Trisaccharide saponin intermediate as well as preparation method and application thereof

Abstract

The invention provides a trisaccharide saponin intermediate as well as a preparation method and application thereof, and relates to the technical field of medicinal chemistry. The general formula of the trisaccharide saponin intermediate is a structure of a compound H1 as shown in the specification: # imgabs0 #, wherein R1 is selected from at least one of triethyl silicon group, tert-hexyldimethylsilicon group, tert-butyldimethylsilyl chloride and triisopropyl silicon group; r2 is selected from at least one of naphthyl methyl, benzyl, p-methoxybenzyl and trimethoxybenzyl. According to the trisaccharide saponin intermediate, naphthyl methyl, benzyl, p-methoxybenzyl, trimethoxybenzyl and the like are used as permanent protecting groups, and propylidene, TES, TDS, TBDMS, TIPS and the like are used as temporary protecting groups, so that efficient synthesis of a compound H3 and trisaccharide saponin TQL1055 can be realized.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular, to a trisaccharide saponin intermediate, a preparation method thereof, and an application thereof. Background Art

[0002] In the field of pharmaceutical chemistry, vaccine adjuvants, as important components for enhancing the immunogenicity of vaccines, their research and development have always been one of the key directions in modern medicine. In recent years, with the in-depth understanding of the immune mechanism, significant progress has been made in the development of novel adjuvants. Among them, QS21, as a key saponin adjuvant, has shown broad application prospects because it can induce a strong Th1 immune response and activate T lymphocytes. QS21 has been applied to the research and development of a variety of important vaccines, such as herpes zoster, malaria, and respiratory syncytial virus vaccines, etc.

[0003] However, the natural plant extraction source of QS21 not only faces problems such as resource scarcity and compositional heterogeneity, but also has safety defects such as hemolysis. These factors have greatly limited its wide application in vaccine research and development. To overcome these limitations, researchers designed TQL1055, which is a structurally simplified analogue of QS21 optimized through structure-activity relationship. It showed comparable immunopotency to QS21 in clinical trials, had no hemolysis, and better tolerance, and was considered a promising novel adjuvant.

[0004] During the synthesis of TQL1055, although the core structure of QS21 was retained, there were still many technical challenges. Especially in the glycosylation reaction, the low yield and the dependence on precious catalysts became the key factors restricting the synthesis efficiency. In addition, the low efficiency of the protecting group strategy led to the inevitable generation of by-products, which not only increased the synthesis cost but also reduced the purity of the final product. In the later stage of the synthesis, when using benzyl as a permanent protecting group, there were significant difficulties in the subsequent deprotection steps. Due to the presence of unsaturated bonds, aldehyde groups, and other hydrogenation-sensitive functional groups in the triterpene saponin aglycone, the deprotection process was extremely complex and difficult to control. The long-term catalytic hydrogenation not only triggered reduction side reactions of unsaturated bonds and aldehyde groups, increasing the generation of impurities, but also reduced the yield of the target product and significantly increased the purification difficulty.

[0005] The deficiencies of these existing technologies have had a profound impact on the synthesis and application of TQL1055. First of all, the low-yield and high-cost synthesis process limits the feasibility of its large-scale production, while the complex deprotection steps and uncontrollable side reactions further increase the difficulty of purification, reducing the purity and quality of the product. Secondly, the efficiency problems in the glycoside construction process, especially in the key glycosylation reaction, often result in low yields and poor stereoselectivity, leading to poor reaction selectivity, further causing purification difficulties, and thus being unfavorable for the implementation of large-scale production. These problems not only affect the clinical application of TQL1055 but also hinder its further promotion in vaccine research and development. Therefore, developing an efficient, low-cost, and easy-to-control synthesis method is of great significance for promoting the clinical industrial application of TQL1055.

[0006] In view of this, the present invention is specifically proposed. Summary of the Invention

[0007] The object of the present invention is to provide a trisaccharide saponin intermediate, a preparation method, and an application thereof. The trisaccharide saponin intermediate uses naphthylmethyl, benzyl, p-methoxybenzyl, and trimethoxybenzyl, etc. as permanent protecting groups, and uses propylidene, as well as triethylsilyl, tert-hexyldimethylsilyl, tert-butyldimethylchlorosilyl, and triisopropylsilyl, etc. as temporary protecting groups, so as to be able to achieve the efficient synthesis of compound H3 and the trisaccharide saponin TQL1055.

[0008] In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:

[0009] In the first aspect, the present invention provides a trisaccharide saponin synthesis intermediate, and its general formula is the structure of compound H1 shown as follows:

[0010]

[0011] Among them, R1 is selected from at least one of triethylsilyl, tert-hexyldimethylsilyl, tert-butyldimethylchlorosilyl, and triisopropylsilyl;

[0012] R2 is selected from at least one of naphthylmethyl, benzyl, p-methoxybenzyl, and trimethoxybenzyl.

[0013] In an optional embodiment, R1 is naphthylmethyl; R2 is TES.

[0014] In the second aspect, the present invention provides a trisaccharide saponin synthesis intermediate, which can be obtained by the compound H1 as described in the foregoing embodiment through reductive amination and amide coupling reactions;

[0015] The general formula of the trisaccharide saponin synthesis intermediate is the structure of compound H3 shown as follows:

[0016]

[0017] Among them, R1 is selected from at least one of tert-butyl ester, naphthylmethyl, and benzyl;

[0018] R2 is selected from at least one of TES, TDS, TBDMS, and TIPS;

[0019] R3 is selected from at least one of naphthylmethyl, benzyl, p-methoxybenzyl, and trimethoxybenzyl;

[0020] In an alternative embodiment, R1 is tert-butyl; R2 is naphthylmethyl; R3 is TES.

[0021] In a third aspect, the present invention provides a method for synthesizing trisaccharide saponin TQL1055, comprising:

[0022] For the trisaccharide saponin synthesis intermediate compound H3 as described in the foregoing embodiments, first remove the carboxyl protecting group, the triterpene hydroxyl protecting group, and the isopropylidene group respectively, and then remove the sugar ring hydroxyl protecting group to obtain trisaccharide saponin TQL1055.

[0023] In an alternative embodiment, the removal of the sugar ring hydroxyl protecting group is carried out by an oxidation reaction to obtain the trisaccharide saponin TQL1055;

[0024] In an alternative embodiment, the oxidation reaction is selected from at least one of DDQ oxidation reaction, CAN oxidation reaction, and IBX oxidation reaction;

[0025] In an alternative embodiment, the oxidation reaction is a DDQ oxidation reaction.

[0026] In an alternative embodiment, the preparation method of the trisaccharide saponin synthesis intermediate compound H3 includes:

[0027] Reduce the azide group of the trisaccharide saponin synthesis intermediate compound H1 as described above to an amino group to obtain an amino intermediate;

[0028] Carry out an amide coupling reaction on the amino intermediate and dodecanedioic acid with a carboxyl protecting group to obtain the trisaccharide saponin synthesis intermediate compound H3.

[0029] In an alternative embodiment, the reduction treatment includes at least one of triphenylphosphine and ammonia reduction method, triphenylphosphine and ammonium chloride solution reduction method, zinc powder reduction method, diphenylselenol reduction method, and sodium borohydride reduction method;

[0030] In an alternative embodiment, the reduction treatment is the triphenylphosphine and ammonia reduction method.

[0031] In an alternative embodiment, the method for preparing the trisaccharide saponin synthetic intermediate compound H1 comprises:

[0032] Taking a monosaccharide raw material and constructing a monosaccharide compound, a disaccharide compound and a trisaccharide compound in sequence through glycosylation reaction;

[0033] Introducing a protecting group into natural quillaic acid to obtain a quillaic acid intermediate;

[0034] Performing glycoside construction on the trisaccharide compound and the quillaic acid intermediate, and reacting to obtain the trisaccharide saponin synthetic intermediate compound H1.

[0035] In an alternative embodiment, the method for preparing the dodecanedioic acid with a carboxyl protecting group comprises:

[0036] Taking dodecanedioic acid and a carboxyl protecting group substance to carry out an esterification reaction under catalytic conditions to obtain the dodecanedioic acid with a carboxyl protecting group.

[0037] In an alternative embodiment, the carboxyl protecting group comprises at least one of tert-butyl ester, naphthylmethyl and benzyl;

[0038] In an alternative embodiment, the carboxyl protecting group is tert-butyl ester.

[0039] Fourthly, the present invention provides an application of the trisaccharide saponin synthetic intermediate as described in the foregoing embodiments in the preparation of trisaccharide saponin TQL1055.

[0040] Compared with the prior art, the beneficial effects of the present invention are:

[0041] (1) Through the protecting group strategy designed in the structure, compound H1 significantly improves the synthesis efficiency and product purity. Specifically, R1 is a triterpene hydroxyl protecting group, selected from at least one of TES, TDS, TBDMS and TIPS, and R2 is a sugar ring hydroxyl protecting group, as a permanent protecting group, selected from at least one of naphthylmethyl, benzyl, p-methoxybenzyl and trimethoxybenzyl. The selection of this combination of protecting groups not only improves the reaction efficiency in the synthesis process, but also reduces the generation of by-products. This optimized protecting group strategy makes the synthesis process more efficient, while ensuring high yields and high purities for each step of the reaction.

[0042] (2) When the permanent protecting group (sugar ring hydroxyl protecting group) selects naphthylmethyl as the protecting group (R2), mild oxidation reactions (such as DDQ oxidation) can be used for deprotection. This strategy avoids the reduction side reactions of unsaturated bonds and aldehyde groups that may occur during the removal of benzyl protecting groups using chemical hydrogenation in traditional methods. Since there are unsaturated bonds and aldehyde groups in the triterpene ring structure of TQL1055, chemical hydrogenation for deprotecting the protecting group will cause these functional groups to be reduced, thereby introducing impurities and reducing the product quality. In contrast, mild oxidation deprotection conditions not only improve the controllability of the reaction but also significantly reduce the generation of impurities. In addition, by the method of stepwise deprotection, the reaction conditions for each step can be precisely controlled, further enhancing the controllability of the synthesis process and the quality of the final product.

[0043] (3) By optimizing the selection of protecting groups and the synthesis route, the synthesis method of TQL1055 based on compound H1 significantly improves the yield and purity of the target product. Compared with the prior art, the multi-step synthesis method of the present invention greatly improves the yield, with the yield increased by more than three times compared to the original research process. At the same time, due to the efficient deprotection step and extremely low generation of impurities, the purification process is also simpler, and the purity of the finally obtained TQL1055 product can be as high as over 98%. This high-yield and high-purity synthesis method not only reduces the production cost but also improves the product quality, making it more suitable for large-scale production.

[0044] (4) The synthesis method of compound H1 not only performs well under laboratory conditions but also has the potential for large-scale production. Through the optimized protecting group strategy and mild deprotection conditions, the synthesis process is more efficient, controllable, and easy to operate. In addition, new compound H1 is efficiently synthesized through reductive amination and amide coupling reactions, and this reaction process is easy to prepare on a large scale.

[0045] (5) Due to the reduction of by-products and the improvement of product purity during the synthesis process, the purification process of compound H1 is simpler. Through the optimized protecting group strategy and mild deprotection conditions, the generation of impurities is reduced, thereby reducing the purification difficulty. This simplified purification process not only improves the production efficiency but also reduces the production cost, further enhancing the application value of compound H1 in large-scale production.

[0046] In summary, the trisaccharide saponin intermediate compound H1 provided by the present invention significantly improves the synthesis efficiency, product purity, and reaction controllability of trisaccharide saponin TQL1055 by optimizing the selection of protecting groups and the synthesis route, while reducing the synthesis cost and improving the feasibility of large-scale production. These beneficial effects make compound H1 have important application value and innovation in the field of trisaccharide saponin TQL1055 synthesis. Description of the Drawings

[0047] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0048] Figure 1 Synthetic route diagram for preparing compound H4 from compound H3 in Example 1 of this application;

[0049] Figure 2 Synthetic route diagram for preparing compound TQL1055 from compound H4 in Example 1 of this application;

[0050] Figure 3 MS diagram of compound H4 in Example 1 of this application;

[0051] Figure 4 1H NMR spectrum of compound H4 in Example 1 of this application;

[0052] Figure 5 13C NMR spectrum of compound H4 in Example 1 of this application;

[0053] Figure 6 MS diagram of compound TQL1055 in Example 1 of this application;

[0054] Figure 7 1H NMR spectrum of compound TQL1055 in Example 1 of this application;

[0055] Figure 8 13C NMR spectrum of compound TQL1055 in Example 1 of this application;

[0056] Figure 9 Synthetic route diagram for preparing compound TQL1055 from compound H4-II in Comparative Example 1 of this application;

[0057] Figure 10 Total synthetic route diagram for preparing compound H2 in Example 1 of this application;

[0058] Figure 11 Synthetic route diagram for preparing compound H2 from compound H1 in Example 2 of this application;

[0059] Figure 12 Synthetic route diagram for preparing compound H3 from compound H2 in Example 2 of this application;

[0060] Figure 13 MS diagram of compound H2 in Example 2 of this application;

[0061] Figure 14 It is the 1H NMR spectrum of compound H2 in Example 2 of this application;

[0062] Figure 15 It is the 13C NMR spectrum of compound H2 in Example 2 of this application;

[0063] Figure 16 It is the MS spectrum of compound H3 in Example 2 of this application;

[0064] Figure 17 It is the 1H NMR spectrum of compound H3 in Example 2 of this application;

[0065] Figure 18 It is the 13C NMR spectrum of compound H3 in Example 2 of this application;

[0066] Figure 19 It is the synthesis route diagram of compound A in Example 3 of this application;

[0067] Figure 20 It is the synthesis route diagram of compound B1 in Example 3 of this application;

[0068] Figure 21 It is the synthesis route diagram of compound B2 in Example 3 of this application;

[0069] Figure 22 It is the synthesis route diagram of compound C1 in Example 3 of this application;

[0070] Figure 23 It is the synthesis route diagram of compound C2 in Example 3 of this application;

[0071] Figure 24 It is the synthesis route diagram of compound C3 in Example 3 of this application;

[0072] Figure 25 It is the synthesis route diagram of compound C4 in Example 3 of this application;

[0073] Figure 26 It is the synthesis route diagram of compound C5 in Example 3 of this application;

[0074] Figure 27 It is the synthesis route diagram of compound C6 in Example 3 of this application;

[0075] Figure 28 It is the synthesis route diagram of compound D1 in Example 3 of this application;

[0076] Figure 29 It is the synthesis route diagram of compound D2 in Example 3 of this application;

[0077] Figure 30It is the synthetic route diagram of compound D3 in Example 3 of this application;

[0078] Figure 31 It is the synthetic route diagram of compound D4 in Example 3 of this application;

[0079] Figure 32 It is the synthetic route diagram of compound D5 in Example 3 of this application;

[0080] Figure 33 It is the synthetic route diagram of compound D6 in Example 3 of this application;

[0081] Figure 34 It is the synthetic route diagram of compound E1 in Example 3 of this application;

[0082] Figure 35 It is the synthetic route diagram of compound E2 in Example 3 of this application;

[0083] Figure 36 It is the synthetic route diagram of compound E3 in Example 3 of this application;

[0084] Figure 37 It is the synthetic route diagram of compound E4 in Example 3 of this application;

[0085] Figure 38 It is the synthetic route diagram of compound F5 in Example 4 of this application;

[0086] Figure 39 It is the synthetic route diagram of compound G1 in Example 5 of this application;

[0087] Figure 40 It is the synthetic route diagram of compound H1 in Example 6 of this application;

[0088] Figure 41 It is the MS diagram of compound H1 in Example 2 of this application;

[0089] Figure 42 It is the 1H NMR spectrum diagram of compound H1 in Example 2 of this application;

[0090] Figure 43 It is the 13C NMR spectrum diagram of compound H1 in Example 2 of this application. Detailed implementation manners

[0091] Next, the implementation schemes of the present invention will be described in detail in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. For the reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchases.

