Chemistry:Dienedione

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Dienedione, also known as estra-4,9-diene-3,17-dione, is a synthetic, orally active anabolic-androgenic steroid (AAS) of the 19-nortestosterone group that was never introduced for medical use. It is thought to be a prohormone of dienolone.[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 States Controlled Substances Act. Previous to this, it was sold as a bodybuilding supplement within the United States, and often mistakenly marketed as a prohormone for trenbolone, a veterinary steroid. Prior to its scheduling, it was part of a number of supplements that were seized during FDA enforcement of Bodybuilding.com for selling unapproved new drugs.[3] The actual active metabolite, dienolone, is almost identical to trenbolone structurally, but lacks the C11 double bond.

Dienedione use is also prohibited in horses. In addition, small amounts are endogenously produced in horses.[4]

Applications

Dienedione finds use in the synthesis of more privileged steroids, e.g.:

  1. Trenbolone[5]
  2. Mifepristone,[6] Ulipristal, Asoprisnil, Onapristone, Org-34850[7] etc. Most of these agents are actually made from "ethylene deltenone" [5571-36-8] which is the ethyleneglycol cyclic ketal of dienedione, which is accompanied by reorganization of the diene regiochemistry. A methanol acetal protecting group is also very common.
  3. Dienogest[8][9] One-pot method:[10]
  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.
  5. Trimegestone[12]
  6. Estrogen[13]

Chemistry

Synthesis

Dienedione was synthesized from dienolone (cmp16) in 90% yield.[14]

The semi-synthetic chemical synthesis has been reported by Organon:[8]

The starting material is called Sitolactone [126784-20-1] (1);[15] 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 of t-BuOK base completed the synthesis of dienedione (6).

Improvements to the general scheme have recently been reported in modern Chinese patents:[16][17][18][19]

See also

References

  1. ↑ "Rules - 2009 - Final Rule: Classification of Three Steroids as Schedule III Anabolic Steroids Under the Controlled Substances Act". https://www.deadiversion.usdoj.gov/fed_regs/rules/2009/fr1204.htm. 
  2. ↑ "Rules - 2009 - Final Rule: Classification of Three Steroids as Schedule III Anabolic Steroids Under the Controlled Substances Act". http://www.deadiversion.usdoj.gov/fed_regs/rules/2009/fr1204.htm. 
  3. ↑ Office of Regulatory Affairs. "Enforcement Reports - Enforcement Report for July 7, 2010". https://www.fda.gov/Safety/Recalls/EnforcementReports/ucm218212.htm. 
  4. ↑ "Endogenous nature of estra-4,9-diene-3,17-dione in entire male horses". Drug Testing and Analysis 17 (1): 75–87. January 2025. doi:10.1002/dta.3685. PMID 38532598. 
  5. ↑ Wang Youfu, et al. WO2021012673 (to Zhejiang Shenzhou Pharmaceutical Co Ltd).
  6. ↑ "Structural Studies of Intermediates in the Synthesis of Mifepristone (RU 486). III. 3,3-Ethylenedioxy-5(10),9(11)-estradien-17-one". Acta Crystallographica Section C Crystal Structure Communications 51 (7): 1327–1330. 15 July 1995. doi:10.1107/S010827019401468X. https://journals.iucr.org/paper?S010827019401468X. 
  7. ↑ Ronald Gebhard & Hendrikus A. A. van der Voort, U.S. Patent 5,620,966 (1997 to Organon NV).
  8. ↑ 8.0 8.1 Franciscus Theodorus Leonardus Brands & Pieter Vrijhof, U.S. Patent 5,955,622 & U.S. Patent 6,005,124 (1999 to Organon NV).
  9. ↑ Suhas Ganpat Tambe, et al. WO2011132045 (to Lupin Ltd).
  10. ↑ 张峥斌, et al. CN120136946 (2025 to Jiangxi Junye Biological Pharmaceutical Co ltd).
  11. ↑ Liu Xirong, et al. CN117106002 (2023 to Hunan Xinhexin Biological Medicine Co ltd).
  12. ↑ "Synthesis of Trimegestone: The First Industrial Application of Bakers’ Yeast Mediated Reduction of a Ketone". Organic Process Research & Development 1 (1): 2–13. 1 January 1997. doi:10.1021/op960004h. https://pubs.acs.org/doi/10.1021/op960004h. 
  13. ↑ Zhang Zhengbin, et al. WO2023126014 (to Jiangxi Junye Biological Pharmaceutical Co Ltd, Zhejiang Xianju Junye Pharmaceutical Co Ltd).
  14. ↑ "Transition-Metal Catalyzed Oxidations. 7. Zirconium-Catalyzed Oxidation of Primary and Secondary Alcohols with Hydroperoxides". The Journal of Organic Chemistry 61 (4): 1467–1472. 1 January 1996. doi:10.1021/jo9518720. https://pubs.acs.org/doi/10.1021/jo9518720. 
  15. ↑ Joachim Schindler & Rolf Schmid, US4784953 (1988 to Diosynth BV).
  16. ↑ 曾培玮, et al. CN113861158 (2021 to Hunan Xinhexin Biological Medicine Co ltd).
  17. ↑ 马小燕 & 胡新军, CN108997463 (2021 to Sichuan University of Science and Engineering).
  18. ↑ 米超杰, et al. CN109293723 (2019 to Shandong Saituo Biotechnology Co Ltd, Shandong Sirui Biomedical Co Ltd).
  19. ↑ 刘喜荣 & 曾春玲, CN104592339 (2015 to HUNAN XINHEXIN BIOLOGICAL PHARMACEUTICAL Co Ltd).




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