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Preparation method for idarubicin hydrochloride

A technology for idarubicin hydrochloride and its compounds, which is applied in the field of drug synthesis, can solve problems such as long reaction steps, difficult separation and purification, and harsh reaction conditions, and achieve the effects of improving quality, shortening reaction steps, and reducing synthesis costs

Active Publication Date: 2018-02-16
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This route has the following disadvantages: ethylene glycol needs to use a class of solvent benzene to protect the C-13 ketone carbonyl; there is a problem of stereoselectivity in the glycosidation reaction, and the reaction conditions are harsh; the reaction steps are long
[0011] In the process of studying the reported idarubicin synthesis method, the inventor found that the final product contained a certain amount of impurity A and impurity B, and the polarity of these two impurities was very similar to idarubicin hydrochloride. It is very difficult to separate and purify

Method used

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  • Preparation method for idarubicin hydrochloride
  • Preparation method for idarubicin hydrochloride
  • Preparation method for idarubicin hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation of embodiment 1 idarubicin hydrochloride

[0038] (1) Preparation of Compound 15 (R is trifluoroacetyl)

[0039] Dissolve 10 g of daunorubicin hydrochloride in 100 ml of dichloromethane, add 10 g of triethylamine and 7.5 g of ethyl trifluoroacetate, and stir at room temperature for 4 hours; add 100 ml of dichloromethane to dilute the reaction solution, wash twice with water, spin dry the organic phase, 10.5 g of solid was obtained (yield 95%, HPLC purity 97%).

[0040] (2) Preparation of Compound 10 (R is trifluoroacetyl)

[0041] Under anhydrous and oxygen-free conditions, 8g of compound 15 was dissolved in anhydrous toluene (80ml), Ni(COD)2 (0.15eq) and PCy3 (0.075eq), TMDSO (1eq) were added, stirred at 80°C for 2h, and the temperature was raised React at 110° C. for 10 h, add 100 ml of ethyl acetate to dilute the reaction solution, wash twice with water, and spin dry the organic phase to obtain 5.7 g of solid (yield 75%).

[0042] (3) preparation o...

Embodiment 2

[0044] The preparation of embodiment 2 idarubicin hydrochloride

[0045] (1) Preparation of compound 15 (R is benzyloxycarbonyl)

[0046] Dissolve 10g of daunorubicin hydrochloride in 100ml of anhydrous dichloromethane, add 2.3g of N,N'-diisopropylethylamine, 4.5g of benzyl chloroformate, stir at room temperature for 10h; add 100ml of dichloromethane to dilute the reaction solution , washed twice with water, and spin-dried the organic phase to obtain 10.6 g of solid (yield 92%, HPLC purity 96%).

[0047] (2) Preparation of compound 10 (R is benzyloxycarbonyl)

[0048] Under anhydrous and oxygen-free conditions, 8g of compound 15 was dissolved in anhydrous toluene (80ml), Ni(COD)2 (0.15eq) and PCy3 (0.075eq), TMDSO (1eq) were added, stirred at 80°C for 2h, and the temperature was raised After reacting at 110°C for 10 h, 100 ml of ethyl acetate was added to dilute the reaction solution, washed twice with water, and the organic phase was spin-dried to obtain 5.9 g of solid (yie...

Embodiment 3

[0051] The preparation of embodiment 3 idarubicin hydrochloride

[0052](1) Preparation of compound 15 (R is p-methoxybenzyl)

[0053] Dissolve 10g of daunorubicin hydrochloride in 100ml of acetonitrile, add 4.9g of potassium carbonate and 4.2g of p-methoxybenzyl chloride, and stir at room temperature for 10h; add 100ml of dichloromethane to dilute the reaction solution, wash twice with water, and spin dry the organic phase to obtain Solid 9.6g (yield 88%, HPLC purity 96%).

[0054] (2) Preparation of compound 10 (R is p-methoxybenzyl)

[0055] Under anhydrous and oxygen-free conditions, 8g of compound 15 was dissolved in anhydrous toluene (80ml), Ni(COD)2 (0.15eq) and PCy3 (0.075eq), TMDSO (1eq) were added, stirred at 80°C for 2h, and the temperature was raised React at 110° C. for 10 h, add 100 ml of ethyl acetate to dilute the reaction solution, wash twice with water, and spin dry the organic phase to obtain 5.6 g of solid (yield 73%).

[0056] (3) preparation of idarubi...

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Abstract

The invention belongs to the field of drug synthesis, and discloses a preparation method for idarubicin hydrochloride. The idarubicin hydrochloride is prepared by adopting a metal nickel catalyst / anorganic phosphine ligand / a silane reducing agent to remove a methoxy group located at a 4-position of an anthracycline compound in one step. According to the invention, the method has the advantages that the steps are short and the synthesis costs are reduced, can reduce generation of an impurity A and an impurity B, and improves the quality of the final product idarubicin hydrochloride.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of idarubicin. Background technique [0002] Idarubicin, namely 4-demethoxydaunorubicin, is a semi-synthetic anthracycline antineoplastic drug, which is clinically used to treat acute myelogenous leukemia (AML) and was launched in the United States in 1990. Its mechanism of action is that idarubicin with a rigid structure inserts into DNA to interfere with nucleic acid synthesis, and idarubicin can also interact with topoisomerase II to further interfere with nucleic acid synthesis. At present, the combination of idarubicin and cytarabine is the first choice for the treatment of AML. [0003] The synthesis of idarubicin reported in the literature mainly includes the following two methods: [0004] method one: [0005] [0006] The literature "Chinese Journal of Antibiotics, 2006, 31(3): 181-183" reported a semi-synthetic route of idarubicin hydrochloride, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/252C07H1/00
CPCC07H1/00C07H15/252Y02P20/55
Inventor 刘丹苏进财代清宇吴舰王华萍柴雨柱徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA