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Synthesis method of agrimophol B and intermediate pseudo-aspidinol of agrimophol B

A synthetic method, the technology of escorol, applied in the field of drug synthesis, can solve the problems of expensive and toxic reagents used, many types of reagents used, and low yield of some reactions, and achieve the effects of reducing the types of reagents, easy operation, and high yield

Pending Publication Date: 2021-11-23
ZHEJIANG MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN108947787A describes a method for selectively protecting the two hydroxyl groups of butyrylphloroglucinol by acid chlorides, and then preparing pseudocephol through the method of methylation-deprotection. The shortcoming is that the step of protecting phenolic hydroxyl groups uses organic Acid is used as a protective reagent, the yield is not high, more reagents are used and the operation is cumbersome
[0007] In summary, the technological development in recent years has improved the efficiency of the total synthesis of Agrimol B, but there are still defects such as cumbersome operation steps, expensive or highly toxic reagents, many types of reagents used, and low yields in some reactions.

Method used

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  • Synthesis method of agrimophol B and intermediate pseudo-aspidinol of agrimophol B
  • Synthesis method of agrimophol B and intermediate pseudo-aspidinol of agrimophol B
  • Synthesis method of agrimophol B and intermediate pseudo-aspidinol of agrimophol B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 (synthesis of compound a): in a 50ml round bottom flask, add phloroglucinol (1.2611g, 10mmol), zinc chloride (6.815g, 50mmol), 12ml carbon disulfide, add dropwise about 10ml nitro Benzene completely dissolves the solid. Pass condensed water, stir at 45°C for 30 minutes, then slowly add (α-methyl)butyryl chloride (1.45ml, 11.5mmol) dropwise, and continue stirring for 2h after the dropwise addition. The reaction was quenched by pouring into ice water, and a large amount of yellow solid was precipitated. Ethyl acetate was added to dissolve the solid, extracted with water / ethyl acetate, the ester layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol-water to obtain 1.936 g of a light yellow solid (92% yield). 1 H NMR (400MHz, DMSO-d6) δ5.82(s, 2H), 3.77(sext, J=6.8Hz, 1H), 1.76-1.66(m, 1H), 1.35-1.25(m, 1H), 1.05( d,J=6.8Hz,3H),0.83(t,J=7.6Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ209.5,165.0,164.8,104.0,95.3...

Embodiment 2

[0066] Example 2 (synthesis of compound 1): in a 2000ml there-necked flask, add phloroglucinol dihydrate (100g, 0.8mol), DMF (138g, 1.9mol), with 1500ml ethyl acetate as solvent, the initial reaction temperature - 10°C, with mechanical stirring. Thionyl chloride (356 g, 3 mol) was slowly added dropwise, and the reaction was continued for 0.5 h under ice bath after the dropwise addition. Remove the ice bath, stir at room temperature for 3h, and a yellow solid precipitates out, which is filtered. Add 200 g of water to the filter cake and heat until completely dissolved, cool in the refrigerator overnight, and filter to obtain a yellow solid. The filtrate was spin-dried, and 100 g of water was added to recrystallize again. A total of 110.931 g of solids were obtained (yield 90%). 1 H NMR (600MHz, DMSO-d6) δ11.46(s, 2H), 10.65(s, 1H), 9.94(s, 1H), 5.80(s, 2H). 13 C NMR (150MHz, DMSO-d6) δ191.4, 167.7, 164.6, 105.0, 94.6.

Embodiment 3

[0067] Example 3 (synthesis of compound 2): in a 25ml round bottom flask, add zinc powder (0.654g, 10mmol) and 5ml of water successively, and add 0.3g concentrated hydrochloric acid dropwise under stirring in an ice bath, and stir for 5min after the dropwise addition . After the reaction solution was allowed to stand for 30 min, the water was poured off, and 5 ml of ethyl acetate and compound 1 (0.462 g, 3 mmol) were added. When the temperature of the reaction solution dropped below 5°C, a total of 1 g of concentrated hydrochloric acid was added dropwise, and the reaction was continued for 2 hours after the dropwise addition was completed. The reaction solution was filtered, the reaction flask and solids were washed with ethyl acetate, the organic phase was washed with saturated brine and distilled water successively, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and eluted with dichloromethane / methanol (30:1) Separation and p...

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Abstract

The invention discloses a synthesis method of agrimonol B and an intermediate pseudo-aspidinol thereof. The synthetic method of the pseudo-aspidinol comprises a step E, a step F and a step G. According to the synthesis method of the agrimonol B, the agrimonol B is prepared by taking the pseudo-aspidinol synthesized by the method as a raw material through a step H and a step J in sequence, or the agrimonol B is prepared by taking the pseudo-aspidinol synthesized by the method as a raw material through a step I in sequence. In the step E, a novel amino protection reagent which is well reacted with a phenolic hydroxyl group is used as a protection reagent to selectively protect the phenolic hydroxyl group of each intermediate in the synthesis process of an intermediate molecular fragment a, so that the types of used reagents are reduced, and the use of toxic reagents such as benzyl chloride and the like is avoided; and moreover, the protective group loading reaction is rapid, the yield is higher, the deprotection is simple, and the operation is easy.

Description

technical field [0001] The invention relates to a simple synthesis method of the natural product agrimonol B and a synthesis method of the intermediate product pseudocephol, belonging to the technical field of drug synthesis. Background technique [0002] Agrimony is a commonly used Chinese herbal medicine in my country. Existing studies have shown that the phenolic substances contained in Agrimony may be the main source of its pharmacological activity. Agrimol B, one of the main components of fat-soluble phenols, has been proven to have anti-malarial, anti-ascaris, and anti-tapeworm effects, and is an important component of compound prescription drugs and an important raw material for derivatization activity research. At present, the method of obtaining agrimonol B is still mainly extraction. However, its content in Agrimony is low and extraction is difficult, which seriously restricts the progress of research on the activity of agrimonol B and its derivatives. Therefore, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C45/64C07C49/84C07C68/00C07C69/96C07C37/00C07C39/10C07C45/46C07C49/825C07C45/45C07C47/565C07C45/68
CPCC07C45/64C07C68/00C07C69/96C07C37/002C07C45/46C07C45/455C07C45/68C07C49/84C07C39/10C07C49/825C07C47/565Y02P20/55
Inventor 王剑丁宗琦黄岩毅虞思思李军
Owner ZHEJIANG MEDICAL COLLEGE