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Preparation method of dexrazoxane and pharmaceutical salts thereof

A technology for delazox and medicinal salts, which is applied in the field of preparation of delazox or its pharmaceutically acceptable salts, can solve the problems of low purity, low yield, patient side effects, etc., and achieves reasonable process design and product purity. High and stable effect

Active Publication Date: 2010-03-31
CHONGQING HAITENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] Recrystallization with a mixed solvent tetrahydrofuran and ethanol is too much solvent, and about 70 times the weight and volume of the crude product of Derazoxa should be refined by thermal dissolution, decolorization, hot filtration, cooling crystallization, and drying. The method is cumbersome to operate, the yield is low, the cost is relatively high, and it is difficult to industrialized production; and the appearance of the product refined by this method is pink, the purity is low, and the general HPLC is about 99%.
[0021] The general refining method disclosed in patent EP330381 and WO93 / 08172 mainly uses the toxic solvent dioxane to refine. This method uses a relatively small amount of solvent, generally 4 times the volume of the crude product weight, because the concentration of the solution is relatively high. , the crystalline particles that it precipitates are relatively large, and the solid contains a large amount of toxic solvent dioxane. It takes a relatively high temperature and a long time to slowly remove most of the residual solvent. After drying, it is analyzed by gas chromatography , the residual toxic solvent dioxane is still above 0.1%, far exceeding the maximum limit of 0.038% in the Pharmacopoeia. The residual solvent dioxane is highly toxic and has anesthetic and stimulating effects on human health. There is a relatively serious accumulation effect, and the injection made of Derazoxa containing the solvent dioxane will have unforeseen side effects on patients; , the related substances of the product will increase significantly, the purity will decrease, and the color will gradually become darker; and it is difficult to remove the original color in the crude product by refining dioxane, and the refined product is still pink.
[0022] Due to the poor stability of derazoxate, especially unstable in the solution state, it needs to be made into a freeze-dried preparation, but how to ensure that the freeze-dried preparation knows itself and the preparation process Stability in is still a problem to be solved now
The freeze-dried preparation of Deprazolate abroad is also pink. After testing, its content of related substances is relatively high, and higher impurities (related substances) may bring potential toxic and side effects, which may easily lead to hidden dangers in clinical drug safety. Therefore, the better delazoxal of preparation stability is the problem that people try to solve always

Method used

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  • Preparation method of dexrazoxane and pharmaceutical salts thereof
  • Preparation method of dexrazoxane and pharmaceutical salts thereof
  • Preparation method of dexrazoxane and pharmaceutical salts thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0047] Add 1193g of chloroacetonitrile into a 3000ml three-necked reaction flask, add 3580g of saturated hydrogen chloride methanol solution, stir at 25°C for 8 hours, heat up to 125°C for 1 hour, cool to 30°C, pour into 3000ml of water, stir for 2 hours, filter, Purified with ethanol to obtain 843.7g of N,N-dichloroacetimide (II), mp=195-197°C.

[0048] In a 2000ml three-necked reaction flask, add 170g of the above-mentioned N,N-dichloroacetimide (II) and 2040g of methanol, add 40g of sodium ethoxide under stirring, mix and dissolve for 1 hour, and dropwise add 34g of dextrorotatory 1,2-propylenediamine And 510g of ethanol solution, heated to 50°C for 4 hours, cooled to 45°C, added 35g of sodium ethylate, heated to 80°C to continue the reaction for 4 hours, during the reaction, crystals slowly precipitated, cooled to 20 ℃, filter, wash with ethanol, filter dry, and vacuum-dry at 60-80 ℃ to obtain 160.4 g of Delazolate (I). (mp=192°-195°; Optical Rotation: [a]D+11.35°-+11.40°...

example 2

[0051] Add 1193g of chloroacetonitrile into a 3000ml three-necked reaction flask, add 3580g of sulfuric acid, stir at 25°C for 8 hours, heat up to 100°C for 1 hour, cool to 30°C, pour into 3000ml of water, stir for 2 hours, filter, and refine with ethanol. 840.3 g of N,N-dichloroacetimide (II) were obtained, mp=194-196°C.

