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Preparation method of bosentan metabolite (hydroxy bosentan)

A technology for hydroxybosentan and its metabolites, which is applied in the field of medicine, can solve problems such as the preparation method report of bosentan metabolite hydroxybosentan, and achieve the effects of low production cost, low adverse reactions and high production efficiency

Inactive Publication Date: 2015-03-18
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the prior art, there is no report on the preparation method of the bosentan metabolite hydroxybosentan

Method used

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  • Preparation method of bosentan metabolite (hydroxy bosentan)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] In a 100 ml three-necked flask, add 4-(2-acetoxy-1,1-dimethylethyl) benzenesulfonamide (948 mg, 4.44 mmol), and add 20 ml of dry DMF solution, stir, Dissolve, control the temperature at 0°C, then add 2.1 molar equivalents of sodium hydride (containing 60% sodium hydride) in mineral oil to the system, gradually raise the temperature to 20°C, and stir for ten minutes. Add 1.552 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine to the system, stir and maintain the temperature for 16 hours. After the reaction was complete, the reaction system was poured into ice water, stirred, and acidified with 1 mol / L hydrochloric acid. The resulting suspension was filtered to obtain a filter cake. After the filter cake was drained, it was dissolved in 20 ml of methanol, dried with anhydrous sodium sulfate for 2 hours, and the solid was removed by filtration. Sentan precursor crude product 2.22 grams.

[0026] In a 100 ml three-necked flask, add 40 ml of dry ethylene glycol, and...

Embodiment 2

[0030] In a 100 ml three-necked flask, add 4-(2-acetoxy-1,1-dimethylethyl) benzenesulfonamide (948 mg, 4.44 mmol), and add 20 ml of dry DMSO solution, stir, Dissolve, control the temperature at 0°C, then add 2.1 equivalents of potassium mineral oil to the system, gradually raise the temperature to 40°C, and stir for ten minutes. Add 1.552 grams of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine to the system, stir and maintain the temperature for 20 hours, and pour the reaction system after the reaction is complete. Stir in ice water and acidify with 1 mol / L hydrochloric acid. The resulting suspension was filtered to obtain a filter cake. After the filter cake was drained, it was dissolved in 20 ml of methanol, dried with anhydrous sodium sulfate for 2 hours, and the solid was removed by filtration. Sentan precursor crude product 2.12 grams.

[0031] In a 100 ml three-necked flask, add 40 ml of dry ethylene glycol, and add 0.28 g of sodium metal. After the reaction is co...

Embodiment 3

[0035]In a 100 ml three-necked flask, add 4-(2-acetoxy-1,1-dimethylethyl)benzenesulfonamide (948 mg, 4.44 mmol), and add 20 ml of dry tetrahydrofuran solution, stir, Dissolve, control the temperature at 5°C, then add 2.1 equivalents of butyllithium mineral oil to the system, gradually raise the temperature to 30°C, and stir for ten minutes. Then add 1.552 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2,2'-dipyrimidine to the system, stir and maintain the temperature for 10 hours. After the reaction was complete, the reaction system was poured into ice water, stirred, and acidified with 1 mol / L hydrochloric acid. The resulting suspension was filtered to obtain a filter cake. After the filter cake was drained, it was dissolved with 20 ml of ethanol alcohol, dried with anhydrous sodium sulfate for 2 hours, and the solid was removed by filtration. Crude bosentan precursor 2.224 g.

[0036] In a 100 ml three-neck flask, add 40 ml of dry ethylene glycol, and add 0.28 g of metal potassium...

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Abstract

The invention discloses a preparation method of a bosentan metabolite (hydroxy bosentan). Abundant screening experiments are performed to determine the optimal reactant consumption, reaction temperature, reaction time, reaction solvent and the like in the preparation technique; and the whole preparation technique has the advantages of high operability, high preparation efficiency and low production cost, and can implement industrialized mass production. The bosentan metabolite (hydroxy bosentan) prepared by the method has the advantages of higher bioavailability and lower untoward effect, and directly can have the antihypertensive effect.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to an antihypertensive drug and a preparation method of bosentan metabolite hydroxybosentan, belonging to the technical field of medicine. Background technique [0002] Bosentan is an endothelin receptor antagonist belonging to a class of highly substituted pyrimidine derivatives with affinity for ETA and ETB receptors. Bosentan reduces pulmonary and systemic vascular resistance, thereby increasing cardiac output without increasing heart rate. The neurohormone endothelin is a potent vasoconstrictor that promotes fibrosis, cell proliferation, and tissue remodeling. Bosentan tablets are indicated for the treatment of pulmonary arterial hypertension in patients with WHO stage III and IV primary pulmonary hypertension, or pulmonary hypertension caused by scleroderma. Bosentan is metabolized in the liver by the cytochrome P450 isoenzymes CYP3A4 and CYP2C9. There are three bosentan...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/52
CPCC07D239/69
Inventor 石庆然张池朱军刘春
Owner TLC NANJING PHARMA RANDD CO LTD