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551
7a-CHLORO-A-NOR STEROIDS
of saturated aqueous Rochelle salt solution was added, and the Anal. Calcd for C22H390?: C, 80.44; H, 9.83. Found: C, 80.69; H, 10.00. mixture was steam distilled t,o remove nonaqueous solvents. The solid precipitak was collect,ed, washed with water, dried, A solution of 800 mg of 11 in 8 ml of methanol with 0.6 ml of and recrystallized from ethyl acet,ate t,o yield 620 mg of 21b: concent,rat,edHC1, and 0.6 ml of H 2 0 was held a t room temperamp 129-134'; 6.00,6.19 1.1. ture for 2 hr and then dilrited with 40 ml of H20. The preA n a l . Calcd for C21H300?: C, 80.21; H, 9.62. Found: cipit,ate was collected, washed with H20, dried, and recryst,alC, 80.15: H, 9.48. lized from et.hyl acet,at,e to yield 10b (550 mg): mp 135-141'; Following tmheabove procedure identically, 1.0 g of 17 was 2.74, 6.00, 6.18 M ; A, 238.5 mp ( E 16,000). oxidized and t,he crride react,ion product. was recrystallized from A n a l . Calcd for C21H300y: C, 80.21; H, 9.62. Found: ethyl acet,ate t.o yield 480 mg of 16b: mp 144-150'; nmr, 68 C, 80.15: H, 9.59. (17-CHa),7 2 (19-CH,), 225 (mnlt,iplet,,21-CH2), 344 (4-H) cps. 13,173-Epoxy-10,17fl-dimethyl-l7~-propyl-l3~-gon-4-en-3-one Anal. Calcd for CnlHaOOj: C, 80.21; H, 9.62. Found: ( 16c) and 1 7 4 3-Hydroxypropyl)-lO,l7fl-dimethylgona-4,3-dienC, 80.21; H, 9.37. %one (10c).--A reaction mixture of 15 g of 17a-(3-hydroxy1 7 43-Hydroxypropyl)-3-methoxy-17fl-methylgona-l,3,5( lo),propy1)-4-androsten-lip-ol-3-one,360 ml of ethanol, and 15 ml 13-tetraene (9b) and 13,173-Epoxy-3-methoxy-17fl-methyl-17~-of concentrated HC1 was stirred aiid refluxed for 50 min during propyl-13~~gona-1,3,5( 10)-triene (13b).-A reaction mixture of which time solution became complete. \Tater (300 ml) was 25 g of 17~-(3-h~drox~propy1)-3-methoxy-1,3,5(10)-estratrien- added and the precipitat,e was extracted with beiizene and 17p-ol (6d)," 100 ml of et,hanol, and 25 ml of concentrated HCl chromatographed. The fraction eluted with 157,; ethyl acetate,tiired and refluxed for 45 min with solution being cumplete benzene was recr>-stallized from hexane to yield 2.35 g of 1 6 ~ . 10 miii. It, was cooled and st,irred, aiid 350 nil of cold H,O An analytical sample was ohtailled by a second recrystallizat,ion was added prodiiciiig an oil which congealed when cooled t,o 5'. from hexaiie: mp 100-105°; 5.9'1, 6.18 p ; nmr, 45 (17The oil was collect,ed, washed wit,h HZO, dried, and recryst>allized CH,), 72 i19-CHa), 222 (mriltiplet,, 22-CH?), 343 (4-H) cps. from et>hylacetate t,o give 8.0 g of 9b. A sample was recrystal=ln,al. Calcd for CyPH3.20P:C, 80.44; H, 9.83. Folnld: lized from acet,one for anal mp 85-90': 3'::A: 2.76 p ; nmr, C, 80.63; H, 9.89. 