March 1966
RING-D-BRIDGED STEROIDANALOGS.IT
179
Ring-D-Bridged Steroid Analogs. 11.' 14a,17a-Etheno-16a-carbomethoxypregn-4-ene-3,2O-dione2 A. J. SOLO^
AND
BALDEV SINGH
Department of Medicinal Chemistry, School of Pharmacy, State University of S e w Y o l k at Buffalo, Buffalo, S e w York 14214 Received M a y 25, 1965 Diela-Alder addition of methyl acrylate t o 3p-acetoxy-2O-keto-5,14,16-pregnatriene ( I ) afforded an adduct, IIa, which has been transformed into 14a,17a-etheno-16ol-carbomethoxypregn-4-ene-3,2O-dione (111). Synthesis of I11 has also been achieved by Diels-Alder additions of methyl acrylate to 4,14,16-pregnatriene-3,2O-dione. Although I11 is inactive in the modified Clauberg assay, it appears capable of enhancing the activity of progesterone in that test.
Many steroid hormone analogs bearing 17a-alkyl or 17a-0-acyl groups are known to be biologically a ~ t i v e . As ~ the 17 substituents in these compounds are, in general, capable of free rotation, it seemed of interest to determine the effect, on biological activity, of restricting the conformational freedom of the 17a group. JIolecular models show that steroid analogs, IIa,R =COCH,; R'= CH, I a , R = COCH3 which bear two-atom bridges between the 14a and 17a b, R = H; R'= CH3 b,R=H positions, are geometrically similar to one of the rotoc, R = R' =H mers of 17a-substituted steroids. We therefore decided to determine the effect of such two-atom bridges on the biological activity of various hormone analogs. Recently, 3p-acetoxy-17-cyano-~,l4,16-androstatriene was demonstrated to undergo the Diels-Alder reaction with a variety of dienophiles. Difficulties which we encountered in the attempted conversion of these adducts to analogs of progesterone caused us to abandon that path in favor of one involving DielsAlder addition to dienes more closely related to the final product. 111 Chemistry.-Heat ing 3p-ace toxy-20-keto-5, Id, 16and 16a-cyanopr~gesterone~ have been synthesized by pregnatrienej with an excess of methyl acrylate a t 120" several research groups, progestational activity has not for 165 hr resulted in the formation of the Diels-Alder been claimed for any of them.'O Despite this, we adduct IIa in 82% yield. Selective hydrolysis of the believed it worthwhile to test I11 for progestational and acetate group of IIa readily afforded hydroxy comantiproges t ational activity . pound IIb. Oxidation617of I I b afforded the progesterone As shown in Table I, subcutaneous injections of up analog 111. to 20 mg of I11 failed to elicit any response in the Hydrolysis of the acetate group of I a was followed by oxidation? to afford 4,14,16-pregnatriene-3,20-dione modified Clauberg assay.'l An attempt was then made to detect possible antiprogestational activity for 111, (IV). Diels-Alder addition of methyl acrylate to by administering it together with progesterone. HowIV provided a second path to lda,l7a-etheno-l6aever, as shown in Table I, when I1 was administered carbomethoxypregn-4-ene-3,20-dione(111). The sterin a dose 6-25 times that of progesterone, the activity eochemistry of the above adducts is tentatively asof the progesterone, in the Clauberg test, waq enhanced. signed on the basis of analogies previously cited.' The latter effect appears to diminish with increasing Biological Activity.-Assuming our assignment of dose ratios of 1II:progesterone until, at a dose stereochemistry to be correct, 14a,l7a-etheno-l6aratio of 50, 111 does appear to weakly antagonize the carbomethoxypregn-4-ene-3,20-dione(111) may be reeffect of progesterone. garded as a close analog of 16a-carbomethoxyprogesterThese results may be rationalized by assuming that one. Although 16a-carbomet h o ~ y - , ~16a-carboxy-, 8, 111, or its metabolic degradation products, may be (1) P a r t I: A. J. Solo, H. S.Sachdev, and S.S. H. Gilani, J . Org. Chem. able to block both the enzymic degradation of progesterSO, 769 (1965). one and the action of progesterone at the site respcn(2) This work was supported in part b y Grants bhI-05900-02 and AMsible for the effects monitored by the Clauberg aspay. 06900-03 from the National Institutes of Arthritis and Metabolic Diseases, t h e National Institutes of Health, U. S.Public Health Service. If the first effect is stronger than the second, low dose (3) To whom inquiries regarding this work should be addressed. ratios of 111:progesterone should enhance the activity (4) N. Applezweig, "Steroid Drugs," McGraw-Hill Book Co., Inc., New of progesterone, while high dose ratios should repress York, N. Y.. 1962, p p 313-320,337-344. I.
