Oxaspiro compounds and intermediates and processes for their preparation

Abstract

The application relates to the technical field of chemical synthesis, and provides an oxaspirocyclic compound and an intermediate, and a preparation method of the oxaspirocyclic compound and the intermediate. The preparation method of the oxaspirocyclic compound comprises the following steps: an olefin metathesis reaction of a compound VII occurs in the presence of a catalyst, so that the oxaspirocyclic compound shown in formula VIII is obtained. The preparation method is simple in operation, does not need to use dangerous reagents, is safe and controllable in a reaction process, and is high in yield.

Description

Technical Field

[0001] This application relates to the field of synthetic chemistry, and in particular to an oxaspirocyclic compound and intermediate, and a method for preparing the same. Background Technology

[0002] Spirocyclic compounds are widely found in nature, with numerous natural products possessing spirocyclic structures discovered in animals, plants, and microorganisms. Because spirocycles are stable and rigid structures, their introduction into drug molecules not only makes the compound structure more novel but also improves its activity, solubility, and lipid solubility. Therefore, employing spirocyclic structures is a common strategy in drug molecule design, and many pesticides and clinically used drugs currently contain spirocyclic structures. As a large class of spirocyclic compounds, oxaspirocyclic compounds have attracted great interest from scientists over the past thirty years and have been widely used in pesticide and pharmaceutical research and production, such as Eribulin, Ivermeclin, Cevimeline, Troleandomycin, spirodiclofen, and Cibopardol; the antidepressant 2'-substituted-spiro[3H-benzofuran-2,1'-cyclohexane]; and IRAK4 kinase inhibitors, all of which contain spirocyclic structures. Studies have shown that inserting oxaspirocycles into drug structures can significantly improve their pharmacological activity, enhance therapeutic effects, and reduce toxic side effects.

[0003]

[0004] Cyclic alkenes are important intermediates in the synthesis of 1,5-diols, 1,5-diamines, oxacyclopropanes, and azircyclopropanes. Many of these cyclic alkene derivatives possess good pharmacological activities, such as deserpidine, reserpine, tacrolimus (prograf), budesonide, natamycin, picrotoxin, and scopolamine. Among them, oxacycloheterocyclic spirocyclic alkenes, such as U69593, Spiradoline, Enadoline, U50488, and PD11703, exhibit high selectivity and affinity for kappa opioid receptors, making them highly selective kappa opioid receptor agonists and of significant value in the development of analgesics. Therefore, this application discloses a series of novel oxacycloheterocyclic alkenes and their synthetic methods, providing more molecular scaffold structures for the development of kappa opioid receptor agonists.

[0005]

[0006] Currently, there are relatively few reported methods for the synthesis of spirocyclic compound VIII in the literature. For example, the synthesis method of spirocyclic compound VIII disclosed in "China Pharmaceutical Industry Magazine 2001, 32(8), 342-345" is as follows:

[0007]

[0008] The synthetic route is as long as 111 steps, with an overall yield of only about 3%. Furthermore, diethyl ether is used as a reaction solvent or post-treatment solvent in many steps of the preparation process. Diethyl ether has a low flash point, is volatile, flammable and explosive, posing a high safety risk. The synthetic method has poor reproducibility.

[0009] The synthesis method of 1-oxaspiro[4,5]dec-7-ene published in "Journal of Organic Chemistry 1991, 56(19), 5567-72" uses protoanemonin and butadiene as starting materials. Protoanemonin is expensive (about 7,000 RMB per gram), which is too costly. In addition, butadiene is a gas, and the reaction requires high temperature and pressure. Scale-up requires a reaction vessel, which has high equipment requirements. Furthermore, the method uses lithium borohydride, which is flammable and belongs to dangerous chemical reagents, making the operation relatively dangerous.

[0010] In the synthesis method of 1-oxaspiro[4,5]dec-7-ene disclosed in patent "US4438130A", the first step uses lithium metal to prepare alkyl lithium reagent, which is flammable and poses a high safety risk; in addition, nitrogen protection is required, and the operation and transfer must be carried out in an anhydrous and oxygen-free environment, which is complicated and dangerous; furthermore, diethyl ether is used as a reaction solvent or post-treatment solvent in many steps of the preparation process. Diethyl ether has a low flash point, is volatile, flammable and explosive, and poses a high safety risk.

[0011] The method for synthesizing 1-oxaspiro[4,5]dec-7-ene disclosed in patent "WO2023277116A1" is a Birch reduction dearomatization method using phenylpropanol compounds in the presence of lithium metal reagent and in liquid ammonia at -78°C. However, lithium metal is flammable, and liquid ammonia is highly toxic and prone to leakage, posing a high safety risk and making it unsuitable for scale-up. Furthermore, careful handling is required after the reaction, as handling 1 liter of liquid ammonia takes up to 12 hours, while each mole of substrate often requires 7.5 liters of liquid ammonia, making the long processing time difficult to operate on an industrial scale.

[0012] Therefore, there is an urgent need for a new method for preparing oxaspirocyclic compounds to solve the problems of synthesis, economy and safety in the process of synthesizing oxaspirocyclic compounds, and to provide assistance for the design and synthesis of new compounds. Summary of the Invention

[0013] The purpose of this application is to provide a method for preparing oxaspirocyclic compounds, so as to achieve the economical and safe synthesis of oxaspirocyclic compounds. The specific technical solution is as follows:

[0014] The first aspect of this application provides a method for preparing an oxaspirocyclic compound, comprising the following steps:

[0015] (5) Compound VII undergoes an olefin metathesis reaction in the presence of a catalyst to give the oxaspirocyclic compound shown in Formula VIII;

[0016]

[0017] Where n is selected from 1, 2, 3 or 4.

[0018] In some embodiments of this application, in step (5), the catalyst is selected from Grubbs catalysts, which include first-generation Grubbs catalysts (Grubbs first generation catalysts) and second-generation Grubbs catalysts (Grubbs second generation catalysts), preferably selected from first-generation Grubbs catalysts.

[0019] In some embodiments of this application, in step (5), the molar ratio of compound VII to the catalyst is 1:(0.01-0.1).

[0020] In some embodiments of this application, in step (5), the reaction solvent is selected from at least one of dichloromethane, chloroform, dichloroethane, and toluene.

[0021] In some embodiments of this application, in step (5), the reaction temperature is 40-60°C and the reaction time is 10-30 hours.

[0022] A second aspect of this application provides a method for preparing compound VII, comprising the following steps:

[0023] (4) Compound VI reacts with a condensing agent to give compound VII;

[0024]

[0025] Where n is selected from 1, 2, 3 or 4.

[0026] In some embodiments of this application, in step (4), the condensing agent is Y-SO2Cl, wherein Y is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 18 Aryl or C3-C 18 Heteroaryl; the C3-C 18 The heteroatom in the heteroaryl group is selected from N, O, or S; the C6-C 18 When the aryl group is selected from phenyl, the hydrogen atoms on the phenyl group can be independently replaced by halogen, nitro, cyano, hydroxyl or C1-C3 alkyl, wherein the halogen is selected from F, Cl, Br or I; preferably, the condensing agent is selected from p-toluenesulfonyl chloride.

[0027] In some embodiments of this application, in step (4), the reaction is carried out under the co-catalysis of triethylamine and 4-dimethylaminopyridine, and the molar ratio of compound VI, the condensing agent, the triethylamine and the 4-dimethylaminopyridine is 1:(1-2):(5-10):(0.1-0.2).

[0028] In some embodiments of this application, in step (4), the reaction solvent is selected from at least one of 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, and toluene.

[0029] In some embodiments of this application, in step (4), the reaction temperature is -10 to 10°C and the reaction time is 10 to 30 hours.

[0030] A third aspect of this application provides a method for preparing compound VI, comprising the following steps:

[0031] (3) Compound V reacts with a deprotecting agent to give compound VI;

[0032]

[0033] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

[0034] In some embodiments of this application, in step (3), the molar ratio of compound V and the deprotecting reagent is 1:(1-10).

[0035] In some embodiments of this application, in step (3), the deprotecting agent is selected from tetrabutylammonium fluoride or hydrochloric acid.

[0036] In some embodiments of this application, in step (3), the reaction solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, dioxane, chloroform, and toluene.

[0037] In some embodiments of this application, in step (3), the reaction temperature is 15-30°C and the reaction time is 2-4 hours.

