Tamoxifen derivatives for treatment of neoplastic diseases, especially with high HER2 protein level
A technology of tamoxifen and derivatives, which can be used in antitumor drugs, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., and can solve problems such as secondary toxicity
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Embodiment 1
[0088] Dissolve (9-((tert-butyldimethylsilyl)oxy)nonyl)triphenylphosphonium bromide (634 mg, 1.057 mmol) in anhydrous tetrahydrofuran (THF) (6 ml) and Atmosphere covered and cooled to -78°C. Under argon atmosphere, butyllithium (1.2 ml, 0.9 MTHF solution) was slowly added dropwise to the reaction mixture. The solution was allowed to warm to 0°C, the color changed to deep red, cooled to -78°C again and a solution of the aldehyde of formula III (160mg, 0.430mmol) in anhydrous THF (3ml) was added dropwise. The reaction mixture was then allowed to warm to laboratory temperature and stirred under argon atmosphere for 16 hours. The progress of the reaction was monitored by thin layer chromatography (TLC) in chloroform-methanol mixture (10:1). Then, a saturated solution of ammonium chloride and water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. The solution was filtered and conc...
Embodiment 2
[0093] The silylated derivative of formula 4 (147mg, 2.240mmol) was dissolved in THF (5ml), and then covered with an argon atmosphere and under stirring at a temperature of 0°C, tetrabutylammonium fluoride was added dropwise (TBAF) (260 μl, 1M THF solution). The reaction mixture was then allowed to warm to laboratory temperature and stirred for an additional 6 hours. The progress of the reaction was monitored by TLC in a chloroform-methanol mixture (10:1). Then, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated soda solution and brine and dried over magnesium sulfate. The drying agent was filtered and the solution was concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel using a chloroform / methanol system (0 to 10% methanol gradient) to afford 115 mg (96% yield) of the desired enol of formula 5.
[0094]
[0095] 1 HNMR (500MHz, cdcl3) δ7.43-7.14 (m, 5H)...
Embodiment 3
[0097] The enol derivative of Formula 5 (115 mg, 0.231 mmol) was dissolved in absolute ethanol (6 ml) and covered with an argon atmosphere. 10% Pd / C (10 mg) was added to the mixture and the flask with the reaction suspension was evacuated and covered with a hydrogen atmosphere several times. The reaction mixture was then stirred at laboratory temperature under hydrogen atmosphere for 24 hours. The progress of the reaction was monitored by TLC in a chloroform-methanol mixture (10:1). The mixture was filtered through a pad of celite and rinsed several times with ethanol. Ethanol was evaporated to give 101 mg (87% yield) of the desired alcohol of formula 6 which was used in the next step of the synthesis without any further purification.
[0098]
[0099] 1 HNMR (500MHz, cd3od) δ7.40-7.01 (m, 10H), 6.85 (d, J = 8.1, 2H), 6.68 (d, J = 8.1, 2H), 4.20 (s, 2H), 3.55 (t, J=6.4,2H),3.46(s,2H),2.89(s,6H),2.42(t,J=7.8,2H),1.57-1.48(m,2H),1.38-1.11(m,12H). ESIMS: 500.
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