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Method for preparing Repaglinide

A compound and a selected technology, applied in the field of preparing repaglinide, can solve the problems of increasing the difficulty and danger of industrialized production of intermediates, increasing the production cost and danger of repaglinide, increasing costs, and the like

Active Publication Date: 2007-10-10
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But it is undeniable that in the synthesis of the important intermediate (VI) used in it, as reported in the document CN1800139, the super base n-butyllithium needs to be used in the reaction, and it is carried out at -80 ° C; in the document CN1500772 In the report, it is necessary to use super strong alkali sodium hydrogen in the reaction, and one reaction needs to be carried out at a high temperature of 150°C; in the report of document US2004249188, the reaction needs to use highly toxic sodium cyanide; in the document Organic Process Research Development, 6(2) , 184-186, 2002 report, the reaction needs to use dangerous and expensive reagents such as n-butyllithium and DMPU; in the report of document WO2001035900, the reaction needs to use dangerous and expensive reagents such as diisopropylamide lithium and DMPU , the above-mentioned methods inevitably increase the difficulty and danger of the industrialized production of intermediate (VI), increase the cost, thereby increasing the cost and danger of repaglinide production

Method used

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Examples

Experimental program
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Embodiment 1

[0018] Preparation of (S)-3-(4-methyl-2-(2-(piperidin-1-yl)phenyl)pent-2-ylamino)-3-oxopropionic acid methyl ester

[0019] Dissolve (S)-3-methyl-2(2-piperidinylphenyl)-1-butylamine (12 g, 0.049 mol) in 120 ml of methanol, and add anhydrous potassium carbonate (25 g) under stirring , dimethyl malonate (20 g, 0.15 mol), reflux for 6 hours, filter while hot to remove the solid, concentrate the mother liquor to dryness, add ethyl acetate / n-hexane (1:5) to stir and crystallize, filter to obtain white Solids: 12.5 g. MP: 82-84°C.

Embodiment 2

[0021] 2-ethoxy-4-(3-methoxy-1-((S)-4-methyl-2-(2-(piperidin-1-yl)phenyl-2-amino)-1, Preparation of 3-dioxopropan-2-yl) ethyl benzoate

[0022] Dissolve the intermediate (10 g, 0.029 mol, prepared in Example 1) in 100 ml of absolute ethanol, add sodium ethoxide (10 g, 0.147 mol), and cool in an ice-salt bath (-5°C-0°C) , dropwise added compound 4-iodo-2-ethoxy ethyl benzoate (8.8 g, 0.03 mol) dissolved in 50 ml of dehydrated ethanol solution, added in one hour, reacted at room temperature for 2 hours, concentrated to dryness, added 100 ml of water , extracted with ethyl acetate (50 ml×3), washed with saturated brine, dried, filtered, and concentrated to dryness to obtain a solid, which was recrystallized from ethyl acetate:n-hexane=1:8 to obtain intermediate (7): 12.3 g.

Embodiment 3

[0024] Preparation of S(+)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1-butyl}aminocarbonylmethyl]benzoic acid

[0025] Dissolve the intermediate (12 grams, 0.0235 moles, prepared in Example 2) in 120 milliliters of methanol, add 40 milliliters of water, 6 grams of sodium hydroxide (0.15 moles) and stir under reflux for 3 hours, concentrate to remove most of the solvent, add Concentrated hydrochloric acid 13.5 ml, slowly heated to above 80°C until bubbles appeared, then heated to 100°C, kept warm for 30 minutes, added 120 ml of water, stirred, adjusted to PH=4, cooled, filtered, and washed with water to obtain the target compound, Rui Glinide: 9.6 grams.

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Abstract

This invention relates to a method for preparing repaglinide. Compared with other methods, the method has such advantages as high efficiency, low toxicity, high safety, easy operation, wide raw materials, and low cost, thus is suitable for industrialization.

Description

technical field [0001] The invention relates to a method for preparing repaglinide with low cost and suitable for industrial production. Background technique [0002] The chemical name of repaglinide is S(+)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1-butyl}aminocarbonylmethyl Base] benzoic acid is a new type of oral hypoglycemic drug that can promote insulin secretion and has the characteristics of fast absorption and short action time. It can simulate physiological insulin secretion in patients with type II diabetes and effectively control postprandial hyperglycemia. It has a high protein binding rate, does not accumulate in tissues, and has good safety. Repaglinide can be used alone as a first-line antidiabetic drug, or it can be used in combination with other hypoglycemic drugs to increase the efficacy, providing a new means for the treatment of type II diabetes. [0003] A variety of documents have reported the synthesis of repaglinide. The route is mainly to ob...

Claims

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Application Information

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IPC IPC(8): C07D295/135
CPCY02P20/55
Inventor 钟慧娟
Owner JIANGSU HANSOH PHARMA CO LTD
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