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Preparation method of macitentan related substances

The technology of a compound, bromophenyl, is applied in the field of preparation of macitentan-related substances, and can solve problems such as the synthesis method of the compound of formula (I) that has not been reported, and achieve the effects of rapid preparation, simple reaction, and simple purification method

Active Publication Date: 2020-12-22
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the clinical research of macitentan, a compound of formula (I) with a certain purity is required as a reference substance, but there is no report on the synthesis method of the compound of formula (I) in the literature

Method used

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  • Preparation method of macitentan related substances
  • Preparation method of macitentan related substances
  • Preparation method of macitentan related substances

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add macitentan (1.2g), methanol (40mL) into a 250mL three-neck flask, heat to 60°C for 24 hours, and detect by HPLC, the reaction solution contains 5.1% of the compound of formula (I), 87.2% of macitentan .

Embodiment 2

[0029] Add macitentan (1.2g) and ethylene glycol (40mL) into a 250mL three-neck flask, heat to 80°C for 24 hours, and detect by HPLC, the reaction solution contains 10.2% of the compound of formula (I), 79.9% of macitentan Titan.

Embodiment 3

[0031] Add macitentan (1.2 g) and ethylene glycol (40 mL) into a 250 mL three-necked flask, and heat to 110° C. for 3 hours. Add water (200mL) to the reaction solution, extract with dichloromethane (100mLx2), wash the organic layer with water (50mL) and brine (50mL), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the formula (I) Crude compound. Add methanol (50 mL) to the crude compound of formula (I) and stir for 2 hours, filter with suction, and vacuum-dry the filter cake to obtain compound of formula (I) (0.5 g). The purity of the product is 99.5% as detected by HPLC. (a, MS-ESI(m / z): 465.9[M+H] + ; b. 1 H-NMR (DMSO-d 6 )δ:8.70(s,2H),8.11(s,1H),7.51-7.53(d,J=8Hz,2H),7.17-7.19(d,J=8.0Hz,2H),6.29(s,2H) ,4.55(br,4H).

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Abstract

The invention discloses a method for preparing a macitentan related substance. Specifically, the invention relates to a method for preparing a metabolic product (a compound of a formula I) of a pulmonary hypertension-resistant drug macitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidyl)oxo] ethyoxyl]-4-pyrimidyl]-N'-propanesulfonamide). The method comprises the following steps: carrying out a heating reaction on macitentan, and obtaining a target compound. According to the method, the target product can be efficiently prepared at high purity. The structural formula is as shown in the specification.

Description

technical field [0001] The invention relates to the preparation of a macitentan metabolite 5-(4-bromophenyl)-6-[2-[(5-bromopyrimidin-2-yl)oxy]ethoxy]-4-aminopyrimidine method. Background technique [0002] Macitentan (Macitentan, structure as follows) was developed by Actelion Company. On October 18, 2013, it was approved by the US FDA (trade name Opsumit) for the treatment of PAH (WHO Group I). [0003] [0004] Macitentan is an endothelin receptor antagonist (ERA) indicated for the treatment of PAH (WHO class I) to slow disease progression, including delaying death, intravenous or subcutaneous prostacyclin or exacerbation of PAH symptoms ( decrease in 6-minute walk distance, worsening of PAH symptoms, and need for additional PAH medication). This product can also reduce the hospitalization of PAH. [0005] The literature Xenobiotica (2012); 42(9):901-910 reports the metabolic process of macitentan, as follows: [0006] [0007] Wherein, the compound of formula (...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47
CPCC07D239/47
Inventor 张相海陈海超乔智涛周炳城冯芮茂葛旭钱明明
Owner JIANGSU HANSOH PHARMA CO LTD
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