[0092] In the embodiments of the present application, a trisaccharide saponin synthesis intermediate is provided, and its general formula is the structure of compound H1 shown as follows:

[0093]

[0094] Among them, R1 is selected from at least one of triethylsilyl (TES), tert-hexyldimethylsilyl (TDS), tert-butyldimethylchlorosilyl (TBDMS), and triisopropylsilyl (TIPS);

[0095] R2 is selected from at least one of naphthylmethyl, benzyl, p-methoxybenzyl, and trimethoxybenzyl.

[0096] In some embodiments, R1 is naphthylmethyl; R2 is TES.

[0097] The above trisaccharide saponin synthesis intermediate is named compound H1 in this embodiment.

[0098] Compound H1 provided in this embodiment is an important intermediate for synthesizing the target product (trisaccharide saponin TQL1055). It gradually constructs a complex glycoside structure through a series of chemical reactions and finally transforms into the target product. Specifically, the structural design of H1 allows for the efficient introduction of other functional groups or further structural modifications in subsequent reactions.

[0099] The structure of compound H1 takes into account the efficiency and controllability in the synthesis process. By optimizing the selection of protecting groups (such as TES, TDS, TBDMS, TIPS, etc.) and reaction conditions, H1 can achieve high-yield and high-purity transformation in the synthesis process. This efficient synthesis route reduces the generation of by-products, simplifies the purification steps, and improves the overall synthesis efficiency.

[0100] During the synthesis process, the structure of compound H1 contains multiple protecting groups (such as naphthylmethyl, benzyl, p-methoxybenzyl, trimethoxybenzyl, etc.), and these protecting groups play a key role in subsequent reactions.

[0101] The triterpene hydroxyl protecting group, that is, R1, is a protecting group used to protect the hydroxyl group (-OH) in the triterpene saponin structure in the structure of compound H1. Among them, R1 can be selected from at least one of TES (triethylsilane), TDS (tert-hexyldimethylsilyl), TBDMS (tert-butyldimethylchlorosilyl), and TIPS (triisopropylsilane). In the structure, the role of the triterpene hydroxyl protecting group is to protect the hydroxyl group. During the synthesis process, the hydroxyl group is a highly reactive functional group and is prone to participating in unwanted side reactions. By introducing the R1 protecting group, the hydroxyl group can be temporarily "blocked" to prevent it from being oxidized or undergoing other side reactions in subsequent reactions; in addition, the introduction of the protecting group enables more precise control of the reaction site in the synthesis process, improving the selectivity and efficiency of the reaction.

[0102] It should be noted that silyl ether protecting groups such as triterpene hydroxyl protecting groups TES, TDS, TBDMS, and TIPS can generally be removed under specific acidic conditions (such as hydrofluoric acid or tetrabutylammonium fluoride TBAF), with mild conditions and no impact on other functional groups.

[0103] The sugar ring hydroxyl protecting group, namely R2, is a permanent protecting group used to protect the hydroxyl group (-OH) in the sugar ring structure in compound H1. There are 5 sugar ring hydroxyl protecting groups in compound H1, and R2 can be selected from at least one of naphthylmethyl (Nap), benzyl (Bn), p-methoxybenzyl (PMB), and trimethoxybenzyl (TMB).

[0104] The role of the sugar ring hydroxyl protecting group is to protect the hydroxyl group. The hydroxyl group in the sugar ring also has high reactivity and is prone to participating in unwanted side reactions. By introducing the R2 protecting group, the hydroxyl group can be temporarily "blocked" to prevent it from being oxidized or undergoing other side reactions in subsequent reactions. In addition, it can also improve the reaction selectivity. The introduction of the protecting group enables more precise control of the reaction site during the synthesis process, improving the selectivity and efficiency of the reaction.

[0105] Among the deprotection conditions of the sugar ring hydroxyl protecting group, naphthylmethyl (Nap) can be removed through a mild oxidation reaction (such as DDQ oxidation), with mild conditions and no impact on other functional groups. Benzyl (Bn) is usually removed by catalytic hydrogenation (H2 / Pd-C), but there is a risk of triggering reduction side reactions of other functional groups. p-methoxybenzyl (PMB) and trimethoxybenzyl (TMB) can be removed under acidic or basic conditions, with mild conditions, but PMB and TMB have the disadvantage of chemical instability. This protecting group strategy makes the synthesis process more mild and controllable, reducing the generation of impurities.

[0106] The acetone protecting group (Acetone Protecting Group, AcPG) is a protecting group used to protect the carbonyl group (-C=O) or the hydroxyl group (-OH). In compound H1, its role is to protect the carbonyl group or the hydroxyl group. That is, during the synthesis process, the carbonyl group and the hydroxyl group are highly reactive functional groups and are prone to participating in unwanted side reactions. By introducing the acetone protecting group, these functional groups can be temporarily "blocked" to prevent them from being oxidized or undergoing other side reactions in subsequent reactions; it can improve the reaction selectivity. The introduction of the protecting group enables more precise control of the reaction site during the synthesis process, improving the selectivity and efficiency of the reaction.

[0107] The deprotection condition of the acetone protecting group can be to remove it under acidic conditions (such as hydrofluoric acid or trifluoroacetic acid TFA), with mild conditions and no impact on other functional groups.

[0108] Each substituent in compound H1, namely the triterpene hydroxyl protecting group R1 (temporary protecting group), the sugar ring hydroxyl protecting group R2 (permanent protecting group), and the isopropylidene protecting group (temporary protecting group), plays a crucial protecting role in the synthesis process. The selection and use of these protecting groups not only improve the synthesis efficiency and product purity but also reduce the formation of by-products and simplify the purification steps. By optimizing the types of protecting groups and the deprotection conditions, the synthesis method of compound H1 is more efficient, mild, and suitable for large-scale production. The reasonable design and application of these protecting groups are important guarantees for the efficient synthesis of trisaccharide saponins.

[0109] In the embodiments of this application, a trisaccharide saponin synthesis intermediate is provided, which can be obtained by reductive amination and amide coupling reactions from compound H1 as described in the foregoing embodiments.

[0110] The general formula of the trisaccharide saponin synthesis intermediate is the structure of compound H3 shown as follows:

[0111]

[0112] Among them, R1 is selected from at least one of tert-butyl ester, naphthylmethyl, and benzyl;

[0113] R2 is selected from at least one of TES, TDS, TBDMS, and TIPS;

[0114] R3 is selected from at least one of naphthylmethyl, benzyl, p-methoxybenzyl, and trimethoxybenzyl.

[0115] The above compound H3 can be obtained by reductive amination and amide coupling reactions of compound H1 with dodecanedioic acid having a carboxyl protecting group, and the final product trisaccharide saponin TQL1055 can be efficiently synthesized through compound H3.

[0116] Among them, the chemical structure of dodecanedioic acid having a carboxyl protecting group can be: Named compound G1 in this embodiment, R1 in this structure is the same as R1 in the structure of compound H3, that is, the carboxyl protecting group.

[0117] In compound H3, the carboxyl protecting group R1 is a protecting group used to protect the carboxyl group (-COOH). R1 can be selected from at least one of tert-butyl ester (t-Bu), naphthylmethyl (Nap), and benzyl (Bn). Its function is to protect the carboxyl group. During the synthesis process, the carboxyl group is a highly reactive functional group and is prone to participating in unwanted side reactions. By introducing the tert-butyl ester protecting group, the carboxyl group can be temporarily "blocked" to prevent it from being oxidized or undergoing other side reactions in subsequent reactions; moreover, it can improve the reaction selectivity. The introduction of the protecting group enables more precise control of the reaction sites during the synthesis process, improving the selectivity and efficiency of the reaction.

[0118] Among the deprotection conditions of carboxyl protecting groups, the tert-butyl ester protecting group can be removed under acidic conditions (such as trifluoroacetic acid TFA or dilute sulfuric acid). The conditions are mild and will not affect other functional groups. Due to the relatively high stability of the tert-butyl ester, the deprotection process is usually more controllable, reducing the formation of by-products.

[0119] In addition, the triterpene hydroxyl protecting group R2 (temporary protecting group), the sugar ring hydroxyl protecting group R3 (permanent protecting group), and the isopropylidene protecting group (temporary protecting group) in compound H3 are the same as the corresponding protecting groups at the same positions in the structure of compound H1.

[0120] In some embodiments, R1 is a tert-butyl group; R2 is a naphthylmethyl group; R3 is a TES group.

[0121] In the embodiments of the present application, a method for synthesizing trisaccharide saponin TQL1055 is provided, including:

[0122] For the trisaccharide saponin synthesis intermediate compound H3 as described in the foregoing embodiments, first remove the carboxyl protecting group, the triterpene hydroxyl protecting group, and the isopropylidene group respectively, and then remove the sugar ring hydroxyl protecting group to obtain trisaccharide saponin TQL1055.

[0123] It should be noted that according to the reported technology, in the synthesis of TQL1055, benzyl (Bn) is generally used as the permanent protecting group. However, when using benzyl as the permanent protecting group, there are significant difficulties in the subsequent deprotection steps. Although the hydrogenation reaction can effectively remove the benzyl protecting group, due to the structural characteristics of the triterpene saponin aglycone itself and the presence of unsaturated functional groups such as aldehyde groups and double bonds in the ester chain fragment, the long-term hydrogenation process is prone to the formation of by-products. This not only increases the purification difficulty but also reduces the yield of the target product, making large-scale preparation more difficult. For example, the reported yield in the existing method is only 17.5%, and the purity is 96.4%. Moreover, the purification and separation process is complex and it is difficult to achieve large-scale production.

[0124] The published literature "Mild Method for 2-Naphthylmethyl Ether Protecting Group Removal Using a Combination of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and β-Pinene" and "ON THE SELECTIVITY OF DEPROTECIION OF BENZYL, MPM (4-METHOXYBENZYL) AND DMPM (3,4_DIMETHOXYBENZYL) PROTECTING GROUPS FOR HYDROXY FUNCTIONS" indicate that when using DDQ to oxidatively remove the naphthylmethyl (Nap) protecting group, acidic by-products will be generated. This acidity is detrimental to sensitive groups such as deoxysugars and may lead to the degradation of deoxysugars or other side reactions.

[0125] In the examples of this application, the sugar ring hydroxyl protecting group (such as naphthylmethyl) is selected as the permanent protecting group in compound H3, rather than the traditional benzyl protecting group. This selection is based on the characteristics of the parent nucleus structure of compound H3, enabling the parent nucleus to effectively tolerate the acidity generated during the removal process by DDQ. By reasonably selecting the protecting group, the adverse effects on sensitive groups are reduced during the removal process in this example, improving the selectivity of the reaction and the purity of the product.

[0126] Moreover, the preparation method provided in the examples of this application adopts a strategy of stepwise removal of protecting groups. First, the temporary protecting groups: carboxyl protecting group, triterpene hydroxyl protecting group, and isopropylidene are removed separately, and finally, the permanent protecting group: sugar ring hydroxyl protecting group is removed. This sequential treatment method can effectively solve the acidity problem generated during the removal process by DDQ. Before removing the sugar ring hydroxyl protecting group, removing other protecting groups first can reduce the impact of acidic by-products on sensitive groups and ensure the mildness of the reaction conditions.

[0127] In the examples of this application, the characteristics of the parent nucleus structure of compound H3 are fully utilized, enabling the parent nucleus to effectively tolerate the acidity generated during the removal process by DDQ. This tolerance is based on the stability of the parent nucleus structure, reducing the adverse effects of acidity on sensitive groups.

[0128] In summary, in the preparation method provided in the embodiments of the present application, by optimizing the protecting group selection and stepwise deprotection strategy, the problems of difficult deprotection of the benzyl protecting group and the acidity generated by the deprotection of the naphthylmethyl protecting group by DDQ in the prior art are effectively solved. Specifically, the present application adopts a stepwise deprotection strategy, first deprotecting the carboxyl protecting group, the triterpene hydroxyl protecting group and the propylidene respectively, and finally deprotecting the sugar ring hydroxyl protecting group. This sequential treatment method not only achieves efficient deprotection of the protecting group under mild conditions, reduces the generation of acidic by-products, but also ensures the high efficiency and selectivity of each step of the reaction, reduces the occurrence of side reactions, and improves the purity and yield of the final product. In addition, this technology makes full use of the stability of the parent nucleus structure of compound H3, enabling it to effectively tolerate the acidity generated during the DDQ deprotection process, reducing the adverse effects of acidity on sensitive groups, and further improving the overall efficiency of the reaction. This innovative method provides a more efficient and mild protecting group strategy for the synthesis of trisaccharide saponin compounds, significantly improving the synthesis efficiency and product quality.

[0129] In some embodiments, the deprotection of the sugar ring hydroxyl protecting group is achieved by an oxidation reaction to obtain the trisaccharide saponin TQL1055.

[0130] In some embodiments, the oxidation reaction is selected from at least one of DDQ oxidation reaction, CAN oxidation reaction and IBX oxidation reaction.

[0131] In some embodiments, the oxidation reaction is a DDQ oxidation reaction.

[0132] As described above, in the synthesis process of the trisaccharide saponin TQL1055, the deprotection of the sugar ring hydroxyl protecting group is achieved by an oxidation reaction. Specifically, the oxidation reaction can be selected from at least one of DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) oxidation, CAN (ammonium cerium nitrate) oxidation or IBX (2-iodobenzoic acid) oxidation. Among them, the DDQ oxidation reaction is particularly recommended as the preferred method.

[0133] The DDQ oxidation reaction is a relatively mild oxidation method that can efficiently deprotect the sugar ring hydroxyl protecting group without triggering side reactions of other sensitive functional groups. DDQ oxidation has high selectivity and can specifically deprotect the sugar ring hydroxyl protecting group without affecting other functional groups; although DDQ oxidation produces acidic by-products, by optimizing the reaction conditions (such as controlling the reaction temperature, solvent selection and reaction time), the influence of acidity on sensitive groups can be reduced.

[0134] In this method, the core structure characteristics of compound H3 are fully utilized, enabling it to effectively tolerate the acidity generated during the DDQ oxidation process. This tolerance reduces the adverse effects of acidity on sensitive groups (such as deoxysugars), improving the overall efficiency of the reaction and the purity of the product.

[0135] In some embodiments, the method for preparing the trisaccharide saponin synthesis intermediate compound H3 comprises:

[0136] (1) Reducing the azide group of the trisaccharide saponin synthesis intermediate compound H1 as described above to an amino group to obtain an amino intermediate.

[0137] (2) Performing an amide coupling reaction between the amino intermediate and dodecanedioic acid having a carboxyl protecting group to obtain the trisaccharide saponin synthesis intermediate compound H3.

[0138] In this step, the preparation of the trisaccharide saponin synthesis intermediate compound H3 based on compound H1 is carried out. Starting from compound H1, its structure contains an azide group (-N3). The azide group (-N3) is converted to an amino group (-NH2) through a reduction reaction. This process can be carried out using a chemical reducing agent under mild conditions to obtain an amino intermediate, whose structure contains a free amino group (-NH).

[0139] Furthermore, the obtained amino intermediate is subjected to an amide coupling reaction with dodecanedioic acid having a carboxyl protecting group (such as compound G1).

[0140] The carboxyl protecting group of dodecanedioic acid can be tert-butyl ester (t-Bu), naphthylmethyl (Nap), or benzyl (Bn), etc. The specific choice depends on the synthesis strategy and subsequent reaction requirements. Condensing agents (such as DCC, EDC) and catalysts (such as DMAP) can be used to promote the formation of the amide bond, and through the amide coupling reaction, the trisaccharide saponin synthesis intermediate compound H3 is obtained.

[0141] In some embodiments, the reduction treatment includes at least one of the triphenylphosphine and ammonia reduction method, the triphenylphosphine and ammonium chloride solution reduction method, the zinc powder reduction method, the diphenylselenol reduction method, and the sodium borohydride reduction method.

[0142] In some embodiments, the reduction treatment is the triphenylphosphine and ammonia reduction method.

