Cortisone from bile acids

For a detailed account of the many years of work taken to achieve a working process to produce cortisone from bile acids, see Fieser, L. F., and Fieser, M. Steroids, Reinhold Publishing Co., New York, 1959, Chapter 19. 

Merck and Co. had produced the cortisone used by Hench in research quantities using a 36-step synthesis from bile acids. Hench s revelation rapidly escalated interest in steroidal anti-inflammatories. A brief outline of ongoing developments in each of these fields follows. 

In 1948 cortisone was made from bile acids in quantity sufficient for clinical trial, and the dramatic demonstration of its power to induce remission of rheumatoid arthritis was published the following year. In 1950 it was realised that cortisone was biologically inert and that the active natural hormone is hydrocortisone (cortisol). Since then an embarrassingly large number of synthetic steroids has been made and offered to the clinician. They are derived from natural substances (chiefly plant sterols), the constitutions of which approach most nearly to that of the steroids themselves. A principal aim in research is to produce steroids with more selective action than hydrocortisone, which induces a greater variety of effects than desired in any patient who is not suffering from adrenal insufficiency. 

The outer layer or cortex of the adrenal gland is the source of a large group of sub stances known as corticosteroids Like the bile acids they are derived from cholesterol by oxidation with cleavage of a portion of the alkyl substituent on the D ring Cortisol IS the most abundant of the corticosteroids but cortisone is probably the best known Cortisone is commonly prescribed as an antiinflammatory drug especially m the treat ment of rheumatoid arthritis... 

Pregniines. In 1944, Sarrett completed the first partial synthesis of cortisone (172). Like many of the early syntheses of corticosteroids, Sarrett began with the a bile acid, deoxychoHc acid (14). Because bile acids are isolated from animal sources, their supply is by necessity limited (173). Following these early syntheses, several improvements and innovations have resulted in a number of industrial syntheses of cortisol and other corticosteroids. 

Bile acids were the logical starting point for the manufacture of cortisone in the late 1940s, but steroids from plant sources, and particularly diosgenin ex yams, were gaining credibility as time passed. The chemical synthesis challenges associated with each of these raw materials are outlined in Scheme 7. 

One such synthesis began with desoxycholic acid (from ox bile), which was laboriously converted to cortisone in 32 steps, many of which were required to transpose the oxygen function from the 12 to the 11 position, to introduce the 17 a-hydroxyl and to construct the a,P-keto arrangement in ring A. Over a 3-year period (1946-1949) some 1,200 pounds of the bile acid laboriously yielded less than 1 kg of cortisone. Workers at the Mayo Clinic (Hensch et al., 1949) reported on their dramatic success in controlling rheumatoid arthritis pain with cortisone. This gave the impetus to find a better way to provide cortisone than by the 32-step synthesis from desoxycholic acid or the laborious extraction from ox adrenals. 

Desoxycorticosterone was the first naturally occurring corticoid to be synthesized. It was prepared, before its isolation from the adrenal cortex, by Steiger and Reichstein (32). As a result of his synthesis of 11-desoxycorticosterone and other early work with corticoids, Reichstein later shared the Nobel Prize with Kendall, another chemist who was instrumental in carrying out early steroid syntheses, and with Hench, a rheumatologist who in 1929 discovered that cortisone is effective in the treatment of rheumatoid arthritis. Kendall s basic research ultimately led to the synthesis of cortisone from naturally occurring bile acids (33). 

The subsequent stages from pregnan-3a-ol-ll,20-dione acetate (I) to cortisone have been recorded by Kritchevsky et al. (1952) (Fig. 4). The enol acetate (II) of I upon treatment with perbenzoic acid forms the epoxide (III), which without isolation is hydrolyzed directly to pregnane-3a,17 -diol-ll,20-dione (IV). Bromination at C-21 (V) and mild treatment with alkali produces the 21-hydroxy derivative (VI), which is oxidized with N-bromoacetamide to dihydrocortisone (VII). Bromination (at C-4) of the 21-acetate of VII followed by dehydrobromination with semi-carbazide leads to the semicarbazone of cortisone acetate (VIII), which can be cleaved in a facile manner with pyruvic acid to cortisone acetate. Under suitable conditions, it is possible to accomplish the oxidation at C-3 and bromination of the ketone at C-4 in one step by means of N-bromoacetamide (Hershberg, Gerold, and Oliveto, 1952b). This synthesis of cortisone acetate from desoxycholic acid outlined in Figs. 3 and 4 is one of the most efficient bile acid processes, since it does not suffer from the difficulties outlined under Section II.2. 

Deoxycholic acid was an important starting material for the early synthesis of cortisone and other cortical steroids. It was obtained principally from cholic acid by selective oxidation and subsequent Wolff-Kishner reduction. Cholic acid was obtained from beef bile which also contains substantial amounts of deoxycholic acid. The history of this period of steroid investigation is reviewed by Fieser and Fieser (1). 

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