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Crackable chain small in chemical steric hindrance and preparation method and application of crackable chain

A steric hindrance and chemical technology, applied in the field of prodrugs and fluorescent probe materials, can solve the problems of serious influence of esterification reaction, limited design and synthesis of prodrug models and fluorescent probe materials, difficult connection of responsive groups, etc.

Active Publication Date: 2019-01-04
LINGNAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] However, the commonly used cleavable chain 2,6-bis(hydroxymethyl)-4-methylphenol has obvious disadvantages. Because its alcoholic hydroxyl group is more active than the phenolic hydroxyl group, it involves However, after protecting the alcoholic hydroxyl group, a large steric hindrance will be generated, making it difficult for the responding group to connect to its phenolic hydroxyl group, which has a particularly serious impact on the esterification reaction, which greatly limits the prodrug model and fluorescence. Design and synthesis of probe materials

Method used

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  • Crackable chain small in chemical steric hindrance and preparation method and application of crackable chain
  • Crackable chain small in chemical steric hindrance and preparation method and application of crackable chain
  • Crackable chain small in chemical steric hindrance and preparation method and application of crackable chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Synthesis of Example 1 Compound 2

[0081] 1.0 g 5.95 mmol of compound 1 (2,6-bis(hydroxymethyl)-4-methylphenol) and 5.0 g 17.86 mmol of 2-iodoylbenzoic acid were placed in a round bottom flask, its compounds 1 and 2 -The molar ratio of iodoyl benzoic acid is 1:3, add 20 mL of ethyl acetate, heat under reflux at 70°C for 3 h, cool to room temperature, filter, and wash the filter cake with ethyl acetate for 2 to 3 times, remove the organic solvent by rotary evaporation , carry out column chromatography with an eluent whose volume ratio is petroleum ether:ethyl acetate=10:1 to obtain compound 2 as a white solid;

[0082] The obtained compound 2 is 2-hydroxy-5-methyl isophthalaldehyde, and the structural formula of its compound 2 is The yield was 76.3%;

[0083] Compound 2 was characterized by H NMR spectroscopy, and the results were as follows figure 1 As shown, the characterization data is as follows: 1 HNMR (400MHz, CDCl 3 ,ppm)δ11.47(s,1H), 10.23(s,2H), 7.78(s,2H...

Embodiment 2

[0084] Example 2 Synthesis of Compound 3

[0085] 745 mg 4.543 mmol of compound 2 obtained in Example 1 and 6.3 g of 18.1 mmol of ethoxyformylmethylene triphenylphosphine were placed in a round bottom flask, and its compound 2 was mixed with ethoxyformylmethylene triphenylphosphine. The molar ratio of phosphine was 1:4, 30 mL of dichloromethane was added, and the reaction was stirred at room temperature for 6 h; after the reaction was completed, the solvent was removed by rotary evaporation, and the eluent was carried out with a volume ratio of petroleum ether:ethyl acetate=1.5:1. Column chromatography gave compound 3 as a white solid;

[0086] The structural formula of the obtained compound 3 is The yield was 86.4%.

[0087] Compound 3 was characterized by H NMR spectroscopy, and the results were as follows figure 2 As shown, the characterization data is as follows: 1 HNMR (400MHz, CDCl 3 ,ppm)δ8.10~8.20(d,2H), 7.35(s,2H), 6.45~6.55(d,2H), 4.25~4.40(m,4H), 2.32(s,1H), ...

Embodiment 3

[0088] Example 3 Synthesis of Severable Chains

[0089] 800 mg 2.63 mmol of compound 3 obtained in Example 2 was placed in a round-bottomed flask, 30 mL of tetrahydrofuran was added to dissolve it, cooled to -5°C under nitrogen protection, and 10.5 mL of 10.5 mmol of diisobutylaluminum hydride ( 1M n-hexane solution) was slowly added dropwise to the reaction flask, the molar ratio of compound 3 and diisobutylaluminum hydride was 1:4, and the reaction was carried out at -5 °C for 1 h; after the reaction was completed, 20 mL of water was slowly added dropwise. Quenched, extracted three times with ethyl acetate, filtered when a white solid was precipitated, and dried the filtrate with anhydrous sodium sulfate; finally, eluted with a volume ratio of petroleum ether:ethyl acetate=1:2 The agent is subjected to column chromatography to obtain a yellow solid product;

[0090] The yellow solid product is a cleavable chain, and its molecular formula is C 13 H 16 O 3 , the structural...

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Abstract

The invention discloses a crackable chain small in chemical steric hindrance and a preparation method and application of the crackable chain. The molecular formula of the crackable chain is C13H16O3,the structural formula of the crackable chain is as shown in the formula (I) (as shown in the description), phenolic hydroxyl groups of the crackable chain can be connected with a model response basegroup, alocholic hydroxtyl groups of the crackable chain can be connected with medicines or fluorophores, and after the model response base groups leave under the effect of response species, the medicines or the fluorophores can be released out through a 1,6-elimination reaction. The crackable chain has the advantage of being small in chemical steric hindrance, and the problem of steric hindranceof the model response base groups on the medicines or the fluorophores is solved. In addition, the crackable chain can quickly and effectively release the medicines or the fluorophores, has favorablebiocompatibility, can be widely used for design synthesis of prodrugs or fluorescent probe materials, and has favorable application prospects and wider development space.

Description

technical field [0001] The invention belongs to the technical field of prodrugs and fluorescent probe materials, and more particularly relates to a cleavable chain with small chemical steric hindrance and a preparation method and application thereof. Background technique [0002] In the early 1980s, cleavable chains were discovered for the first time in the design and synthesis of prodrugs. The cleavable chains were derivatives of a class of benzyl alcohol-like structures with phenolic hydroxyl groups. The alcoholic hydroxyl group is connected to the drug through a carbonate or carbamate bond, and the responsive group leaves under the action of the responsive species to obtain an intermediate with a hydroxyl group. Such an intermediate is structurally unstable and can occur through rapid electron transfer. 1,6-elimination or 1,4-elimination breaks the carbonate or carbamate bond, releasing the drug. Since the discovery of cleavable chains, they have been widely used in the ...

Claims

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Application Information

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IPC IPC(8): C07C39/215C07C29/147C07F7/18C09K11/06
CPCC07C39/215C07F7/1892C09K11/06C09K2211/1007C09K2211/1088
Inventor 刘培炼贾永梅黄丽平余彪王胜
Owner LINGNAN NORMAL UNIV
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