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Estrone methyl ether

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical 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
  • (8R,9S,13S,14S)-3-methoxy-13-methyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-one
CAS Number
PubChemCID
ChemSpider
UNII
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.015.104Edit this at Wikidata
Chemical and physical data
FormulaC19H24O2
Molar mass284.399 g·mol−1
3D model (JSmol)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CCC2=O)CCC4=C3C=CC(=C4)OC
  • InChI=1S/C19H24O2/c1-19-10-9-15-14-6-4-13(21-2)11-12(14)3-5-16(15)17(19)7-8-18(19)20/h4,6,11,15-17H,3,5,7-10H2,1-2H3/t15-,16-,17+,19+/m1/s1
  • Key:BCWWDWHFBMPLFQ-VXNCWWDNSA-N

Estrone methyl ether, orestrone 3-methyl ether, is asyntheticestrogen andestrogen ether – specifically, the C3methylether ofestrone – which was never marketed.[1][2]

Chemistry

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Synthesis

[edit]

Despite recent advances in the total synthesis, the majority of estrogen is manufactured semi-synthetically e.g. fromboldione precursor.

A couple of enantioselective routes were disclosed byE.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]

The starting material in the above schematic was named "Dane’s diene" [2811-50-9] (1) afterElisabeth Dane.[8][9][10] The first step is aDiels-Alder reaction with 2-Methyl-2-cyclopenten-1-one [1120-73-6] (2) to givePC12811167 (3). The next step yieldsPC11119485 (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 thecatalyst is shown underneath.

Theracemic version was also reported:[11]

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

The starting material is called6-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 compoundsLasofoxifene &Nafoxidine. It can be rearranged to 6-methoxy-2-tetralone [2472-22-2],[19] one known application is in the synthesis ofTolnapersine.

Smith & Hughes work is also worthy of consideration {This has been covered on thenorgestrel andnorboletone 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

[edit]

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 toNorgesterone.
  2. Dienogest.[28]
  3. Norethandrolone[29] For the purposes of comparison, see the related compoundEthylmetrienone [848-04-4], which is totally synthetic but finds use in the synthesis ofNorboletone. N.B. although Birch reduction of Estrone methyl ether was the original method of synthesizingNorethandrolone, 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 calledBolandione.
  4. The reduction of the ketone in estrone methyl ether givesestradiol methyl ether. This in-turn, was used in the synthesis ofNoretynodrel. Another use is in the synthesis of 11-Keto-3-methoxy-estra-1,3,5(10),8-tetraen-17beta-ol [17401-32-0].[31] This compound in-turn is of interest because it is the starting material used in the synthesis of8β-VE2.[32]
  5. The Birch reduction of Estrone methyl ether givesNandrolone since the 17-keto group is reduced concomitantly during this step. Back-oxidation occurs to giveBolandione; this in-turn can be used to makeNorethisterone &Allylestrenol.
  6. With a suitable demethylating agent can be used to makeestrone.
  7. Clomestrone
  8. Prenortestosterone [1089-78-7] (see under nandrolone synthesis) can be brominated. 2x dehydrohalogenation step then leads todienolone.[33]
  9. Epimestrol
  10. Ethylestrenol
  11. TheNandrolone also finds use in the synthesis ofmibolerone,LS-1727,Cingestol,Lynoestrenol, Estradiol-3-amine [10427-24-4][34][35] & as the starting material thatfulvestrant is made from.[36] &tibolone &trestolone.
  12. Estr-5(10)-ene-3,17-dione [3962-66-1] can be used to makePlomestane, or halogenation, double dehydrohalogenation can lead todienedione.
  13. Estrone methyl ether was employed in the11β-Methyl-19-nortestosterone patent,[37] e.g. for 11β-Fluoro-4-estren-17-ol-3-one (PC23396842). This in-turn can be aromatized to 11beta-fluoro-estradiol.[38] {Although it is facile to get from Estrone methyl ether to 11beta-fluoro-estradiol w/o passing through 11β-Fluoro-4-estren-17-ol-3-one.}

