Anamycin intermediate as well as preparation method and application thereof

Abstract

The invention relates to an anamycin intermediate as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The technical problem to be solved by the invention is to provide the novel-structure anamycin intermediate and the preparation method thereof, the synthesis route of the anamycin is shortened, the reaction yield is improved, and the production cost is reduced. The key point of the technical scheme is that the structure of the anamycin intermediate is as shown in the following formula V,

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and more specifically, to an anamycin intermediate, its preparation method, and its application. Background Technology

[0002] Annamycin, also known as Naxtarubicin, has the chemical name (7S,9S)-7-(((2R,3R,4R,5R,6S)-4,5-dihydroxy-3-iodo-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7,8,9,10-tetrahydrotetracene-5,12-dione, and its structural formula is as follows:

[0003] .

[0004] Anamycin is an anthracycline drug with significant antitumor activity, demonstrating unique efficacy against various drug-resistant tumor cell lines, particularly acute lymphoblastic leukemia (ALL) and lung cancer brain metastasis models. Unlike traditional anthracyclines such as doxorubicin, anamycin, due to its liposomal properties, can effectively circumvent P-glycoprotein-mediated multidrug resistance mechanisms and has higher lipid solubility, making it easier to formulate into liposomal targeted preparations, thereby increasing drug concentration at tumor sites and reducing cardiotoxicity.

[0005] The prior art discloses some methods for preparing anamycin preparations, such as lyophilized liposomal anamycin precursors.

[0006] Relevant patent documents retrieved: This document, published in China (CN114641296A) on May 27, 2025, discloses a method for preparing lyophilized anamycin. The method includes the following steps: preparing a solution containing one or more lipids, a nonionic surfactant, and one or more solvents with a pH of 4.8-5.9; adding anamycin solution to the lipid solution, the anamycin solution containing 8-12 wt% anamycin in DMSO to provide a lipid-containing anamycin solution; aseptically filtering the lipid-containing anamycin solution; and lyophilizing the lipid-containing anamycin solution to provide an anamycin liposome precursor lyophilized product; wherein the one or more lipids are selected from DMPC and DMPG, and the nonionic surfactant is polysorbate 20.

[0007] Although the application of anamycin in cancer is currently a hot research topic, there are very few reports on its preparation in existing technologies. In the 1990s, Ohio State University in the United States applied for a paper on the semi-synthetic route of anamycin as follows: ; The synthetic route uses 4-demethoxydaunolide as a starting material, and anamycin is obtained through a series of reactions. This involves silane and acetyl protection, is lengthy and complex, and results in low yields that are difficult to scale up. Therefore, researching and providing a synthetic method for anamycin is of great significance. Summary of the Invention

[0008] The purpose of this invention is to provide: A novel anamycin intermediate, its preparation method and application, and related technologies, to solve technical problems such as shortening the synthetic route of anamycin, avoiding cumbersome protection and deprotection reactions, improving reaction yield, and reducing production costs, or combinations thereof.

[0009] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0010] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0011] The definition of standard chemical terms can be found in the reference "Basic Organic Chemistry (Volumes 1 & 2), Xing Qiyi, Higher Education Press, 3rd Edition, 2005-06."

[0012] Unless otherwise stated, conventional methods within the scope of the art, such as mixing, drying, filtering, and concentration, shall be used.

[0013] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0014] In this article, compounds with the same serial number refer to the same substance, regardless of the form of expression. For example, in "compound of formula V", "compound shown in formula V", "compound described in formula V", "compound of formula V", and "compound V", the compound serial number is "V", referring to the same compound, that is: .

[0015] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0016] As used in this article, "drying" refers to the process of removing moisture or other solvents from a compound by heating, vacuuming, or using a desiccant.

[0017] As used in this article, "mixing" refers to the process of uniformly distributing two or more components through manipulation, with the aim of achieving consistency in component content. For example, in pharmaceutics, mixing involves combined operations of solids with solids, solids with liquids, or liquids with liquids to ensure the homogeneity of the final product.

[0018] The term "filtration" as used in this article refers to the core operation in organic chemistry for separating solid-liquid mixtures. It involves using a porous medium to trap solid particles, allowing the liquid to pass through, thus achieving separation. Specifically, it is the physical process of using a filter medium (such as filter paper) to trap solid particles in a suspension, allowing the liquid to pass through; relying on gravity, pressure, or centrifugal force to drive the liquid through the pores of the medium, while the solids are trapped to form a filter cake.

[0019] The term "stirring" as used in this article refers to the process of thoroughly mixing reactants by mechanical or magnetic means, which is especially crucial in heterogeneous reactions (such as solid-liquid and liquid-liquid reactions). It accelerates the contact of reactants, promotes uniform heat distribution, and avoids localized overheating that could lead to side reactions.

[0020] In a first aspect, the present invention provides: an anamycin intermediate, the structure of which is shown in formula V below: .

[0021] Secondly, the present invention provides a method for preparing the above-mentioned anamycin intermediate, wherein the reaction formula of the preparation method includes: ; The preparation method includes the following steps: Compounds of Formula III and IV, molecular sieve, and solvent 1 are mixed, and trimethylsilane trifluoromethanesulfonate is added. The mixture is reacted to obtain compound V.

