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Preparation method of atropine sulphate

A technology of atropine sulfate and tropin ester, applied in the direction of organic chemistry, etc., can solve the problems of unfavorable increase in product yield, cumbersome operation, high cost, etc., achieve simplification of salt formation and post-treatment steps, simple process operation, and reduce production cost Effect

Active Publication Date: 2015-03-11
河南豫辰药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the problem that intermediate α-formylphenylacetic acid tropin is incompletely hydrolyzed in sulfuric acid, and the hydrolysis effect is poor in a single solvent, so the yield of atropine sulfate prepared is low and the cost is high
In addition, in this method, the crude product of atropine is salt-formed in the salt-formation process and then crystallized to obtain the product after recovery of the solvent, which is too cumbersome to operate and is not conducive to improving the yield of the product.

Method used

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  • Preparation method of atropine sulphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Add 50 ml of methanol, 200 ml of chloroform, and 20 g (0.06 mol) of α-formylphenylacetic acid tropinate into the reaction flask and stir evenly. Add 5 g of potassium borohydride (0.09 mol), stirred and hydrolyzed for 4 hours. Add 200 ml of water to the above mixture, separate the chloroform organic layer, extract the water layer once with chloroform and merge into the original chloroform layer, after the chloroform layer is distilled to recover chloroform, freeze and crystallize for 2 hours, filter to obtain 16.9 g (0.058mol ).

[0025] Put 16.9 g (0.058 mol) of the crude product of atropine, 30 ml ethanol, and 100 ml acetone into the reaction bottle, stir, add sulfuric acid dropwise in an ice-water bath at 0-10°C to adjust the pH of the solution to 5-6, refrigerate overnight for crystallization, filter, 16.1 g (0.049 mol) of atropine sulfate were obtained.

Embodiment 2

[0027] Add 30 ml of methanol, 200 ml of chloroform, and 20 g (0.06 mol) of α-formylphenylacetic acid tropinate into the reaction flask and stir evenly. Add 6.5 g of potassium borohydride (0.12 mol), stirred and hydrolyzed for 4 hours. Add 200 ml of water to the above mixture, separate the chloroform layer, extract the water layer once with chloroform and merge into the original chloroform layer, recover the chloroform by distillation from the chloroform layer, freeze and crystallize for 2 hours, and filter to obtain 17.1 g (0.059 mol) of atropine crude product ).

[0028] Put 17.1 g (0.059 mol) of the crude product of atropine, 30 ml ethanol, and 150 ml acetone into the reaction bottle, stir, add sulfuric acid dropwise in an ice-water bath at 0-10°C to adjust the pH of the solution to 5-6, freeze overnight to crystallize, filter, 16.8 g (0.051 mol) of atropine sulfate was obtained.

Embodiment 3

[0030] Add 50 ml of ethanol, 200 ml of chloroform, and 20 g (0.06 mol) of α-formylphenylacetic acid tropinate into the reaction flask and stir evenly. Add potassium borohydride 5 (0.09 mol) three times in an ice-water bath at 0-10°C. ) g, stirred and hydrolyzed for 4 hours. Add 200 ml of water to the above mixture, separate the chloroform organic layer, extract the water layer once with chloroform and merge into the original chloroform layer, after the chloroform layer is distilled and recovered chloroform, freeze and crystallize for 2 hours, filter to obtain 16.8 g (0.058 mol) of atropine crude product ).

[0031] Put 16.8 g (0.058 mol) of the crude product of atropine, 30 ml diethyl ether, and 100 ml acetone into the reaction bottle, stir, add sulfuric acid dropwise in an ice-water bath at 0-10°C to adjust the pH of the solution to 5-6, refrigerate overnight for crystallization, and filter. 16.5 g (0.050 mol) of atropine sulfate was obtained.

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Abstract

The invention discloses a preparation method of atropine sulphate and solves the problem that an intermediate alpha-formoxyl phenylacetic acid tropeine is incompletely hydrolyzed in sulfuric acid and poor in hydrolysis effect in a single solvent, and an atropine crude product salt forming process is tedious in operation. The preparation method specifically comprises the following steps: I, adding potassium borohydride into a mixture containing alpha-formoxyl phenylacetic acid tropeine, alcohol and chloroform; II, adding an appropriate amount of water into the mixture and separating out an organic layer; III, distilling the organic layer to recover chloroform so as to obtain a faint yellow oily liquid; IV, adding acetone into the faint yellow oily liquid for freezing crystallization to obtain an atropine crude product; V, dropwise adding sulfuric acid into a solution containing the mixed solvent and the atropine crude product to adjust the pH of the solution to be greater than 4 but less than 7 at the temperature of 5 DEG C below zero to 10 DEG; VI, freezing the mixture overnight and crystallizing, filtering and drying to obtain atropine sulphate white crystals. The preparation method disclosed by the invention not only greatly improves the content and molar yield of the atropine sulphate crude product, but also lowers the cost to a great extent, and further has the characteristics of being simple and convenient to operate.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of an anticholinergic drug, especially a preparation method of atropine sulfate. Background technique [0002] Atropine sulfate, English name Atropine sulfate monohydrate, chemical name α-hydroxymethyl phenylacetyl tropinol sulfate monohydrate, is an anticholinergic drug, which can inhibit the secretion of glands and diffuse pupils, and is mainly used for the treatment of smooth muscle spasm , Gastric ulcer and duodenal ulcer disease, organophosphorus pesticide poisoning, septic shock and other diseases. [0003] At present, most pharmaceutical companies use α-formyl phenylacetate to be hydrolyzed with sulfuric acid and then extracted with chloroform solvent to obtain atropine crude product after crystallization, and then add sulfuric acid-ethanol solution dropwise to the mixed solution of atropine crude product and ethanol to recover Atropine s...

Claims

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Application Information

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IPC IPC(8): C07D451/10
CPCC07D451/10
Inventor 李明哲胡新奇王心久丁朝旺
Owner 河南豫辰药业股份有限公司
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