[0143] Above, the combination of the triphenylphosphine and ammonia reduction method can efficiently reduce the azide group (-N3) to an amino group (-NH2) under mild conditions. This method has high selectivity and can specifically reduce the azide group without affecting other functional groups.

[0144] In the above-mentioned reduction method using triphenylphosphine and ammonium chloride solution, the combination of triphenylphosphine (PPh3) and ammonium chloride solution can rapidly reduce azide groups. Moreover, this method is relatively environmentally friendly, producing fewer by-products and is suitable for large-scale production.

[0145] In the above-mentioned reduction method using zinc powder, zinc powder can reduce azide groups under acidic conditions (such as hydrochloric acid or sulfuric acid), and the reaction conditions are mild. Zinc powder reduction has high selectivity and can specifically reduce azide groups without affecting other functional groups.

[0146] In the above-mentioned reduction method using diphenylselenol, diphenylselenol can efficiently reduce azide groups. This method has high selectivity and can specifically reduce azide groups without affecting other functional groups. In addition, fewer by-products are generated, making it suitable for green chemical synthesis.

[0147] In the above-mentioned reduction method using sodium borohydride, sodium borohydride (NaBH4) can reduce azide groups under mild conditions. Sodium borohydride reduction has high selectivity and can specifically reduce azide groups without affecting other functional groups.

[0148] It should be noted that in conventional synthesis methods, triphenylphosphine (PPh3) and water are usually used as reduction conditions to reduce azide groups (-N3) to amino groups (-NH2). However, this method has some limitations: First, there is an incomplete reaction. In the conventional method, the combination of triphenylphosphine and water may lead to an incomplete reaction, and the intermediate cannot be completely converted into the target product. Second, the yield is low. In the original research process, using the reduction conditions of triphenylphosphine and water, the product yield is only 65%.

[0149] In contrast, in the examples of this application, by optimizing the reduction conditions and using reduction treatment methods such as triphenylphosphine and ammonia water as reducing agents, the reaction efficiency and product yield are significantly improved. The combination of triphenylphosphine and ammonia water can more efficiently reduce azide groups, and the intermediate can be completely converted into the target product. Through the optimized reduction conditions, the yield of the final reductive amination product is as high as 91%, which is a 25% increase in yield compared to the conventional process.

[0150] In summary, in the synthesis process of trisaccharide saponin TQL1055, the specific method for reducing the azide group of compound H1 to an amino group. By optimizing the reduction conditions and using reducing agents such as triphenylphosphine and ammonia water, the reaction efficiency and product yield are significantly improved, solving the problems existing in the prior art. This innovative method not only improves the selectivity of the reaction and the purity of the product, but also reduces the adverse effects of acidity on sensitive groups, providing a more efficient and mild strategy for the synthesis of trisaccharide saponin compounds.

[0151] In some embodiments, the method for preparing the trisaccharide saponin synthetic intermediate compound H1 includes:

[0152] (1) Taking monosaccharide raw materials and constructing monosaccharide compounds, disaccharide compounds, and trisaccharide compounds in sequence through glycosylation reactions.

[0153] (2) Introducing a protecting group to natural quillaic acid to obtain a quillaic acid intermediate.

[0154] (3) Conducting glycoside construction on the trisaccharide compound and the quillaic acid intermediate, and reacting to obtain the trisaccharide saponin synthetic intermediate compound H1.

[0155] It should be noted that in the conventional synthesis process of trisaccharide saponin TQL1055, the construction of glycosides, especially the synthesis of monosaccharide, disaccharide, trisaccharide building blocks and saponins, faces the problem of low synthesis efficiency. Especially in the key glycosylation reaction, low yields and poor stereoselectivity often occur, resulting in poor selectivity of the reaction, further causing difficulties in purification, and thus being unfavorable for the implementation of large-scale production.

[0156] The embodiment of the present application provides a method for preparing the trisaccharide saponin synthetic intermediate compound H1, which is one of the key steps in the synthesis of trisaccharide saponin TQL1055.

[0157] First, it is necessary to select appropriate monosaccharide raw materials as starting materials. These monosaccharide raw materials can be commercially available and have high purity and reactivity. Then, the monosaccharides are gradually linked through glycosylation reactions to construct disaccharide and trisaccharide compounds. This process usually requires the use of specific glycosylation reagents (such as TMSOTf, BF3·Et2O, etc.) and appropriate solvents (such as toluene, dichloromethane, etc.).

[0158] Among them, the conditions of the glycosylation reaction need to be precisely controlled to ensure high yields and high stereoselectivity. For example, by optimizing the reaction temperature, solvent, and dosage of the catalyst, the generation of by-products can be reduced, and the purity of the target product can be improved.

[0159] It should be noted that natural quillaic acid (QUILA) is a triterpenoid compound extracted from Quillaja Saponaria Molina. In this method, natural quillaic acid is selected as the starting material. Quillaic acid is an important triterpenoid compound with multiple hydroxyl functional groups and needs to be modified through a protecting group strategy.

[0160] In this method, the hydroxyl groups in quillaic acid are protected using suitable protecting groups (such as TES, TDS, TBDMS, TIPS, etc.). This process generally requires the use of protecting group reagents (such as TBDMSOTf, TESCl, etc.) and appropriate solvents (such as DMF, THF, etc.). By optimizing the reaction conditions, efficient introduction of the protecting group is ensured, and the occurrence of side reactions is reduced.

[0161] As described above, in the glycoside construction reaction, the trisaccharide compound and the quillaic acid intermediate are mixed in a suitable solvent, and a glycosylation reagent (such as TMSOTf, BF3·Et2O, etc.) is added for the coupling reaction. By optimizing the reaction conditions (such as reaction temperature, solvent, and dosage of the catalyst), efficient progress of the reaction is ensured, and the generation of by-products is reduced.

[0162] After the reaction is completed, the product can be further purified by methods such as silica gel column chromatography to ensure the obtaining of compound H1 with high purity. The purification step needs to be optimized according to the polarity of the product and the solubility of the solvent to improve the purification efficiency.

[0163] By optimizing the reaction conditions, this technology realizes an efficient glycosylation reaction, ensuring the step-by-step construction of monosaccharide, disaccharide, and trisaccharide compounds. This process not only improves the selectivity of the reaction but also reduces the generation of by-products, increasing the purity and yield of the target product; in the preparation of the quillaic acid intermediate, by selecting suitable protecting groups (such as TES, TDS, TBDMS, TIPS, etc.), this technology ensures the efficient protection of hydroxyl groups and reduces the influence on sensitive groups in subsequent reactions; by optimizing the glycoside construction reaction conditions, this method ensures the efficient coupling of the trisaccharide compound and the quillaic acid intermediate, obtaining compound H1 with high purity. This process not only improves the overall efficiency of the reaction but also reduces the generation of by-products and simplifies the purification step.

[0164] In some embodiments, the method for preparing dodecanedioic acid with a carboxyl protecting group includes:

[0165] Taking dodecanedioic acid and a carboxyl protecting group substance to carry out an esterification reaction under catalytic conditions to obtain the dodecanedioic acid with a carboxyl protecting group. Among them, the carboxyl protecting group includes at least one of tert-butyl ester, naphthylmethyl, and benzyl.

[0166] In some embodiments, the carboxyl protecting group is tert-butyl ester.

[0167] In the above method, dodecanedioic acid reacts with a substance containing a protecting group (such as tert-butyl ester, naphthylmethyl, or benzyl, etc.) under catalytic conditions to form dodecanedioic acid with a carboxyl protecting group.

[0168] The key to this process is the use of catalytic conditions, which is more efficient and milder than the esterification reaction under non-catalytic conditions, avoiding side reactions that may be caused by excessive temperature or over-catalysis.

[0169] For example, the following steps can be adopted:

[0170] (1) Take dodecanedioic acid and dissolve it in dichloromethane, and then add thionyl chloride to the reaction system. Dichloromethane acts as a solvent, providing a suitable environment for the reaction.

[0171] (2) Add TEA and tert-butanol to the reaction solution; among them, TEA, as a basic substance, can act as a co-catalyst to help the acid-base balance in the reaction and promote the progress of the reaction. Tert-butanol, on the other hand, is a substance that provides a carboxyl protecting group. The carboxyl protecting group is introduced through tert-butanol. After concentration and purification, dodecanedioic acid with a tert-butyl carboxyl protecting group, that is, compound G1, is obtained.

[0172] In the embodiments of the present application, there is provided an application of the trisaccharide saponin synthesis intermediate as described in the foregoing embodiment in the preparation of trisaccharide saponin TQL1055.

[0173] In the above trisaccharide saponin synthesis intermediate, both compound H1 and compound H3 can be used as adjuvants for the preparation of the final product trisaccharide saponin TQL1055, thus providing an efficient and simple preparation method for the preparation of the final product.

[0174] The present invention will be further illustrated by specific embodiments below, but it should be understood that these embodiments are only for more detailed illustration and should not be construed as limiting the present invention in any form.

[0175] Example 1: Preparation of TQL1055

[0176] In this example, trisaccharide saponin TQL1055 was prepared based on compound H3.

[0177] The final product is trisaccharide saponin TQL1055, and the structure is as follows:

[0178]

[0179] Preparation method:

[0180] 1. Compound H4 was prepared using compound H3: Stepwise deprotection was adopted, and the synthesis route is as Figure 1 shown.

[0181] (1) Deprotection of tert-butyl ester: Dissolve compound H3 (2.0 g, 0.92 mmol, 1 eq) in dichloromethane (30 mL, 15 vol), stir until clear, add 2,6-dimethylpyridine (2.0 g, 18.4 mmol, 20 eq), and then slowly dropwise add tert-butyldimethylsilyl trifluoromethanesulfonate (2.0 g, 9.2 mmol, 10 eq). Stir the reaction at room temperature for 1 h. Monitor the reaction by TLC until the starting material disappears. Quench the reaction by adding water (20 mL, 10 vol). Separate the layers and collect the organic layer. Extract the aqueous layer with dichloromethane (20 mL, 10 vol) once. Combine the organic layers and concentrate them at 40 °C using a rotary evaporator to obtain the crude product of the tert-butyl ester deprotected intermediate.

[0182] (2) Deprotection of silyl ether (TES): Add tetrahydrofuran (12 mL, 6 vol), water (6 mL, 3 vol), and trifluoroacetic acid (6 mL, 3 vol) to the tert-butyl ester deprotected intermediate in sequence. Stir the mixture at room temperature for 2 h and monitor the reaction by TLC until the starting material disappears. (3) Deprotection of isopropylidene: Sequentially add tetrahydrofuran (18 mL, 9 vol), water (9 mL, 4.5 vol), and trifluoroacetic acid (24 mL, 12 vol). Stir the mixture at room temperature overnight. Monitor the reaction by TLC until the starting material disappears and the product spot is single. Dilute the reaction mixture with dichloromethane (60 mL, 30 vol). Wash the organic phase with sodium bicarbonate (60 mL, 30 vol) and saturated sodium chloride (6 mL, 30 vol) in sequence. Separate the layers and collect the organic phase. Concentrate the organic phase at 40 °C using a rotary evaporator to obtain the crude product of compound H4. Purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 1:1 → petroleum ether:ethyl acetate = 2:1) to obtain compound H4 (1.7 g, overall yield of three steps: 97%, colorless foamy solid), HPLC: 98.7%.

[0183] 2. Compound TQL1055 is prepared using compound H4, and the synthetic route is as Figure 2 shown.

[0184] (1) Dissolve compound H4 (1 g, 0.54 mmol, 1 eq) in chloroform (75 mL, 75 vol) and methanol (25 mL, 25 vol), stir until clear, and add DDQ (9.87 g, 43.5 mmol, 80 eq) in three portions at 1 h intervals. Stir the mixture at room temperature for 10 h.

[0185] (2) TLC detection showed the disappearance of the raw materials and intermediates. The reaction solution was dropped into toluene (1000 mL, 100 vol) for dilution, and methanol and chloroform were removed by concentration at 30 °C using a rotary evaporator. The concentrated solution was filtered through 60 g of silica gel and eluted successively with acetonitrile (100 mL) and chloroform (100 mL) to remove DDQ and DDQH. The product was eluted with chloroform:methanol (3:1) (200 mL), and the crude product of compound TQL1055 (0.7 g) was obtained by concentration at 40 °C using a rotary evaporator. After purification by silica gel column chromatography (chloroform 100% → chloroform:methanol = 10:1 → chloroform:methanol = 2:1), compound TQL1055 (0.46 g, 87%, white solid) was obtained, HPLC: 98.5%.

[0186] Experimental results:

[0187] 1. Compound H4:

[0188] (1) Reference Figure 3 。TOF-MS: m / z: 1838.965 [M+H] + 。

[0189] (2) Reference Figure 4 。 11H NMR (600 MHz, CDCl3) δ 9.28 (s, 1H), 7.83 - 7.61 (m, 19H), 7.41 (dddd, J = 29.9, 21.5, 11.5, 5.0 Hz, 14H), 5.71 (d, J = 9.9 Hz, 1H), 5.37 (d, J = 7.1 Hz, 2H), 5.22 (s, 1H), 5.14 (d, J = 11.2 Hz, 1H), 5.08 (d, J = 11.4 Hz, 1H), 5.00 (d, J = 11.4 Hz, 1H), 4.95 (d, J = 11.2 Hz, 1H), 4.92 (d, J = 10.1 Hz, 1H), 4.88 (d, J = 11.7 Hz, 2H), 4.83 (d, J = 11.8 Hz, 1H), 4.71 (d, J = 12.1 Hz, 1H), 4.62 (dd, J = 15.2, 10.0 Hz, 2H), 4.49 - 4.38 (m, 2H), 4.12 (q, J = 7.1 Hz, 3H), 3.99 (dd, J = 11.7, 4.8 Hz, 1H), 3.90 (s, 1H), 3.87 - 3.64 (m, 7H), 3.61 (dd, J = 8.8, 4.3 Hz, 1H), 3.58 - 3.51 (m, 3H), 3.48 (t, J = 8.3 Hz, 1H), 3.27 - 3.21 (m, 1H), 2.91 (dd, J = 14.3, 3.8 Hz, 1H), 2.72 (s, 1H), 2.26 (td, J = 7.2, 3.4 Hz, 2H), 2.17 - 2.07 (m, 3H), 1.85 (d, J = 3.5 Hz, 4H), 1.65 - 1.52 (m, 7H), 1.35 - 1.25 (m, 14H), 1.19 - 1.13 (m, 8H), 0.97 (s, 3H), 0.89 (d, J = 12.4 Hz, 6H), 0.81 (s, 3H), 0.73 (s, 3H).

[0190] (3) Reference Figure 5 。 1313C NMR (151 MHz, CDCl3) δ 177.60 (s), 173.70 (s), 171.33 (s), 135.86 (s), 135.34 (s), 134.62 (s), 133.53 - 132.93 (m), 128.68 - 127.95 (m), 127.72 (dd, J=23.2, 16.7 Hz), 126.97 - 125.74 (m), 125.50 (s), 122.17 (s), 105.04 (s), 94.49 (s), 84.52 (s), 84.07 (s), 82.12 (s), 79.75 (s), 78.44 (s), 75.68 (d, J=21.8 Hz), 74.20 (s), 73.78 - 73.38 (m), 71.73 (s), 71.46 (s), 70.42 (s), 68.41 (s), 67.40 (s), 64.16 (s), 60.55 (s), 55.25 (s), 49.36 (s), 48.23 (s), 46.88 (s), 46.65 (s), 46.28 (s), 41.66 (s), 41.18 (s), 40.03 (s), 38.20 (s), 37.03 (s), 35.98 (s), 35.44 (s), 33.86 (s), 32.80 (s), 32.34 (s), 30.34 (s), 29.74 - 29.05 (m), 29.01 (d, J=8.6 Hz), 28.73 (s), 26.89 (s), 26.13 (s), 25.85 (s), 24.91 (s), 24.73 (s), 23.41 (s), 21.20 (s), 20.97 (s), 17.86 (s), 17.27 (s), 15.90 (s), 14.33 (s), 9.04 (s).