[0022] Preferably, the mass ratio of the compound of formula III to the compound of formula IV is 1:2-2.5.

[0023] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:2-2.5, including but not limited to 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, and 1:2.5.

[0024] Preferably, the mass ratio of the compound of formula III to the molecular sieve is 1:1.2-2.

[0025] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1.2-2, including but not limited to 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, and 1:2.0.

[0026] Preferably, the solvent 1 is selected from at least one of dichloromethane and 1,4-dioxane.

[0027] More preferably, the solvent 1 is a mixture of dichloromethane and 1,4-dioxane.

[0028] Preferably, the volume ratio of dichloromethane to 1,4-dioxane is 1-10:1-10.

[0029] The technical effects of this invention can be achieved by any point value or any subrange value within the range of 1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 2:2, 2:3, 2:4, 2:5, 2:6, 2:7, 2:8, 2:9, 2:10, 3:1, 3:2, 3:3, 3:4, 3:5, 3:6, 3:7, 3:8, 3:9, 3:10, 4:1, 4:2, 4:3, 4:4, 4:5, 4:6, 4:7, 4:8, 4:9, 4:10, 5:1, 5:2, 5:3, 5:4, 5:5, 5:6, 5 :7, 5:8, 5:9, 5:10, 6:1, 6:2, 6:3, 6:4, 6:5, 6:6, 6:7, 6:8, 6:9, 6:10, 7:1, 7:2, 7:3, 7:4, 7:5, 7:6, 7:7, 7:8, 7:9, 7:10, 8:1, 8:2, 8:3, 8:4, 8:5, 8:6, 8:7, 8:8, 8:9, 8:10, 9:1, 9:2, 9:3, 9:4, 9:5, 9:6, 9:7, 9:8, 9:9, 9:10, 10:1, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 10:10.

[0030] More preferably, the volume ratio of dichloromethane to 1,4-dioxane is 3:1.

[0031] Preferably, the molar ratio of the compound of formula III and trimethylsilane trifluoromethanesulfonate is 1:1-15.

[0032] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1-15, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, and 1:15.

[0033] More preferably, the molar ratio of the compound of formula III and trimethylsilane trifluoromethanesulfonate is 1:12.

[0034] Preferably, the reaction temperature is -20 to 40°C and the time is 10 to 60 minutes.

[0035] The technical effects of this invention can be achieved at any point or sub-range within the temperature range of -20 to 40℃, including but not limited to -20℃, -19℃, -18℃, -17℃, -16℃, -15℃, -14℃, -13℃, -12℃, -11℃, -10℃, -9℃, -8℃, -7℃, -6℃, -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, and 3℃. 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃.

[0036] The technical effects of this invention can be achieved at any point or sub-range within the range of 10-60 minutes, including but not limited to 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 21 min, 22 min, 23 min, 24 min, 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, 35 min, 36 min, 37 min, 38 min, 39 min, 40 min, 41 min, 42 min, 43 min, 44 min, 45 min, 46 min, 47 min, 48 min, 49 min, 50 min, 51 min, 52 min, 53 min, 54 min, 55 min, 56 min, 57 min, 58 min, 59 min, and 60 minutes.

[0037] Preferably, the mass-to-volume ratio of the compound of formula III to the solvent is 1 g: 70-90 mL.

[0038] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1g:70-90mL, including but not limited to 1g:70mL, 1g:75mL, 1g:80mL, 1g:85mL, and 1g:90mL.

[0039] Preferably, the preparation method further includes post-processing.

[0040] Preferably, the post-processing includes the following steps: after the reaction is completed, the reaction solution is washed with water until neutral, the organic phase is dried, filtered, concentrated, and purified.

[0041] Preferably, the reaction formula for preparing the compound of formula III includes: ; Includes the following steps: Compound II, base, acetylation reagent and solvent 2 are mixed and reacted to obtain compound III.

[0042] Preferably, the solvent 2 is selected from at least one of N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran.

[0043] More preferably, the solvent 2 is N,N-dimethylformamide.

[0044] Preferably, the alkali is an organic alkali.

[0045] More preferably, the organic base is selected from at least one of 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, and pyridine.

[0046] More preferably, the organic base is triethylamine.

[0047] Preferably, the molar ratio of the compound of formula II to the base is 1:1-10.

[0048] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.

[0049] Preferably, the acetylation reagent is selected from at least one of silver acetate, sodium acetate, and acetic acid.

[0050] More preferably, the acetylation agent is acetic acid.

[0051] Preferably, the molar ratio of the compound of formula II to the acetylation reagent is 1:1-10.

[0052] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.

[0053] Preferably, the preparation method further includes post-processing.

[0054] More preferably, the post-processing includes the following steps: extraction, washing with water, drying, and concentration.

[0055] Preferably, the solvent for extraction is selected from dichloromethane / water or ethyl acetate / water.

[0056] Thirdly, the present invention provides the application of the aforementioned anamycin intermediate in the preparation of anamycin, wherein the reaction formula for preparing anamycin includes: ; Includes the following steps: Compound V reacts with a solvent, and upon addition of a base, deacetylation is achieved to produce anamycin.

