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Preparation method of macitentan intermediate

A technology for macitentan and intermediates, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of subsequent purification difficulties, high production costs, and long reaction steps, and achieve short reaction steps and reaction time, low cost, and easy purification Effect

Inactive Publication Date: 2017-09-08
吴宁怡
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chlorosulfonyl isocyanate raw materials are easy to deteriorate after long-term storage, and subsequent purification is difficult; at the same time, the reaction steps are relatively long, resulting in low yield and high production cost

Method used

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  • Preparation method of macitentan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] (1) Synthesis of n-propylaminosulfonyl chloride

[0028] Under the protection of nitrogen, put 135g of compound of formula I (1mol) into a clean four-necked reaction flask, add 250ml of dichloromethane, stir and cool down to -10°C, slowly add 59.1g of compound of formula II (1mol) and triethyl A mixed solution of 101.2 g of amine was added dropwise for about 60 minutes. After the dropwise addition was completed, the temperature was controlled and stirred at 10° C. for about 3 hours. The reaction solution was concentrated under reduced pressure to obtain 155 g of the compound of formula III, which could be directly used in the next step.

[0029] (2) Synthesis of n-propylaminosulfonamide

[0030] Under the protection of nitrogen, put 155g of the compound of formula III obtained in the previous step into a clean four-necked reaction flask, add 300ml of dichloromethane, stir, control the temperature at about 20°C, and slowly introduce ammonia gas for about 1 hour. The re...

Embodiment 2

[0034] (1) Synthesis of n-propylaminosulfonyl chloride

[0035] Under the protection of nitrogen, put 135g of the compound of formula I into a clean four-necked reaction flask, add 250ml of dichloromethane, stir and cool down to 0°C, slowly add the mixed solution of 59.1g of the compound of formula II and 79.1g of pyridine dropwise, and control the dropwise The addition time is about 60 minutes, the dropwise addition is completed, the temperature is controlled at 10°C and the mixture is stirred for about 2 hours. The reaction solution was concentrated under reduced pressure to obtain 150 g of the compound of formula III, which could be directly used in the next step.

[0036] (2) Synthesis of n-propylaminosulfonamide

[0037] Under the protection of nitrogen, put 150g of the compound of formula III obtained in the previous step into a clean four-necked reaction flask, add 300ml of dichloromethane, stir, control the temperature at about 10°C, and slowly introduce ammonia gas f...

Embodiment 3

[0041] (1) Synthesis of n-propylaminosulfonyl chloride

[0042] Under the protection of nitrogen, put 135g of the compound of formula I into a clean four-necked reaction flask, add 250ml of dichloromethane, stir and cool down to 10°C, and slowly drop the mixed solution of 59.1g of the compound of formula II and 101.2g of triethylamine, Control the dropwise addition time for about 60 minutes, after the dropwise addition is completed, stir at 10° C. for about 2 hours under temperature control, and complete. The reaction solution was concentrated under reduced pressure to obtain 146 g of the compound of formula III, which could be directly used in the next step.

[0043] (2) Synthesis of n-propylaminosulfonamide

[0044] Under the protection of nitrogen, put 146g of the compound of formula III obtained in the previous step into a clean four-necked reaction flask, add 300ml of dichloromethane, stir, control the temperature at about 30°C, and slowly inject ammonia gas for about 1 ...

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Abstract

The invention discloses a preparation method of n-propylamine sulfonamide serving as a macitentan intermediate. The preparation method comprises the following steps: by taking n-propylamine and sulfonyl chloride as start raw materials and taking triethylamine as an acid-binding agent, preparing an n-propylamine sulfonamide coarse product through two-step reaction, and performing post-treatment distillation, so as to obtain the n-propylamine sulfonamide. According to the preparation method disclosed by the invention, raw materials which are low in cost and readily available are used; reactions and operations in all the steps are simple; the reaction steps and the reaction time are short; the n-propylamine sulfonamide is easy to popularize, high in yield, low in cost and suitable for industrial large-scale production.

Description

technical field [0001] The present invention relates to a kind of preparation method of medicine intermediate, be specifically related to a kind of preparation method of macitentan intermediate (being n-propylamine sulfonamide). Background technique [0002] Macitentan (macitentan) is an oral ETA and ETB dual antagonist developed by Actelion Pharm in Switzerland. In October 2013, it was approved by the FDA for the treatment of pulmonary hypertension, pulmonary fibrosis and other diseases. Its trade name is Opsumit, and its chemical name is N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl ]-N'-Propylsulfonamide. Since the product was launched, its efficacy, safety and tolerability have all performed well, and the market prospect is promising. Its structural formula is as follows: [0003] [0004] N-propylaminosulfonamide is the key intermediate for the synthesis of macitentan. The original patent WO2002053557 reported the synthesis method of...

Claims

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Application Information

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IPC IPC(8): C07C303/34C07C307/06
CPCC07C303/34C07C307/06C07C307/02
Inventor 吴宁怡周益峰
Owner 吴宁怡
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