[0038] The fourth aspect of this application provides a method for preparing compound V, comprising the following steps:

[0039] (1) Compound III undergoes an addition reaction with the first organometallic reagent to give compound IV;

[0040]

[0041] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl;

[0042] The first organometallic reagent is selected from CH2CHCH2CH2MgX 1 Or CH2CHCH2CH2Li, wherein X 1 Selected from Cl, Br, or I; preferably, the first organometallic reagent is selected from 3-butenyl magnesium bromide;

[0043] (2) Compound IV undergoes an addition reaction with the second organometallic reagent to give compound V;

[0044]

[0045] The second organometallic reagent is selected from CH2CHCH2MgX. 2 Or CH2CHCH2CH2Li, wherein X 2 The reagent is selected from Cl, Br, or I; preferably, the second organometallic reagent is selected from allyl magnesium bromide.

[0046] In some embodiments of this application, in step (1), the molar ratio of compound III to the first organometallic reagent is 1:(1.2-2.0).

[0047] In some embodiments of this application, the reaction solvent in step (1) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, diethyl ether, and dipropyl ether.

[0048] In some embodiments of this application, the reaction temperature of step (1) is -10 to 10°C, and the reaction time of step (1) is 1 to 6 hours.

[0049] In some embodiments of this application, in step (2), the molar ratio of compound IV and the second organometallic reagent is 1:(1-1.5).

[0050] In some embodiments of this application, the reaction solvent in step (2) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, diethyl ether, and dipropyl ether.

[0051] In some embodiments of this application, the reaction temperature of step (2) is -10 to 10°C, and the reaction time of step (2) is 1 to 6 hours.

[0052] The fifth aspect of this application provides a method for preparing compound III, comprising the following steps:

[0053] A) N,O-dimethylhydroxylamine hydrochloride was mixed with an organic solvent, and then aluminum reagent was added at -78 to 0°C. The temperature was raised to 20 to 30°C to carry out the first reaction. After the reaction was completed, the temperature was cooled to 0 to 10°C, and compound Ia was added to carry out the second reaction to obtain compound II-a.

[0054]

[0055] Where n is selected from 1, 2, 3 or 4;

[0056] B) Compound II-a and the hydroxyl protecting agent react in the presence of the first basic substance to give compound III;

[0057]

[0058] Wherein, R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

[0059] In some embodiments of this application, in step A), the molar volume ratio of the N,O-dimethylhydroxylamine hydrochloride to the organic solvent is (1-2) mol: 0.5 L.

[0060] In some embodiments of this application, in step A), the organic solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, and toluene.

[0061] In some embodiments of this application, in step A), the molar ratio of the aluminum reagent and the N,O-dimethylhydroxylamine hydrochloride is (0.5-1.5):1.

[0062] In some embodiments of this application, in step A), the aluminum reagent is selected from at least one of trimethylaluminum and diisobutylaluminum hydride.

[0063] In some embodiments of this application, in step A), the molar ratio of compound Ia and N,O-dimethylhydroxylamine hydrochloride is (0.2-0.5):1.

[0064] In some embodiments of this application, in step A), the reaction time of the first reaction is 3-5 hours; the reaction time of the second reaction is 1-2 hours.

[0065] In some embodiments of this application, in step A), the aluminum reagent is added by dripping for 0.5-1.5 hours.

[0066] In some embodiments of this application, in step B), the molar ratio of compound II-a, the hydroxyl protectant, and the first basic substance is 1:(1-1.5):(1.5-2.5), preferably 1:(1-1.1):(1.5-2.5).

[0067] In some embodiments of this application, in step B), the hydroxyl protecting agent is selected from at least one of tert-butyldiphenylchlorosilane, tert-butyldimethylsilylmethanesulfonate, tert-butyldimethylchlorosilane, 3,4-dihydro-2H-pyran, chloromethyl methyl ether, 1-(chloromethoxy)-2-methoxyethane, triphenylchloromethane, trimethylchlorosilane, and triisopropylchlorosilane.

[0068] In some embodiments of this application, in step B), the first alkaline substance is selected from at least one of triethylamine, N,N-diisopropylethylamine, 2,6-dimethylpyridine, and imidazole.

[0069] In some embodiments of this application, the reaction temperature of step B) is 15-30°C, and the reaction time of step B) is 2-4 hours.

[0070] The sixth aspect of this application provides a method for preparing compound III, comprising the following steps:

[0071] A') Diol and tert-butyldiphenylchlorosilane react in the presence of a second basic substance to give compound Ib;

[0072]

[0073] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl;

[0074] Compound Ib was oxidized using Jones' reagent to give compound II-b;

[0075]

[0076] C') The compound II-b was activated with a condensing agent, and then reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of a third basic substance to give compound III;

[0077]

[0078] In some embodiments of this application, in step A'), the molar ratio of the diol, the second alkaline substance, and the tert-butyldiphenylchlorosilane is (1-2):(1-2):1.

[0079] In some embodiments of this application, in step A'), the second alkaline substance is selected from at least one of N,N-diisopropylethylamine and triethylamine.

[0080] In some embodiments of this application, the reaction solvent in step A') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, and toluene.

[0081] In some embodiments of this application, the reaction temperature of step A') is 10-30°C, and the reaction time of step A') is 14-18 hours.

[0082] In some embodiments of this application, in step B'), the molar volume ratio of compound Ib to the Jones reagent is (1-2) mol: 1 L.

[0083] In some embodiments of this application, the solvent for the oxidation reaction in step B') is selected from acetone.

[0084] In some embodiments of this application, the oxidation reaction temperature of step B') is 10-30°C, and the oxidation reaction time of step B') is 0.5-2 hours.

[0085] In some embodiments of this application, in step C'), the molar ratio of compound II-b, N,O-dimethylhydroxylamine hydrochloride, the condensing agent and the third basic substance is 1:(1-1.5):(1.2-2):(2-3).

[0086] In some embodiments of this application, in step C'), the condensing agent is selected from at least one of HATU, HOBT / EDCI, CDI, DCC, and Caterpillar condensing agent.

[0087] In some embodiments of this application, in step C'), the third alkaline substance is selected from at least one of N,N-diisopropylethylamine and triethylamine.

[0088] In some embodiments of this application, the reaction solvent in step C') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, toluene, and DMF.

[0089] In some embodiments of this application, the reaction temperature of step C') is 10-30°C, and the reaction time of step C') is 1-3 hours.

[0090] The seventh aspect of this application provides a compound as shown in Formula VIII:

[0091]

[0092] Where n is selected from 1, 3 or 4.

[0093] The eighth aspect of this application provides a compound as shown in Formula VII:

[0094]

[0095] Where n is selected from 1, 2, 3 or 4.

[0096] The ninth aspect of this application provides a compound as shown in Formula VI:

[0097]

[0098] Where n is selected from 1, 2, 3 or 4.

[0099] The tenth aspect of this application provides a compound as shown in Formula V:

[0100]

[0101] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

[0102] The beneficial effects of this application are:

[0103] This application provides a method for preparing oxaspirocyclic compounds. This method is simple to operate, highly safe, and avoids the use of hazardous reagents. This application allows the preparation of oxaspirocyclic compounds using inexpensive and readily available compounds as starting materials, achieving an overall yield of 50% or higher, and has achieved 100-gram-scale synthesis.

[0104] Of course, implementing any product or method of this application does not necessarily require achieving all of the advantages described above at the same time. Attached Figure Description

[0105] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other embodiments can be obtained based on these drawings.

[0106] Figure 1 The 1H NMR spectrum of compound III prepared in Example 3 (when the hydroxyl protecting group (R) is tert-butyldimethylsilyl) is shown.

[0107] Figure 2The 1H NMR spectrum of compound III prepared in Example 11 (when the hydroxyl protecting group (R) is tert-butyldiphenylsilyl);

[0108] Figure 3 The 1H NMR spectrum of compound V prepared in Example 16;

[0109] Figure 4 The 1H NMR spectrum of compound VI prepared in Example 17;

[0110] Figure 5 The 1H NMR spectrum of compound VII prepared in Example 19;

[0111] Figure 6 The 1H NMR spectrum of compound VIII prepared in Example 20;

[0112] Figure 7 The image shows the carbon NMR spectrum of compound VIII prepared in Example 20.

[0113] Figure 8 The 1H NMR spectrum of compound II'-a prepared in Example 21 is shown.

