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Preparation method of selexipag intermediate and application of selexipag intermediate in preparation of selexipag

A technology of celecipal and intermediates, which is applied in the preparation of celecipal intermediates and the application field in the preparation of celecipal, can solve the problems of high industrial production risk and phosphorus-containing waste water, etc., and achieve production costs. Low effect, high yield and purity, mild reaction conditions

Pending Publication Date: 2021-11-30
湖北石河医药科技有限公司
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Problems solved by technology

[0004] Document J.Am.Chem.Soc.1952,74,1580-158 reported that 5,6-diphenyl-2-hydroxypyrazine was obtained by condensation of diphenylethanedione and aminoacetamide hydrochloride as raw materials, Phosphorus oxychloride is then chlorinated to synthesize 5-chloro-2,3-diphenylpyrazine, but this method uses a large amount of phosphorus oxychloride, and there are more phosphorus-containing wastewater, so the risk of industrial production is very high

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  • Preparation method of selexipag intermediate and application of selexipag intermediate in preparation of selexipag
  • Preparation method of selexipag intermediate and application of selexipag intermediate in preparation of selexipag
  • Preparation method of selexipag intermediate and application of selexipag intermediate in preparation of selexipag

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preparation example Construction

[0053]The application provides a preparation method of a Selexipa intermediate, which is

[0054]

[0055] 5-X-2,3-diphenylpyrazine, its structural formula is:

[0056] , wherein, X is halo, preferably Cl or Br;

[0057] The above preparation method comprises: mixing and reacting raw materials including an organic solvent, an ion-pairing reagent, a dehydrating agent and 5,6-diphenyl-2-hydroxypyrazine, and then performing purification treatment to obtain an intermediate of Selexipah.

[0058] In some embodiments, the mass ratio of the 5,6-diphenyl-2-hydroxypyrazine, organic solvent, ion-pair reagent and dehydrating agent is 1:(6-10):(1.5-3.2):( 0.86-1.4).

[0059] Preferably, the mass ratio of the 5,6-diphenyl-2-hydroxypyrazine, organic solvent, ion-pair reagent and dehydrating agent is 1: (8-9): (2.3-2.6): (1.2-1.3 ).

[0060] In some embodiments, the organic solvent includes, but is not limited to, at least one of 1,2-dichloroethane, toluene, and xylene.

[0061] In s...

Embodiment 1

[0081] Add dry toluene 870g, 5,6-diphenyl-2-hydroxypyrazine 100g (0.4mol), tetrabutylammonium bromide 260g (0.8mol) and phosphorus pentoxide 136g (0.96 mol), turn on the stirring, heat up to 105°C for 10 hours, then take a sample and control it, and HPLC detects that the purity of 5,6-diphenyl-2-hydroxypyrazine is ≤1%, and the temperature is lowered to ≤15°C; then add 500g of water, and statically The layers were separated, the obtained water layer was extracted twice with dichloromethane (350g*2), the organic layers were combined, washed with sodium bicarbonate solution to pH=7-8, and the layers were left to stand again; the separated organic layer was Concentrate under reduced pressure until it becomes viscous, add 400g of ethanol, beat and stir for 2h, filter to obtain 108g of off-white solid 5-Br-2,3-diphenylpyrazine, the yield of 86.5% , 99.7% purity. The HPLC spectrogram of this Selexipa intermediate is as follows Figure 1a Shown; The HNMR spectrogram of this Selexipa ...

Embodiment 2

[0083] Add dry toluene 500g, 5,6-diphenyl-2-hydroxypyrazine 50g (0.2mol), tetrapropyl ammonium chloride 88g (0.4mol) and phosphorus pentoxide 68g (0.48 mol), turn on the stirring, heat up to 105°C for 10 hours, then take a sample and control it, and HPLC detects that the purity of 5,6-diphenyl-2-hydroxypyrazine is ≤1%, and the temperature is lowered to ≤15°C; then add 500g of water, and statically The layers were separated, the obtained water layer was extracted twice with dichloromethane (250g*2), the combined organic layers were washed with sodium bicarbonate solution to pH=7-8, and the layers were left to stand again; the separated organic layer was Concentrate under reduced pressure until it becomes viscous, add 200g of ethanol, beat and stir for 2h, and filter to obtain 55.3g of off-white solid, 5-Br-2,3-diphenylpyrazine, the yield of 89% %, purity 99.3%; the HPLC spectrogram of the Selexipa intermediate is as follows Figure 2a Shown; The HNMR spectrogram of this Selexi...

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Abstract

The invention provides a preparation method of a selexipag intermediate and application of the selexipag intermediate in preparation of selexipag, and the preparation method of the selexipag intermediate comprises the following steps: mixing and reacting raw materials including an organic solvent, an ion pair reagent, a dehydrating agent and 5,6-diphenyl-2-hydroxypyrazine, and then conducting purifying to obtain the selexipag intermediate. According to the preparation method of the selexipag intermediate, the organic solvent, the ion pair reagent, the dehydrating agent and the 5,6-diphenyl-2-hydroxypyrazine are mixed for reaction, then purification treatment is carried out, the reaction condition is mild, the yield and purity of the obtained product selexipag intermediate are high, the operation process is simple, the selexipag intermediate is safer and more environmentally friendly, the production cost is low, and the method is suitable for industrial mass production.

Description

technical field [0001] The present application relates to the field of drug synthesis, in particular to a preparation method of an intermediate of Selesipah and its application in the preparation of Selesipah. Background technique [0002] Pulmonary hypertension is a pathological process characterized by progressive elevation of pulmonary vessels and progressive failure of right heart function, and is a common clinical complication of many diseases. Pulmonary hypertension (PH) is a type of chronic cardiovascular disease that is currently clinically difficult to cure. About 1% of the world's population is troubled by PH, and the incidence rate of people over 65 years old is even as high as 5% to 10%. . The etiology of PH is complex, and there are no clear biomarkers for clinical diagnosis. Surgery and interventional therapy are effective for a small number of specific types of PH. Currently, the most important clinical treatment method is vasodilation drugs, but this method...

Claims

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Application Information

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IPC IPC(8): C07D241/16C07D241/20
CPCC07D241/16C07D241/20
Inventor 乔凌翔王念陈赟
Owner 湖北石河医药科技有限公司
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