Cortisone total

Efforts toward producing synthetic steroids, particularly cortisol, expanded during World War II to enable researchers to explore the possibiUty of medicinal appHcations of corticosteroids. In 1948, the discovery that cortisone dramatically alleviates the symptoms of arthritis led to intensive research on the antiinflammatory properties of corticosteroids. The development of partial and total syntheses for the commercial preparation of cortisone, alternative methods for producing cortisone, and the search for more potent antiinflammatory analogues gready stimulated both academic and industrial steroid research. 

A similar intramolecular Diels-Alder strategy was employed in an efficient synthesis to an appropriately functionalized hydrindanone nucleus (212). After functionalization, Diels-Alder cyclization, and appropriate functional group manipulation, this hydrindanone was converted into ( )-cortisone. The overall process afforded ( )-cortisone in a total of 18 chemical steps in approximately 3% yield. 

A third variation of this strategy has been appHed to an enantioselective total synthesis of cortisone. From an appropriately functionalized, scalemic hydrindan that possessed an 11-oxo-group and a masked corticoid side-chain, (+)-cortisol was produced in an 11-step total synthesis (213). 

In Sarett s total synthesis of cortisone, mild acid conditions were developed for the hydration of an ethoxyacetylenic carbinol to the ester without complete dehydration of the tertiary hydroxyl group. An acid-sensitive ketal group in another part of the molecule was also maintained. 

Hydroxycortisone BMD) (48) A solution of 4 g of 17a,20 20,21-bis-methylenedioxypregn-4-ene-3,l 1-dione (cortisone BMD) (46) dissolved in 300 ml of t-butanol and 5 ml of water is treated with 34 ml of 35 % hydrogen peroxide and 0.45 g of osmium tetroxide predissolved in 36 ml of /-butanol. The resulting mixture is allowed to stand at room temperature for 2 days. Diol (47) which crystallizes during the reaction is collected by filtration and washed with /-butanol and water. The filtrate is diluted with ethyl acetate and washed sequentially with aqueous sodium chloride, aqueous 10% sodium bisulfite, aqueous 10% sodium bicarbonate and finally with water to neutrality. The solvent is evaporated and a second crop of the diol (47) is collected, providing a total of about 3.8 g. 

Recommended starting total daily doses are hydrocortisone 15 mg, cortisone acetate 20 mg, or prednisone 2.5 mg (Table 18-2). Two-thirds of the dose is given in the morning, and one-third is given in the evening. 

Corticoid side chain.5 The final step in a recent total synthesis of cortisone (2) employed a novel double hydroxylation of an enol silyl ether (1) for construction of the side chain. Thus treatment of 1 with 3 equiv. of the peracid and KHC03 in CH2C12 at 0° results in hydroxylation at both Cl7 and C,. 

The first synthesis of cortisone (8), for instance,was a partial synthesis from desoxycholic acid (9), performed in 1948 by a group of chemists at Merck and Co under the leadership of Kendall [19], three years before Woodward [20] and Robinson [21], independently, accomplished the first total synthesis of steroids. 

Several total syntheses of cortisone have been described [25-32]. One of these is the highly stereospecific synthesis of Sarett et al. [30], which is described below and outlined in Scheme 1. This synthesis is of the type C -> BC -> ABC ABCD, where one constructs ring-C at first, followed by conversion to rings BC, then rings ABC, and finally to rings ABCD. 

C=CHC02H).7 It has been used in the synthesis of vitamin A aldehyde 8 and in the preparation of an intermediate in one of the total syntheses of cortisone.9... 

The method measures cortisone (urinary free cortisone, UFE), cortisol (urinary free cortisol, UFF), 6/1-hydroxycortisol, and 18-OHF using deuterated internal standards [62]. Commercial tetradeuterocortisol was used as an internal standard for cortisol, and the remaining dideutero homologs prepared in the laboratory by deuteration of A1 analogues. UFF and UFE are considered better indicators of hormone availability and hypersecretion than the F and E (free plus conjugated) quantified in the comprehensive profile. Typically the values of total F and E are about three times that of... 

Attenuated conversion of cortisol to cortisone in AME causes inhibition of cortisol synthesis (negative feedback), and excretion of total cortisol metabolites is typically 50% lower than normal. The condition is most commonly diagnosis by determining... 

The total synthesis of cortisone has been achieved from an intermediate prepared by Woodward and co-workers in 1951 by the following route ... 

An anecdote illustrates Tishler s drive. The total synthesis of cortisone, as devised by Lewis Sarrett, comprised approximately 30 steps and required weeks of intense and painstaking effort. Max was in charge of the first commercial production of cortisone in the pilot plant. One of the final steps is the isomerisation of a double bond into conjugation with the 3-ketone function with the formation of a 2,4-dinitrophenylhydrazone, causing the development of a brilliant, scarlet color. Tishler was inspecting the first production run. To his horror, he spotted a bright-red liquid leaking near the vessel. "I hope that s blood ", he exclaimed. Actually, Max was very concerned for individuals, beneath a rather formidable exterior. 

Figure 10 CEC-UV chromatogram (240 nm) of a mixture of 10 corticosteroids (100 qg/mL) using a linear gradient elution program. Voltage = 30 kV, HPLC injection volume = 10 pL, flow-rate = 10 pL/min for 3 min, then decreased to 100 pL/ min. Gradient program = initial ammonium acetate, 5 mM, in acetonitrile/water (17/83), held for 3 min, then ramped to 38% acetonitrile at 15 min and maintained to end of run. Column = Hypersil ODS, 3 pm, 42 cm total length, 30 cm packed length, 30.1 cm to window, 1 = triamcinolone, 2 = hydrocortisone and prednisolone co-eluting, 3 = cortisone, 4 = methylprednisolone, 5 = betamethasone, 6 = dexamethasone, 7 = adrenosterone, 8 = fluocortolone, 9 = triamcinolone aceto-nide. (Reprinted from Ref. 57, with permission.)...

Although these findings may apply to an experimental cortisone ulcer in animals, Hitzelberg in our laboratory obtained less definite results in man (H22, H23). Fifteen arthritic patients received 1 g prednisolone in 6 weeks. In the course of treatment, there was never an indication of peptic ulcer formation, although the output and concentration of pepsin in the basal secretion increased on the average about 2-fold. Paper electrophoresis of the dialyzed and lyophilized gastric juice, following steroid administration, frequently showed decrease of total carbohydrate... 

One step in the Sarett total synthesis of cortisone involved addition of ethoxy-vinylmagnesium bromide to the reactive carbonyl group of the diketone (6) to produce... 

During World War II, Glaxo became Britain s primary producer of penicillin, much as Pfizer did in the United States. By 1944 Glaxo, using Pfizer s fermentation process, had built four factories that produced 7.5 billion units, or about 80 percent of total British output. After the war, it remained Britain s leader in penicillin. At the same time, the company continued to expand its vitamin lines. Its managers then exploited this learning to enter the field of hormones by developing Britain s first commercial cortisones and then a series of corticosteroids. 

Woodward, R.B., Sondheimer, F. and Taub, D. (1951) The total synthesis of cortisone. Journal of the American Chemical Society, 73, 4057. 

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