Preparation method of ranitidine hydrochloride with low NDMA content

A technology of ranitidine hydrochloride and ranitidine base, which is applied in the field of preparation of ranitidine hydrochloride with low NDMA content, can solve the problems of high processing cost, increased N-dimethylnitrosamine impurity content, and salt formation Problems such as poor properties and color of the final product, to achieve the effect of simple operation, reduced processing cost, and good product properties

Inactive Publication Date: 2020-12-04
北京云鹏鹏程医药科技有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0007] Through repeated tests, there are following disadvantages in forming salt with ethanol hydrochloric acid solution: the preparation process of ethanol hydrochloric acid solution is loaded down with trivial details, and the processing cost is high, and the color of the final product of salt formation is not good, and the residual ethanol solvent of the product exceeds the standard, and more importantly, this process will make N - Dimethylnitrosamine (NDMA) impurity content significantly increased

Method used

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  • Preparation method of ranitidine hydrochloride with low NDMA content
  • Preparation method of ranitidine hydrochloride with low NDMA content

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preparation example Construction

[0023] A preparation method of ranitidine hydrochloride with low NDMA content, comprising the following steps:

[0024] S1. Add ranitidine base to ethanol and stir until completely dissolved; the mass ratio of ranitidine base to ethanol is 1:3-5;

[0025] S2. Cool the solution to -5-5°C, add hydrochloric acid aqueous solution, adjust the pH to 4.5-6.5, and stir evenly; the concentration of the aqueous hydrochloric acid solution is 20%-38%, preferably 20%-25%;

[0026] S3, adding seed crystals, heat-preserving, stirring and crystallizing for 3-5 hours; the heat-preserving crystallization temperature is -5-5°C, and the stirring speed is 100-300rpm;

[0027] S4. The crystals are filtered, washed, drained and dried to obtain off-white crystalline solid ranitidine hydrochloride. Absolute ethanol is used for washing; vacuum drying is used, the temperature is controlled at 65-75°C, the time is 3-5h, and the vacuum degree is 0.09Mpa.

[0028]

Embodiment 1

[0030] Add 50g of ranitidine base to a 500ml reaction bottle, then add 300ml of absolute ethanol, stir and dissolve at room temperature; cool down to about -5°C, then slowly add 20% hydrochloric acid aqueous solution to the reaction bottle to adjust the pH value between 4.5-5.5 After the dropwise addition, add seed crystals, keep warm at -5°C for 5 hours, and stir and crystallize at 100rpm; the precipitated solid is filtered out with suction, and the filter cake is rinsed with 50ml of absolute ethanol; the filter cake is vacuum-dried at 65°C for 5 hours under reduced pressure to obtain Off-white crystalline solid 44.79g, molar yield 80.28%. HPLC content 99.6%, residual ethanol 0.24%, NDMA content 0.018PPM.

Embodiment 2

[0032] Add 120g of ranitidine base to a 1L reaction bottle, then add 600ml of absolute ethanol, stir and dissolve at room temperature; cool down to about 0°C, then slowly add 23% hydrochloric acid aqueous solution to the reaction bottle to adjust the pH value between 5.0-6.0 After the dropwise addition, add seed crystals, insulate at about 0°C and stir for crystallization for 4 hours, and the rotating speed is 200rpm; the precipitated solid is filtered out by suction, and the filter cake is rinsed with 100ml of absolute ethanol; the filter cake is vacuum-dried at 70°C for 4 hours under reduced pressure to obtain a White crystalline solid 117.42g, molar yield 83.67%. HPLC content 99.7%, residual ethanol 0.31%, NDMA content 0.036PPM.

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Abstract

The invention relates to the technical field of ranitidine hydrochloride preparation, in particular to a preparation method of ranitidine hydrochloride with low NDMA content, which comprises the following steps: adding a ranitidine base into ethanol, and stirring until complete dissloving is achieved; cooling the solution to -5 to 5 DEG C; controlling the temperature, adding a hydrochloric acid aqueous solution, adjusting the pH value to 4.5-6.5, and uniformly stirring; adding a seed crystal, preserving heat, stirring and crystallizing for 3-5 hours; and filtering a crystal, washing, drainingand drying to obtain the off-white crystal solid ranitidine hydrochloride. The salifying method disclosed by the invention has the advantages that the steps are simple, the raw material hydrochloric acid aqueous solution is easy to obtain, the product character is good, and the impurity content of the final product NDMA (N-Nitrosodimethylamine) is low.

Description

technical field [0001] The invention relates to the technical field of preparation of ranitidine hydrochloride, in particular to a preparation method of ranitidine hydrochloride with low NDMA content. Background technique [0002] Ranitidine Hydrochloride (Ranitidine Hydrochloride), the chemical name is N'-methyl-N-[2[[5-[(dimethylamino)methyl-2-furyl]methyl]thio]ethyl] -2-nitro-1,1-ethylenediamine hydrochloride, the structural formula is as follows: [0003] [0004] Ranitidine hydrochloride is H 2 - Receptor antagonist, which has obvious inhibitory effect on gastric acid secretion caused by physiology and pentagastrin, etc., and is used to relieve gastric pain, heartburn (heartburn) and acid regurgitation caused by hyperacidity, and at the same time treat benign gastric Ulcers, duodenal ulcers, anastomotic ulcers, reflux esophagitis, and Zoller-Ellison syndrome also have good therapeutic effects. Due to the rapid oral absorption, small dosage, less frequency of taking,...

Claims

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Application Information

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IPC IPC(8): C07D307/52
CPCC07D307/52
Inventor 赵玉山孟国彬贺斌
Owner 北京云鹏鹏程医药科技有限公司
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