Preparation method of high-purity dexrazoxane

A high-purity technology of dextropropylimine, which is applied in the field of pharmaceutical and chemical engineering, can solve the problems of low refining yield, toxic and side effects of patients, and long-term crystallization, so as to achieve easy control of process conditions, stable product yield, and time-saving short effect

Active Publication Date: 2012-09-19
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

And the method for dioxane refining, only need the dioxane of 5 times weight of crude product weight to be dissolved under reflux condition, use this method to obtain the product with higher content, but product crystallization needs longer time, and Due to the high solubility of dioxane, the refined yield is not very high
More importantly, the residue of dioxane solvent is relatively high. In the actual test, its content is higher than 0.2%, while the pharmacopoeia maximum is 0.038%. It is difficult to drop to the limit specified in the pharmacopoeia by various means. Larger, and there is a more serious accumulation in the human body, the use of dextropropimine injection containing dioxane will have unpredictable toxic side effects on patients

Method used

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  • Preparation method of high-purity dexrazoxane
  • Preparation method of high-purity dexrazoxane
  • Preparation method of high-purity dexrazoxane

Examples

Experimental program
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Effect test

Embodiment 1

[0042] 80kg of water, 116kg of chloroacetic acid, 24kg of 50% sodium hydroxide solution, 30kg of (S)-1,2-propanediamine hydrochloride and 0.5kg of potassium iodide in 70kg of water were added to the 500L reactor in turn. Keep temperature 15-25 o C for 4 hours, then heated to 60 o C was reacted for 20 hours. About 30kg of concentrated hydrochloric acid was added to adjust the pH value to about 5.3. keep 60 o C was concentrated under reduced pressure, and about 220kg of water was distilled off. Filtrate while hot, transfer the filtrate to a 1000L crystallization kettle, and add 600kg of methanol in batches. Crystallize for about 5 hours and centrifuge. Filter cake 70 o C was dried for 8 hours to obtain 62.5kg of tetraacetic acid with a content of 78.3% and a moisture content of 5.2%.

Embodiment 2

[0044] Put tetraacetic acid (100g), formamide (150mL) and polyethylene glycol 300 (10g) into the reaction flask in turn, and heat to 100g under reduced pressure. o C reaction for 1 hour, the obtained clear solution was heated to 150-155 o C, continue vacuum distillation reaction for 5 hours. Keep vacuum distillation to internal temperature 120-130 o C No distillate. cool down to 20 o C, ethanol (100 mL) was added to give a yellow solid. The solid was put into a reaction flask containing dioxane (200mL), heated to reflux for about 20 minutes, filtered, the filtrate was concentrated under reduced pressure to obtain most of the dioxane, added 80mL of methanol, stood still for about 30 minutes, filtered, and the filter cake was vacuum 50 o C was dried for 3 hours to give 34.1 g of crude dextropropimine (pale yellow solid).

Embodiment 3

[0046] Put tetraacetic acid (100g), formamide (150mL) and polyethylene glycol 600 (40g) into the reaction flask in turn, and heat to 100g under reduced pressure. o C reaction for 1 hour, the obtained clear solution was heated to 150-155 o C, continue vacuum distillation reaction for 5 hours. Keep vacuum distillation to internal temperature 120-130 o C No distillate. cool down to 50 o C, a mixed solution (100 mL) of tert-butanol and tetrahydrofuran was added to obtain a yellow solid. The solid was put into a reaction flask containing dioxane (200mL), heated to reflux for about 20 minutes, filtered, the filtrate was concentrated under reduced pressure to obtain most of the dioxane, added 80mL of tert-butanol, stood still for about 30 minutes, filtered, and the filter cake Vacuum 50 o C was dried for 3 hours to obtain 32.8 g of crude dextranimine.

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Abstract

The invention relates to a preparation method of high-purity dexrazoxane, which comprises the following steps of: (1) cyclization reaction: carrying out cyclization reaction between (S)-1, 2-propane diamine-N, N, N', N'-tetracetic acid or disodium salt of (S)-1, 2-propane diamine-N, N, N', N'-tetracetic acid and formamide, wherein a high boiling point solvent is used; (2) preparation of salt-containing crude product: evaporating the mixture, which is obtained after reaction, for removing the formamide by pressure reduction and concentration, adding organic solvent into the mixture, and filtering to obtain solid; (3) preparation of crude product: adding dioxane into the salt-containing crude product, heating for backflow, filtering, concentrating the filtrate, adding organic solvent into the filtrate to obtain the crude product of dexrazoxane; and (4) refining: adding the crude product of dexrazoxane into N, N'-dimethyl formamide, heating for dissolving, dropwise adding the solvent, carrying out crystallization, filtering to obtain solid, washing the obtained solid with the solvent, drying to finally obtain the high-purity dexrazoxane. The method for synthesizing dexrazoxane is stable in yield and easy in condition control; the product purity is higher than 99.5% and residual organic solvent is little, and the synthesis cost can be reduced.

Description

technical field [0001] The invention relates to a preparation method of high-purity dextropropylimine, which belongs to the field of medicine and chemical industry, and more specifically relates to a synthesis process of high-purity dextropropylimine, including a preparation method and a refining method. Background technique [0002] The chemical name of dexrazoxane is (S)-4,4'-(1-methyl-1,2-ethanediyl)-bis-(2,6-piperazinedione), as shown in the structural formula ( i) as shown: [0003] [0004] Dextropropyl imine is the d-isomer of razoxane, also known as dexrazoxane or derazoxa or ICRF-187, which is a lipophilic derivative of chelating agent ethylenediaminetetraacetic acid, produced by the United States Developed by Chiron Company, it was first launched in Italy in 1992, and was approved by the FDA in July 1995. At present, dextromethyridine is the only drug clinically used to reduce the cardiotoxicity induced by anthracycline antineoplastic drugs. After intracellul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/08
Inventor 赵俊赵宇宗在伟蔡开明
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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