Acotiamide hydrochloride impurity and preparation method thereof

A technology for acotiamide hydrochloride and impurities, which is applied in the field of new impurities of acotiamide hydrochloride and its preparation, can solve problems such as searching for structural information, achieve high yield and purity, simple post-treatment, and mild reaction conditions Effect

Pending Publication Date: 2022-01-28
NANJING HEALTHNICE MEDICAL TECH +2
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] A new impurity was found in the research on the synthesis process of acotiamide hydrochloride, but it was not described in the re

Method used

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  • Acotiamide hydrochloride impurity and preparation method thereof
  • Acotiamide hydrochloride impurity and preparation method thereof
  • Acotiamide hydrochloride impurity and preparation method thereof

Examples

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Embodiment 1

[0056] Example 1: (Z)-S-(2-amino-3-((2-(diisopropylamino)ethyl)amino)-3-oxoprop-1-en-1-yl)(2- Preparation of hydroxy-4,5-dimethoxybenzoyl) carbamate (impurity shown in formula II)

[0057] Add compound IV (10.00g, 22.20mmol) and 60mL of 80% isopropanol aqueous solution into a 250ml reaction flask, stir well and heat up to 60-70°C to completely dissolve the solid. Then, sodium hydroxide (0.44 g, 11.00 mmol) was added to the resulting mixed solution, and the temperature was raised to 70-80° C. while stirring, and the reaction was continued for 48 h while insulated and stirred, and the reaction of compound IV was monitored by TLC to complete. After the reaction is over, stop stirring, lower the temperature to 20-30°C, stir and crystallize for 4 hours, a large amount of solids precipitate, filter with suction, rinse the filter cake with 20mL of purified water, and vacuum the obtained solids under the conditions of 50°C and -0.09MPa After drying, 9.56 g of the compound of formula ...

Embodiment 2

[0059] Example 2: (Z)-2-amino-3-(((2-hydroxyl-4,5-dimethoxybenzoyl)carbamoyl)thio)acrylic acid (impurity shown in formula III) preparation

[0060] Add compound V (10.00g, 30.83mmol) and 100mL of 80% isopropanol aqueous solution into a 250ml reaction flask, stir well and heat up to 50-60°C to completely dissolve the solid. Then, sodium hydroxide (0.25 g, 6.25 mmol) was added to the resulting mixed solution, and the temperature was raised to 70-80° C. while stirring, and the reaction was continued for 50 h while insulated and stirred, and the reaction of compound V was monitored by TLC to complete. After the reaction is over, stop stirring, lower the temperature to 20-30°C, stir and crystallize for 4 hours, a large amount of solids precipitate, filter with suction, rinse the filter cake with 20mL of purified water, and vacuum the obtained solids under the conditions of 50°C and -0.09MPa After drying, 9.82 g of the compound of formula III was obtained, with a yield of 93.03% an...

Embodiment 3

[0062] Embodiment 3: the detection of acotiamide hydrochloride finished product

[0063] Get an appropriate amount of acotiamide hydrochloride finished product, accurately weigh, dissolve in an appropriate amount with diluent (mobile phase A-mobile phase B (85:15)), and dilute to make the solution that contains about 0.5mg in every 1ml, as test product solution. With reference to the high performance liquid chromatography (Chinese Pharmacopoeia 2015 edition four general rules 0512) test, use pentafluorophenyl bonded silica gel as filler (250 × 4.6mm, 5 μm); use 20nmol / L ammonium formate solution (ammonium formate 1.26g, Add 1000ml of water to dissolve, adjust the pH value to 3.0 with formic acid) as mobile phase A, and acetonitrile as mobile phase B, and carry out gradient elution as shown in the table below; the detection wavelength is 280nm, and the column temperature is 30°C. Precisely measure 20 μl of the test solution, inject it into the liquid mass spectrometry detector...

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Abstract

The invention relates to acotiamide hydrochloride impurity and a preparation method thereof, wherein the structure formula of the acotiamide hydrochloride impurity as shown in a formula II and a formula III is defined in the specification. The invention also provides a preparation method of the acotiamide hydrochloride impurity as shown in the formula II (formula III). The method comprises the following steps: (1) dissolving a compound IV (compound V) in a solvent at 30-90 DEG C; and (2) adding alkali into the mixed solution obtained in the step (1), and carrying out hydrolysis reaction at 60-90 DEG C to prepare the impurity as shown in the formula II (formula III), wherein the specific synthesis route is defined in the specification. The acotiamide hydrochloride impurity provided by the invention provides a new reference substance for impurity detection in an acotiamide hydrochloride raw material medicine, can be used for calibrating the content of the impurity in the acotiamide hydrochloride raw material medicine, and is more beneficial to development of a method for detecting related substances in the acotiamide hydrochloride raw material medicine, so that the product quality is controlled.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a new impurity of acotiamide hydrochloride and a preparation method thereof. Background technique [0002] Functional dyspepsia (FD), also known as dyspepsia, is a symptom primarily in the stomach and duodenum area, and is a common clinical syndrome. According to the Rome III diagnostic criteria, no metabolic, systemic or organic disease was found in the routine examination, and upper abdominal pain, postprandial fullness discomfort, burning sensation in the upper abdomen, and early satiety occurred for more than three months within six months. One or more symptoms of functional dyspepsia. [0003] Acotiamide hydrochloride was jointly developed by Astellas Pharmaceuticals and Zeli Shinyaku Co., Ltd., and was approved in Japan in February 2013 for the treatment of functional dyspepsia (FD). Its main mechanism of action is to increase the amount of acetylc...

Claims

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Application Information

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IPC IPC(8): C07C333/10G01N30/02G01N30/06
CPCC07C333/10G01N30/02G01N30/06
Inventor 周力薛亚军王华娟
Owner NANJING HEALTHNICE MEDICAL TECH
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