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Synthetic method of bazedoxifene and analogues thereof

A synthesis method and technology of bazedoxifene, which are applied in the field of synthesis of bazedoxifene and its analogs, can solve the problems of difficult control of substitution reaction, increase the difficulty of processing, etc., and achieve the advantages of large-scale testing and reduction of reaction steps. , the effect of reducing the cost of synthesis

Active Publication Date: 2020-12-22
FUJIAN INST OF RES ON THE STRUCTURE OF MATTER CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The limitation of this synthetic route is reflected in: the substitution reaction of hexamethyleneimine to 1,2-dibromoethane is difficult to control, and the reaction is easy to obtain a mixture of monosubstituted products and disubstituted products, which improves the efficiency of post-reaction treatment. difficulty
[0017] In summary, the existing synthetic route of bazedoxifene has certain limitations, therefore, it is necessary to develop an efficient and easy-to-operate synthetic route to meet the synthetic needs of bazedoxifene

Method used

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  • Synthetic method of bazedoxifene and analogues thereof
  • Synthetic method of bazedoxifene and analogues thereof
  • Synthetic method of bazedoxifene and analogues thereof

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Experimental program
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preparation example Construction

[0061] The preparation method of the present invention will be further described in detail in conjunction with specific examples below. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

[0062] The experimental methods used in the following examples are conventional methods unless otherwise specified; the reagents and materials used in the following examples can be obtained from commercial sources unless otherwise specified.

Embodiment 1

[0064] N-benzyl substituted aniline compound 30 (0.1mmol), methylphenyl alkyne compound 31 (0.15mmol), dichloro(pentamethylcyclopentadienyl) rhodium (trivalent) dimer (2.5 mol%, 0.0016g), AgSbF 6 (10mol%, 0.0035g), pivalic acid (50mol%, 0.0051g), nitrosoisoamyl ester (0.1mmol, 20uL), DCM (1.0mL). 90°C, 24h. After the reaction, it was cooled to room temperature, filtered, rotary evaporated, and used for column chromatography to obtain bazedoxifene precursor compound 32 (47%, purity greater than 95%) as a yellow solid.

[0065]

[0066] Compound 32: 1 H NMR (400MHz, CDCl 3 ): δ7.50(d, J=7.2Hz, 2H), 7.46(d, J=6.6Hz, 2H), 7.44–7.32(m, 6H), 7.24(d, J=8.6Hz, 2H), 7.15 (d, J=2.4Hz, 1H), 7.07(d, J=8.8Hz, 1H), 7.02(d, J=8.6Hz, 2H), 6.93–6.84(m, 3H), 6.77(d, J= 8.7Hz, 2H), 5.14(s, 2H), 5.13(s, 2H), 5.10(s, 2H), 4.17(t, J=5.9Hz, 2H), 3.78(t, J=5.9Hz, 2H) ,2.25(s,3H). 13 C NMR (100MHz, CDCl 3 ): δ158.7, 157.3, 153.4, 138.5, 137.9, 136.9, 132.2, 131.8, 131.6, 129.2, 128.8, 128.7...

Embodiment 2

[0068] Bazedoxifene precursor compound 32 (0.2mmol) and hexamethyleneimine 16 (0.4mmol) were refluxed in an acetonitrile solution, a nucleophilic substitution reaction occurred to generate bazedoxifene precursor compound 7 (92%);

[0069]

[0070] Compound 7: 1 H NMR (400MHz, CDCl 3 ): δ7.48-7.46(m,4H),7.45–7.37(m,4H),7.37–7.32(m,2H),7.30(d,J=8.8Hz,2H),7.21(d,J=8.8 Hz, 1H), 7.13(m, 3H), 6.81(dd, J=8.8, 2.4Hz, 1H), 6.74(s, 4H), 5.16(s, 2H), 5.15(s, 2H), 5.12(s ,2H),3.91(t,J=6.1Hz,2H),2.77(t,J=6.0Hz,2H),2.63(m,4H),2.16(s,3H),1.58–1.46(m,8H) . 13 C NMR (100MHz, CDCl 3 ): δ158.1,156.6,152.6,137.8,136.9,131.5,131.3,128.8,128.5,128.4,128.0,127.9,127.7,127.6,127.4,123.8,111.9,111.2,105.6,102.16,6,499. 46.1, 3.10, 9.5. HRMS (ESI) theoretical value C 44 h 47 N 2 o 3 ([M+H]+): 651.3581, measured value: 651.3582.

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Abstract

The invention provides a synthetic method of bazedoxifene and analogues thereof; a simple and easily available initial raw material is used as the starting end of a synthetic route, an N-substituted aniline compound with guiding groups such as -Ac, -NO and -NH2 on amino groups does not need to be prepared in advance, and an oxidant used in the reaction process has dual effects, not only has an oxidation effect,NO guide groups can be formed in situ, excessive metal compounds are prevented from being used as oxidizing agents, the synthesis cost and the post-treatment difficulty are reduced, andthe requirements of green chemistry are met; the reaction temperature is relatively mild, large-scale tests are facilitated, and the obtained product is high in purity. The synthetic method of the bazedoxifene and the analogues thereof is easy to operate, good in atom economy, high in selectivity, environmentally friendly, novel and practical, the method is suitable for structural synthesis with the core of bazedoxifene, and research and development of lead compounds are facilitated.

Description

technical field [0001] The invention belongs to the field of organic and pharmaceutical synthetic chemistry, and specifically relates to a synthesis method of bazedoxifene and its analogues. Background technique [0002] The chemical name of Bazedoxifene is 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3- Methyl-1H-indole-5ol, its salt formed by reacting with acetic acid, bazedoxifene acetate, is a selective estrogen receptor modulator, which can be used to prevent and treat postmenopausal osteoporosis, Thereby reducing the risk of vertebral fractures in menopausal women, and at the same time, it has potential value in the treatment of breast cancer. The drug was developed by Wyeth in 1997 and later transferred to Pfizer. In April 2009, the drug was approved by the European Food and Drug Administration (EMEA) and launched in Spain and Italy (trade name: Conbriza); in July 2010, the drug was launched in Japan; in 2013, the drug was launched in the United States ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07D209/12Y02P20/55
Inventor 尚亚平黄世俊娄鑫涂桦张敏苏伟平
Owner FUJIAN INST OF RES ON THE STRUCTURE OF MATTER CHINESE ACAD OF SCI
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