61 (li-CHa), 216 (triplet., 22-CH,), 226 (OCH,) cps. The oily peak fractions eluted with 4 0 5 et,hyl acetat.e-benzene =Inal. Calcd for Ca2H300y:C, 80.93; H, 9.26. Found: C, (8.44 g) Ivere critde 1Oc contaminated with a >mall amount. of t'he 80.74; H, 8.92. acetate ester of the C-22 hydroxyl group (from transest'erifica6ion The mot,her liqiiors from 9 b were chromat,ographed and t,he wit,h et.hyl acet,ate). A 2-g sample was dissolved in 20 ml of first fractioiis eluted wit,h lYc ethyl acetate-benzene were comwarm methanol, 5 ml of 2 7 , aqiteous KHCO, was added, and bined and recryst,allized twice from et,hyl acetate t,o yield 1.1 g after 5 hr at, room temperatiire 100 ml of HZ0 was added. The of 13b: mp93-95'; nmr, 44 (17-CH3), ca. 225 (mitltiplet, 22-CH?), separated oil was extracted with et8heraiid the et,her solution was 227 (OCH,) C ~ S . washed wit,h H10, dried (Xa,SO4), and evaporat,ed t.o yield 1.7 g Anal. Calcd for C Y ~ H ~ ~ O C,Y 80.93; : H, 9.26. Found: 2.73, 2.88, 5.98, 6.18 p ; Am,, 239 mp ( e 17,100); of 1Oc: C, 81.23; H, 9.22. nmr, 49 (17-CH3), 59 (lS-CHS), 216 (triplet 22-CHy), 345 (4-H) 1 7 4 3-Hydroxypropyl)-3-methoxy-l7p-methylgona-2,5( lo),13-triene (11) and 1 7 4 3)-Hydroxypropyl)-17fl-methylgona-4,- cps. Anal. Calcd for C2PHP2O2: C, 80.44; H, 9.83. Found: 13-dien-3-one (lob).-Lithium wire (1.6 g) was added over a C, 80.33; H, 9.72. 10-min period to a stirred solution of 2.5 g of 9 b in 75 ml of THF, 75 ml of t-butyl alcohol, and 150 ml of liquid "3. After 2.5 hr, 6 ml of methanol was added dropwise over 15 min with deAcknowledgment.-The author wishes t o thank colorizatioii of sol\it8ionaft,er 3 hr. NH, was allowed to evaporate for 2 hr and then 150 ml of HsO was added. Nonaqrieotts solDr. E. F. Sutting and N r . Roger Bergstrom of the vents were removed by vacitum distillation and the precipitat,e Division of Biological Research for the biological data was collected, washed wit,h HjO, dried, and recrystallized from and Dr. Roy H. Bible, Jr., for interpretation of timr et,hyl acet8at,econtaining 1 drop of pyridine to yield 1.3 g of spectra. 11 : nip 83-89' ; ?!A: 2.74, 5.88, 6.00 p.
Xz3 ;l
6-Chloro-6-dehydro-A-norSteroids w i t h Progestational Activity.
7a-Chloro-A-nor Steroids
PATRICK A. DIBSSI,SEYMOUR D. LEVIXE,IlXD
RAYMOND
11. PALAIERE
The Squibb Institute f o r X e d i c a l Research, S e w Brunswick, S e w Jersey
Received January 21, 1967 The synthesis of several 6-chloro-6-dehydro-8-nor steroids is described. Two of these compounds, 6-chloro6-dehydro-17a-acetoxy-A-norprogesterone(16)and 6-chloro-6-dehydro-l6a, lia-dimethylmethylenedioxS.-$-norprogesterone (14),are potent progestat~ioiislagents. These represent t>hefirst examples of A-nor steroids having and this hormonal activity. Reaction of A3-2-keto-A-nor steroids with 2,3-dichloro-5,6-dicyanobenzoquinone HCl results in the format,ion of 7a-chloro compounds as well as the 6-dehydro derivatives. The mechanism of this reaction is discussed.