[0114] Figure 9 The 1H NMR spectrum of compound III' (with hydroxyl protecting group (R) being tert-butyldimethylsilyl) prepared in Example 22;

[0115] Figure 10 The 1H NMR spectrum of compound V' prepared in Example 24;

[0116] Figure 11 The 1H NMR spectrum of compound VI' prepared in Example 25;

[0117] Figure 12 The 1H NMR spectrum of compound VII' prepared in Example 26;

[0118] Figure 13 The 1H NMR spectrum of compound VIII' prepared in Example 27;

[0119] Figure 14 The image shows the carbon NMR spectrum of compound VIII' prepared in Example 27. Detailed Implementation

[0120] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. All other embodiments obtained by those skilled in the art based on this application are within the scope of protection of this application.

[0121] The first aspect of this application provides a method for preparing compound V, comprising the following steps:

[0122]

[0123] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl (THP), methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), methylthiomethyl (MTM), triphenylmethyl (Trt), trimethylsilyl (TMS) or triisopropylsilyl (TIPS).

[0124] In step (1), compound III and the first organometallic reagent undergo an addition reaction to give compound IV; wherein the first organometallic reagent is selected from CH2CHCH2CH2MgX. 1 Or CH2CHCH2CH2Li, wherein X 1 Selected from Cl, Br, or I.

[0125] In some embodiments of this application, in step (1), the first organometallic reagent is selected from 3-butenyl magnesium bromide.

[0126] In some embodiments of this application, in step (1), the molar ratio of compound III to the first organometallic reagent is 1:(1.2-2.0), preferably 1:(1.2-1.5).

[0127] In some embodiments of this application, the reaction solvent in step (1) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, diethyl ether, and dipropyl ether; this application does not have any particular limitation on the amount of reaction solvent added in step (1), as long as the purpose of this application can be achieved.

[0128] In some embodiments of this application, the reaction temperature of step (1) is -10 to 10°C, and the reaction time of step (1) is 1 to 6 hours.

[0129] In some embodiments of this application, the specific operation method of step (1) includes: dissolving compound III in a reaction solvent, slowly adding 0.5-1.5 mol / L 3-butenyl magnesium bromide solution at -10-10℃, and stirring for 1-6 hours; after the reaction is completed, quenching with 100-300 mL saturated zinc chloride solution; and then separating the product to obtain compound IV.

[0130] This application does not impose any particular restrictions on the method for separating the product obtained in step (1), as long as the purpose of this application can be achieved. For example, the product obtained from the reaction can be extracted with dichloromethane multiple times, such as three times, the organic phase can be washed with saturated sodium chloride solution, dried and concentrated with anhydrous sodium sulfate, and purified by silica gel chromatography (the eluent is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:(4-10)) to obtain compound IV.

[0131] In step (2), compound IV and the second organometallic reagent undergo an addition reaction to give compound V; wherein the second organometallic reagent is selected from CH2CHCH2MgX. 2 Or CH2CHCH2CH2Li, wherein X 2 Selected from Cl, Br, or I.

[0132] In some embodiments of this application, in step (2), the second organometallic reagent is selected from allyl magnesium bromide.

[0133] In some embodiments of this application, in step (2), the molar ratio of compound IV and the second organometallic reagent is 1:(1-1.5).

[0134] In some embodiments of this application, the reaction solvent in step (2) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, diethyl ether, and dipropyl ether. This application does not have any particular limitation on the amount of reaction solvent added in step (2), as long as the purpose of this application can be achieved.

[0135] In some embodiments of this application, the reaction temperature of step (2) is -10 to 10°C, and the reaction time of step (2) is 1 to 6 hours.

[0136] In some embodiments of this application, the specific operation method of step (2) includes: dissolving compound IV in a reaction solvent, slowly adding 1 mol / L allyl magnesium bromide at -10-10℃, and stirring for 1-6 hours; after the reaction is completed, quenching with 100-300 mL of saturated zinc chloride solution; and then separating the product to obtain compound V.

[0137] This application does not impose any particular restrictions on the method for separating the product obtained in step (2), as long as the purpose of this application can be achieved. For example, the product obtained from the reaction can be extracted with dichloromethane multiple times, such as three times, the organic phase can be washed with saturated sodium chloride solution, dried and concentrated with anhydrous sodium sulfate, and purified by silica gel chromatography (the eluent is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:(4-10)) to obtain compound V.

[0138] The inventors of this application discovered in their research that, in the synthesis of compound V, if the order of the reaction reagents is changed, for example, if a second organometallic reagent, such as allyl magnesium bromide, is used to react with compound III first, and then reacted with a first organometallic reagent, such as 3-butenyl magnesium bromide, the reaction effect is poor and the yield of compound V is very low; while if a first organometallic reagent, such as 3-butenyl magnesium bromide, is used to react with compound III first, and then reacted with a second organometallic reagent, such as allyl magnesium bromide, the yield of compound V obtained is higher.

[0139] A second aspect of this application provides a compound as shown in Formula V:

[0140]

[0141] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

[0142] A third aspect of this application provides a method for preparing compound VI, comprising the following steps:

[0143] (3) Compound V reacts with a deprotecting agent to give compound VI;

[0144]

[0145] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

[0146] In some embodiments of this application, in step (3), the molar ratio of compound V to the deprotecting agent is 1:(1-10).

[0147] In some embodiments of this application, in step (3), the deprotecting agent is selected from tetrabutylammonium fluoride or hydrochloric acid, preferably hydrochloric acid. Using hydrochloric acid as the deprotecting agent results in high yield and easy separation and removal from the product. Preferably, the concentration of hydrochloric acid is 1-3 mol / L.

[0148] In some embodiments of this application, the reaction solvent in step (3) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, dioxane, chloroform, and toluene. This application does not have any particular limitation on the amount of reaction solvent added in step (3), as long as the purpose of this application can be achieved.

[0149] In some embodiments of this application, the reaction temperature of step (3) is 15-30°C and the reaction time of step (3) is 2-4 hours.

[0150] In some embodiments of this application, the specific operation method of step (3) includes: dissolving compound V in a reaction solvent, slowly adding 1-3 mol / L hydrochloric acid at 15-30°C, and stirring for 2-4 hours; after the reaction is completed, quenching with 100-300 mL of saturated sodium bicarbonate solution; and then separating the product to obtain compound VI.

[0151] This application does not impose any particular restrictions on the method for separating the product obtained in step (3), as long as the purpose of this application can be achieved. For example, the product obtained from the reaction can be extracted with dichloromethane multiple times, such as three times, the organic phase can be washed with saturated sodium chloride solution, dried and concentrated with anhydrous sodium sulfate, and purified by silica gel chromatography (the eluent is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:(4-10)) to obtain compound of formula VI.

[0152] The fourth aspect of this application provides a compound as shown in Formula VI:

[0153]

[0154] Where n is selected from 1, 2, 3 or 4.

[0155] The fifth aspect of this application provides a method for preparing compound VII, comprising the following steps:

[0156] (4) Compound VI reacts with a condensing agent to give compound VII;

[0157]

[0158] Where n is selected from 1, 2, 3 or 4.

[0159] In some embodiments of this application, in step (4), the condensing agent is Y-SO2Cl, wherein Y is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 18 Aryl or C3-C 18 Heteroaryl; the C3-C 18 The heteroatom in the heteroaryl group is selected from N, O, or S; the C6-C 18When the aryl group is selected from phenyl, the hydrogen atoms on the phenyl group can be independently replaced by halogen, nitro, cyano, hydroxyl or C1-C3 alkyl, wherein the halogen is selected from F, Cl, Br or I; preferably, the condensing agent is selected from p-toluenesulfonyl chloride.

[0160] In some embodiments of this application, in step (4), the reaction is carried out under the co-catalysis of triethylamine and 4-dimethylaminopyridine, and the molar ratio of compound VI, p-toluenesulfonyl chloride, triethylamine and 4-dimethylaminopyridine is 1:(1-2):(5-10):(0.1-0.2).

[0161] In some embodiments of this application, the reaction solvent in step (4) is selected from at least one of 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, and toluene; this application does not have any particular limitation on the amount of reaction solvent added in step (4), as long as the purpose of this application can be achieved.

[0162] In some embodiments of this application, the reaction temperature of step (4) is -10 to 10°C, and the reaction time of step (4) is 10 to 30 hours.

[0163] In some embodiments of this application, the specific operation method of step (4) includes: dissolving compound VI in a reaction solvent, slowly adding p-toluenesulfonyl chloride, triethylamine and 4-dimethylaminopyridine at -10-10℃, and stirring for 10-30 hours; then separating the product to obtain compound VII.

[0164] This application does not impose any particular restrictions on the method for separating the product obtained in step (4), as long as the purpose of this application can be achieved. For example, the product obtained from the reaction can be extracted with dichloromethane multiple times, such as three times, the organic phase can be washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel chromatography (the eluent is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:(4-10)) to obtain compound of formula VII.

