Synthetic method of epirubicin hydrochloride and intermediate of epirubicin hydrochloride

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a synthetic method of epirubicin hydrochloride and an intermediate of the epirubicin hydrochloride, and the epirubicin hydrochloride with higher purity can be simply, efficiently and cheaply obtained by utilizing an intermediate compound. Reagents used in the synthesis method are cheap and easy to obtain, operation steps are simple and easy to implement, aftertreatment is simple and convenient, and epirubicin hydrochloride synthesized through the synthesis method is few in impurity, high in purity, stable in quality and high in yield.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of epirubicin hydrochloride and an intermediate thereof. Background technique [0002] Epirubicin hydrochloride (EPI, also known as epirubicin, Famaxin), chemical name (8S,10S)-10-[(3′-amino-2′,3′,6′-tri Deoxy-α-L-arabinopyranosyl)oxy]-6,8,11-trihydroxy-8-glycolyl-1-methoxy-7,8,9,10-tetrahydrotetracene- 5,12-diketone hydrochloride is a third-generation anthracycline antibiotic antitumor drug. Its main mechanism of action is to directly embed into the base pairs of DNA, interfere with the transcription process, and prevent the formation of mRNA to exert an antitumor effect. EPI can inhibit the synthesis of DNA and RNA, so it has effects on all stages of the cell cycle. It is a non-specific drug for the cell cycle. The cardiotoxicity of EPI to rabbits is only 1 / 4 of that of doxorubicin, that is, cardiotoxicity and other toxicity. Smaller, wider range o...

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Problems solved by technology

[0008] The 4'-position hydroxyl inversion mode in the prior art mainly contains Mitsunobu method and Swern oxidation-reduction method, and Mitsunobu method is complicated to operate, and reagent used is expensive, and overall yield is lower (30%), for example US5945518 and US5874550, therefore in industrial production Swern redox method

The Swern redox method has short steps and low cost, but still has the following disadvantages: when using reducing agents such as sodium borohydride or its analogs to reduce carbonyl groups, the product has certain configuration selectivity, but still requires column chromatography to separate isomers and, the 13-position carbonyl in the molecular structure is easily reduced, so that the product yield and purity are reduced, such as WO2006096665A, CN101341166A and CN103204888A, WO2006096665 uses the higher borohydride derivatives of selectivity, and carries out the halogenation reaction to improve the reaction yield and purity, but the reaction conditions are harsh, the reaction cycle is long, the purity is not high, and the yield still needs to be improved

[0009] DE2510866, Grynkiewicz G, Fokt I, Skibicki P, et al.Synthesis of 1-Omikron-Silylated 3-Azido-and 3-N-Trifluoroacetamido-2,3,6-trideoxy-L-arabinoand L-lyxo-hexopyranoses, Convenient Glycosyl Donors for Preparation ofAnthracycline Antibiotics and Related DNA-Binding Agents[J].polish journal ofchemistry,2005,79:335-347. Publicly reported taking doxorubicin hydrochloride as raw material to synthesize epirubicin hydrochloride, only need The hydroxyl group at the 4'-position on the flip sugar does not need to introduce a hydroxyl group in the side chain, but the glycosidic bond needs to be broken first and then glycosylated under the catalysis of the highly toxic catalyst mercury bromide, or explosive sodium azide is required, or Mitsunobu method is required to reverse the defect of hydroxyl group, which is not conducive to environmental protection, long reaction route, low overall yield and high cost

[0010] CN 106749447 A discloses an intermediate compound of epirubicin hydrochloride, but part of the reaction needs to be carried out under anhydrous conditions, and the resulting intermediate has low acid tolerance and will degrade even under weak acid; the carbonyl reduction product Will produce isomers, increase the purification steps and difficulty; the preparation process may lead to etherification of phenolic hydroxyl groups, increased impurities, and reduced yield

[0011] It can be seen that the preparation method of epirubicin hydrochloride has long reaction route, complex operation, expensive reagents, low yield and purity, difficult separation and purification, intermediate compounds have high requirements for moisture and are easy to decompose, and need to use toxic or environmental pollution. Serious technical problems such as catalysts and high production costs are not conducive to industrialized large-scale production

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