[0052] In a 2000ml three-necked reaction flask, add 170g of the above-mentioned N,N-dichloroacetimide (II) and 510g of methanol, add 40g of potassium carbonate under stirring, mix and dissolve for 1 hour, and add 17g of dextrorotatory 1,2-propanediamine dropwise And 3400g of ethanol solution, heated up to 30°C to react for 4 hours, added 35g of sodium ethylate, heated to 80°C to continue reaction for 4 hours, during the reaction, crystals slowly precipitated, cooled to 20°C, filtered, ethanol Wash, filter dry, and vacuum-dry at 60-80° C. to obtain 156.8 g of Delazolate (I). (mp=192°-196°; Optical Rotation: [a]D+11.30°-+11.40° (c=5, DMF); total yield 74.3%)...

example 3

[0055] Add 1193g of chloroacetonitrile and 597g of phosphoric acid into a 3000ml three-necked reaction flask, stir at 25°C for 8 hours, heat up to 150°C for 1 hour, cool to 30°C, pour into 3000ml of water, stir for 2 hours, filter, and refine with ethanol. 835.5 g of N,N-dichloroacetimide (II) were obtained, mp=195-198°C.

[0056] In a 2000ml three-necked reaction flask, add 170g of the above-mentioned N,N-dichloroacetimide (II) and a mixture of 3400g of methanol and propanol (mass ratio 1:1), add 40g of sodium carbonate under stirring, stir, mix and dissolve for 1 hour , add dropwise a solution of 51g of dextrorotatory 1,2-propylenediamine and 2040g of ethanol, heat up to 80°C for 4 hours, cool to 45°C, add 35g of sodium ethylate, heat up to 80°C to continue the reaction for 4 hours after adding, During the reaction process, crystals were slowly precipitated, cooled to 20°C, filtered, washed with ethanol, filtered and dried, and vacuum-dried at 60-80°C to obtain 152.3g of Del...

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Abstract

The invention belongs to chemical synthesis pharmacy technology field, the invention provides a preparation method of medicine dexrazoxane which has a function of antitumor, the process includes: N,N-dichloroacetyl imine (II) is prepared by chloroacetonitrile in the presence of acid, then the (+)- dexrazoxane (I) is obtained by condensation of the N,N-dichloroacetyl imine (II) and the (+)-1,2-propanediamine (III), the obtained dexrazoxane is made into pharmaceutically acceptable salt. The method according to the invention has advantages of simple route, convenient operation, easy industrialization and short period, and the obtained product has high purity. Route of the process is shown in the upper right.

Description

Technical field: [0001] The invention relates to a preparation method of a compound delazoxa with antitumor effect and a pharmaceutically acceptable salt thereof. Background technique: [0002] Dexrazoxane, also known as dexrazoxane or ICRF-187, chemical name [(S)-4,4-(1-methyl-1,2-ethylenediyl)bis-2,6-piperazine Diketone] structural formula is shown in the following formula (I): [0003] [0004] Dexrazoxane is the d-isomer of propylene imine (razoxane), and it is also a lipophilic cyclic derivative of the chelating agent ethylenediaminetetraacetic acid (EDTA). It is clinically used as a chemical protective agent, mainly For the prevention of anthracycline-induced cardiotoxicity. Derazoxa was developed by Chiron Corporation of the United States, first launched in Italy in 1992, and approved by FDA in July 1995. Afterwards, it was successively launched in Europe, Asia, Africa and other countries. Delazoxa is clinically applicable to the prevention of anthracycline-ind...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/08A61P35/00
Inventor 兰志银莫启壮
Owner CHONGQING HAITENG PHARMA
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