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One-pot method for preparing acotiamide hydrochloride

A technology for acotiamide hydrochloride and salt formation, which is applied in the field of preparation of acotiamide hydrochloride, can solve problems such as cumbersome industrial operations, high operating requirements, environmental problems, etc., and achieve the goal of overcoming cumbersome industrial operations and simplifying Operation process, the effect of improving production efficiency

Active Publication Date: 2014-09-17
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But there are following disadvantages in this route: 1. Thionyl chloride is used in the preparation process, which will produce sulfur dioxide and hydrogen chloride, which has high requirements for equipment and worker protection, and will also cause certain environmental problems; 2. The preparation of acid chlorides It is greatly affected by the ambient humidity and the quality of thionyl chloride, and the operation requirements are relatively high; 3. A class of solvent 1,2-dichloroethane is used; 4. Multiple material transfers are required
And the compound III in this route is often separated and purified first, and then the next step of reaction is carried out, which makes the industrial operation cumbersome

Method used

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  • One-pot method for preparing acotiamide hydrochloride
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  • One-pot method for preparing acotiamide hydrochloride

Examples

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example 1

[0037] Example 1: Preparation of Acotiamide Hydrochloride

[0038] Add 2,4,5-trimethoxybenzoic acid (20 g, 94.3 mmol) and 200 ml N,N-dimethylformamide into a 500 ml reaction flask. Add TBTU (30.88 g, 113.2 mmol), add N,N - Diisopropylethylamine (14.59g, 113.2mmol), stirred at room temperature for 2 hours. Add methyl 2-aminothiazole-4-carboxylate (14.92 g, 94.3 mmol), DMAP (2.30 g, 18.9 mmol), heat to 75°C, and stir for 24 hours. join in N,N -Diisopropylethylenediamine (27.16g, 188.6mmol), heated to 140°C and stirred for 10 hours. After cooling, add 400ml of n-butanol, stir, and let stand to separate layers. The upper layer was taken, washed with 400ml of saturated saline, and allowed to stand to separate layers. The upper layer was taken, and 120 ml of isopropanol hydrogen chloride was added dropwise at low temperature to precipitate a solid. Filter under reduced pressure, and put the filter cake into a blast drying oven at 60° C. for 1 hour to dry. 28.5 g of acot...

example 2

[0040] Example 2: Preparation of Acotiamide Hydrochloride

[0041] Add 2,4,5-trimethoxybenzoic acid (20g, 94.3mmol) to a 500ml reaction bottle, 200ml N,N - Dimethylacetamide. Add TBTU (30.88g, 113.2mmol), add N,N- diisopropylethylamine (14.59g, 113.2mmol)), stirred at room temperature for 2 hours. Add methyl 2-aminothiazole-4-carboxylate (14.92g, 94.3mmol), DMAP (2.3g, 18.9mmol), heat to 75°C, and stir for 24 hours. join in N,N -Diisopropylethylenediamine (27.16g, 188.6mmol), heated to 140°C and stirred for 10 hours. After cooling, add 400ml of n-butanol, stir, and let stand to separate layers. The upper layer was taken, washed with 400ml of saturated saline, and allowed to stand to separate layers. Take the upper layer, add 120 ml of isopropanol hydrogen chloride dropwise at low temperature, precipitate solid, filter under reduced pressure, and put the filter cake into a blast drying oven at 60°C for 1 hour to dry. 31.7 g of acotiamide hydrochloride (compound V)...

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Abstract

The invention relates to a one-pot method for preparing an acotiamide hydrochloride (a compound V). The method comprises the following steps: by taking 2,3,5-trimethoxybenzoic acid as shown in a formula (I) and 2-aminothiazole-4-methyl formate as shown in a formula (II) as raw materials, carrying out a condensation reaction to obtain a compound III; selecting an appropriate solvent and controlling a reaction condition, directly carrying out an aminating reaction between an intermediate III which is not separated and purified and N,N-diisoprylamino ethylamine as shown in a formula (IV), and finally obtaining the acotiamide hydrochloride (the compound V) by use of the one-pot method. The one-pot method for preparing the acotiamide hydrochloride has the advantages that the reaction steps are reduced, the operation process is simplified, and the production efficiency is improved; besides, the method is safe and environmental friendly, and suitable for industrial production. The formulas (I, II, III, IV and V) are as shown in the specification.

Description

technical field [0001] The invention relates to the technical field of preparation methods of acotiamide hydrochloride. Background technique [0002] Acotiamide (acotiamide), chemical name N-{2-[bis(1-methylethyl)amino]ethyl}-2-[(2-hydroxy-4,5-dimethoxybenzyl) Acyl)amino]thiazole-4-carboxamide hydrochloride trihydrate, jointly developed by Astellas Pharmaceuticals and Zeli Shinyaku Co., Ltd., was approved in Japan on June 6, 2013 for the treatment of functional Dyspepsia (FD), the world's first FD treatment drug, has good curative effect, no drug resistance and shows high safety. [0003] The methods for preparing acotiamide hydrochloride (compound V) reported in the literature mainly include the following: [0004] Route 1: (1. WO2012077673 (CN103237781 A) (2011)) [0005] [0006] Route 1 uses 4,5-dimethoxybenzoic acid as the starting material to obtain 2-bromo-4,5-dimethoxybenzoic acid through bromination and hydrolysis. 2-Bromo-4,5-dimethoxybenzoic acid ...

Claims

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Application Information

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IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 杜焕达丁建圣何永富王万青刘艳华
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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