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Preparation method of gliclazide

A technology of phenyl and compound, which is applied in the field of drug synthesis and can solve problems such as the difficulty in quality control of Gliclazide API

Pending Publication Date: 2021-10-22
浙江四维医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process will inevitably introduce nitrogen and nitroso genotoxic impurities, making the quality control of gliclazide API difficult

Method used

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  • Preparation method of gliclazide
  • Preparation method of gliclazide
  • Preparation method of gliclazide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment 1: the synthesis of compound 1

[0088]

[0089] N-tosylhydraziecarboxamide (5 g, 0.0218 mol), cyclopentanone (1.83 g, 0.0218 mol), paraformaldehyde (0.5 g) and ethanol (50 mL) were put into a 250 ml four-necked flask. Turn on the magnetic stirring, stir and dissolve at 0-5°C. Concentrated hydrochloric acid (5 mL) was added at 0-5°C. The temperature was raised to reflux for 6 hours, and the conversion of the raw materials was complete. The reaction solution was concentrated to dryness at 35-40°C under reduced pressure, ethyl acetate (30g) and water (30g) were added, the organic phase was separated, ethyl acetate (30g) was added to the aqueous phase, the organic phases were combined, and saturated bicarbonate Wash once with 15g of sodium aqueous solution, separate the organic phase, and concentrate to dryness under reduced pressure at 35-40°C to obtain a yellow viscous substance, add 7g of isopropanol, heat to 75-80°C to dissolve, stop heating, and natura...

Embodiment 2

[0090] Embodiment 2: the synthesis of compound 2-1

[0091]

[0092] Compound 1 (3.25 g, 0.01 mol), DCM (30 mL), triethylamine (1.1 g), DMAP (0.12 g) and acetic anhydride (1.12 g) were put into a 100 ml four-neck flask. Turn on magnetic stirring, and react at 20-25°C for 3 hours. After the reaction, add 20 mL of water, separate the organic phase, wash once with 10 mL of saturated sodium bicarbonate solution, separate the organic phase, and concentrate to dryness at 35-40 ° C under reduced pressure to obtain the crude product, then wash with ethyl acetate (3 ml) and n-heptyl The alkane (15ml) was recrystallized to obtain a pale yellow solid (2.64g), namely the target compound 2-1, with a yield of 72%.

Embodiment 3

[0093]Embodiment 3: the synthesis of compound 3-1

[0094]

[0095] Compound 2-1 (4.2 g, 0.011 mol), ethyl chloroacetate (1.34 g), and THF (40 ml) were put into a 100 ml four-neck flask. Turn on magnetic stirring, slowly add t-BuOK (1.85g) at 20-25°C, and react at 20-25°C for 15 hours after the addition is complete. After the reaction, add 20mL saturated ammonium chloride aqueous solution and 20mL ethyl acetate, stir and separate the layers, extract the aqueous phase twice with ethyl acetate (20mL x2), combine the organic phases, and concentrate to dryness under reduced pressure at 35-40°C to obtain Brown oil, the crude product was separated by column chromatography [mobile phase is n-heptane: ethyl acetate = 2: 1 (volume ratio)] to obtain light yellow oil (2.6g), the target product compound 3-1, yield rate 52%.

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Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of gliclazide and an intermediate of gliclazide. The preparation method comprises a Mannich reaction, an amino protection reaction, a Perkin reaction, an epoxidation reaction, a hydrolysis reaction, a decarboxylation reaction and a reductive amination reaction. The preparation method is mild in reaction condition, green and environment-friendly, few three wastes are generated, a high-risk reducing agent does not need to be used, nitrosation reaction does not need to be carried out, and introduction of nitroso-nitroso impurities is successfully avoided.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, specifically, the invention relates to a new method for synthesizing gliclazide. The technology adopted in the invention has the advantages of mild route conditions, environmental protection, and low production cost. Background technique [0002] Gliclazide, English name: Gliclazide; molecular formula: C 15 h 21 N 3 o 3 S; CAS number: 21187-98-4; chemical name is 1-(hexahydrocyclopenta[c]pyrrol-2(IH)-yl)-3-(4-methylphenyl-)sulfonylurea (l -(hexahgdroeycloxpenta[c]pyrrol-2(IH)-yl)-3-[(4-methylphangl)sulphonyl]urea)); chemical structure is as shown in formula I: [0003] [0004] Gliclazide is a second-generation sulfonylurea oral hypoglycemic agent, mainly used for the treatment of type II (non-insulin-dependent) diabetes. It can not only lower blood sugar, but also improve blood coagulation function in diabetic patients, improve or delay The occurrence of vascular complications in ...

Claims

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Application Information

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IPC IPC(8): C07C311/61C07C303/40C07D303/48C07D301/02C07D209/52
CPCC07C311/61C07C303/40C07D303/48C07D301/02C07D209/52C07C2601/08
Inventor 于帅刘阿情郭雷雷王锦裕郑辉高照波
Owner 浙江四维医药科技有限公司
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