Journal of Medicinal Chemistry, 1971, Vol. 14, No. 10 999
NOTES
mercuri substitution product in 59% crude yield. Conversion to the chloromercuri compd was effected in 96y0 yield. This product, after recrystallization, WAS identical in mp and nmr spectrum with the 2-chloro-4-chloromercuri compd synthesized unequivocally. I n order to determine the isomer distribution produced in the mercuration reaction, the crude chloromercuri derivative was treated with Ip. The total product of iodination was converted to Are ester and submitted to gas chromatography; it was found to contain 5y0 of 2-clilorophenoxyacetic acid and 94% of a fraction shown to be 2-chloro-4-iodophenoxyacetic acid. S o 2-chloro-6-iodophenoxyacetic acid that would arise via ortho-mercuration could be detected in the chromatogram. It has thus been demonstrated that the original mercuration procedure leads to para substitution and that merbaphen therefore has the structure that is derived from Ia. Hence, its structure, as depicted by conventional methods, is represented bs 111.
product was collect,ed, washed wit,h H20, and oven-dried a t 65'. The wt of crude acetoxymercuri-2-chlorophenoxyacetic acid was 39.2 g (,59Yc). This material (20 g, 0.045 mole) was added to 200 ml of a 2% XaOII soln; insol material was removed by filtration. T h e filtrate was chilled and treated with 6 N HC1 (35 ml). T h e crude chloromerci1ri-2-chlorophenoxyacetic acid t h a t pptd weighed 18.2 g (96%), m p 169-170". Anal. (CsH~Cl2Hgoa) H, Hg; calcd: 47.59; found46.97. A sample, after recrystn from 95'33 EtOH (50% recovery), had mp 191-194O; mmp with 2-chloro-4-chloromerci1riphenoxyacetic acid imdepressed; nmr spectrum identical with that of the same compd. Isomer Distribution by Iodination.-A mixt of crude chloromerciiri-2-chlorophenoxyacetic acid (4.2 g, 0.01 mole), IZ (2.5 g, 0.01 mole), and AcOH (30 ml) was stirred a t 25" for 3 hr and then dild with HzO (80 ml). T h e ppt was collected, dried, and extd with boiling CsHs (60 ml). T h e ext was filtered and evapd t o give 2.4 g (785%)of crude chloroiodiphenoxyacetic acid, mp 127140", shown by glpc analysis to contain 2-chlorophenoxyacetic ideiitified by admixt of authentic material) and one acid (5:, fraction of longer retention time (947c). The latter fraction was shown to be 2-chloro-4-iodophenoxyacetic acid b y the nmr spectrum (C2D6SO): 6 4.90 is, 2, CHZ),7.01 (d, 1, J = 9 Hz, ArH6), 7.77 (doublet of doublets, 1, J = 9, 2 Hz, ArH5), 7.81 (d, I, J = 2 Hz, ArH3). A sample recrystd from C F " had mp 136-1383' (lit. mp of 2-chloro-4-iodophenoxyaceticacid is 138-141°).10 2-Chlorophenoxyacetic acid does not react wit,h IZ under t h e conditions of this expeiiment.
e,
Acknowledgment.-The authors t'hank I350". For anslypis a sample was recrystd 3 times from €T20.AcOII ( 5 : l ) . Anal. (C8HsClN02)C, H, PI;. 2-Chloro-4-chloromercuriphenoxyaceticAcid (Ib). A. By Diazotization and Mercuration.4-Amiiio-2-chloropheiioxyacetic acid ( 5 g) was dissolved in hot 12 S €IC1 (25 ml). The s o h was cooled t o 4" in an ice bath. A s o h of NaN02 (2.5 g) in H20 ( 5 nil) was added with stirring over a period of 2min. Themixt was kept for an addnl 2 min and then filtered throiigh sintered glass. T h e filtrate was cooled i i i an ice bath aiid t o it was added a mixt of HgClz (8 g), coiled HCl ( 8 ml), aiid ice ( 8 g ) followed b j freshly prepd CII powder ( 4 g). The mixt was kept at' 0" for 4 hr and then made basic with 405; KaOTT. T h e green t o black ppt was rempved by filtratioii. The filtrate was acidified with HCl. T h e tan ppt was piirified by alteriiate repptn from NaOII sohi with HC1 arid recrystn from 95YG EtOII t o obtain 0.7 g of product, mp 194-195'. Anal. (csH&hIfgo,j C, H, Hg; nmr (c21)Bso) 6 4.84 (s, 2, CH2), 7.12 (d, 1, J ' = 9 Hz, ArH6), 7.51 (doublet of doublets, 1, J = 9, 1 Hz, ArHj), 7.70 (d, 1,J = 1 Hz, ArH3).
