Dienedione, also known asestra-4,9-diene-3,17-dione, is asynthetic,orally activeanabolic-androgenic steroid (AAS) of the19-nortestosterone group that was never introduced for medical use. It is thought to be aprohormone ofdienolone.[1] The drug became a controlled substance in the US on January 4, 2010,[2] and is classified as a Schedule III anabolic steroid under the United StatesControlled Substances Act. Previous to this, it was sold as abodybuilding supplement within the United States, and often mistakenly marketed as aprohormone fortrenbolone, a veterinary steroid. Prior to its scheduling, it was part of a number of supplements that were seized during FDA enforcement ofBodybuilding.com for selling unapproved new drugs.[3] The actual active metabolite, dienolone, is almost identical to trenbolone structurally, but lacks the C11double bond.
Dienedione use is also prohibited in horses. In addition, small amounts are endogenously produced in horses.[4]
Altrenogest[11] The dimethyl acetal [10109-76-9] was used in this patent. Owing to the "chelate effect", cyclic ketals are more stubborn to remove than the dimethyl acetals, which means more forceful conditions that can lead to formation of impurities. Although, "ethylene deltenone" had been used in the prior state of the art.
A congenial synthesis of dienedione starts from Estra-4-ene-3,17-dione (PC12346074).[15] This is produced fromestrone 3-methyl ether by protection as the ketal, Birch reduction of the aromatic group, and acid hydrolysis. The procedure involved ketalization of both carbonyl groups with concomitant olefin migration from C4 to C5(10), epoxide formation with m-CPBA, hydrolysis of the oxirane and dehydration in concentrated acid solution. However no yields were disclosed in the patent. In thedienolone method, the C5(10) olefin is brominated followed by a 2x dehydrohalogenation procedure, with high yields being reported.
Dienedione was synthesized fromdienolone (cmp16) in 90% yield.[16]
Thesemi-synthetic chemical synthesis has been reported by Organon:[8]
The starting material is calledSitolactone [126784-20-1] (1);[17] It is a commercially available product obtained by microbiological degradation of phytosterols which are waste products from the processing of soy. The first step consists of a Grignard reaction with 5-chloro 2-pentanone-neopentylacetal [88128-57-8] (2) to give (3aS,4S,5R,7aS)-5-hydroxy-7a-methyl-4-(3-oxo-6-(2,5,5-trimethyl-1,3-dioxan-2-yl)hexyl)octahydro-1H-inden-1-one (3). Halogenation with chlorine gas in the presence of pyridine base gave (+)-3,3-(dimethylpropylendioxy)-4,5-seco-estr-9-ene-5,17-dione [88128-61-4] (4). The hydrolysis of the ketal in weak acid led to (+)-4,5-seco-estr-9-ene-3,5,17-trione [10582-53-3] (5). Lastly, an intramolecular aldol condensation in the presence oft-BuOK base completed the synthesis of dienedione (6).
Improvements to the general scheme have recently been reported in modern Chinese patents:[18][19][20][21] For example, oxidation of3 with concomitant deprotection of the ketal can allow for a one-pot double Aldol condensation to yield dienedione in a single step.
^Ho HS, Ho EN, Wong WT (January 2025). "Endogenous nature of estra-4,9-diene-3,17-dione in entire male horses".Drug Testing and Analysis.17 (1):75–87.doi:10.1002/dta.3685.PMID38532598.
^Wang Youfu, et al. WO2021012673 (to Zhejiang Shenzhou Pharmaceutical Co Ltd).
