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Method for producing repaglinide

A compound and catalyst technology, applied in the field of preparation of repaglinide and its intermediates, can solve the problems of high reaction temperature, low total yield, low reaction temperature, etc., and achieve high optical purity, environmental friendliness, and simple operation

Active Publication Date: 2008-07-16
ZHEJIANG NEXCHEM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The disadvantage of this method is that the reaction time is long and the production cycle is long; the reaction temperature is high, the production cost is high, and the total yield is only about 21%, so it is not suitable for industrialized production
The disadvantage of this method is that the use of dangerous reagents such as n-butyllithium is easy to absorb moisture and cause fire, the tetrahydrofuran and dimethyl sulfoxide used are not easy to recycle, and the reaction temperature is too low, so it is not suitable for industrial production.
The disadvantage of this method is that the used esterification reagent dimethyl sulfate is highly toxic and carcinogenic, so it is not suitable for industrialized production

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0040] Example 1 Synthesis of 2-ethoxyl group-4-(ethoxycarbonylmethyl) ethyl benzoate

[0041] Dissolve 4-carboxymethyl-2-ethoxybenzoic acid (90g, 0.401mol) in 900mL ethanol, add concentrated sulfuric acid (4g, 0.041mol), heat to reflux with stirring, and react for 8h. After completion of the reaction, concentrate, add 250 mL of dichloromethane to the residue to dissolve, wash twice with 500 mL of 5% sodium bicarbonate solution, and then wash with 200 mL×2 water. Dry over anhydrous sodium sulfate, filter with suction, and concentrate to obtain 99.6 g of ethyl 2-ethoxy-4-(ethoxycarbonylmethyl)benzoate, with a yield of 88.6%.

Embodiment 2

[0042] Example 2 Synthesis of 2-ethoxy-4-(ethoxycarbonylmethyl) ethyl benzoate

[0043] Dissolve 4-carboxymethyl-2-ethoxybenzoic acid (90g, 0.401mol) in 900mL ethanol, add SO 4 2- / TiO 2 Solid superacid (6g), heated to reflux with stirring, reacted for 8h. After the reaction was completed, filter with suction, concentrate, add 250 mL of dichloromethane to the residue to dissolve, wash twice with 500 mL of 5% sodium bicarbonate solution, and then wash with 200 mL×2 water. Dry over anhydrous sodium sulfate, filter with suction, and concentrate to obtain 98.7 g of ethyl 2-ethoxy-4-(ethoxycarbonylmethyl)benzoate, with a yield of 87.8%.

Embodiment 3

[0044] Example 3 Synthesis of 2-ethoxy-4-(methoxycarbonylmethyl)methyl benzoate

[0045] 4-Carboxymethyl-2-ethoxybenzoic acid (90g, 0.401mol) was dissolved in 900mL of methanol, concentrated sulfuric acid (4.5g, 0.0459mol) was added, heated to reflux under stirring, and reacted for 8h. After completion of the reaction, concentrate, add 250 mL of dichloromethane to the residue to dissolve, wash twice with 500 mL of 5% sodium bicarbonate solution, and then wash with 200 mL×2 water. Dry over anhydrous sodium sulfate, filter with suction, and concentrate to obtain 88.9 g of methyl 2-ethoxy-4-(methoxycarbonylmethyl)benzoate, with a yield of 87.9%.

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Abstract

The invention relates to a novel method for preparing repaglinide, which adopts a 4- carboxymethyl-2-ethoxybenzoic acid as raw material and derives a repaglinide intermediate 4-carboxymethyl-2-ethoxy methyl benzoate via esterification and hydrolysis; a product is condensed with an S(+)-1-(2-piperidino-phenyl)-3-methyl n-butylamine to derive an S(+)-2-oxethyl-4-[N-{1-(2-piperidino-phenyl)-3-methyl-1- butyl} amido carbonyl methyl] benzoate; a repaglinide is derived via one more hydrolysis. Compared with the other technologies, the invention has the advantages of simple operation, high efficiency, higher yield, low toxicity, and environmental friendliness. The product repaglinide has quite high optical purity, the ee value is not less than 99.8 percent; the invention is a novel technology for producing repaglinide with industrial prospect.

Description

technical field [0001] The invention relates to a new method for preparing repaglinide and its intermediate. technical background [0002] The chemical name of repaglinide is S(+)-2-ethoxy-4-[N-[1-(2-piperidinylphenyl)-3-methyl-1-butyl]amino Carbonylmethyl] benzoic acid, the specific structural formula is as follows: [0003] [0004] A new type of short-acting oral non-sulfonylurea insulin-stimulating hypoglycemic drug, which specifically binds to the 36KDA protein on the ATP-dependent potassium ion channel outside the islet β cell membrane, closing the potassium channel and depolarizing the β cell. Calcium channels open, calcium ions flow inward, and promote insulin secretion. Its action is faster than that of sulfonylureas, so the postprandial hypoglycemic effect is faster. It will not accumulate in tissues, has good safety, and has a synergistic effect with biguanide drugs. It can be used alone as a first-line antidiabetic drug or combined with other hypoglycemic dr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/135
CPCY02P20/55
Inventor 贾春祥陈辉陈浩
Owner ZHEJIANG NEXCHEM PHARMA
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