B. By Mercuration of 2-Chlorophenoxyacetic Acid.-2Chloropheiioxyace1,ir arid (28 g, 0.15 mole) was added to a solti of Hg(0Ac)z (57.2 g , 0.18 mole) i n € 1 2 0 (1050 ml). T h e suspeiision was stirred aiid heated a t 80-85" for 3.3 hr. T h e solid ~
~
-
(8) Melting points were determined in capillary tubes a n d are uncorrected. N m r s p e r t r a were taken on a Varian A-60 spectrometer and are reported i n 6 p p m os. ThIS standard. Glpc analysis \vas o h t d on an F a n d M Model A-10 gas chromatography with 6 f t X 3 m m glass column packed with 6% QF-1 silicone o n chromosorb G , a t 200'. Where analyses are indicated only b y symbols of t h e elements, results obtained were within f0.47, of t h e theoretical value. (9) J. P. Brown and E. €3. McCall, J . Chem. Soc., 3687 (1955).
illeta1 Chelate Steroid Analogs. 2. (7-Amino-8(aniinomethyl)-1,2,3,4,4a,4b,5,6,7,8,8a,9dodecahydro-4a,7-dimethyl-2-phenanthrol]bis(ethylenediamine)cobalt(3+) Trichloride &Acetate (Ester)' L.
GUY I)ONARUMA* A N D PATRICIA
u. FLATH
Clarkson College of Technology, Potsdam, h'ew York
13676
Received March 23, 1971
I n a previous publication,2 x e reported the synthesis, characterization, and properties of the first metal chelate steroid analog. Since then, our st'udies in these areas have continued, and in this paper we would like t o describe a homosteroidal metal chelate analog (111). Scheme I displays the react'ions employed to prepare I11 and the requisite ligand (11). I1 was prepared in 86% yield by react'ion of I3 with HN;. The ir and nmr spectra of I1 were in agreement with structure I1 in all respects. Elemental analyses performed on 11, its 2HC1 salt, and selected bis derivatives (a-naphthylurea, benzenesulfonamide, p-chlorobenzamide), prepared in a fashion identical with analogous derivatives described previously,2 were all within experimental error. ( 1 ) T a k e n in p a r t from t h e thesis submitted by Patricia U. F l a t h i n partial fulfillment of t h e requirements for t h e M.S.degree a n d i n p a r t from t h e thesis t o be submitted by Rlrs. F l a t h in partial fulfillment of t h e requirem e n t s for t h e P1i.D. degree. ( 2 ) L. G . D o n a r u m a a n d P. U, F l a t h , J . Med. Chem., 13,966 (1970). (3) B. & Regan 'I, a n d F. N. Hayes, J . A m s r . Chem. SOC.,78, 639 (1956); Ai. Hassner and 1. €1. Pomerantz, J . O r g , Chem., 27, 1760 (1960).
