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Synthesis method of prucalopride impurities

A technology of prucalopride and synthetic method, which is applied in the field of organic drug synthesis, can solve the problems of unobserved degradation, unobserved full degradation, etc., and achieve the effects of short reaction time, high purity and high yield

Active Publication Date: 2021-03-26
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Acid hydrolysis was initiated under milder conditions in 0.1N HCl at room temperature, but no degradation was observed
The acidity strength was gradually increased to 1N, and refluxed at 75°C for 24h, but no sufficient degradation was observed

Method used

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  • Synthesis method of prucalopride impurities
  • Synthesis method of prucalopride impurities
  • Synthesis method of prucalopride impurities

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Add 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzofuran carboxamide ( 74.7mg, 0.20mmol), Cu 2 O (1.4mg, 0.01mmol), 4-dimethylaminopyridine (24.4mg, 0.20mmol), N-hydroxyphthalimide (6.6mg, 0.04mmol), and acetonitrile (2.0ml) were stirred and dissolved. The reaction mixture was washed with O 2 Bubble for 30min and seal quickly. Then the reaction solution was stirred at 120° C. for 12 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by column chromatography to give 4-amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)benzofuran-7-carboxamide (38.8 mg, Yield 53%).

[0032] LC-MS (m / z): 364.1 [M-H] - ; 1 H-NMR (400MHz, DMSO-d6) δ: 7.92(d, J=0.4Hz=CH), 7.58(2H, CONH and ArH), 7.25(d, J=0.4Hz,=CH), 6.42(1H, s,-NH 2 ),3.78(1H,m,-CH),3.21(5H,m,-OCH 2and OCH 3 ),2.77(2H,m,-CH 2 in Piperidine),2.30(2H,m,-CH 2 ),2.01(2H,m,-CH 2 in Piperidine), 1.83 (2H, m, -CH 2 in Piperidine), 1.65 (...

Embodiment 2

[0034] Under air, add 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzo Furocarboxamide (74.7mg, 0.20mmol), N-hydroxyphthalimide (6.6mg, 0.04mmol) and acetonitrile (3.0mL) were stirred and dissolved. The reaction vial was sealed and the reaction mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain 4-amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)benzofuran -7-Carboxamide (40.2 mg, yield 55%).

Embodiment 3

[0036] Under air, add 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7-benzo Furocarboxamide (74.7mg, 0.20mmol), N-hydroxyphthalimide (6.6mg, 0.04mmol) and Cu(OAc) 2 ·H 2 O (2.0 mg, 0.01 mmol), the reaction vial was sealed and the reaction mixture was stirred at 120 °C for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain 4-amino-5-chloro-N-(1-(3-methoxypropyl)piperidin-4-yl)benzofuran -7-Carboxamide (49.8 mg, yield 68%).

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Abstract

The invention discloses a synthesis method of a prucalopride impurity, and relates to the technical field of organic synthesis of medicines. 4-amino-5-chloro-2, 3-dihydro-N-[1-(3-methoxypropyl)-4-piperidyl]-7-benzofuranformamide is used as a raw material, the target product is prepared by taking easily available N-hydroxyphthalimide, butylated hydroxytoluene (BHT) and tetramethylpiperidine nitrogen oxide (TEMPO) as catalysts through a one-pot method, a high-purity reference substance is provided for detection and content control of the two impurities in the prucalopride product, and the methodis short in reaction time, high in yield, high in purity and suitable for industrial production.

Description

Technical field: [0001] The invention relates to the technical field of organic synthesis of medicines, in particular to a synthesis method of prucalopride impurities. Background technique: [0002] Prucalopride succinate, chemical name 4-amino-5-chloro-2,3-dihydro-N-[1-(3-methoxypropyl)-4-piperidinyl]-7- Benzofuran carboxamide succinate is a new generation of selective and high-affinity 5-hydroxytryptamine 4 (5-HT4) receptor agonist developed by Belgian company Movetis. In October 2009, it was approved by the European Union for the treatment of chronic constipation. [0003] The EMEA (https: / / www.ema.europa.eu / en / documents / assessment-report / resolor-epar-public-assessment-report_en.pdf) publishes the prucalopride succinate assessment report. The report shows that three batches of commercial-scale batches of samples were subjected to stability studies under different storage conditions, including 6 long-term stability studies completed under the conditions of 25°C and 60% RH...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 冯乙巳冯慧怡谢大乐何勇
Owner HEFEI UNIV OF TECH
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