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Method for preparing macitentan impurity standard substance

A technology of macitentan and standard products, applied in the field of medicine, can solve the problems of unreported synthesis and content calibration methods, high risk of macitentan, high risk of missed detection, etc., and achieve low synthesis cost and simple preparation process , The effect of short synthesis cycle

Inactive Publication Date: 2017-03-08
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent CN201510926610.9 reports that the generation of this impurity is related to the fact that there are two reactive sites (hydroxyl groups) with the same activity in the molecule of the reaction raw material "ethylene glycol", and the impurity is produced in the previous step of macitentan synthesis. High risk with macitentan
At the same time, the patent CN201510926624.0 reported that the UV response value of the impurity measured at 250-270nm was significantly weaker than that of macitentan, and the response factor was only 0.77. It is not easy to detect during the detection of macitentan-related substances, and the risk of missed detection is high
At present, there is no report on the synthesis and content calibration method of this impurity

Method used

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  • Method for preparing macitentan impurity standard substance
  • Method for preparing macitentan impurity standard substance
  • Method for preparing macitentan impurity standard substance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048]1. Put 50ml of N,N-dimethylformamide, 10g (72.4mmol) of N-propylsulfonamide, and 2.6g (108.3mmol) of sodium hydrogen into a 250ml three-necked reaction flask in sequence, and stir at 10-15°C for 30min. Put in 22g (72.4mmol) of 5-(4-bromophenyl)-4,6-dichloropyrimidine, first stir the reaction at 20-25°C for 8h, then stir the reaction at 35-40°C for 1h, and cool down to 10-15°C Put in 2.2g (35.4mmol) of ethylene glycol and 13.5g (70.8mmol) of p-toluenesulfonyl chloride, raise the temperature to 85-95°C, continue stirring for 8h, cool down to 0-10°C, add 10wt% citric acid aqueous solution to crystallize , filtered, and the filter cake was washed with purified water until the filtrate was neutral, and the solid was collected and dried at 40-50° C. under reduced pressure (vacuum degree ≥ 0.08 MPa) for 6 hours to obtain 21.3 g of impurity crude product, with a yield of 75.2%.

[0049] 2. Add 70ml of ethyl acetate to 21.3g of crude impurity product, heat and stir at 75-85°C to ...

Embodiment 2

[0059] 1. Add 80ml of N,N-dimethylformamide, 10g (72.4mmol) of N-propylsulfonamide, and 5g (208.3mmol) of sodium hydrogen into a 250ml three-necked reaction flask in turn, stir at 10-15°C for 30min, and put in 22g (72.4mmol) of 5-(4-bromophenyl)-4,6-dichloropyrimidine, stirred and reacted at 20-25°C for 8h, then stirred at 35-40°C for 2h, cooled to 10-15°C, Add 2.2g (35.4mmol) of ethylene glycol and 16.8g (88.1mmol) of p-toluenesulfonyl chloride, raise the temperature to 85-95°C, continue stirring for 10h, cool down to 0-10°C, add 10wt% citric acid aqueous solution to crystallize, After filtering, the filter cake was washed with purified water until the filtrate became neutral, and the solid was collected and dried under reduced pressure (vacuum degree ≥ 0.08 MPa) at 40-50°C for 8 hours to obtain 22.2 g of impurity crude product, with a yield of 78.3%.

[0060] 2. Add 100ml of ethyl acetate to 21.3g of impurity crude product, heat and stir at 75-85°C to dissolve, filter while ...

Embodiment 3

[0064] 1. Put 500ml of N,N-dimethylformamide, 100g (724mmol) of N-propylsulfonamide, 26g (1083mmol) of sodium hydrogen into a 1L three-necked reaction flask in turn, stir at 10-15°C for 30min, and put in 5- (4-Bromophenyl)-4,6-dichloropyrimidine 220g (724mmol), first stirred and reacted at 20-25°C for 8h, then stirred and reacted at 35-40°C for 1h, cooled to 10-15°C, and put into ethylene di 22.3g (35.9mmol) of alcohol and 137g (71.9mmol) of p-toluenesulfonyl chloride, heat up to 85-95°C, continue to stir for 9h, cool down to 0-10°C, add 10wt% citric acid aqueous solution to crystallize, filter, filter cake Wash with purified water until the filtrate is neutral, collect the solid, and dry it under reduced pressure (vacuum degree ≥ 0.08 MPa) at 40-50°C for 8 hours to obtain 212.5 g of crude impurity product, with a yield of 73.9%.

[0065] 2. Add 700ml of ethyl acetate to 212.5g of impurity crude product, heat and stir at 75-85°C to dissolve, filter while hot, add 3000ml of met...

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Abstract

The invention discloses a method for preparing a macitentan impurity standard substance. The method includes the steps of using 5-(4-bromophenyl)-4,6-dichloropyrimidine as a raw material, conducting condensation of 5-(4-bromophenyl)-4,6-dichloropyrimidine, N-propanesulfonamide and ethylene glycol to prepare a 1,2-di[[N-[5-(4-bromophenyl)]-N'-propanesulfonamide-6-oxo]pyrimidyl] ethyl diether crude product, refining the crude product to obtain a pure product, and calibrating the content of the pure product by a conventional analysis method. The method has a simple process and a short preparation period, and the calibrated product content is more than 99.0%. The provided macitentan impurity can serve as the impurity standard substance and be applied to qualitative and quantitative research and detection of impurities in macitentan raw materials and preparations thereof.

Description

[0001] 1. Technical field [0002] The invention relates to a method for preparing a pharmaceutical impurity standard, specifically a macitentan impurity standard 1,2-bis[[N-[5-(4-bromophenyl)]-N'- The preparation method of propylsulfonamide-6-oxo]pyrimidinyl]ethyl diether belongs to the field of medical technology. [0003] 2. Background technology [0004] Macitentan is a bidirectional endothelin receptor antagonist, clinically used to treat pulmonary arterial hypertension (PAH, WHO grade I) to slow down disease progression, including delaying death, intravenous or subcutaneous injection of prostacyclins or worsening of PAH symptoms (decrease in 6-minute walking distance, worsening of PAH symptoms, and need for additional PAH medication). [0005] The chemical name of macitentan is N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]- N'-propylsulfonamide is the third endothelin receptor antagonist to be launched after bosentan and ambrisentan. It wa...

Claims

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Application Information

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IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 吴标唐胜国谭红春
Owner HEFEI JIUNUO MEDICAL TECH
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