[0057] Preferably, the solvent is selected from at least one of tetrahydrofuran, methanol, and dichloromethane.

[0058] More preferably, the solvent is a mixture of methanol and dichloromethane.

[0059] Preferably, the volume ratio of methanol to dichloromethane is 1-10:1-10.

[0060] The technical effects of this invention can be achieved by any point value or any subrange value within the range of 1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 2:2, 2:3, 2:4, 2:5, 2:6, 2:7, 2:8, 2:9, 2:10, 3:1, 3:2, 3:3, 3:4, 3:5, 3:6, 3:7, 3:8, 3:9, 3:10, 4:1, 4:2, 4:3, 4:4, 4:5, 4:6, 4:7, 4:8, 4:9, 4:10, 5:1, 5:2, 5:3, 5:4, 5:5, 5:6, 5 :7, 5:8, 5:9, 5:10, 6:1, 6:2, 6:3, 6:4, 6:5, 6:6, 6:7, 6:8, 6:9, 6:10, 7:1, 7:2, 7:3, 7:4, 7:5, 7:6, 7:7, 7:8, 7:9, 7:10, 8:1, 8:2, 8:3, 8:4, 8:5, 8:6, 8:7, 8:8, 8:9, 8:10, 9:1, 9:2, 9:3, 9:4, 9:5, 9:6, 9:7, 9:8, 9:9, 9:10, 10:1, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 10:10.

[0061] Preferably, the alkali is selected from at least one of sodium methoxide, potassium carbonate, sodium hydroxide, and sodium ethoxide.

[0062] More preferably, the alkali is sodium methoxide.

[0063] Preferably, the molar ratio of the compound of formula V to the base is 1:1-10.

[0064] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.

[0065] Preferably, the reaction temperature is -20 to 20°C.

[0066] The technical effects of this invention can be achieved at any point or sub-range value within the range of -20 to 20℃, including but not limited to -20℃, -19℃, -18℃, -17℃, -16℃, -15℃, -14℃, -13℃, -12℃, -11℃, -10℃, -9℃, -8℃, -7℃, -6℃, -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, and 20℃.

[0067] Fourthly, the present invention provides a method for preparing anamycin, comprising the following steps:

[0068] S1: Using the compound of formula I as a substrate, the methyl hydrogen at position 14 is substituted with a halogen to obtain the compound of formula II. S2: Compound of formula II, base, acetylation reagent and solvent are mixed and reacted to obtain compound of formula III; S3: Compound of Formula III, compound of Formula IV, molecular sieve and solvent are mixed, trimethylsilane trifluoromethanesulfonate is added, and the reaction is carried out to obtain compound of Formula V; S4: Compound V is mixed with a solvent, and alkali is added to deacetylate it to obtain anamycin.

[0069] Preferably, in step S2, the solvent is selected from at least one of N,N-dimethylformamide, 1,4-dioxane, and tetrahydrofuran.

[0070] More preferably, the solvent is N,N-dimethylformamide.

[0071] Preferably, in step S2, the alkali is an organic alkali.

[0072] More preferably, the organic base is selected from at least one of 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, and pyridine.

[0073] More preferably, the organic base is triethylamine.

[0074] Preferably, in step S2, the molar ratio of the compound of formula II to the base is 1:1-10.

[0075] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.

[0076] Preferably, in step S2, the acetylation reagent is selected from at least one of silver acetate, sodium acetate, and acetic acid.

[0077] More preferably, the acetylation agent is acetic acid.

[0078] Preferably, in step S2, the molar ratio of the compound of formula II to the acetylation reagent is 1:1-10.

[0079] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.

[0080] Preferably, in step S2, the preparation method further includes post-processing.

[0081] More preferably, the post-processing includes the following steps: extraction, washing with water, drying, and concentration.

[0082] Preferably, the solvent for extraction is selected from dichloromethane / water or ethyl acetate / water.

[0083] Preferably, in step S3, the mass ratio of the compound of formula III to the compound of formula IV is 1:2-2.5.

[0084] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:2-2.5, including but not limited to 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, and 1:2.5.

[0085] Preferably, in step S3, the mass ratio of the compound of formula III to the molecular sieve is 1:1.2-2.

[0086] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1.2-2, including but not limited to 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, and 1:2.0.

[0087] Preferably, in step S3, the solvent is selected from at least one of dichloromethane and 1,4-dioxane.

[0088] More preferably, the solvent is a mixture of dichloromethane and 1,4-dioxane.

[0089] Preferably, in step S3, the volume ratio of dichloromethane to 1,4-dioxane is 1-10:1-10.

