:ite and the inethyl estrr iif the appropriate i x h c q - l i c . :ic.id were dissolved in 400 nil. of hcptnne and 1.25 K. of sodium iriet,hosidr:n l u r e %-asstirred and heated, : ~ i i d:I solution I :ivet:tte was s11iwIy distilled froiii the re:tt,tion vessel over :t periiitl of about 1 111.. 'Thi. reniltion niisturc \vas woled, \vv;ished thortiuglily with wuter, :iiid cxtr:Lcted wit11 2 .\. PiiiOH, ziiitl tho oil? base TTX takeii up i i i ether. 'The e t h r ~ solutioii wvas dried (3Ig;iOi) : i i i t l treated with HCI to 1)rec.ipitate :iii oily hydriwhloritif~s d l n-liich solidified o n cooling.
Ii:tth, and neutralized w i t h 2 WRS
Experimental'
4-Dialkyl- (or 4-Polymethylene-) amino-2-butynols \\.ere prepired from 4-chloro-2-butynol and t,he c>orrespondingsecondary :imines as previously described for 4-riiorpholino-2-hut~-iiol.~ The following known 2-butynols were prepared: 4-dimethylamino-,9~10 4-diethylaniino-," 4-pyrrolidino-,2 4-piperidino-,z and 4-morpholino-.8 General Procedures for the Preparation of Esters of 4-Dialkyl(or 4-Polymethylene-) amino-2-butynols. A. Mannich Reaction. ---This proredure is analogous 10 that described by Jones, IA U I . ~ S'arious aromatic esters of propargyl alcohol were eniployed and the products ivere isolated as the hydrochloride salts. The solvents used for the recrystallization of the hydrorhlorides obt:tined by this : ~ n dthe subsequent methods are available from Tables I arid 11. B. Ester-Alcohol Interchange.-Equivaleiit ainouiits of tlie iiiethyl ester (0.035 mole) and the appropriate ~ - ~ I I I ~ I ~ I ~ - ~ - ~ ~ I I ~ ~ - I I ~ J ~ Acknowledgment.----Tlica hiologic~al \vercx dissolved in 50 nil. of heptane and about 0.2 g. of si~diu~ir c~mipouiids\\-a*cmricd oui hy vario niethositle (or 0.2 g. of sodium niet:tl) cat,:ilyst was :idded. T h e the Pharmacology l k p a r t ineu t , I\ i'c:LCt ion niisture \?:is stirred and :illowed to reflux, ;iiid thi, liepta~~e--metIia~iol azeotrope R'BS rollected :tnd measured in :L warc*liCenter. T 1 1 ~autliors wisli t o Ihaiik 1 1 r s Saiii:y I )ean-Stark trap to determine the extent of reacltion. The L l e y Duiiii for Iior tec.hriic.ala reaction mixture \viis cooled in an i1.e hatli and washed with \?:iter. The heptane solution x t s xashed with 2 S HC1 and t h e ;ic:idic extract \vas neutralized with 2 .IrK:iOH. The oily frer h s e W L S dissolved in e l her, :ind the resu1t:int solut inn \vas dried New Antifertility Ageiits. ( lIgS04) :tnd treated wit,h HC1 t o jjrecipitale the hydrochloridr ",3-l)iphenS.1benzofuraiis1~ Sllt. C. Esterification with an Acid Chloride. ( ~ a ) . - - - ':Ik stirred solution of w i d c,hloride (0.074 niiilt,), triethyl~niine( 2 2 . 0 g., 0.:37 illole), :ind 70 nil. of benzene wts :itlded, dropnise, t h r :tpl)ropriate 4-~~iiiiii1~-2-Iii1t~yiii~l (0.07 rnole) dissolved in 25 inl. of 1)c:nzenr. The re:tciion mixture was heated on :I steam tinth for :j hr. :mtl poured I J I I ~ O i~rusheti ice and water. The organic l:tyei, TWS separated, washed n.ilh v-atcr, :tnd estr:ic.ted with scvei~:tlS-iiil. portions of 2 .I-HC1 1 (I remove excess triet1iyl:~niiiie (1 estrwts wel'e 111:idc basic: t o delerniirie if insti1ut)le prvduc.1 W:LS beiiig c~sir:rc.ted). Addit,ioii~il eAirai,tions with 2 HCI a e w ia:twied out :ind tlie ex1 rncts ere coml)ined, cooled in an ice h c 3
72 1
September 1'365 TABLE I
No.
x
--
Mp.,
R
X'
OC.