[0165] The sixth aspect of this application provides a compound as shown in Formula VII:

[0166]

[0167] Where n is selected from 1, 2, 3 or 4.

[0168] The seventh aspect of this application provides a method for preparing an oxaspirocyclic compound, comprising the following steps:

[0169] (5) Compound VII undergoes an olefin metathesis reaction in the presence of a catalyst to give the oxaspirocyclic compound shown in Formula VIII;

[0170]

[0171] Where n is selected from 1, 2, 3 or 4.

[0172] When n is 2, the oxaspirocyclic compound shown in Formula VIII is 1-oxaspiro[4,5]dec-7-ene.

[0173] In some embodiments of this application, in step (5), the catalyst is selected from Grubbs catalysts, which include first-generation Grubbs catalysts (Grubbs Generation 1 catalysts) and second-generation Grubbs catalysts (Grubbs Generation 2 catalysts), preferably selected from first-generation Grubbs catalysts (Grubbs Generation 1 catalysts).

[0174] In some embodiments of this application, in step (5), the molar ratio of compound VII to the catalyst is 1:(0.01-0.1).

[0175] In some embodiments of this application, the reaction solvent in step (5) is selected from at least one of dichloromethane, chloroform, dichloroethane, and toluene; this application does not have any particular limitation on the amount of reaction solvent added in step (5), as long as the purpose of this application can be achieved.

[0176] In some embodiments of this application, the reaction temperature of step (5) is 40-60°C and the reaction time of step (5) is 10-30 hours.

[0177] In some embodiments of this application, the specific operation method of step (5) includes: dissolving compound VII and the first-generation Grubbs catalyst in a reaction solvent and reacting at 40-60°C for 10-30 hours under nitrogen protection; then separating the product to obtain the oxaspirocyclic compound shown in formula VIII.

[0178] This application does not impose any particular restrictions on the method for separating the product obtained in step (5), as long as it can achieve the purpose of this application. For example, the product obtained from the reaction can be filtered with diatomaceous earth, extracted with dichloromethane multiple times, such as three times, the organic phase can be washed with saturated NaCl solution, dried with anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel chromatography (the eluent is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:(4-10)) to obtain the oxaspirocyclic compound shown in Formula VIII.

[0179] The eighth aspect of this application provides a compound as shown in Formula VIII:

[0180]

[0181] Where n is selected from 1, 3 or 4.

[0182] The ninth aspect of this application provides a method for preparing compound III, comprising the following steps:

[0183]

[0184] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

[0185] In step A), N,O-dimethylhydroxylamine hydrochloride is mixed with an organic solvent, and then aluminum reagent is added at -78 to 0°C. The temperature is raised to 20 to 30°C to carry out the first reaction. After the reaction is completed, the temperature is cooled to 0 to 10°C, and compound Ia is added to carry out the second reaction to obtain compound II-a.

[0186] In some embodiments of this application, in step A), the molar volume ratio of N,O-dimethylhydroxylamine hydrochloride to organic solvent is (1-2) mol: 0.5 L.

[0187] In some embodiments of this application, in step A), the organic solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, and toluene.

[0188] In some embodiments of this application, in step A), the molar ratio of the aluminum reagent and N,O-dimethylhydroxylamine hydrochloride is (0.5-1.5):1.

[0189] In some embodiments of this application, in step A), the aluminum reagent is selected from at least one of trimethylaluminum and diisobutylaluminum hydride. When the aluminum reagent is trimethylaluminum, it can be added at a temperature of -78 to -60°C; when the aluminum reagent is diisobutylaluminum hydride, it can be added at a temperature of -78 to 0°C. The aluminum reagent is preferably selected from diisobutylaluminum hydride, which has lower cost and higher safety.

[0190] In some embodiments of this application, in step A), the molar ratio of compound Ia to N,O-dimethylhydroxylamine hydrochloride is (0.2-0.5):1.

[0191] In some embodiments of this application, in step A), the reaction time of the first reaction is 3-5 hours; the reaction time of the second reaction is 1-2 hours.

[0192] In some embodiments of this application, in step A), the aluminum reagent is added by dripping for 0.5-1.5 hours.

[0193] In some embodiments of this application, step A) specifically includes the following steps: Under nitrogen protection, N,O-dimethylhydroxylamine hydrochloride is dissolved in a reaction solvent. Over 0.5-1.5 hours, metallic aluminum reagent is slowly added dropwise at -78 to 0°C. After the addition is complete, the mixture is heated to 20-30°C and stirred for 3-5 hours to carry out the first reaction. The solution is then cooled to 0-10°C, compound Ia is added, and the mixture is stirred for 1-2 hours to carry out the second reaction. While maintaining the temperature of the second reaction, a saturated solution of potassium sodium tartrate tetrahydrate is carefully added to quench the reaction, and stirring continues for 10-30 hours. The product is then separated to obtain compound II-a.

[0194] This application does not impose any particular limitation on the method for separating the product obtained in step A), as long as it can achieve the purpose of this application. For example, the product obtained from the reaction can be filtered with diatomaceous earth, extracted with dichloromethane multiple times, such as three times, the organic phase dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain compound II-a.

[0195] In step B), compound II-a and the hydroxyl protecting agent react in the presence of the first basic substance to give compound III.

[0196] In some embodiments of this application, in step B), the molar ratio of compound II-a, the hydroxyl protectant, and the first basic substance is 1:(1-1.5):(1.5-2.5), preferably 1:(1-1.1):(1.5-2.5).

[0197] In some embodiments of this application, in step B), the hydroxyl protectant is selected from at least one of tert-butyldiphenylchlorosilane, tert-butyldimethylsilylmethanesulfonate, tert-butyldimethylchlorosilane, 3,4-dihydro-2H-pyran, chloromethyl methyl ether, 1-(chloromethoxy)-2-methoxyethane, triphenylchloromethane, trimethylchlorosilane, and triisopropylchlorosilane.

[0198] In some embodiments of this application, in step B), the first basic substance is selected from at least one of triethylamine, N,N-diisopropylethylamine, 2,6-dimethylpyridine, and imidazole.

[0199] In some embodiments of this application, the reaction temperature of step B) is 15-30°C, and the reaction time of step B) is 2-4 hours.

[0200] In some embodiments of this application, the specific operation method of step B) includes: dissolving compound II in a reaction solvent at -10 to -10°C, adding a hydroxyl protectant and a first basic substance in sequence, and stirring at 15 to 30°C for 2 to 4 hours; then separating the product to obtain compound III.

[0201] This application does not impose any particular limitation on the method for separating the product obtained in step B), as long as it can achieve the purpose of this application. For example, the product obtained from the reaction can be extracted with dichloromethane multiple times, such as three times, the organic phase can be washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel chromatography (eluent is ethyl acetate / petroleum ether, the volume ratio of ethyl acetate and petroleum ether is 10:90) to obtain compound III.

[0202] When compound III is prepared using the method provided in aspect nine of this application, the overall yield of compound III can reach approximately 82%.

[0203] The tenth aspect of this application provides a method for preparing compound III, comprising the following steps:

[0204]

[0205] Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl.

[0206] In step A'), the diol and tert-butyldiphenylchlorosilane react in the presence of a second basic substance to give compound Ib.

[0207] In some embodiments of this application, in step A'), the molar ratio of the diol, the second basic substance, and tert-butyldiphenylchlorosilane is (1-2):(1-2):1.

[0208] In some embodiments of this application, in step A'), the second alkaline substance is selected from at least one of N,N-diisopropylethylamine and triethylamine.

[0209] In some embodiments of this application, in step A'), the reaction solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, and toluene.

[0210] This application does not impose any particular restrictions on the amount of reaction solvent used in step A'), as long as the purpose of this application can be achieved. For example, in step A'), the molar volume ratio of 1,4-butanediol to reaction solvent is (2-3) mol: 1 L.

[0211] In some embodiments of this application, the reaction temperature of step A') is 10-30°C, and the reaction time of step A') is 14-18 hours.

[0212] In some embodiments of this application, the specific operation method of step A') includes: dissolving 1,4-butanediol in a reaction solvent, adding a second basic substance and tert-butyldiphenylchlorosilane at 10-30°C, and stirring for 14-18 hours; then separating the product to obtain compound Ib.

[0213] This application does not impose any particular limitation on the method for separating the product obtained in step A'), as long as it can achieve the purpose of this application. For example, the product obtained from the reaction can be purified by column chromatography (the eluent is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 100:1-10:1) to obtain compound Ib.