9
( 5 ) A. J. Solo and B. Singh, J . Org. Chem., SO, 1658 (1965). (6) A. Bowers, T. G. Halsall, E. R. H . Jones, and A. J. Lemin, J . Chem. Soc., 2548 (1953). (7) C. Djerassi, Org. Reactions, 6 , 207 (1951). (8) J. Romo, Tetrahedron, 3, 37 (1958). (Y) B. Ellis, V. Petrow, and D. Wedlake, J . Chem. Soc., 87-18 ( 1958).
(10) A claim of selectixe anticortisone acti\ity has been advanced for 16a-cyanoprogesterone. R . H. hlazur, U S. Patent 2 817,671 (Dec 24, 19571, Chem. Abstr , 52, 8220 (1958) (11) Biological testing u a s performed a t the Endocrine Lahorator) , RIadison, I\ IS.
180
Experimental Sectioni2 3p-Hydroxy-20-keto-5,14,16-pregnatriene(Ib).-- A iiiisture t r i 0.519 g of 3p-acetosy-20-keto-5,14,16-pregnatrietie (nip 1 5 9 ~ 160°), 0.523 g of KOH, 10 ml of t-b~itylalcohol, :ind 0.6 ml of water was stirred at room temperatiire for 2.5 hr. The mistrircs was then partitioned between chloroform aiid water. After the CHCl3 layer had been dried (3IgSO4), the chloroform wits distilled iiiider rediicetl pressitre. The residiie was tone t o give Ib in it yield of 0.452 g (91 a ,,l.,i 310 n i (~e , , ~ , , 12,600) [lit.13 inp 186-18io, X,,,,, 307 nip l q, 9 a > X':tolI (log B,,,,,, 4.23)], V N i 1 j O ' :%(IO m d 16:s; cni-1. The rimr spectrillti showetl a iiiiglet :it 6 2.38 (2t-CHlj a i d peaks a t 6 5.45, 6.05, a i d 7.27 (doublet, .I = 2 ( y s ) ~orreq~oiitlitigto the 6, 15, aiid lii pro1 oii*, respec*tively. CPLH?&::: ( ' ) hO.7;;; H, 9.0:3. Foiliid:
s),
t>
th Methyl Acrylate.---i\ illisture of 1.947 g of regiiat,rieii-20-otic (Ix), 3.0 nil of freshly h t e , atid 1.5 ]rig r ) f hydroquinoiie was -;ealetl i i 1 :I g h s s tube under reduced pre-surc. After the re:ic.t:iiith h:itl l~eriiheated :it 120" f o r 165 hr, the iiiisture w:ib cooled t o r o o i i l teniper:iture, the tulle T V ~ Sopeiietl, iiud t h e volatile Inatt,er was rtniiovetl k>y distillatioii under reduced pressure at 100°. Tht. rcssiclue TWS purified by filtration through ii coliinui of 50 g of RIercli :ii.icl-washed :ilurnitia, uriiig herizerie cviitaiiiirig up to 10:; of ethyl acetitie as elueiit. The adduct II:i ~ i i then s obtained froin wetolie iti it yield of 1.9S4 g ( 8 2 ? ; ) it': white rod::: nip 1641 t G " : u C ( ' I ~1740, 1706, l2S2 cin-I. The iinir spertrum showed .iiigleth :it 6 2.02 (:wetate), 2 . 2 3 (21-C&), :ind 3.59 (CH3 of ester), : i i i t l p e ; h i i i the viiiyl prototr regioir :it 5.44 (riiiiltiplet), G.lC: ([1011t)let,.J = i j rp-), :tiit1 6.25 fcloiil~let,.I = (j ip) 11' ('?;HasOi: (', i:l.til: €1, lysis of Adduct 1Ia.--A iiiisture of 2.63 g of II:i, 2.48 g of KOH, 55.0 rril of metliniiol, atid 5.0 nil of water n-as yiirreci :it rooni teriiper:iture for 2.i lir. After the mixture had I ) e c > i i c~oiic~t:titr:iteclunder reduced pressure, it was partitioned l r o t ~ ~ e ew t i i t e r i i t i d ether. .After the organic phase had bee11 dried ( A I g S O r ) , it w:w filtered aiid the ether vias distilled. T h r rwidite w i s chiornutographed on :i coiumil of 55.0 g of hIerck . .. ..... 12) AIi4tinn: points were deteriiliried i n rapillary tubes on a .