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Preparation method of anticholinergic agent atropine sulphate

A technology of atropine sulfate and atropine, applied in the direction of organic chemistry, can solve the problems of high requirements for reaction equipment, unfavorable industrial production, harsh reaction conditions, etc., and achieve the effect of low production cost, low cost and mild reaction conditions

Active Publication Date: 2015-02-11
WUHAN WUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The reaction conditions of this route are relatively harsh, and the requirements for reaction equipment are relatively high. At the same time, the reaction conversion rate is low, and the production cost is high, which is not conducive to industrial production.

Method used

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  • Preparation method of anticholinergic agent atropine sulphate
  • Preparation method of anticholinergic agent atropine sulphate
  • Preparation method of anticholinergic agent atropine sulphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the preparation method of compound III

[0032] Add 250g (1.66mol) of methyl phenylacetate (compound II), 66.75g (1.66mol) of sodium hydroxide into a 1L three-necked flask, and then add 833ml of purified water and stir to raise the temperature to 70-85°C. After reacting for 4-5 hours, the temperature was lowered to about 30°C, and concentrated hydrochloric acid was added to adjust the pH to 1, and a large amount of white solid was precipitated immediately. Stir and crystallize, filter and dry with suction to obtain 185 g of compound III as a white solid with a yield of 85%.

Embodiment 2

[0033] Embodiment 2: the preparation method of compound IV

[0034] Add 100g (0.73mol) of phenylacetic acid (compound III) and 105g (0.88mol) of thionyl chloride into a 1L three-necked flask, then add 500ml of dichloromethane, add DMF as a catalyst, stir and heat up to 40°C under reflux, and react for 5 to 6 hours Finally, the solution was transferred to a 500ml single-necked flask and spin-dried. 110 g of light yellow liquid was obtained. Yield 97%

Embodiment 3

[0035] Embodiment 3: the preparation method of compound V

[0036] Add 110g (0.71mol) of compound IV to a 500ml three-necked flask and stir at room temperature, add 93.3g (0.66mol) of tropine alcohol and 80ml of chloroform into a 500ml beaker and stir until dissolved, and slowly drop the prepared tropine alcohol solution Add it to a three-necked flask, heat up vigorously, and react at 70-85°C for 6-7h. After the reaction is over, pour the reaction solution into a 2L beaker, stir, add 800-1000L of purified water, a large amount of white solids are precipitated, adjust the pH to 1-2 with 5% HCl solution, let stand for stratification, and separate the acidic water layer, three Keep the chloromethane layer; add 5% HCl to the chloroform layer to readjust the pH to 1~2, and let it stand for stratification; separate the water layer, combine the above water layers, wash twice with 50*2 dichloromethane, and let stand Separate the layers, separate the water layer, discard the dichloro ...

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Abstract

The invention provides a synchronizing method of atropine sulphate. The method is characterized in that hydrolyzing methyl phenoxyacetate (II) is hydrolyzed to obtain a compound (III); the compound (III) and thionyl chloride are subjected to acylation reaction to obtain a compound (IV); the compound (IV) and 8-methyl-8-azabicyclo[3.2.1]oct-3-alchol are subjected to condensation reaction to obtain a compound (V); the compound (V) and paraformaldehyde are used for producing atropine (VI) under an alkaline condition; the atropine (VI) is salified under an acidic condition to obtain the atropine sulphate (I). The preparation method is simple in technology, high in yield, high in purity, low in monomer impurity and easy for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of an anticholinergic drug atropine sulfate. Background technique [0002] Atropine sulfate: the chemical name is α-(hydroxymethyl)phenylacetic acid-8-methyl-8-azabicyclo[3.2.1]-3-octyl sulfate, and its chemical structure is as follows: [0003] [0004] Atropine sulfate is an anticholinergic drug that inhibits glandular secretion and dilates the pupil. For gastrointestinal tract, biliary colic, mydriatic examination optometry, keratitis, organophosphorus pesticide poisoning, septic shock, smooth muscle spasm, gastric and duodenal ulcer disease, administration before anesthesia, etc. [0005] The atropine synthetic route that has been publicly reported is as follows: [0006] 1. Using tropic acid as the starting material, the esterification product of tropic acid obtained through hydroxyl protection, reacts with tropin alcohol after acylati...

Claims

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Application Information

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IPC IPC(8): C07D451/10
CPCC07D451/10
Inventor 皮金红张伟丁友友赵涛涛李文阳魏金维张琦谢国范
Owner WUHAN WUYAO PHARMA
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