111 a preceding paper' of this series t h e reactiuti pregnan-:-:(p)-ol-20-one with an eyuitnolecular quantity of bromine to yirl:l thc C- 17 bromo dcri\-ative was descrilxtl. Lye I I C wish ~ tlJ report that 1 7 . hromopregriari - :$( $1 - 01 - 3 1 - om' wlieri treated with a rnild base uiirierg~)cs a rtarraiigc irictit which puts iiiethv! :IS:\ r~nrii:mc.thoxyl yroupsori C-17 ( 1 1 ) ~ Recently, Aston arid (;reeiiLurg' show-ctl that tu-bromo secondary alkyl ketones reacting with sodium alcoholates readily unclergo a rearrangeiiierit to give esters oi' trrtiar?, acids. For es:iiiiplr. :bbrc~rrin-:i-~neth~l-"-but:.rlollc trc.at:.tl with a suspensiorr of sodium methylate iii arihj,tirou:; ether vi elded methyl trimet,hylacet atc anti :i,: Lc!i 11ret! i ~)s!--.~-~~ietliyl-"-hutaii~jl. I%>-trcati?:? 17-1,r,i!ii ;CI-Ir)l.CHr-CC)-CH:i-+- SaOCH, ----+ of
I
CH3)sC-COOCII: -4- .C" ,I,C'(JHC'( IC lla!!L'll
pregnan-:{(.fl)-ol-2O-one acetate with ail aqueous iiiethaiiolic solution of potassium bicarbonate we hak7e obtairiect the riiethyl ester of 2i $)-hydtoxyI ;-trietliyi-eiio-cholanic acitl i11). I'his .;ul)stanct: is the ma.in product oi- the reactioii arid represents ; I change entirely analogous to that obtained hy .-\ston and Greenburg cxccpt that !io second wl)stance could be isolated. We had hoped that tlic rcact.ion ~ v o u l dproc"r(i a simple replacerneat of the t)rmiiiiie t o give thr C ' - 17 hytlrusy c-lerivativc. .Whough cllo-prqi i a n -:i( 8),17-diol-2O-one is easily susceptible II I c ,sidation a t I.?' and hydrogenatiori ," the acetylated cninpcsuntl i II'j obtained hy tis tlicl 1 i i ) I I w r l itself to any such reactions. I t KJS reco\-ercd iiii i*haiigetl from ari c;sidi,:iIig iiiisturc. hcatci a t ;iO ic r five !lours ailil froni iiIi attempted hytlrogeriat.itrii with Adaiiis catalyst t t a l . ; ~f : d ( , t l 11) rilai't with smiicarbuzitie acctatc.. Vurf.litAr, i t \]:as ;liTc~I.t~ 1 t>J- ph~sphor1is >:-chI() 4 i o w i i i ~ tlic F!iJw1liYd 01 2; ! i r t \ '
1.;
111 s t
cause of its isomeric relation to the pregnanediols we have named this compound 17-methyl-21-norpregrian-3(P),L'O-diol (117). The ester (11) resembles many esters of tertiary acids in that it reacts only after prolonged heating with alcoholic potash. Thc resulting :3ip)-hydroxy-li-methyld o -cholanic acid (IT)was converted back to the original methyl ester (11) by diazornethane. The aciri was oxidized with chromic anhydride t o gi1;e the same keto acitl (I,-II')as that obtained bp a siiiiilar oxidation oi thc. 1 i-methyl-? I -nor-pregtiaii-i$[$),WdioI (11.). Because 01' the excellent yields of this tearrangemerit product the analogous coinpouiicls having he alpha cimfiguration a t C-3 were prepared to c.*haracterizth it further. 'The non-acetylated 111~t.hy1 ester w a s oxidized a t room tetnperaturc t l i ;;-kcto.i ;-iiiethyl-eiio-cholanic acid (ITI). Catal>-tic hytirogenatioii oi the latter iii a neutral ~nctiiuriiwith Adanis catalyst gave as the major product the methyl ester of ;l(cu)-hytlroxy-l7 iiieth!.l-erio-cholaiiic acid (IT1) . .I Bouveault t e iiuctioii o f this same keto ester gave 1 i-methyl2 1 -Ilor-pregtian-::ituj,.'O-diol (VIII). The appiicnt i o i l o f the &toti- Greenburg reactioii in the stcrchis is Ixing further studied. i k ~reactions clisciissed are picturctd iii tht, cxii:irt i i - c , wish to thank Parke, Davis and Co~npan!, ior thcir help. Lye also wish to thank Dr. J . (;.istoii far his advice and assistaiice.
Experimental Part Reaction of 17-Bromopregnan-3( p)-ol-20-one Acetate with Methanolic Potassium Bicarbonate.-(a) To a soluI inri uf g. of l;-br~iiioi,regnan-3(13j-ol-20-one acetate i i i 2 1 ' 1 c r . oi i1:etliallol was added a wlutioti of 10 g. of potak 4 5 , 1 1 1 1 l>icart)oiiatrit1 10 cc. of u-arer. The ini\ture was rci l u u rl :I: ilcaiii-lmth tcinpcrature for I hree hours and then ntl-atL.ii \Vatcr was added to t h e concentrate anti ilie p i - w i p i t a t ~ d zolid was extracted with ether. .in a c c t i i ~
was heated under reflu\ Yhat our prvciuct is a:! ester i-, sliown i)!~ t h c ai~hydi~icl:wlution of the i-esi Thc esc olverit was rciiioved arid :i Rouyeauit rer!uctioii intrcxiucei I : o r cweiity niiiiiiica. oiici hJ-droxy group. I ne product w:i? isolatctl I he rriidue was crystallized froni iiiethanol t o give long ilai nt~cdles,111. p. 130-138": yield 2.2 g. This product is rht t h e diacetatc anti as tlic irec t l i o l ' 11. I . F ? t - aciktatc uf the methyl ester of X-j9i-hydrosy-l;-incthyI-
I;ict that
I T '
ii\
Original manuscript rrcei\cd h l a y :,, iil Marker, Crooks and Wagner. ' T m s Joi Aston and Greenburg, i b i d . , 62, 23!>0 (1.
r:I'n-cholariic acid (11,. A v o % . Calcd. for CrrHlxO4: C.