[0191] 2. Compound TQL1055:

[0192] (1) Reference Figure 6 . TOF-MS: m / z: 1138.652 [M+H] + .

[0193] (2) Reference Figure 7 . 1HNMR (800 MHz, MeOD) δ 9.25 (s, 1H), 7.51 (s, 1H), 5.29 (s, 1H), 5.27 (s, 1H), 5.22 (d, J = 7.7 Hz, 1H), 4.39 (d, J = 7.4 Hz, 1H), 4.36 (s, 1H), 4.23 (s, 2H), 3.88 - 3.84 (m, 2H), 3.78 (d, J = 8.3 Hz, 1H), 3.75 (d, J = 6.8 Hz, 2H), 3.72 - 3.67 (m, 1H), 3.59 (s, 2H), 3.48 (d, J = 8.1 Hz, 2H), 3.44 (d, J = 4.8 Hz, 2H), 3.26 (d, J = 10.2 Hz, 4H), 3.20 - 3.16 (m, 1H), 3.13 (t, J = 10.9 Hz, 1H), 2.83 (d, J = 12.2 Hz, 1H), 2.26 (s, 2H), 2.20 (t, J = 7.1 Hz, 2H), 1.85 (d, J = 5.5 Hz, 2H), 1.82 (d, J = 11.7 Hz, 2H), 1.74 - 1.59 (m, 6H), 1.59 - 1.49 (m, 6H), 1.31 (s, 3H), 1.25 (dd, J = 21.8, 11.3 Hz, 15H), 1.15 - 1.07 (m, 2H), 1.03 (s, 1H), 0.95 (s, 3H), 0.90 (d, J = 12.0 Hz, 3H), 0.87 (s, 3H), 0.85 (s, 1H), 0.81 (s, 3H), 0.69 (s, 3H).

[0194] (3) Reference Figure 8 。 1313C NMR (201 MHz, MeOD) δ 178.08 (s), 176.43 (s), 143.89 (s), 129.45 (s), 128.68 (s), 125.76 (s), 122.47 (s), 106.15 (s), 100.25 (s), 94.93 (s), 83.71 (s), 77.38 (s), 75.32 (d, J = 12.0 Hz), 74.00 (s), 73.86 (s), 73.50 (s), 72.21 (s), 71.33 (s), 70.91 (s), 70.18 (s), 68.13 (s), 66.69 (s), 60.82 (s), 56.26 (s), 51.74 (s), 48.33 (s), 47.30 (s), 42.11 (s), 41.70 (s), 40.42 (s), 38.92 (s), 36.44 (s), 35.85 (s), 34.87 (s), 33.00 (d, J = 24.0 Hz), 30.80 (d, J = 6.4 Hz), 29.84 (dd, J = 19.6, 10.8 Hz), 29.66 (s), 26.99 (s), 26.56 (s), 26.32 (s), 25.56 (s), 24.74 (s), 23.91 (s), 21.53 (s), 21.28 (s), 17.91 (s), 17.43 (s), 16.16 (s), 9.17 (s).

[0195] Comparative Example 1

[0196] In this comparative example, for compound H4 (with the sugar ring hydroxyl protecting group being Nap) in step 2 of Example 1 (preparing compound TQL1055 using compound H4), the DDQ oxidative deprotection effect of a similar compound (with the sugar ring hydroxyl protecting group being Bn) was investigated by comparison.

[0197] Final product: The same as in Example 1.

[0198] Preparation method: The synthetic route is as Figure 9 shown.

[0199] (1) Dissolve compound H4-II (0.5 g, 0.31 mmol, 1 eq) in chloroform (37.5 mL, 75 vol) and methanol (12.5 mL, 25 vol), stir until clear, and add DDQ (5.71 g, 24.8 mmol, 80 eq) in three batches at intervals of 1 h each, and stir at room temperature for 10 hours.

[0200] (2) TLC detection showed that the raw materials disappeared. The reaction time was extended to 24 h, but there were still a large number of intermediates, and there was no progress in HPLC color development. The reaction solution was added dropwise to toluene (1000 mL, 100 vol) for dilution, and methanol and chloroform were removed by concentration at 30 °C through a rotary evaporator. The concentrated solution was filtered through 60 g of silica gel and eluted successively with acetonitrile (100 mL) and chloroform (100 mL) to remove DDQ and DDQH. The product was eluted with chloroform:methanol (3:1) (200 mL), and concentrated at 40 °C through a rotary evaporator to obtain 0.2 g of the crude product of compound TQL1055. The crude product was purified by silica gel column chromatography (chloroform 100% → chloroform:methanol = 10:1 → chloroform:methanol = 2:1) to obtain compound TQL1055.

[0201] Experimental results: The final product, compound TQL1055, was 0.11 g, with a yield of 30.7%, a white solid; HPLC: 92.1%.

[0202] Based on the experimental results of the foregoing Example 1 and Comparative Example 1, it can be seen that compared with compound H4 in Example 1, the method of using DDQ oxidation can remove the sugar ring hydroxyl protecting group Bn of compound H4-II, but the synthesis efficiency is low and the yield of the final product is low. This indicates that the DDQ oxidation removal method is more compatible with the sugar ring hydroxyl protecting group (such as Nap), and this method is suitable for TQL1055 with a sugar ring hydroxyl protecting group (such as Nap) in this example relative to Bn.

[0203] Example 2

[0204] In this example, compound H3 was prepared based on compound H1.

[0205] The final product is compound H3, and the structure is as follows:

[0206]

[0207] Preparation method: The total synthesis route refers to Figure 10

[0208] 1. Compound H2 was prepared from compound H1, and the synthesis route refers to Figure 11 。

[0209] (1) Dissolve compound H1 (18 g, 9.4 mmol, 1 eq) in 1,4-dioxane (360 mL, 20 vol) and methanol (72 mL, 4 vol), stir until dissolved clearly, add triphenylphosphine (19.6 g, 75.2 mol, 8 eq), and stir at room temperature for 6 hours.

[0210] (2) TLC detection showed that raw material H1 disappeared, and two active intermediates were generated. Add ammonia water (72 mL, 4 vol) and stir at room temperature for 2 h.

[0211] (3) TLC detection shows that one of the intermediates has disappeared. Heat up the temperature to 60 °C and stir the reaction for 5 h.

[0212] (4) TLC detection shows that the other intermediate has disappeared. Concentrate at 50 °C using a rotary evaporator, add dichloromethane (180 mL, 10 vol) to dissolve, wash the organic phase successively with water (180 mL, 10 vol) and saturated sodium chloride (180 mL, 10 vol), separate the organic phase by liquid separation, and concentrate the organic phase at 40 °C using a rotary evaporator to obtain the crude product of compound H2. Purify it by silica gel column chromatography (petroleum ether 100% → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 3:1) to obtain compound H2 (16.2 g, 91%, colorless glassy solid), HPLC: 99.3%.

[0213] 2. Compound H3 is prepared from compound H2, and the synthetic route is referred to Figure 12 。

[0214] (1) Dissolve compound G1 (12 g, 41.9 mmol, 10 eq) in tetrahydrofuran (140 mL, 20 vol)), stir until clear, add triethylamine (12.8 g, 126.6 mmol, 30 eq), and cool to 0 °C in an ice bath; slowly dropwise add isobutyl chloroformate (5.76 g, 42.1 mmol, 10 eq).

[0215] (2) After dropping, a large amount of white solid precipitates, and stir at the same temperature for 30 min.

[0216] (3) Add H2 (7.2 g, 3.8 mmol, 1 eq) to the above reaction solution, and stir at room temperature overnight.

[0217] (4) TLC detection shows that the raw material H2 has disappeared. Quench with water (72 mL, 10 vol), dilute with dichloromethane (72 mL, 10 vol), separate the organic layer, wash the organic phase with saturated sodium chloride (72 mL, 10 vol), separate the organic phase by liquid separation, and concentrate the organic phase at 40 °C using a rotary evaporator to obtain the crude product of compound H3. Purify it by silica gel column chromatography (petroleum ether 100% → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1 → petroleum ether:ethyl acetate = 3:1) to obtain compound H3 (7.0 g, 85.3%, colorless glassy solid) HPLC: 99.2%.

[0218] Experimental results:

[0219] 1. Compound H2:

[0220] (1) Refer to Figure 13 。TOF-MS: m / z: 1895.028 [M + H] + 。

[0221] (2) Reference Figure 14 。 1 H NMR (600 MHz, CDCl3) δ 9.29 (s, 1H), 7.81 - 7.67 (m, 17H), 7.62 (dd, J = 8.2, 5.1 Hz, 3H), 7.48 - 7.38 (m, 15H), 5.41 (d, J = 7.8 Hz, 1H), 5.32 (t, J = 3.3 Hz, 1H), 5.26 (s, 1H), 5.03 (q, J = 11.4 Hz, 3H), 4.94 (d, J = 7.5 Hz, 1H), 4.89 (d, J = 11.9 Hz, 1H), 4.83 (d, J = 11.7 Hz, 2H), 4.71 (t, J = 8.5 Hz, 3H), 4.61 (d, J = 11.6 Hz, 1H), 4.50 (s, 1H), 4.29 - 4.23 (m, 1H), 4.21 (d, J = 5.9 Hz, 1H), 3.98 (dd, J = 11.6, 4.5 Hz, 1H), 3.86 (t, J = 8.4 Hz, 1H), 3.80 - 3.71 (m, 6H), 3.68 - 3.50 (m, 3H), 3.49 - 3.37 (m, 2H), 3.26 (dd, J = 12.7, 8.1 Hz, 1H), 2.92 (dd, J = 14.2, 4.0 Hz, 1H), 2.22 (t, J = 13.6 Hz, 1H), 1.83 (dd, J = 16.6, 5.7 Hz, 6H), 1.73 - 1.51 (m, 6H), 1.46 (s, 3H), 1.36 (s, 3H), 1.24 (dd, J = 18.0, 11.7 Hz, 11H), 1.01 (s, 3H), 0.94 (dt, J = 25.3, 8.0 Hz, 24H), 0.86 (d, J = 7.9 Hz, 8H), 0.73 (s, 3H), 0.67 - 0.62 (m, 6H), 0.56 - 0.51 (m, 6H).

[0222] (3) Reference Figure 15 。 1313C NMR (151 MHz, CDCl3) δ 175.32 (s), 143.57 (s), 136.43 (s), 136.33 (s), 135.83 (s), 135.47 (s), 134.84 (s), 133.31 (dd, J = 22.3, 16.0 Hz), 128.60 - 128.19 (m), 128.03 (dd, J = 8.0, 3.1 Hz), 127.77 (d, J = 9.3 Hz), 126.69 (s), 126.53 (s), 126.48 - 125.48 (m), 121.76 (s), 109.55 (s), 102.52 (s), 98.15 (s), 94.52 (s), 83.84 (s), 82.21 (s), 78.68 (s), 78.38 (s), 78.09 (s), 75.61 (s), 75.31 (s), 74.83 (s), 73.69 (s), 73.38 (s), 71.84 (s), 68.44 (s), 66.71 (s), 63.93 (s), 60.53 (s), 56.14 (s), 38.37 (s), 35.90 (s), 35.34 (s), 34.80 (s), 32.86 (s), 32.49 (s), 31.00 (s), 30.60 (s), 27.85 (s), 26.95 (s), 26.39 (d, J = 28.1 Hz), 24.51 (s), 23.47 (s), 20.71 (s), 18.10 (s), 17.18 (s), 15.84 (s), 14.35 (s), 9.63 (s), 7.27 (s), 7.12 (d, J = 46.4 Hz), 6.97 (s), 5.22 (s), 6.08 - 4.46 (m), 5.06 (s).

[0223] 2. Compound H3:

[0224] (1) Reference Figure 16 . Maldi-TOF-MS: m / z: 2186.8219 [M+Na] + .

[0225] (2) Reference Figure 17 . 11H NMR (600 MHz, CDCl3) δ 9.30 (s, 1H), 7.84 - 7.66 (m, 20H), 7.50 - 7.39 (m, 15H), 5.64 (s, 1H), 5.43 (d, J = 6.9 Hz, 1H), 5.28 (d, J = 13.2 Hz, 2H), 5.12 - 5.00 (m, 3H), 4.96 - 4.79 (m, 6H), 4.67 (dd, J = 34.8, 12.2 Hz, 2H), 4.56 (d, J = 11.1 Hz, 1H), 4.49 (s, 1H), 4.17 (d, J = 6.6 Hz, 1H), 3.96 (dd, J = 11.6, 4.9 Hz, 1H), 3.86 - 3.76 (m, 2H), 3.75 - 3.68 (m, 4H), 3.66 (dd, J = 8.6, 4.3 Hz, 1H), 3.62 - 3.52 (m, 3H), 3.42 (t, J = 8.1 Hz, 1H), 3.25 (dd, J = 11.4, 9.4 Hz, 1H), 2.90 (dd, J = 14.3, 4.0 Hz, 1H), 2.34 (t, J = 7.5 Hz, 1H), 2.27 - 2.16 (m, 4H), 2.11 (td, J = 7.5, 2.9 Hz, 2H), 1.82 (td, J = 13.7, 4.8 Hz, 5H), 1.66 - 1.53 (m, 10H), 1.45 (s, 13H), 1.38 (s, 1H), 1.28 (d, J = 18.3 Hz, 11H), 1.23 - 1.17 (m, 13H), 1.02 (s, 3H), 0.96 - 0.90 (m, 21H), 0.85 (d, J = 19.1 Hz, 8H), 0.72 (s, 3H), 0.67 - 0.61 (m, 6H), 0.53 (ddd, J = 15.8, 7.7, 4.5 Hz, 6H).

[0226] (3) Reference Figure 18 。 1313C NMR (151 MHz, CDCl3) δ 175.33 (s), 173.39 (d, J = 15.3 Hz), 143.78 (s), 136.37 (d, J = 16.0 Hz), 135.83 (s), 135.34 (s), 134.94 (s), 133.39 (d, J = 6.6 Hz), 133.11 (dd, J = 15.9, 3.6 Hz), 128.38 (d, J = 4.0 Hz), 128.35 - 127.89 (m), 127.89 - 127.55 (m), 127.26 (s), 126.68 (s), 126.55 (s), 126.45 - 125.67 (m), 121.55 (s), 109.56 (s), 102.48 (s), 98.08 (s), 82.22 (s), 79.07 (s), 78.58 (s), 78.29 (s), 78.08 (s), 76.18 (s), 75.64 (s), 75.48 (d, J = 4.8 Hz), 74.92 (s), 73.75 (s), 73.39 (s), 73.10 (s), 71.77 (s), 68.52 (s), 66.57 (s), 63.94 (s), 56.08 (s), 49.27 (s), 47.92 (s), 46.96 (s), 46.60 (s), 46.14 (s), 41.69 (s), 40.69 (s), 39.96 (s), 38.34 (s), 37.07 (s), 35.82 (d, J = 16.6 Hz), 35.33 (s), 34.66 (s), 32.82 (s), 32.48 (s), 31.65 (s), 31.01 (s), 30.60 (s), 30.28 (s), 29.51 (ddd, J = 52.3, 41.6, 10.7 Hz), 29.22 (d, J = 16.5 Hz), 29.22 (d, J = 16.5 Hz), 28.27 (s), 27.84 (s), 26.93 (s), 26.47 (s), 26.26 (s), 25.91 (s), 25.26 (s), 24.48 (s), 23.50 (s), 20.70 (s), 17.97 (s), 17.31 (s), 15.90 (s), 9.68 (s), 7.26 (s), 6.96 (s), 5.22 (s), 5.07 (s).

[0227] Example 3

[0228] In this example, compound E4 was prepared based on monosaccharide raw materials such as compound A.

