Chemistry:Estrone methyl ether

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Short description: Chemical compound
Estrone methyl ether
Clinical data
Other namesOestrone methyl ether; Estrone 3-methyl ether; 3-Methoxyestrone; 3-Methoxyestra-1,3,5(10)-trien-17-one
Drug classEstrogen; Estrogen ether
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC19H24O2
Molar mass284.399 g·mol−1
3D model (JSmol)

Estrone methyl ether, or estrone 3-methyl ether, is a synthetic estrogen and estrogen ether – specifically, the C3 methyl ether of estrone – which was never marketed.[1][2]

Chemistry

Synthesis

A couple of enantioselective routes were disclosed by E.J. Corey et al:

  1. Dane's diene route:[3][4]
  2. & 1-vinyl-6-methoxy-1-tetralol [3125-36-8] route:[5][6][7]
File:Estrone 3-methyl ether synthesis.svg

The starting material in the above schematic was named "Dane’s diene" [2811-50-9] (1) after Elisabeth Dane.[8][9][10] The first step is a Diels-Alder reaction with 2-Methyl-2-cyclopenten-1-one [1120-73-6] (2) to give PC12811167 (3). The next step yields PC11119485 (4). Conjugation of the enone olefin double bond with the other olefin for the next step resulted in the "Torgov diene" (PC1259524) (5). Reduction of the olefin bonds completes the synthesis of the target molecule (6). An 88% yield was reported for the last step. The preparation of the catalyst is shown underneath.

The racemic version is very high yielding:[11]

The Torgov Cyclization[12] has some fundamental differences from Dane's route but both methods give the intermediate Torgov diene [966-47-2]. It is named after a USSR chemist called Igor Torgov.[13][14]

The starting material is called 6-Methoxy-1-tetralone [1078-19-9][15][16] Some older methods are included for historical context.[17][18] This compound finds dual use in the synthesis of the SERM compounds Lasofoxifene & Nafoxidine. It can be rearranged to 6-methoxy-2-tetralone [2472-22-2],[19] one known application is in the synthesis of Tolnapersine.

Smith & Hughes work is also worthy of consideration {This has been covered on the norgestrel and norboletone pages}. In Lednicer's book on steroids reference is made to 6-oxaestrogens.[20] Although no references were provided in the book the following citations could be found online:[21][22][23] In this process the catalytic hydrogenation step of the two olefins adds the hydrogens to the alpha face of the steroid. This is not the same as natural configuration. Lednicer claims that if the catalytic hydrogenation is performed in acetic acid then the 8-iso hydrogen equilibrates so as to yield the favored trans 8–9 ring juncture.

Other learning materials:[24][25][26]

Applications

Estrone methyl ether has use in the synthesis of the following steroids:

  1. Mestranol (ethinylestradiol 3-methyl ether).[27] Mestranol in-turn is the precursor chemical to Norgesterone.
  2. Dienogest.[28]
  3. Norethandrolone[29] For the purposes of comparison, see the related compound Ethylmetrienone [848-04-4], which is totally synthetic but finds use in the synthesis of Norboletone. N.B. although Birch reduction of Estrone methyl ether was the original method of synthesizing Norethandrolone, it is interesting to learn that a newer method than this was patented recently.[30] This newer improved method of synthesis relied of a precursor that is called Bolandione.
  4. The reduction of the ketone in estrone methyl ether gives estradiol methyl ether. This in-turn, was used in the synthesis of Noretynodrel.
  5. The Birch reduction of Estrone methyl ether gives Nandrolone since the 17-keto group is reduced concomitantly during this step. Back-oxidation occurs to give Bolandione; this in-turn can be used to make Norethisterone & Allylestrenol.
  6. With a suitable demethylating agent can be used to make estrone.
  7. Clomestrone
  8. Prenortestosterone [1089-78-7] (see under nandrolone synthesis) can be brominated. 2x dehydrohalogenation step then leads to dienolone.[31]
  9. Epimestrol
  10. Ethylestrenol
  11. The Nandrolone also finds use in the synthesis of mibolerone, LS-1727, Cingestol, Lynoestrenol, Estradiol-3-amine [10427-24-4][32][33] & as the starting material that fulvestrant is made from.[34] & tibolone & trestolone.
  12. Plomestane

