Description
Quinestrol is a synthetic estrogen that is effective in hormone replacement therapy. It is a 3-
cyclopentyl ether of ethynyl estradiol. After gastrointestinal absorption, it is stored in adipose tissue, where it is slowly released and metabolized in the liver to its active form, ethinyl estradiol. Quinestrol has found limited use in suppressing lactation in postpartum women and, in combination with synthetic progestogens, as contraceptive therapy, although additional studies are needed for both applications.
Synthesis
The general procedure for the synthesis of (8R,9S,13S,14S,17R)-3-(cyclopentyloxy)-17-ethynyl-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-ol using nilestrol impurity 1 and trimethylsilylacetylene was carried out as follows: firstly, a mixture of 1x and 1x was prepared according to literature methods from 19-hydroxy androst-4-ene-3,17-dione to prepare a mixture of 1 and 1x in 80% overall yield. A solution of the 1-mixture (2.04 g, 6.0 mmol), tricyclopentyl orthoformate (8.04 g, 30 mmol) and TfOH (552 μL, 6.0 mmol) in cyclopentanol (60 mL) was stirred for 2 h at 100 °C under inert atmosphere. After completion of the reaction, the reaction was quenched with saturated NaHCO3 solution. The organic solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and washed with brine. The organic phase was dried over Na2SO4, concentrated under reduced pressure and separated by silica gel column chromatography to give the 2b-mixture as a white solid (1.63 g). Next, Raney Ni (1.6 g) was washed several times with dry THF under inert atmosphere. A solution of anhydrous THF (180 mL) of the 2b-mixture (1.63 g) was added to Raney Ni. The suspension was stirred at room temperature and the progress of the reaction was monitored by HPLC. After completion of the reaction (1.5 h), the suspension was filtered. The filtrate was concentrated and separated by silica gel column chromatography to afford estrone 3-cyclopentyl ether (2b) as a white solid (1.62 g, 79% overall yield). Subsequently, n-BuLi (1.2 mL, 3.0 mmol, 2.5 N) was added to a THF (2 mL) solution of ethynyltrimethylsilane (424 μL, 3.0 mmol) under an inert atmosphere at -20 °C. After 0.5 h, a THF (4 mL) solution of ketone 2b (338 mg, 1.0 mmol) was added to a lithium acetate solution at -20 °C After 1 h, methanol (6 mL) and KOH (224 mg, 4 mmol) were added to the mixture and stirred at room temperature for 0.5 h. The reaction was subsequently quenched with 2N hydrochloric acid. The organic solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and washed with saturated NaHCO3 and brine. The organic phase was dried over Na2SO4, concentrated under reduced pressure and separated by silica gel column chromatography to give the target product as a white solid (340 mg, 93%). The melting point of the product was 94-96 °C; [α]D23.4 = +11.3 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8.6 Hz, 1H), 6.68 (dd, J=8.5,2.3 Hz, 1H), 6.61 (d, J=2.7 Hz, 1H), 4.74-4.70 ( m, 1H), 2.91-2.79 (m, 2H), 2.61 (s, 1H), 0.89 (s, 3H); 13C NMR (101MHz, CDCl3) δ155.9,137.8,132.0,126.2,115.5,112.9,87.5,79.9,79.0,74.0,49.4,47.1 ,43.5,39.4,38.9,32.9,32.7,29.8,27.3,26.3,24.0,22.8,12.7; HRMS (ESI) calculated value of C25H33O2[M+H]+: 365.2402, measured value 365.2472.
References
[1]. baumgardner sb, condrea h, daane ta, et al. replacement estrogen therapy for menopausal vasomotor flushes. comparison of quinestrol and conjugated estrogens. obstet gynecol. 1978 apr;51(4):445-52.
[2]. skouby, s.o. criteria for the selection of an optimal estrogen replacement. gynecological endocrinology 15, 60-67 (2001).
[3]. li j, chen f, li c,et al. quinestrol induces spermatogenic apoptosis in vivo via increasing pro-apoptotic proteins in adult male mice. tissue cell. 2014 oct;46(5):318-25.
[4]. li j, chen f, chen y, et al. mitochondrial- and fas-l-mediated pathways involved in quinestrol induced spermatogenic apoptosis in adult rat testes. toxicol mech methods. 2014 dec;24(9):609-15.
