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Patented 0a.s,194e ‘ s 2,408,834 _ v REISSUEB ‘UNITED ‘STATES PATENT» OFFICE 2,408,834 ’ STEROIDAL CONIPOUNDS AND ‘METHODS FOR OBTAINING THE SAME Romeo vB. Wagner, State College, Pa., 'assignor 'to Parke, Davis & Company, Detroit, Mich.;'a “core ~ ' poratio'n-of Michigan NoDrawing. Application May 15, 1944, Serial No. 535,758 I » '5 Claims. w > ‘ (Cl. 260‘23915) _ The invention relates to new steroidal sa- tive steroidal compounds of the typed'erived'from' pogenin type compounds and methods for Yob~ the mammalian suprarenal cortex taining the same. oxygen containing group'in ring 0' of the cyclo ‘ ' _ . I have obtained for the v?rst ‘time the hereto- pentanopolyhydrophenanthrene nucleus. fore .unknown steroidal sapogemn which compound hereinafter to as rockogen'in has 5 the followingreferred structural formula. OH: CH’ OH ‘OH’ ‘ ’ / GENERAL'PROCEDUREFRACTION FOR ‘OBTAINING A SAPOGENIN In obtaining ‘the new compounds, the plant or CEBU-Ha 4} . ‘ part of the same which is to be extracted 'is‘cut _ p 10 up, ground or ‘shredded and then extracted either 'H'*c\o-0§i -CH‘“C'H* with hot ‘water or a7 lower aliphatic alcohol such ~ ' as ethyl ‘alcohol. The :plant may be dried before extraction, but I ‘prefer ‘to extract the ‘plant without v‘any I ‘ p ? _ 15 preliminary drying. , ‘I I also prefer to anal cohol solvent such as ethanol orabout 95% ‘hot . , aqueous ethanol. For example, if one "has about HOX/A/ plants; such as stems, soft roots, leaves ‘or fruit; H 20 these can ‘be covered over with about 32 liters of 139:0,‘ I. _ OH 25 two 7-liter portions of hot ethanol and then squeezed dry The extract and wash alcohol can y evaporated to a syrup and the syrup con cen'trated by passing a current of ‘air over its sur ‘ . and groups hydrolyzablefto H , a , ' ‘ _ 30 ‘slowly. agent, the evaporation ‘takes place ‘much more 7 H the invention have the _. The new compoundsof After evaporation, the‘ concentrate containing saponins andmust like combinations .of in the order steroidal sapogenin's be hydrolyzed, "to 0H following'general formula, ‘ ' _ liberate the sapogenins. This ‘is best accom Y CH. CHECK: on, I on, | / \ . _ CH__Q\ —— D . \/_ JA CH‘Cm o_._e§, 3° plished by aqueous or alcoholic strong mineral acid. ‘For'exampl'e, the above mentioned con centrate from 25 kg. of ‘plant material .can be hy drolyzed ‘by re?uxing it 'for'2‘hours with 3 liters l 40 of 2N ethanolic hydrochloric acid The reaction B y X_\/\/ _ c I where x and Y are members of the class =0, <QH H ‘ _ t0 ' and'grGHPS hydrolyzable _ , > of hot. alcohol. The combined alcoholic ?ltrates 45 are diluted with 20 liters of diethyl ether and the sodiumlghydr-oxide and water and evaporated. i 7' OH. These compounds are new valuable starting ma- hydrolyzed by alcoholic refluxing potash the residue with 3 vol 50 lanes of ‘10% for 30 minutes. The cooled mixture from the alkaline hydrolysis a sapogenin fraction which is dissolved in ace terials for the preparation of physiologically ac- 55 tone, treated with active-charcoal such as the v 2,408,834. .T. .. 