\Iel-Tenip a p p a r a t u s an11 are uni,orrtv,ted. Elemental analyses v-rre performed h y (:albrait!i Alir~roanalyticnlI.ulrovatories, linu.;\-ille, Tenil. T i l e infraverl iliwtr:i \ l e r t . deterniine(1 irii a I'erkiIl-~~llKlPi.Infracord lIo(Ie1 111.; Srnr s p e r t r a I\ ere determined ill C ' L i C I ? o n a \.arian . L B O spectroineter and arp r q m v t f v l in p a r i s prr Inlillun dowriht,l r i r a tetrarnetiiy1ailan-r iriiernid si u i d : i r < l . ( 1 3 ) 1'. \ . I'laiiner, 11. tIruss!xr, a11~1.\. S c y s , , tfelr.. C t i i n i . 2 4!1 l1!1 &a), I
March 1966
SYNTHESIS OF ~-PHENPLPIPERAZINE
crystallized from acetone-hexane to afford 0.683 g (71.5% yield) of white crystals: mp 169-170'; ident'ical, by mixture melting point and nmr comparison, with 111 prepared above. C. By Diels-Alder Addition of Methyl Acrylate to 1V.-A mixture of 0.311 g of IV, 1.3 ml of freshly distilled methyl acrylate, and 10 mg of hydroquinone was sealed in a glass tube, under reduced pressure. After the tube had been heated a t 120" for 96 hr, i t was cooled and then opened. The contents were concentrated under reduced pressure. The residue was chromatographed over 20 g of Merck acid-washed alumina. Elution with benzene-ethyl acetate afforded 0.319 g of material which crystallized from acetone-hexane to afford 0.288 g of white flakes, mp 171-172". The identity of this material with the 14a,17c~etheno-16a-carbomethoxypregn-4-ene-3,20-dioneobtained in A was demonstrated by nmr spectroscopy and by a mixture melting point determination. 4,14,16-Pregnatriene-3,20-dione(IF').-A mixture of 1.93 g of 5,14,16-pregnatrien-3p-o1-20-one,13.0 ml of cyclohexanone, and 300 ml of toluene was dried by refluxing under a Dean-Stark head until no further water separated (4 hr). The mixture was then cooled to room temperature, and 2.03 g of aluminum iso-
181
proxide was added. The reactants were heated under reflux for 1 hr. After the toluene had been distilled under reduced pressure, the residue was partitioned between CHC1, and aqueous HC1. The chloroform solution was then dried (MgSOd), filtered, and evaporated to dryness under reduced pressure. The residue, in benzene solution, was chromatographed over 210 g of Merck acid-washed alumina. Benzene (150 ml) eluted 200 mg of impurities followed by 334 mg of impure product. A solution (150 ml) of 5% ethyl acetate in benzene followed by 100 ml of 10% ethyl acetate in benzene then eluted 1.32 g of semisolid material which crystallized from acetone to afford 1.22 g of an acetone complex of I V as pale yellow crystals, mp 105-106". A n a l . Calcd for CZLH2602.0.5C&0: C, 79.61; H, 8.61. Found: C, 79.72, 79.54; H, 8.53, 8.37. The product was recrystallized from ethanol to afford an eth~ anol complex as pale yellow crystals: mp 114-115'; v 1669, 1647, 1629, 1618 em-'. The nmr spectrum had a singlet at 2.33 (21-CH3) and peaks in the vinyl proton region at 5.80, 6.07, and 7.25 (doublet, J = 2 cps). A n a l . Calcd for CnH&~0.5C&0: c, 79.24, H, 8.77. Found: C, 79.47; H, 8.53.
Derivatives of Piperazine. XXXV. l a Synthesis of 2-Phenylpiperazine and Some Derivatives WILLIAMR. RODE RICK,'^ HOWARD J. PLATTE,~' AXD C. B.
