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A kind of synthetic method of macitentan impurity standard substance

A synthesis method and technology of macitentan, applied in the field of medicine, can solve the problems such as unreported synthesis and content calibration methods, and achieve the effects of low synthesis cost, short synthesis period and simple preparation process

Active Publication Date: 2018-09-11
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no report on the synthesis and content calibration method of this impurity

Method used

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  • A kind of synthetic method of macitentan impurity standard substance
  • A kind of synthetic method of macitentan impurity standard substance
  • A kind of synthetic method of macitentan impurity standard substance

Examples

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Effect test

Embodiment 1

[0046] The synthetic method of macitentan impurity standard substance in the present embodiment is as follows:

[0047] 1. Add 20g (34mmol) of macitentan into 120ml ethanol, heat and stir to dissolve, add 50ml (125mmol) of 10% sodium hydroxide aqueous solution dropwise, heat and stir at 70-80°C for 6h, cool down to 0- 10°C, pour the reaction solution into 480ml (125mmol) of 5% citric acid aqueous solution, control the temperature at 0-10°C, stir for 1h, filter, wash the filter cake with purified water until the filtrate is neutral, collect the solid, and put it at 50-55°C After drying under reduced pressure (vacuum degree: 0.096 MPa) at ℃ for 6 hours, 12.2 g of impurity crude product was obtained, yield: 76.82%.

[0048]2. Add 120ml of ethanol to 12.2g of impurity crude product, reflux at 75-85°C and stir to dissolve, filter while hot, slowly cool the filtrate to 0-5°C, stir and crystallize for 4 hours, filter, and use an appropriate amount of ethanol at 0-5°C for the filter c...

Embodiment 2

[0058] The synthetic method of macitentan impurity standard substance in the present embodiment is as follows:

[0059] 1. Add 20g (34mmol) of macitentan into 150ml ethanol, heat and stir to dissolve, add dropwise 70ml (125mmol) of 10% potassium hydroxide aqueous solution, heat and stir at 70-80°C for 7h, and cool down to 0- 10°C, pour the reaction solution into 500ml (130mmol) of 5% citric acid aqueous solution, control the temperature at 0-10°C, stir for 1h, filter, wash the filter cake with purified water until the filtrate is neutral, collect the solid, and put it at 50-55°C After drying under reduced pressure (vacuum degree: 0.097 MPa) at ℃ for 8 hours, 11.8 g of impurity crude product was obtained, yield: 74.30%.

[0060] 2. Add 120ml of ethanol to 11.8g of impurity crude product, reflux at 75-85°C and stir to dissolve, filter while hot, slowly cool the filtrate to 0-5°C, stir and crystallize for 3 hours, filter, and use an appropriate amount of ethanol at 0-5°C for the ...

Embodiment 3

[0064] The synthetic method of macitentan impurity standard substance in the present embodiment is as follows:

[0065] 1. Add 20g (34mmol) of macitentan into 200ml ethanol, heat and stir to dissolve, add 68ml (170mmol) of 10% aqueous sodium hydroxide solution dropwise, heat and stir at 70-80°C for 6h, and cool down to 0- 10°C, pour the reaction solution into 780ml (203mmol) of 5% citric acid aqueous solution, control the temperature at 0-10°C, stir for 1h, filter, wash the filter cake with purified water until the filtrate is neutral, collect the solid, and put it at 50-55°C ℃ and dried under reduced pressure (vacuum degree 0.092MPa) for 7 hours to obtain 12.8 g of crude impurity product, yield: 80.60%.

[0066] 2. Add 150ml of ethanol to 12.8g of crude impurity product, reflux at 75-85°C and stir to dissolve, filter while hot, slowly cool the filtrate to 0-5°C, stir and crystallize for 3 hours, filter, and use an appropriate amount of ethanol at 0-5°C for the filter cake Wa...

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Abstract

The invention discloses a method for synthesizing a macitentan impurity standard substance. The method comprises that macitentan as a raw material is hydrolyzed through inorganic base so that a crude product is obtained, and the crude product is refined to form a 5-(4-bromophenyl)-6-[2-[(5-bromopyrimidinyl)-2-oxo]ethoxy]-4-aminopyrimidine pure product. The impurity synthesis method provided by the invention utilizes cheap and easily available raw materials and has simple processes and a short preparation period. After standardization, product content is more than 99.0%. The macitentan impurity can be used as an impurity standard substance for the qualitative and quantitative research and detection of a macitentan raw material and its preparation impurity.

Description

1. Technical field [0001] The invention relates to a method for synthesizing a drug impurity standard product, in particular to a method for synthesizing a macitentan impurity standard product, and belongs to the technical field of medicine. 2. Background technology [0002] Macitentan (Macitentan) is a bidirectional endothelin receptor antagonist, clinically used in the treatment of pulmonary arterial hypertension (PAH, WHO grade Ⅰ), to slow down the progression of the disease, including delaying death, intravenous or subcutaneous injection of prostacyclin drugs or worsening of PAH symptoms (decrease in 6-minute walk distance, worsening of PAH symptoms, and need for additional PAH medications). [0003] 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 listed after Bosentan and Ambrisentan, developed by Swiss Actelion Pharmaceutical Company. In N...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 吴标凌林唐胜国
Owner HEFEI JIUNUO MEDICAL TECH
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