[0214] In step B'), compound Ib undergoes an oxidation reaction with Jones reagent to give compound II-b.

[0215] In some embodiments of this application, in step B'), the molar volume ratio of compound Ib to Jones reagent is (1-2) mol: 1 L. The preparation method of Jones reagent described in this application is as follows: dissolve 53.44 g of chromium trioxide in 100 mL of water, then slowly add 46 mL of concentrated sulfuric acid, and then dilute with water to 200 mL.

[0216] In some embodiments of this application, in step B'), the solvent for the oxidation reaction is selected from acetone.

[0217] This application does not impose any particular limitation on the amount of solvent used in the oxidation reaction of step B'), as long as the purpose of this application can be achieved. For example, in step B'), the molar volume ratio of compound Ib to the solvent of the oxidation reaction is (0.3-1) mol: 4 L.

[0218] In some embodiments of this application, the oxidation reaction temperature of step B') is 10-30°C, and the oxidation reaction time of step B') is 0.5-2 hours.

[0219] In some embodiments of this application, the specific operation method of step B') includes: dissolving compound Ib in a reaction solvent, adding Jones reagent at 10-30°C, and stirring for 0.5-2 hours; then separating the product to obtain compound II-b.

[0220] This application does not impose any particular limitation on the method for separating the product obtained in step B'), as long as it can achieve the purpose of this application. For example, the product obtained from the reaction can be concentrated, ethyl acetate can be added, and the product can be washed with water multiple times, such as twice. The organic phase can be dried with anhydrous sodium sulfate, filtered, and concentrated to obtain compound II-b.

[0221] In step C'), compound II-b is activated with a condensing agent and then reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of a third basic substance to give compound III.

[0222] In some embodiments of this application, in step C'), the molar ratio of compound II-b, N,O-dimethylhydroxylamine hydrochloride, condensing agent and third basic substance is 1:(1-1.5):(1.2-2):(2-3).

[0223] In some embodiments of this application, in step C'), the condensing agent is selected from at least one of HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate), HOBT (1-hydroxybenzotriazole) / EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride), CDI (N,N′-carbonyldiimidazole), DCC (N,N′-dicyclohexylcarbodiimide), and Carter condensing agent.

[0224] In some embodiments of this application, HOBT and EDCI are used together in step C'). This application does not impose any particular restrictions on the molar ratio of HOBT and EDCI, as long as the purpose of this application can be achieved.

[0225] In some embodiments of this application, in step C'), the third alkaline substance is selected from at least one of N,N-diisopropylethylamine and triethylamine.

[0226] In some embodiments of this application, the reaction solvent in step C') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, toluene, and DMF (N,N-dimethylformamide).

[0227] This application does not impose any particular restrictions on the amount of reaction solvent used in step C'), as long as the purpose of this application can be achieved. For example, in step C'), the molar volume ratio of compound II-b to reaction solvent is (0.2-1) mol: 1 L.

[0228] In some embodiments of this application, the reaction temperature of step C') is 10-30°C, and the reaction time of step C') is 1-3 hours.

[0229] In some embodiments of this application, the specific operation method of step C') includes: dissolving intermediate II-b, N,O-dimethylhydroxylamine hydrochloride, condensing agent and third basic substance in a reaction solvent, stirring at 10-30°C for 1-3 hours; then separating the product to obtain compound III.

[0230] This application does not impose any particular limitation on the method for separating the product obtained in step C'), as long as it can achieve the purpose of this application. For example, the solvent of the product obtained from the reaction can be dried by rotary evaporation, the residue can be dissolved in ethyl acetate, and purified by column chromatography (the eluent is ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:5) to obtain compound III.

[0231] Compound III can be prepared using the method provided in aspect 10 of this application, and the overall yield of compound III can reach about 76%.

[0232] Compound III is prepared using the preparation method provided in the ninth aspect of this application. Then, compound III is sequentially prepared using the method provided in the first aspect of this application to prepare compound V, the method provided in the third aspect to prepare compound VI, the method provided in the fifth aspect to prepare compound VII, and the method provided in the seventh aspect to prepare the oxaspirocyclic compound shown in formula VIII. The total yield of the oxaspirocyclic compound shown in formula VIII can reach about 55%.

[0233] Compound III is prepared using the preparation method provided in the tenth aspect of this application. Then, compound III is sequentially prepared into compound V using the method provided in the first aspect of this application, compound VI using the method provided in the third aspect, compound VII using the method provided in the fifth aspect, and oxaspirocyclic compound VIII using the method provided in the seventh aspect. The total yield of oxaspirocyclic compound VIII can reach about 52%, which is much higher than the yield of the prior art.

[0234] Example

[0235] The embodiments and comparative examples provided below illustrate the implementation of this application in more detail. Various tests and evaluations were performed according to the methods described below. Unless otherwise specified, "parts" and "%" refer to mass. All raw materials and reagents used in this application are commercially available AR or CP grade.

[0236] In the following examples, overnight means 12 hours and room temperature means 25°C.

[0237] The structure of this application was confirmed by nuclear magnetic resonance spectroscopy (NMR). Solution: CDCl3; internal standard: TMS (tetramethylsilane).

[0238] Yield calculation: Yield = (actual mass of synthesized product / theoretical mass of synthesized product) × 100%.

[0239] Example 1

[0240] Synthesis of compound II-a

[0241]

[0242] Under nitrogen protection, 97.03 g of N,O-dimethylhydroxylamine hydrochloride (1.578 mol) was dissolved in dichloromethane. Diisobutylaluminum hydride (250 mL, 1.389 mol) was slowly added dropwise to the reaction solution over 1 hour at -78 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 4 hours. The solution was then cooled to 5 °C, and 54.3 g of compound Ia (0.631 mol) was added. The mixture was stirred for another 1.5 hours. The solution was carefully quenched at 0 °C with a solution of potassium sodium tartrate tetrahydrate and stirred overnight. The resulting precipitate was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The mixture was separated, and the aqueous phase was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 83.34 g of compound II-a, with a yield of 93%.

[0243] Example 2

[0244] Except for replacing diisobutylaluminum hydride with trimethylaluminum, the process was identical to that in Example 1. The yield of compound II-a was 90%.

[0245] Example 3

[0246] Synthesis of Compound III

[0247]

[0248] 83.34 g of compound II-a (0.567 mol) was dissolved in dichloromethane at 0 °C, followed by the sequential addition of 102 g of tert-butyldimethylchlorosilane (0.680 mol) and 77.2 g of imidazole (1.334 mol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was poured into water, separated, and the aqueous phase was extracted three times (3 × 100 mL) with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. Gradient elution using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio 10:90) yielded 130.2 g of compound III, with a yield of 88%. The 1H NMR spectrum of the obtained compound III is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 3.69 (s, 3H), 3.66 (d, J = 6.1Hz, 2H), 3.18 (s, 3H), 2.52 (t, J = 7.5Hz, 2H), 1.90–1.78 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H), its ¹H NMR spectrum is as follows: Figure 1 As shown.

[0249] Examples 4-8

[0250] Apart from adjusting the relevant parameters as shown in Table 1, the rest is the same as in Example 3.

[0251] The relevant parameters and yield of compound III in Examples 3-8 above are shown in Table 1 below.

[0252] Table 1. Relevant parameters and product yields for Examples 3-8

[0253] Example 3 tert-butyldimethylchlorosilane imidazole 88％ Example 4 tert-butyldiphenylchlorosilane Triethylamine 50％ Example 5 tert-butyldiphenylchlorosilane N,N-Diisopropylethylamine 52％ Example 6 tert-butyl dimethicone methanesulfonate 2,6-Dimethylpyridine 73％ Example 7 tert-butyldimethylchlorosilane Triethylamine 56％ Example 8 tert-butyldimethylchlorosilane N,N-Diisopropylethylamine 56％

[0254] Example 9

[0255] Synthesis of compound Ib

[0256]

[0257] In a 3000 mL three-necked flask, 1,4-butanediol (196.73 g, 2.18 mol) was dissolved in 1000 mL of dichloromethane. N,N-diisopropylethylamine (423.22 g, 3.27 mol) and tert-butyldiphenylchlorosilane (500 g, 1.82 mol) were added at room temperature, and the mixture was stirred for 16 hours at room temperature. After the reaction was complete, the reaction mixture was poured into water, separated, and the aqueous phase was extracted three times (3 × 100 mL) with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. Gradient elution using a normal silica gel column chromatography column (eluting solvent: ethyl acetate / petroleum ether, volume ratio 10:1) yielded 642 g of compound Ib, with a yield of 90%.