Previously reported A-nor analogs of sterodial horrnones have shown litt'le or none of the biological properties of the parent hormones. Thus A-norprogesterone (1) l does not exhibit progestat,ional properties but is a potent antiandrogenic compound;2 A-nortestosterone (2)l is weakly a n d r ~ g e n i c ,and ~ A-
norhydrocortisone and A-norcortisone4 do not show the glucocorticoid or antiinflammatory properties of hydrocortisone or cortisone. The chemical modificat,ion of steroid structures designed t o enhance progestational activity has been the subject of much interest in recent years. I n certain
(1) F. L. IVeisenborn and H. E. Applegate, J . A m . Chem. Soc., 81, 1960 (1959). (2) L. .J. Lerner, A. Uianchi, and A. Borman, I'TOC. Soe. Erptl. Biol. .Wed.,
( 3 ) L. J. Lerrer, .\. 13ianctii, hl. Dzelzkalns, and A. Barman, I'roc. SOC. E r p t l . B i d . .lZud.. 115, 924 (1964). (1) R. Hirschmann, G . .I. I h i l e y , R . \\alker, a n d .J. 11.Cliernerda, J . A m . Chem. Sac., 81, 2822 (1959).
103, 172 (1960).
--
;I;>'
COCH,
1
2
1 CH,COAC
COCH,
0&--OR 4. R = H 3
5. R=Ac
OH
July 1967 COCH,
0
553
~ ~ - C H L O R O - L ~ - ? ~STEROIDS OR
dP
odp COCHB
R
8
9, R = H
12, R=C1
10
11
k
I
R 13, R = H
and, indeed, reaction of 9 with HCI in dioxane gave an equilibrium mixture of 8 arid 9 in approximately the same ratio as had been observed in the DDQ-HC1 reectiori. S o 7a-chloro compounds have been reported to be obtained by either DDQ-HC1 treatment of A4-3ketones or by Alichael addition of HCl to A 4 6-3-ones. Reaction of testosterone or lGcu,l'7cu-dimethylniethylenedioxyprogesteroile20 with CCQ and HC1 gave the Gdehydro derivatives as the 0 1 . 1 ~ isolable products. That some 1:6 addition of HC1 actually does occur in the reaction mixture under these condition^ is iuggested by the ultraviolet spectrum of G-deh? drotestosteroneZ1 in dioxane containing HC1 which iiidicated a11 equilikriurn mixture of 7a-chloro (1 %b n-p, -40%) and Gdehydro (h 277 mp, A G @ ~ ) cornpoiients.22 The ultraviolet spectrum of 11 txken 111 dioxane containing HC1 showed just the presence of the 7a-chloro derivative (h 23s nip). We attribute the fact that the 7achloro compound can be iso1:ited i l l the A-nor series to the difficulty of formation of the Tcu-chloro-2,~-dieiiolb from e , while in the normal wries the 7a-chloro-3,5dieriol b' forms easily from c' and leads to dehydrochlorination upon IF orli-up of the reaction mixture (Scheme 11).
15, R = H 16, R = C1
14, R=C1
SCHEME I1
&--C=CH
a
0
a'
R 17, R = H
18, R = C1
It was apparent, that the rate of dehydrogenation of A-nor steroids was slower t,han that of normal steroids as evidenced by the delayed precipit'at'iori of t'he 2,3dichloro-5,6-dicyanohydroquirione during the reaction. With normal steroids this hydroquinone begins t o separate as HC1 is bubbled into the s o l u t i o ~ iwhile , ~ ~ in t'he case of A-nor st,eroids, precipitation does not begin for ca. 15 miii. That this is a reflection of the difficulty of enolization of A3-2-keto-A-nor st'eroids as compared to A4-3-keto normal steroids is supported by the failure to obt'ain a A2-j-dieriolacet,ategand t'he failure of formation of the aj-?-ketal during lietalization.16 Under similar condit'ions the A3,j-dienol acetat'e" and aj-3ketal form readily in the normal series.18 Although formation of the A2a5-dienolin t'he A-nor series is not as facile a process as in the normal series, once any dienol forms, the 7a-prototi is irreversibly removed by the D D Q and the G-dehydro product accumulates. The unique formation of a 7a-chloro compound from the DDQ-HC1 reaction is po~t~ulatedto occur by Michael addition of HClI9 to t'he 6-dehydro derivat,ive (16) 5. L).Lerine and P. .4. Diassi, J . Ory. Chem., 30, 1326 (1965). (17) See J. F.I\-.Reana in "Steroid Reactions." C. Djerassi, Ed., Holden Day. Inc., San Francisco, Calif.. 1963, pp 37-12, for references in t h i s area.
