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A kind of preparation method of azedipine impurity b

A technology for azeldipine and impurities, which is applied in the field of raw material drug preparation and can solve the problems of large solvent ratio, long reaction time, low conversion rate and content, etc.

Active Publication Date: 2020-09-22
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction conditions disclosed in this document are easy to implement and can only be used to study its degradation method. It is very inappropriate as a process for preparing impurity reference substances. There are three reasons: first, the reaction solvent is thin, the solvent ratio is too large, and the enrichment amount in one reaction is very high. The second is that the reaction time is long and the efficiency is very low; the third is that the conversion rate and content are very low, which makes its separation and purification difficult, and it needs to be prepared by a liquid phase preparative column

Method used

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  • A kind of preparation method of azedipine impurity b
  • A kind of preparation method of azedipine impurity b
  • A kind of preparation method of azedipine impurity b

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Experimental program
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Effect test

Embodiment 1

[0026] Add 2.0 g (3.4 mmol) of azelnidipine and 30 ml of dichloromethane into a 100 ml three-neck flask, dissolve and cool to -15°C. Add 0.6g (3.5mmol) m-chloroperoxybenzoic acid (dissolved in 10ml of dichloromethane) dropwise to the reaction system, keep the dropwise addition process at -10°C, add it in about 20 minutes, and react at -15°C for 10 minutes , TLC monitors that the reaction is complete, moves to room temperature, adds 30ml of saturated aqueous solution of sodium bisulfite and stirs for 20min, separates to take the dichloromethane phase, adds 20ml of saturated sodium bicarbonate and washes twice, retains the organic phase, and decomposes at 30-35°C. The dichloromethane solvent was removed by autoclaving to obtain a viscous oil.

[0027] Put the above viscous oil into a chromatographic column containing 60g of chromatographic silica gel, use dichloromethane:methanol=20:1 as the eluent, collect the part with ultraviolet absorption, concentrate, crystallize, filter, ...

Embodiment 2

[0039] Add 10.0 g (17.2 mmol) of azelnidipine and 100 ml of dichloromethane into a 500 ml three-neck flask, dissolve it, and cool down to -10°C. Add 3.0g (17.4mmol) m-chloroperoxybenzoic acid (dissolved in 50ml of dichloromethane) dropwise into the reaction system, keep the dropwise addition process at -10°C, add about 30min, and react at -10°C for 10min , TLC monitors that the reaction is complete, move to room temperature, add 200ml of saturated aqueous solution of sodium bisulfite and stir for 20min, separate layers to take the dichloromethane phase, add 200ml of saturated sodium bicarbonate to wash twice, keep the organic phase, and reduce The dichloromethane solvent was removed by autoclaving to obtain a viscous oil.

[0040] Put the above viscous oil into a chromatographic column containing 200g of chromatographic silica gel, use dichloromethane:methanol=20:1 as the eluent, collect the part with ultraviolet absorption, concentrate, crystallize, filter, Dried at 50°C to ...

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Abstract

The invention relates to a method for preparing an azelnidipine impurity B and belongs to the technical field of preparation of bulk drugs. According to the technical scheme, the method disclosed by the invention comprises the following steps: carrying out an oxidizing reaction on azelnidipine and metachloroperbenzoic acid, and generating an intermediate of formula I; performing silica gel columnchromatography on the intermediate of the formula I, and generating the impurity B under catalysis of silica. The invention provides a preparation method of the high-purity azelnidipine impurity B.

Description

technical field [0001] The invention relates to a preparation method of azedipine impurity B, which belongs to the technical field of preparation of raw materials. Background technique [0002] Azeldipine belongs to the dihydropyridine (DHP) class of calcium channel blockers. Azedipine can significantly reduce blood pressure in elderly patients with essential hypertension, and the blood pressure fluctuation is small, and the antihypertensive effect is better than amlodipine [Huang Rongjie; Chinese Journal of New Drugs and Clinics [J]; 2014, 33 (7): 542- 545]. [0003] Although azelnidipine has obvious advantages in the treatment of mild to moderate hypertension, it is not listed in many international pharmacopoeias. Currently only the Japanese Pharmacopoeia has records. According to the latest edition of the Japanese Pharmacopoeia (JP17)), there are four impurities with relative retention times of about 0.1, 0.3, 0.5, and 1.42, respectively. However, the Japanese Pharmac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 门连彬崔仰仰徐可岭薛复照王常德
Owner 迪嘉药业集团股份有限公司
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