Norgestrienone
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| ECHA InfoCard | 100.011.544 |
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| Formula | C20H22O2 |
| Molar mass | 294.387 g/mol g·mol−1 |
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Norgestrienone is a steroidal progestin.[1]
Synthesis
Extension of the conjugation of the 3-ketone in the 19-norprogestins has been found to increase significantly the potency of these agents. A total synthesis has been evolved for preparing one of these agents that was first obtained by partial synthesis.[2] This consists of adding each of the steroid rings sequentially starting add D.
Rxn of the unsaturated ketone Methyl 5-oxo-6-heptenoate[6][7][8] (1), with 2-methylcyclopentane-1,2-dione[9][10] (2) in a Robinson annelation (conjugate addition followed by aldol cyclization]]) affords the C/D fragment 3. This is then saponified and resolved into its optical isomers. Reduction of the S isomer proceeds at the α face opposite the angular methyl group, as in the steroids, to establish in one step the stereochemistry at 8 and 13. The 17-ketone is the converted to the 17β benzoate (4) in several steps and the keto acid converted to the enol lactone (5). Rxn of 5 with the Grignard reagent from 6. affords after deketalization of the diketone, 7. (This last presumably proceeeds by addn of the Grignard to the lactone carbonyl, followed by opening to a 1,5-diketone and then cyclization.) Treatment of the tricyclic diketone 7, with pyrrolidine affords the tetracyclic steroid skeleton as the enamine, 8. Exposure of this last to weak acid results in the hydrolysis of the enamine to the ketone (9). This is then converted to triene 10 with DDQ. (An alternate procedure consists in forming the 11 hydroxy-4,9-diene by oxidation of the diene with molecular oxygen in the presence of triethylamine followed by reduction of the intermediate hydroperoxide; dehydration of the alcohol affords the triene.) The triene is then oxidized to the 3,7-diketone. This compound regioselectively forms a cyanohydrin at 17 (11); the 3 ketone is then protected as its oxime and the cyanohydrin is removed with mild base (12) and the resulting ketone ethynylated at 17 (13). Removal of the oxime affords norgestatriene (14).[3]
See also
References
- ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 720075, please use {{cite journal}} with
|pmid=720075instead. - ^ a b R. Joly, J. Warnant, J. Jolly, and J. Mathieu, Comp. Rend.,258, 5669 (1964).
- ^ a b L. Velluz, G. Nomine, R. Bucourt, and J. Mahieu, Comp. Rend.,257, 569 (1963).
- ^ Nominé et al., Compt. Rend. 260, 4545 (1965)
- ^ FR M3060 and NL 6517141 (1965 and 1966, both Roussel Uclaf), C.A. 63, 8449b (1965) and 65, 15470b (1966).
- ^ Template:Cite DOI
- ^ Template:Cite DOI
- ^ U.S. patent 5,659,070
- ^ Template:Cite DOI
- ^ Template:Cite DOI
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