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Preparation method of (E)-N-[3-(methylamino)propyl]-3-(thiophene-2-yl) acrylamide and salt thereof

A technology of acrylamide salt and acrylamide, which is applied in the field of medicine and chemical industry, and can solve the problems of no public information reporting synthesis methods, etc.

Active Publication Date: 2015-03-11
SHAOXING MINSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, pyrantel impurity A has been sold in the market, but pyrantel impurity B has not been sold in the market, and there is no public information about its synthesis method

Method used

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  • Preparation method of (E)-N-[3-(methylamino)propyl]-3-(thiophene-2-yl) acrylamide and salt thereof
  • Preparation method of (E)-N-[3-(methylamino)propyl]-3-(thiophene-2-yl) acrylamide and salt thereof
  • Preparation method of (E)-N-[3-(methylamino)propyl]-3-(thiophene-2-yl) acrylamide and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The synthetic route is:

[0061]

[0062] (1) Preparation of (2E)-3-(2-thienyl)acryloyl chloride (VI)

[0063] Add 15.4g (0.1mol) of (2E)-3-(2-thienyl)acrylic acid (V), 300ml of dichloromethane and 2ml of dimethylformamide into a four-neck flask, cool down to 10°C under nitrogen protection, and dropwise add 21.6 g (0.17 mol) of oxalyl chloride. After the dropwise addition, the system was heated to reflux, and stirred and reacted at reflux temperature for 3 hours. After the reaction, dichloromethane was distilled off under reduced pressure to obtain 17.7 g of off-white solid, namely (2E)-3-(2-thienyl)acryloyl chloride (VI), with a yield of about 100%.

[0064] (2) Preparation of (E)-N-[3-(methyl-tert-butoxycarbonylamino)propyl]-3-(thiophen-2-yl)acrylamide (VIII)

[0065] Add 28.2g (0.15mol) of N-tert-butoxycarbonyl-N-methyl-1,3-propanediamine (VII), 380ml of dichloromethane and 20.2g (0.2mol) of triethylamine into a four-necked flask, nitrogen The temperature was l...

Embodiment 2

[0074] (1) Preparation of (2E)-3-(2-thienyl)acryloyl chloride

[0075] Add 15.4g (0.1mol) of (2E)-3-(2-thienyl)acrylic acid and 300ml of dichloromethane into a four-neck flask, cool down to 5°C under nitrogen protection, and add 23.8g (0.2mol) of thionyl chloride dropwise After the dropwise addition, the system was heated to reflux, and stirred and reacted at reflux temperature for 2 hours. After the reaction, dichloromethane was distilled off under reduced pressure to obtain a light yellow solid, namely (2E)-3-(2-thienyl)acryloyl chloride.

[0076] (2) Preparation of (E)-N-[3-(methyl-tert-butoxycarbonylamino)propyl]-3-(thiophen-2-yl)acrylamide

[0077]Add 24.5g (0.13mol) of N-tert-butoxycarbonyl-N-methyl-1,3-propanediamine, 300ml of tetrahydrofuran and 19g (0.24mol) of pyridine into a four-necked flask, cool down to 10°C under nitrogen protection, and slowly A solution of 16.4g (0.095mol) (2E)-3-(2-thienyl)acryloyl chloride dissolved in 100ml tetrahydrofuran was added dropw...

Embodiment 3

[0087] synthetic route:

[0088]

[0089] (1) Preparation of (E)-N-[3-(methylbenzyloxycarbonylamino)propyl]-3-(thiophen-2-yl)acrylamide

[0090] Add 0.1mol of N-benzyloxycarbonyl-N-methyl-1,3-propanediamine, 200ml of dioxane and 1-ethyl-(3-dimethylaminopropyl)carbonyl diamine into a four-neck flask Imine hydrochloride (EDC.HCL) 0.15 mol, 4-dimethylaminopyridine (DMAP) 0.03 mol, triethylamine 0.3 mol, under nitrogen protection, lower the temperature to 5-10°C, stir for 2 hours, add 0.1 mol A solution of (2E)-3-(2-thienyl)acrylic acid dissolved in 100ml of dioxane was stirred and reacted at 30-35°C for 23 hours after the dropwise addition. After the reaction is completed, filter, spin the filtrate to dryness, add diethyl ether to the residual solid, stir at room temperature and filter to remove the solid, and concentrate the filtrate to dryness under reduced pressure to obtain (E)-N-[3-(methylbenzyloxycarbonylamino)propyl ]-3-(thiophen-2-yl)acrylamide.

[0091] (2) Prepara...

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Abstract

The invention relates to a preparation method of (E)-N-[3-(methylamino) propyl]-3-(thiophene-2-yl) acrylamide and salt thereof. The method comprises the following steps of: firstly, carrying out amidation on N-protecting group-N-methyl-1, 3-propane diamine (II) and (2E)-3-(2-thienyl) acrylic acid or a derivative (II) thereof to generate (E)-N-[3-(methyl protecting group amino) propyl]-3-(thiophene-2-yl) acrylamide (IV); and removing a proecting group of a acrylamide compound (IV) to obtain the (E)-N-[3-(methylamino) propyl]-3-(thiophene-2-yl) acrylamide (I), i.e. a pyrantel impurity B. The pyrantel impurity B synthesis process is available in raw materials, moderate in reaction condition, high in product purity, and the reaction process is easy to control; and a reference product meeting the requirement can be provided for the quality control of the pyrantel by preparing the pyrantel impurity B.

Description

technical field [0001] The invention belongs to the technical fields of medicine and chemical industry, and in particular relates to a preparation method of (E)-N-[3-(methylamino)propyl]-3-(thiophen-2-yl)acrylamide and salts thereof. Background technique [0002] Pyrantel is a broad-spectrum, high-efficiency, and low-toxicity gastrointestinal nematode expelling drug, which is commonly used in the treatment of ascariasis, pinworm disease and duodenal hookworm disease. Pyrantel was synthesized for the first time in 1965, developed by Pfizer, and listed in 1970. Pyrantel is mostly made into salt form, including pamoate, tartrate and citrate. At present, pyrantel pamoate is included in the US Pharmacopoeia, European Pharmacopoeia, Japanese Pharmacopoeia and Chinese Pharmacopoeia. [0003] In the United States Pharmacopoeia and European Pharmacopoeia, when the quality standard of pyrantel pamoate is detected by high performance liquid chromatography, two known impurities are spe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/24
CPCY02P20/55
Inventor 张奎周慧滕南鑫
Owner SHAOXING MINSHENG PHARMA