[0229] The final product is compound E4, and its structure is shown below:

[0230]

[0231] Preparation method:

[0232] 1. Prepare compound A, and refer to the synthetic route Figure 19 .

[0233] (1) Add 100 g of 732 hydrogen-form cation exchange resin to 150 mL of allyl alcohol and soak it. After 20 min, filter, and wash the filter cake with allyl alcohol until the filtrate is colorless, then set aside. Add rhamnose (100 g, 0.06 mol, 1 eq), the filtered resin (100 g, 1.0 wt.), and allyl alcohol (800 mL, 8 vol) into a 2 L three-necked round-bottom flask. Heat the reaction solution to 90 °C and stir. After 6 hours, the reaction is complete by TLC. Cool to room temperature, filter, wash with acetone (200 mL), and concentrate until constant weight.

[0234] (2) Dissolve the obtained oily substance with acetone (400 mL, 4 vol), add 2,2-dimethoxypropane (270 mL, 2.7 vol), add p-toluenesulfonic acid monohydrate (1 g, 0.01 wt.) under stirring, stir overnight at room temperature, analyze the reaction by TLC until it is complete, and after rotary evaporation of the reaction solution, purify it by silica gel column chromatography (petroleum ether 100% → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1 → petroleum ether:ethyl acetate = 3:1) to obtain compound A (83.3 g, 56%, light yellow oily substance).

[0235] 2. Prepare compound B1, and refer to the synthetic route Figure 20 .

[0236] (1) Add D-xylose (100 g, 0.67 mol, 1 eq) to pyridine (500 mL, 5 vol). After stirring until clear, add acetic anhydride (500 mL, 5 vol), and heat the reaction mixture to 45 °C. After reacting for 8 h;

[0237] (2) After TLC detects that the raw materials are consumed, concentrate the reaction solution by rotary evaporator at 70 °C to obtain an oily substance. Add dichloromethane (500 mL, 5 vol) to dissolve the rotary-evaporated oily substance, and wash and separate it successively with saturated sodium bicarbonate solution (500 mL, 5 vol), water (500 mL, 5 vol), and saturated brine (500 mL, 5 vol). Dry the organic phase with anhydrous sodium sulfate, filter, and after rotary evaporation of the reaction solution, obtain compound B1 (212 g, 100%, light yellow oily substance).

[0238] 3. Prepare compound B2, and refer to the synthetic route Figure 21 .

[0239] (1) Dissolve compound B1 (212 g, 0.67 mol, 1 eq) in 2 L of tetrahydrofuran, add 3-dimethylaminopropylamine (102.1 g, 1 mol, 1.5 eq), stir at room temperature, and after reacting for 3 h;

[0240] (2) After detecting the reaction by TLC, add 1 M HCl (500 mL) to quench the reaction, extract three times with dichloromethane (250 mL * 3), separate the liquid to obtain the organic phase, combine the organic phases, add saturated sodium chloride (500 mL), stir to separate the layers, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate on a rotary evaporator at 40 °C to obtain 166 g of crude oil. Add methyl tert-butyl ether (500 mL, 3 vol) to the crude product, stir at room temperature to precipitate a white solid, filter to obtain the white solid, and dry it in a vacuum drying oven at 40 °C to obtain compound B2 (114 g, 62%, white solid powder).

[0241] 4. Prepare compound C1, and refer to the synthetic route Figure 22 。

[0242] (1) Dissolve compound B2 (114 g, 0.41 mol, 1 eq) in dichloromethane (570 mL, 5 vol), stir until dissolved and clear, add trichloroacetonitrile (178.8 g, 1.23 mol, 3 eq), and then add 1,8-diazabicyclo[5.4.0]undec-7-ene (6.28 g, 0.043 mol), and stir at room temperature for 2 hours.

[0243] (2) After detecting the reaction by TLC, filter the reaction solution through silica gel (228 g, 2 wt.), elute the product with dichloromethane, collect the eluate, combine the filtrates and concentrate on a rotary evaporator at 40 °C to obtain crude compound B3 (184 g, 106%, light yellow oil), and directly proceed to the next step.

[0244] (3) Dissolve the crude compound B3 (184 g, 0.41 mol, 1.2 eq) in dichloromethane (600 mL, 3.3 vol), add compound A1 (83.5 g, 0.34 mol, 1 eq), and add 4A molecular sieve (39 g, 0.2 wt.). After adding, cool the reaction solution to -20 °C under nitrogen protection, and dropwise add trimethylsilyl trifluoromethanesulfonate (15.1 g, 68 mmol, 0.2 eq), and keep the temperature for reaction for 1.5 h.

[0245] (4) TLC detected the disappearance of compound A1. Triethylamine (10 mL) was added to quench the reaction. The reaction mixture was filtered through diatomaceous earth to remove 4A molecular sieve. The filtrate was concentrated at 40 °C using a rotary evaporator and purified by silica gel column chromatography (petroleum ether 100% → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1 → petroleum ether:ethyl acetate = 3:1) to obtain compound C1 (152.8 g, 89%, yellow oil).

[0246] 5. Preparation of compound C2. The synthetic route is referred to Figure 23 。

[0247] (1) Compound 5 (130 g, 0.27 mol) was dissolved in methanol (650 mL, 5 vol). Sodium methoxide (21.78 g, 0.40 mol) was added at room temperature, and the mixture was stirred at room temperature for 1 h.

[0248] (2) When TLC detected the end of the reaction, 1M HCl was added to adjust the pH to 7 - 8. Dichloromethane (250 mL * 3) was added for extraction three times. The organic phases were combined, washed successively with water (650 mL, 5 vol) and saturated brine (650 mL, 5 vol), separated, and the organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated at 40 °C using a rotary evaporator and then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1 → ethyl acetate 100%) to obtain compound C2 (80 g, 82%, white solid powder).

[0249] 6. Preparation of compound C3. The synthetic route is referred to Figure 24 。

[0250] (1) Compound C2 (42.7 g, 0.11 mol) was dissolved in N,N-dimethylformamide (470 mL, 11 vol). The temperature was lowered to 0 °C in an ice bath, and NaH (60%, 22 g, 0.57 mol) was added in six portions, controlling the temperature at 0 - 5 °C. After stirring for 30 min after addition, 2-(bromomethyl)naphthalene (100.3 g, 0.45 mol) was added, and the mixture was stirred at room temperature for 2 h.

[0251] (2) When TLC detected the end of the reaction, methanol (25 mL) was added to quench the reaction. Dichloromethane (427 mL, 10 vol) was added for dilution. The mixture was washed successively with water (210 mL, 5 vol) and saturated sodium chloride (427 mL, 10 vol), separated, and the organic phase was collected. The organic phase was concentrated at 40 °C using a rotary evaporator to obtain the crude product of compound C3 (120 g, 133.3%, yellow oil).

[0252] 7. Preparation of compound C4. The synthetic route is referred to Figure 25 。

[0253] (1) Dissolve compound C3 (90 g, 0.11 mol) in dichloromethane (360 mL, 4 vol), add methanol (360 mL, 4 vol), and add p-toluenesulfonic acid monohydrate (32.2 g, 0.17 mol) under stirring at room temperature. Heat the mixture to 35 °C and stir for 4 h.

[0254] (2) When the reaction is completed as detected by TLC, adjust the pH to 7 - 8 with 1 M NaOH. Separate the organic phase by liquid separation. Extract the aqueous phase with dichloromethane (180 mL, 2 vol), combine the organic phases, wash with saturated sodium chloride (360 mL, 4 vol), separate the organic phase by liquid separation, concentrate it at 40 °C using a rotary evaporator, and purify it by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 → petroleum ether:ethyl acetate = 3:1 → petroleum ether:ethyl acetate = 1:1) to obtain compound C4 (71 g, 83%, light yellow solid powder).

[0255] 8. Preparation of compound C5, with the synthetic route referring to Figure 26 。

[0256] (1) Dissolve compound C4 (67 g, 0.09 mol) in pyridine (210 mL, 3 vol), slowly add acetic anhydride (210 mL, 3 vol) dropwise, and after dropping, heat to 40 °C for reaction and keep stirring for 8 h;

[0257] (2) When the reaction is completed as detected by TLC, concentrate the reaction solution at 70 °C using a rotary evaporator to obtain an oily substance. Dissolve it in dichloromethane (670 mL, 10 vol), wash it successively with 1 M HCl (210 mL, 5 vol), water (670 mL, 10 vol), and wash the organic phase with saturated sodium chloride (670 mL, 10 vol). Separate and collect the organic phase, and concentrate it at 40 °C using a rotary evaporator to obtain the crude product of compound C5 (58 g, 78%, yellow oily substance).

[0258] 9. Preparation of compound C6, with the synthetic route referring to Figure 27 。

[0259] (1) Dissolve compound C5 (52 g, 0.06 mol) in acetonitrile (400 mL, 8 vol), and successively add formic acid (50 mL, 1 vol), triethylamine (50 mL, 1 vol), triphenylphosphine (48.7 g, 0.19 mol), and palladium acetate (3.47 g, 0.015 mol) to the reaction solution. Heat the mixture to 82 °C for reaction overnight.

[0260] (2) TLC detection showed that the reaction was completed. The reaction solution was concentrated at 50 °C using a rotary evaporator to obtain an oily substance. Dichloromethane (200 mL, 4 vol) was added to dissolve it, and it was washed twice successively with water (520 mL × 2, 10 vol × 2), and the organic phase was washed with saturated sodium chloride (520 mL, 10 vol). The organic phase was separated and collected, and concentrated at 40 °C using a rotary evaporator to obtain the crude product of compound C6. After purification by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 → petroleum ether:ethyl acetate = 3:1 → petroleum ether:ethyl acetate = 1:1), compound C6 (43 g, 87%) was obtained as a pale yellow oily substance.

[0261] 10. Prepare compounds D1 - D3.

[0262] (1) Prepare compound D1, and the synthetic route refers to Figure 28 .

[0263] 1) Add D - hexose (250 g, 1.7 mol, 1 eq) to a 10 L reaction kettle, dissolve it with pyridine (3750 mL, 15 vol), then dilute it with dichloromethane (5000 mL, 10 vol), and cool the temperature to 0 °C.

[0264] 2) Dropwise add benzoyl chloride (508 g, 3.6 mol, 2.1 eq) over 2 h, and stir the reaction at 0 °C for 3 h.

[0265] 3) TLC showed that the main spot was double - protected, with single - protected and triple - protected products. Slowly dropwise add benzoyl chloride (5.08 g, 0.21 eq) over 0.5 h, and stir overnight at 0 °C.

[0266] 4) TLC detection showed that the reaction was completed. Quench the reaction by dropwise adding methanol (250 mL, 1 vol) under the condition of controlling the temperature at 0 - 5 °C. The reaction solution was concentrated at 60 °C using a rotary evaporator to obtain an oily substance. Dichloromethane (2000 mL, 8 vol) was added to dissolve it, and it was washed successively with water (1000 mL, 4 vol) and saturated sodium chloride (1000 mL, 4 vol). The organic phase was separated and collected, and concentrated at 40 °C using a rotary evaporator to obtain the crude product of compound D1. After purification by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 3:1), compound D1 (449 g, 74%) was obtained.

[0267] (2) Prepare compound D2, and the synthetic route refers to Figure 29 .

[0268] 1) Add triphenylphosphine (82.9 g, 316 mmol, 2.8 eq) to a 1 L reaction flask, dissolve it with tetrahydrofuran (400 mL, 10 vol), and cool it to 0 °C in an ice bath.

[0269] 2) Slowly add DIAD (68.5 g, 339 mmol, 3 eq), maintain stirring at 0 °C - 5 °C. After addition, the solution becomes turbid. Keep stirring at 0 °C for 30 min.

[0270] 3) Add diphenylphosphoryl azide (87 g, 316 mmol, 2.8 eq) and D1 (40 g, 113, 1 eq) successively. After stirring, the fluidity becomes better and better. Resume stirring at room temperature for 30 min, then heat up to 50 °C and stir overnight.

[0271] 4) TLC detects the end of the reaction. The reaction solution is concentrated at 50 °C by a rotary evaporator to obtain an oily substance; add dichloromethane (2000 mL, 8 vol) to dissolve it, add anhydrous magnesium sulfate (60 g, 1.5 wt.), stir at room temperature for 2 h, filter to remove the triphenylphosphine complex, wash successively with water (400 mL, 10 vol) and saturated sodium chloride (400 mL, 10 vol). Separate the organic phase, collect the organic phase, and concentrate it at 40 °C by a rotary evaporator to obtain the crude product of compound D2. Purify it by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 3:1) to obtain compound D2 (64.2 g, 150%), and directly proceed to the next step.

[0272] (3) Prepare compound D3, the synthetic route refers to Figure 30 。

[0273] 1) Add D2 (64.2 g, 169 mmol, 1 eq) to a 1 L reaction flask, add methanol (600 mL, 10 vol) to dissolve it clearly, and cool it to 0 °C in an ice bath.

[0274] 2) Add sodium methoxide (15.8 g, 292.6 mmol, 1.7 eq) in three batches at intervals of 1 h. After addition, stir overnight.

[0275] 3) TLC detects the end of the reaction. Add 1 M hydrochloric acid to adjust the pH to 7 - 8, concentrate it at 50 °C by a rotary evaporator to obtain an oily substance; purify it by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 → petroleum ether:ethyl acetate = 3:1 → ethyl acetate 100%) to obtain compound D3 (19 g, the two-step yield is 98%).

[0276] 11. Prepare compound D4, the synthetic route refers to Figure 31 。

[0277] (1) Add D3 (19 g, 111 mmol, 1 eq) to a 500 mL reaction flask, add DMF (200 mL, 10 vol) to dissolve it clearly, and cool it to 0 °C in an ice bath.

[0278] (2) Sodium hydride (17.8 g, 60%, 444 mol, 4 eq) was added in four batches over 1 h while maintaining stirring at 10°C - 20°C for 30 min.

[0279] (3) 2-(Bromomethyl)naphthalene (116 g, 525 mmol, 4.7 eq) was added in three batches over 30 min. After addition, stirring was resumed at room temperature overnight.

[0280] (4) When TLC indicated the reaction was complete, the reaction was quenched by dropwise addition of methanol (20 mL, 1 vol) while controlling the temperature at 0 - 5°C; Dichloromethane (380 mL, 20 vol) was added to dissolve the mixture, and it was washed successively with water (190 mL, 10 vol) and saturated sodium chloride solution (190 mL, 10 vol). The organic phase was separated and collected, and concentrated at 40°C using a rotary evaporator to obtain the crude product of compound D4. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound D4 (48.5 g, 99.8%).

[0281] 12. Preparation of compound D5, with the synthetic route referring to Figure 32 .

[0282] (1) D4 (50 g, 110.7 mmol, 1 eq) was added to a 1 L reaction flask, followed by the addition of tetrahydrofuran (150 mL, 3 vol), tert-butanol (350 mL, 7 vol), and water (50 mL, 1 vol). The mixture was stirred until clear, and then diluted with 50% N-methylmorpholine N-oxide (40 g, 332 mmol, 3 eq).

[0283] (2) Finally, potassium osmate dihydrate (0.8 g, 5.5 mmol, 0.05 eq) was added, and the temperature was raised to 30°C and stirred overnight.

[0284] (3) When TLC indicated the reaction was complete, water (250 mL, 5 vol) and sodium sulfite (70 g, 554 mmol, 5 eq) were added to quench the reaction; the reaction solution turned brown; it was stirred at room temperature for 2 h, and the aqueous phase was extracted with ethyl acetate (250 mL * 2, 10 vol * 2). The organic phases were combined and concentrated at 40°C using a rotary evaporator to obtain an oily substance; the oily substance was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound D5 (41.9 g, 78%).

[0285] 13. Preparation of compound D6, with the synthetic route referring to Figure 33 .

[0286] (1) Add D5 (32 g, 66 mmol, 1 eq) to a 500 mL reaction flask, add DMF (160 mL, 5 vol), stir until dissolved and clear, and cool to 0 °C in an ice bath.

