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Preparation method of gliclazide

A technology of cyclopentane ortho, hydrazine hydrate, applied in the field of medicine, can solve the problems of inconvenient setting, high price, high reaction cost and the like

Inactive Publication Date: 2014-01-15
WEIHAI WEITAI PHARMA TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the one hand, LiAlH 4 The higher price makes the reaction cost high; on the other hand, LiAlH 4 It is a high-risk chemical. Because of its high reactivity, it can react violently with substances with active hydrogen and release a lot of heat. Therefore, when using this substance, the water content in the system is extremely strict, and the reaction requirements Oxygen-free, which brings great inconvenience to the operation and setting of the reaction system

Method used

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  • Preparation method of gliclazide
  • Preparation method of gliclazide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1: N-amino-1,2-cyclopentane phthalimide

[0016] Add 1,2-cyclopentane phthalic anhydride (50 g, 357 mmol) and 250 mL of ethanol into a 1 L four-ring bottle equipped with a mechanical stirrer, a condenser, and a dropping funnel, and heat to reflux. Slowly add 80% hydrazine hydrate (24.4 mL, 375 mmol) dropwise, and continue to reflux after the dropwise addition, and follow the gas phase to complete the reaction. The reaction takes about 8 hours. Heating was stopped, and it was cooled down to room temperature naturally, and the solvent was removed by rotary evaporation under reduced pressure to obtain a viscous liquid, and the solid was washed out after cooling. Crush the solid, beat with 50mL of cold water for half an hour under ice-water bath cooling, filter with suction, and dry the solid in a vacuum oven at 30°C for 12 hours to obtain 46g of the product, with a yield of 83.6%, a melting point of 11.3-114.6°C, and a gas-phase purity of 98.2%. .

Embodiment 2

[0017] Example 2: Hexahydro-2-cyclopentopyrrolylamine hydrochloride

[0018] Carefully dilute 75.0mL of concentrated sulfuric acid into 200mL of tetrahydrofuran, turn black, and let it cool to room temperature.

[0019] Add N-amino-1,2-cyclopentane phthalimide (212.7g, 1.38mol) and 1.5L tetrahydrofuran into a 3L three-necked flask, stir at room temperature until the solid is completely dissolved, and add hydroboration in batches Sodium (130 g, 3.45 mol). The system was cooled under an ice-water bath. When the temperature of the system drops to 5-10°C, dilute concentrated sulfuric acid in tetrahydrofuran is added dropwise. After the dropwise addition is completed, heat to reflux and follow the gas phase to complete the reaction, which takes about 14-16 hours.

[0020] After the reaction was finished, it was cooled down to room temperature naturally, and methanol was added dropwise to quench the reaction, and stirred for 30 min. Most of the solvent (about 1 L) was evaporated ...

Embodiment 3

[0023] Embodiment 3: Preparation of Gliclazide

[0024] Add hexahydro-2-cyclopentapyrrolylamine hydrochloride (20g, 123mmol), p-toluenesulfonylurea (29g, 135mmol), 100mL toluene in the 250mL three-strand bottle equipped with mechanical stirring and condenser, and heat Reflux, TLC tracking reaction complete ester, about 2 ~ 3h. After the reaction, the toluene was distilled off under reduced pressure, 100 mL of water was added, and the crystallization was stirred at room temperature for 12 h. Suction filtration, wash the solid with a small amount of cold water, recrystallize from ethyl acetate, and dry in a vacuum oven at 80°C for 12 hours to obtain 34.1 g of the product with a yield of 85.8%.

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Abstract

The invention discloses a synthetic process for preparing gliclazide with low-cost raw materials and high yield. The synthetic process comprises the following reaction steps: 1, preparing N-amino-1,2-cyclopentane phthalic amide by a reaction of 1,2-cyclopentane phthalic anhydride and hydrazine hydrate; 2, reducing the N-amino-1,2-cyclopentane phthalic amide; and 3, preparing the gliclazide by a reaction of methylphenylsulfonylurea and the product reduced in the step 2. By adopting the synthetic process, the N-amino-1,2-cyclopentane phthalic amide is reduced by using an NaBH4 / concentrated H2SO4 system from cheap 1,2-cyclopentane phthalic anhydride; an expensive reagent LiA1H4 is avoided. Therefore, the production cost is greatly reduced.

Description

Technical field: [0001] The invention relates to a preparation method of Gliclazide used for treating mild and medium-sized diabetes mellitus with no tendency to ketosis and whose onset is ineffective in adulthood, and belongs to the field of medicine. Background technique: [0002] Gliclazide, developed by the French SERVIER company, is a second-generation sulfonylurea oral hypoglycemic drug, which has hypoglycemic effects on both normal people and diabetic patients. It is mainly used for mild and medium-sized diabetes mellitus that is ineffective in diet control alone and has no ketosis tendency. It was first listed in France in 1972, and after being introduced to China in 1985, it has won unanimous praise from doctors and experts. Its chemical structural formula is as follows: [0003] [0004] The traditional synthetic method of Gliclazide is as follows: [0005] [0006] The reaction starts from 1,2-cyclopentane phthalimide, which is easy to obtain in industry,...

Claims

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Application Information

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IPC IPC(8): C07D209/52
CPCC07D209/52
Inventor 蔡华军
Owner WEIHAI WEITAI PHARMA TECH DEV
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