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. ↑ Drugs: Synonyms and Properties: Synonyms and Properties. Taylor & Francis. 8 May 2018. pp. 1406–. ISBN 978-1-351-78989-9. https://books.google.com/books?id=xUlaDwAAQBAJ&pg=PT1406. 
  3. ↑ "Synthesis of Estrone Methyl Ether". Synfacts 2009 (02): 0117–0117. 22 January 2009. doi:10.1055/s-0028-1087603. http://www.thieme-connect.de/DOI/DOI?10.1055/s-0028-1087603. 
  4. ↑ "Highly Enantioselective [4 + 2 Cycloaddition Reactions Catalyzed by a Chiral N -Methyl-oxazaborolidinium Cation"]. Organic Letters 10 (15): 3271–3273. 7 August 2008. doi:10.1021/ol8011502. https://pubs.acs.org/doi/10.1021/ol8011502. 
  5. ↑ "Role of Diethylaniline in the Reduction of 1,3-Dicarbonyl Compounds". Synfacts 2009 (07): 0755–0755. 22 June 2009. doi:10.1055/s-0029-1217291. http://www.thieme-connect.de/DOI/DOI?10.1055/s-0029-1217291. 
  6. ↑ "Synthesis of Estrone Methyl Ether". Synfacts 2008 (01): 0003–0003. 18 December 2007. doi:10.1055/s-2007-991492. http://www.thieme-connect.de/DOI/DOI?10.1055/s-2007-991492. 
  7. ↑ "Conversion of Torgov’s Synthesis of Estrone into a Highly Enantioselective and Efficient Process". Journal of the American Chemical Society 129 (34): 10346–10347. 1 August 2007. doi:10.1021/ja0742434. https://pubs.acs.org/doi/10.1021/ja0742434. 
  8. ↑ "Synthesen in der Reihe der Steroide". Angewandte Chemie 52 (44): 655–659. 4 November 1939. doi:10.1002/ange.19390524402. https://onlinelibrary.wiley.com/doi/10.1002/ange.19390524402. 
  9. ↑ "Synthesen in der hydroaromatischen Reihe. III. 1. Weitere Diensynthesen des 1‐Äthinyl‐6‐methoxy‐3,4‐dihydro‐naphtalins und des 1‐Vinyl‐6‐methoxy‐3,4‐dihydro‐naphtalins. 2. Die Kondensation von Cyclopentandionen mit Acetylen". Justus Liebigs Annalen der Chemie 536 (1): 183–196. January 1938. doi:10.1002/jlac.19385360117. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/jlac.19385360117. 
  10. ↑ "Synthesen in der hydroaromatischen Reihe. IV. 1. Die Kondensation von 1‐Methyl‐cyclopenten‐dion‐2,3 mit 1‐Vinyl‐6‐methoxy‐3,4‐dihydro‐naphtalin. 2. Darstellung und Diensynthesen von 3‐Oxy‐2,6‐dimethyl‐benzochinon‐(1,4)". Justus Liebigs Annalen der Chemie 536 (1): 196–203. January 1938. doi:10.1002/jlac.19385360118. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/jlac.19385360118. 
  11. ↑ "E. Dane’s route to estrone revisited". Tetrahedron Letters 32 (28): 3357–3360. July 1991. doi:10.1016/S0040-4039(00)92705-9. https://linkinghub.elsevier.com/retrieve/pii/S0040403900927059. 
  12. ↑ "New syntheses of estrone, d,1-8-iso-oestrone and d,1-19-nortestosterone". Tetrahedron Letters 4 (23): 1553–1558. January 1963. doi:10.1016/S0040-4039(01)90870-6. https://linkinghub.elsevier.com/retrieve/pii/S0040403901908706. Retrieved 24 January 2026. 
  13. ↑ "Torgov Cyclization". Synfacts 15 (12): 1443. December 2019. doi:10.1055/s-0039-1691123. http://www.thieme-connect.de/DOI/DOI?10.1055/s-0039-1691123. 
  14. ↑ "In memorium Igor Torgov: Torgov’s way to total steroid synthesis". Steroids 74 (9): 723–724. September 2009. doi:10.1016/j.steroids.2009.03.004. https://linkinghub.elsevier.com/retrieve/pii/S0039128X09000774. 