[0287] (2) Add imidazole (11 g, 158.4 mmol, 2.4 eq) and DMAP (0.82 g, 6.6 mmol, 0.1 eq) successively, and then slowly add triisopropylchlorosilane (15.6 g, 79.2 mmol, 1.2 eq). After the addition, warm to 40 °C and stir overnight.

[0288] (3) When TLC shows that the reaction is complete and a small amount of 2-position protected byproduct is produced, add water (320 mL, 10 vol) dropwise to quench the reaction under the condition of controlling the temperature at 0 - 5 °C; add ethyl acetate (640 mL, 20 vol) to extract the product, wash the organic phase with saturated sodium chloride (320 mL, 10 vol), separate the liquid and collect the organic phase, and concentrate it to obtain the crude product of compound D6 at 50 °C by a rotary evaporator. Purify it by silica gel column chromatography (petroleum ether:ethyl acetate == 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound D6 (30.5 g, 72.1%).

[0289] 14. Preparation of compound E1, with the synthetic route referring to Figure 34 。

[0290] (1) Dissolve compound C6 (62 g, 77.5 mmol, 1.0 eq) in dichloromethane (620 mL, 10 vol), stir until dissolved and clear, add trichloroacetonitrile (33.6 g, 232.4 mol, 3 eq), and then add 1,8-diazabicyclo[5.4.0]undec-7-ene (2.36 g, 15.5 mmol, 0.2 eq), and stir at room temperature for 4 hours.

[0291] (2) After TLC shows that the reaction is complete, filter the reaction solution through silica gel (120 g, 2 wt.), elute the product with dichloromethane, collect the eluate, and concentrate the combined filtrate at 40 °C by a rotary evaporator to obtain the crude product of compound C7 (73 g, 97.5%, light yellow oil), and directly proceed to the next step.

[0292] (3) Dissolve the crude product of compound B3 (73 g, 77 mmol, 1.0 eq) in dichloromethane (7300 mL, 10 vol), add compound D6 (49.7 g, 77 mmol, 1.0 eq), and add 4A molecular sieve (12 g, 0.2 wt.). After the addition, cool the reaction solution to -20 °C under nitrogen protection, add trimethylsilyl trifluoromethanesulfonate (3.44 g, 15.5 mmol, 0.2 eq), and keep the temperature for reaction for 1.5 h.

[0293] (4) After the reaction was monitored by TLC, triethylamine (3 mL) was added to quench the reaction. The reaction mixture was filtered through diatomaceous earth to remove 4A molecular sieve, and the filtrate was concentrated at 40 °C using a rotary evaporator. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound E1 (110 g, 99.7%, yellow oil).

[0294] 15. Preparation of compound E2, with the synthetic route referring to Figure 35 。

[0295] (1) E1 (110 g, 77 mmol, 1.0 eq) was added to a 1 L reaction flask, and methanol (330 mL, 3 vol) and dichloromethane (330 mL, 3 vol) were added to dissolve it. The solution was cooled to 0 °C in an ice bath.

[0296] (2) Sodium methoxide (16.7 g, 310 mmol, 4 eq) was added in three portions at intervals of 1 h. After addition, the mixture was stirred overnight.

[0297] (3) After the reaction was monitored by TLC to be complete, 1 M hydrochloric acid was added to adjust the pH to 7 - 8. The mixture was concentrated at 50 °C using a rotary evaporator to obtain an oily substance. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound E2 (93.2 g, 90%).

[0298] 16. Preparation of compound E3, with the synthetic route referring to Figure 36 。

[0299] (1) E2 (75 g, 56 mmol, 1.0 eq) was added to a 1 L reaction flask, and acetone (400 mL, 5 vol) was added to dissolve it. 2,2 - Dimethoxypropane (23.3 g, 224 mmol, 4 eq) and p - toluenesulfonic acid monohydrate (1.07 g, 5.6 mmol, 0.1 eq) were successively added. After addition, the mixture was stirred at room temperature overnight.

[0300] (2) After the reaction was monitored by TLC to be complete, 1 g of triethylamine was added to quench the reaction. Dichloromethane (750 mL, 10 vol) was added to dilute the mixture. The organic phase was successively washed with water (375 mL, 5 vol) and saturated sodium chloride (750 mL, 10 vol), and the organic phase was separated and collected. The organic phase was concentrated at 40 °C using a rotary evaporator to obtain the crude product of compound H3, an oily substance. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound E3 (71 g, 92%).

[0301] 17. Preparation of compound E4, with the synthetic route referring to Figure 37 。

[0302] (1) Add E3 (58 g, 42 mmol, 1.0 eq) to a 1 L reaction flask, dissolve it in tetrahydrofuran (300 mL, 5 vol), and cool the solution to 0 °C in an ice bath.

[0303] (2) Add tetrabutylammonium fluoride trihydrate (19.88 g, 63 mmol, 1.5 eq) and acetic acid (3 g, 50 mol, 1.2 eq) successively. After addition, stir at room temperature overnight.

[0304] (3) When the reaction is completed as detected by TLC, concentrate it at 40 °C using a rotary evaporator to obtain an oily substance; add dichloromethane (580 mL, 10 vol) for dilution, wash the organic phase successively with water (580 mL, 10 vol) and saturated sodium chloride (580 mL, 10 vol), separate and collect the organic phase, and concentrate it at 40 °C using a rotary evaporator to obtain the crude product of compound H4, an oily substance; purify it by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 4:1) to obtain compound E4 (59.4 g, 96%).

[0305] Experimental results:

[0306] 1. Compound A1:

[0307] (1) TOF-MS: m / z: 267.1271 [M+Na] + 。

[0308] (2) 1 1H NMR (CDCl3, 400 MHz): δ 5.89 - 5.86 (m, 1H, CH=), 5.29 - 5.17 (m, 2H, CH2=), 4.96 (s, 1H, H-1), 4.30 - 4.17 (m, 2H, CH2a, incl. d, 4.15, J2,3 = 5.5 Hz, H-2), 4.06 (dd, 1H, J3,4 = 7.1 Hz, H-3), 4.02 - 3.97 (m, 1H, CH2b), 3.74 - 3.65 (m, 1H, H-5), 3.38 - 3.43 (ddd, 1H, J4,5 = 9.3, J4,OH = 5.4 Hz, H-4), 2.64 (d, 1H, OH-4), 1.53 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.29 (d, 3H, J5,6, = 6.6 Hz, H-6).

[0309] (3) 1313C NMR (CDCl3, 100 MHz): δ 133.53 (CH=), 117.80 (CH2=), 109.44 (C(CH3)2), 96.18 (C-1), 86.03 (C-3), 75.77 (C-2), 74.42 (C-4), 67.89 (CH2), 65.89 (C-5), 27.92, 26.08 (2CH3), 17.41 (C-6).

[0310] 2. Compound B1:

[0311] (1) TOF-MS: m / z: 319.42 [M+H] + .

[0312] (2) 1 1H NMR (400 MHz, CDCl3): δ 2.02 - 2.18 (m, 12H), 3.53 (dd, J=8.5, 12.1 Hz, 1H), 4.15 (dd, J=5.0, 11.7 Hz, 1H), 4.95 - 5.06 (m, 2H), 5.21 (t, J=8.1 Hz, 1H), 5.72 (d, J=6.8 Hz, 1H).

[0313] (3) 13 13C NMR (100 MHz, CDCl3): δ 20.6 - 21.0 (3C, Ac), 62.9, 68.4, 69.4, 69.6, 92.2, 169.1 (3C, Ac).

[0314] 3. Compound B2:

[0315] (1) TOF-MS: m / z: 293.13 [M+H] + .

[0316] (2) 1 1H NMR (400 MHz, CDCl3): δ 5.51 (t, J=9.6 Hz, 1H, H3); 5.38 (br t, J=3.4 Hz, 1H, H1); 4.96 (ddd, J=10.2 Hz, 9.9 Hz, 6.0 Hz, 1H, H4); 4.83 (dd, J=9.9 Hz, 3.4 Hz, 1H, H2); 4.20 (br, 1H, OH); 3.88 (t, J=11.0 Hz, 1H, H5a); 3.81 (dd, J=11.0 Hz, 6.0 Hz, 1H, H5b); 2.09 (s, 3H, H2 / H4 / H6); 2.05 (s, 3H, H2 / H4 / H6); 2.05 (s, 3H, H2 / H4 / H6).

[0317] (3)13 C NMR (125 MHz, CDCl3): δ 170.5 (C1 or C3 or C5); 170.3 (s, C1 or C3 or C5); 170.3 (C1 or C3 or C5); 90.1 (d, C1); 71.3 (d, C2); 69.4 (d, C3 or C4); 69.3 (d, C3 or C4); 58.3 (t, C5); 20.8 (q, C2 or C4 or C6); 20.8 (q, 2C, C2 or C4 or C6).

[0318] 4. Compound C1:

[0319] (1) TOF-MS: m / z: 503.13 [M+H] + .

[0320] (2) 1 H NMR 1.25 (d, 3H, J = 6.4 Hz, H-6), 1.35, 1.54 (2s, 6H, C(C#3)2), 2.02, 2.03, 2.08 (3s, 9H, 3C#3CO), 3.36 (dd, 1H, H-5'a), 3.41 - 3.55 (m, 2H, CH2=CH-C#2-), 3.90 - 4.20 (m, 6H, H-l', H-5'b, H-2, H-3, H-4, H-5), 4.80 - 5.02 (m, 3H, H-l, H-2', H-4'), 5.20 (t, 1H, J = 9.7 Hz, H-3'), 5.22 - 5.38 (m, 2H, C#2=CH-CH2-), 5.80 - 6.00 (m, 1H, CH2=C#-CH2-).

[0321] 5. Compound C2:

[0322] (1) TOF-MS: m / z: 399.18 [M+Na] + .

[0323] (2) 11H NMR (600 MHz, CDCl3) δ 5.86 (ddd, J = 23.2, 11.0, 5.8 Hz, 1H), 5.27 (dd, J = 9.5, 7.6 Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 4.97 (s, 1H), 4.60 (d, J = 7.5 Hz, 1H), 4.27 - 4.22 (m, 1H), 4.14 - 4.07 (m, 2H), 4.00 - 3.87 (m, 2H), 3.63 (dt, J = 10.6, 5.4 Hz, 2H), 3.56 - 3.45 (m, 2H), 3.23 (dt, J = 21.6, 9.3 Hz, 2H), 1.49 (s, 3H), 1.32 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H).

[0324] (3) 13 13C NMR (101 MHz, CDCl3) δ 133.66 (s), 118.08 (s), 109.73 (s), 102.70 (s), 95.98 (s), 79.86 (s), 78.06 (s), 76.52 (s), 76.19 (s), 74.05 (s), 69.75 (s), 68.10 (s), 65.74 (s), 64.44 (s), 27.94 (s), 27.10 (s), 26.48 (s), 17.55 (s).

[0325] 6. Compound C3:

[0326] (1) TOF-MS: m / z: 819.36 [M + Na] + 。

[0327] (2) 1 1H NMR (500 MHz, CDCl3) δ 7.74 - 7.59 (m, 11H), 7.38 - 7.30 (m, 8H), 5.83 (ddd, J = 22.4, 10.9, 5.8 Hz, 1H), 5.22 (dd, J = 17.2, 1.4 Hz, 1H), 5.13 (d, J = 10.3 Hz, 1H), 5.02 - 4.87 (m, 5H), 4.79 (dd, J = 11.6, 6.5 Hz, 2H), 4.72 (d, J = 11.9 Hz, 1H), 4.20 (t, J = 6.1 Hz, 1H), 4.14 - 4.02 (m, 2H), 3.97 - 3.86 (m, 2H), 3.69 - 3.52 (m, 4H), 3.34 (t, J = 8.1 Hz, 1H), 3.24 - 3.14 (m, 1H), 1.45 (s, 3H), 1.27 (s, 3H), 1.17 (s, 3H).

[0328] (3) 13 13C NMR (126 MHz, CDCl3) δ 136.30 (d, J = 18.8 Hz), 135.74 (s), 133.76 (s), 133.32 (d, J = 10.4 Hz), 133.19 - 132.88 (m), 128.29 (s), 127.99 (d, J = 4.0 Hz), 127.71 (d, J = 3.9 Hz), 126.81 (s), 126.75 - 126.34 (m), 125.94 (ddd, J = 24.8, 15.3, 5.0 Hz), 117.86 (s), 109.36 (s), 102.06 (s), 96.22 (s), 83.89 (s), 82.04 (s), 78.33 (s), 78.16 (s), 78.06 (d, J = 22.2 Hz), 76.15 (s), 75.59 (s), 74.92 (s), 73.30 (s), 68.07 (s), 64.38 (s), 63.90 (s), 29.76 (s), 27.91 (s), 26.48 (s), 17.64 (s).

[0329] 7. Compound C4:

[0330] (1) TOF - MS: m / z 779.36 [M + Na] + .

[0331] (2) 1 1H NMR (500 MHz, CDCl3) δ 7.84 - 7.66 (m, 23H), 7.53 - 7.40 (m, 18H), 5.93 (ddd, J = 22.3, 10.8, 5.6 Hz, 2H), 5.32 (dd, J = 17.2, 1.5 Hz, 2H), 5.23 (dd, J = 10.4, 1.0 Hz, 2H), 5.16 (d, J = 11.3 Hz, 2H), 5.11 (d, J = 11.3 Hz, 2H), 5.04 (dd, J = 11.3, 6.6 Hz, 4H), 4.90 - 4.79 (m, 6H), 4.66 (d, J = 7.9 Hz, 2H), 4.19 (dd, J = 13.0, 5.1 Hz, 2H), 4.07 - 3.95 (m, 6H), 3.91 (d, J = 6.7 Hz, 4H), 3.83 - 3.69 (m, 6H), 3.55 (dt, J = 16.7, 8.8 Hz, 4H), 3.36 - 3.23 (m, 2H), 2.62 (s, 2H), 1.36 (d, J = 6.2 Hz, 6H).

[0332] (3) 13 13C NMR (126 MHz, CDCl 3)δ 135.83 (s), 135.36 (s), 134.76 (s), 133.83 (s), 133.42 - 132.80 (m), 128.27 (d, J = 7.6 Hz), 128.17 - 127.75 (m), 127.63 (d, J = 4.3 Hz), 126.87 (s), 126.64 (s), 126.43 (s), 126.38 - 125.58 (m), 117.30 (s), 104.75 (s), 98.44 (s), 84.40 (s), 83.68 (s), 81.86 (s), 78.16 (s), 75.74 (s), 75.45 (s), 73.26 (s), 71.63 (s), 70.78 (s), 67.90 (s), 66.27 (s), 64.00 (s), 17.47 (s).

[0333] 8. Compound C5:

[0334] (1) TOF - MS: m / z: 863.37 [M + Na] + .

[0335] (2) 1 1H NMR (500 MHz, CDCl3) δ 7.76 - 7.55 (m, 12H), 7.40 - 7.27 (m, 9H), 5.83 (ddd, J = 22.3, 10.9, 5.7 Hz, 1H), 5.32 (dd, J = 9.7, 3.3 Hz, 1H), 5.24 (dd, J = 18.8, 1.3 Hz, 2H), 5.14 (d, J = 10.4 Hz, 1H), 4.93 (s, 2H), 4.85 (d, J = 11.5 Hz, 1H), 4.77 (d, J = 11.9 Hz, 1H), 4.74 - 4.65 (m, 3H), 4.51 (d, J = 7.6 Hz, 1H), 4.11 (dd, J = 13.0, 5.1 Hz, 1H), 3.99 - 3.86 (m, 2H), 3.75 (dq, J = 12.2, 6.1 Hz, 1H), 3.71 - 3.58 (m, 2H), 3.54 (t, J = 8.8 Hz, 1H), 3.26 (ddd, J = 52.4, 12.4, 8.9 Hz, 2H), 2.05 (s, 3H), 1.83 (s, 3H), 1.25 (d, J = 6.1 Hz, 3H).