POLLARD'^
Department of Chemistry, University of Florida, Gainesville, Florida Received August 10, 1965 Three methods for the synthesis of 2-phenylpiperazine (3), two of them new, have been investigated. One method concerned the condensation of ethyl a-bromophenylacetate with ethylenediamine to form 3-oxo-2-phenylpiperazine ( 4 ) followed by hydride reduction to 3. This method was superior to t'he condensation of styrene oxide with ethylenediamine, previously employed. The second method involved condensation of ethyl glycinat e, cyanide, and benzaldehyde to ethyl N-( a-cyanobenzy1)glycir~ate(ti), which was hydrolyzed to the amido ester 6. The latter was cyclized by sodium hydride to 3,5-dioxo-2-phenylpiperazine (7) which was reduced to 3. The 1alkyl derivatives of 3 were obtained unambiguously by alkylation of 3-oxo-2-phenylpiperazine followed by hydride reduction. The 4-alkyl and 1,4-dialkyl derivatives were prepared by alkylation of 3.
Of the very large number of derivatives of piperazine, many of which have been investigated for various pharmacological activities, relatively few C-subst'ituted derivatives have been studied.2 Aside from the 2,5disubstituted piperazines obtained by dehydration of amino acids to diketopiperazines followed by reduction, the synthesis of C-substitut'ed piperazines offers several diffic~lt~ies.~ The first synthesis of 2phenylpiperazine (3) was reported in 19434; no ot'her synthesis or papers concerning this compound have appeared, although related keto derivatives and further C-substituted derivatives have been reported. The structure of 3, since it contains the phenethylamine inoiet'y of the sympathomimetic amines, should be of special interest t'o medicinal chemistry. We report here an improved synthesis of 3 and the synthesis (1) (a) P a r t X X X I V : C. B. Pollard, IT. JI. Lauter, and N. 0. Nuessle, J . Org. Chem., 24, 764 (1959). (b) Communications regarding this paper should be addressed to the Department of Organic Chemical Research, Abbott Laboratories, North Chicago, Ill. 60064. (c) This paper was abstracted from the Ph.D. Dissertation, University of Florida, June 1962. (d) Deceased: formerly Professor of Chemistry, University of Florida. (2) E. Jucker and E. Rissi. Hela. Chim. Acta, 46, 2383 (1962). (3) For example, the synthesis of N-phenylpiperazines from arylamines and diethanolamine hydrochloride could not be extended to the synthesis of C-substituted piperazines: J. P. Bain and C. B. Pollard, J . A m . Chem. Soc., 61, 2704 (1939). (4) L. J. Kitchen, Ph.D. Dissertation, University of Florida, Feb. 1943; C. B. Pollard and L. J. Kitchen, U. S. P a t e n t 2,400,022 (1946); Chem. Abslr., 40, 5074 (1946): I,. .J. IGtrhen and C. R. Pollard, .I. Am. Chem. Sor., 69, 884 (1447).
of some N-alkyl and oxo derivatives, prepared for pharmacological evaluation. The first method of synthesis of 3 consisted of the reaction of styrene oxide with excess ethylenediamine to form N-(P-hydroxy-P-phenethy1)ethylenedianiine(1) which was catalytically cyclodehydrated at high pressure in the presence of Raney nickel. The adducts of styrene oxide and amines have been assumed to result from attack a t the P-carbon of styrene oxide.5 For the reaction of several amines with styrene oxide, the major but not exclusive product has been shown to result from attack at the less substituted carbon atom.6 This method of synthesis of 3 was reinvestigated in an attempt to improve the yield, and data were obtained t o support the structure previously assigned (without proof) to the styrene oxide-ethylenediamine adduct. From the reaction of 1 mole of styrene oxide with 2 moles of ethylenediamine, the 1: 1 adduct (1) was obtained in 60% yield based on styrene oxide. A 2 : 1 adduct (2) was also obtained, in 11% yield based on styrene oxide. The structures of 1 and 2 were based on elemental analyses, nmr spectral comparisons, and the absence of primary amine in 2 as shown by the Hinsberg test. The nmr spectrum of 1 showed the ( 5 ) TV. S. Emerson, ibid., 67, 516 (1945).
(6) R. E. Parker and h-.8. Ieaacs, C / , e m . Ret,., 69, 737 (1059).
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