Synthesis method of diphenyl pyrazine derivative

A diphenylpyrazine and synthesis method technology, applied in the direction of organic chemistry, etc., can solve problems such as difficult long-term storage, potential safety hazards, instability of diphenylpyrazine, etc., and achieve high feasibility, good safety, and reasonable design Effect

Pending Publication Date: 2021-06-11
NANJING UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The starting material 5-chloro-2,3-diphenylpyrazine in the two routes is unstable and not easy to store for a long time, and an ultra-high temperature reaction of 170°C-200°C is used in the preparation of intermediate II, which has certain safety Hidden danger

Method used

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  • Synthesis method of diphenyl pyrazine derivative
  • Synthesis method of diphenyl pyrazine derivative
  • Synthesis method of diphenyl pyrazine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Synthesis of 5,6-diphenyl-2-hydroxypyrazine (compound NS-300)

[0040]

[0041] Reaction steps:

[0042] Add methanol (350mL) to a 1000mL three-necked flask equipped with a condenser, add benzil (35.02g) and glycinamide hydrochloride (19.75g, 1.1eq), cool in an ice-water bath to 10°C, and slowly add 12N Sodium hydroxide solution (30mL), temperature control ≤ 30°C, after dropwise addition, turn to oil bath for heating, heat up to 70°C for reflux reaction for 12h, HPLC detects that raw materials disappear, stop heating, turn on cooling and cool down to 10°C, add ice to the system Acetic acid was used to adjust the pH to 6-7, and the retested pH remained unchanged. A large amount of light yellow solid precipitated out, and the bright yellow solid was obtained by suction filtration, which was air-dried at 70°C and directly put into the next step without purification.

Embodiment 2

[0044] Synthesis of 5-bromo-2,3-diphenylpyrazine (compound NS-301)

[0045]

[0046] Reaction steps:

[0047]Add acetonitrile (350mL) to a 500mL three-necked flask equipped with a condenser, stir and add NS-300 (30.00g), add phosphorus oxybromide (103.92g, 3.0eq), stir and heat up to 70°C, react for 30h, and detect by HPLC When the reaction was complete, the reaction solution was slowly added to 850mL of water to quench the reaction, and a large amount of light purple solid was precipitated, which was filtered with suction, and the filter cake was beaten with dilute NaOH solution, adjusted to neutrality, and 33.46g of solid was obtained by suction filtration. Yield about 89%. ESI-MS:m / z=313.0(M+H) + . 1 H NMR (500MHz, DMSO-d 6 )δ8.84 (s, 1H), 7.43-7.30 (m, 10H).

Embodiment 3

[0049] Synthesis of N-isopropyl-5,6-diphenylpyrazin-2-amine (Compound NS-302)

[0050]

[0051] Reaction steps:

[0052] Add dioxane (250mL), NS-301 (30.03g), isopropylamine (8.62g, 1.5eq), KI (4.80g, 0.3eq) and potassium carbonate (41.14g, 2.0eq ), stirred evenly, heated to 40-45° C. for 12 hours, and TLC monitored that the reaction was complete. The reaction mixture was cooled to around 10°C, quenched with water (100 mL) and extracted with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 20.41 g of a solid. The yield is about 73%. ESI-MS:m / z=290.4(M+H) + .

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Abstract

The invention discloses a synthesis method of a diphenyl pyrazine derivative. The method is characterized in that benzil and glycinamide are used as raw materials, and a target product is prepared through five-step reaction. The obtained target product is high in purity, subsequent production of high-quality drugs is facilitated, and the synthesis method is reasonable in route design, mild in reaction condition, free of high-temperature reaction, good in safety and high in feasibility.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a diphenylpyrazine derivative and a synthesis method thereof. Background technique [0002] Pulmonary arterial hypertension (Pulmonary Arterial Hypertension, PAH) is a malignant pulmonary vascular disease characterized by increased pulmonary artery pressure, with or without small pulmonary artery disease, often leading to right heart failure and even death. PAH can be an independent disease, a complication, or a syndrome. The NIH of the United States reported that the natural median survival period of PAH is only 2.8 years, and it is known as a "malignant tumor" of the cardiovascular system. In recent years, with the launch of targeted drugs and the improvement of diagnosis and treatment methods, the survival rate of PAH patients has improved significantly, but it is still incurable, and the five-year survival rate is still only 60%. [0003] Prostacyclin (PGI2) and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/20
CPCC07D241/20
Inventor 张晶煜罗军
Owner NANJING UNIV OF SCI & TECH
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