(18) ( a ) E. F. Fernliolz and H. E . Stax-ely, .\hstracts, 102nd National Meeting of the .lrnerican Chemical Society, Atlantic City. N. J., Sept 1911, p 39AI; ( b ) R . .\ntonocci. S. I3ernstein, R. Littel, IC. J. Sax, and J. H. TYilliams, J . O w . Chem., 17, 1341 (1952); ( e ) G. I. Poos, G . E. .\rtli, R. E. Ijeyler, and L. H. Sarett, J . A m . Chem. Soc., 75, 422 (1953). (19) R . T. Rapala and AI. F. Morray, Jr. [ J . -%fed. Chem., 6 , 1019 ( l 9 6 2 ) ] , have reported on the hlichael addition of HCI t o a Als-ZO-one steroid t o give the 160-chloro derirative.
b' jt
0&c, C
C'
Epoxidatiori of the 6-dehydro compounds with vichloroperhenzoic acid gave the Ga,ia-oxides which on treatment with excehs E C l in CHCl3 were converted to the desired 6-chloro-6-dchydro derivatives. Biological Activity.-Table I lists the approximate oral and subcutaneous progestational activity in the Clauberg aiiay of several of these A4-norsteroids and the corres1)onding normal steroids. Com1)ounds 14 and 16 represent the first examples of A-nor steroids having this hormonal activity. Compounds 8 and 15 have no significant activity in this assay by both the oral and subcutaneous routes. ( 2 0 ) G. Coole?. 1 3 . Ellis, I;. Ilartley. and V. Petrow, .I. C h e m . S o c . , 1 : J Z (1955). (21) C. Djerassi, G. Rosenkranz, J. Ronio. Sc. Iiarifmann, and J. Pataki. J . .4m. Chem. Soc., 7 2 , 4534 (1950). (22) T h e spectra of 6-deliydrotestogterone in dioxane containing either 0 . 5 S H d O a or concentrated HC1 only exliil>ited ahsorption at 27i mp indicatine: the exclusive presence of the A*,8-;3-~1ne system.
July 1967
555
7a-CHLORO-A-NOR STEROIDS
ml) for 3 min. The reaction mixture was left at room temperature 6-Chloro-A-norpregna-3,6-diene-2,20-dione ( 12).-A solution for 2 hr, and then a t 45' for 1 day. It was washed (HzO, satuof 19 (502 mg) in a CHC13 solution (25 ml) saturated with HC1 rated NaHC03, and 8% salt solution), dried, and evaporated. was kept a t 4045' for 22 hr. The mixture was washed with HzO Plate chromatography of the residue using neutral alumina and evaporated. Plate chromatography of the residue on neutral (activity V) as the adsorbent and CHCl3 containing 20% hexane alumina (activity V) using ethyl acetate-CHC13 (1:9) as the as the developing solvent gave a major band a t about Rf 0.8, developing solvent gave an ultraviolet-absorbing band a t about which was detectable by ultraviolet light. Elution with ethyl Xf 0.1 which on elution with ethyl acetate, evaporation, and acetate gave a residue which was crystallized from isopropyl crystallization of the residue from acetone-hexane gave 12 (195 ether-ethyl acetate to give 16 (177 mg, mp 183-184"). The mg): mp 138-140'; [CZ]~~D +98" (CHCla); X 279 mp ( e analytical sample was prepared by recrystallization from iso20,400); 7 9.26 (s, 18-Me), 8.86 (s, 19-Me), 7.87 (s, 21-Me), 7.67 propyl ether-ethyl acetate; mp 195.5-196.5', [cy] 2 8 ~ - 7 j 0 2.5 CPS, 7-H). (s, 1-CHz), 3.95 (s, 3-H), 3.78 (d, J (EtOH); X 5.78 (sh), 5.87, 6.18, and 6.33 p ; X 280 mp ( t 19,700); Anal. Calcd for CBH&102: C, 72.19; H, 7.57. Found: 9.26 (s, lB-LIe), 8.84 (s, lQ-JIe), 7.95 (6, li-OCOCH,), 7.91 C, 72.20; H, 7.70. 