3 . Calc’d for Carl-14204: 4 C, 75.3; H, 9.8. product known as “Norite" and ?ltered. The clari?ed ?ltered acetone solution contains the Found: C, 74.9; H, 9.8. The ?rst mother liquor is evaporated to dryness. sapogenin fraction of the plant and can be sep the acetone by evaporating the lat whitecrystals, M. P. and niixedlvl, P. with rocko~ The residue is genin from (a), 209-210;" yield- some: , arated from ter. Such sapogenin fractions consist of mix tures of_ sapogenins: The individual, sapogenins 1 Ariel; 'Calc’d'for C2'IH4I4O4: C, 75.0","H, 10.3. Found: C, 74.9; H, 10.4, “The diacetate is prepared with boiling acetic anhydride .and the product is crystallized from are next isolated or separated out of this frac a general procedure tion. The above description is which I use for obtaining a sapogenin fraction or. from methanol as M. P. and mixed 15.1’. with, rockogenin diacetate from (a), M P. 205 mixture. It is merely illustrative and is capable ,7 . of considerable variation, as will be understood by .2 Calc’d'ifo'r CnHmOa: C, 72.1; H, 9.4. T'Analxi methodior,‘ ‘' .2070. those skilledsapogenin in the art. Any known hydrolytic and hecogenin ace (0)‘ Rockogem'n acetate from g. of the acetate procedures may make possible ‘they I > tate.-‘-An ethereal solution of 0.5 and Adams vided solvents are used which with hydrogen the plant ketone tissue‘ subof‘ v‘ ' ofhecogenlin is shaken above. Rockogenin 3-mono catalyst as described from methanol as white the greater part of the hydroxyl and by the hy liberated acetate . crystallizes 10 . ' ' methanol‘ as white needles, 20 drolytic steps, . _ pl'ates.M.-P. Anal; Calc’d 2l1-213°. for ‘Cad-14605; ‘ C,, v734; H,.' 9.8. . Example. 1.'-‘-Hecogenin from ‘Agave, .toumeyana a 1 Found: C, 73.8; H, 9.7. '. ' v _, . ' When re?uxed with acetic anhydride for one .Trel‘ 5 kg. of medium age plants of the species Agave 25 hour it forms rockogenin ‘diacetate, 1M‘. '2. and mixed M. P., 203-205‘. ,_ ' .. _. -. . . toumeyana Trel., collected; above the tunnel on Example 3.--Szmth.esis of hecogenone route 60-70, east of Superior, Arizona, in Novem treated by the above described gen (a) Fnom hec0genin.-A_ solution of 0.1 g. or eral procedurein'or'der to obtain a I sapog'e hecogenin in 30 cc. of acetic acid is mixed with iractionlwhich consists largely of hecogenin, the 30 a solution of 0.1 g. of chrornlc anhydride in 5 cc. starting material for the synthesis‘ of rockogenin acetic'acid. vAfter standing thirty min described in Example 2. The sapogenin fraction from ether is acetylated and crystallized'irom methanol-ethyl acetate togive plates of heco utes at 25°, water is added and the product is gen'in acetate, M. P. 246-2482 Yield, 13g. , layer gives no acid fraction. The ethereal solu tion is concentrated and cooled to give white needles of hecogenone, M. P, 237-240°. .7; H, 9.4. AnaL: Calc’d for CmHmOr. C, 75 ether extracted. An alkali wash of the ethereal solution followed by acidificationv Anal.‘:d Calc’d for Casi-14405: C, 73.7; H, 9.4. Foundi 0,755.4; H, 9.3.'f ‘Y ' ' "The acetate is’hydr'olyzed ' and the product'is crystallized ".AnaL-z- Calc’d from for methanol, CwzHizOra' M. P,C,265-268". 75.35 H, 9.8; Foundi‘C, 75.0; H, 9.7, ‘ .- Found: C, 75.5; H, 9A. ., ._ 40 I, (5) From rockoge?irlLl-The above mother liquor from the preparationfoi rockogenin by catalytic l reduction'of hecogenin described under, ‘Example ‘ . vThe residuefdise Example 2.