Industrial preparation method of aclatonium napadisilate

A technology of ethacylcholine naphthalene disulfonate and acetyllactoylcholine, which is applied in the field of industrial preparation of acetyllactone naphthalene disulfonate, and can solve the problems of difficult acquisition of raw materials, unfriendly environment, poor stability of intermediates, etc. , to avoid the use of volatile strong corrosive reagents, improve product purity, and reduce unit operations

Active Publication Date: 2019-10-29
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The problems in the synthetic method of reported naphthalene disulfonate ethacyl ammonium or its analogs include: the raw material (acetolactic anhydride) used is difficult to obtain, a large amount of environmentally unfriendly volatile, highly corrosive Reagents (such as acetyl chloride, thionyl chloride) and high-cost catalysts (such as solid superacids), high requirements for process equipment (such as high-temperature vacuum distillation, etc.), and poor stability of intermediates cause higher production costs, making Synthetic methods are difficult to achieve good industrial production
Due to factors such as raw materials or synthesis processes, the official production of ethyl lactocholesterol naphthalene disulfonate has not yet been realized in China

Method used

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  • Industrial preparation method of aclatonium napadisilate
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  • Industrial preparation method of aclatonium napadisilate

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Step 1): Small-scale preparation of acetolactic acid catalyzed by hydrochloric acid - add 200g of lactic acid (85% aqueous solution, 1.00 equivalent) and 5mL of concentrated hydrochloric acid into a 1L three-necked flask and stir mechanically, reduce the reaction to 0-10°C, and control the reaction temperature At 10-20°C, add 360g (1.90 equivalent) of acetic anhydride dropwise for 45 minutes. After the dropwise addition, transfer the reaction solution to a 1L single-necked bottle, slowly raise the temperature to 90-100°C and concentrate under reduced pressure until the weight of the residue is about 250g. , to obtain acetolactic acid with a yield of about 100%, which is directly used in subsequent reactions.

Embodiment 2

[0034] Step 1): Small-scale preparation of acetolactic acid catalyzed by improved hydrochloric acid - add 200g of lactic acid (85% aqueous solution, 1.00 equivalent) to a 1L three-neck flask, reduce the reaction to 0-10°C, add 1mL of acetyl chloride, dropwise After stirring for 5 minutes, continue to add 360 g (1.90 equivalents) of acetic anhydride dropwise. Control the reaction temperature at 10-20°C for 25 minutes. Concentrate under pressure until the weight of the residue is about 250g to obtain acetolactic acid with a yield of about 100%, which is directly used in subsequent reactions.

Embodiment 3

[0036] Step 1): small-scale preparation of acetolactic acid catalyzed by sulfuric acid—similar to Example 1, add 200 g of lactic acid (85% aqueous solution, 1.00 equivalent) and 5 mL of concentrated sulfuric acid into a 1 L three-necked flask, stir mechanically, and reduce the reaction to 0 At ~10°C, add 360g (1.90 equivalent) of acetic anhydride dropwise for 30 minutes. After the dropwise addition, transfer the reaction solution to a 1L single-necked bottle, slowly raise the temperature to 90-100°C and concentrate under reduced pressure until the weight of the residue is about 270g, that is Acetolactic acid (containing sulfuric acid) is obtained with a yield of about 100%, which can be directly used in subsequent reactions.

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Abstract

The invention discloses an industrial preparation method of aclatonium napadisilate. The industrial preparation method comprises the following steps that lactic acid reacts with acetic anhydride, chloroformate and N,N-dimethylethanolamine in sequence to obtain acetyllactylcholine, acetyllactylcholine is added with acid to be prepared into a salt and then separated, and a product reacts with 1,5-naphthalenedisulfonic acid dimethyl ester to obtain aclatonium napadisilate. The industrial preparation method has the advantages that aclatonium napadisilate is prepared by a ''mixed acid anhydride strategy'', and the use of a volatile highly corrosive reagent can be avoided; water can be used as a solvent for preparation of an intermediate, and the amount of an organic solvent can be avoided or reduced; a ''one-pot method'' can be adopted to prepare the intermediate to reduce unit operation; the solvent can be directly added for crystallization in the post-processing process of the preparationof a finished product to improve the purity of the product; and the reaction scale can be enlarged to more than ten kilograms.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an industrialized preparation method of ethyl lactocholine naphthalene disulfonate. Background technique [0002] Naphthalene disulfonate ethyl lactoammonium (chemical name 2-[2-(acetyloxy)-1-oxypropoxy]-N,N,N-trimethylethylammonium-1,5-naphthalene disulfonate Aclatonium Napadisilate, English name is Aclatonium Napadisilate) is a synthetic cholinergic drug that enhances smooth muscle and digestive tract motility. It was developed by Toyama Chemical Industry Co., Ltd. and launched in 1981. It has an excitatory effect and is suitable for the treatment of abnormal digestive tract function, chronic gastritis, biliary tract dyskinesia, and postoperative digestive tract surgery. Its chemical structure is as follows: [0003] [0004] U.S. Patent US 3903137 has reported two kinds of synthetic methods of naphthalene disulfonate ethyl lactocholamine, the first method us...

Claims

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Application Information

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IPC IPC(8): C07C213/08C07C219/06C07C303/32C07C309/35
CPCC07C213/08C07C303/32C07C213/06C07C51/56C07C67/08C07C219/06C07C309/35C07C57/34C07C69/14
Inventor 李博徐浩宇蔡伟顾国庆韩林李飞飞陈小青陈亮
Owner YANGTZE RIVER PHARM GRP CO LTD
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