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A kind of preparation method of triptolide derivative

A technology of triptolide and derivatives, which is applied in the field of preparation of triptolide derivatives, and can solve the problems of low yield, high cost, safety and environmental hazards, etc.

Active Publication Date: 2021-07-27
CINKATE PHARMA INTERMEDIATES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The method has three steps in total, wherein the yield of the second step is relatively low, only 49% is reported, and the total yield of the three-step reaction is 25%, and the cost is high
In addition, the mercury chloride used in the third step reaction is highly toxic and heavy metal, which affects the quality of the final product and has great safety and environmental risks

Method used

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  • A kind of preparation method of triptolide derivative
  • A kind of preparation method of triptolide derivative
  • A kind of preparation method of triptolide derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: the preparation of compound CK21S-006

[0041] 1.1 Synthesis of compound CK21S-006-a

[0042]

[0043] At room temperature, put triptolide (3.60g, 10mmol) into a dry round bottom flask, add 180ml of anhydrous tetrahydrofuran, then cool down to -78°C, slowly add 2,2,6,6-tetramethylpiperidine Lithium chloride magnesium chloride complex solution (40ml, 40mmol) was reacted for half an hour, then benzoyl chloride (2.8g, 20mmol) was added, and the reaction was continued for two hours. After the reaction was completed, 180ml of 0.5N hydrochloric acid aqueous solution was added to quench, and then 180ml was added for extraction. The organic phase was washed with saturated aqueous sodium chloride solution (2×180ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel (200-300 mesh) column chromatography (n-hexane: ethyl acetate = 5:1), and the target product (white s...

Embodiment 2

[0047] Embodiment 2: the preparation of compound CK21S-006

[0048] 2.1 Synthesis of compound CK21S-006-a

[0049]

[0050] At room temperature, put triptolide (3.60g, 10mmol) into a dry round bottom flask, add 180ml of anhydrous 2-methyltetrahydrofuran, then cool down to -78°C, slowly add LiHMDS solution (40ml, 40mmol), and react After half an hour, benzoyl chloride (2.8 g, 20 mmol) was added and the reaction was continued for two hours. After the reaction was completed, 180ml of 0.5N hydrochloric acid aqueous solution was added to quench, and then 180ml was added for extraction. The organic phase was washed with saturated aqueous sodium chloride solution (2×180ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel (200-300 mesh) column chromatography (n-hexane: ethyl acetate = 5:1), and the target product (white solid, 3.2 g, 70%) was collected. 1 H NMR (CDCl 3 )δ: 8.04(d...

Embodiment 3

[0054] Embodiment 3: the preparation of compound CK21S-006

[0055] 3.1 Synthesis of compound CK21S-006-a

[0056]

[0057] At room temperature, put triptolide (3.60g, 10mmol) into a dry round bottom flask, add 180ml of anhydrous tetrahydrofuran, then cool down to -40°C, slowly add LiHMDS solution (40ml, 40mmol), react for half an hour, and then Benzoic anhydride (4.5 g, 20 mmol) was added and the reaction was continued for two hours. After the reaction was completed, 180ml of 1N hydrochloric acid aqueous solution was added to quench, and then 180ml was added for extraction. The organic phase was washed with saturated aqueous sodium chloride solution (2×180ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel (200-300 mesh) chromatographic column (n-hexane:ethyl acetate=5:1), and the target product was collected (white solid, 2.78g, 60%). 1 H NMR (CDCl 3 )δ: 8.04(d, J=8.0H...

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Abstract

The invention discloses a preparation method of triptolide derivatives. The compound of formula II reacts with an organic metal base in an organic solvent, and then adds an acylating reagent. After the reaction is completed, it is quenched by adding an acidic aqueous solution to obtain the general formula III Compound; the compound of general formula III, an acylating agent and an organic base are reacted in an organic solvent to obtain a triptolide derivative as shown in general formula I, and the definitions of substituents in each formula are as described in the specification and claims. The preparation method of the invention overcomes the disadvantages of the original method, such as low yield, long route, use of heavy metals, etc., and has high application value.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of triptolide derivatives. 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. [0003] CN 1925852A describes a compound with general ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J73/00
CPCC07J73/003
Inventor 张鹏刘祥超仇波肖飞
Owner CINKATE PHARMA INTERMEDIATES