阅读说明：本技术 两种磺酰基吡咯烷P-CABs的合成方法及用途 (Synthesis method and application of two sulfonyl pyrrolidine P-CABs ) 是由 桑锋 李媛媛 孙炳夏 张静 付林 于 2020-06-17 设计创作，主要内容包括：本发明公布了两种磺酰基吡咯烷P-CABs的合成方法及用途,其结构通式(I)如下。具有优异的胃酸分泌抑制作用。本发明制备路线工艺步骤较少,原料易得,适合工业化生产。<Image he="223" wi="254" file="100004_DEST_PATH_IMAGE001.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a synthesis method and application of two sulfonyl pyrrolidine P-CABs, and the structural general formula (I) is as follows. Has excellent gastric acid secretion inhibiting effect. The preparation route of the invention has fewer process steps and easily obtained raw materials, and is suitable for industrial production.)

1. The synthesis method and the application of two sulfonyl pyrrolidine P-CABs are disclosed, and the structural general formula (I) is as follows:

2. the synthesis method and use of two sulfonyl pyrrolidines P-CABs according to claim 1, wherein the synthesis route is as follows:

3. the two sulfonyl pyrrolidine P-CABs are used for preparing the medicine with the gastric acid secretion inhibition activity.

Technical Field

The invention relates to the field of compound synthesis, in particular to two sulfonyl pyrrolidine P-CABs with gastric acid secretion inhibition activity.

Background

Potassium-Competitive Acid Blockers (P-CABs) are a novel class of Acid Blockers that can competitively bind H⁺To inhibit H⁺/K⁺-the activity of an ATPase. P-CABs are characterized by lipophilicity, alkalescence, high dissociation constant and stability at low pH values. Proton pump inhibitors represented by pantoprazole inhibit the secretion of gastric acid to treat peptic ulcer, zollinger syndrome, upper gastrointestinal hemorrhage, and the like, and have been widely used in clinical practice. P-CABs have the following potential advantages: the effect is quick, and the maximum effect can be achieved within 1 hour; the plasma concentration is linearly related to the oral administration dosage, which indicates that the medicine can easily reach the optimal acid inhibition state.

Although a series of potassium competitive acid blocker (P-CABs) inhibitors are disclosed at present, novel efficient compounds and simple and feasible preparation methods are required to be developed for different indications, and through continuous optimization, the invention designs a synthesis method of the compound with the structure shown in the general formula (I) and finds that the compound has excellent gastric acid secretion inhibition effect.

。

Disclosure of Invention

The invention aims to provide a synthetic method and application of a compound with a structure shown in a general formula (I).

Wherein:

r is selected from methylamine and ethanolamine.

It is a further object of the present invention to provide two sulfonylpyrrolidines, P-CABs, which are intended to evaluate H at pH 6.5⁺-K⁺-ATPase inhibitory Activity (in vitro, IC)₅₀Value) is applied.

The general formula (I) of the two sulfonyl pyrrolidine P-CABs is as follows:

the general formula of the sulfonyl pyrrolidine P-CABs is as follows:

。

example 1:

the synthesis route of the sulfonyl pyrrolidine P-CAB is as follows:

the preparation method of the sulfonyl pyrrolidine P-CAB comprises the following steps:

(1) 4-hydroxy sodium benzenesulfonate, methyl bromoacetate and potassium carbonate are refluxed in methanol until the reaction is finished, and a product 2 is removed by spin drying and ethyl acetate;

(2) reacting the product 2 obtained in the step (1), thionyl chloride and DMF, and extracting, drying, concentrating under reduced pressure and carrying out column chromatography to obtain a product 3;

(3) reacting the product 3 obtained in the step (2), the raw material 4, triethylamine and DMAP overnight, and obtaining a product 5 through extraction, drying, reduced pressure concentration and column chromatography;

(4) and (3) adding the product 5 obtained in the step (3) and a methylamine methanol solution into the methanol solution, reacting for a period of time, adding sodium borohydride until the raw materials react completely, and extracting, drying, concentrating under reduced pressure and performing column chromatography to obtain a final product 6.

Wherein:

in the step (1), the ratio of the amounts of the sodium 4-hydroxybenzenesulfonate, the methyl bromoacetate and the sodium carbonate is 1 mmol to 3.1 mmol to 2.3 mmol.

In step (1), the oil bath was controlled at a temperature of 75 deg.C^oAnd C, reacting for 6-8 h.

In the step (2), the ratio of the product 2 obtained in the step (1) to thionyl chloride and DMF is 1 mmol: 4.2 mmol: 0.09 mmol.

In the step (2), the mixture is stirred for 4 hours under the control of an oil bath at 60 ℃ and then cooled to room temperature for reaction overnight.

In the step (3), the ratio of the amount of the product 3, the raw material 4, triethylamine and DMAP in the step (2) is 1 mmol: 2 mmol: 2.2 mmol: 0.2 mol.

In the step (3), the temperature of the oil bath is controlled to be 50 ℃, and the reaction is carried out overnight.

In the step (4), the ratio of the product 5 in the step (3) to the methylamine methanol solution is 1 mmol: 5 mmol.

In the step (4), after reacting for 25-30min, adding sodium borohydride, and reacting for 1-1 h and 30 min.

The sulfonyl pyrrolidine P-CAB is used for preparing a medicament for inhibiting gastric acid secretion.

The invention has the following beneficial effects:

the preparation route of the invention has fewer process steps and easily obtained raw materials, and is suitable for industrial production. The obtained sulfonyl pyrrolidine P-CABs have excellent gastric acid secretion inhibition effect.