Mikolasek 1969

November 1969 XOTES 1103
Experimental Section tion of the Scherrer method to the synthesis of meso-

AIclting points were determined wit,h an electrically heated 3 ,+his (4-aminophenyl) hexane (I I) from n?eso-hexestrol
ineta1 block, using calibrat,ed Anschuta t,hermometers. Micro- (1) require(] forcing wnditions in order to ensure hi+
analyses were performed by Dr. A. Bernhardt, Mulheim, West arylation of (I). The meso-hexestrol (I) was condensed
Germany. I r spectra were determined on a Perkin-Elmer with 2 moles of 4-chloro-2-phenylq~inazoline~ in DMSO
spectrophotometer Model 337 in KBr.
2-Methylbenzhydr01,~2-ahlorobenzhydr01,~ 4-chlorobenxhy- using KO-t-Ru as the condensing agent. The X,4-
dr01,g and 2,2'-dimet,hvlbenxhydro11a were prepared as described hiii [4-(2-phenyl-4-quinazolinyloxyphcnyl) ]hexane (VI
in the literature. thus formed, was heated at 3x0" to yield 3,4-bir[3-(4-
Preparation of quinuclidiilyl ethers was accomplished as oxo-2-phenyl-3 (4H)-quinazolinylphenyl) ]hexane (VI).
illustrated for 3-quinuclidinyl benzhydryl ether (1). Benzhydrol
(7.4 g, 0.04 mole) and 3-quinuclidinol (5.6 g, 0.044 mole) iyere This material was hydrolyzed in ethanolic SaOH to
thororighly mixed arid heated to 70' to form a homogenoiib give 11.; Amines I1 and J711gave the respective meth-
melt. p-Toluenesiilfonic acid (8.75 g, 0.046 mole) was added and ane and butanesulfonamides 111, IT, VIII, arid IX.
the flask was evaciiated. This caused H20to evaporate from the SaBH4 reduction of 3-methanesulfonamidoestra-l.~3,.i-
mixtiire, and the melt solidified. The temperature was then (lO)-trien-l'l-one (VIII) gave the estradiol analog. 3-
raised to 140' when the solid melted, and the evacuat>edflask
was kept at, this temperature for 3 hr. After cooling, the solid met hanesulfonamidoe5t ra- 1,X,5 (10)-trien- 176-01 (X).
material was dissolved in 5 S NaOH mid extracted with EttO.
The extract was washed with H,O and dried (NaZS04) and the
hydrochloride precipitated wit,h dry HC1. Recrystallization from
EtOH-Et20 afforded 8.3 g (69Tc) of 1, mp 194-1955'. CH, H
The X e I derivative (6)was obtained when a solution of the
base 1 and 1 eqiiiv of M e 1 in dry MezCO was allowed to st,and at
room temperature for 24 hr. The quakrnary salt precipitated
in an analytically piire stat,e, mp 193-194'. Recrystallizat,ion
from EtOH-Et,O did not raise the melting point.
Acknowledgments.-The authors are indebted to I.X=OH
Xstra Pharmaceutical Products, Worcester, Mass., and 11, X = NH2
AB Astra, Sodertalje, Sweden, for carrying out t'he
111, X = CH3S02NH
pharmacological tests.
IV, X = n-C,H,SO,NH
(8) J. H . Lamneck. Jr.. and P. H. \Vise, N a t l . Advisory Comm. Aeron.,
Tech. S o t e 2330, 15 (1950); Chem. Ahstr., 46, 6609k (1951).
(Y) A . E . Chichibahin and A. A. Shesler, J . Russ. Phys. Chem. Soc.. 66,
149 (192,;): Chem. Abstr.. 19, 3269 (1925).
(10) Ll. R . Boyd and H . H. Hatt, J . Chem. SOC.,898 (1927).
Alkylsulfonamido Estrogens
nOL6L\S ~ ~ I h O L I S I , K1,) U k N E G. GILLO,
J O i l I" L. ?\IIhII LLI, G O K D O It.~ MCKIKNFY,
\>I) A A L ~ R S E N
0
Jleud Johnson Research Cider, Mead Johnson R- Cornpanu,
ELanszille, Indzana 47721
R c c e i d March 17, 1969
Recent papers from these laboratories have described

the novel bioisosteric relationship between the methane- VI
sulfonamido group and the phenolic hydroxyl group in
a phenethanolamine series.' As a logical extension of
this work, we have attempted to determine whether
this bioisosteric relationship could be projected to other
compounds of biological interest possessing a phenolic
hydroxyl group. The application of this bioisosteric "U CA I T
relationship to steroidal and nonsteroidal estrogens was VII, R = NH2
of special interest because of the potential usefulness VIII, R = CH3S02NH X
of these compounds as antiuterotropic and/or anti- IX, R = C4H9SO2NH
fertility agents.?
The amines and diamines used as starting materials
These alkylsulfonamido analogs were tested in our
were prepared according to the general method of
laboratories for one or more of the following three types
Scherrer for conversion of phenols to a n i l i n e ~ .Applica-
~
of biological activity, uterotropic,6antiuter~tropic,~and
(1) (a) .I. h. Larsen and P.>I. Lish, .Vature. 103, 1283 (1964): (h) R . H .
Uloth. J. R . Klrk, K.-1 Gould, and .i. A. Larsen, J . .Wed. Chem.. 9 , 88 (4) A l . hI. Endicott, E . Wick. AI. L. Mercury, and h l . L. Sherrill, J . A m .
(1966); (0) A . A. Larsen. N'. A. Gould. H . R . Roth, W.T. Comer, R . H . Chem. S o c . , 68, 1299 (1946).
Uloth, K . W.Dungan, and P XI. Lish. T h t d . , 10, 462 (1907). ( 5 ) B . R . Raker, ihid., 66, 1672 (1943); (h) G. Fodor and J. Wein.
(2) C. W. Emmons, J . R e p r o d . Fertilzty, 9 , 227 (1965); (h) D. J Collins J . Chem. Soc.. 684 (1948). report mp 80° for the racemic diamine.
and J. J. Hobhs. Aust. J . Chem., 110, 1413 (1967). (6) B. L. Ruhin. A. S. Dorfman, L. Black, and R . I . Dorfman, Endo-
(3) R . A . Scherrer, Abstracts of Papers, 145th National Meeting of the crinology. 49, 429 (1951).
American Chemical Society, New York, E.Y . , Sept 1963, p 334. ( 7 ) R . I . Dorfman and F. A. Kinel, Steroids, 1, 185 (1903).

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November 1969 XOTES 1103

Experimental Section tion of the Scherrer method to the synthesis of meso-

Recent papers from these laboratories have described

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