Protein degradation targeting chimeric compound, application and preparation method thereof

A protein degradation and chimera technology, applied in and its preparation, protein degradation targeting chimera compounds, application fields, can solve the problems of difficulty in entering cells, large molecules of polypeptide PROTACs, etc., achieve small molecular weight, good leaving performance, good size effect

Pending Publication Date: 2020-07-10
SUZHOU HIGHFINE BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, peptide PROTACs are still large and difficult to enter cells

Method used

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  • Protein degradation targeting chimeric compound, application and preparation method thereof
  • Protein degradation targeting chimeric compound, application and preparation method thereof
  • Protein degradation targeting chimeric compound, application and preparation method thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0033] As the method for preparing the above-mentioned protein degradation targeting chimera compound, it may include the following steps:

[0034] Step S1: fluorination reaction of 3-chlorophthalic anhydride to generate 3-fluorophthalic anhydride.

[0035] Specifically, the reaction equation can be as shown in the following equation (2):

[0036]

[0037] More specifically, it can generate 3-fluorophthalic anhydride by performing a chlorination reaction and then a fluorination reaction. In other words, the fluorination process may include the following steps:

[0038] Step S11, dissolving 3-chlorophthalic anhydride in sulfolane, and adding a chlorinating reagent to cause a chlorination reaction.

[0039] Further, the chlorinating reagent is oxalyl chloride, and the chlorination reaction is performed at 80-120°C, and the reaction time may be, for example, 2-6 hours.

[0040] Step S12, after the chlorination reaction is completed, the fluorination reaction occurs with potassium fluoride ...

Embodiment 1

[0059] In a 1L three-necked flask, add 500ml of sulfolane, then add 180g of 3-chlorophthalic anhydride to it, cool down to below 10°C in an ice bath, add 300g of oxalyl chloride dropwise to it, and after the dropwise addition, heat to about 100°C and react for 3 hours, then cool to At room temperature, remove oxalyl chloride by rotary evaporation. Then 180g of anhydrous potassium fluoride was added to it, after adding potassium fluoride, the system was heated to 100°C for 6 hours, and then cooled to room temperature. The inorganic salt was filtered off with suction. The filtrate was slowly poured into 900ml of ice water to precipitate a large amount of solids. Stirring is continued for 2 hours, and filtered with suction to obtain a filter cake, which is vacuum dried to obtain crude 3-fluorophthalic anhydride.

[0060] The crude 3-fluorophthalic anhydride was dissolved in 800ml of dichloromethane, dried with anhydrous magnesium sulfate, filtered with suction, the filter cake was s...

Embodiment 2

[0066] In a 1L three-necked flask, add 500ml of sulfolane, then add 180g of 3-chlorophthalic anhydride to it, cool down to below 10°C in an ice bath, add 360g of phosphorus oxychloride dropwise to it, after the dropwise addition, heat up to about 100°C for 3 hours. Cool to room temperature and remove phosphorus oxychloride by rotary evaporation. Then 180g of anhydrous potassium fluoride was added to it, after adding potassium fluoride, the system was heated to 100°C for 6 hours, and then cooled to room temperature. The inorganic salt was filtered off with suction. The filtrate was slowly poured into 900ml of ice water to precipitate a large amount of solids. Stirring is continued for 2 hours, and filtered with suction to obtain a filter cake, which is vacuum dried to obtain crude 3-fluorophthalic anhydride.

[0067] The crude 3-fluorophthalic anhydride was dissolved in 800ml of dichloromethane, dried with anhydrous magnesium sulfate, filtered with suction, the filter cake was spu...

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PUM

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Abstract

The invention provides a novel protein degradation targeting chimeric compound, application and a preparation method thereof. The protein degradation targeting chimeric compound is 2-(2, 6-dioxo-piperidine-3-yl)-4-fluoro-isoindole-1, 3-dione. The preparation method comprises the following steps: S1, carrying out a fluorination reaction on 3-chlorophthalic anhydride to generate 3-fluorophthalic anhydride; and step S2, carrying out a condensation reaction on the 3-fluorophthalic anhydride and 3-amino-2, 6-piperidinedione hydrochloride so as to obtain the 2-(2, 6-dioxo-piperidine-3-yl)-4-fluoro-isoindole-1, 3-dione. According to the protein degradation targeting chimeric body, the compound is moderate in molecular size, good in fluorine leaving performance, small in molecular weight and stable in performance, target protein and E3 ubiquitin enzyme can be effectively close to each other, and the protein degradation targeting chimeric body can be effectively used for preparing targeting drugs. And the preparation method is simple and convenient, less in three wastes and low in raw material price, so that the preparation cost is low, and the method is suitable for industrial large-scaleproduction.

Description

Technical field [0001] The invention relates to the technical field of compound preparation, in particular to a protein degradation targeting chimera compound, application and preparation method thereof. Background technique [0002] PROteolysis TArgeting Chimera (PROTAC) is a bifunctional small molecule. One end is a ligand that binds to the target protein, and the other end is a ligand that binds to E3 ubiquitin ligase, connected by a chain. The PROTAC can bring the target protein and E3 enzyme closer in vivo, so that the target protein is labeled with ubiquitin, and then the target protein is ubiquitinated to modify the target protein, and then degraded through the ubiquitin-proteasome pathway. [0003] At present, PROTACs have become a hot spot in drug research due to their highly specific targeted degradation function and good safety. By using the ubiquitin-proteasome system existing in the cell to degrade the target protein reversibly, the drug resistance caused by the mutat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K47/54
CPCC07D401/04A61K47/555A61K47/545
Inventor 孙豪义顾耿峰刘梦梦
Owner SUZHOU HIGHFINE BIOTECH
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