FEUHUARY
1957
lizations from methanol gave 0.16 g. of hecogenin acetate, m.p. 245-247", infrared spectrum identical to an authentic reference sample. Correllogenin, 2O~~,d2a,~5~-spirost-5-en-S~-ol-ld-one. The mother liquors from the ethyl acetate crystallization of gentrogenin acetate contained both correllogenin and gentrogenin acetates. Repeated crystallizations from ethyl acetate removed more gentrogenin acetate, leaving the soluble fractions enriched in correllogenin acetate. Chromatography on Florisil and silica gel was not particularly effective but gave a slight enrichment of correllogenin acetate in the more polar eluates. The residues from these treatments were crystallized repeatedly from ethyl acetatemethanol and finally methanol to give correllogenin acetate, needles from methanol, m.p. 213-214", [a]2 -BO0, infrared spectrum similar to gentrogenin acetate but showed typical 2 5 fingerprint ~ bandsllajb, 986 (s), 920 (a), 897 (w), and 852 (w) em.-' Anal. Calcd. for C2~H420;: C, 74.01; H, 9.00. Found: C, 73.90; H, 9.18. Hydrolysis of the acetate gave correllogenin, m.p. 209211", [alas -69". Anal. Calcd. for C27H4004: C, 75.66; H, 9.41. Found: C, 75.14; H, 9.63. Yanaogenin from correllogenin. Wolff-Kishner reduction of correllogenin gave yamogenin, m.p. 187-189", infrared spectrum identical to an authentic specimen. Sisalagenin from correllogenin. Catalytic hydrogenation of correllogenin acetate followed by chromium trioxide oxidation in the same manner described for gentrogenin gave a product20 which we believe is the recently isolated sisalagenin acetate,12m.p. 214-216", [CY] -12" (lit.I2 gives m.p. 228-232", [CY]? -12"), infrared spectrum showed peaks a t 1733 (s), 1712 (s), 1071 (s), 1037 (a), 987 (s), 919 (s), 899 (w), 849 (w) em.-' which were in agreement with data of Callow and James.I2 6,16-Pregnadien,-3P-ol-l d180-dione 3-acetate ( I ) . Eight g. of gentrogenin acetate was refluxed 5 hr. in 40 ml. of acetic anhydride to which was added 1.9 g. of pyridine hydrochloride. The crude pseudogentrogenin diacetate thus obtained was oxidized in our usual manner13 and the oxidation intermediate treated with potassium hydroxide in t-butyl alcohol.13 Bfter the standard work-up, the product was acetylated and chromatographed on Florisil. Elution with benzene and chloroform followed by crystallization from
:
(20) We were unable to obtain enough pure correllogenin acetate to purify adequately the reduction product or obtain analytical data.
[COSTRIBUTIOK FROM
185
HYPOTENSIVE AGESTS, VI.
THE
DEPARTMEST OF
ether gave 2.3 g. of I, m.p. 170-173". The analytical sample after 3 ether crystallizations had m.p. 173-175", [CY]: 57",": : :A 227.5 mp, log e 3.98; 1737, 1720, and 1684 cm. -I. Anal. Calcd. for CZ3H3004: C, 74.56; H, 8.16. Found: C, 74.35; H, 8.20. Alkaline hydrolysis of I in t-butyl alcohol-potassium hydroxide gave 5,16-pregnadien-3P-ol-12,20-dione (11), needles from ethyl acetate, m.p. 198-202', [CY]: +67.4". 6-Pregnen-SfJ-ol-12,dO-dione S-acetate ( I I I ) . Two-tenths g. of I was dissolved in 100 ml. of ethanol and catalytically hydrogenated in the presence of 0.4 g. of 10% palladium on barium sulfate a t 3 atmospheres for 16 hr. After filtration and removal of the ethanol the residue m-as crystallized from methanol, long rods, m.p. 222-223", [CY] +90.4", infrared spectrum shows absence of conjugated carbonyl, and presence of two strong carbonyl bands, 1735 em.-' (acetate), ~ C20 carbonyl). 1710 cm.-l ( C I and Allopregnane-SP-ol-ld,f?O-dione %acetate ( I B ) . One-tenth g. of I in 47 ml. of ether containing 3 ml. of glacial acetic acid was catalytically hydrogenated in the presence of 0.1 g. of platinum oxide at 3 atmospheres pressure for 16 hr. After the usual work-up, the residual glass was oxidized in chromium trioxide-pyridine.21 Dilution with water, and ether extraction gave a crude product which was taken up in a small volume of methylene chloride to which was added a large volume of ether. The solution was concentrated on the steam bath. On standing, 30 mg. of crystalline product was obtained, m.p. 190-192" with infrared spectrum identical to an authentic specimen of IV from hecogenin.13 Allopregnane-S,1I,bO-trione( V ) . Two-tenths g. of I1 were reduced and oxidized as described under IV. The crude product was chromatographed on Florisil and the benzene and chloroform eluates were combined and triturated with ether. The ether-insoluble residue was crystallized from ethyl acetate as irregular plates, m.p. 210-212" (lit.Qagives m.p. 207-208"), infrared spectrum identical with that of an authentic specimen derived from hecogenin.
+
PZ,
:
Acknowledgment. We wish to thank R. F. Mininger for optical rotation data and K. Zbinden for C and H analyses. The infrared spectra were obtained by C. S. Fenske under the supervision of C. R. Eddy. PHILADELPHIA 18, PENSSYLVASIA (21) G. I. POOS,G. E. Arth, R. E. Beyler, and I,. H. Sarett, J . Am. Chem. SOC.,75, 422 (1953).
PATHOLOGY,
GEORGETOWN UKIVERSITY LfEDICAL CENTER]
Hypotensive Agents. VI. Substituted 3-Azabicyclo[3.2.l]octane Derivatives' LEONARD ill. RICE
AKD
CHARLES H. GROGAN
Received July 18, 1956
A series of unsymmetrical a,w-bis-tertiary amines has been prepared in which 3-azabicyclo [3.2.l]octane is employed as one of the bridgehead substituents. The acid addition and bis-quaternary salts of these bases have been prepared and screened for pharmacological activity. These bases were prepared by reaction of d- or dl-camphoric anhydride and the dialkylaminoalkylamines followed by reduction of the resulting imides. Several members of these series were potent hypotensive agents in mammals and were effective when administered orally.
As part of a continuing search for hypotensive agents, many series of symmetrically and unsymmetrically substituted a,@-bisaminesand their acid
addition and quaternary salts have been prepared Among the most active of these substances mere members in several series in which various modifi-
(1) L. M. Rice, C. 1% Grognn, and E. E. Reid, J . Am. Chem. Roc.,77,616(1955).
(2) Supported by a research grant from the Geschickter Fund for Medical Research, Inc.
186
IUCE AND GIZOGAN
cations of the isoindole nucleus were employed as one or both of the bridgehead substituents, I . l . 3 In exploring the effects of modifying the heretocyclic nucleus employed as one or both of the terminal substituents, both symmetrically and unsymmetrically substitutcd series employing the 1,8,8-trimethyl-3-azabicyclo [3.2.1]octane nucleus, 11, have been synthesized.
c-c-c-c 1
22
/
6-C-C
\O
CH,
1 c-c-c
