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Synthetic method of selexipag

A synthetic method, the technology of Selexipa, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of complex and cumbersome operation, short process flow, unfavorable scale-up production and industrial promotion, etc., and achieve reasonable technical scheme, high yield and simplified operation Effect

Inactive Publication Date: 2016-09-21
湖南欧亚药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because 4-(isopropylamino)-1-butanol is used as a raw material, there are -NH and -OH groups on its structure, so that the substitution reaction of the first step produces competitive side reactions in different positions, and impurities are introduced. The quality and purification process of the intermediates and products under the influence will cause adverse effects, resulting in complex and cumbersome operations, which is not conducive to scale-up production and industrial promotion. Therefore, it is necessary to explore a short process flow, simple operation, and low cost. Synthesis of Lexipa

Method used

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  • Synthetic method of selexipag

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] A) Preparation of [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy]acetate tert-butyl ester:

[0028] 4-[(tert-butoxycarbonyl)(isopropyl)amino]-1-butanol (20.0 g, 0.09 mol) and tert-butyl bromoacetate (21.1 g, 0.11 mol) were dissolved in dichloromethane (90 mL), Tetrabutylammonium chloride (0.72g, 2.6mmol), potassium hydroxide (7.3g, 0.13mol) and water (12.0g) were added, the reaction mixture was stirred and reacted at 25°C for 2 hours, and the reaction solution was concentrated to dryness by rotary evaporation under reduced pressure. , added ethyl acetate for extraction, dried over magnesium sulfate, concentrated to dryness by rotary evaporation, and recrystallized from a mixed solvent of ethanol and isopropanol to obtain [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy]acetate tert-butyl Ester, pale yellow oil (26.6g), yield 89.0%, the reaction formula of this step is as follows:

[0029]

[0030] B) Preparation of [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy]acetic...

Embodiment 2

[0039] A) Preparation of [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy]acetate tert-butyl ester:

[0040] 4-[(tert-butoxycarbonyl)(isopropyl)amino]-1-butanol (23.0g, 0.10mol) and tert-butyl bromoacetate (25.2g, 0.13mol) were dissolved in 1,2-dichloroethyl Alkane (110mL), tetrabutylammonium bromide (1.1g, 3.5mmol), sodium hydroxide (6.4g, 0.16mol) and water (14.0g) were added, the reaction mixture was stirred at 30°C for 3 hours, and the reaction solution was depressurized Concentrate by rotary evaporation to dryness, add ethyl acetate for extraction, dry over magnesium sulfate, concentrate by rotary evaporation to dryness, recrystallize from a mixed solvent of ethanol and isopropanol to obtain [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy Base] tert-butyl acetate, light yellow oil (30.3g), yield 88.2%, the reaction formula of this step is the same as embodiment 1;

[0041] B) Preparation of [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy]acetic acid:

[0042] [4-(tert-butox...

Embodiment 3

[0047] A) Preparation of [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy]acetate tert-butyl ester:

[0048] 4-[(tert-butoxycarbonyl)(isopropyl)amino]-1-butanol (12g, 0.05mol) and tert-butyl bromoacetate (12.1g, 0.06mol) were dissolved in chloroform (70mL), and tetrabutyl Ammonium iodide (0.5g, 1.3mmol), lithium hydroxide (1.7g, 0.07mol) and water (6.5g), the reaction mixture was stirred at 20°C for 4 hours, the reaction solution was concentrated to dryness by rotary evaporation under reduced pressure, and acetic acid was added Extracted with ethyl ester, dried over magnesium sulfate, concentrated to dryness by rotary evaporation, recrystallized from a mixed solvent of ethanol and isopropanol to obtain [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy]acetate tert-butyl ester, shallow Yellow oil (15.6g), yield 86.8%, the reaction formula of this step is the same as Example 1;

[0049] B) Preparation of [4-(tert-butoxycarbonyl)(isopropyl)aminobutoxy]acetic acid:

[0050] [4-(tert-...

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Abstract

The invention discloses a synthetic method of selexipag. According to the method, 4-[(t-butyloxycarboryl)(isopropyl) amino]-1-butanol and tert-butyl bromoacetate are subjected to a condensation reaction, and obtained 4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl] tert-butyl acetate is subjected to a hydrolysis reaction under an alkaline reaction; obtained 4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl] acetic acid and methanesulfonamide are subjected to a condensation reaction; obtained 2-[4-[(t-butyloxycarboryl)(isopropyl) amino butoxyl]-N-(methylsulfonyl) acetamide is subjected to a deprotection reaction under an acid condition, obtained 2-[4-(isopropyl) amino butoxyl]-N-(methylsulfonyl) acetamide and 5-chloro-2,3-diphenyl pyrazine are subjected to a substitution reaction, and the finished product selexipag is obtained. The method has a reasonable and concise process route and is environment-friendly and suitable for industrial production, the operation is simplified, and the cost is relatively low.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis of medicines, and in particular relates to a synthesis method of a new drug Selexipah for treating pulmonary arterial hypertension. Background technique [0002] The chemical name of the selective non-prostanoid IP prostacyclin receptor agonist Selexipag is 2-[4-(5,6-diphenylpyrazin-2-yl)(isopropyl) Aminobutoxy]-N-(methylsulfonyl)acetamide, its chemical structural formula is: [0003] [0004] Selexipa is a new drug for the treatment of pulmonary arterial hypertension (PAH) developed by Actelion Biopharmaceutical Company of Switzerland. It was approved by the FDA at the end of 2015 and is being promoted as an add-on therapy after the basic treatment for patients with pulmonary arterial hypertension. It is expected to achieve 200 million in the first year of marketing The sales revenue in 2020 is expected to reach more than 600 million US dollars. Pulmonary hypertension is a chronic...

Claims

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Application Information

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IPC IPC(8): C07D241/20
CPCC07D241/20
Inventor 李兴民
Owner 湖南欧亚药业有限公司
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