Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound

A technology of cyclic compounds and tetrahydrofuran, which is applied in 3 fields, can solve the problems of low substrate universality and harsh reaction conditions, and achieve the effects of low synthesis cost, short preparation route and simple synthesis route

Active Publication Date: 2014-02-05
广东和博制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the methods above all have defects such as low substrate universality and harsh reaction conditions.

Method used

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  • Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound
  • Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound
  • Preparation method of 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1 prepares compound 5a of the present invention:

[0027] Weigh 5-chlorophenylnitroalkene 3a (0.20mmol), rhodium acetate (1.70mg, 0.004mmol), p-bromobenzaldehyde 2a (0.30mmol), Molecular sieves (70 mg) were put into a small test tube reactor, and 1.0 mL of redistilled dichloromethane was added at room temperature. N-Methylisatin diazo 1a (0.30mmol) was dissolved in 0.7mL redistilled dichloromethane, and injected into the reaction system through a peristaltic pump for 1 hour. After the injection was completed, DBU (0.04mmol) was added, and the reaction was continued for 2h , the reaction was completed, and the solvent was removed by rotary evaporation at 40 ° C, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1: 50 ~ 1: 20) to obtain 3,3-spiro (2-tetrahydrofuran) oxidation Indole polycyclic compound 5a. Yield 80%, d.r. 91:9. See Table 1.

[0028]

[0029] The characterization of the present embodiment product 3,3-spi...

Embodiment 2-16

[0032] Embodiment 2-16 prepares compound (5b~5p)

[0033] Embodiment 2-16 is the same as embodiment 1. See Table 1 for the changes of substituents, compound number, d.r. value, yield, etc. in the reaction.

[0034] Table 1

[0035]

[0036] The characterization of the product 3,3-spiro(2-tetrahydrofuran)oxindole polycyclic compound 5b~5p is as follows:

[0037] 5b:

[0038] 1 H NMR (400MHz, CDCl 3 , 25°C, TMS): δ=8.21(d, J=8.2Hz, 1H), 8.03(d, J=7.5Hz, 1H), 7.47(dd, J=11.9, 4.9Hz, 1H), 7.42-7.33 (m, 1H), 7.24(d, J=8.5Hz, 1H), 7.18(s, 1H), 7.12(dd, J=8.7, 2.4Hz, 1H), 6.88(d, J=8.7Hz, 1H) , 6.49(d, J=2.2Hz, 1H), 6.27(s, 1H), 5.30(dd, J=9.1, 2.8Hz, 1H), 4.89(s, 1H), 3.58(s, 3H), 2.77- 2.41(m, 2H), 2.12(s, 3H);

[0039] 13 C NMR (400MHz, CDCl 3 ,25℃,TMS):δ=175.39,169.56,169.49,150.04,140.25,132.27,132.05,131.94,130.05,128.62,127.89,126.71,126.09,126.06,125.21,124.49,122.18,120.45,117.14,99.15,86.29 , 85.55, 72.23, 52.31, 51.58, 34.29, 29.70, 25.69.

[0040] 5c:

[0...

Embodiment 17

[0080] Example 17 Inhibition of Aurora Kinase Activity by 3,3-spiro(2-tetrahydrofuran)oxindole polycyclic compounds 5a-5p of the present invention

[0081] Aurora kinase is necessary for the mitotic process. AURKA plays an important role in the formation of mitotic spindle and centrosome maturation. AURKB is necessary for chromosome segregation and cytoplasmic movement. Studies have shown that inhibiting the activity of Aurora kinase disrupts the cell cycle , prevent cell proliferation, cause apoptosis of many types of tumor cells, and have no effect on non-dividing cells. Finding specific inhibitors of Aurora kinase provides a new method for tumor treatment.

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Abstract

The invention discloses a preparation method of a 3, 3-spiro (2-tetrahydrofuranyl)-oxindole polycyclic compound as shown in a formula (I). The preparation method comprises the following steps: performing (3+2) cycloaddition on isatin diazo, aldehyde and ortho-nitro-substituted phenylene under the catalysis of rhodium acetate to construct an intermediate containing a 3, 3-spiro (2-tetrahydrofuranyl)-oxindole structure, adding a base, and then performing intramolecular Michael addition to further perform ring-closure synthesis of a target product. According to the preparation method, raw materials are available, and five cyclic structures are constructed by adopting one-pot method. The preparation method is short in preparation route, simple to operate, mild in reaction conditions and high in yield, and has high atom economy and no environment pollution. The product prepared according to the method can be used for providing various compound frameworks, and has the property of inhibiting the activity of AURKA.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry and relates to a preparation method of 3,3-spiro (2-tetrahydrofuran) oxindole polycyclic compound. Background technique [0002] As an important structural monomer, the naked ring skeleton of oxindole exists in many natural products and active pharmaceutical intermediates (Angew.Chem., Int.Ed.2007,46,8748-8758; Tetrahedron Lett.2011, 52, 3945-3948). Among them, the naked ring structure of oxindole and tetrahydrofuran is not only an intermediate fragment of many natural products, but also has good biological activity. For example, the following Ia-b is a progesterone receptor inhibitor, and Ic is used to treat hypertension , IIa-b are used for the treatment of skin itching and cancer etc. [0003] [0004] In 2004, Professor Muthusamy constructed 3,3-spiro(2-tetrahydrofuran)oxindole compound for the first time through Rh-catalyzed multi-component reaction of diazoami...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20A61P35/00
CPCC07D491/20
Inventor 胡文浩王冬伟邱林刘顺英
Owner 广东和博制药有限公司
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