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Preparation method for intermediate of epirubicin hydrochloride

A technology of epirubicin hydrochloride and intermediates, which is applied in the field of medicine, can solve the problems of poor reduction selectivity and side reactions of sodium borohydride, achieve mild reaction conditions, prevent by-products, and reduce side reactions.

Active Publication Date: 2013-07-17
SHANDONG NEWTIME PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] Aiming at the existing problems in the process of synthesizing 4'-epidaunorubicin hydrochloride in the prior art, the oxidation is prone to produce side reactions, generate unpleasant methylthiomethyl ether, and the problem of poor selectivity of sodium borohydride reduction. The experiment provides a method for synthesizing 4'-epidaunorubicin hydrochloride with a simple process, which effectively prevents the generation of methyl thiomethyl ether by-products that pollute the environment, and at the same time improves the hydroboration process during the reduction process. Sodium selectivity, mild reaction conditions, a total reaction yield of over 40% (calculated as daunorubicin hydrochloride), and a purity of 99.5%

Method used

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  • Preparation method for intermediate of epirubicin hydrochloride
  • Preparation method for intermediate of epirubicin hydrochloride
  • Preparation method for intermediate of epirubicin hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0032] The preparation of embodiment 1N-trifluoroacetyl-daunorubicin

[0033] Add 80L of dichloromethane and 750g of daunorubicin hydrochloride to the reaction kettle, stir under the protection of argon, cool down to 0°C, add 1.3L of trifluoroacetic anhydride dropwise, stir for 1 hour, and add 20L of methanol to the reaction solution Use sodium bicarbonate aqueous solution to adjust pH=7.0~8.0, stir at 20±5°C for 3~5 hours, TLC detection and control reaction, use chloroform / isopropanol (volume ratio=96 / 4) as developer, use raw material Until the reaction is complete or almost disappears, intermediate I Rf ≈ 0.3, daunorubicin Rf ≈ 0, separate the organic phase and concentrate it to about 20L under reduced pressure, add 20L ethyl acetate, and concentrate under reduced pressure to 5~ 8 L, directly added to 65 L of n-hexane for crystallization under stirring, and suction-filtered and dried to obtain 739 g of N-trifluoroacetyl-daunorubicin as a solid, with a yield of 95%.

Embodiment 2

[0034] The preparation of embodiment 2N-trifluoroacetyl-daunorubicin

[0035] Add 60L of dichloromethane and 750g of daunorubicin hydrochloride to the reaction kettle, stir under the protection of argon, cool down to 5°C, add 1.1-1.3L of trifluoroacetic anhydride dropwise, stir for 1 hour, and add 20L of After methanol, use sodium bicarbonate aqueous solution to adjust pH=7.0~8.0, stir at 20±5°C for 3~5 hours, TLC detection and control reaction, using chloroform / isopropanol (volume ratio=96 / 4) as developing solvent, Until the raw material reacts completely or almost disappears. Intermediate I Rf≈0.3, daunorubicin Rf≈0, separate the organic phase and concentrate it under reduced pressure to about 15L, add 20L ethyl acetate, concentrate under reduced pressure to 5-8L at a water bath temperature of 50°C, and directly add to 65L of n-hexane was crystallized, filtered and dried to obtain 735g of N-trifluoroacetyl-daunorubicin as a solid, with a yield of 93%.

Embodiment 34

[0036]The preparation of embodiment 34'-keto-N-trifluoroacetyl-daunorubicin

[0037] Put 30L of dichloromethane and 0.9L of dimethyl sulfoxide into the reaction kettle, lower the temperature to -70°C under the protection of argon, slowly add 532.9g of phosphorus pentoxide, keep stirring for 20 to 40 minutes, and dissolve 780g of N-trifluoroacetyl - Dissolve daunorubicin in 15L of dichloromethane, slowly add to the above reaction solution, dropwise for 60-70 minutes, stir for 2 hours, then slowly drop into the system 0.65L of triethylamine, stir at -30°C React for 1 hour, directly add a mixed solution of 0.6L glacial acetic acid and 4L dichloromethane, stir for more than about 10 minutes, TLC to detect the reaction progress, using chloroform / isopropanol (volume ratio=96 / 4) as the developer, Until intermediate I disappears or almost disappears, intermediate I Rf ≈ 0.3, intermediate II Rf ≈ 0.8, the temperature of the reaction solution is raised to 0-10°C, and the organic phase i...

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Abstract

The invention relates to a preparation method for an intermediate 4'-epidaunorubicin hydrochloride of epirubicin hydrochloride. The preparation method comprises the steps of trifluoroacetyl protection, oxidation, reduction, hydrolyzation, etc. The method effectively inhibit generation of (methylthio)methyl ether, increases selectivity for sodium borohydride during the reduction process and is mild in reaction conditions. The total yield of the reaction is over 40% (based on epidaunorubicin hydrochloride) and the purity reaches 99.5%.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an epirubicin hydrochloride intermediate. Background technique [0002] Epirubicin hydrochloride, also known as epirubicin hydrochloride, belongs to anthracycline antibiotics, chemical name: (8S, 10S)-10-[(3′-amino-2′, 3′, 6′-trideoxy-alpha -L-arabinopyranosyl)-O-]-6,8,11-trihydroxy-8-hydroxyacetyl-1-methoxy-7,8,9,10-tetrahydrotetracene-5 , 12-diketone hydrochloride, the structural formula is as follows: [0003] [0004] Anthracyclines form one of the largest families of naturally occurring bioactive compounds. Some members of this family are clinically effective antineoplastic agents. For example, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, arubicin, and carminemycin. These compounds have been shown to be useful in bone marrow transplantation, stem cell transplantation, breast cancer treatment, acute lym...

Claims

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Application Information

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IPC IPC(8): C07H15/252C07H1/00
Inventor 王如
Owner SHANDONG NEWTIME PHARMA
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