[0090] The technical effects of this invention can be achieved by any point value or any subrange value within the range of 1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 2:2, 2:3, 2:4, 2:5, 2:6, 2:7, 2:8, 2:9, 2:10, 3:1, 3:2, 3:3, 3:4, 3:5, 3:6, 3:7, 3:8, 3:9, 3:10, 4:1, 4:2, 4:3, 4:4, 4:5, 4:6, 4:7, 4:8, 4:9, 4:10, 5:1, 5:2, 5:3, 5:4, 5:5, 5:6, 5 :7, 5:8, 5:9, 5:10, 6:1, 6:2, 6:3, 6:4, 6:5, 6:6, 6:7, 6:8, 6:9, 6:10, 7:1, 7:2, 7:3, 7:4, 7:5, 7:6, 7:7, 7:8, 7:9, 7:10, 8:1, 8:2, 8:3, 8:4, 8:5, 8:6, 8:7, 8:8, 8:9, 8:10, 9:1, 9:2, 9:3, 9:4, 9:5, 9:6, 9:7, 9:8, 9:9, 9:10, 10:1, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 10:10.

[0091] More preferably, the volume ratio of dichloromethane to 1,4-dioxane is 3:1.

[0092] Preferably, in step S3, the molar ratio of the compound of formula III and trimethylsilane trifluoromethanesulfonate is 1:1-15.

[0093] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1-15, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, and 1:15.

[0094] More preferably, the molar ratio of the compound of formula III and trimethylsilane trifluoromethanesulfonate is 1:12.

[0095] Preferably, in step S3, the reaction temperature is -20 to 40°C and the time is 10 to 60 minutes.

[0096] The technical effects of this invention can be achieved at any point or sub-range within the temperature range of -20 to 40℃, including but not limited to -20℃, -19℃, -18℃, -17℃, -16℃, -15℃, -14℃, -13℃, -12℃, -11℃, -10℃, -9℃, -8℃, -7℃, -6℃, -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, and 3℃. 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃.

[0097] The technical effects of this invention can be achieved at any point or sub-range within the range of 10-60 minutes, including but not limited to 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 21 min, 22 min, 23 min, 24 min, 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, 35 min, 36 min, 37 min, 38 min, 39 min, 40 min, 41 min, 42 min, 43 min, 44 min, 45 min, 46 min, 47 min, 48 min, 49 min, 50 min, 51 min, 52 min, 53 min, 54 min, 55 min, 56 min, 57 min, 58 min, 59 min, and 60 minutes.

[0098] Preferably, in step S3, the mass-to-volume ratio of the compound of formula III to the solvent is 1 g: 70-90 mL.

[0099] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1g:70-90mL, including but not limited to 1g:70mL, 1g:75mL, 1g:80mL, 1g:85mL, and 1g:90mL.

[0100] Preferably, in step S3, the preparation method further includes post-processing.

[0101] Preferably, the post-processing includes the following steps: after the reaction is completed, the reaction solution is washed with water until neutral, the organic phase is dried, filtered, concentrated, and purified.

[0102] Preferably, in step S4, the solvent is selected from at least one of tetrahydrofuran, methanol, and dichloromethane.

[0103] More preferably, the solvent is a mixture of methanol and dichloromethane.

[0104] Preferably, in step S4, the volume ratio of methanol to dichloromethane is 1-10:1-10.

[0105] The technical effects of this invention can be achieved by any point value or any subrange value within the range of 1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 2:1, 2:2, 2:3, 2:4, 2:5, 2:6, 2:7, 2:8, 2:9, 2:10, 3:1, 3:2, 3:3, 3:4, 3:5, 3:6, 3:7, 3:8, 3:9, 3:10, 4:1, 4:2, 4:3, 4:4, 4:5, 4:6, 4:7, 4:8, 4:9, 4:10, 5:1, 5:2, 5:3, 5:4, 5:5, 5:6, 5 :7, 5:8, 5:9, 5:10, 6:1, 6:2, 6:3, 6:4, 6:5, 6:6, 6:7, 6:8, 6:9, 6:10, 7:1, 7:2, 7:3, 7:4, 7:5, 7:6, 7:7, 7:8, 7:9, 7:10, 8:1, 8:2, 8:3, 8:4, 8:5, 8:6, 8:7, 8:8, 8:9, 8:10, 9:1, 9:2, 9:3, 9:4, 9:5, 9:6, 9:7, 9:8, 9:9, 9:10, 10:1, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 10:10.

[0106] Preferably, in step S4, the alkali is selected from at least one of sodium methoxide, potassium carbonate, sodium hydroxide, and sodium ethoxide.

[0107] More preferably, the alkali is sodium methoxide.

[0108] Preferably, the molar ratio of the compound of formula V to the base is 1:1-10.

[0109] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 1:1-10, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10.

[0110] Preferably, in step S4, the reaction temperature is -20~20℃.

[0111] The technical effects of this invention can be achieved at any point or sub-range value within the range of -20 to 20℃, including but not limited to -20℃, -19℃, -18℃, -17℃, -16℃, -15℃, -14℃, -13℃, -12℃, -11℃, -10℃, -9℃, -8℃, -7℃, -6℃, -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, and 20℃.