-—Synthesis of rockogenin from. heco . ' . genin ' . . , , solved in 25 cc. of acetic acid is oxidized with a solution of 0.15 g. of chromic anhydride in 10 cc. of 80% acetic acid for thirty minutes at 20°. The product is isolated as described above and crys (a) By catalytic hydrogenatiom-e-An ethereal solution of ‘0.3 g. of hecogenin containing several drops of acetic acidis shaken with.hydrogenfand 0.2 .g. ‘of. Adams catalyst for twohoursat room temperature 'and three atoms. _ After ?ltering the solventfislrenioved. I The oily residue is re?uxed with acetic anhydride‘ror one hour. ‘ The solvent 50 tallized from ether as ‘white needles, M. P. and mixed M. P. with hecogenone, 237-240°; yield C, 75.7; H, 9.4. 0.1 g. Anal: Calc’d for Carl-140042 , , _, I _, . , Hecogenone "has the; ielewins structural: .102. is removed in vacuo on the steam bath and‘rocko genin'fdiacetate is crystallized from methanol“ as long‘ needles, M. P. 204-206"; yield, 0.12 g. ' Found: C, 7.5.5;_H, 9.4,._ j1 _.-. Calc’d' ior C31H4a0a2, C, 72.1; H, 9.4. Found: C,71.9';H, 9.2. ‘ ' ‘ the aqueous f ' > ._ .1‘ . .1 mula ’ ‘ When hydrolyzed 'with5% alcoholicpotassium hydroxide ‘for twenty minutes on the steam bath, the 'diacetate is .-~converted' to the" rockog'enin which crystallizes" from methanolv as , ' dies, M. P."208-—210°. Repeated crystallizations from ether gives material melting 217-2202 ‘ 60 . ‘ 'AnaLY‘Calc’d for (1211714404? C, 75.0; H, 10.3. Found: C, 74.5; H, 10.2; ‘ , ' auction-4T6 a' sold ‘ " '(b) By sodium-ethanol 1' in 100 cc. of absolute 65 tion of 300mg-of hecogenin ethanolwis added 7 'g. of 'sodium'insmall strips The mixture ‘is ‘over a ‘period of thirty minutes. cooled and poured _ Ring dihydroxy compounds-,such as rockosenin. r _ can be diacylated at the ring ‘hydroxyls' and ' ‘solid ‘is extracted with ‘ether and theethereal partially saponifled .to obtain a mono-acylated solution is washed with water, 10% hydrochloric acid’and water. The eth'erealsolution is con? and cooled to give white crystals, M. P. centrated 233-244“, wt, 160 mg. :Recrystallization from ether gives starting material melting260-262"; a (265°) ' melted‘ 262-265°. hydroxy derivative which can then be oxidized 75 withchromic acid at ‘the free hydroxyl'to give the corresponding monoacylated ketone. acylated ketone-upon hydrolysis gives the ‘latter 2,408,834 and ester groups hydrolyzable to OH 3. The new steroidal sapogenln, roekogemn, 01' The monoacylated ketone can be hy drolyzed to the free hydroxy keto e, for example the formula, by methanolic potassium hydroxide. CH HOCH CH3 /CH2—C€1 What I claim is: ' 1- A crz-substituted steroidal sapogenln 01' the 10 ' err-o 0114211; formula, ona]YcH:CH $11’ / “gas O A HO D l H 4. The new steroidal sapogenln compound hav ing the formula, 20 on O CH (fH' / CHr-CH: ' I ' CH-C CH-CH! Where X and Y are members of the class =0, OH O /\ H and ester groups hydrolyzable to D \/ B OH rt H 2- A C1z—keto steroidal sapogenin of the for 30 mula, 5. The method of synthesizing rockogenln which comprises reducing hecogenin having the formula OH: OI CH: 4}CH: ‘ / CHHCH: H—C\ CH-CH: was, X_ A 35 I 40 where X is a member of the class =0, OH H 45 ROMEO B. WAGNER.