1000 Journal of Medicinal Chemistry, 1971, Val. 14, AVO.10
SCHEME I &COOH
To a stirred s o h of 0.50 g (1.S X mole) of 1,' i i i 10 m1 of CHCL was slowly added 3 ml of coiicd TT2SOJ; 0.5 g of NaN3 was added very slowly to this mixture at a r;tte which kept the temp of the s o h below 40". after the addii was coinplete, ihe mist was warmed to 40" for 2 hr, iieiitralized with roiicd NII,OII :it 0-5", and filtered, aiid the filtrate w w extd 4 times wiih cr1C-l~. I!emoval of the solveiit from the cfombiiiect ex(-. ntid rerryst i i from ligroin (bp 00-120") yielded 0.20 g ( 5 4 y i ) of prodiic.t : mp 110-112°: [ a ] % - 7 2 " . A n a l . (CIdI,SsO,) C , 11, S . 7-Amino-8-(aminomethyl)-l,2,3,4,4a,4b,5,6,7,8,8a,9-dodecahydro-4a,7-dimethyl-2-phenanthrol@-Acetate (Ester) .2HCI.--II (1 g, 3.13 X mole) was dissolved i i r 15 nil of dry CsIie. HC1 gas was t)iilibled through t h e solii for 5 n i i i i . After f i l t l a t i o i l aiid recr!ti (H~O-coiicd HCl), 1 . I % g ($165;) of prodrict \va* obtained: nip 225-227": ireiit eqriiv, calcd, 197: f o i i i i d I$i5, 19%. A n a l . C C I , H ~ ~ ~ C ~ IC, ~ ~11, \ ~ ('1, , O ,S ) . Bis derivatives of I1 (a-naphthylurea, benzenesulfonamide, p-chlorobenzamide) kvere prepd i i i the same maiiiier as previoii>ly reported aiialog\:* a-riaphthyliirea, h j c yield ire mp 230-231' [Anal. IC,,Ht$J401) C , 11, N]; 1) amide, 7 0 r ; yield ire( t KtOII), nip 137-148" [.Ann/. ( ( ' , , I H : o XO26SL) c, €1, x, SI 1.'-chlor[rt)ciiz:rmide! SG' 1 yield ( r( EiOII), m p 111-112° [Anal. C:a.ll13sC
d2
I
\
A d I1
r
1
[7-Amino-8-(aminomethyl)-l decahydro -4a,7 dimethyl 2-phenanthrol] bis(ethy1enediamine L cobalt(3+ ) Trichloride @-Acetate (Ester)(IIIa).--'rci 0.625 y (2.19 X 10-3 mole) of cis-tlic.~ilor.obi~ieth~leiiedi~~miiie)c.ohNi~ ( 3 - t ) chloride i i i 3 0 nil of Ale011 i%-:ik added a y o l i i of 0.70 g (2.19 X IOF3 mole) (if I1 i i i 1 0 nil of di.!. C6Flb. After stirriiiy for 48 hr, the protiiict was filtered : i i i d r e c ~ y s r dfrom I ~ ~ O - I ~ t O I ~ . T h e yield of gold-cdtrred c.r!-stnl* w n ~0.SO g i80c; !: nip 21-7217"; A,,,,, 472 m p : [a]% ( . o c ~ r i p i c .part irlc I I O . , c*:il(,d. 4.00: forlrld, 4.13, 4.11. A n n / . )r2:3114"cl,K(j02)Chi< C S , 11,
-
IIIa X = C1, en = H2N(CH2)2NH2
IIIa
NaI
H20
IIIb (where X = 1)
-
c1, K. When I1 was added t o czs-dichlorobis(ethy1enedi[7-Amino-8-(aminomethyl)-1,2,3,4,4a,4b,5,6,7,8,8a,9-d0amine)cobalt(3+) chloride in JIeOH, [i-amino-Sdecahydro - 4a,7 - dimethyl -2 phenanthrol] bis(ethy1enediamine ) (aminomethyl) - l,2,3,4,4a,4bJ5,6,i,S,Sa,9-dodecahydrocobalt(3+ ) Triiodide @-Acetate (Ester) IIIIb).--1Iln (0. I y i i v ; i 4a,i -dimethyl- 2 - phenanthrol]bis(ethylenediamine)cotiihsolved i i i a m i i i vol of I I Z ~ ..\ lO-f(ild esce.5 IJf XaI M'Xndded i o the i o l n . T h e oraiige ppt W R f~i l t e i d aiid i ~ e r r y ~ tf ti ,lo n i balt(3+) trichloride @-acetate (ester), IIIa, was prohot Tl?O. T h e yield ( i f prodiic-t 1111) L'T,F-267°, A,,,, 47,5 nip, duced in 60y0yield. The ir and nmr spectra of IIIa was qiiaiititative; c,rytrsc.opic- pnrt i d c i i o . , c d c d , 4,OO: fo1lnd, were consistent with the assigned structure. Ir 4.02, 4.06. A n d . ~ ' ? O C : ~ ~ I I ~ ~(I: o~ ,?C:;,~FT, O ~I,) N. maxima reported t o be characteristic of Co-N bonds Acknowledgments.