Formula
3 4
ORIe 0Me OMe OAIe
H H H H
H COCH3 CHKWj CH&H,N( C*Hj),*IlCl
167-168 134-135 127-128 185-186
5
OJIe
H
CHzCHzN
209-210 CnHn?j03*HC1
6 7 8
ORIe ORIe OMe
OMe OMe OhIe
9
ORIe
OMe
10 12
CH3 CHI CH3
CHI CHI CH3
13
CH3
CH3
1 2
11
x
*HCl
C21H1603 C23H1804 C28Hzz03 C27H2gNOa.HCl
% oalcd. C
79.70 76.88 82.75 71.68
H
N
5.00 . . 5.00 . . 5.41 . . 6.60 3 09
--C
%found H
80.12 76.98 82.42 71.23
N
5.35 , . 5.32 . . 5.82 . . 7.02 3.26
72.20 6.23 3.01 72.49 6.63 2.75
187-188 C22Hi804 76.30 5.21 . . 76.50 5.63 . . 181-182 C2gHza04 70.82 5.50 . . 80.26 6 02 .. 158-159 C28HjiN04.HCI.0.5HilO 68.50 6.73 2.83 68.35 7.19 3.03 229-230 C28H2gN04. HC1
70.07 6.25 2.92 70.23 6.41 3.08
H COCHI CH&H2N( C2Hj)i * HCl
199-200 C22H1802 170 C24H2003 167-168 CesHzgNOa.HCl
84.07 5.76 . . 83.94 6.32 . . 80.89 5.78 . . 80.77 6 18 . . 74.70 7.10 3.11 74.65 7.42 2.8s
C H 2 C H 2 N ZHCl
225-226 C28HiTiY102.HCl
75.08 6.73 3.13 75.02 7.05 3.20
benzofurans seemed a worthy choice for exploration in view of the incorporation of the triarylethylene pattern in their structure though in a more rigid form, the association of estrogenic activity with many benzof u r a n ~ ,and ~ their close structural similarity to 1,2diphenylindenes3J which have been shown to possess antiimplantation properties. The synthesis of certain 2-phenyl-3-(p-substitutedpheny1)benzofurans and biological evaluation of one of these is described in this note, Experimental These compounds were synthesized by a modification of the method of Brown, et a1.6 I n a typical run resorcinol monomethyl ether (0.01 mole) and p-benzyloxybenzoin (0.01 mole) in peroxide-free dioxane (30 ml.) were heated under reflux with concentrated HCl (10 ml.) for 24 hr., when a mixture of 2phenyl-3-p-benzyloxyphenyl-6-methoxybenzofuranand the corresponding 2-phenyl-3-p-hydroxyphenyl compound was obtained. Addition of a further quantity of concentrated HC1 (10 ml.) and work-up of the reaction mixture after 72 hr. yielded which was exclusively the 2-phenyl-3-p-hydroxyphenylbenzofuran purified through its acetate. Saponification of the acetate gave 2-phenyl-3-p-hydroxyphenyl-6-methoxybenzofuran which on treatment with P-diethylaminoethyl chloride hydrochloride in the presence of anhydrous K2C03 in refluxing acetone for 24 hr. gave 2-phenyl-3-p-(i3-diethylaminoethoxy)phenyl-6-m e t ho x y b e n z ofuran, isolated as the hydrochloride. The different compounds thus prepared are listed in Table I. (4) (a) E. M. Bickoff, A. L. Livingston. and A. N. Booth, U.9. P a t e n t 3,077,404 (1961); (b) E. M. Biokoff, R. L. Lyman, A. L. Livingston, a n d 8 . N. Booth, J . A m . Chem. Soc., 80, 3969 (1958); (e) W. Longeman, G. Cavagna, and G . Tesolini. Chem. Ber., 96, 1680 (1963); (d) H . Singh and R. S. Kapil, J . Indian Chem. SOC.,37, 695 (1960); (e) H. Singh and R. S. Kapil, J . Org. Chem., 24, 2064 (1959). ( 5 ) G. W. Duncan, J. C. Stucki, S. C. Lyster, and D. Lednioer, Proc. Soc. Ezptl. Biol. M e d . , 109, 163 (1962). (6) B. R. Brown, G . A. Somerfield, and P. D. J. Weitaman. J . Chem. Soc., 4305 (1958).
Biological Activity.-Colony bred female albino rats of the Institute (130-150 g.) were mated to coeval males of proven fertility. The day on which the vaginal smears showed the presence of spermatozoa was considered day 1 of pregnancy. The compound was macerated with an equal amount of gum acacia and suspended in 1 ml. of distilled water. The suspension was introduced into the lower part of the esophagus by a feeding needle. The control animals received a mixture of gum acacia and distilled water. The results were scored as positive only if implantations were absent in both uterine horns examined on day 10 of pregnancy. It will be seen from the results presented in Table I1 that compound 4 administered daily a t doses of 1, 2, and 4 mg. on days 1 to 5 of pregnancy was 100% effective in preventing imTABLE I1 EFFECT OF C ~ M P ~ U4S OD N ImL.wr,wwN Dose, mg./rat
Days
No. of rats
1-5 1-5 1-5 1-5 1-5 1,2,or 3 4 5
12 12 6 12 8 12 5 4 4
Control
0.5 0.75 1
2 4 20 20 20
IS
RATS
Total mean of implantations (range)
7.3(4.C-9.0) 7.5(5.0-9.0) 1.8 (0.G4.0) 0.0(0.0-0.0) 0.0(0.0-0.0) 0.0 (0.0-0.0) 0.0(0.0-0.0) 0,75(0.0-3.0)
5.8 (5.G7.0)
plantation. A single dose of 20 my. given on days 1 to 3 of pregnancy was equally effective in preventing implantation. The failure of the compound t o prevent implantation on days 4 and 5 suggested that its primary site of action was the Fallopian tubes rather than the uterus. Detailed studies of this group of compounds are in progress.
Acknowledgment.-The authors are grateful to Dr. AI. L. Dhar for his interest in this study. Thanks are due to N r . J. Saran and his associates for microanalyses.
