Impurity generated in production of indapamide as well as synthesis method and application

A kind of technology of indapamide and synthesis method, applied in the field of chemical substance preparation

Pending Publication Date: 2020-05-19
TIANJIN LISHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesized impurity D of indapamide can provide impurity control monitoring f...

Method used

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  • Impurity generated in production of indapamide as well as synthesis method and application
  • Impurity generated in production of indapamide as well as synthesis method and application
  • Impurity generated in production of indapamide as well as synthesis method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] A synthetic method for impurity D produced in the production of indapamide, including the following steps:

[0035] 1) Add 10.00 g (0.042 mol) compound A, 25.4 g (0.0.21 mol) thionyl chloride, and 0.05 mL N,N- to a 250 ml three-neck flask equipped with a thermometer, a reflux tube, and mechanical stirring. Dimethylformamide, heat preservation at 80 ℃, heat preservation reaction for 4 hours, TLC monitors the reaction, after the reaction is complete, steam the thionyl chloride in the reaction solution, put the materials on the tray and put it in the oven, turn on the oven and heat up to 80°C, 8 hours. 10.3 g of compound B was obtained with a yield of 95.52%.

[0036] 2) Under the protection of nitrogen, add 5.00 g (0.37 mol) compound C, 9.50 g (0.93 mol) triethylamine, 100 ml dry tetrahydrofuran to a 250 ml three-neck flask equipped with a thermometer and mechanical stirring, and add 10 g ( 0.39 mol) Compound B was dissolved in 50 mL of tetrahydrofuran and added dropwise to ...

Embodiment 2

[0039] 1) Add 15.00 g (0.042 mol) compound A, 50.4 g (0.42 mol) thionyl chloride, and 0.05 mL of N,N-dimethyl into a 250 ml three-neck flask equipped with a thermometer, a reflux tube, and mechanical stirring. Methyl formamide, heat preservation at 80℃, heat preservation reaction for 4 hours, TLC monitors the reaction, after the reaction is over, distill the thionyl chloride in the reaction solution, put the materials on the tray and put it in the oven, turn on the oven and raise the temperature to 80℃ ,8 hours. 15.2 g of compound B was obtained with a yield of 95.52%.

[0040] 2) Under the protection of nitrogen, add 5.00 g (0.37mol) of compound C, 9.50 g (0.93 mol) of triethylamine, 100 ml of dry tetrahydrofuran to a 250 ml three-neck flask equipped with a thermometer and mechanical stirring, and add 10.5 g ( 0.39 mol) Compound B was dissolved in 50 mL of tetrahydrofuran and added dropwise to the reaction within 30 minutes. The reaction was carried out for 2 hours. The reactio...

Embodiment 3

[0044] Agilent 1200 high performance liquid chromatograph, octadecylsilane-bonded silica gel is used as filler, methanol-water-glacial acetic acid (volume ratio is 45:55:0.5) is used as mobile phase, 20 mg of indapamide reference substance is taken, Precisely weigh, put in a 100mL measuring flask, add 5mL methanol to dissolve, dilute to the mark with mobile phase, shake well, measure 5mL, add 1mol / L sodium hydroxide solution 2mL, put it in a water bath to heat for one hour, let cool , Adjust to neutral with 1 mol / L hydrochloric acid solution. Dilute to 50 mL with mobile phase. The injection volume is 100μl, the flow rate is 1~3ml / min, the detection wavelength is 246nm, and the column temperature is 30°C. Under the chromatographic conditions, indapamide peaked in about 12 minutes, and impurities peaked in about 24.8 minutes.

[0045] Take an appropriate amount of the impurity monomer and prepare a solution of 0.5 mg / ml with a diluent. The purity of the main peak is 98.87% calcul...

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Abstract

The invention discloses an impurity generated in production of indapamide as well as a synthesis method and application. The synthesis method of the indapamide impurity D comprises the following stepsof: reacting an initial raw material A with thionyl chloride, and carrying out reduced pressure distillation to obtain a compound B, carrying out acylation reaction on the compound B and C, and recrystallizing petroleum ether and ethyl acetate to obtain a compound D. The invention provides a simple synthesis method of the indapamide impurity D. The synthesized indapamide impurity D can provide impurity contrast monitoring for reaction, and the problem of impurity analysis and control of indapamide is solved. And a strong support is provided for large-scale industrial production of indapamide.

Description

Technical field [0001] The invention relates to the technical field of chemical substance preparation, in particular to an impurity produced in the production of indapamide and a synthetic method and application. Background technique [0002] Hypertension is a common disease and frequently-occurring disease. It can also cause cardiovascular, cerebrovascular, kidney and other diseases. It is currently one of the highest human mortality diseases in the world. Humans began to use diuretics to lower blood pressure in 1948. For a long time, thiazide diuretics have been one of the main forces of antihypertensive drugs. Whether used alone or in combination with other antihypertensive drugs, they have a clear effect. The results of large-scale international clinical trials for decades have further confirmed its status in antihypertensive treatment. Several European and American committees on the principles of hypertension management have recommended diuretics as the first choice for pat...

Claims

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Application Information

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IPC IPC(8): C07D209/08G01N30/04
CPCC07D209/08G01N30/04
Inventor 姚志雄霍志甲姜根华张瑜
Owner TIANJIN LISHENG PHARM CO LTD
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