See also

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References

[edit]
  1. ^Elks J (14 November 2014).The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 900–.ISBN 978-1-4757-2085-3.
  2. ^Milne GW (8 May 2018).Drugs: Synonyms and Properties: Synonyms and Properties. Taylor & Francis. pp. 1406–.ISBN 978-1-351-78989-9.
  3. ^"Synthesis of Estrone Methyl Ether".Synfacts.2009 (02):0117–0117. 22 January 2009.doi:10.1055/s-0028-1087603.
  4. ^Canales, E., Corey, E. J. (7 August 2008)."Highly Enantioselective [4 + 2] Cycloaddition Reactions Catalyzed by a Chiral N -Methyl-oxazaborolidinium Cation".Organic Letters.10 (15):3271–3273.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.
  6. ^"Synthesis of Estrone Methyl Ether".Synfacts.2008 (01):0003–0003. 18 December 2007.doi:10.1055/s-2007-991492.
  7. ^Yeung, Chein, R.-J., Corey, E. J. (1 August 2007)."Conversion of Torgov's Synthesis of Estrone into a Highly Enantioselective and Efficient Process".Journal of the American Chemical Society.129 (34):10346–10347.doi:10.1021/ja0742434.
  8. ^Dane, E. (4 November 1939)."Synthesen in der Reihe der Steroide".Angewandte Chemie.52 (44):655–659.doi:10.1002/ange.19390524402.
  9. ^Dane, E., Höss, O., Eder, K., Schmitt, J., Schön, O. (January 1938)."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.doi:10.1002/jlac.19385360117.
  10. ^Dane, E., Schmitt, J. (January 1938)."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.doi:10.1002/jlac.19385360118.
  11. ^Quinkert, G., Del Grosso, M., Bucher, A., Bats, J. W., Dürner, G. (July 1991)."E. Dane's route to estrone revisited".Tetrahedron Letters.32 (28):3357–3360.doi:10.1016/S0040-4039(00)92705-9.
  12. ^Ananchenko, S. N., Torgov, I. V. (January 1963)."New syntheses of estrone, d,1-8-iso-oestrone and d,1-19-nortestosterone".Tetrahedron Letters.4 (23):1553–1558.doi:10.1016/S0040-4039(01)90870-6. Retrieved24 January 2026.
  13. ^"Torgov Cyclization".Synfacts.15 (12): 1443. December 2019.doi:10.1055/s-0039-1691123.
  14. ^Zhdanov, R. I., Corey, E. J. (September 2009)."In memorium Igor Torgov: Torgov's way to total steroid synthesis".Steroids.74 (9):723–724.doi:10.1016/j.steroids.2009.03.004.
  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. ^Thomas, D. G., Nathan, A. H. (January 1948)."6-Methoxy-1-tetralone".Journal of the American Chemical Society.70 (1):331–334.doi:10.1021/ja01181a103.
  18. ^Papa, Domenick. (September 1949)."6-Methoxy-1-tetralone".Journal of the American Chemical Society.71 (9):3246–3247.doi:10.1021/ja01177a515.
  19. ^Banerjee, A. K., Jossblerys, D., Bedoya, L., Arrieche, D. A., Poon, P. S. (19 February 2018)."A concise approach for the synthesis of 6-methoxy-2-tetralone".MOJ Bioorganic & Organic Chemistry.2 (1).doi:10.15406/mojboc.2018.02.00052.
  20. ^Lednicer, D. (2011).Steroid chemistry at a glance. Chemistry at a glance (1. publ ed.). Wiley.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. ^Prévost, S., Dupré, N., Leutzsch, M., Wang, Q., Wakchaure, V., List, B. (11 August 2014)."Catalytic Asymmetric Torgov Cyclization: A Concise Total Synthesis of (+)‐Estrone".Angewandte Chemie International Edition.53 (33):8770–8773.doi:10.1002/anie.201404909.
  25. ^Weimar, M., Dürner, G., Bats, J. W., Göbel, M. W. (16 April 2010)."Enantioselective Synthesis of (+)-Estrone Exploiting a Hydrogen Bond-Promoted Diels−Alder Reaction".The Journal of Organic Chemistry.75 (8):2718–2721.doi:10.1021/jo100053j.
  26. ^Tanaka, K., Nakashima, H., Taniguchi, T., Ogasawara, K. (1 June 2000)."A Concise Route to (+)-Estrone".Organic Letters.2 (13):1915–1917.doi:10.1021/ol005988g.
  27. ^Ravina E (11 January 2011).The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 190–.ISBN 978-3-527-32669-3.
  28. ^Thomas Döhler, Dirk Walther, & Michael Werner, US20100298585 (2010 to Heyl Chemisch pharmazeutische Fabrik GmbH and Co KG).
  29. ^Colton, F. B., Nysted, L. N., Riegel, B., Raymond, A. L. (March 1957)."17-Alkyl-19-nortestosterones".Journal of the American Chemical Society.79 (5):1123–1127.doi:10.1021/ja01562a028.
  30. ^Left Power, et al. CN115286672 (2022 to Huanggang Renfu Pharmaceutical Co ltd).
  31. ^Dwivedy, I., Gupta, A., Grover, A., Srivastava, V., Singh, M. M., Ray, S. (July 2008)."Synthesis and in vivo evaluation of 11-substituted estradiol derivatives as anti-implantation agents".Bioorganic & Medicinal Chemistry Letters.18 (14):4102–4105.doi:10.1016/j.bmcl.2008.05.093.
  32. ^Olaf Peters, et al. WO2001077139 (to Bayer Pharma AG).
  33. ^Menzenbach, B., Hübner, M. (October 1986)."Synthese von 3‐Keto‐4,9‐diensteroiden mit polymeren Reagenzien".Zeitschrift für Chemie.26 (10):371–371.doi:10.1002/zfch.19860261007.
  34. ^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.
  35. ^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).
  36. ^Zeng Chunling, et al. CN118290508 (2024 to Hunan Xinhexin Biological Medicine Co ltd).
  37. ^Richard P. Blye & Hyun K. Kim, WO2006083618 (to US Department of Health and Human Services).
  38. ^Alexander Hillisch, et al.U.S. patent 20,050,282,791 (to Bayer Pharma AG).


ERTooltip Estrogen receptor
Agonists
Mixed
(SERMsTooltip Selective estrogen receptor modulators)
Antagonists
GPERTooltip G protein-coupled estrogen receptor
Agonists
Antagonists
Unknown


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