Corfisone: me Quest for Oxygen af C- 11 George G. Hazen Merck Sharp & Dohme Research Laboratories Division of Merck a Co., Inc. Rahway. NJ 07065
edited by: W. Conard Fernellus, Harold Wlttcoff, and Robert E. Varnerin
In 1941 allied intelligence erroneously reported that German scientists had unraveled the secret of the adrenal glands providing the Nazis with an adrenal product which allowed Luftwaffe pilots to fly a t 40,000 feet with impunity, prevented shock, and caused wounds to heal rapidly. At the behest of the U.S. Government, industrial, university and foundation lahoratories were joined in a massive effort to provide allied forces with the potion. At this time 26 corticords had been isolated from the adrenal cortex. These vital hormones have a cvco~entenophenanthrene nucleus. The four rings arc designated A, U, C & D and the carbons numbered as shown below. Since there are only a few mi1ligra;ns of any of these compounds in a ton of adrenals, isolation of enough for testing, let alone treatment, was impossible. Synthesis was required. T. Reichstein, a Swiss chemist and Nohel Laureate-to-be, had synthesized one of the simnler memhers of the series. ll-desoxvcorticosterone. mating i t available for treatment df ~ddison's"~isease in 1938: Left untreated this disease of the adrenal elands is alwavs fatal. The war group set out to synthesize t h e ll-keto analog, ll-dehydrocorticosterone.
C~elopenten~phenanth.ene nucleus
Reichde+
vations by still another future Nohel Prize winner, P. S. Hench of the Mayo Foundation, led to the administration of cortisone to a bedridden arthritic. The miraculous results are legendary. In a few days the patient went downtown on a shopping spree. Demands for the drue were enormous and emotional. The research and development which followed are unparalleled and the beneficial results to medicine and chemistry cannot he overstated. Cortisone was found useful in the treatment of a score of diseases and manv new drues. includine "The Pill," found their origin$ in theiesearch &at followed: Competition in the search for economical Drocesses and for compounds with fewer side effects, greater efficacy, and broader utility proceeded in huge carefullv planned Dromams in most of the major pharmac&tical cokpanies. TO tell the whole story would require volumes. I propose to concentrate on a single but key portion of the development, efficient introduction of the ll-oxygen.2 The quest began with the synthesis of ll-dehydrocorticosterone. Since no known, abundant, natural steroid had oxygen a t C-11, introduction by synthesis was required. Both American and Swiss chemists turned to the readilv available hile acids where moviagoxygen from C-12 t o C l l is required as can be seen hy romparing the structure of desoxvcholic acid (DCA) to cortisone.
Q
ll-desoxycort~co~terone CHOH
I
c=o
Cortisone
Desoxvcholie acid. DCA
Dehydrating DCA through its 12-benzoate (I) formed the ll-olefin (11) which on addition of HOBr and subsequent oxidation afforded the ll-ketone (IV). 0
Kendau's A ll-dehydrocortl~~~terone This compound had heen isolated by E. C. Kendall, another future Nohel Prize winner. He called it compound A. Synthesis was accomplished during the war, but the 30-step process was deemed impractically complex and the national effort was abandoned in 1944 in an aura of failure. Undaunted, Merck and Co., continued working closely with the Mayo Foundation. After two more years nearly 100 g of compound A had been synthesized, chiefly through the genius and fortitude of J. van de Kamp and S. M. Miller a t Merck.' It was inactive. Nevertheless Merck management decided to invest further. The next challenge had already been met by L. H. Sarett of Merck who had synthesized the 17-hydroxylated analog of Kendall's A, cortisone, in 1944 (see structure). Enormous developmental effort was applied and 5 g of cortisone was in hand in 1948. Cortisone, like ll-dehydrocorticosterone,failed in the treatment of adrenal insufficiency. But certain ohser-
'The following quote from Edward C. Kendall ["cortisone," Charles Serihner's Sons, New York, 1971, p.. 118.1 gives us a rare glimpse inside the lahoratory of a pharmiceutd company involved in the search for an exciting new medicine. "Only those who have worked in a chemical laboratory similar to that of Merck and Co. can appreciate the contribution made by van de Kamo and Miller.For camoound A the startinematerial. desoxvcholic aeid,hghed 65 pounds. here was not much"changein'weighi in the first few steps, hut after many months of work the entire product could be contained in one small flask. If the flask were broken at that stage and the material lost, the project would have to be started over from the beginning. To continue under this psychic strain for more than a year requires more than technical ability and more than unusual patience and persistence; it requires strength of character. Had these two men failed in their assienment it is ouestionable whether anvone else would have ventured'to make the attemnt." 'For mme de1-4~and ref~rmrrslo original article* see: Fieser, I.oui3 F., and Fcrser, Mary, "Stenids" Heinhold I'ublirhing Corp., Sew Yurk and Chapman & Hnll, 1.rd.. I.ondon. 1959, pp. 634-675. ~~
