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Preparation method of selexipag

A compound and reaction technology are applied in the field of preparation of medicines for treating pulmonary arterial hypertension, can solve the problems of high boiling point of solvent N-methylpyrrolidone, unsuitable for large-scale industrial production, central nervous system dysfunction and the like, and achieve reactivity and selectivity. High, no toxic side effects, quick response effect

Active Publication Date: 2016-10-12
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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Problems solved by technology

[0009] The disadvantages of this preparation method are: CDI is very sensitive to moisture and can be decomposed when exposed to water. The reaction requires high solvent moisture; the reaction steps are cumbersome and the yield is low, only 34.5%. (2) and compound A are purified by column chromatography, which is not suitable for large-scale industrial production
Moreover, the solvent N-methylpyrrolidone (NMP) used has a high boiling point. At 203°C, chronic effects can cause central nervous system dysfunction, cause lesions in the respiratory organs, kidneys, and vascular system, and damage fertility. Countries have strict limits on the minimum solubility of NMP in the working environment, from Japan (1PPM) to South Africa (100PPM), the European Union and the United States (10PPM), not suitable for industrial production
[0013] It can be seen that there are following defects in the process of preparing selexipag: the reaction steps of Scheme 1 are loaded down with trivial details, and the yield is low, and the post-reaction treatment of key intermediates in the reaction process needs column chromatography, which is not suitable for industrialized production; mentioned in Scheme 2 The synthetic method is only theoretically feasible, but in reality most of the raw materials are unreacted, and the solvent N-methylpyrrolidone has a high boiling point and high toxicity, so it is not suitable for industrial production

Method used

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  • Preparation method of selexipag

Examples

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Effect test

Embodiment 1

[0031] A preparation method for selexipag, comprising the steps of: sequentially adding 1,4-dioxane (700 mL), a compound represented by formula I (60 g, 0.166 mol), a compound represented by formula II (85.44 g, 0.498mol) and potassium tert-butoxide (111g, 0.996mol), stirred at 30-35°C for 3h, TLC detected that the reaction was complete, and the reaction was stopped. Suction filtration, the filtrate was evaporated under reduced pressure to remove the solvent, the residual liquid was diluted with water (300mL), the pH was adjusted to 6-7 with 1N hydrochloric acid aqueous solution, extracted with dichloromethane (3×50mL), and the organic layer was separated with water (300mL ), dried over anhydrous magnesium sulfate, decolorized with activated carbon (15g), removed the solvent by rotary evaporation under reduced pressure, recrystallized the residual solution with a mixed solution (THF:n-hexane volume ratio = 1:1.1) (700mL), and dried under reduced pressure to obtain 68.4g light ...

Embodiment 2

[0034] A method for preparing selexipag, comprising the steps of: sequentially adding 1,4-dioxane (700 mL), a compound represented by formula I (60 g, 0.166 mol), a compound represented by formula II (107.57 g, 0.498mol) and potassium tert-butoxide (111g, 0.996mol), stirred at 25-30°C for 3h under the protection of nitrogen, the reaction was complete by TLC detection, and the reaction was stopped. Filtrate with suction, remove the solvent by rotary evaporation of the filtrate under reduced pressure, dilute the residual liquid with water (300 mL), adjust the pH to 6-7 with 1N hydrochloric acid, extract with dichloromethane (3×50 mL), separate the organic layer with water ( 300mL), washed with anhydrous magnesium sulfate, decolorized with activated carbon (15g), removed the solvent by rotary evaporation under reduced pressure, recrystallized the residual solution with a mixed solution (THF:n-hexane volume ratio = 1:1.5) (700mL), dried under reduced pressure, Obtained 69.07g ligh...

Embodiment 3

[0038]A preparation method for selexipag, comprising the steps of: sequentially adding 1,4-dioxane (300 mL), a compound represented by formula I (20 g, 0.055 mol), a compound represented by formula II (47.52 g, 0.22mol) and potassium tert-butoxide (49.36g, 0.44mol), stirred at 23-28°C for 3h, TLC detected that the reaction was complete, and stopped the reaction. Filtrate with suction, remove the solvent by rotary evaporation of the filtrate under reduced pressure, dilute the residual liquid with water (100 mL), adjust the pH to 6-7 with 1N hydrochloric acid aqueous solution, extract with dichloromethane (3×20 mL), separate the organic layer with water ( 100mL), washed with anhydrous magnesium sulfate, decolorized with activated carbon (5g), removed the solvent by rotary evaporation under reduced pressure, recrystallized the residual solution with a mixed solution (THF:n-hexane volume ratio = 1:1.3) (200mL), dried under reduced pressure, 22.86 g of light yellow powdery solid wa...

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Abstract

The invention discloses a preparation method of selexipag, and relates to the technical field of preparation of drugs for treating pulmonary hypertension. The preparation method comprises the following steps: adding a compound as shown in the formula I and a compound as shown in the formula II in an organic solvent; adding alkali; stirring at the reaction temperature of 10-40 DEG C and carrying out Williamson reaction; synthesizing a compound as shown in the formula A, namely the selexipag. The organic solvent is 1-4-dioxane; the alkali is sodium tert-butoxide, potassium tert-butoxide or mixed alkalis of sodium tert-butoxide and potassium tert-butoxide. A synthetic route is reasonable in design, reaction conditions are mild, the cost is low, special equipment is not required, a product is high in purity and high in yield, and aftertreatment is simple and convenient, so that the preparation method of the selexipag is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of medicines for treating pulmonary hypertension. Background technique [0002] selexipag, chemical name: 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide, USA Chemical Abstracts registration number CAS: 475086-01-2, with the formula A structural formula: [0003] [0004] Selexipag is a novel oral long-acting PGI 2 Receptor agonists can relax the muscles of the blood vessel wall to dilate the blood vessels and reduce the elevated blood pressure of the blood vessels supplying the lungs. The drug is used to treat pulmonary arterial hypertension in adults, and its safety and efficacy are higher than placebo for the treatment of similar diseases, and it has been proven to reduce the hospitalization time and the risk of disease progression of pulmonary arterial hypertension. [0005] Currently, the preparation methods of selexipag disclosed in internationa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 尚振华王辉方倩
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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