[0336] (3) 1313C NMR (126 MHz, CDCl3) δ 136.11 (s), 135.83 (s), 135.62 (s), 133.45 (s), 133.37 - 133.17 (m), 133.17 - 132.76 (m), 128.24 (s), 127.99 (dd, J = 29.7, 15.7 Hz), 127.72 - 127.39 (m), 127.02 (s), 126.54 (d, J = 17.3 Hz), 126.19 (d, J = 19.2 Hz), 126.10 - 125.57 (m), 117.91 (s), 104.28 (s), 96.37 (s), 83.82 (s), 81.67 (s), 78.11 (s), 75.82 (s), 75.28 (d, J = 20.0 Hz), 73.15 (s), 71.96 (s), 70.33 (s), 68.24 (s), 67.30 (s), 63.81 (s), 29.66 (s), 20.89 (d, J = 14.4 Hz), 17.74 (s).

[0337] 9. Compound C6:

[0338] (1) TOF - MS: m / z: 801.33 [M + H] + .

[0339] (2) 1 1H NMR (500 MHz, CDCl3) δ 7.81 - 7.67 (m, 11H), 7.45 (dd, J = 14.0, 6.3 Hz, 8H), 5.48 (dd, J = 9.9, 3.2 Hz, 1H), 5.33 (dd, J = 3.0, 1.8 Hz, 1H), 5.14 (d, J = 0.9 Hz, 1H), 5.05 (s, 2H), 4.96 (d, J = 11.4 Hz, 1H), 4.92 - 4.76 (m, 4H), 4.63 (d, J = 7.6 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.83 - 3.63 (m, 4H), 3.48 - 3.29 (m, 3H), 2.16 (s, 3H), 1.94 (d, J = 3.4 Hz, 3H), 1.35 (d, J = 6.2 Hz, 3H).

[0340] (3) 1313C NMR (126 MHz, CDCl3) δ 136.23 (s), 135.93 (s), 135.73 (s), 133.53 - 133.28 (m), 133.28 - 132.91 (m), 128.38 (s), 128.07 (t, J = 8.7 Hz), 127.99 - 127.55 (m), 127.19 (s), 126.69 (d, J = 11.0 Hz), 126.43 (s), 126.31 - 125.68 (m), 104.39 (s), 92.19 (s), 83.91 (s), 81.82 (s), 78.23 (s), 75.89 (s), 75.45 (d, J = 19.0 Hz), 73.32 (s), 71.84 (s), 70.81 (s), 67.44 (s), 63.95 (s), 29.81 (s), 20.99 (s), 17.95 (s).

[0341] 10. Compound D1:

[0342] (1) TOF-MS: m / z: 377.13 [M + Na] + .

[0343] (2) 1 1H NMR (400 MHz, CDCl3) δ 8.15 - 8.02 (m, 4H), 7.63 - 7.53 (m, 2H), 7.45 (td, J = 7.7, 4.3 Hz, 4H), 6.53 (dd, J = 6.1, 1.2 Hz, 1H), 5.59 (ddd, J = 6.6, 2.3, 1.7 Hz, 1H), 4.86 (ddd, J = 16.7, 9.2, 3.5 Hz, 2H), 4.68 (dd, J = 12.3, 2.6 Hz, 1H), 4.26 - 4.03 (m, 2H).

[0344] 11. Compound D2:

[0345] (1) TOF-MS: m / z: 402.11 [M + Na] + .

[0346] (2) 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 18.9, 7.4 Hz, 4H), 7.59 (dd, J = 13.2, 7.2 Hz, 2H), 7.47 (dd, J = 14.1, 7.6 Hz, 4H), 6.53 (dd, J = 6.2, 1.5 Hz, 1H), 5.97 - 5.88 (m, 1H), 4.94 (dt, J = 6.2, 1.7 Hz, 1H), 4.68 (dd, J = 11.6, 7.1 Hz, 1H), 4.58 (dd, J = 11.6, 5.4 Hz, 1H), 4.46 (t, J = 6.1 Hz, 1H), 4.24 (d, J = 4.9 Hz, 1H).

[0347] 12. Compound D3:

[0348] (1) TOF-MS: m / z: 194.06 [M+Na] + .

[0349] (2) 1 1H NMR (400 MHz, CDCl 3 ) δ 6.33 (dd, J = 6.2, 1.5 Hz, 1H), 4.84 (dt, J = 6.2, 1.7 Hz, 1H), 4.68 (dd, J = 11.6, 7.1 Hz, 1H), 4.56 (m, 1H), 3.82 (t, J = 11.6, 5.4 Hz, 1H), 3.71 (t, J = 6.1 Hz, 1H), 1.82 (d, J = 4.9 Hz, 1H).

[0350] 13. Compound D4:

[0351] (1) TOF-MS: m / z: 451.15 [M+Na] + .

[0352] (2) 1 1H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 7.5 Hz, 8H), 7.49 (dd, J = 9.1, 3.5 Hz, 5H), 6.39 (dd, J = 6.3, 1.5 Hz, 1H), 4.86 (dd, J = 9.3, 4.9 Hz, 2H), 4.81 - 4.75 (m, 2H), 4.72 (d, J = 12.0 Hz, 1H), 4.50 - 4.43 (m, 1H), 4.11 (t, J = 6.6 Hz, 1H), 4.01 (d, J = 4.7 Hz, 1H), 3.76 (d, J = 2.0 Hz, 2H).

[0353] 14. Compound D5:

[0354] (1) TOF-MS: m / z: 508.21 [M+Na] + 。

[0355] (2) 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J=5.3 Hz, 7H), 7.49 - 7.46 (m, 5H), 5.29 (d, J=3.8 Hz, 1H), 4.90 (d, J=2.2 Hz, 1H), 4.85 (d, J=3.6 Hz, 1H), 4.75 - 4.65 (m, 3H), 4.23 (t, J=6.7 Hz, 1H), 3.89 (dd, J=9.7, 3.5 Hz, 1H), 3.82 - 3.74 (m, 1H), 3.60 (d, J=6.7 Hz, 2H).

[0356] 15. Compound D6:

[0357] (1) TOF-MS: m / z: 664.28 [M+Na]+.

[0358] (2) 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J=6.2 Hz, 7H), 7.82 (s, 1H), 7.62 - 7.46 (m, 6H), 5.28 (d, J=3.6 Hz, 1H), 4.99 - 4.67 (m, 4H), 4.37 - 4.29 (m, 1H), 4.12 (d, J=2.3 Hz, 1H), 4.04 - 3.88 (m, 1H), 3.68 (dd, J=12.4, 7.7 Hz, 2H), 1.33 (dd, J=17.5, 10.4 Hz, 1H), 1.15 (dd, J=18.4, 5.1 Hz, 18H), 1.11 (s, 3H).

[0359] 16. Compound E1:

[0360] (1) TOF-MS: m / z: 1424.61 [M+H] + 。

[0361] (2) 11H NMR (600 MHz, CDCl3) δ 7.90 - 7.65 (m, 19H), 7.54 - 7.41 (m, 14H), 5.44 (s, 2H), 5.41 (d, J = 10.0 Hz, 1H), 5.04 (s, 2H), 4.89 (ddd, J = 35.0, 24.5, 11.5 Hz, 4H), 4.75 - 4.65 (m, 5H), 4.60 (d, J = 7.6 Hz, 1H), 4.29 (dq, J = 12.4, 6.1 Hz, 1H), 4.08 (d, J = 3.3 Hz, 1H), 3.99 (ddd, J = 42.8, 10.5, 6.3 Hz, 2H), 3.82 (dd, J = 9.4, 3.4 Hz, 1H), 3.75 - 3.70 (m, 2H), 3.69 - 3.63 (m, 3H), 3.37 (ddd, J = 21.4, 10.1, 8.9 Hz, 2H), 1.87 (d, J = 37.6 Hz, 6H), 1.35 (d, J = 6.2 Hz, 3H), 1.21 - 1.11 (m, 3H), 1.08 (d, J = 6.9 Hz, 17H).

[0362] (3) 13 13C NMR (151 MHz, CDCl3) δ 170.35 (s), 169.99 (s), 136.27 (s), 136.13 (s), 135.79 (s), 135.21 (s), 134.45 (s), 133.56 - 132.94 (m), 128.47 (d, J = 14.8 Hz), 128.39 - 127.89 (m), 127.89 - 127.61 (m), 127.31 (s), 126.99 (s), 126.80 (s), 126.62 (s), 104.66 (s), 97.65 (s), 97.05 (s), 78.25 (s), 76.21 (s), 75.62 (d, J = 7.1 Hz), 74.60 (s), 73.89 (s), 73.21 (s), 72.74 (s), 72.15 (s), 71.71 (s), 70.10 (s), 68.75 (s), 67.26 (s), 63.86 (s), 59.50 (s), 20.99 (s), 20.75 (s), 18.24 (s), 18.09 (s), 12.64 (s).

[0363] 17. Compound E2:

[0364] (1) TOF-MS: m / z: 1362.59 [M+Na] + .

[0365] (2) 11H NMR (600 MHz, CDCl3) δ 7.89 - 7.66 (m, 19H), 7.63 (d, J = 7.9 Hz, 1H), 7.52 - 7.50 (m, 2H), 7.46 (dd, J = 14.8, 7.3 Hz, 10H), 7.39 (t, J = 8.1 Hz, 2H), 5.50 (s, 1H), 5.13 (d, J = 11.3 Hz, 1H), 5.00 (dt, J = 11.0, 8.0 Hz, 3H), 4.90 - 4.80 (m, 3H), 4.78 - 4.62 (m, 4H), 4.59 (d, J = 7.3 Hz, 1H), 4.14 - 4.05 (m, 2H), 4.03 (dd, J = 11.7, 3.6 Hz, 1H), 3.94 - 3.85 (m, 3H), 3.77 - 3.60 (m, 6H), 3.55 (t, J = 9.5 Hz, 1H), 3.47 (t, J = 8.2 Hz, 1H), 3.32 - 3.21 (m, 1H), 1.32 (s, 3H), 1.14 - 1.11 (m, 3H), 1.06 (s, 17H).

[0366] (3) 13 13C NMR (151 MHz, CDCl3) δ 136.03 (s), 135.56 (s), 135.18 (d, J = 3.2 Hz), 134.45 (s), 133.21 (ddd, J = 23.8, 14.5, 9.8 Hz), 128.62 (s), 128.54 - 128.31 (m), 128.31 - 127.95 (m), 127.81 (dd, J = 8.6, 5.1 Hz), 127.29 (s), 126.83 (d, J = 6.7 Hz), 126.58 (d, J = 9.9 Hz), 126.43 - 125.60 (m), 105.04 (s), 99.48 (s), 97.37 (s), 84.43 (s), 83.71 (s), 78.21 (s), 75.86 (s), 75.62 (s), 74.78 (s), 73.34 (s), 72.08 (s), 71.71 (s), 71.03 (s), 68.85 (s), 66.47 (s), 64.08 (s), 59.17 (s), 29.83 (s), 18.17 (d, J = 17.9 Hz), 17.89 (s), 12.54 (s).

[0367] 18. Compound E3:

[0368] (1) TOF - MS: m / z: 1380.57 [M + H] + .

[0369] (2) 11H NMR (500 MHz, CDCl3) δ 7.87 - 7.67 (m, 18H), 7.62 (d, J = 7.9 Hz, 1H), 7.53 - 7.42 (m, 13H), 7.39 (d, J = 8.4 Hz, 1H), 5.80 (s, 1H), 5.12 (d, J = 11.4 Hz, 1H), 5.08 - 5.00 (m, 3H), 4.87 (dt, J = 11.9, 9.1 Hz, 4H), 4.70 (dt, J = 11.9, 8.0 Hz, 3H), 4.52 (d, J = 7.4 Hz, 1H), 4.32 - 4.21 (m, 1H), 4.11 (d, J = 5.4 Hz, 2H), 4.01 (ddd, J = 25.3, 14.1, 6.8 Hz, 3H), 3.81 - 3.57 (m, 7H), 3.45 (t, J = 8.2 Hz, 1H), 3.31 (dd, J = 11.3, 7.2 Hz, 1H), 1.58 (s, 3H), 1.39 (s, 3H), 1.31 (s, 3H), 1.06 (dd, J = 15.2, 6.2 Hz, 3H), 0.99 (t, J = 7.4 Hz, 17H).

[0370] (3) 13 13C NMR (126 MHz, CDCl3) δ 136.44 (d, J = 5.0 Hz), 135.82 (s), 135.19 (s), 134.43 (s), 133.65 - 132.91 (m), 128.62 (s), 128.40 (d, J = 11.3 Hz), 127.97 (dd, J = 35.1, 11.1 Hz), 127.80 - 127.64 (m), 127.45 (s), 126.89 (s), 126.87 - 125.62 (m), 109.23 (s), 102.74 (s), 97.24 (s), 97.07 (s), 83.88 (s), 82.33 (s), 82.13 (s), 78.52 (d, J = 23.4 Hz), 78.07 (s), 76.24 (s), 75.61 (s), 74.78 (s), 73.92 (d, J = 10.3 Hz), 73.30 (s), 71.68 (d, J = 5.7 Hz), 68.80 (s), 64.51 (s), 63.91 (s), 58.92 (s), 29.83 (s), 28.08 (s), 26.72 (s), 17.99 (d, J = 16.8 Hz), 12.40 (s).

[0371] 19. Compound E4:

[0372] (1) TOF - MS: m / z 1224.41 [M + H] + .

[0373] (2) 1 1H NMR (600 MHz, CDCl3) δ 7.84 - 7.73 (m, 20H), 7.50 - 7.44 (m, 15H), 5.37 (d, J = 18.7 Hz, 1H), 5.32 (d, J = 3.5 Hz, 1H), 5.12 - 5.09 (m, 1H), 5.05 (d, J = 4.0 Hz, 2H), 4.99 (d, J = 7.5 Hz, 1H), 4.89 (dd, J = 10.7, 3.2 Hz, 3H), 4.84 (dd, J = 18.6, 6.9 Hz, 3H), 4.73 (t, J = 6.9 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.35 - 4.29 (m, 1H), 4.25 (t, J = 6.4 Hz, 1H), 4.19 (d, J = 5.7 Hz, 1H), 4.14 - 4.10 (m, 1H), 4.06 - 4.00 (m, 2H), 3.74 (dd, J = 10.4, 6.7 Hz, 2H), 3.71 - 3.66 (m, 2H), 3.64 - 3.61 (m, 2H), 3.45 (dd, J = 10.4, 5.8 Hz, 1H), 3.34 - 3.26 (m, 1H), 1.32 (s, 6H), 1.28 (s, 3H).

[0374] (3) 1313C NMR (151 MHz, CDCl3) δ 136.39 (t, J = 6.9 Hz), 135.78 (s), 135.13 (d, J = 5.1 Hz), 133.23 (ddd, J = 22.1, 15.4, 4.1 Hz), 128.70 - 128.22 (m), 128.05 (d, J = 3.3 Hz), 127.91 - 127.65 (m), 127.03 (s), 126.91 - 126.55 (m), 126.55 - 125.67 (m), 109.41 (d, J = 10.7 Hz), 102.51 (s), 102.43 (d, J = 24.8 Hz), 99.74 (s), 96.27 (s), 92.91 (s), 83.87 (s), 82.16 (s), 78.16 (s), 78.01 (s), 76.11 (s), 75.82 (s), 75.71 (d, J = 31.5 Hz), 74.92 (s), 73.91 (s), 73.11 (d, J = 88.9 Hz), 72.81 - 72.67 (m), 69.24 (s), 67.38 (s), 65.26 (s), 63.93 (s), 61.00 (s), 29.83 (s), 27.88 (s), 26.44 (s), 22.83 (s), 17.74 (s), 14.27 (s).

[0375] Example 4

[0376] In this example, compound F5 was prepared based on Quila.