[0112] The beneficial effects of this invention are as follows: This invention provides a novel compound of formula V, which is an intermediate for anamycin. The synthesis of this compound is simple and easy to control, skipping the cumbersome silicon protection and deprotection steps of the old semi-synthetic route. The preparation of anamycin using this compound is simple in operation, saving costs and time, and is more suitable for industrial production. Detailed Implementation

[0113] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0114] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0115] Example 1 Preparation of an anamycin intermediate, compound of formula V:

[0116] Preparation of compound V: 0.4 g of compound III was dissolved in 22 mL of anhydrous dichloromethane and 10 mL of dioxane, then 0.88 g of compound IV and 0.8 g of molecular sieve were added. The mixture was stirred at room temperature for 10 min, then transferred to 0 °C, and 2.1 mL of trimethylsilane trifluoromethanesulfonate was added. The mixture was stirred for another 50 min. The reaction was monitored by TLC (ethyl acetate: n-hexane = 1:1, v / v). The organic phase was washed with water until neutral, dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: dichloromethane: acetone = 98:2). The fraction was collected and concentrated under reduced pressure to dryness to obtain 400 mg of orange-red solid, which is compound V, with a yield of 100% (w / w) and a purity of 90% (HPLC).

[0117] MRI:1 H NMR (400 MHz, DMSO)δ13.55 (s, 1H), 13.28 (s, 1H), 8.31-8.23(m, 2H), 8.04-7.95 (m, 2H), 5.52 (s, 1H), 5.50 (s, 1H), 4.97 (dd, J = 5.8,3.2 Hz, 1H), 4.59 (s, 2H), 4.35 (d, J = 4.0 Hz, 1H), 3.99 (dq, J = 9.0, 6.2Hz, 1H), 3.23 (t, J = 9.0 Hz, 1H), 2.99 (d, J = 50.5 Hz, 2H), 2.83-2.76 (m,1H), 2.27-1.99 (m, 2H), 2.10-2.03(d,9H),1.23 (d, J = 6.3 Hz, 3H).

[0118] Example 2 Preparation of an anamycin intermediate, compound of formula V: 0.4 g of compound III was dissolved in 2.8 mL of anhydrous dichloromethane and 25.2 mL of dioxane. Then, 0.80 g of compound IV and 0.48 g of molecular sieve were added. The mixture was stirred at room temperature for 10 min, followed by the addition of 0.525 mL of trimethylsilane trifluoromethanesulfonate and stirring for another 60 min. The reaction was monitored by TLC (ethyl acetate: n-hexane = 1:1, v / v). The organic phase was washed with water until neutral, dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: dichloromethane: acetone 98:2, v / v). The fraction was collected and concentrated under reduced pressure to dryness to give 300 mg of orange-red solid, which is compound V, with a yield of 75% (w / w) and a purity of 92% (HPLC).

[0119] Example 3 Preparation of an anamycin intermediate, compound of formula V: 0.4 g of compound III was dissolved in 32.4 mL of anhydrous dichloromethane and 3.6 mL of dioxane. Then, 1.0 g of compound IV and 0.64 g of molecular sieve were added. The mixture was stirred at room temperature for 10 min, followed by the addition of 2.625 mL of trimethylsilane trifluoromethanesulfonate and stirring at 40 °C for 10 min. The reaction was monitored by TLC (ethyl acetate: n-hexane = 1:1, v / v) until completion. The organic phase was washed with water until neutral, dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: dichloromethane: acetone 98:2, v / v). The fraction was collected and concentrated under reduced pressure to dryness to obtain 250 mg of orange-red solid, which is compound V, with a yield of 62.5% (w / w) and a purity of 89% (HPLC).

[0120] Application Example 1 A method for preparing anamycin includes the following steps: .

[0121] (1) Preparation of compound II: 0.28 g of compound I (4-demethoxydaunolide) was dissolved in 34 mL of chloroform, and 0.675 g of bromine was added at 30 °C and stirred overnight. The reaction was monitored by TLC (mobile phase: dichloromethane: acetone = 10:1, v / v) to ensure complete reaction. The reaction solution was then concentrated under reduced pressure to dryness to obtain 0.3 g of dark red solid, which is compound II, with a yield of 107.1% (w / w).

[0122] (2) Preparation of compound III: 0.3 g of compound II was dissolved in 13 mL of LMF, and then 0.74 g of acetic acid and 0.25 mL of triethylamine were added at room temperature. After stirring for 1 h, the reaction was monitored by TLC (mobile phase: dichloromethane: acetone = 10:1, v / v) to ensure complete reaction. The reaction solution was washed with water 3 times and dried with anhydrous sodium sulfate. The solution was concentrated under reduced pressure to dryness to obtain 0.4 g of dark red oil, which is compound III, with a yield of 133.3% (w / w).

[0123] (3) Preparation of compound V: Compound V prepared in Example 1, yield 100% (w / w).

[0124] (4) Preparation of compound VI: Dissolve 0.4 g of compound V in 30 mL of dichloromethane and 15 mL of methanol. Add 0.152 g of sodium methoxide in portions at 0 °C and stir for 2 hours. Monitor the reaction by TLC (dichloromethane:methanol = 10:1, v / v). After neutralization with 0.1 mol / L dilute hydrochloric acid, extract with dichloromethane and wash with water until neutral. Dry with anhydrous sodium sulfate, separate by column chromatography (eluent: dichloromethane:methanol = 98:2, v / v), collect the fraction, concentrate under reduced pressure to dryness to obtain an orange-red solid, namely compound VI - anamycin 120 mg, yield 30% (w / w), purity 94.7% (HPLC), total yield of four steps 42.83% (w / w).

