Subs titutetl hininoalkoxy tviaPylhaloethyleiies'
Jariuary 196i TABLEI AMISOILKOXYTRI.I~YLH.ILOETHYLESES
x
R2 Carbon, % Hydrogen, % Halogen, % Calcd Found Calcd Found Calcd Found
\-ield,
No.
X
U p , OCn
3Iethod
1 la 1b
Cl
116-118 156.5-158.0 149.0-150.5e 125-12 7
A E
2
CI C1 Br
3
C1
4
c1
I
C1
6
Br C1
I
8 9
Br
c1
Formula
64.26 70.58 70.58 59.81
64.38 70.45 70.84 60.31
6.07 6.61 6.61 5.65
6.36 5.93 6.64 16.03 6,54 16.03 5.72 12.45
5.50 15.87 15.92 12.06
91
CmH&lNOC
E C
37
C?sH?sCIPiOb C?sHz8ClxOb C?sHzsBrNOC
203
B
42
C ? ~ H ? I C I N O ~ ~68.40 68.16 5.96 5.86
110-112 100-102 114-116 127 128-130 149-153
B
B
62 51 9.3 71 6.2 33
64.i4 C?;HaoC1?;OC C ? S H Z ~ C I N O ? ~62.04 57.76 CnH&r?;OP 63.10 CiiH~oCINO& C?iH30BrNO?C 58.93 i0.43 C31H1sC1?;0?*
6.32 5.79 6.09 5.91 5.55 12.10 6.36 5.64 5.58 11.88 7.40 13.42
5.40 5.92 12.94 5.33 11.47 13.44
38
C ? S H ~ U C I K O ? ~69.42 69.56 6.45 6.84 14.64
14.14
13 D I3 C
10
CI
186-187
B
11
CI
12
C1
111-112 180-183 103-107 199-201
A D
C1 c1
70
... ...
52 63 .-I 68 A 8
a Melting points are those of the >alt; indicated ill the formiila. aiialy;iis. e -4polymorphic form of this isomer melts a t 159-161".
60.i6 c ? , H ~ ~ c I ~ N o63.97 ~~ 63.10 CwHaoCINOzC 67.82 C2aHnClFNO'
C?sHnCh~OC
Hydrochloride salt.
64.39 62.31 57.54 63.32 5K54 70.38
60.14 63.88 63.12 6T.43
6.26 5.71 5.32 6.10 5,69 7.44
3.0id
3.18
5.58 5.70 2.2Zd 2.26 5 . 9 7 6.10 20.99 21.18 5.62 6.10 6 . 1 0 5,64 6.13 6.44 3.04d 2.95
Dihydrogen citrate salt.
Indicates S
clinical studies shom-ed that 1 induced ovulatory-type nieiises in anovulatory, amenorrheic women.
Experimental Section la (trans)
l b (cis)
R =HC1. (C2H;)IS CHZCH?
performed on the day after the last injection, arid the organs were removed and weighed. In coniparisori with the untreated controls, ininiature male rats treated with high doses of the haloethylenes shon-ed significantly lower weights of t'he sex arid sex accessory organs. Confirmatory tests in parabiotic rats also showed the potent gonadotrophin inhibitory qualities of the haloethylenes. One representative compound, 2- [p-(2-chloro-l,2diphenylvinyl)phenoxy ] t riet hyluniirie dihydrogen cit rate (l! clomiphene citrate),$ gave 50% inhibition of ovarian hypertrophy in parabiotic rats at a dose of 0.1 mg/kg/day.10 Animal studies further suggested that in addition to gonadotrophin-inhibiting properties, 1 had estrogenic and antiestrogenic actions.lO,ll Testsl0$l2 perfornied with low doses (0.1-0.5 nig/kg/day) of 1 in intact, ininiature rats resulted in increased ventral Ixostate weight of the test aninials above that of the vontrols. These results suggest gonadotrophin stiniuhtiori by low doses of 1. R e p ~ r t s on ~ ~subsequent j~~ (9) Clomidb is the I V m . 9. 3Ierrell Co. trademark name. The accepted generic name is clomiphene citrate. I n earl\- literature reports, i t v a s also referred to as chloramiphene citrate. (10) D. E. Holtkamp, J . G. Greslin, C. .-\. Rout, and I,. J . Lerner, I'roc. Sor. E r p t l . B i d . .lied., 105, 1'Ji (1960). (11) 11. E. Ifoltkamp. R . 1.2. Staples, J. G . Greslin, and R. H. I)a\-is, Kxrerpln .\led., in press. (121 i.ncJl,v. 13. l i : d l d 1 , : 1 1 1 d n . 13. (:rwu1>1att,.qit,, / < , , ( I (19Iit).
(13) It. 13. Greenblatt, I\-. E. k r f i e l d , 1;. C. ,Jungck, and A , I \ . Roh-, .I. -4m. X e d . A S S O C . , 178, 101 11961). (14) R . JI-. Iiistner, A m . J . O b d e t . G y n e c u l . , 92, 380 (1965).
The ethylene starting materials for 1-4 and 7 are described in ref 7 while those for the remaining haloethylenes (except 13) are described in ref 15. The starting material for 13 was prepared from 4-(B-dieth~laminoethox~)-4'-methoxybenzophenonel~ according to ref 15. Method A. Direct Chlorination. Z-i~-(2-ChIoro-1.2-diahenvl. viny1)phenoxyltriethylamine Dihydrogen Citrate (~).-TO a soiution of 250 g (0.615 mole) of 2 - [ p - ( 1,2-diphenylvinyl)phenoxy]t,riethylamine hydrochloride in 900 ml of dry chloroform was added, over a period of 2 hr, 1190 ml of a CCl, solution containing 38.6 g (0.646 mole) of Cln/l. Bfter the addition was completed, the solution w-as stirred at room temperature for 30 min and then refluxed for 1 hr. The solution was cooled and made basic by addit,ion of a Ya2C03or S a O H solution. The organic layer was removed and dried (AIgs04). The chloroform was removed iuider reduced pressure and the residue that remained R-as converted to t,he dihydrogen citrate salt using 115 g (0.615 mole) of citric acid in 1000 ml of butanone and 300 ml of hot, methanol. On cooling 334 g (91%) of product, melting a t 116-118', was obtained. I n a number of trials, the yields varied from 41-93%, with most of them being near 90%. Method B. Halogenation with N-Chlorosuccinimide. N- [Z{ p Chloro-2-p- methoxyphenyl-1 -phenyl)vinylphenoxy ] ethyl] dibutylamine Hydrochloride (9).-To a solution of 14.5 g (0.029 mole) of S-[2-{p- (2-p-methox~-phenyl-l-phenylvin~-l)phenoxy)ethyl]dihutylamine hydrochloride in 150 ml of dry chloroform was added a solution of 4.4 g (0.033 mole) of ?j-chlorosucciiiimide in 100 ml of dry CHC1,. The reaction mixture was refluxed for 14 hr, cooled, and washed with water. hfter drying the chloroform solution (11gso4), the chloroform was removed by distillation and ethyl acetate was added. The white crystalline product obtained was recrystallized twice from et,hyl acetate t,o give 5.0 g (33%) of product, which melted a t 118", then resolidified and
-
(15) R.1.; Allen, 1'. P . Palopoli, 17. L. Schiimann, :ind 1 1 . G , Van Camgen, J r . , L-. S.Patent 2,914,561(Nov 24, 1959); C i i e m . rlbstr., 54, 5d81r (1960). (16) nritisli Patent 929,254 (June 19, 1963); Chem. d b s t r . , 60, 28278 (1964).