[0258] Example 10

[0259] Synthesis of compound II-b

[0260]

[0261] Compound Ib (100 g, 304.38 mmol) was dissolved in 4000 mL of acetone in a 5000 mL three-necked flask. 200 mL of Jones' reagent (Jones' reagent: 53.44 g of chromium trioxide dissolved in 100 mL of water, then slowly added dropwise with 46 mL of concentrated sulfuric acid, and then diluted with water to 200 mL) was added at room temperature, and the mixture was stirred for 1 hour. Thin-layer chromatography (TLC) was used to detect the completion of the reaction. The reaction solution was concentrated, and 1000 mL of ethyl acetate was added to the crude product. The mixture was washed with water (500 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and 100 g of compound II-b was obtained, with a yield of 95%.

[0262] Example 11

[0263] Synthesis of Compound III

[0264]

[0265] Compound II-b (100 g, 291.96 mmol), N,O-dimethylhydroxylamine hydrochloride (34.17 g, 350.35 mmol), HATU (166.52 g, 437.94 mmol), and N,N-diisopropylethylamine (94.34 g, 729.9 mmol) were dissolved in 1000 mL of dichloromethane in a 2000 mL single-necked flask and stirred at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated to dryness, and the residue was dissolved in ethyl acetate. Gradient elution was performed using a normal silica gel column chromatography column (eluting solvent: ethyl acetate / petroleum ether, volume ratio 1:5) to give 100.3 g of compound III, in 89% yield. The 1H NMR spectrum of the obtained compound III is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.70 (dd, J = 7.9, 1.7Hz, 4H), 7.54–7.35 (m, 6H), 3.76 (t, J = 6.1Hz, 2H), 3.69 (s, 3H), 3.20 (s, 3H), 2.59 (t, J = 7.6Hz, 2H), 2.01–1.83 (m, 2H), 1.09 (s, 9H), its ¹H NMR spectrum is shown below. Figure 2 As shown.

[0266] Example 12

[0267] Except for replacing HATU with Carter's condensing agent, the process was identical to Example 11. The yield of compound III was 82%.

[0268] Example 13

[0269] Synthesis of Compound IV

[0270]

[0271] 130.2 g of compound III (0.499 mol) was dissolved in tetrahydrofuran, and 600 mL of 1 mol / L 3-butenyl magnesium bromide (0.598 mol) was slowly added at 0 °C, with stirring for 5 hours. The reaction was detected by thin-layer chromatography (TLC) and quenched with 200 mL of saturated zinc chloride solution. Extraction was performed with dichloromethane (3 × 500 mL), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Gradient elution was performed using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) to give 121.3 g of compound IV, with a yield of 95%.

[0272] Example 14

[0273] Except for adjusting the amount of 3-butenyl magnesium bromide added to 0.998 mol, the rest was the same as in Example 13. The yield of compound IV was 87%.

[0274] Example 15

[0275] Except for adjusting the amount of 3-butenyl magnesium bromide added to 0.748 mol, the rest was the same as in Example 13. The yield of compound IV was 90%.

[0276] Example 16

[0277] Synthesis of compound V

[0278]

[0279] 121.3 g of compound IV (0.473 mol) was dissolved in tetrahydrofuran, and 570 mL of 1 mol / L allyl magnesium bromide was slowly added at 0 °C, with stirring for 2 hours. The reaction was detected by thin-layer chromatography (TLC) and quenched with 200 mL of saturated zinc chloride solution. Extraction was performed with dichloromethane (3 × 500 mL), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Gradient elution was performed using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) to give 135.56 g of compound V, yield 96%. The 1H NMR spectrum of the obtained compound V is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 7.69 (d, J = 4.6Hz, 4H), 7.40 (m, 6H), 5.98–5.78 (m, 2H), 5.33–4.87 (m, 4H), 3.70 (t, J = 5.9Hz, 2H), 2.26 (d, J = 7.5Hz, 2H), 2.13 (m, 2H), 1.62–1.54 (m, 6H), 1.08 (s, 9H), its ¹H NMR spectrum is as follows: Figure 3 As shown.

[0280] Example 17

[0281] Synthesis of Compound VI

[0282]

[0283] 135.56 g of compound V (0.455 mol) was dissolved in tetrahydrofuran, and 300 mL of 2 mol / L dilute hydrochloric acid was slowly added while stirring for 3 hours. The reaction was detected by thin-layer chromatography (TLC) and quenched with 200 mL of saturated sodium bicarbonate solution. Extraction was performed with dichloromethane (3 × 500 mL), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Gradient elution was performed using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) to give 69.6 g of compound VI, in 90% yield. The 1H NMR spectrum of compound VI is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 6.00–5.70 (m, 2H), 5.37–4.81 (m, 4H), 3.64 (t, J = 6.16 Hz, 2H), 2.59 (s, 2H), 2.28 (d, J = 7.44 Hz, 2H), 2.13 (q, J = 7.96 Hz, 2H), 1.65 (m, 6H). Its ¹H NMR spectrum is shown below. Figure 4 As shown.

[0284] Example 18

[0285] Except for replacing 2 mol / L dilute hydrochloric acid with tetrabutylammonium fluoride, it is the same as in Example 17. The yield of compound VI is 90%.

[0286] Example 19

[0287] Synthesis of Compound VII

[0288]

[0289] 69.6 g of compound VI (0.409 mol) was dissolved in dichloromethane. At 0 °C, 117.0 g of p-toluenesulfonyl chloride (0.614 mol), 342 mL of triethylamine (2.45 mol), and 7.5 g of 4-dimethylaminopyridine (0.061 mol) were slowly added, respectively. The mixture was stirred overnight. Thin-layer chromatography (TLC) was used to detect the complete reaction. The reaction mixture was poured into water, and the layers were separated. The aqueous phase was extracted three times with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. Gradient elution using a normal silica gel column (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) yielded 62.5 g of compound VII, with a yield of 92%. The 1H NMR spectrum of compound VII is as follows: 1¹H NMR (400MHz, CDCl₃) δ 5.84 (m, 2H), 5.12 (m, 4H), 3.88 (t, J = 6.6 Hz, 2H), 2.34 (m, 2H), 2.13 (m, 2H), 1.96 (m, 2H), 1.73 (m, J = 53.7 Hz, 2H), 1.61 (m, 2H). Its ¹H NMR spectrum is shown below. Figure 5 As shown.

[0290] Example 20

[0291] Synthesis of Compound VIII

[0292]

[0293] 62.5 g of compound VII (0.376 mol) and 15 g of Grubbs' first-generation catalyst (0.019 mol) were dissolved in dichloromethane and refluxed overnight at 60 °C under nitrogen protection. The reaction was detected by thin-layer chromatography (TLC) after completion. The catalyst was filtered off with diatomaceous earth. The reaction mixture was poured into water, and the mixture was separated. The aqueous phase was extracted three times (3 × 100 mL) with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. Gradient elution using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) yielded 46.8 g of compound VIII, with a yield of 90%.

[0294] The 1H NMR spectrum of compound VIII prepared in Example 20 of this application is as follows: 1 1H NMR (400MHz, CDCl3) δ 5.82–5.45 (m, 2H), 4.05–3.72 (m, 2H), 2.36–1.50 (m, 10H); 1H NMR spectrum as shown Figure 6 As shown; Carbon NMR spectroscopy data: 13 C10 NMR (400MHz, CDCl3) δ 126.68, 125.22, 80.63, 66.91, 37.39, 36.07, 32.82, 25.63, 24.17, [The following appears to be a separate, unrelated section:] The carbon NMR spectrum is shown below. Figure 7 As shown. The compound of formula VIII was identified as 1-oxaspiro[4,5]dec-7-ene by the proton NMR spectrum and carbon NMR spectrum.

[0295] Example 21

[0296] Synthesis of compound II'-a

[0297]

[0298] Under nitrogen protection, 9.31 g of N,O-dimethylhydroxylamine hydrochloride (96 mmol) was dissolved in dichloromethane. 1 mol / L diisobutylaluminum hydride (95 mL, 92 mmol) was slowly added dropwise to the reaction solution over 1 hour at -30 °C. After the addition was complete, the mixture was heated to room temperature and stirred for 4 hours. The solution was then cooled to 5 °C, and 4 g of delta-valerol (I'-a, 40 mmol) was added. The mixture was stirred for another 1.5 hours. The solution was carefully quenched at 0 °C with a solution of potassium sodium tartrate tetrahydrate and stirred overnight. The resulting precipitate was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The mixture was separated, and the aqueous phase was extracted with dichloromethane (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give 5.9 g of compound II'-a, in 92% yield. The 1H NMR spectrum of compound II'-a is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 3.69 (s, 3H), 3.63 (t, J = 6.2Hz, 2H), 3.18 (s, 3H), 2.47 (t, J = 7.2Hz, 2H), 1.79–1.55 (m, 4H), its ¹H NMR spectrum is shown below. Figure 8 As shown.