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Volume 57, Number 4, April 1980 / 291
111
IV
Even after thorough development the yield was too low for preparation of the original 100 g of 11-dehydrocorticosterone. However the 110, 12&epoxide (V), formed by treating bromohydrin (111) with hase, afforded the llb-ol (VI) on reductive fission. This sparked a drive for a better route to the epoxide (V). Reacting olefin (11) with perbenzoic acid gave the l l a , 12a-epoxide (VII) in good yield. Unfortunately, change from the 0 to a configuration reversed reactivities of the oxygen bonds and reductive scission left the oxygen a t C-12, reforming DCA. Br
vl
Gallagher, contributing from the University of Chicago, explored a different approach. After esterifying the acid and 3-hydroxyl groups of DCA, oxidation produced the 12-ketone (VIII) which was hrominated at the now activated 11-position. Hydrolysis of the mixture ofthe 11-aand 11-15-hromo isomers (IX) afforded the 11-01-12-one (X) which'isomerized to the 11-one-12-01 (XI). Reaction with PBr3, after appropriate blocking of the acid and 3-01 functions, gave the familiar 12-bromo-11-ketone (IV) of the hromohydrin series. The overall yield was still only about 20% and the route was longer than the original 11-olefin route. r 0 1 n o
IV
XI
Meanwhile Kendall attempted to prepare the 110, 12Pepoxide (V) through the 11,12-dihromide (XII). Treatment of the dibromide with base gave a product shown by Sarett to be the 9,ll-ene-12-a-01 (XIII). This allylic alcohol reacted with HBr to give the 12-bromide (XIV), which with hase gave the novel 11-ene-3,9-epoxide(XV) in excellent yield. At first this structure seems unlikely, but the epoxide ring has six members and from models i t is seen that the 3a-01 is close to the 9-position. Thus closure on C-9 is favorable. Addition of bromine to XV afforded the 11-P,12a-dihromide (XVI). The verv active 11-B-bromine was easily displaced by chromate ion-forming the chromate ester which~decomposedto the 11-ketone (XVII). 292 1 Journal of Chemical Education
xv Xvl
The route looked good from heo onset hut enthnsinsm was damoened h\r thc low vields on rnnveriion of the dibromide (XIIj to the allylir a h ~ ~ h(Xlllj, ol and the inefficient preparation of the 11-olefin(111.However, solutiun to both prvblems was provided by the unexpected finding of E. Schwenk & E. Stahl of Schering, U.S.A. These chemists hoped to introduce a hydroxyl or ketone at C-11 by reaction of the familiar 12ketone (VIII) with selenium dioxide. Instead dehydrogenation occurred nffnrdine the 9.11-ene-12-one (XVIII) which K e n d d .. hydrogenated forking his allylic alcohol (XIII). He converted XI11 to XVII as before. Bothdehydrogenation and hydrogenation were eventually developed into almost quantitative reactions. This a t last afforded an acceptable method of meparing an 11-ketone. o n
The route became operable in 1944and the overall yield for the 11steps from DCA to the 11-ketone (XVII) reached 67% after many years of development. This is 96.5% per chemical step. With the high yields it was not necessary to purify or even isolate each compound since few impurities were formed. Use of minimum quantities of inexpensive solvents such as methanol, acetone, benzene and acetic acid which were recovered in high yields further reduced expenses. Quantities nf . - solvents ..- - - - - werereduced below that reauired to dissolve the starting materials. As the dissolved portion reacted, the nroduct crvstallized and more startine compound dissolved and reactei. Minimizing solvent also increased concentration, often allowine 500 lb batches to be run in 500 gallon vessels. In addition, ihe reaction rate usually quadrupled each time the concentration was doubled which greatly increased production. The process was so eflirit:nt that Milerck used it until 1966. The erunomic effects ctf the aggressive development effort are best seen by looking at the end product costs. The first commercial cortisone cost about $200/g. By 1966, when Merck abandoned the bile acid process, the price was $0.48/g. The yield over the 30-step synthesis had increased from 0.16% to 23.4%, almost 150-fold!!! Thus, in 1948,600 kg of DCA were required to make a kilo of cortisone. In 1966, only 4 kg were needed. While the bile acid route was being pursued with such enormous success other investigations proceeded feverishly both at Merck and throughout the industry. Even such giants as Monsanto got into the act. One approach was to find an abundant natural 11-oxygenated substance. Indeed in 1948, A. Katz in Reichstein's laboratory established that sarmentogenin obtained from a very rare seed of uncertain identity and origin carries an oxygen a t C-11. Expeditions proceeded to Africa from Europe and the U.S. in search of a plant source. Plants providing traces of sarmentogenin were found and sarmentogenin was converted to cortisone hut the plants
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contained too little sarmentogenin for practical use. Another anoroach was total svnthesis from simple chemicals. This waa'firrt achieved by I
