Steroids
Julian's research at Glidden changed direction in 1940 when he began work on synthesizing progesterone, estrogen and testosterone from the plant sterols, stigmasterol and sitosterol, isolated from soybean oil by a foam technique he invented and patented,. At that time clinicians were discovering many uses for the newly discovered hormones. However, only minute quantities could be produced from the extraction of hundreds of pounds of spinal cords.
In 1940 Julian was able to produce 100 lb of mixed soy sterols daily, which had a value of $10,000, in sex hormones. Julian was soon ozonizing 100 pounds daily of mixed sterol dibromides. The result was the female hormone progesterone which was put on the American market in bulk for the first time.The soy stigmasterol was easily converted into commercial quantities of the female hormone, progesterone, and the first pound of progesterone he made, valued at $63,500 was shipped to the buyer in an armored car. Production of other sex hormones soon followed.
His work made possible the production of these hormones on a larger (kilogram) industrial scale, with the potential of reducing the cost of treating hormonal deficiencies. Julian and his co-workers obtained patents for Glidden on key processes for the preparation of progesterone and testosterone from soybean plant sterols. Product patents held by a former cartel of European pharmaceutical companies prevented a significant reduction in wholesale and retail prices for clinical use of these hormones in the 1940s.
On April 13, 1949, rheumatologist Philip Hench at the Mayo Clinic announced the dramatic effectiveness of cortisone in treating rheumatoid arthritis. The cortisone was produced by Merck at great expense using a complex 36-step synthesis developed by chemist Lewis Sarett. It started with deoxycholic acid from cattle bile acids. On September 30, 1949, Julian announced an improvement in the process of producing cortisone. This eliminated the need to use osmium tetroxide (a rare and expensive chemical). By 1950, Glidden could begin producing closely related compounds which may have partial cortisone activity. Julian also announced the synthesis, starting with the cheap and readily available pregnenolone synthesized from the soybean oil sterol, stigmasterol of the steroid cortexolone (also known as Reichstein's Substance S), a molecule that differed from cortisone by a single missing oxygen atom; and possibly 17α-hydroxyprogesterone and pregnenetriolone, which he hoped might also be effective in treating rheumatoid arthritis, unfortunately they were not.
On April 5, 1952, biochemist Durey Peterson and microbiologist Herbert Murray at Upjohn published the first report of a fermentation process for the microbial 11α-oxygenation of steroids in a single step (by common molds of the order Mucorales). Their fermentation process could produce 11α-hydroxyprogesterone or 11α-hydroxycortisone from progesterone or Compound S, respectively, which could then by further chemical steps be converted to cortisone or 11β-hydroxycortisone (cortisol). After two years, Glidden abandoned production of cortisone to concentrate on Substance S. Julian developed an excellent multistep process for conversion of pregnenolone, available in abundance from soybean oil sterols to cortexolone. In 1952, Glidden, which had been producing progesterone and other steroids from soybean oil, shut down its own production and began importing them from Mexico through an arrangement with Diosynth (a small Mexican company founded in 1947 by Russell Marker after leaving Syntex). Glidden's cost of production of cortexolone was relatively high, so Upjohn decided to use progesterone, available in large quantity at low cost from Syntex, to produce cortisone and hydro cortisone.
In 1953, Glidden decided to leave the steroid business which had been relatively unprofitable over the years despite Julian's innovative work. On December 1, 1953, Julian left Glidden after 18 years, giving up a salary of nearly $50,000 a year, to found his own company, Julian Laboratories, Inc., taking over the small, concrete-block building of Suburban Chemical Company in Franklin Park, Illinois.
On December 2, 1953, Pfizer acquired exclusive licenses of Glidden patents for the synthesis of Substance S. Pfizer had developed a fermentation process for microbial 11β-oxygenation of steroids in a single step that could convert Substance S directly to 11β-hydrocortisone (cortisol), with Syntex undertaking large-scale production of cortexolone at very low cost.
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