[0299] Example 22

[0300] Synthesis of Compound III'

[0301]

[0302] 5.9 g of compound II'-a (36.6 mmol) was dissolved in dichloromethane at 0 °C, followed by the addition of 6.62 g of tert-butyldimethylchlorosilane (43.9 mmol) and 5.5 g of imidazole (80.8 mmol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was poured into water, separated, and the aqueous phase was extracted three times (3 × 50 mL) with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. Gradient elution using a normal silica gel column (eluting solvent: ethyl acetate / petroleum ether, volume ratio 10:90) yielded 9.1 g of compound III', with a yield of 90%. The 1H NMR spectrum of the obtained compound III' is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 3.69 (s, 3H), 3.65 (t, J = 6.4Hz, 2H), 3.19 (s, 3H), 2.46 (t, J = 7.5Hz, 2H), 1.72–1.51 (m, 4H), 0.91 (s, 9H), 0.06 (s, 6H), its ¹H NMR spectrum is shown below. Figure 9 As shown.

[0303] Example 23

[0304] Synthesis of compound IV'

[0305]

[0306] 9.1 g of compound III' (33.1 mmol) was dissolved in tetrahydrofuran, and 40 mL of 1 mol / L 3-butenylmagnesium bromide (39.7 mmol) was slowly added at 0 °C. The mixture was stirred for 5 hours, and the reaction was detected by thin-layer chromatography (TLC) after completion. The solution was quenched with 30 mL of saturated zinc chloride solution. The mixture was extracted with dichloromethane (3 × 50 mL), and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Gradient elution was performed using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio: 2:8) to give 8.22 g of compound IV', in 92% yield.

[0307] Example 24

[0308] Synthesis of compound V'

[0309]

[0310] 8.22 g of compound IV' (30.4 mmol) was dissolved in tetrahydrofuran, and 31 mL of 1 mol / L allyl magnesium bromide was slowly added at 0 °C, with stirring for 2 hours. The reaction was detected by thin-layer chromatography (TLC) and quenched with 30 mL of saturated zinc chloride solution. Extraction was performed with dichloromethane (3 × 50 mL), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Gradient elution was performed using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) to give 8.61 g of compound V', in 91% yield. The 1H NMR spectrum of the obtained compound V' is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 5.82 (m, 2H), 5.30–4.79 (m, 4H), 3.64 (t, J = 6.4 Hz, 2H), 2.25 (d, J = 7.3 Hz, 2H), 2.13 (m, J = 14.9 Hz, 2H), 1.65–1.25 (m, 11H), 0.91 (s, 9H), 0.07 (s, 6H), its ¹H NMR spectrum is as follows: Figure 10 As shown.

[0311] Example 25

[0312] Synthesis of compound VI'

[0313]

[0314] 3 g of compound V' (10.1 mmol) was dissolved in tetrahydrofuran, and 5 mL of 6 mol / L dilute hydrochloric acid was slowly added while stirring for 3 hours. The reaction was detected by thin-layer chromatography (TLC) and quenched with 50 mL of saturated sodium bicarbonate solution. Extraction was performed with dichloromethane (3 × 50 mL), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. Gradient elution was performed using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) to give 1.82 g of compound VI', in 95% yield. The 1H NMR spectrum of the obtained compound VI' is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 5.99–5.71 (m, 2H), 5.37–4.74 (m, 4H), 3.64 (t, J = 6.4 Hz, 2H), 2.23 (d, J = 7.5 Hz, 4H), 2.18–2.01 (m, 2H), 1.64–1.34 (m, 8H). Its ¹H NMR spectrum is shown below. Figure 11 As shown.

[0315] Example 26

[0316] Synthesis of compound VII'

[0317]

[0318] 1.82 g of compound VI' (9.2 mmol) was dissolved in dichloromethane. 2.63 g of p-toluenesulfonyl chloride (13.8 mmol), 8 mL of triethylamine (55.1 mmol), and 0.17 g of 4-dimethylaminopyridine (1.4 mmol) were slowly added at 0 °C, and the mixture was stirred overnight. After the reaction was complete, the reaction mixture was poured into water, separated, and the aqueous phase was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. Gradient elution using a normal silica gel column (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) yielded 1.21 g of compound VII', in 73% yield. The 1H NMR spectrum of the obtained compound VII' is as follows: 1 ¹H NMR (400MHz, CDCl₃) δ 5.73–5.89 (m, 2H), 5.23–4.84 (m, 4H), 3.36 (t, J = 6.5 Hz, 2H), 2.21 (d, J = 9.9 Hz, 2H), 2.03–2.14 (m, 2H), 1.60–1.35 (m, 8H). Its ¹H NMR spectrum is shown below. Figure 12 As shown.

[0319] Example 27

[0320] Synthesis of compound VIII'

[0321]

[0322] 1.0 g of compound VII' (5.6 mmol) and 0.35 g of Grubbs' first-generation catalyst (0.28 mmol) were dissolved in dichloromethane and refluxed overnight at 60 °C under nitrogen protection. The reaction was detected by thin-layer chromatography (TLC) after completion. The catalyst was filtered off with diatomaceous earth. The reaction mixture was poured into water, and the mixture was separated. The aqueous phase was extracted three times (3 × 50 mL) with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. Gradient elution using normal silica gel column chromatography (eluting solvent: ethyl acetate / petroleum ether, volume ratio 2:8) yielded 0.77 g of compound VIII', 91% yield.

[0323] Nuclear magnetic resonance hydrogen spectrum data of compound VIII' prepared in Example 27 of this application: 1 ¹H NMR (400MHz, CDCl₃) δ 5.53–5.76 (m, 2H), 3.40 (t, J = 6.4 Hz, 2H), 2.34–1.94 (m, 4H), 1.72–1.45 (m, 8H). ; ¹H NMR spectrum as shown. Figure 13 As shown; Carbon NMR spectroscopy data: 13 C NMR (101MHz, CDCl3) δ 126.61, 124.49, 72.80, 58.54, 41.11, 37.91, 33.04, 30.14, 22.68, 19.72. (The C NMR spectrum is shown below.) Figure 14 As shown. Ozespirocyclic compounds are important synthetic intermediates in the pharmaceutical field. However, existing preparation methods suffer from poor reproducibility, low yield, and operational hazards, which directly affect their yield, cost, and safety. Therefore, this application provides a new method for preparing oxespirocyclic compounds. This method is green, environmentally friendly, inexpensive, and efficient, overcoming the aforementioned defects and facilitating large-scale industrial production.

[0324] The above description is only a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of protection of this application.

Claims

1. A method for preparing an oxaspirocyclic compound, comprising the following steps: Compound VI reacts with a condensing agent to give compound VII; ； in, n is selected from 1, 2, 3, or 4; Compound VII undergoes an olefin metathesis reaction in the presence of a catalyst to give the oxaspirocyclic compound shown in Formula VIII; ； Where n is selected from 1, 2, 3 or 4; The catalyst is selected from first-generation Grubb catalysts.

2. The preparation method according to claim 1, wherein, The molar ratio of compound VII to the catalyst is 1:(0.01-0.1).

3. The preparation method according to claim 1, wherein, In the olefin metathesis reaction of compound VII, the reaction solvent is selected from at least one of dichloromethane, chloroform, dichloroethane, and toluene.

4. The preparation method according to claim 1, wherein, In the olefin metathesis reaction of compound VII, the reaction temperature is 40-60℃ and the reaction time is 10-30 hours.

5. The preparation method according to claim 1, wherein, The condensing agent is Y-SO2Cl, wherein Y is selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C6 cycloalkyl, and C6-C6 cycloalkyl groups. 18 Aryl or C3-C 18 Heteroaryl; the C3-C 18 The heteroatom in the heteroaryl group is selected from N, O, or S; the C6-C 18 When the aryl group is selected from phenyl, the hydrogen atoms on the phenyl group can be independently replaced by halogen, nitro, cyano, hydroxyl or C1-C3 alkyl, wherein the halogen is selected from F, Cl, Br or I.

