Dexrazoxane preparation method

A technology of dexrazoxane and reaction is applied in the field of preparation of dexrazoxane, which can solve the problems of tediousness, high price and high cost, and achieve the effects of simple reaction steps, good product quality and convenient post-processing.

Inactive Publication Date: 2019-06-04
辽宁博美医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] These three synthetic routes all use the chiral compound (3) as the starting material, which is expensive and costly; the separation of the intermediate uses column chromatography, which is cumbersome; and highly toxic cyanide is used, which should not be used

Method used

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Embodiment example 1

[0017] Preparation of (S)-1,2-propanediamine dihydrochloride (3): Add 30.0g D-(-)-tartaric acid and 105mL water and 8.0g (±)-1,2- Propylenediamine, stirred to dissolve, cooled, added dropwise, heated to reflux for 2 hours with stirring. Stop stirring, first raise the temperature to 80°C, keep it warm for 1 hour, then gradually lower the temperature to room temperature, filter with suction, and dry in vacuum to obtain 16.1 g of (S)-1,2-propanediamine bitartrate. Add 16.1g (S)-1,2-propanediamine bitartrate and 150mL water into the reaction flask, heat to dissolve, then add a solution made of 7.43g potassium chloride and 20mL water, and keep stirring at 70°C for 2 Hour. Cool, and let stand in the refrigerator for crystallization. After suction filtration, the filtrate was distilled to dryness under reduced pressure to obtain 5.1 g of yellow solid (3), with a yield of 84%, [α]2 OD=-4.02° (C=1%, H2O).

[0018] (S)-N, N, N', N'-1, the preparation of 2-propanediaminetetraacetic ac...

Embodiment example 2

[0021] Preparation of (S)-1,2-propanediamine dihydrochloride (3): Add 50.0g D-(-)-tartaric acid and 105mL water and 8.0g (±)-1,2- Propylenediamine, stirred to dissolve, cooled, added dropwise, heated to reflux for 4 hours with stirring. Stirring was stopped, the temperature was slowly lowered to room temperature, suction filtered, and vacuum-dried to obtain 17.1 g of (S)-1,2-propanediamine bitartrate. Add 17.1g (S)-1,2-propanediamine bitartrate and 150mL water into the reaction flask, heat to dissolve, then add a solution made of 7.96g potassium chloride and 20mL water, keep stirring at 70°C 2 hours. Cool, and let stand in the refrigerator for crystallization. After suction filtration, the filtrate was distilled to dryness under reduced pressure to obtain 4.3 g of yellow solid (3), with a yield of 75%, [α]2 OD=-4.02° (C=1%, H2O).

[0022] (S)-N, N, N', N'-1, the preparation of 2-propanediaminetetraacetic acid (4): add 9.2g chloroacetic acid 90mL water successively in reacti...

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Abstract

The invention belongs to the field of drug synthesis, and provides a completely-new dexrazoxane preparation method, which comprises: carrying out a reaction on (S)-1,2-propanediamine ditartrate splitby using inexpensive and easily-available (+ / -)-1,2-propanediamine as a starting raw material and using D-(-)-tartaric acid as a splitting agent and potassium chloride to obtain (S)-1,2-propanediaminedihydrochloride, carrying out condensation on the (S)-1,2-propanediamine dihydrochloride and chloroacetic acid to prepare (S)-N,N,N',N'-1,2-propanediaminetetraacetic acid, and finally carrying out cyclization to obtain dexrazoxane, wherein the total yield is 38.3%. According to the present invention, the route has advantages of simple reaction step, convenient post-treatment, no requirement of column chromatography separation, good product quality and the like.

Description

technical field [0001] The invention relates to the field of pharmacy and provides a preparation method of dexrazoxane. Background technique [0002] Dexrazoxane (Dexrazoxane, 1), the chemical name is (S)-4,4'-(1-methyl-1,2-ethylenediyl)bis-2,6-piperazinedione, which is an antineoplastic drug Razosen (propanimine, razoxane) in the right-handed enantiomer of the mixture. As a cardioprotective drug, it is clinically used to prevent cardiotoxicity caused by anthracycline antineoplastic drugs and heart damage caused by chemotherapy in children with leukemia, and is often used as an adjuvant drug in cancer treatment. Dexrazoxane significantly reduced doxorubicin-induced cardiotoxicity without affecting antitumor activity, survival-free survival, or noncardiotoxicity; thus suggesting that it may increase doxorubicin dose intensity or cumulative dose . The drug was developed by Chiron Corporation of the United States. It was first launched in Italy in 1992, and then successively...

Claims

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Application Information

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IPC IPC(8): C07D241/08
Inventor 鲁执佳刘勇潘大林王艳刘镇
Owner 辽宁博美医药科技有限公司
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