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Preparation method of prucalopride succinate

A technology of reaction and dioxolane, which is applied in the field of preparation of prucalopride, can solve problems such as inconvenient operation, and achieve the effects of simple and convenient operation, high product purity and mild reaction conditions

Active Publication Date: 2018-12-11
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route uses butyllithium twice, which requires a low temperature of -78°C, and the isomers produced by chlorination need to be separated by column chromatography, which is inconvenient to operate

Method used

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  • Preparation method of prucalopride succinate
  • Preparation method of prucalopride succinate
  • Preparation method of prucalopride succinate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Step 1, the preparation of 2-(4-nitrophenyl)-1,3-dioxolane: take 151g of 4-nitrobenzaldehyde, 62g of ethylene glycol, and 190g of p-toluenesulfonic acid, and dissolve them in 300mL of toluene , after heating to reflux for 12 hours, the toluene was recovered under reduced pressure, the residue was added to 300 mL of ethyl acetate, washed with water, the organic layer was dried over anhydrous sodium sulfate, and the filtrate was filtered and distilled under reduced pressure to obtain 180 g of a light yellow solid.

[0046] Step 2, the preparation of 2-(4-aminophenyl)-1,3-dioxolane: Take 195g of 2-(4-nitrophenyl)-1,3-dioxolane, dissolve it in 400mL In water ethanol, add palladium carbon catalyst (Pd / C) 10g, feed hydrogen, after heating to reflux reaction for 12h, cool to room temperature, filter to remove palladium carbon catalyst (Pd / C), filtrate decompression recovery solvent white solid 165g.

[0047] Step 3, the preparation of 2-(4-acetylaminophenyl)-1,3-dioxolane: Tak...

Embodiment 2

[0055] Step 1, the preparation of 2-(4-nitrophenyl)-1,3-dioxolane: take 151g of 4-nitrobenzaldehyde, 70g of ethylene glycol, and 200g of p-toluenesulfonic acid, dissolve in 300mL of toluene , after heating to reflux for 12 hours, the toluene was recovered under reduced pressure, the residue was added to 300 mL of ethyl acetate, washed with water, the organic layer was dried over anhydrous sodium sulfate, and the filtrate was filtered and distilled under reduced pressure to obtain 191 g of a light yellow solid.

[0056] Step 2, the preparation of 2-(4-aminophenyl)-1,3-dioxolane: Take 195g of 2-(4-nitrophenyl)-1,3-dioxolane, dissolve it in 400mL In water ethanol, add palladium carbon catalyst (Pd / C) 10g, feed hydrogen, after heating to reflux reaction for 12h, cool to room temperature, filter to remove palladium carbon catalyst (Pd / C), filtrate decompression recovery solvent white solid 165g.

[0057] Step 3, the preparation of 2-(4-acetylaminophenyl)-1,3-dioxolane: Take 165g of...

Embodiment 3

[0065] Step 1, the preparation of 2-(4-nitrophenyl)-1,3-dioxolane: take 151g of 4-nitrobenzaldehyde, 75g of ethylene glycol, and 210g of p-toluenesulfonic acid, and dissolve them in 300mL of toluene , after heating to reflux for 12 hours, the toluene was recovered under reduced pressure, the residue was added to 300 mL of ethyl acetate, washed with water, the organic layer was dried over anhydrous sodium sulfate, and the filtrate was filtered and distilled under reduced pressure to obtain 195 g of a light yellow solid.

[0066] Step 2, the preparation of 2-(4-aminophenyl)-1,3-dioxolane: Take 195g of 2-(4-nitrophenyl)-1,3-dioxolane, dissolve it in 400mL In water ethanol, add palladium carbon catalyst (Pd / C) 10g, feed hydrogen, after heating to reflux reaction for 12h, cool to room temperature, filter to remove palladium carbon catalyst (Pd / C), filtrate decompression recovery solvent white solid 165g.

[0067] Step 3, the preparation of 2-(4-acetylaminophenyl)-1,3-dioxolane: Tak...

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PUM

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Abstract

The invention provides a preparation method of prucalopride succinate. The method comprises the steps that 4-nitrobenzaldehyde is taken as an initial raw material, and protected by formyl group, nitroreduction, amino protection, aromatic hydrocarbon chlorination, nucleophilic substitution, molecular internal cyclization, chlorination, deprotection and oxidative amidation are conducted sequentially, and prucalopride succinate is synthesized. The preparation method is safe in technology, no highly toxic reagents is used, the preparation method is green and environmentally friendly, the by-products generated in the reaction are less, and the yield is improved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of prucalopride. Background technique [0002] Prucalopride, the chemical name is 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7- Benzofuran carboxamide is a selective 5-HT developed by Belgium Movetis NV company 4 Receptor agonist. In October 2009, the European Medicines Agency approved its monosuccinate for marketing. It is clinically used to treat female constipation that cannot be relieved by laxatives. The trade name is Resolor. This product is the first new type of dihydrobenzofuran carboxylic acid derivatives to promote intestinal motility agent, which can efficiently and selectively stimulate 5-HT 4a and 5-HT 4b Receptors, increase gastrointestinal motility, improve constipation symptoms. [0003] The synthetic scheme of prucalopride mainly contains following three kinds: [0004] Scheme 1, Yuan Youzhi and othe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 冯成亮严宾张民
Owner IANGSU COLLEGE OF ENG & TECH
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