Method for preparing repaglinide

A compound and the selected technology are applied in the field of preparation of the drug repaglinide, which can solve problems such as unfavorable industrial production, high toxicity, and long reaction time

Inactive Publication Date: 2011-05-04
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But it is undeniable that in these condensation reactions, the condensing agents used are mostly DCC, triphenylphosphine+CCl4, etc., which have disadvantages such as long reaction time and high toxicity, which are not conducive to industrial production

Method used

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  • Method for preparing repaglinide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of (S)-N-(4-methoxybenzyl)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl-1-amine

[0034] The raw material 3-methyl-1-(2-piperidin-1-yl)phenyl)-1-butanone (3.3Kg, 13.4mol), toluene (30L), p-toluenesulfonic acid (330g), 4- Methoxybenzylamine (4.5Kg, 32.5mol) was put into the reaction kettle, and refluxed to separate water for five hours. About (1.6Kg) of anhydrous sodium sulfate was added, and the reaction was continued overnight. The next day, the reaction solution was cooled to room temperature, poured into saturated sodium bicarbonate solution (20L), separated into layers, the aqueous layer was extracted with ethyl acetate (10L), the organic layers were combined, dried, and concentrated to dryness to obtain an oil: 8.0Kg .

[0035] TLC: petroleum ether / ethyl acetate=20 / 1, Rf starting material=0.7, Rf product=0.3

[0036] Put the previous step oil (8.0Kg), methanol (30L), nickel chloride hexahydrate (7Kg) into the reaction kettle, and cool to 0°C. Sodium bo...

Embodiment 2

[0043] (S)-4-(2-((4-methoxybenzyl)(3-methyl-1-(2-(1-piperidinyl)phenyl)butyl)amino)-2-oxo Preparation of ethyl)-2-ethoxy ethyl benzoate

[0044] Dry (S)-N-(4-methoxybenzyl)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl-1-amine toluene in the previous step , CDI (640g), side chain acid 2-(3-ethoxy-4-(ethoxycarbonyl) phenyl) acetic acid (750g) were dropped in the 50L reaction kettle, added acetonitrile (4L), room temperature stirring reaction 8 Hour. Add water (6L) and stir, separate the layers, extract the aqueous layer with ethyl acetate (6L×2), combine the organic layers, wash with saturated brine, and dry over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / methanol=100:1), and qualified components were concentrated to dryness to obtain an oil: 1.34Kg.

[0045] TLC: petroleum ether: ethyl acetate = 3: 1, Rf raw material = 0.6, Rf produ...

Embodiment 3

[0048] (S)-2-ethoxy-4-{2-[(3-methyl-1-(2-(1-piperidinyl)phenyl)butyl)amino]-2-oxoethyl} Preparation of Benzoic Acid (Repaglinide)

[0049] 1) Alkaline hydrolysis

[0050] Put intermediate 3 (1.34Kg) of the previous step, methanol (8L), and aqueous sodium hydroxide solution (sodium hydroxide / water=560g / 2.2L) into a 20L reactor, and heat to reflux for 2 hours. Concentrate under reduced pressure to remove methanol, adjust the pH of the residue to 4-5 with 10% hydrochloric acid, extract with dichloromethane (2.8 L×2), combine the organic layers, and dry over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure, and the obtained intermediate was directly used for feeding in the next step.

[0051] TLC: petroleum ether / ethyl acetate=3 / 1, Rf product=0.3, Rf raw material=0.8;

[0052] 2) Acid hydrolysis

[0053]Trifluoroacetic acid (5.4 L) was added to the intermediate of the upward step, and after stirring for 20 minutes, ...

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Abstract

The invention relates to a preparation method of a drug for treating diabetes mellitus, that is, repaglinide. The preparation method comprises the following steps: a (S) type compound as shown in formula (II) and a compound as shown in formula (III) are subject to an amidation reaction in the presence of a condensing agent to generate a (S) type compound as shown in formula (IV); R2 radical is removed from the (S) type compound of the formula (IV) in the presence of alkali, and R1 radical is removed in the presence of acid. The (S) type compounds as shown in the formula (II), the formula (III) and the formula (IV), and the R1 radical and the R2 radical are defined in the specification. In the preparation method, the introduction of the R1 radical and deprotection improvement shorten the reaction time, increase the yield and enhance safety, thus the method is more suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of organic synthesis of medicines, in particular to a preparation method of repaglinide, a medicine for treating diabetes. 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, the structural formula is [0003] [0004] This is known from US Patent (Patent No.: US5312924). Studies have shown that repaglinide is an enantiomer, and R(-)-2-ethoxy-4-[N-{1-(2-piperidinylphenyl)-3-methyl-1 Compared with -butyl}aminocarbonylmethyl]benzoic acid, it has a long-term biological activity in the human body and can be eliminated more quickly. It is a new type of oral hypoglycemic drug that can promote insulin secretion and absorption With the characteristics of fast and short action time, it can simulate physiological insulin secretion in patients with type II diabetes, effectively control postprandial hyperglycem...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/135
CPCC07D295/135Y02P20/55
Inventor 吕爱锋孔双华肖军陈刚胜
Owner JIANGSU HANSOH PHARMA CO LTD
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