A kind of vorinostat derivative based on palladium carbon and its preparation method and application

A technology of vorinostat and derivatives, which is applied in the field of palladium-carbon-based vorinostat derivatives and their preparation, can solve problems such as inability to achieve oral administration, achieve cost control, reduce patient burden, and simple operation Effect

Active Publication Date: 2020-11-06
ZHEJIANG MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Especially, when we are faced with patients who cannot swallow, such as infants, critically ill patients, paralyzed or comatose patients, oral administration cannot be achieved, and the problem of inability to inject drugs becomes particularly prominent at this time (US20100240601A)

Method used

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  • A kind of vorinostat derivative based on palladium carbon and its preparation method and application
  • A kind of vorinostat derivative based on palladium carbon and its preparation method and application
  • A kind of vorinostat derivative based on palladium carbon and its preparation method and application

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preparation example Construction

[0048] The preparation method of the vorinostat derivative based on palladium carbon of the present invention can refer to as follows:

[0049] Condensation reaction with vorinostat, followed by deprotection and reduction reaction to obtain the vorinostat derivative;

[0050] In formula (i), R 9 -R 12 are independently hydrogen, protected hydroxyl, or protected carboxyl, wherein, R 9 -R 12 There is at least one protected hydroxyl group or protected carboxyl group; preferably, R 9 -R 12 are independently protected hydroxyl or protected carboxyl; more preferably, R 9 -R 12 There is at least one protected hydroxyl group and one protected carboxyl group in, for example, R 9 is a protected carboxyl group, R 10 -R 12 is a protected hydroxyl group; alternatively, R 12 is a protected carboxyl group, R 9 -R 11 is a protected hydroxyl group; or, it can be R 9 is a protected hydroxyl group, R 10 -R 12 is a protected carboxyl group; or, R 12 is a protected hydroxyl group...

Embodiment 1

[0075] Example 1 O-[NN-dimethyl-N-4-(2,3,4-tri-O-tert-butyldimethylsilyl-6-benzyl-β-D-glucopyranose Preparation of acid-1-yl)-3-nitrobenzyloxycarbonylethylenediamine]-formyl-vorinostat (iii)

[0076] Dissolve 913 mg (3.46 mmol) of vorinostat in 20 mL of pyridine, and cool at 0° C. for 5 minutes. At 0°C, 3 g (3.14 mmol) of compound (ii) was added to the above solution to form a red suspension. The suspension was warmed up to 25 °C, kept stirring for 5 hours, and then 100 mL of water was added to quench the reaction. The reaction solution was extracted with ethyl acetate (50mL×3 times), the combined organic layers were sequentially extracted with 0.5M HCl (30mL×4 times), saturated brine (30mL×2 times), dried over anhydrous sodium sulfate, and evaporated by rotary evaporation concentrated, and separated by preparative chromatography (dichloromethane:methanol=50:1) to obtain 3.4g of intermediate iii with a yield of 92%.

[0077] Characterization of the product: 1 HNMR (400MHz,...

Embodiment 2

[0078] Example 2 O-[NN-dimethyl-N-4-(6-benzyl-β-D-pyranoglucuronic acid-1-yl)-3-nitrobenzyloxycarbonylethylenediamine]- Preparation of formyl-vorinostat (iv)

[0079] Dissolve 3.4g (2.87mmol) of intermediate iii in 18mL tetrahydrofuran, add 4.63g (28.7mmol) of triethylamine trihydrofluoride at 25°C, heat to 50°C, and keep the reaction for 16 hours. After the reaction is complete, the reaction solution is concentrated with a rotary evaporator, 50 mL of water is added to the concentrated solution, extracted with ethyl acetate / acetonitrile (3 / 1) (20 mL×4 times), the organic layers are combined, washed twice with saturated saline, and anhydrous sulfuric acid Sodium-dried, filtered, the filtrate was concentrated with a rotary evaporator, and separated by preparative chromatography (dichloromethane:methanol=50:1) to obtain 5.0 g of crude product iv with a yield of 74%, which was directly put into the next reaction.

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Abstract

The invention provides a vorinostat derivative based on palladium on carbon, as well as a preparation method and application thereof. According to the vorinostat derivative, vorinostat is used as a parent compound, and the water solubility of vorinostat is improved by binding a water-soluble group, so that the use inconvenience and side effect in the administrating process of vorinostat raw drug can be effectively improved. Furthermore, the preparation method is simple and convenient in process, has simple operation steps, and is applicable to large-scale production.

Description

technical field [0001] The invention relates to the field of preparation of antitumor drugs, in particular to a palladium-carbon-based vorinostat derivative and a preparation method and application thereof. Background technique [0002] Vorinostat, whose chemical name is "N-hydroxy-N'-phenylsuberamide" or "suberoylanilide hydroxamic acid (SAHA)", is the first histone protein developed by Merck in the United States. Deacetylase (HDAC) inhibitor class antineoplastic drugs. Because vorinostat can selectively induce the late differentiation of tumor cells, thereby inhibiting the proliferation of such cells under suitable conditions, vorinostat is used to treat tumor patients with continuous proliferation of cancer cells. It is also clinically indicated for the treatment of cutaneous T-cell lymphoma (CTCL: a type of non-Hodgkin's lymphoma, which is a type of T-cell cancer that affects white blood cells of the skin) ). [0003] Vorinostat It was approved for marketing in the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/203C07H1/00A61K31/7036A61P35/00
CPCY02P20/55
Inventor 杜文婷施菁李军赵栗丽
Owner ZHEJIANG MEDICAL COLLEGE
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