16~,17~-Dimethylmethylenedioxy-A-norpregna-3,6-diene-2,20-(s, 21-Me), 3.95 (s, 3-H), 3.78 (d, J = 2 cps, 7-H). Anal. Calcd for CzzHz7C104: C, 67.66; H, 6.96; C1, (3.07. dione (13).-HC1 was bubbled into a mixture of 6 (2.0 g) and Found: C, 67.42; H, 7.00; C1, 9.09. DDQ (1.5 g) in dioxane (60 ml) for 10 min and the reaction 17~~-Ethynyl-A-norandrosta-3,6-dien-l7~-ol-2-one (17).-A mixture was left overnight a t room temperature. The precipitate mirt,ure of 11 and 17 (375 mg) obtained as described for the was removed by filtration and the dioxane was evaporated. preparation of 11 was refluxed for 1 hr in collidine (8 ml), cooled, The rehidue was dissolved in CHCb (75 ml) and passed through and diluted (CHC13). The CHC13 solution was washed ( 2 HC1, a neutral alumina column (activity I, 90 g) to remove polar saturated S a H C 0 3 ,and 870 salt solution), dried, and evaporated. colored material. Elution with CHCb (350 ml) gave upon evapoPlate chromat,ography of the residue on neutral alumina (activity ration a slight,ly yellow residue (2 g). The residue was refluxed V ) using CHC13 as the developing solvent gave a major band in collidine ( 2 5 ml) for 1 hr. The reaction mixture was diluted detectable by ultraviolet light. Elution with ethyl acetate, HCl and 8yosalt solution, dried, with CHCl,, washed with 2 evaporation, and crystallization from acetone-hexane afforded and evaporated. The residue was dissolved in CHCl3 (50 ml) 17 (58 mg, mp 2OG208O). The analytical sample was prepared and passed through a neutral alumina column (activity I, 90 g) by recrystallization from CHC13-isopropyl ether; mp 206-208'; to remove polar colored material. Elution with CHC13 (300 [aIz5 -141' ~ (EtOH); X 2.97, 3.05, 5.88, 6.00, 6.22, and 6.33 p ; ml) gave after evaporation a residue which was crystallized X 278 m p (E 22,600); T 9.03 (s, 18-?1Ie), 8.88 (s, 19-Me), 7.44 from acetone-hexane to give 13 (1.0 g, mp 211-213'). The (s, 17a-C=CH), 4.27 (s, 3-H), 3.87 (d, d, J 2, 10.5 CPS, 6-H), analytical sample was prepared by crystallization from acetoneand 3.49 (d, d, J 1, 10.5 cps, 7-H). [ O ~ I ~ Z D +36" (CHC13); X 277 m p (e hexane; mp 213-215'; Anal. Calcd for C Z O H Z ~ OC,~ :81.04; H, 8.16. Found: C, '22,500); 7 9.29 (s, 18-Me), 8.89 (s, 19-Me), 8.81 (s, @-Me,ketal), 81.04; H, 8.14. 8.63 (s, a-Me, ketal), 7.76 (s, l-CHz), 4.94 (d, J = 4 cps, 16@-H), 6-Chloro-17~-ethynyl-A-norandrosta-3,6-dien-l7~-ol-2-one 4.26 (s, 3-H), 3.89 (d, d, J = 10, 2 CPS, 6-H), 3.47 (d, d, J = (18).