[0125] Application Example 2 (1) Preparation of compound II: 0.28 g of compound I (4-demethoxydaunolide) was dissolved in 34 mL of chloroform, and 0.475 g of bromine was added at 20 °C and stirred overnight. The reaction was monitored by TLC (mobile phase: dichloromethane:acetone = 10:1, v / v) to ensure complete reaction. The reaction solution was then concentrated under reduced pressure to dryness to obtain 0.3 g of dark red solid, which is compound II, with a yield of 107.1% (w / w).

[0126] (2) Preparation of compound III: 0.3 g of compound II was dissolved in 13 mL of N,N-dimethylformamide. 0.1 mL of acetic acid and 0.25 mL of triethylamine were added at room temperature. After stirring for 1 h, the reaction was monitored by TLC (mobile phase: dichloromethane:acetone = 10:1, v / v) to ensure complete reaction. The reaction solution was washed three times with water and dried with anhydrous sodium sulfate. The solution was concentrated under reduced pressure to dryness to obtain 0.4 g of a dark red oily substance, which is compound III. Yield: 133.3% (w / w).

[0127] (3) Preparation of compound V: Compound V prepared in Example 2. Yield 75.00% (w / w).

[0128] (4) Preparation of compound VI: 0.2 g of compound V was dissolved in 20 mL of dichloromethane and 2.5 mL of methanol. 0.076 g of sodium methoxide was added in portions at 20 °C and stirred for 2 hours. The reaction was monitored by TLC (dichloromethane:methanol = 10:1, v / v) until the reaction was complete. After neutralization with 0.1 mol / L dilute hydrochloric acid, the mixture was extracted with ethyl acetate and washed with water until neutral. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (eluent: dichloromethane:methanol = 98:2, v / v). The fraction was collected and concentrated under reduced pressure to dryness to obtain an orange-red solid, namely compound VI - anamycin 45 mg, with a yield of 22.5% (w / w) and a purity of 92.5% (HPLC). The overall yield of the four steps was 24.09% (w / w).

[0129] 1 H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 13.28 (s, 1H), 8.31 - 8.23(m, 2H), 8.04 - 7.95 (m, 2H), 5.52 (s, 1H), 5.50 (s, 1H), 5.40 (s, 1H), 5.20(s, 1H), 4.97 (dd, J = 5.8, 3.2 Hz, 1H), 4.91 (s, 1H), 4.59 (s, 2H), 4.35 (d,J = 4.0 Hz, 1H), 3.99 (dq, J = 9.0, 6.2 Hz, 1H), 3.23 (t, J = 9.0 Hz, 1H), 2.99 (d, J = 50.5 Hz, 2H), 2.83 - 2.76 (m, 1H), 2.27-1.99 (m, 2H), 1.23 (d, J= 6.3 Hz, 3H).

[0130] ESI-MS (m / z): 639.1 [MH] - ;+ESI-MS(m / z): 663.2 [M+Na]+ 679.2[M+K] + .

[0131] Application Example 3 (1) Preparation of compound II: 0.28 g of compound I (4-demethoxydaunolide) was dissolved in 34 mL of chloroform, and 0.605 g of bromine was added at 30 °C and stirred overnight. The reaction was monitored by TLC (mobile phase: dichloromethane:acetone = 10:1, v / v) to ensure complete reaction. The reaction solution was then concentrated under reduced pressure to dryness to obtain 0.3 g of dark red solid, which is compound II, with a yield of 107.1% (w / w).

[0132] (2) Preparation of compound III: 0.3 g of compound II was dissolved in 13 mL of DMF, and then 0.1 mL of acetic acid and 0.25 mL of triethylamine were added at room temperature. After stirring for 1 h, the reaction was monitored by TLC (mobile phase: dichloromethane: acetone = 10:1, v / v) to ensure complete reaction. The reaction solution was washed with water 3 times and dried with anhydrous sodium sulfate. The solution was concentrated under reduced pressure to dryness to obtain 0.5 g of dark red oil, which is compound III, with a yield of 166.7% (w / w).

[0133] (3) Preparation of compound V: Compound V prepared in Example 3, yield 62.5% (w / w).

[0134] (4) Preparation of compound VI: 0.4 g of compound V was dissolved in 25 mL of dichloromethane and 25 mL of methanol. 0.180 g of sodium methoxide was added in portions at -20 °C and stirred for 1 hour. The reaction was monitored by TLC (dichloromethane:methanol = 10:1, v / v) until it was complete. After neutralization with 0.1 mol / L dilute hydrochloric acid, the mixture was extracted with dichloromethane and washed with water until neutral. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (eluent: dichloromethane:methanol = 98:2, v / v). The fraction was collected and concentrated under reduced pressure to dryness to obtain an orange-red solid, namely compound VI - anamycin 110 mg, with a yield of 27.5% and a purity of 93.6% (HPLC). The total yield of the four steps was 30.68% (w / w).

[0135] Application Comparative Example 1 .

