Ambrisentan preparation method

A technology of ambrisentan and hydroxyl, which is applied in the field of preparation of ambrisentan, can solve the problems of cost, production capacity and recycling, risk reduction, difficult operation, etc., and achieve easy industrial separation, risk reduction, easy-to-handle effects

Active Publication Date: 2018-07-06
济南周行医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] This method uses the chiral reagent PTC to control the chirality of the product from the synthetic precursor, which is creative in similar literature, but the chiral reagent has not yet been produced on a large scale, and the cost, production capacity and recycling are yet to be investigated, and there are large gaps in industrialization. risk
This method still adopts alkalis such as sodium hydride, lithium hydride, and potassium hydride to react, the conditions are harsh, the risk is large, and it is not easy to operate; it also uses alkalis such as sodium amide, lithium amide, and potassium amide to react, and the risk is reduced to some extent, but A large amount of nitrogen-containing wastewater will be produced, causing environmental pollution
During hydrolysis, a strong base is required and a reflux reaction is required, which may easily cause partial racemization and enantiomeric impurities, which require further purification and the departure of organic groups also produces waste water

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] (1) Put 27.2g (R / S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid into a 250mL reaction flask, add 136mL isopropanol, stir, add 7.8g (S )-(-)-1-(2-chlorophenyl)ethanamine, kept at 20°C and stirred for 2h, the chiral product (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid The (S)-(-)-2-chlorophenylethylamine salt was precipitated; suction filtration, the filter cake was washed with isopropanol, dried by suction, and set aside. (R)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in isopropanol solution can be recycled.

[0035] The filter cake was dissolved in 65 mL of ethyl acetate, stirred, slowly added with 4.05 g of sodium methoxide, slowly cooled to 0 °C, and kept for 1 h, the product (2s)-2-hydroxy-3-methoxy-3,3-diphenyl Sodium propionate was precipitated; suction filtration, washed the filter cake with a small amount of isopropanol, and air-dried at 40-50°C to obtain 13.9 g of product, yield 45.1%, HPLC purity: 99.22%, chiral purity: 99.80%. The resolving agen...

Embodiment 2

[0038]Put 27.2g (R / S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid into a 250mL reaction flask, add 136mL ethanol, stir, add 7.8g (S)-(-) -1-(3-Chlorophenyl)ethylamine, kept at 20°C and stirred for 3 hours, filtered with suction, washed the filter cake with ethanol, sucked dry, dissolved the filter cake in 65 mL of ethyl acetate, stirred, and slowly added 5.10 g of sodium ethoxide, Slowly lower the temperature to 5°C, keep the temperature for 2h, filter with suction, wash the filter cake with a small amount of ethanol, and blow dry at 40-50°C to obtain (2s)-2-hydroxy-3-methoxy-3,3-diphenylpropane Sodium 13.2g, yield 42.8%, HPLC purity: 99.06%, chiral purity: 99.85%.

[0039] Put 30.8g of (2s)-2-hydroxy-3-methoxy-3,3-diphenylpropionate sodium into a 500mL reaction flask, add 124mL of tetrahydrofuran, stir, control the temperature to -5-5°C, and dropwise add 2mol / L 55mL of tetrahydrofuran solution of sodium di(isopropyl)amide, temperature controlled at 0-10°C, 22.3g of tetra...

Embodiment 3

[0041] Put 27.2g (R / S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid into a 250mL reaction flask, add 136mL methanol, stir, add 7.8g (S)-(-) -1-(4-Chlorophenyl)ethylamine, kept at 20°C and stirred for 3 hours, filtered with suction, washed the filter cake with methanol, sucked dry, dissolved the filter cake in 65 mL of ethyl acetate, stirred, and slowly added 4.05 g of sodium methoxide, Slowly lower the temperature to 2°C, keep the temperature for 2h, filter with suction, wash the filter cake with a small amount of methanol, and blow dry at 40-50°C to obtain (2s)-2-hydroxy-3-methoxy-3,3-diphenylpropane Sodium 12.9g, yield 42.0%, HPLC purity: 99.10%, chiral purity: 99.83%;

[0042] Put 30.8g of (2s)-2-hydroxy-3-methoxy-3,3-diphenylpropionate sodium into a 500mL reaction flask, add 124mL of tetrahydrofuran, stir, control the temperature to -5-5°C, and dropwise add 2mol / L 55 mL of tetrahydrofuran solution of sodium bis(ethyl)amide, temperature controlled at 0-10 °C, 22.3 g of ...

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Abstract

The invention discloses an ambrisentan preparation method. The method uses a resolving agent with better fat solublility (S)-(-)-chlorphenyl ethylamine a nd (R / S)-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid to react, a chiral product further reacts with sodium alcoholate to obtain (2S)-2-hydroxy-3-methoxy-3,3-diphenyl sodium propionate, then an amine metal salt with an organic group R2NNa is taken as the alkali to have a nucleophilic substitution reaction with 4,6-dimethyl-2-methylsulfonyl pyrimidine, water is added to quench the reaction, an organic solvent is used to extract fat solubleimpurities like organic amine, and the ambrisentan is obtained after the acidizing. The dangerousness of the method is low, the post-processing is simple, the process is environmentally friendly, theoperation is easy, the product purity and the yield are high, and the method is quite suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of ambrisentan, which belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Ambrisentan, chemical name: (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropane acid. Molecular formula: C 22 H 22 N 2 O 4 , molecular weight: 378.42. Chemical Structure: [0003] [0004] Ambrisentan is an endothelin receptor antagonist developed by Abbott, Gilead, GlaxoSmithKline and other companies for the treatment of pulmonary arterial hypertension. The drug is a new type of highly selective endothelin receptor antagonist, which can potently inhibit the vasoconstriction caused by endothelin, and has high bioavailability and long half-life. The product was approved by the FDA in 2007 under the trade name Letairs. [0005] Patent US5932730 and its patent family, J.Med.Chem., 1996, Vol.39, No.11, P.no.2123-2128 and other documents disclose a kind of separation ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/34
CPCC07B57/00C07B2200/07C07D239/34
Inventor 董万荣张雷雷方敬坤张登科郇利刚
Owner 济南周行医药科技有限公司
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