Preparation of 2-Isopropyloestradiol

Abstract

A simple route to 2-alkyloestradiols is demonstrated by the conversion of oestradiol into its 2-isopropyl derivative.2-Alkyl-substituted oestradiols are known, and some of their biological activities have beenThe routes to these compounds, however, are limited. Thus 2-dialkylaminomethyloestradiols can be prepared by the Mannich reaction on oestradiol,' and nucleophilic substitution reactions at the benzylic position can lead to simple a n a 1 0~u e s .~~~ Meanwhile 2-allyloestradiol can be obtained from the Claisen rearrangement of the 3-ally1 ether4 or Cope rearrangement of a 19-alkenyl 1,4-dienone.~ None of these reactions easily lead to branched-alkyl 2-substituted oestradiols.We required 2-isopropyloestradiol (1) for other studies, and found that this compound could be made readily from the known 2-acetyloestradiol (2).6 Thus treatment of oestradiol with aluminium chloride/acetyl chloride afforded 2acetyloestradiol in 50-55% yield; no trace of 4-acetyloestradiol was detected. Reaction of 2-acetyloestradiol (2) with 2-chloroethyl methyl ether in the presence of potassium carbonate in dimethylformamide afforded 2-acetylestra-1,3,5(10)-triene-3,17P-diol 3methoxyethyl ether (3) in 80% yield. This protected oestradiol was then treated with methylmagnesium iodide at room temperature, and the benzylic alcohol (4) produced was treated with hydrogen in the presence of palladium/charcoal. The 2-isopropyl derivative (5) finally gave 2-isopropylestra-1,3,5(10)-triene-3,17~-diol(1) on treatment with boron tribromide. The overall yield of the diol (1) from the methoxyethyl ether (3) was 10%. Kaneko, H., Hashimoto, M., and Kobayashi, A., Chem. Pharm. Bull., 1964, 12, 196. Kaneko, H., Hashimoto, M., and Kawase, M., Japan. 982('67) (Chem. Abstr., l967,67,22086t).

3,17-Disubstituted 2-Alkylestra-1,3,5(10)-trien-3-ol Derivatives: Synthesis, In Vitro and In Vivo Anticancer Activity

“…The mixture was stirred under a H 2 atmosphere for 24 h at room temperature before the catalyst was filtered off and the solvent was removed under reduced pressure. The solid residue was recrystallized from CHCl 3 /hexane to give 21 as fine colorless needles (2.23 g, 89%): mp 149−152 °C (lit . mp 103−105 °C); 1 H NMR (CDCl 3 ) δ 0.78 (s, 3H), 1.23 (d, J = 6.7 Hz, 3H), 1.25 (d, J = 6.7 Hz, 3H), 1.26−1.58 (m, 7H), 1.60 (s, 1H), 1.65−1.74 (m, 1H), 1.82−1.88 (m, 1H), 1.93−1.99 (m, 1H), 2.07−2.23 (m, 2H), 2.31−2.40 (m, 1H), 2.70−2.86 (m, 2H), 3.18 (hpt, J = 6.7 Hz, 1H), 3.72−3.80 (m, 1H), 5.04 (s, 1H), 6.48 (s, 1H), 7.12 (s, 1H); MS (APCI−) m / z 313.5 (100, [M − H] - ); HRMS (ES−) calcd for C 21 H 29 O 2 [M − H] - 313.2173, found 313.2182.…”

“…The product was extracted with EtOAc (2 × 50 mL), and the combined organic layers were washed with water (50 mL) and brine (50 mL) and dried (Na 2 SO 4 ). The solvents were removed under reduced pressure, and the solid white residue was recrystallized from EtOAc/hexane to give 22 as fine colorless needles (2.98 g, 90%): mp 155−158 °C (lit . mp 160−162 °C); 1 H NMR (CDCl 3 ) δ 0.76 (s, 3H), 1.12−1.51 (m, 7H), 1.66 (s, 3H), 1.68 (s, 3H), 1.69−1.73 (m, 1H), 1.80−1.89 (m, 1H), 1.90−1.98 (m, 1H), 2.05 2.19 (m, 2H), 2.23−2.32 (m, 1H), 2.50 (s, 1H), 2.75−2.85 (m, 2H), 3.66−3.75 (m, 1H), 6.60 (s, 1H), 6.98 (s, 1H), 8.70 (s, 1H); MS (APCI−) m / z 329.4 (100, [M − H] - ); HRMS (ES−) calcd for C 21 H 29 O 3 [M − H] - 329.2122, found 329.2129.…”

“…In order to obtain 2-isopropylestradiol ( 21 ), the 2-acetyl compound 15 was reacted with 6 equivalents of methylmagnesium bromide to give the trihydroxy compound 22 . The benzylic hydroxyl group of 22 was removed by catalytic hydrogenation to afford the target 2-isopropyl estradiol ( 21 ) in good yield, as described by Pert and Ridley 1 Syntheses of 2-Alkylestradiol Derivatives a a Reagents and conditions: (a) N,N,N ‘ , N ‘-tetramethyldiaminomethane, (CHO) n , PhMe, EtOH, reflux; (b) (1) MeI, Et 2 O; (2) NaBH 4 , EtOH; (c) t-BuOH, BF 3 ·Et 2 O, CHCl 3 ; (d) NaBH 4 , MeOH, 0 °C; (e) AcCl or (RC(O)) 2 O, AlCl 3 , DCM, 0 °C; (f) AlCl 3 , NMe 3 ·HCl, DCM, reflux; (g) 10% Pd/C, H 2 , MeOH, THF; (h) 6 equiv MeMgCl, THF, 15 ; (i) NaOH, MeOH, H 2 O. …”

Regioselective monoalkylation of 17β-estradiol for the synthesis of cytotoxic estrogens

“…This one-pot protocol is easy to conduct compared to the multi-step protocols previously reported [15,36,37,42]. One-pot protocols offer many advantages, such as avoiding isolation, handling and chromatography of intermediates leading to timecost benefits.…”

Steroids: reactions and partial synthesis

“…~~ Additional products formed with anhydrous toluene-p-sulphonic acid include some which are isomeric at C-20 as well as C-10, and have a spiro C/D ring junction, e.g. (184) and (185). Backbone rearrangement of des-A-cholestene (1 86) and congeners yields products (187) isomeric at C-20 with the methyl group at C-10 in the more stable equatorial…”