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Synlett 2004(10): 1838-1840  
DOI: 10.1055/s-2004-829070
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Simple Synthesis of Gestodene from 18-Methyl-4-estren-3,17-dione

Patrizia Ferraboschi*a, Paride Grisentib, Andrea Onofria, Paolo Prestileoa
a Department of Medical Chemistry, Biochemistry and Biotechnology-Università degli Studi di Milano, Via Saldini 50, 20133 Milan, Italy
Fax: +39(02)50316040; e-Mail: Patrizia.Ferraboschi@unimi.it;
b Poli Industria Chimica, Via Volturno 45/48, Quinto de’ Stampi, 20089 Rozzano, Italy
Further Information

Publication History

Received 22 March 2004
Publication Date:
29 June 2004 (online)

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Abstract

A simple synthesis enables us to obtain the progestin, gestodene, in five steps and satisfactory yields from 18-methyl-4-estren-3,17-dione. This was accomplished through the selective protection of the C-3 carbonyl group as a cyclic ketal and the installation of a phenylsulfoxide group at the C-16 position.

Key words

drugs - steroids - sulfoxides - sulfinylation - progestagen

    References

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  • 6 A mixture of Δ1 5- and Δ1 4-derivatives was obtained from the dehydrobromination and it is known that the conversion of the unconjugated ketone to the conjugated one, occurring in course of the acidic removal of 17-ketal, leads to an epimerization at C-14. See: Johnson WS. Johns WF. J. Am. Chem. Soc.  1957,  79:  2005 
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  • 18 Gestodene (17α-ethynyl-18-methyl-4,15-estradien-3-one) (1). A solution of 7 in acetone was treated with 6 N HCl (1.2 equiv) for 45 min at r.t. Neutralization with a sat. NaHCO3 solution, extraction with EtOAc and usual work-up afforded crude product that gave pure 1 (90%) by crystallization (hexane-acetone). DSC (5 °C/min): endothermic peak at 199.75 °C (onset a 198.90 °C). [α]D 20 -187.8 (c 1, CH2Cl2). The other chemical-physical data are in agreement with the reported ones. See: Von Cleve G. Frost E. Hoyer G.-A. Rosenberg D. Seeger A. Arzneim.-Forsch.  1986,  36 (I):  784 
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7

18-Methyl-3,3-(2′,2′-dimethyl-1′,3′-propylenedioxy)-5- and 5 (10)-estren-17-one ( 3).
3-Carbonylic group of compound 2 (5 g, Keifeng, Shanghai) was selectively protected by reaction with 2,2-dimethyl-1,3-propanediol (3 equiv), triethyl-ortho-formate (1.7 equiv) and p-TsOH (0.5% w/w), in CH2Cl2, at 10 °C (3 h), and the title compound was obtained in 90% yield. Mp 90-110 °C. 1H NMR (500 MHz, CDCl3): δ = 0.73 (t, J = 7 Hz, 0.9 H,
18-CH3), 0.75 (t, J = 7 Hz, 2.1 H, 18-CH3), 0.85 (s, 0.9 H, CH3-C), 0.89 (s, 2.1 H, CH3-C), 1.00 (s, 2.1 H, CH3-C), 1.06 (s, 0.9 H, CH3-C), 3.44-3.66 (m, 4 H, CH2O), 5.50 (m, 0.7 H, CH=). IR (1% KBr): 3449.5, 2952.2, 2866.7, 1732.2. Anal. Calcd for C24H36O3: C, 77.38; H, 9.74; O, 12.88. Found: C, 77.45; H, 9.69; O, 12.95.

12

Due to the new stereocenters at the C-16 and SO group, four diastereoisomers were obtained, as shown by TLC (toluene-EtOAc 8:2) analysis.

13

3,3-(2′,2′-Dimethyl-1′,3′-propylenedioxy)-18-methyl-16ξ-phenylsulfoxide-5- and 5(10)-estren-17-one (5).
To a solution of 3 in anhyd THF, t-BuOK (4 equiv) was added. The mixture was kept, under N2 atmosphere, under vigorous stirring at r.t., and after 10 min, methyl benzenesulfinate (Aldrich, 4 equiv) was added; upon disappearance of starting material (2 h), the crude product was recovered by extraction with EtOAc. The combined organic layers were washed with brine and H2O, dried over Na2SO4 and the solvent was removed under reduced pressure. TLC (toluene-EtOAc 8:2) analysis showed a few spots with very similar Rf values (between 0.16 and 0.35). IR (1% KBr): 3449.9, 2954.9, 2868.9, 1735.9, 1129.6, 1106.5, 1093.8, 1048.7 cm-1. MS: m/z = 497 [M + 1], 496 [M+], 371, 370.

