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Preparation method of disubstituted benzothiophene potassium ion channel agonist

A potassium ion channel, benzothiophene technology, used in organic chemistry, nervous system diseases, drug combinations, etc., can solve the problems of compounds without reducing electron cloud density, side effects, and easy oxidation of intermediate aromatic rings.

Pending Publication Date: 2022-05-13
TAIZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The above-mentioned existing technical solutions have the following defects: the preparation of the above-mentioned method not only has many preparation steps, but also the prepared compounds do not reduce the electron cloud density. Due to the electron-rich characteristics, the middle aromatic ring of the compound of formula I is more likely to be oxidized. It leads to a series of drug side effects, and there are still problems such as low agonistic activity and insufficient selectivity for Kv7.2 potassium ion channels, which need to be improved

Method used

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  • Preparation method of disubstituted benzothiophene potassium ion channel agonist
  • Preparation method of disubstituted benzothiophene potassium ion channel agonist
  • Preparation method of disubstituted benzothiophene potassium ion channel agonist

Examples

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Comparison scheme
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Embodiment 1

[0041] Embodiment 1: It is a preparation method of a disubstituted benzothiophene potassium ion channel agonist disclosed in the present invention. The route of the preparation method is as follows,

[0042]

[0043] The preparation method comprises the following steps,

[0044] S1 puts the compound of the above formula (1) and the compound of the above formula (2) in an organic solvent, selectively adds a condensing agent, and then reacts in the presence of an acid-binding agent, and after the reaction is finished, the above formula (3) is obtained by post-processing compound;

[0045] S2 In a mixed solvent, under the action of a palladium catalyst and a carbonate, the compound of the above formula (3) reacts with the compound of the above formula (4), and after the reaction is finished, the compound of the above formula (5) is obtained through post-treatment;

[0046] Wherein, X is selected from halogen;

[0047] R 1 selected from halogen, hydroxy or alkoxy;

[0048] ...

Embodiment 2

[0051] Embodiment 2: It is a preparation method of a disubstituted benzothiophene potassium ion channel agonist disclosed in the present invention. The difference from Example 1 is that the route of the preparation method is as follows,

[0052]

[0053] The preparation method comprises the following steps,

[0054] S1 Dissolve 1.0mol of the above formula (1) compound, 1.1mol of the above formula (2) compound and 1.2mol of carbodiimide (condensing agent) in 15L of dichloromethane (organic solvent), add 1.5mol of N,N- Diisopropylethylamine (acid-binding agent), stirred and reacted at 23°C for 4h;

[0055] Thin-layer chromatography shows that after the reaction of the raw materials is complete, first slowly add 50L of ethyl acetate to the reaction solution for extraction, stir and separate layers to obtain the first organic phase, then add 25L of ethyl acetate to the separated aqueous phase, and stir Separate the layers to obtain the second organic phase, combine the first o...

Embodiment 3

[0060] Example 3: a method for preparing a disubstituted benzothiophene potassium ion channel agonist disclosed in the present invention, the difference from Example 1 is that the route of the preparation method is as follows,

[0061]

[0062] The preparation method comprises the following steps,

[0063] S1 Dissolve 1.0mol of the above formula (1) compound, 1.6mol of the above formula (2) compound and 0.8mol of carbodiimide (condensing agent) in 15L of dichloromethane (organic solvent), add 1.2mol of N,N- Diisopropylethylamine (acid-binding agent), stirred and reacted at 20°C for 6h;

[0064] Thin-layer chromatography shows that after the reaction of the raw materials is complete, first slowly add 50L of ethyl acetate to the reaction solution for extraction, stir and separate layers to obtain the first organic phase, then add 25L of ethyl acetate to the separated aqueous phase, and stir Separate the layers to obtain the second organic phase, combine the first organic pha...

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Abstract

The invention relates to a preparation method of a disubstituted benzothiophene potassium ion channel agonist, which comprises the following steps: reacting a compound shown as a formula (1) with a compound shown as a formula (2) in an organic solvent in the presence of an acid-binding agent, and after the reaction is finished, carrying out post-treatment to obtain a compound shown as a formula (3); in a mixed solvent, under the action of a palladium catalyst and carbonate, the compound in the formula (3) reacts with the compound in the formula (4), and after the reaction is finished, post-treatment is performed to obtain the compound in the formula (5). According to the preparation method disclosed by the invention, substitution of two sides of a benzothiophene ring can be completed through two-step reaction, the reaction steps are simple, and the purpose of preparing the benzothiophene potassium ion channel agonist with high agonistic activity is achieved.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a disubstituted benzothiophene potassium ion channel agonist. Background technique [0002] The voltage-gated potassium ion channel Kv7 is encoded and expressed by the KCNQ gene. It is widely distributed in organisms and participates in a variety of life, including the maintenance of cell membrane potential, the formation of action potentials, the release of neurotransmitters, the regulation of intracellular calcium signals, hormone secretion and cell proliferation. The voltage-gated potassium ion channel Kv7 includes five subtypes (Kv7.1~Kv7.5), Kv7.1 is mainly expressed in cardiomyocytes, and Kv7.2~Kv7.5 is mainly distributed in the central and peripheral nervous systems. Among them, the voltage-gated potassium channel Kv7.2 (KCNQ 2 ) mainly regulates M currents in neurons, and is an important drug target for pain, epilepsy and other diseases re...

Claims

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Application Information

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IPC IPC(8): C07D277/66A61P25/00
CPCC07D277/66A61P25/00
Inventor 王健邵黎明
Owner TAIZHOU UNIV
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