[0377] The final product is compound F5, and the structure is as follows:

[0378]

[0379] Preparation method: The synthetic route refers to Figure 38 .

[0380] (1) Add F1 (2 kg, Quila with 60% saponin content), pure water (6.6 L), and concentrated hydrochloric acid (4.5 L) into a 50 L reaction kettle. Raise the temperature by 5 °C every 15 min and slowly heat up to 100 °C to prevent excessive foaming and overflow due to rapid temperature increase; keep stirring overnight at the maintained temperature.

[0381] (2) After the reaction is completed as detected by TLC, cool down to room temperature, dilute with ethyl acetate (10 L, 5 vol), filter through diatomaceous earth, collect the filtrate and separate the layers, collect the organic phase, extract the aqueous layer once with ethyl acetate (10 L, 5 vol), combine the organic phases, concentrate at 40 °C by rotary evaporator to obtain a red solid, and purify by silica gel column chromatography to obtain compound F2 (30 g, 1.5% wt.), and directly proceed to the next step.

[0382] (3) Add F2 (30 g, 57 mmol, 1.0 eq) to a 500 mL four-necked round-bottom flask, dissolve it in DMF (300 mL, 10 vol), add cesium carbonate (24.1 g, 74.1 mmol, 1.3 eq), and the pH of the solution is 8; cool the solution to 0 °C in an ice bath, and slowly add allyl bromide (12.0 g, 97 mmol, 1.7 eq); after addition, restore to room temperature and stir for 2 h;

[0383] (4) When the reaction is completed as detected by TLC, dilute it with ethyl acetate (600 mL, 20 vol), wash the organic phase successively with water (600 mL, 20 vol) and saturated sodium chloride (600 mL, 20 vol), separate the organic phase by liquid separation, and concentrate it at 40 °C using a rotary evaporator to obtain the crude product of compound H4; purify it by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound F3 (31 g, 95%).

[0384] (5) Add F3 (31 g, 59 mmol, 1.0 eq) to a 2 L four-necked round-bottom flask, dissolve it in dichloromethane (1240 mL, 40 vol), cool the solution to 0 °C in an ice bath, add 2,6-dimethylpyridine (63 g, 590 mmol, 10 eq), and finally add trimethylsilyl trifluoromethanesulfonate (65.4 g, 295 mmol, 5 eq); after addition, restore to room temperature and stir for 4 h;

[0385] (6) When the reaction is completed as detected by TLC, wash the organic phase successively with water (310 mL, 10 vol) and saturated sodium chloride (310 mL, 10 vol), separate the organic phase by liquid separation, and concentrate it at 40 °C using a rotary evaporator to obtain the crude product of compound F4; purify it by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound F4 (35 g, 79%).

[0386] (7) Add F4 (35 g, 46 mmol, 1.0 eq) to a 2 L four-necked round-bottom flask, dissolve it in dichloromethane (700 mL, 20 vol), successively add pyrrolidine (16.5 g, 230 mmol, 5 eq) and tetrakis(triphenylphosphine)palladium (2.7 g, 2.3 mmol, 0.05 eq); after addition, stir at room temperature for 3 h;

[0387] (8) After the reaction was monitored by TLC, 1 M hydrochloric acid was added to adjust the pH to 5. The turbid solution became clear. The organic layer was separated by liquid-liquid extraction. The aqueous layer was back-extracted once with dichloromethane (10 vol). The combined organic layers were washed with saturated sodium chloride solution (310 mL, 10 vol). The organic layer was separated and concentrated by rotary evaporation at 40 °C to obtain the crude product of compound F5. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1 → petroleum ether:ethyl acetate = 2:1) to obtain compound F5 (30 g, 91%).

[0388] Experimental results:

[0389] Compound F5:

[0390] (1) TOF-MS: m / z: 715.52 [M+H] + 。

[0391] (2) 1 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 5.33 (t, J = 3.0 Hz, 1H), 4.54 (s, 1H), 3.80 (dd, J = 11.2, 4.4 Hz, 1H), 2.95 (dd, J = 14.3, 3.8 Hz, 1H), 2.21 (t, J = 13.6 Hz, 1H), 1.93 - 0.45 (m, 67H).

[0392] (3) 13 13C NMR (126 MHz, CDCl3) δ 207.64, 183.08, 143.40, 122.37, 74.99, 73.46, 56.17, 48.78, 48.01, 46.73, 46.34, 41.44, 40.27, 39.76, 38.29, 36.03, 35.24, 34.79, 32.83, 32.44, 31.76, 30.65, 26.94, 26.65, 24.40, 23.43, 20.72, 17.17, 15.79, 9.62, 7.25, 6.96, 5.23, 5.15.

[0393] Example 5

[0394] In this example, compound G1 was prepared based on dodecanedioic acid.

[0395] The final product was compound G1, and the structure is shown as follows:

[0396]

[0397] Preparation method: The synthetic route refers to Figure 39 。

[0398] (1) Dodecanedioic acid (20 g, 87 mmol, 1 eq) was dissolved in dichloromethane (200 mL, 10 vol). Thionyl chloride (25.8 g, 217 mmol, 2.5 eq) was added dropwise at room temperature. After the addition, the temperature was raised to 35 °C and stirred for 5 hours.

[0399] (2) After the reaction was monitored by TLC and completed, it was concentrated at 50 °C using a rotary evaporator to obtain an oily substance. The oily substance was dissolved in ultradry dichloromethane (200 mL, 10 vol), and TEA (1.75 g, 17.4 mmol, 0.2 eq) and tert-butanol (7.7 g, 104 mmol, 1.2 eq) were added to the reaction solution, and the reaction was carried out at room temperature for 3 h.

[0400] (3) After the reaction was monitored by TLC and completed, it was concentrated at 50 °C using a rotary evaporator to obtain an oily substance, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1 → petroleum ether:ethyl acetate = 2:1) to obtain compound G1 (17.4 g, 70%).

[0401] Experimental results:

[0402] Compound G1:

[0403] (1) TOF-MS: m / z: 309.24 [M+Na] + .

[0404] (2) 1 1H NMR (400 MHz, CDCl3) δ 1.23 (s, 12H), 1.40 (s, 9H), 1.51 - 1.60 (m, 4H), 2.16 (t, J = 7.2 Hz, 2H), 2.30 (t, J = 7.6 Hz, 2H).

[0405] (3) 13 13C NMR (151 MHz, CDCl3) δ ppm 24.85, 25.28, 28.30, 29.24, 29.37, 29.43, 29.55, 34.23, 35.81, 80.13, 173.62, 180.08.

[0406] Example 6

[0407] In this example, compound H1 was prepared based on compound H4.

[0408] The final product is compound H1, and the structure is as follows:

[0409]

[0410] Preparation method: The synthetic route refers toFigure 40 。

[0411] (1) Dissolve compound E4 (20 g, 16.3 mmol, 1 eq) in dichloromethane (200 mL, 10 vol), stir until dissolved clearly, add trichloroacetonitrile (23.6 g, 163 mmol, 10 eq), and then add 1,8-diazabicyclo[5.4.0]undec-7-ene (2.49 g, 16.3 mmol). Stir at room temperature for 5 hours.

[0412] (2) After the reaction is completed as detected by TLC, concentrate it at 40 °C by a rotary evaporator to obtain an oily substance, which is purified by silica gel column chromatography. The eluent is petroleum ether containing acetone (0 - 20%), and compound E5 (16.7 g, 100%) is obtained, and proceed to the next step directly.

[0413] (3) Dissolve compound E5 (16.7 g, 16.3 mmol, 1.66 eq) in toluene (400 mL, 20 vol), add compound F5 (7.0 g, 9.8 mmol, 1 eq), and add 4A molecular sieve (10 g, 0.5 wt.). After adding, cool the reaction solution to -78 °C under nitrogen protection, and dropwise add boron trifluoride diethyl etherate (2.88 g, 13.7 mmol, 1.4 eq). Keep the temperature for reaction for 2 h.

[0414] (4) When compounds E5 and F5 both disappear as detected by TLC, add triethylamine (2 mL) to quench the reaction, filter off the 4A molecular sieve through diatomaceous earth, concentrate the filtrate at 40 °C by a rotary evaporator, and purify it by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 → petroleum ether:ethyl acetate = 10:1 → petroleum ether:ethyl acetate = 5:1) to obtain compound H1 (17.9 g, 95%, colorless glassy solid), HPLC: 98.9%.

[0415] Experimental results:

[0416] Compound H1:

[0417] (1) Refer to Figure 41 。TOF-MS: m / z: 1943.000 [M + Na] + 。

[0418] (2) Refer to Figure 42 。 11H NMR (600 MHz, CDCl3) δ 9.30 (s, 1H), 7.85 - 7.67 (m, 17H), 7.62 (dd, J = 8.0, 5.0 Hz, 3H), 7.55 - 7.32 (m, 15H), 5.35 (d, J = 8.0 Hz, 1H), 5.33 (t, J = 3.5 Hz, 1H), 5.23 (s, 1H), 5.07 - 5.00 (m, 3H), 4.89 (dd, J = 11.9, 9.8 Hz, 2H), 4.83 (d, J = 12.1 Hz, 2H), 4.75 (d, J = 11.6 Hz, 1H), 4.70 - 4.61 (m, 3H), 4.48 (s, 1H), 4.26 - 4.16 (m, 2H), 4.05 (d, J = 4.6 Hz, 1H), 3.99 - 3.88 (m, 2H), 3.83 - 3.65 (m, 6H), 3.63 - 3.54 (m, 3H), 3.47 - 3.34 (m, 1H), 3.28 - 3.19 (m, 1H), 2.90 (dd, J = 14.3, 4.1 Hz, 1H), 2.22 (t, J = 13.6 Hz, 1H), 1.92 - 1.75 (m, 5H), 1.73 - 1.54 (m, 5H), 1.51 - 1.40 (m, 4H), 1.39 - 1.34 (m, 4H), 1.33 - 1.26 (m, 3H), 1.26 - 1.16 (m, 8H), 1.12 (d, J = 7.0 Hz, 1H), 1.08 - 0.99 (m, 4H), 0.97 (s, 2H), 0.96 - 0.90 (m, 18H), 0.87 (s, 7H), 0.72 (s, 3H), 0.67 - 0.60 (m, 6H), 0.57 - 0.49 (m, 6H).

[0419] (3) Reference Figure 43 。 1313C NMR (151 MHz, CDCl3) δ 175.31 (s), 163.60 (s), 143.34 (s), 136.35 (d, J = 15.5 Hz), 135.80 (s), 135.06 (s), 134.43 (s), 133.21 (ddd, J = 26.9, 17.9, 5.4 Hz), 128.65 - 128.24 (m), 128.24 - 127.62 (m), 126.90 (s), 126.72 (d, J = 5.9 Hz), 126.53 (d, J = 3.1 Hz), 126.45 - 125.69 (m), 125.57 (s), 121.90 (s), 109.65 (s), 102.50 (s), 98.30 (s), 94.06 (s), 91.95 (s), 83.80 (s), 82.18 (s), 80.35 (s), 78.73 (s), 78.36 (s), 78.06 (s), 75.65 (d, J = 15.3 Hz), 75.19 (s), 75.01 (s), 74.82 (s), 73.86 (s), 73.36 (s), 72.65 (s), 72.11 (s), 67.86 (s), 67.04 (s), 63.89 (s), 59.20 (s), 56.17 (s), 49.14 (s), 47.96 (s), 46.77 (d, J = 12.8 Hz), 41.61 (s), 40.86 (s), 39.95 (s), 38.38 (s), 35.89 (s), 35.31 (s), 34.87 (s), 32.86 (s), 32.53 (s), 30.92 (s), 30.58 (s), 29.83 (s), 27.79 (s), 26.94 (s), 26.48 (s), 26.15 (s), 24.45 (s), 23.45 (s), 20.72 (s), 18.03 (s), 17.18 (s), 15.82 (s), 9.61 (s), 7.26 (s), 6.96 (s), 5.32 (d, J = 29.4 Hz), 5.04 (s).

[0420] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A trisaccharide saponin synthesis intermediate, characterized in that, The structure of compound H1 with the following general formula: Wherein, R1 is selected from at least one of triethylsilyl, tert-hexyldimethylsilyl, tert-butyldimethylchlorosilane and triisopropylsilyl; R2 is selected from at least one of naphthylmethyl, benzyl, p-methoxybenzyl and trimethoxybenzyl; Preferably, R1 is naphthylmethyl; R2 is TES.

2. A trisaccharide saponin synthesis intermediate, characterized in that, It can be obtained by reductive amination and amide coupling reaction of compound H1 as described in claim 1; The general formula of the trisaccharide saponin synthesis intermediate is the structure of compound H3 as follows: Wherein, R1 is selected from at least one of tert-butyl ester, naphthylmethyl and benzyl; R2 is selected from at least one of TES, TDS, TBDMS and TIPS; R3 is selected from at least one of naphthylmethyl, benzyl, p-methoxybenzyl and trimethoxybenzyl; Preferably, R1 is tert-butyl; R2 is naphthylmethyl; R3 is TES.

3. A method for synthesizing trisaccharide saponin TQL1055, characterized in that, Including: For the trisaccharide saponin synthesis intermediate compound H3 as described in claim 2, first remove the carboxyl protecting group, triterpene hydroxyl protecting group and propylidene respectively, and then remove the sugar ring hydroxyl protecting group to obtain the trisaccharide saponin TQL1055.

4. The synthesis method of trisaccharide saponin TQL1055 according to claim 3, wherein, The removal of the sugar ring hydroxyl protecting group is to remove the sugar ring hydroxyl protecting group by an oxidation reaction to obtain the trisaccharide saponin TQL1055; Preferably, the oxidation reaction is selected from at least one of DDQ oxidation reaction, CAN oxidation reaction and IBX oxidation reaction; Preferably, the oxidation reaction is DDQ oxidation reaction.

5. The synthetic method of trisaccharide saponin TQL1055 as described in claim 3, characterized in that, The preparation method of the trisaccharide saponin synthesis intermediate compound H3 includes: Reducing the azide group of the trisaccharide saponin synthesis intermediate compound H1 as described in claim 1 to an amino group to obtain an amino intermediate; Carrying out an amide coupling reaction on the amino intermediate and dodecanedioic acid with a carboxyl protecting group to obtain the trisaccharide saponin synthesis intermediate compound H3.

6. The synthetic method of trisaccharide saponin TQL1055 as described in claim 5, characterized in that, The reduction treatment includes at least one of triphenylphosphine and ammonia reduction method, triphenylphosphine and ammonium chloride solution reduction method, zinc powder reduction method, diphenylselenol reduction method and sodium borohydride reduction method; Preferably, the reduction treatment is the triphenylphosphine and ammonia reduction method.

7. The synthesis method of trisaccharide saponin TQL1055 according to claim 5, characterized in that, The preparation method of the trisaccharide saponin synthesis intermediate compound H1 includes: Taking monosaccharide raw materials and constructing them successively through glycosylation reaction to obtain monosaccharide compounds, disaccharide compounds and trisaccharide compounds; Introducing a protecting group into natural quillaic acid to obtain a quillaic acid intermediate; Carrying out glycoside construction on the trisaccharide compound and the quillaic acid intermediate to react to obtain the trisaccharide saponin synthesis intermediate compound H1.

8. The synthetic method of trisaccharide saponin TQL1055 according to claim 5, characterized in that, The preparation method of the dodecanedioic acid with a carboxyl protecting group includes: Taking dodecanedioic acid and a carboxyl protecting group substance to carry out an esterification reaction under catalytic conditions to obtain the dodecanedioic acid with a carboxyl protecting group.

9. The synthesis method of trisaccharide saponin TQL1055 according to claim 8, characterized in that, The carboxyl protecting group includes at least one of tert-butyl ester, naphthylmethyl and benzyl; Preferably, the carboxyl protecting group is tert-butyl ester.

10. Use of a trisaccharide saponin synthesis intermediate as described in claim 1 or 2 in the preparation of trisaccharide saponin TQL1055.

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