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Synthetic method of ambrisentan

A synthetic method, ambrisentan technology, applied in the field of medicine and chemical industry, can solve the problems of incapable of large-scale production, complicated synthesis steps, hidden safety hazards, etc., and achieve the effects of low cost, reduced cost of process materials, and high safety

Inactive Publication Date: 2015-08-19
宁波人健化学制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, strong bases such as lithium amide or sodium hydrogen are extremely sensitive to moisture, and there are bound to be certain safety hazards in the scale-up production
[0006] Patent CN102276536 discloses a preparation method of optically pure (+)-ambrisentan, the synthesis steps of which are complex, many reagents participate in the reaction, the yield is low, and large-scale production is not possible

Method used

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  • Synthetic method of ambrisentan
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Examples

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Effect test

Embodiment 1

[0065] Embodiment 1: A kind of synthetic method of ambrisentan

[0066] At room temperature (20-25°C), mix 137g of L-proline methyl ester hydrochloride in 130ml of methanol (MeOH), control the temperature not to exceed 25°C, add dropwise a solution of 44.7g of sodium methoxide and 132ml of MeOH, After the dropwise addition, add 4800ml of methyl tert-butyl ether (MTBE) and 225g of compound 1. After stirring for half an hour, evaporate about 2680ml of MTBE / MeOH mixed solvent under normal pressure. The distillation temperature is 50-55°C, and the distillation process lasts for about 2- After 3 hours, the temperature dropped naturally to 20-25°C, and the solids in the system were removed by filtration under reduced pressure. Evaporate the filtrate to about 900ml under reduced pressure (a water pump can be used to distill under reduced pressure, the temperature is generally -5 ~ 5°C), add 1000ml of water, adjust the pH of the system to acidic with concentrated hydrochloric acid (th...

Embodiment 2

[0068] At room temperature (20-25°C), mix 137g of L-proline methyl ester hydrochloride in 130ml of MeOH, control the temperature not to exceed 25°C, add a solution of 44.7g of sodium methoxide and 132ml of MeOH dropwise, and the addition is complete Then add 4800ml of MTBE and 225g of compound 1, stir for half an hour and evaporate about 2680ml of MTBE / MeOH mixed solvent under normal pressure. The distillation temperature is 50-55℃. °C, the solids in the system were removed by filtration under reduced pressure. Evaporate the filtrate to about 900ml under reduced pressure (a water pump can be used to distill under reduced pressure, the temperature is generally -5 ~ 5°C), add 1000ml of water, adjust the pH of the system to acidic with concentrated hydrochloric acid (the pH value can be controlled from 1 to 4), and let stand to separate. The water layer was removed, and the aqueous phase was back-extracted with 400 ml of MTBE. The MTBE was combined, dried over sodium sulfate, fil...

Embodiment 3

[0070] At room temperature (20-25°C), mix 137g of L-proline methyl ester hydrochloride in 130ml of MeOH, control the temperature not to exceed 25°C, add a solution of 44.7g of sodium methoxide and 132ml of MeOH dropwise, and the addition is complete Then add 4800ml of MTBE and 225g of compound 1, stir for half an hour and evaporate about 2680ml of MTBE / MeOH mixed solvent under normal pressure. The distillation temperature is 50-55℃. °C, the solids in the system were removed by filtration under reduced pressure. Evaporate the filtrate to about 900ml under reduced pressure (a water pump can be used to distill under reduced pressure, the temperature is generally -5 ~ 5°C), add 1000ml of water, adjust the pH of the system to acidic with concentrated hydrochloric acid (the pH value can be controlled from 1 to 4), and let stand to separate. The water layer was removed, the aqueous phase was back-extracted with 400ml MTBE, the MTBE was combined, dried over sodium sulfate, filtered, a...

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Abstract

The invention relates to a synthetic method of ambrisentan and belongs to the technical field of medicine chemistry. The method comprises the steps of taking a racemoid 1 as a reactant, performing L-proline methyl ester hydrochloride resolution on a compound 1 to obtain a crude product of compound 2, performing nucleophilic reaction on the crude product of the compound 2 and a compound 3 to obtain compound 4. After an enantiomer of the compound 2 of compound 1 is filtered our by resolution, methyl tertiary butyl ether phase obtained by extracting hydrochloric acid free filtrate is used for drying a solvent through distillation to obtain the crude product of the compound 2 which is directly subjected to nucleophilic reaction with the compound 3, a qualified compound 4 is obtained by a subsequent process purifying treatment (comprising decoloration and salifying), the process operation is simplified, process stability is enhanced, loss of the compound 2 caused by crystallization of methylbenzene or crystallization for multiple times is avoided, and cost of process materials is greatly reduced. Lithium amide and sodium-hydrogen are innovatively substituted by lithium hydrate, safety is higher, cost is lower, lithium hydrate is proper in alkalinity, and a reaction system has few impurity points and is suitable for industrialized amplification production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and relates to a synthesis method of ambrisentan. Background technique [0002] Ambesentan, the scientific name is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropane Acid, which was approved by the US FDA in 2007, is used for the treatment of pulmonary arterial hypertension to improve the exercise capacity of patients and improve the quality of life. The drug has less adverse reactions to the liver and has a wide range of application scenarios. Therefore, the process synthesis research of the drug is of great significance. [0003] Patent WO9841206 discloses the use of L-proline methyl ester hydrochloride for resolution and filtration of the enantiomers of compound 2, and the filtrate is free and crystallized from toluene to obtain very pure compound 2 (ee. not less than 99%). The total yield of resolution is 35%. The ee value (enantiotropic exce...

Claims

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Application Information

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IPC IPC(8): C07D239/34
CPCC07D239/34
Inventor 丁同健顾华平郑飞陈柯松
Owner 宁波人健化学制药有限公司
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