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Separation method and synthesis method of glimepiride intermediate and isomers thereof

A technology of separation method and synthesis method, which is applied in the field of separation method and synthesis of glimepiride intermediates and its isomers, can solve the problems of not finding a separation method for benzenesulfonyl chloride, and achieve the effect of quality assurance

Inactive Publication Date: 2019-11-29
BEIJING YUEKANGKECHUANG PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] It is found by HPLC monitoring that there are adjacent and meta-isomers in the reaction process, but the prior art does not find a suitable 4-[2-(3-ethyl-4-methyl-2-oxygen-3-pyrrole) Method for Separation of Ortho and Meta Isomers of Phenyl-1-Carboxamido) Ethyl] Benzenesulfonyl Chloride

Method used

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  • Separation method and synthesis method of glimepiride intermediate and isomers thereof
  • Separation method and synthesis method of glimepiride intermediate and isomers thereof
  • Separation method and synthesis method of glimepiride intermediate and isomers thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Glimepiride intermediate and its isomers (4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]benzene Separation method of ortho-isomer and meta-isomer of sulfonyl chloride

[0040] 4-[2-(3-ethyl-4-methyl-2-oxygen-3-pyrroline-1-carboxamido) ethyl] benzenesulfonyl chloride (intermediate ) and its ortho-isomers and meta-isomers are separated, and the chromatographic conditions are as follows:

[0041] Chromatographic column: Agilent Poroshell 120 EC-C18 4.6×150mm, 4μm

[0042] Mobile phase: A (0.1% sodium dihydrogen phosphate solution (adjust the pH value to 3.0±0.5 with phosphoric acid))-B (acetonitrile)=70:30;

[0043] Detection wavelength: 228nm;

[0044] Column temperature: 30°C;

[0045] Flow rate: 1.0mL / min;

[0046] Isocratic elution:

[0047]

[0048] The separation method provided in this application can well separate the ortho isomer and the meta isomer.

Embodiment 2

[0049] Example 2 Glimepiride intermediate and its isomer (4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]benzene Synthetic method of sulfonyl chloride (intermediate) and its ortho isomer and meta isomer)

[0050] Add 27.2g (0.10mol) 3-ethyl-4-methyl-2-oxo-3-pyrroline-1-N-(2-phenylethyl)-formamide to the flask, 34.95g (0.30mol) chlorosulfonic acid ), the addition was completed, and the reaction was stirred at 80°C for 5h, and the HPLC monitoring reaction was complete;

[0051] Add the reaction liquid to 200g of ice water, stir to precipitate a white solid, filter, wash the filter cake with water to obtain white crystals, and dry at 50°C for 12h; to obtain 4-[2-(3-ethyl-4-methyl-2-oxo- 3-pyrroline-1-carboxamido)ethyl]benzenesulfonyl chloride and its ortho and meta isomers were 26.2g in total;

[0052] The white crystals were separated by preparative high-performance liquid chromatography, and the chromatographic conditions were as follows:

[0053] Chromatograph...

Embodiment 3

[0062] Example 3 Glimepiride intermediate and its isomer (4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]benzene Synthetic method of sulfonyl chloride (intermediate) and its ortho isomer and meta isomer)

[0063] Add 27.2g (0.10mol) 3-ethyl-4-methyl-2-oxo-3-pyrroline-1-N-(2-phenylethyl)-formamide to the flask, 69.9g (0.60mol) of chlorosulfonic acid ), the addition was completed, and the reaction was stirred at 100°C for 2h, and the HPLC monitoring reaction was complete;

[0064] Add the reaction liquid to 210g of ice water, stir to precipitate a white solid, filter, wash the filter cake with water to obtain white crystals, and dry at 50°C for 15h to obtain 4-[2-(3-ethyl-4-methyl-2-oxo- 3-pyrroline-1-carboxamido)ethyl]benzenesulfonyl chloride and its ortho and meta isomers were 28.8g in total;

[0065] The white crystals were separated by preparative high-performance liquid chromatography, and the chromatographic conditions were as follows:

[0066] Chromatogra...

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Abstract

The invention provides a separation method and a synthesis method of a glimepiride intermediate and isomers thereof. The separation method utilizes high performance liquid phase preparative chromatography to separate a glimepiride intermediate from ortho-isomer and meta-isomers thereof generated by reaction; and reacts 3-ethyl-4-methyl-2-oxo-3-pyrroline-1-N-(2-phenethyl)-formamide with chlorosulfonic acid at a high temperature of 80-150DEG C, and utilizes high performance liquid phase preparative chromatography for separation. The separation method can effectively separate the glimepiride intermediate from the ortho-isomers and meta-isomers thereof. Also the synthesis method reduces the dosage of chlorosulfonic acid, strictly controls the reaction temperature and the reaction time, and canincrease the yield of ortho-isomers and meta-isomers.

Description

technical field [0001] The invention belongs to the field of isomer separation and synthesis of pharmaceutical intermediates, and in particular relates to a separation method and a synthesis method of a glimepiride intermediate and isomers thereof. Background technique [0002] Glimepiride (glimepiride), the chemical name is 1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-ethyl] -Benzenesulfonyl]-3-(trans-4-methylcyclohexyl)-urea, its chemical structure is as follows: [0003] [0004] Glimepiride is a third-generation sulfonylurea long-acting antidiabetic drug, and its mechanism of action is through binding to the sulfonylurea receptor on the surface of pancreatic β-cells, which is related to the ATP-sensitive K+ (KATP) channel. Coupled to promote the closure of KATP channels, causing depolarization of the cell membrane and opening of voltage-dependent calcium channels, Ca 2+ Influx promotes the release of insulin and inhibits hepatic glucose synthesis. Gli...

Claims

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Application Information

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IPC IPC(8): C07D207/38
CPCC07D207/38
Inventor 宋更申郭勇张婷婷
Owner BEIJING YUEKANGKECHUANG PHARM TECH CO LTD
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