C19-acylated triptolide methyl derivative

A compound and acetyl technology, applied in the field of derivatives of C19-acylated triptolide, can solve the problems of high cost, waste of raw materials, low yield and the like

Active Publication Date: 2018-09-14
CINKATE PHARMA INTERMEDIATES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthetic route adopts the strategy of double acylation and then hydrolysis, which causes waste of raw materials; at the same time, in the double acylation step, benzoyl chloride is used as an acylating reagent, which requires a large excess, and its side reaction with LDA Seriously lead to low yield
Therefore, the cost of this route is high, the operability is poor, and it is not suitable for industrial production.

Method used

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  • C19-acylated triptolide methyl derivative
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  • C19-acylated triptolide methyl derivative

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preparation example Construction

[0062] The invention provides a preparation method of C19-acylated triptolide (IV), comprising the following steps:

[0063] a) The compound of formula (II) is prepared by reacting the compound of formula (I) with an aldehyde compound under alkaline conditions, and the reaction formula is as follows:

[0064]

[0065] b) reacting the compound of formula (III) by the compound of formula (II) under the action of oxidant, the reaction formula is as follows:

[0066]

[0067] c) the compound of formula (Ⅲ) removes the protecting group to obtain the compound of formula (Ⅳ), and the reaction formula is as follows:

[0068]

[0069] Wherein R1 is methylthiomethyl, acetyl, trimethylsilyl, R2 is phenyl, C1-C10 alkyl, C3-C8 cycloalkyl, 5 containing 1-4 heteroatoms selected from N, O or S -10-membered heterocyclic group, preferably R1 is methylthiomethyl, and R2 is phenyl.

[0070] The base used in the condensation reaction described in step (a) is selected from lithium diisop...

Embodiment 1C19

[0098] The synthesis of embodiment 1C19-benzoylated triptolide

[0099] step 1)

[0100]

[0101] Under the protection of argon, the compound 1 (1.26g, 3.0mmol) was dissolved in dry tetrahydrofuran (30mL), stirred completely and then gradually cooled to -78°C, at this temperature, slowly added heptane / ethylbenzene / tetrahydrofuran dropwise LDA solution (2.4 mL, 3.6 mmol). After dropping, continue stirring at this temperature for 30 minutes and then slowly add benzaldehyde (0.48mL, 4.5mmol) dropwise. Then the reaction system was naturally warmed to room temperature and stirred overnight.

[0102] After the reaction was completed, the reaction solution was cooled to 0° C. and quenched by adding water (5 mL). Concentrate under reduced pressure to remove most of THF, and the resulting mixture is extracted with ethyl acetate (25 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was ...

Embodiment 2C19

[0110] The synthesis of embodiment 2C19-(hydroxybenzylation) triptolide

[0111]

[0112] Compound 2 (53 mg, 0.1 mmol) was dissolved in acetonitrile (8 mL) at room temperature, solid mercuric dichloride (270 mg, 1.0 mmol) and water (2 mL) were added, and the reaction was stirred overnight at room temperature. After the reaction was completed, insoluble solids were removed by filtration, and the resulting mother liquor was diluted with ethyl acetate (50mL), washed with saturated sodium chloride (10mL×3), saturated ammonium chloride (10mL×3), water (10mL) and saturated saline ( 10 mL), the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (200-300 mesh silica gel, n-hexane:ethyl acetate=4:1) to obtain 25 mg of the target product (product rate 51%).

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Abstract

The invention provides a C19-acylated triptolide methyl derivative. The invention specifically provides a compound shown in the following formula. The groups of the compound are described in the description. The compound can be used as a prodrug for metabolizing to obtain triptolide and can be used for preparing medicine compositions for treating cancer and immunological diseases. The formula is shown in the description.

Description

technical field [0001] The invention belongs to the fields of organic chemistry, medicinal chemistry and natural medicinal chemistry, and specifically relates to a derivative of C19-acylated triptolide. Background technique [0002] Triptergium wilfordii Hook.f is an annual vine of the Euonymus family, and is a commonly used Chinese herbal medicine in traditional Chinese medicine. It is warm in nature, bitter in taste, and has anti-inflammatory, anti-rheumatic, analgesic and other activities. Triptolide, also known as triptolide, is one of the main active ingredients of triptolide. It is mainly extracted from the leaves and roots of Tripterygium wilfordii. It has various biological activities such as immunosuppression, anti-inflammation, anti-fertility, anti-tumor, and insecticide. It is clinically used to treat psoriasis, rheumatoid arthritis, leukemia, Kidney disease, etc., but its toxicity is the main reason restricting the clinical application of this type of compound....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00A61K31/585A61P37/02A61P29/00A61P35/00
CPCC07J73/003Y02P20/55
Inventor 张鹏荣彬刘祥超王盼梁星贺利军包丽霞仇波肖飞
Owner CINKATE PHARMA INTERMEDIATES
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