--\Ye arc' indcbted to thc Sntion:il were p r e ~ e n t . ~ All elemental analyses for I& were Science Foundatioii for partial support of this n.orli within experimental error. Aq sols of IIIa gave 4 under Trainecship Grant GF,-7SiS, and U'P are indrbt c ~ l particle depressions of the freezing point of H20, and t o Dr. I\. I,. 1,oening of thc Chemical Ab,qtrncts Scrvicck IIIa was diamagnetic. Reaction of I I I a with aq NaI Activity for iinming compounds I1 and ITIa for yielded IIIb. The ir and nmr spectra of I I I b were \\-as done by Ayerst J,aborntoriw. testing consistent with the assigned structure, a 4 particle depression of the freezing point of aq sols was observed, JVhere anal. are iniiicaieii onl) liy tlie s) iniwl. u f the rletnents o r functions, analytical d a t a \\ere within experimental error relative t o the calrti vahie? the elemental analyses were within experimental error, for those elements or functions. N m r spectra n e r e taken o n a Varian and the compd was diamagnetic. A6Oh spectrometer in CI)Cla or IIrO. Visiiile spectra \\ere taken 011 a Biological Activity.-The capacity of the teit compds Perkin-Elmer 202 spectrvi>hotometer. Optical rotations n e r e rneasrireil i n a Rudolpl! hlodel 62 polarimeter in CIITI?. to interfere with the incorporation of labeled acetate and/or mevalonate into cholesterol by rat liver homogenate was determined in vityo by the method of Dvornik, et aZ.j Any test compd producing 40% Synthesis and Hypoglycemic Activity of 3-Aryl(or inhibition of cholesterol synthesis at 1 X low4 114 Pyridyl)-5-alkyl(or aryl)amino-1,3,4-thiadiazoles is considered active and worth further I\ ork. I I I a n as and Some Sulfonylurea Derivatives of active as a hepatic cholesterogenesis inhibitor dis4N-1,2,4-Triazoles playing 65y0 inhibition of cholesterol synthesis. I1 also was screened in identical fashion, but I I I a \\as , I). €31, I Z K \I{, M Y ~ I H AI LSK \ R , 11.H S H I HP. more active than 11. I1 shoned only 26% inhibition s T ~ I I < \ h f ,K. G A\ I K T \ U \ R \ I \ N \ U , \ U D c' l)lJLI\\ \I \ * of cholesterol synthesis. Activity testing continues.
-
!
Haflhne lnstztiile, Honibay 12, Indzu
Experimental Section6 7-Amino-8- (aminomethyl)-l,2,3,4,4a,4b,5,6,7,8,8a,9-dodecahydro-4a,7-dimethyl-2-phenanthrol @-Acetate (Ester) (II).P. Bertin. I. N a k a g a w a , S. RIisushima. T. J . Lane, a n d J. Y, Quagliano. J . Amer. Chem. Soc., 8 0 , 525 (1958). (5) D. Dvornik, M. K r a m l , a n d ,J. Duhue. P r o c . Soc. h'xp. B i d . .Wed., (4) E .
116, 537 (1964). (6) Melting points were taken on a hot stage a n d a r e corrected. I r spectra were taken in K B r wafers on a Beokmann IR-12 spectrophotometer.
Received .\larch 29, 197 1
U'e have described',* the synthesis aiid study of 1,2,4-triazole derivatives and have shown that many ( I ) h l . T.hIhasalkar, 11.H . S h a h , S. T. N i k a m . K . G . h n a n t a n a r a y a n a n , a n d C. V. Delinala, J . M e d . Chem.. 18, 672 (1970). (2) AI, Y. hlhasalkar, hl. IT, Shah, S . T. N i k a m , I