-HC1 was passed into a solution of 22 (218 mg) in CHC13 10, 2 cps, 7-H). (20 ml) for 5 min. The reaction mixture was left a t room temAnal. Calcd for C23H3004: C, 74.56; H, 8.16. Found: C, perature for 2 hr and then at 45" for 19 hr. The reaction mixture 74.64; H, 8.10. was washed (saturated NaHC03, 8% salt solution), dried, and 6-Chloro-16~,17~-dimethylmethylenedioxy-A-norpregna-3,6evaporated. Crystallization of the residue from CHC13-isopropyl diene-2,20-dione (14).-A solution of 20 (200 mg) in CHC13 ether gave 18 (122 mg, mp 214.5-216.5'). The analytical (10 ml saturated with HC1 a t 0") was left overnight at 45'. sample was prepared by recrystallization from CHCla-isopropyl The reaction mixt,ure was diluted with additional CHCL and ether; mp 227.5-228.5'; [ a I z 4-122" wahhed with 5yo NaHC03 solution and HZO, dried, and evapo~ (CHCl3); X 2.88, 3.00, rated. Plate chromatography of the residue on neutral alumina 5.93, 6.22, and 6.35 p ; X 280 m p ( e 20,200); 7 9.05 ( 8 , 18-JIe), (activity V) using CHC13 as the developing solvent and elution 8.86 is, lg-hle), 7.43 (s, 17a-C=CH), 3.80 (d, J = 2 cps, 7-H), of the least polar band with ethyl acetate gave after evaporation and 3.94 (s, 3-H). 14 (32 mg, mp 203-205'). The analytical sample was prepared Anal. Calcd for C Z O H Z ~ C ~C, O Z72.63; : H, 7.08; C1, 10.72. by recrystallization from methanol; mp 203-205"; [a]z z +13" ~ Found: C, 72.67; H, 7.03; C1, 10.94. 6~~,7~O~ido-A-norpregn-3-ene-2,2O-dione (19).-A solution (CHCI,); X 278 mp (e 21,400); T 9.31 (s, 18-Me), 8.85 (s, 19Me), 8.81 (s, p M e , ketal), 8.52 (s, ,-Me, ketal), 7.76 (s, l-CHz), of 9 (400 mg) in CHZClz (50 ml) was cooled to 0" and m-chloro2 CPS, 7-H). 4.93 (d, J = 4 CPS, 16@-H),3.92 (s, 4-H), 3.80 (d, J perbenzoic acid (900 mg) was added in small portions. The Anal. Calcd for Cz3H29C104: C, 68.21; H, 7.22; Cl, 8.75. reaction was then left a t room temperature for 40 hr. The Found: C, 68.15; H, 7.15; C1, 8.97. solution was washed ( 5 % Tu'aHCO3, 57, Ka2S03,H20) and then 17~~Acetoxy-A-norpregna-3,6-diene-2,20-dione ( 15).-HC1 evaporated. The residue on plate chromatography using was bubbled iiito a solution of 5 (1.40 g) and DDQ (1.0 g) in neutral alumina (activity V) as adsorbent and CHC13 as the dedioxaiie ( 3 0 ml) for 5 min and the reaction mixt,ure was left a t veloping solvent gave a major band a t about R f 0.5 detectable room temperature overnight. The precipitate was filtered and by uv light. Elution with ethyl acetate followed by evaporathe filtrate was evaporated. The residue was treated with CHCL tion and crystallization from acetone-hexane gave 19 (151 mg): aiid t,he additional precipitate was filtered. The filtrate was mp 168-170"; [ c Y ] ~ ~+95" D (CHCla); X 234 mp ( e 13,100); diluted with additional CHC1, to a total volume of 80 ml and r 9.27 (s, 18->Ie), 8.89 ( 8 , 19-Me), 7.86 (s, 2l-JIe1, 7.78 is. 1passed through a 40-g neutral alumina (activity I ) column. The CHz), 6.57 (d, d, J 3.5,
