Synthesis method of sodium glycididazole

A kind of technology of glycidazole sodium and synthesis method, applied in the field of medicinal chemistry, can solve the problems such as the possibility of ammonium triazole ester that cannot be ruled out and the total yield is low

Inactive Publication Date: 2011-09-21
NAN JING RHINE PHARM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the overall yield is low, only 21.2-28.9%
It should be noted that the above two methods cannot rule out the pos

Method used

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  • Synthesis method of sodium glycididazole
  • Synthesis method of sodium glycididazole
  • Synthesis method of sodium glycididazole

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Experimental program
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Embodiment 1

[0035] Embodiment 1, the preparation of iminoacetic anhydride-esterification

[0036] (1) 266.2g (2mol) iminodiacetic acid, 220ml (2.9mol) acetyl chloride, 238g (2.9mol) anhydrous sodium acetate and 1600ml DMF were added successively in the three-necked flask of 3000ml, stirred for half an hour, until the stirring was roughly uniform ;

[0037] (2) Continue to stir and heat the oil bath to gradually increase the internal temperature of the system from 30°C to 50°C;

[0038] (3) React at 50°C for 5-6h;

[0039] (4) stop stirring and heating, add 456g metronidazole;

[0040] (5) stirring, heating in an oil bath, raising the internal temperature of the system to 40°C--45°C, and reacting for 2h;

[0041] (6) stop stirring and heating, pour the reaction solution into 2000ml of water, adjust the pH value to 3-4, freeze at -10°C, let stand overnight, and separate out the first batch of imidobisazole ester;

[0042] (7) The filtrate was diluted with 2000ml of water, then frozen at...

Embodiment 2

[0043] Embodiment 2, the preparation-condensation, salify of sodium glycidazole

[0044] (1) in the three-necked flask of 2000ml, successively add 438.2g (1.0mol) imidobisazole ester, 100ml (1.1mol) chloroacetic acid, add 1000ml THF, 67g (1.1mol) sodium acetate;

[0045] (2) Continue stirring and heat the oil bath to raise the system from 30°C to 70-80°C;

[0046] (3) stirring reaction under 70-80 ℃ condition for 4 hours, cooling to room temperature;

[0047] (4) under ice bath condition, slowly drip the ethanol solution of 49ml 5.8% NaOH into the system (200ml ethanol dissolves 11.6g NaOH);

[0048] (5) complete dropwise addition, remove ice bath, stir at room temperature for 24 hours, a small amount of white solid has been separated out;

[0049] (6) Stop stirring, let the solution stand at room temperature for 24 hours, a large amount of solids are precipitated, and 451.6 g of glycidazole sodium salt is obtained by suction filtration, with a yield of 80.5%.

Embodiment 3

[0050] Embodiment three, the refining of glycidazole sodium

[0051] Put 580g of sodium glycidazole crude product into a 2000ml reaction flask, add 800ml of purified water, 200g of 95% ethanol, heat to 40-50°C under stirring, stir to dissolve completely, add activated carbon and an appropriate amount of sodium ETDA with stirring, keep warm for 30 minutes, and take Hot filtration, the filtrate was cooled to 5-10°C, anhydrous ethanol was added under stirring, cooled to 0-5°C, crystals were precipitated, and 464 g of sodium glycobisazole sodium (containing 3 crystal waters) was dried as a white crystalline powder, yield 80 -86%. Glycibisazole sodium salt content (HPLC based on anhydrous): 99.6%, infrared and mass spectrometry are consistent with pharmaceutical standard samples.

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Abstract

Relating to the field of medicinal chemistry, the invention discloses a synthesis method of sodium glycididazole. According to the method, iminodiacetic acid as a starting material reacts with acethlchloride/anhydrous sodium acetate in DMF (dimethyl formamide), and then reacts with metronidazole to generate imido bisazolyl ester which is further condensed with chloroacetic acid into acid glycididazole. And finally, an ethanol solution with 40 wt% of sodium hydroxide is added to generate sodium glycididazole salt trihydrate. According to the invention, the synthesis method of sodium glycididazole, without using pyridine and acetic anhydride, is environmentally friendly. With an overall yield of 34.5%, the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for synthesizing a tumor radiochemotherapy sensitizer---glycidazole sodium. Background technique [0002] Glycibisazole sodium is a sensitizer for tumor radiation and chemotherapy. It belongs to the nitroimidazole compound. It can fix the DNA damage of tumor hypoxic cells during radiation and chemotherapy, inhibit the repair of DNA damage, and improve tumor hypoxic cells. Sensitivity to radiation and chemotherapy, while Glycidazole sodium generally has less loss in aerobic normal cell groups. [0003] Chinese invention patent ZL89102182.5 discloses a method for preparing a radiochemotherapy sensitizer--- metronidazole acid and its calcium salt. The method uses nitrilotriacetic acid as the starting material and reacts with acetic anhydride in the presence of pyridine , and then form esters with metronidazole, and then form salts with oxides of alkaline earth metals, es...

Claims

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Application Information

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IPC IPC(8): C07D233/92
Inventor 陈新程悦
Owner NAN JING RHINE PHARM TECH
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