Synthesizing compound of 1, 1, 2 triaromatic radical-1, 3 butadiene kind by suzuki-miyaura coupling reaction

A technology for butadiene and compounds, which is applied in the field of synthesizing anti-breast cancer natural products, can solve the problems of complex operation, not easy operation, long route, etc.

Inactive Publication Date: 2005-01-05
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Abstract
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  • Application Information

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Problems solved by technology

But as far as we know, all the preparation methods for Tamoxifen and its analogues reported in the literature have relatively long routes, and the conditions of the reaction are all relatively harsh and not easy to operate.
[0006] Not long ago, Itami and his collaborators reported a case of synthesis of Tamoxifen and its analogous four-substituted ethylene (Scheme 1) (Itami, K.; Kamei, T.; Yoshida, J.-I.J.Am .Chem.Soc.2003, 125, 14670.), as shown in Scheme 1, their method requires three-step operations, including one-step carbometalation reaction and two-step metal-catalyzed coupling reaction, and their reaction involves relatively Multi-step anhydrous or oxygen-free and other harsh conditions, so they still have not solved the problems of long preparation routes and complicated operations encountered by the predecessors

Method used

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  • Synthesizing compound of 1, 1, 2 triaromatic radical-1, 3 butadiene kind by suzuki-miyaura coupling reaction
  • Synthesizing compound of 1, 1, 2 triaromatic radical-1, 3 butadiene kind by suzuki-miyaura coupling reaction
  • Synthesizing compound of 1, 1, 2 triaromatic radical-1, 3 butadiene kind by suzuki-miyaura coupling reaction

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The general operation steps of the reaction

[0074] Under argon protection, add diiodide 1 (0.25mmol), aryl boronic acid 2 (0.30mmol), catalyst Pd(PPh 3 ) 4 (0.025mmol), tetrabutylammonium chloride (TBAC) (0.25mmol) and base KOH (1.2mmol), pumped three times after the addition was complete. Cool the system to -78°C with a dry ice-acetone bath, then add tetrahydrofuran and water (1.0 mL / 0.3 mL), and ventilate three times. Heating, stirring, reflux, and maintain reflux reaction for 48 hours. The reaction solution was diluted with dichloromethane and dried over anhydrous sodium sulfate. Spin dry, flash column chromatography to get the corresponding product.

[0075] Product 4. Colorless liquid, 1 H NMR (CDCl 3 , 300MHz, TMS) δ5.33 (dd, 1H, J=0.9, 10.2Hz), 5.65 (dd, 1H, J=0.9, 15.6Hz), 6.13 (dd, 1H, J=10.2, 15.6Hz), 7.16 -7.37(m, 10H, Ar). 13 C NMR (CDCl 3 , 75MHz, TMS) δ105.91, 124.52, 127.61, 127.70, 128.05, 128.19, 129.11, 129.72, 136.84,...

Embodiment 2

[0092] The shortest steps for the synthesis of (E,Z)-Tamoxifen from product 3ba:

[0093] Scheme 1 Synthesis of (E, Z)-Tamoxifen from 3ba.

[0094]

[0095] A. Restoration steps:

[0096] 3ba (0.44mmol) was dissolved in 99% ethanol (0.5mL) and dichloromethane (2.0mL), then added 85% hydrazine hydrate (3.6mmol), cooled to -60°C in a dry ice-acetone bath, and stirred within 10 minutes Additional 35% hydrogen peroxide (2.6 mmol) was added. After the addition was complete, the system was allowed to warm to room temperature naturally and stirred at room temperature for 24 hours. The reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium sulfite, and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, and spin-dried under reduced pressure. Crude product A for 1 Confirmed by H NMR, it was directly used in the next reaction without further treatment.

[00...

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Abstract

The invention relates to a 1, 1, 2-triaryl-1, 3-butadiene compound one-step synthesized from raw materials simple and easy to obtain by applying classical Suzuki-Miyaura coupling reaction and can also obtain anticancer substance Tamoxifen by using simple and known converting steps. In structure, the obtained compound contains a triaryl tetra-substituted ethylene unit similar to Tamoxifen, therefore it possibly has a certain clinical medicinal application value and has the value of screening and applying anticancer drugs of a kind.

Description

technical field [0001] The present invention utilizes the ring-opening product of methylene cyclopropane 1,1-diaryl-2,4-diiodo-1-butene and the Suzuki-Miyaura coupling reaction of arylboronic acid to synthesize 1, The method of 1,2-triaryl-1,3-butadiene, which is a convenient method for synthesizing the anti-breast cancer natural product Tamoxifen (Figure 1) and its skeleton. Background technique [0002] Figure 1 Structure of Tamoxifen [0003] [0004] Estrogen-containing antagonists are found in several steroidal and non-steroidal compounds (Mukku, V.R.; Kirkland, J.L.; Stancel, G.M. Trends Pharmacol. Sci. 1981, 2, 98.). The most notable of these non-steroidal compounds are the triarylethylenes represented by Tamoxifen (Figure 1) (Jordan, V.C.; Dix, C.J.; Naylor, K.E.; Prestwich, G. ; Rowsby, L.J. Toxicol. Environ. Helth. 1978, 4, 363.). The antagonistic properties of Tamoxifen make this compound clinically useful in the treatment of malignancies, especially breast ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C2/00C07C15/16C07C217/60
Inventor 施敏邵黎雄
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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