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Method for preparing medicament midbody 5-bromine-6-amido quinoxaline

A technology of aminoquinoxaline and nitroquinoxaline, which is applied in the field of preparation of 5-bromo-6-aminoquinoxaline, an intermediate of brimonidine tartrate, a glaucoma drug, can solve the problem of volatile, low yield, iron Ion residues and other problems, to achieve the effect of being conducive to industrial production, high product yield, and low equipment requirements

Inactive Publication Date: 2008-12-10
中国科学院嘉兴应用化学工程中心
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Problems solved by technology

[0002] 5-Bromo-6-aminoquinoxaline is an important intermediate of the glaucoma drug brimonidine tartrate. There are many studies at home and abroad, but there is no report of industrialization
The reduction yield of iron powder is generally not high, a large amount of iron sludge and sewage will seriously pollute the environment, and iron ions will form residues, which will affect product quality; bromine is highly toxic and volatile, and there is a great risk in large-scale production
And route (1) yield is low, and total yield is 45%; Route (2) intermediate 1,2,4-triaminobenzene hydrochloride is unstable in nature, is easy to oxidize and change color, directly affects product quality; So above two The process is not suitable as a production process for pharmaceutical products

Method used

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  • Method for preparing medicament midbody 5-bromine-6-amido quinoxaline
  • Method for preparing medicament midbody 5-bromine-6-amido quinoxaline
  • Method for preparing medicament midbody 5-bromine-6-amido quinoxaline

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Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1: the preparation of 6-nitroquinoxaline

[0029] Glyoxal (40% aqueous solution, 74ml) was added dropwise to 600ml aqueous solution of 39.25g of 4-nitrophenylenediamine, after the dropping was completed, it was heated to 100°C under nitrogen protection, and kept for 5 hours. TLC tracking detection, cooling, filtration, washing with water, extraction with dichloromethane, drying over magnesium sulfate and precipitation to obtain 43.5 g of orange solid (m.p. 177°C, yield 97.5%).

Embodiment 2

[0030] Embodiment 2: the preparation of 6-aminoquinoxaline

[0031] 100ml methanol as solvent, mix 10g (II) and 0.5g palladium-carbon catalyst (5%), add to a 250ml autoclave, replace with hydrogen, feed hydrogen, the temperature is about 70°C, the pressure is 2MPa, after about three hours, It was detected by liquid chromatography that the reaction was complete, taken out, filtered, washed, and the brown-red filtrate was precipitated to obtain a brick-red powdery solid, which was recrystallized from toluene to obtain 6.9 g of a yellow solid, with a yield of 83%.

Embodiment 3

[0032] Embodiment 3: the preparation of 6-aminoquinoxaline

[0033] 100ml of ethanol was used as solvent, mixed with 10g (II) and 0.3g palladium carbon catalyst (5%), added to a 250ml autoclave, replaced by hydrogen, fed with hydrogen, the temperature was about 80°C, and the pressure was 2MPa. After about three hours, It was detected by liquid chromatography that the reaction was complete, taken out, filtered, washed, and the brown-red filtrate was precipitated to obtain a brick-red powdery solid, which was recrystallized from toluene to obtain 6.2 g of a yellow solid, with a yield of 75%.

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Abstract

The invention provides a method for preparing an intermediate 5-bromo-6-quinoxalinamine of glaucoma drug brimonidine tartrate. The method adopts 4-nitro-o-phenylenediamine as a raw material to prepare the intermediate 5-bromo-6-quinoxalinamine through cyclization, drogen reduction and high-selective bromination by using dibromohydantoin as a brominating agent, with a total yield reaching 77 percent. The method has the advantages of easily obtained raw materials, mild reaction condition, safe and environment-friendly process and good product quality, and convenience for industrial production.

Description

Technical field [0001] The present invention relates to the field of pharmaceutical intermediates, and more specifically to a preparation method of glaucoma drug brimonidine tartrate intermediate 5-bromo-6-aminoquinoxaline. Background technique [0002] 5-Bromo-6-aminoquinoxaline is an important intermediate for the glaucoma drug brimonidine tartrate. There have been many studies at home and abroad, but there are no reports of industrialization. [0003] The following two routes are currently the most studied routes. Route (1) is reported in patents GE2309160 and GE2538620. The reaction formula is as follows: [0004] [0005] Route (2) is European patent EP0422878 and Document 1 (Zhang Wanjin, Zhang Yanmei, Luo Yan, "Synthesis of Brimonidine Tartrate", "Henan Chemical Industry" 2005, 22(4), 18-19) and Document 2 (Ge Zongming , Wang Cunde, "Synthesis of brimonidine tartrate", "Chinese Pharmaceutical Industry Journal" 2002, 33 (1), 1-3) reported, the reaction formula is a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/42
Inventor 陈奇文陈笃慧吴长江
Owner 中国科学院嘉兴应用化学工程中心
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