The synthesis of 17-(methyl-C14)-testosterone and 21-C14-progesterone.

The use of steroid hormones containing tagged atoms promises to have an important part in the study of their metabolism. The relative availability of radioactive Cl4 manufactured in the uranium chain-reacting pile at Oak Ridge has facilitated the synthesis of such compounds containing labeled carbon atoms (1). Through the cooperation of Dr. Konrad Dobriner of the Sloan-Kettering Institute for Cancer Research we have been able to synthesize two important members of this group of substances, methyltestosterone and progesterone, having the radioactive atom in the side chain. Since the radioactive carbon was available to us in the form of methyl iodide, both syntheses used Grignard reactions. The usual procedure for the preparation of methyltestosterone is to start with dehydroisoandrosterone acetate and to use a large excess of methylmagnesium iodide. Obviously this method was not suitable for our synthesis. We, therefore, used the method of Miescher (2) in which androstene3,17-dione 3-enol ether was allowed to react with 1 mole of the Grignard reagent. This proved to be a satisfactory method, giving in one step a yield of 42 per cent of purified product based on the methyl iodide used. Our synthesis of progesterone was based on the general method for the preparation of ketones developed by Gilman and Nelson (3, 4). In this method the desired organocadmium derivative is made from the corresponding Grignard reagent and then allowed to react with an acid chloride. This has been applied to steroid syntheses with good success (5, S), and Teemed to us to afford the most suitable method for the synthesis of progesterone. In spite of the fact that a large excess of Grignard reagent is usually used, we were able to obtain a yield of 50 per cent of pregnenolone acetate with only equimolecular quantities of methyl iodide and 3-acetoxy-A5-etiocholenic acid chloride. Subsequent hydrolysis to pregnenolone followed by an Oppenauer oxidation gave an over-all yield of 26 per cent of purified product based on the methyl iodide used.