Chemistry:Mecigestone

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Mecigestone, also known as pentarane B, as well as 6α-methyl-16α,17α-cyclohexanoprogesterone, 6α-methylcyclohexano[1',2';16,17]pregn-4-ene-3,20-dione, or 17α-acetyl-6α-methyl-16β,24-cyclo-21-norchol-4-en-3-one, is a steroidal progestin that was developed by the Zelinskii Institute of Organic Chemistry of the Russian Academy of Sciences and has been proposed for clinical use as a progestogen but has not been marketed.[1][2][3][4][5] It is the 6α-methylated analogue of pentarane A, which is also known as D'6-pentarane or pregna-D'6-pentarane.[5]

Synthesis

The synthesis has been reported:[6] Patent:[7] Precursor:[8] Micronization technology:[9]

  • The Diels-Alder reaction of 16-DPA [979-02-2] (1) with butadiene gives PC99565806 (2). It is important to recognize that for mecigestone the stereochemistry about the E-ring is cis and not trans. The trans isomer is PC99565808.
  • Ex 1: Epoxidation of the olefin with ethereal Monoperphthalic acid [2311-91-3] occurs to give (3). A search of the pubchem registry only gave the trans configuration about the E-ring (PC11873237), and not the expected cis stereochemistry.
  • The reaction with methyl magnesium iodide occurs with a regioselectivity to the 6 position from the beta face. Saponification of the acetate ester also occurs during the work-up to give (4).
  • The Jones oxidation leads to the enone of the finished product. Epimerization of the beta-methyl group also occurred during this step. Thus, completing the synthesis of mecigestone (5).

See also

References

  1. ↑ The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 8–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA8. 
  2. ↑ "Molecular docking and 3D-QSAR of 16α,17α-cycloalkanoprogesterone derivatives as ligands of the progesterone receptor". Biochemistry (Moscow) Supplement Series B 8 (2): 168–176. 2014. doi:10.1134/S1990750814020048. ISSN 1990-7508. 
  3. ↑ "Pregna-D'-pentaranes - a new class of active gestagenes". Journal of Steroid Biochemistry 16 (1): 61–67. January 1982. doi:10.1016/0022-4731(82)90144-3. PMID 7062740. 
  4. ↑ "Preparation and Bioavailability Evaluation of Micronized Steroidal Mecigestone Drug Substance". Pharmaceutical Chemistry Journal 49 (10): 706–710. 2016. doi:10.1007/s11094-016-1357-6. ISSN 0091-150X. 
  5. ↑ 5.0 5.1 "Interaction of cycloalkanoprogesterones with mammalian progesterone receptor: binding of pregna-D'-pentaranes in the calf uterine cytosol". Molecular and Cellular Biochemistry 125 (2): 153–161. August 1993. doi:10.1007/BF00936444. PMID 8283970. 
  6. ↑ "Biological activity of transformed steroids XV. Synthesis and hormonal activity of 6-methyl-substituted 16α, 17α-cyclohexanoprogesterones". Pharmaceutical Chemistry Journal 14 (9): 632–635. September 1980. doi:10.1007/BF01156378. https://link.springer.com/10.1007/BF01156378. 
  7. ↑ , GB1427645 (1976 to Inst Orch Khim); CA, 85, 21727
  8. ↑ "Synthesis of 6-methylidene-16α,17α-cyclohexapregn-4-ene-3,20-dione". Russian Chemical Bulletin 63 (9): 2064–2066. September 2014. doi:10.1007/s11172-014-0701-9. http://link.springer.com/10.1007/s11172-014-0701-9. 
  9. ↑ "Preparation and Bioavailability Evaluation of Micronized Steroidal Mecigestone Drug Substance". Pharmaceutical Chemistry Journal 49 (10): 706–710. January 2016. doi:10.1007/s11094-016-1357-6. https://link.springer.com/10.1007/s11094-016-1357-6. 



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