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Method for preparing and purifying selexipag intermediate

A technology of Selensipa and purification method, which is applied in the field of preparation and purification of Selexipah intermediates, can solve the problems of long operation time, reduced product purity, unsatisfactory yield, etc., and achieve refined purity and product yield. High efficiency, improve the purity and yield, improve the effect of product purity

Pending Publication Date: 2022-03-22
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of this method are: an alkaline substance needs to be added as an acid-binding agent, and although the generated salt can be dissolved in water, it may still be introduced into the product, reducing the product purity; the product is purified by silica gel column chromatography, which takes a long time and costs Higher; the yield is low, only 49%, not suitable for the industrialized production of Selexipa
The disadvantages of this method are: expensive palladium catalyst and organophosphorus ligand are used, the cost is high, the post-treatment needs to adjust the pH is more cumbersome, the reaction is easy to cause heavy metal impurities in the product, and it has no practical guiding significance for industrial production
The disadvantage of this method is that although the reactivity of 5-iodo-2,3-diphenylpyrazine is higher than that of 5-chloro-2,3-diphenylpyrazine, it is expensive, while 5-i

Method used

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  • Method for preparing and purifying selexipag intermediate
  • Method for preparing and purifying selexipag intermediate
  • Method for preparing and purifying selexipag intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] To 1 L N-methylpyrrolidone, 5-chloro-2,3-diphenylpyrazine (100 g, 0.375 mol) butanol (150 g, 1.145 mol) was added to the 1L N-methylpyrrolidone. ), The temperature rose to 170-180 ° C for 20-25 hours. The TLC was stopped after the reaction was completely stopped, and the reaction solution was cooled to room temperature. 500 ml of isopropyl alcohol was added to the reaction mixture, and 2.5 L purified water stirred is added dropwise. Filtration, sampling feed phase purity 98.8%. The filter cake was dissolved with 300 ml of dichloromethane, and 1.5L n-hexane stirred was added dropwise. After filtration, the filter cake was dried under vacuum, 96.5 g of light yellow solid, yield was 71.2%, and the liquid phase purity was 99.3%.

Embodiment 2

[0055] To 1 L N-methylpyrrolidone, 5-chloro-2,3-diphenylpyrazine (100 g, 0.375 mol) butanol (150 g, 1.145 mol) was added to the 1L N-methylpyrrolidone. ), The temperature rose to 170-180 ° C for 20-25 hours. The TLC was stopped after the reaction was completely stopped, and the reaction solution was cooled to room temperature. 600 ml of acetone was added to the reaction mixture, and a 3l purified water mixture was added dropwise. Filter, sampling the test liquid phase purity 99.0%. The filter cake was dissolved with 300 ml of dichloromethane, and 1.5L n-hexane stirred was added dropwise. After filtration, the filter cake was dried under vacuum, 95.4 g of light yellow solid, yield 70.4%, and the liquid phase purity was 99.4%.

Embodiment 3

[0057] To 1 L N-methylpyrrolidone, 5-chloro-2,3-diphenylpyrazine (100 g, 0.375 mol) butanol (150 g, 1.145 mol) was added to the 1L N-methylpyrrolidone. ), The temperature rose to 170-180 ° C for 20-25 hours. The TLC was stopped after the reaction was completely stopped, and the reaction solution was cooled to room temperature. 500 ml of acetone was added to the reaction mixture, and 2.5 L purified water stirlated was added dropwise. Filtration, sampling the test liquid phase purity 98.9%. The filter cake was dissolved with ethyl acetate, and 2 l of n-hexane stirred was added dropwise. After filtration, the filter cake was dried under vacuum, and the yield was 74.2%, and the purity was 99.1%.

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Abstract

The invention relates to a preparation and purification method of a selexipag intermediate, and belongs to the field of chemical preparation. The chemical name of the selexipag intermediate is 4-[(5, 6-diphenylpyrazine-2-yl) (isopropyl) amino]-1-butanol, and the preparation method of the selexipag intermediate comprises the following steps: reacting 5-chloro-2, 3-diphenylpyrazine with 4-(isopropyl) amino butanol; optionally, after the reaction is completed, adding a diluting solvent, and then adding water for crystallization; the method can also comprise the following steps: dissolving the obtained crystallized substance or the crude product of the selexipag intermediate with a first organic solvent, and then adding a second organic solvent for crystallization to obtain the selexipag intermediate. The preparation and purification method provided by the invention is simple and convenient to operate, improves the purity and yield of the intermediate, and is suitable for industrial production.

Description

Technical field [0001] The present invention relates to a preparation and purification method thereof, which is a chemical preparation. Background technique [0002] SELEXIPAG, its chemical name is 2- [4 - [(5,6-diphenylpyrazine-2-yl) (isopropyl) amino] butoxy] -N- (methyl) Acryl) Acetamide, CAS: 475086-01-2, the structural formula is as follows: [0003] [0004] Pulmonary hypertension is a chronic conductive pulmonary disease with poor prognosis, and patients may die premature or need pulmonary transplantation. Saul Xpa is an oral LP prostatic cycline receptor agonist, can relax vascular wall smooth muscle, expanded blood vessel, and reduce pulmonary artery pressures. The FDA approved the SELEXIPAG tablet from ACTelion, on December 21, 2015. The trade name is UPTRAVI, used to treat adult pulmonary hypertension, Sai Xipa has high selectivity, long Safety and easy tolerance. [0005] 4 - [(5,6-diphenylpyrazine-2 y) (isopropyl) amino] -1-butanol is an important intermediate of s...

Claims

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Application Information

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IPC IPC(8): C07D241/20
CPCC07D241/20
Inventor 杨勇李德峰陈安丰余俊
Owner JIANGSU HANSOH PHARMA CO LTD
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