6. The preparation method according to claim 5, wherein, The condensing agent is selected from p-toluenesulfonyl chloride.

7. The preparation method according to claim 5, wherein, The reaction of compound VI and the condensing agent is carried out under the co-catalysis of triethylamine and 4-dimethylaminopyridine, and the molar ratio of compound VI, the condensing agent, the triethylamine and the 4-dimethylaminopyridine is 1:(1-2):(5-10):(0.1-0.2).

8. The preparation method according to claim 5, wherein, In the reaction of compound VI and the condensing agent, the reaction solvent is selected from at least one of 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, and toluene.

9. The preparation method according to claim 5, wherein, In the reaction of compound VI and the condensing agent, the reaction temperature is -10 to 10°C and the reaction time is 10 to 30 hours.

10. The preparation method according to claim 1, wherein, The compound VI was prepared by the following method: Compound V reacts with a deprotecting agent to give compound VI; ； Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

11. The preparation method according to claim 10, wherein, The molar ratio of compound V to the deprotecting reagent is 1:(1-10).

12. The preparation method according to claim 11, wherein, The deprotecting agent is selected from tetrabutylammonium fluoride or hydrochloric acid.

13. The preparation method according to claim 11, wherein, In the reaction of compound V with the deprotecting reagent, the reaction solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, dioxane, chloroform, and toluene.

14. The preparation method according to claim 11, wherein, In the reaction of compound V and the deprotecting reagent, the reaction temperature is 15-30℃ and the reaction time is 2-4 hours.

15. The preparation method according to claim 10, wherein, The compound V was prepared by the following method: (1) Compound III undergoes an addition reaction with the first organometallic reagent to give compound IV; ； Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl; The first organometallic reagent is selected from CH2CHCH2CH2MgX 1 Or CH2CHCH2CH2Li, wherein X 1 Selected from Cl, Br, or I; (2) Compound IV undergoes an addition reaction with the second organometallic reagent to give compound V; ； The second organometallic reagent is selected from CH2CHCH2MgX. 2 Or CH2CHCH2CH2Li, wherein X 2 Selected from Cl, Br, or I.

16. The preparation method according to claim 15, wherein, The first organometallic reagent is selected from 3-butenyl magnesium bromide.

17. The preparation method according to claim 15, wherein, The second organometallic reagent is selected from allyl magnesium bromide.

18. The preparation method according to claim 15, wherein, In step (1), the molar ratio of compound III to the first organometallic reagent is 1:(1.2-2.0).

19. The preparation method according to claim 15, wherein, The reaction solvent in step (1) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, diethyl ether, and dipropyl ether.

20. The preparation method according to claim 15, wherein, The reaction temperature in step (1) is -10 to 10℃, and the reaction time in step (1) is 1 to 6 hours.

21. The preparation method according to claim 15, wherein, In step (2), the molar ratio of compound IV and the second organometallic reagent is 1:(1-1.5).

22. The preparation method according to claim 15, wherein, The reaction solvent in step (2) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, diethyl ether, and dipropyl ether.

23. The preparation method according to claim 15, wherein, The reaction temperature in step (2) is -10 to 10℃, and the reaction time in step (2) is 1 to 6 hours.

24. The preparation method according to claim 15, wherein, Compound III was prepared by the following method: A) N,O-dimethylhydroxylamine hydrochloride was mixed with an organic solvent, and then aluminum reagent was added at -78 to 0°C. The temperature was raised to 20 to 30°C to carry out the first reaction. After the reaction was completed, the temperature was cooled to 0 to 10°C, and compound Ia was added to carry out the second reaction to obtain compound II-a. ； Where n is selected from 1, 2, 3 or 4; B) Compound II-a and the hydroxyl protecting agent react in the presence of the first basic substance to give compound III; ； R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

25. The preparation method according to claim 24, wherein, In step A), the molar volume ratio of the N,O-dimethylhydroxylamine hydrochloride to the organic solvent is (1-2) mol: 0.5 L.

26. The preparation method according to claim 24, wherein, In step A), the organic solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, and toluene.

27. The preparation method according to claim 24, wherein, In step A), the molar ratio of the aluminum reagent and the N,O-dimethylhydroxylamine hydrochloride is (0.5-1.5):

1.

28. The preparation method according to claim 24, wherein, In step A), the aluminum reagent is selected from at least one of trimethylaluminum and diisobutylaluminum hydride.

29. The preparation method according to claim 24, wherein, In step A), the molar ratio of compound Ia to N,O-dimethylhydroxylamine hydrochloride is (0.2-0.5):

1.

30. The preparation method according to claim 24, wherein, In step A), the reaction time of the first reaction is 3-5 hours; the reaction time of the second reaction is 1-2 hours.

31. The preparation method according to claim 24, wherein, In step A), the aluminum reagent is added by dripping, and the dripping time is 0.5-1.5 hours.

32. The preparation method according to claim 24, wherein, In step B), the molar ratio of compound II-a, the hydroxyl protectant, and the first basic substance is 1:(1-1.5):(1.5-2.5).

33. The preparation method according to claim 32, wherein, In step B), the molar ratio of compound II-a, the hydroxyl protectant, and the first basic substance is 1:(1-1.1):(1.5-2.5).

34. The preparation method according to claim 24, wherein, In step B), the hydroxyl protecting agent is selected from at least one of tert-butyldiphenylchlorosilane, tert-butyldimethylsilylmethanesulfonate, tert-butyldimethylchlorosilane, 3,4-dihydro-2H-pyran, chloromethyl methyl ether, 1-(chloromethoxy)-2-methoxyethane, triphenylchloromethane, trimethylchlorosilane, and triisopropylchlorosilane.

35. The preparation method according to claim 24, wherein, In step B), the first alkaline substance is selected from at least one of triethylamine, N,N-diisopropylethylamine, 2,6-dimethylpyridine, and imidazole.

36. The preparation method according to claim 24, wherein, The reaction temperature in step B) is 15-30℃, and the reaction time in step B) is 2-4 hours.

37. The preparation method according to claim 15, wherein, Compound III was prepared by the following method: A') The diol and tert-butyldiphenylchlorosilane react in the presence of a second basic substance to give compound Ib; ； Wherein, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl; B') Compound Ib was oxidized using Jones' reagent to give compound II-b; ； C') The compound II-b was activated with a condensing agent, and then reacted with N,O-dimethylhydroxylamine hydrochloride in the presence of a third basic substance to give compound III; 。 38. The preparation method according to claim 37, wherein, In step A'), the molar ratio of the diol, the second alkaline substance, and the tert-butyldiphenylchlorosilane is (1-2):(1-2):

1.

39. The preparation method according to claim 37, wherein, In step A'), the second alkaline substance is selected from at least one of N,N-diisopropylethylamine and triethylamine.

40. The preparation method according to claim 37, wherein, The reaction solvent in step A') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, and toluene.

41. The preparation method according to claim 37, wherein, The reaction temperature for step A') is 10-30℃, and the reaction time for step A') is 14-18 hours.

42. The preparation method according to claim 37, wherein, In step B'), the molar volume ratio of compound Ib to Jones reagent is (1-2) mol: 1 L.

43. The preparation method according to claim 37, wherein, The solvent for the oxidation reaction in step B') is selected from acetone.

44. The preparation method according to claim 37, wherein, The oxidation reaction temperature in step B') is 10-30℃, and the oxidation reaction time in step B') is 0.5-2 hours.

45. The preparation method according to claim 37, wherein, In step C'), the molar ratio of compound II-b, N,O-dimethylhydroxylamine hydrochloride, the condensing agent and the third basic substance is 1:(1-1.5):(1.2-2):(2-3).

46. ​​The preparation method according to claim 37, wherein, In step C'), the condensing agent is selected from at least one of HATU, HOBT / EDCI, CDI, DCC, and Caterpillar condensing agents.

47. The preparation method according to claim 37, wherein, In step C'), the third alkaline substance is selected from at least one of N,N-diisopropylethylamine and triethylamine.

48. The preparation method according to claim 37, wherein, The reaction solvent in step C') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, toluene, and DMF.

49. The preparation method according to claim 37, wherein, The reaction temperature for step C') is 10-30℃, and the reaction time for step C') is 1-3 hours.

50. A compound as shown in Formula VII: ； in, n is selected from 1, 2, 3 or 4.

51. A compound as shown in Formula VI: ； in, n is selected from 1, 2, 3 or 4.

52. A compound as shown in formula V: ； in, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, triphenylmethyl, trimethylsilyl or triisopropylsilyl.

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