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Repaglinide compound and novel production method thereof

Inactive Publication Date: 2014-04-16
HAINAN MEILAN SMITH KLINE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to overcome the defect of low purity of repaglinide provided by the above-mentioned prior art, the present invention provides a method for refining repaglinide compound

Method used

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  • Repaglinide compound and novel production method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Take 10 g of repaglinide raw material with a long production date (Wante Pharmaceutical (Hainan) Co., Ltd., batch number: 20091101), and the content of repaglinide was determined to be 95% by high performance liquid chromatography. The crude repaglinide was dissolved in 80ml of chloroform, and after stirring thoroughly, the repaglinide was dissolved, and the insoluble impurities were removed by filtration, and the filtrate was collected once.

[0048] Add 0.6 g of activated carbon to the primary filtrate, keep warm at 35° C., stir for 20 min, filter the deactivated carbon, and collect the secondary filtrate.

[0049] Add 20ml of 1M sodium ethoxide aqueous solution to the above-mentioned secondary filtrate for treatment, the treatment temperature is 60°C, and the treatment time is 3 hours, then cool down to room temperature, stand to separate layers, and then separate the aqueous phase to obtain repaglinide-containing the organic phase.

[0050] Heat the obtained organi...

Embodiment 2

[0053] Take 10 g of expired repaglinide bulk drug, and the content of repaglinide as measured by high performance liquid chromatography is 92%. Dissolve the crude repaglinide in 100ml of toluene, stir well, dissolve the repaglinide, filter to remove insoluble impurities, and collect the filtrate once.

[0054] Add 0.5 g of alumina to the primary filtrate, keep warm at 40° C., stir for 30 min, filter the de-alumina, and collect the secondary filtrate.

[0055] Add 30ml of 0.5M sodium methoxide aqueous solution to the above-mentioned secondary filtrate for treatment, the treatment temperature is 65°C, the treatment time is 2 hours, then the temperature is lowered to room temperature, the layers are left to stand, and then the aqueous phase is separated to obtain the Nai's organic phase.

[0056] Heat the obtained organic phase to 70-75°C for concentration, then add anhydrous methanol accounting for 70% of the volume of the solution, slowly lower the temperature while stirring, ...

Embodiment 3

[0059] Take 10 g of repaglinide raw material (Wante Pharmaceutical (Hainan) Co., Ltd., batch number: 20111101), and the content of repaglinide as measured by high performance liquid chromatography is 96.5%. The crude repaglinide was dissolved in 90 ml of ethyl acetate, and after stirring well, the repaglinide was dissolved, filtered to remove insoluble impurities, and the filtrate was collected once.

[0060] Add 0.5 g of A-type molecular sieves to the primary filtrate, keep warm at 40° C., stir for 25 minutes, filter and remove the molecular sieves, and collect the secondary filtrate.

[0061] Add 25ml of 0.8M potassium ethoxide aqueous solution to the above-mentioned secondary filtrate for treatment, the treatment temperature is 50°C, and the treatment time is 4 hours, then cool down to room temperature, let stand to separate layers, and then separate the water phase to obtain repaglide-containing Nai's organic phase.

[0062] Heat the obtained organic phase to 65-75°C for ...

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Abstract

The invention relates to a repaglinide compound and a novel production method thereof. The method comprises the following steps: step 1) dissolving the raw material repaglinide in an organic solvent which is not immiscible with water, and filtering to remove insoluble impurities, so as to obtain primary filtrate; step 2) adding adsorptive inorganic substances into the primary filtrate, fiercely stirring, standing, and filtering to remove the adsorptive inorganic substances, so as to obtain a secondary filtrate; step 3) adding the aqueous solution of alkali metal or alkali earth metal alkyls oxide into the secondary filtrate for treatment, heating optionally during the treatment process, then reducing the temperature, standing, layering, and separating out a water phase, so as to obtain an organic phase containing repaglinide; and step 4) adding an alcohols solvent into the organic phase, regulating the pH value to be 3.0-5.5 with acid, recrystallizing by controlling the temperature, centrifuging and washing precipitated crystal, and drying so as to obtain the refined repaglinide compound. According to the invention, the situation that the repaglinide raw material has lower purity both in home and abroad is basically changed, the problems of rough repaglinide and repaglinide active pharmaceutical ingredients are solved; the method is simple and easy to control and be used for industrialized production; and the product quality of the preparation is improved and the toxic and side effects are reduced.

Description

technical field [0001] The invention relates to a repaglinide compound and a new preparation method thereof, belonging to the technical field of medicine. Background technique [0002] Repaglinide is white or off-white crystalline powder, odorless, and its chemical name is (S+)-2-ethoxy-4-[2-[3-methyl-1-[2-(1 -piperidinyl)phenyl]butyl]-amino]-2-carbonylethylbenzoic acid, molecular formula C 27 h 36 N 2 o 4 , molecular weight: 452.59, structural formula: [0003] [0004] Repaglinide is a new type of oral hypoglycemic drug of the methylbenzylamine benzoic acid family. It is a non-sulfonylurea oral hypoglycemic drug for the treatment of type 2 diabetes. Its mechanism of action is that repaglinide interacts with pancreatic beta Binding to specific receptors on the cell membrane promotes the closure of ATP-sensitive potassium channels coupled with the receptors, inhibits the outflow of potassium ions from β cells, depolarizes the cell membrane, opens calcium channels, in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/135
Inventor 杨明贵
Owner HAINAN MEILAN SMITH KLINE PHARMA
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