14

The 1H NMR spectrum of 5 was very complex due to the presence of four diastereoisomers of a mixture of Δ5 and
Δ5 (10) isomers. Except for the signals due to the 5,6-double bond (two multiplets at δ = 5.38 and 5.44 ppm in a ratio 4:6, respectively), it was not possible to assign any other signals. For analytical purposes, the 18-methyl-16ξ-phenylsulf-oxide-4-estren-3,17-dione was prepared by removal (6 N HCl in acetone) of the 3-cyclic ketal from 5. 1H NMR (500 MHz, CDCl3): δ = 0.63, 0.69, 0.74, 0.75 (4 t, J = 8Hz, in a ratio 0.14:0.11:0.35:0.40, 18-CH3), 3.20 (dd, J = 8.4 and 10 Hz, 0.34 H, CHSO), 3.41 and 3.43 (two overlapped dd, 0.53 H, CHSO), 3.48 (dd, J = 8.4 and 10 Hz, 0.13 H, CHSO), 5.72, 5.73, 5.75 (three m, in a ratio 0.18:0.32:0.50, CH=), 7.27-7.42 (m, 5 H, Ar).

15

We observed a cleaner reaction by employing Et3N instead of the N,N-dimethylaniline reported in the original paper (ref. [11] ).

16

3,3-(2′,2′-Dimethyl-1′,3′-propylenedioxy)-18-methyl-5- and 5(10),15-estradien-17-one (6). A solution of 5 in xylene (20 mL/g substrate) and Et3N (1 mL/g substrate) was kept at 140 °C under N2 atmosphere and the reaction progress was monitored by TLC (toluene-EtOAc 8:2) until the starting material disappeared (2.5 h). After cooling to r.t. the crude product was recovered after addition of toluene, washing of the organic phase with brine and H2O and usual work-up. Purification by silica gel column chromatography (1:25, elution with hexane-EtOAc 9:1) afforded pure 6, in 65% yield from 3. Mp 115-125 °C. 1H NMR (500 MHz, CDCl3): δ = 0.74 (t, J = 8 Hz, 1.2 H, 18-CH3), 0.77 (t, J = 8 Hz, 1.8 H, 18-CH3), 0.86 (s, 1.8 H, CH3-C), 0.90 (s, 1.2 H, CH3-C), 1.01 (s, 1.2 H, CH3-C), 1.08 (s, 1.8 H, CH3-C), 3.40-3.70 (m, 4 H, CH2O), 5.50 (m, 0.4 H, CH=), 5.99 (dd, J = 2.8 and 5.6 Hz 1 H, CH=), 7.47 (d, J = 5.6 Hz, 0.6 H, CH=), 7.54 (d, J = 5.6 Hz, 0.4 H, CH=). IR (1% KBr): 3454.0, 2951.3, 2863.7, 1706.0 cm-1. MS: m/z = 371 [M + 1], 370 [M+], 341.

17

3,3-(2′,2′-Dimethyl-1′,3′-propylenedioxy)-17α-ethynyl-17β-hydroxy-18-methyl-5-and 5(10),15-estradiene (7). To a solution of 6 in anhyd THF (25 mL/g of substrate) the commercially available (Fluka) lithium acetylide-ethylene-diamine complex (4 equiv) was added, at 0 °C and under N2 atmosphere. The mixture was kept at 0 °C (2 h) under stirring. The reaction progress was monitored by TLC (toluene-EtOAc 8:2) until the starting material disappeared. To this mixture, 6 N HCl was added to pH 6 and the mixture was brought to r.t. Extraction with EtOAc and usual work-up afforded 17α-ethynyl derivative 7 (94%). Differential Scanning Calorimetry (DSC, 5 °C/min): two endothermic peaks at 174 °C and 192 °C. 1H NMR (500 MHz, CDCl3):
δ = 0.82 (t, J = 8 Hz, 1.35 H, 18-CH3), 0.85 (s, 1.35 H,
CH3-C), 0.86 (t, J = 8 Hz, 1.65 H, 18-CH3), 0.90 (s, 1.65 H, CH3-C), 1.00 (s, 1.65 H, CH3-C), 1.06 (s, 1.35 H, CH3-C), 2.60 (s, 0.45 H, H-21), 2.61 (s, 0.55 H, H-21), 3.40-3.70 (m, 4 H, CH2O), 5.46 (m, 0.55 H, CH=), 5.67 (dd, J = 3.5 and 5.6 Hz, 1 H, CH=), 5.90 (dd, J = 2.0 and 6.0 Hz, 0.55 H, CH=), 5.99 (dd, J = 2.0 and 6.0 Hz, 0.45 H, CH=).