[0136] (1) 4-Demethoxydaunorubicin ketone ① (10 mg, 0.025 mmol) was added to 1 mL of chloroform, and bromine (13.5 mg dissolved in 0.25 mL of chloroform) was added. The mixture was stirred at 23 °C for 16 hours. The reaction was observed by TLC to indicate that the reaction was complete. The mixture was then evaporated to dryness under reduced pressure to obtain solid ②.

[0137] Solid ② was dissolved in 5 mL of acetone:water (4:1), and NaOH (1.1 mg 0.028 mmol) was added. The blue solution turned red after stirring and refluxing for 5 min. The solution was concentrated under reduced pressure to 2 mL, and 10 mL of water was added. The solution was extracted with 10 mL × 3 of chloroform:methanol (1:1, v / v), and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and the residue was crystallized from chloroform / methanol / petroleum ether to give 9.0 mg of 4-demethoxydoxomilone ③, with a yield of 90% (w / w).

[0138] (2) 4-Demethoxydoxomilone ③ (891.2 mg, 2.32 mmol) was dissolved in DMF (12 mL), and imidazole (686 mg, 10.115 mmol) and tert-butyldimethylchlorosilane (559.4 mg, 3.71 mmol) were added. The mixture was stirred at 25 °C for 0.5 h, then poured into dichloromethane, washed three times with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (100 g silica gel), eluted with 20:1 toluene-acetone, and the main fraction was collected to give product ④: 629 mg, yield 70.57% (w / w).

[0139] (3) Compound ④ (629 mg, 1.26 mmol) was dissolved in 8 mL of tetrahydrofuran, and then 3,4-di-O-acetyl-L-rhamnaldehyde (417 mg, 1.95 mmol) was added to 15 mL of acetonitrile. The solution was kept under a dry argon atmosphere, and N-iodosuccinimide (604 mg, 2.68 mmol) was added. After stirring for 3 hours, 3,4-di-O-acetyl-L-rhamnaldehyde (410 mg, 1.91 mmol) and N-iodosuccinimide (594 mg, 2.64 mmol) were added. After continuing the reaction for 3 hours, the mixture was poured into 150 mL of dichloromethane and washed successively with 10% sodium thiosulfate aqueous solution and water. The organic phase was dried with magnesium sulfate, evaporated to dryness, and subjected to column chromatography with silica gel (100 g) using toluene-acetone (50:1) as the eluent. The crystallization yielded 151 mg of compound ⑤. Yield 24% (w / w).

[0140] (4) Compound ⑤ (197 mg, 0.23 mmol) was dissolved in methanol (12 mL), followed by the addition of sodium methoxide solution (1.7 mL, 0.45 mmol / mL). At the end of the reaction, the solution was neutralized with solid carbon dioxide, and TLC (toluene-acetone = 4:1, v / v) showed the disappearance of ⑤. The solution was poured into water, extracted with dichloromethane, the organic phase was washed twice with water, dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure. Crystallization with acetone-n-hexane yielded 90.5 mg of compound ⑥ as red crystals, in a yield of 45.93% (w / w).

[0141] (5) Compound ⑥ (90.0 mg, 0.12 mmol) was dissolved in a mixture of dichloromethane (1 mL) and tetrahydrofuran (5 mL), followed by the addition of pyridine (50 μL) and 180 μL of a 1 mol / L tetrabutylammonium fluoride tetrahydrofuran solution. After the reaction proceeded for 40 min, the reaction was terminated by dilution with dichloromethane and washing with water. The organic phase was dried over magnesium sulfate, filtered, concentrated to dryness under reduced pressure, and crystallized from a mixture of dichloromethane, acetone, and n-hexane to give 31 mg of a red solid compound ⑦. Yield 34.44% (w / w), purity 89% (HPLC), overall yield 2.41% (w / w).

[0142] Application Comparative Example 2 (1) 10 mg of 4-demethoxydaunorubicin ketone ① (0.025 mmol) was added to 1 mL of chloroform, and bromine (13.5 mg dissolved in 0.25 mL of chloroform) was added. The mixture was stirred at 23 °C for 16 h. The reaction was observed by TLC to indicate that the reaction was complete. The mixture was then evaporated to dryness under reduced pressure to obtain solid ②. Solid ② was dissolved in 5 mL of acetone:water (4:1), and NaOH (1.1 mg 0.028 mmol) was added. The blue solution turned red after stirring and refluxing for 5 min. The solution was concentrated to 2 mL under reduced pressure, and 10 mL of water was added. The solution was extracted with 10 mL × 3 of chloroform:methanol (1:1, v / v). The extracts were combined, dried, and evaporated to dryness. The residue was crystallized with chloroform / methanol / petroleum ether to obtain 9.0 mg of 4-demethoxydaunorubicin ketone ③, with a yield of 90% (w / w).

[0143] (2) 4-Demethoxydoxomilone ③ (891.2 mg, 2.32 mmol) was dissolved in DMF (12 mL), and imidazole (686 mg, 10.115 mmol) and tert-butyldimethylchlorosilane (559.4 mg, 3.71 mmol) were added. The mixture was stirred at 25 °C for 0.5 h, then poured into dichloromethane, washed three times with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (100 g silica gel). The residue was eluted with 20:1 toluene-acetone, and the main component was collected to give compound ④ 629 mg, with a yield of 70.57% (w / w).

