Chemistry:Almestrone

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Almestrone (INN) (developmental code names Ba 38372, Ciba 38372), also known as 7α-methylestrone, is a synthetic, steroidal estrogen which was synthesized in 1967 but was never marketed.[1] It is used as a precursor in the synthesis of several highly active steroids.[2][3]

Applications

Almestrone is an intermediate in the original synthesis of tibolone by Organon.[4][5][6] However this method of synthesis is now thought to be largely obsolete. Tibolone is used to synthesize ERA-63.

It is also used in the syntheses of dimethandrolone,[7] dimethyldienolone, dimethyltrienolone, and other closely related compounds.[8][9] They share the same precursor compound, 7α-methyl-estra-4,9(10)-diene-3,17-dione.

Another use for almestrone is in the synthesis of TAS-108.[10]

Almesterone methyl ether can be used to make 19-nor-D-homosteroids (c.f. mibolerone).[11]

Synthesis

The original synthesis of almestrone is quite old and dates back to 1967:[12][13] Aromatization method:[14] Precursor:[15]

The dehydrogenation of testosterone propionate (1) by chloranil gives the corresponding 4,6-diene (2). Conjugate addition of methylmagnesium bromide gives, after saponification, 7α-methyltestosterone (3) along with some of the 7β-epimer. Oxidation of the alcohol with pyridinium chlorochromate gives 7α-methylandrost-4ene-3,17-dione (4). Oxidation with DDQ gives 7α-methyl-1,4-androstadiene-3,17-dione (5). It is likely that the direction of this second dehydrogenation is mandated by the presence of the methyl group at C-7; this group may hinder the approach of reagent to the center which would lead to the alternate diene. Ketalization with ethylene glycol affords ketal 6. Elimination of the angular methyl group at C-19 with consequent aromatization is achieved by treatment of the diene with lithium in the presence of biphenyl. Deprotection of the ketal affords almestrone (7).

It can also be made from dehydronandrolone acetate.[16] Mentabolan is oxidized with a catalytic amount of a copper halide in the presence of oxygen.[17]

The chemical synthesis starting from trestolone acetate has alo been described.[18]

See also

References

  1. ↑ The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 900–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA900. 
  2. ↑ "Copper-Mediated and Copper-Catalyzed Addition and Substitution Reactions of Extended Multiple Bond Systems". PATai's Chemistry of Functional Groups. 2011. doi:10.1002/9780470682531.pat0450. ISBN 978-0-470-68253-1. 
  3. ↑ "C7-Substituted Estranes and Related Steroids". Mini-Reviews in Organic Chemistry 3 (3): 229–251. 2006. doi:10.2174/1570193X10603030229. ISSN 1570-193X. 
  4. ↑ "Synthese von 7α‐Methyl‐3‐oxo‐Δ 4,9,11 ‐19‐norandrostatrienen. Über Steroide, 211. Mitteilung". Helvetica Chimica Acta 50 (6): 1453–1461. January 1967. doi:10.1002/hlca.19670500602. https://onlinelibrary.wiley.com/doi/10.1002/hlca.19670500602. 
  5. ↑ Lednicer, D. (2011). Steroid chemistry at a glance. Wiley. ISBN 978-0-470-66084-3. 
  6. ↑ NL 6406797 idem Jongh Hendrik Paul De, Nicolaas Pieter Van Vliet, US3340279 (1967 to Organon).
  7. ↑ Richard Blye & Hyun Kim, US20030069215 (to US Department of Health and Human Services, Government of the United States of America)
  8. ↑ For example: CID 10125553 from PubChem
  9. ↑ Richard P. Blye, et al. WO2003045398 (to US Department of Health and Human Services).
  10. ↑ Masato Tanabe, et al. WO1999033859 (to SRI International Inc).
  11. ↑ Jaap Van Der Louw, et al. WO2005061528 (to Akzo Nobel NV).
  12. ↑ "Synthese von 7α‐Methylöstron. Über Steroide, 210. Mitteilung". Helvetica Chimica Acta 50 (1): 289–296. January 1967. doi:10.1002/hlca.19670500136. https://onlinelibrary.wiley.com/doi/10.1002/hlca.19670500136. 
  13. ↑ "7α‐Methylöstrogene. Über Steroide, 209. Mitteilung". Helvetica Chimica Acta 50 (1): 281–288. January 1967. doi:10.1002/hlca.19670500135. https://onlinelibrary.wiley.com/doi/10.1002/hlca.19670500135. 
  14. ↑ "The Reductive Aromatization of Steroidal Dienones. A New Method for the Preparation of Estrone". Journal of the American Chemical Society 86 (4): 742–743. February 1964. doi:10.1021/ja01058a048. https://pubs.acs.org/doi/abs/10.1021/ja01058a048. 
  15. ↑ "Sexualhormone XXI. Über zweifach ungesättigte Ketone der Androstanreihe". Helvetica Chimica Acta 20 (1): 328–332. January 1937. doi:10.1002/hlca.19370200148. https://onlinelibrary.wiley.com/doi/10.1002/hlca.19370200148. 
  16. ↑ Zeng Chunling, et al. CN118290508 (2024 to Hunan Xinhexin Biological Medicine Co ltd).
  17. ↑ Kuniaki Tatsuta, Kazuo Maruhashi, & Shingo Yano, WO2007049672 (to Taiho Pharmaceutical Co Ltd).
  18. ↑ FR1434172 (1966 to Novartis AG, BASF Schweiz AG).



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