TX 8 ; H.
R.h.
t'r~tini!.
'REARRANGEMENT OF 17-BROMOPREGNAN-3( P)-OL-20-ONE
Feb., 1942
217
CHII
I c=o
COOCHI
COOCH,
c1 / I 1
It
Ro
/+I d H I
IV
/
(b) The same product (XI) with a free 3-hydroxyl was made under the above conditions with the exception that the period of refluxing was prolonged an additional two hours and the reaction product was not acetylated. It was crystallized from aqueous methanol to give white crystals, m. p. 143-145'. This gave a depression of 60' when acetate, in. p. 142mixed with 16-pregnen-3(p)-ol-20-one 144". I t depressed the melting point of the methyl ester of 3 (6)-hydroxy-etio-cholanicacid. Anal. Calcd. for CzaHssOa: C, 75.7; H, 10.4. Found: C,75.7; H, 9.9. When refluxed with acetic anhydride it gave the above acetate, m. p. and mixed m. p. 136". The unacetylated ester was also obtained as a polymorphic form which crystallized from methanol and melted at 124-126". Anal. Calcd. for C Z ~ H S ~C, O~ 75.7; : H, 10.4. Found: C, 75.9; H, 10.4. The acetate (11)was recovered unchanged after refluxing a t 135' for forty-five minutes with pyridine and phosphorus oxychloride. When subjected to catalytic hydrogenation in methanol-ether with Adams catalyst a t 3 atm. pressure for two hours it was recovered unchanged. It did not react with semicarbazide acetate under the usual conditions. From an oxidizing mixture of chromic acid and acetic acid heated a t 55" for five hours the acetate (11)was recovered unchanged. Hydrolysis of the Methyl Ester of 3(p)-Acetoxy-l7methyl-etio-cholanic Acid (II).-A solution of one gram of the above methyl ester of 3(j3)-acetoxy-17-methyl-etiocholanic acid in 50 cc. of ethanol was heated with a solution
of 10 g. of potassium hydroxide in 10 cc. of water for four days. The reaction product was precipitated with water and washed with ether. I t was then acidified and extracted with ether. The ethereal solution was washed with water and evaporated. The residue was crystallized from methanol to give white crystals, m. p. 222-224"; yield 0.8 g. This depressed the melting point of 3(,9)hydroxy-etio-cholanic acid. Anal. Calcd. for C Z I H ~ ~ O C,~75.4; : H, 10.3. Found: C, 75.1 ; H , 10.2. When treated with an excess of diazomethane in ether it gave tlic original methyl ester, m. p. and mixed m . p. 112-144". 3(~)-Acetoxy-17-methyl-etio-cholanicAcid.-A mixture of 100 mg. of 3(P)-hydroxy-l7-methyl-etio-cholanic acid, 5 cc. of dry distilled pyridine and A cc. of acetic anhydride was allowed to stand at room temperature for fourteen hours. I t was then warmed on the steam-bath with 5 cc. of water for thirty minutes. Ether was added to the cooled mixture and the ethereal solution was washed with 10% hydrochloric acid and water. The ether was evaporated and the residue crystallized from methanol to give white crystals, m. p. 220-222'. This substance depressed the melting point of the starting material 45'. Anal. Calcd. for C28H3601: C, 73.3;H, B.G. Found: C, 72.9; H, 9.5. Oxidation of 3( ~)-Hydroxy-l7-methyl-etio-chol~c Acid to 3-Keto-17-methy1-etio-cholanicAcid.-To a solution of 100 mg. of 3((3)-hydroxy-17-methyl-etio-cholanic acid in 7 cc. of acetic acid was added 60 mg. of chromic acid dissolved in 3 cc. of acetic acid. After standing for one hour
RI-SSELLE.XYRKER AND K. B. U'.IGSEK
21 \
Yoi. ci4
Reduction of the Methyl Ester of 3-Keto-17-methylaiio-cholanic Acid to the Methyl Ester of 3(a)-Hydroxy17-methyl-efio-cholanic Acid.-% a solution of 0.2 g. of washed thoroughly with water and thcn with 10% potasthe metlivl ester of 3-Leto-17-methyl-elio-cholanic acid disYiiiin hydroxide. 'The alkaline wa4iiiigs were combincd, .iridificti, :itid c s t r a c t r d with i t h c i 'l'hr crlier I ~ S i O i V C C i in :i.7 ce. of diosanc was added 200 mg. of . 4 d a I l l S rooii: teinperaLure tliv i-eactioii mixture vas diluted with water and extracted with ether. The cthcreal solution was
;it
The iiiisturc was shaken with hydrogen at threc. pressure for two hours. The reaction inixrure va.1 :iltered :inti the filtrat e evaporated to dryness iu i'iicilo. l'he residue wa. i h c n refluxed with acetic anhydride for :went p niinute,, 'l'hc wlvent was removed in iaciio aiicl .-I~ifii. Calcti frit. C!.€i. .a;: ;.,' ;ri s I f , !{ 7 I ~ I N I I K ~ llizctl from methanol as w-hite plate.;, i i i . tiit. rebiciuc i., ,-