[0144] (3) Compound IV (0.99 g, 2.095 mmol) and compound ④ (0.684 g, 1.05 mmol) were dissolved in 20 mL of anhydrous dichloromethane and added to 1 g of 4A molecular sieve. Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (3.12 mmol, 0.693 g, 0.6 mL) was then added at room temperature. The mixture was stirred and the reaction was monitored by TLC (hexane-ethyl acetate 1:1, v / v). The mixture was filtered, washed with water until neutral in 50 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and the residue was separated by column chromatography with dichloromethane:acetone (98:2) as the eluent. The fractions were collected, combined, and evaporated to dryness to give 0.50 g of red solid compound ⑤, with a yield of 73.1% (w / w).

[0145] (4) Dissolve compound ⑤ (0.50 g, 0.5 mmol) in a mixture of dichloromethane and methanol = 2:1 (V / V) in 16 mL, add anhydrous potassium carbonate (0.5 g, 3.6 mmol), and stir at room temperature until compound ⑤ is completely eliminated. Detect using TCL (n-hexane-ethyl acetate 1:1, v / v). Add 50 mL of dichloromethane, then neutralize with an equivalent amount of 1 mol / L hydrochloric acid. Pour the mixture into 100 mL of water, separate the organic layer, wash twice with water, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 0.417 g of compound ⑥, with a yield of 83.4% (w / w). This compound can be purified by dissolving a small amount of tetrahydrofuran and then adding n-hexane to precipitate and crystallize, or by column chromatography. The eluent is dichloromethane:acetone = 98:2, v / v (the volume ratio can also be 95:5 or 9:1), or chloroform:methanol = 8:2 (v / v).

[0146] (5) Compound ⑥ (0.5 g, 0.57 mmol) was dissolved in tetrahydrofuran (6 mL), followed by the addition of 1 mol / L HCl (4 mL). The mixture was stirred at room temperature and monitored by TLC (toluene-acetone 2:1, v / v) until compound ⑥ disappeared. 50 mL of chloroform was added to the reaction mixture, and the pH was adjusted to 9.0 with 10% sodium bicarbonate aqueous solution while stirring. The chloroform layer was separated, and the aqueous layer was extracted again with 50 mL of a chloroform-methanol 95:5, v / v mixture. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue was eluted by column chromatography with chloroform / methanol 98:2, v / v and chloroform / methanol 95:5, v / v, respectively. The main component was collected and dried under reduced pressure to give 0.299 g of red solid compound ⑦, yield 59.8% (w / w) and purity 91.6%. The overall yield was 23.16% (w / w).

[0147] The yields and purities of anamycin applied in Examples 1-3 and Comparative Examples 1-2 are shown in Table 1 below: Table 1

[0148] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An anamycin intermediate, characterized in that, The structure is shown in equation V below: 。 2. The method for preparing the anamycin intermediate according to claim 1, characterized in that, The reaction formula of the preparation method includes: ； The preparation method includes the following steps: Compounds of Formula III and IV, molecular sieve, and solvent 1 are mixed, and trimethylsilane trifluoromethanesulfonate is added. The mixture is reacted to obtain compound V.

3. The preparation method according to claim 2, characterized in that, The mass ratio of compound III to compound IV is 1:2-2.5, the mass ratio of compound III to molecular sieve is 1:1.2-2, the molar ratio of compound III to trimethylsilane trifluoromethanesulfonate is 1:1-15, the mass-volume ratio of compound III to solvent is 1g:70-90mL, and the reaction temperature is -20-40℃ for 10-60min.

4. The preparation method according to claim 2, characterized in that, Solvent 1 is selected from at least one of dichloromethane and 1,4-dioxane.

5. The preparation method according to claim 4, characterized in that, The solvent is a mixture of dichloromethane and 1,4-dioxane; the volume ratio of dichloromethane to 1,4-dioxane is 1-10:1-10.

6. The preparation method according to claim 2, characterized in that, The reaction formula for preparing the compound of formula III includes: The method for preparing the compound of formula III includes the following steps: Compound II, base, acetylation reagent and solvent 2 are mixed and reacted to obtain compound III.

7. The preparation method according to claim 6, characterized in that, The solvent 2 is selected from N,N-dimethylformamide; the base is an organic base; and the acetylation reagent is acetic acid.

8. The preparation method according to claim 6, characterized in that, The molar ratio of the compound of formula II to the base is 1:1-10; the molar ratio of the compound of formula II to the acetylation reagent is 1:1-10.

9. The use of the anamycin intermediate according to claim 1 in the preparation of anamycin, characterized in that, The reaction formula for preparing anamycin includes: Includes the following steps: Compound V reacts with a solvent, and upon addition of a base, deacetylation is achieved to produce anamycin.

10. The application according to claim 9, characterized in that, The solvent is selected from at least one of tetrahydrofuran, methanol, and dichloromethane; the base is selected from at least one of sodium methoxide and potassium carbonate; the molar ratio of the compound of formula V to the base is 1:1-10; and the reaction temperature is -20 to 20°C.

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