  15. ↑ Zou Xiaomao, et al. CN120398657 (2025 to Nankai University).
  16. ↑ 林晓辉, 杨庆垂, & 淡勇德, CN111333494 (2023 to Wuhan Haixin Pharmaceutical Research Co ltd).
  17. ↑ "6-Methoxy-1-tetralone". Journal of the American Chemical Society 70 (1): 331–334. January 1948. doi:10.1021/ja01181a103. https://pubs.acs.org/doi/abs/10.1021/ja01181a103. 
  18. ↑ "6-Methoxy-1-tetralone". Journal of the American Chemical Society 71 (9): 3246–3247. September 1949. doi:10.1021/ja01177a515. https://pubs.acs.org/doi/abs/10.1021/ja01177a515. 
  19. ↑ "A concise approach for the synthesis of 6-methoxy-2-tetralone". MOJ Bioorganic & Organic Chemistry 2 (1). 19 February 2018. doi:10.15406/mojboc.2018.02.00052. https://medcraveonline.com/MOJBOC/a-concise-approach-for-the-synthesis-of-6-methoxy-2-tetralone.html. 
  20. ↑ Steroid chemistry at a glance. Chemistry at a glance (1. publ ed.). Wiley. 2011. ISBN 9780470660843. 
  21. ↑ Gordon Alan Hughes & Herchel Smith, GB1069842, GB1069843, GB1069844, GB1069845, GB1069846, GB1069847 (all 1967 to Individual).
  22. ↑ Ulrich Pison, et al. WO2009059806 (to Topass GmbH).
  23. ↑ Александр Григорьевич Шавва, et al. RU2057140 (1996).
  24. ↑ "Catalytic Asymmetric Torgov Cyclization: A Concise Total Synthesis of (+)‐Estrone". Angewandte Chemie International Edition 53 (33): 8770–8773. 11 August 2014. doi:10.1002/anie.201404909. https://onlinelibrary.wiley.com/doi/10.1002/anie.201404909. 
  25. ↑ "Enantioselective Synthesis of (+)-Estrone Exploiting a Hydrogen Bond-Promoted Diels−Alder Reaction". The Journal of Organic Chemistry 75 (8): 2718–2721. 16 April 2010. doi:10.1021/jo100053j. https://pubs.acs.org/doi/10.1021/jo100053j. 
  26. ↑ "A Concise Route to (+)-Estrone". Organic Letters 2 (13): 1915–1917. 1 June 2000. doi:10.1021/ol005988g. https://pubs.acs.org/doi/10.1021/ol005988g. 
  27. ↑ The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. 11 January 2011. pp. 190–. ISBN 978-3-527-32669-3. https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA190. 
  28. ↑ Thomas Döhler, Dirk Walther, & Michael Werner, US20100298585 (2010 to Heyl Chemisch pharmazeutische Fabrik GmbH and Co KG).
  29. ↑ "17-Alkyl-19-nortestosterones". Journal of the American Chemical Society 79 (5): 1123–1127. March 1957. doi:10.1021/ja01562a028. https://pubs.acs.org/doi/abs/10.1021/ja01562a028. 
  30. ↑ Left Power, et al. CN115286672 (2022 to Huanggang Renfu Pharmaceutical Co ltd).
  31. ↑ "Synthese von 3‐Keto‐4,9‐diensteroiden mit polymeren Reagenzien". Zeitschrift für Chemie 26 (10): 371–371. October 1986. doi:10.1002/zfch.19860261007. https://onlinelibrary.wiley.com/doi/10.1002/zfch.19860261007. 
  32. ↑ Gold, A. M.; Schwenk, E. (1959). "The Reaction of Steroidal p-Quinol Acetates with Benzylamine: Amine Analogs of Estrone and Estradiol1". Journal of the American Chemical Society. 81 (9): 2198–2200. doi:10.1021/ja01518a046.
  33. ↑ Schwenk Erwin & Allen M Gold, U.S. Patent 3,060,205 & U.S. Patent 3,100,209 (1962 & 1963 both to Worcester Foundation for Biomedical Research).
  34. ↑ Zeng Chunling, et al. CN118290508 (2024 to Hunan Xinhexin Biological Medicine Co ltd).





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