Oxaspiro compound, intermediate and preparation method thereof

Abstract

The invention relates to the technical field of chemical synthesis, and provides an oxa-spiro compound, an intermediate and a preparation method of the oxa-spiro compound and the intermediate. The preparation method of the oxa-spiro compound comprises the step that a compound VII is subjected to an olefin metathesis reaction in the presence of a catalyst, and the oxa-spiro compound shown in the formula VIII is obtained. The preparation method is simple to operate, free of dangerous reagents, safe and controllable in reaction process and high in yield. # imgabs0 #

Description

Technical Field

[0001] The present application relates to the technical field of synthetic chemistry, and in particular to an oxaspiro compound and an intermediate and a preparation method thereof. Background Art

[0002] Spirocyclic compounds are widely present in nature, and a large number of natural products with spirocyclic structures have been found in animals, plants and microorganisms. Since the spirocyclic ring is a stable rigid structure, introducing it into the drug molecule can not only make the compound structure more novel, but also improve the activity of the compound as well as the solubility and lipid solubility of the compound. Therefore, the use of spirocyclic structure is a very common strategy in drug molecule design. Many current pesticides and clinically used drugs contain spirocyclic structures. As a large category of spirocyclic compounds, oxaspirocyclic compounds have aroused great interest among scientists in the past three decades and have been widely used in the research and development and production of pesticides and medicines, such as Eribulin, Ivermeclin, Cevimeline, Troleandomycin, spirodiclofen and Sibopadol; antidepressant drugs 2'-substituted-spiro[3H-benzofuran-2,1'-cyclohexane]; IRAK4 kinase inhibitors all contain spirocyclic structures. Studies have shown that inserting oxaspirocyclic rings into the drug structure can significantly improve its pharmacological activity, enhance therapeutic effects and reduce toxic side effects.

[0003]

[0004] Cycloolefins are important intermediates for synthesizing vicinal diols, vicinal diamines, oxadiazoles and aziridines. Many of these cycloolefin derivatives have good pharmacological activities, such as Deserpidine, Reserpine, Tacrolimus (prograf), Budesonide, Natamycin, Picrotoxin, Scopolamine, etc. Among them, oxygen-containing spirocyclic olefin derivatives such as U69593, Spiradoline, Enadoline, U50488, PD11703, etc. show high selectivity and affinity for kappa opioid receptors, and are highly selective kappa opioid receptor agonists, which are of great value in the research and development of analgesics. Therefore, the present application invents a series of new oxadiazole spirocyclic olefins and their synthesis methods, which can provide more molecular skeleton structures for the research and development of kappa opioid receptor agonists.

[0005]

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

[0007]

[0008] The synthetic route is as long as 111 steps, and the total yield is only about 3%. In addition, ether is used as a reaction solvent or post-treatment solvent in many steps of the preparation process. However, ether has a low flash point, is volatile, flammable and explosive, and has high safety risks. The synthetic method has poor reproducibility.

[0009] In the synthesis method of 1-oxaspiro[4,5]dec-7-ene disclosed in "Journal of Organic Chemistry 1991,56(19),5567-72.", the starting materials used are protoanemonin and butadiene. Protoanemonin is expensive (1g of protoanemonin costs about RMB 7,000), which is too costly. In addition, butadiene is a gas, and the reaction requires high temperature and pressure. A reactor is required for scale-up, which places high demands on equipment. In addition, the method uses lithium borohydride, which is flammable and a hazardous chemical reagent, and the operation is relatively dangerous.

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

[0011] The patent "WO2023277116A1" discloses a method for synthesizing 1-oxaspiro[4,5]dec-7-ene by dearomatization of a phenylpropanol compound under the action of a metallic lithium reagent and in liquid ammonia at -78°C through Birch reduction. However, metallic lithium is flammable, liquid ammonia is highly toxic and easy to leak, and has high safety risks, making it unsuitable for scale-up; and after the reaction, it must be handled carefully. It takes up to 12 hours to handle 1 liter of liquid ammonia, and 7.5 liters of liquid ammonia are often required for each mole of substrate. The long processing time makes it difficult to operate on an industrial scale.

[0012] Therefore, there is an urgent need for a new method for preparing an oxaspirocyclic compound to solve the problems of synthesis of an oxaspirocyclic compound and the economic and safety issues during its synthesis, 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 an oxaspirocyclic compound to achieve an economical and safe synthesis of the oxaspirocyclic compound. The specific technical scheme is as follows:

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

[0015] (5) Compound VII undergoes olefin metathesis reaction in the presence of a catalyst to obtain an oxaspirocyclic compound represented by formula VIII;

[0016]

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

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

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

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

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

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

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

[0024]

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

[0026] In some embodiments of the present application, in step (4), the condensing agent is Y-SO2Cl, and 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; 18 When the aryl group is selected from phenyl, the hydrogen atoms on the phenyl group can be independently substituted by halogen, nitro, cyano, hydroxyl or C1-C3 alkyl, and 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 the present application, in step (4), the reaction is carried out under the co-catalysis of triethylamine and 4-dimethylaminopyridine, and the molar ratio of the compound VI, the condensation agent, the triethylamine and the 4-dimethylaminopyridine is 1:(1-2):(5-10):(0.1-0.2).

[0028] In some embodiments of the present 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 the present application, in step (4), the reaction temperature is -10-10°C, and the reaction time is 10-30 hours.

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

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

[0032]

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

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

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

[0036] In some embodiments of the present 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 the present application, in step (3), the reaction temperature is 15-30° C., and the reaction time is 2-4 hours.

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

[0039] (1) Compound III undergoes an addition reaction with a first organometallic reagent to obtain 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, trityl, trimethylsilyl or triisopropylsilyl;

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

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

[0044]

[0045] Wherein, the second organometallic reagent is selected from CH2CHCH2MgX 2 or CH2CHCH2CH2Li, the X 2 is selected from Cl, Br or I; preferably, the second organometallic reagent is selected from allylmagnesium bromide.

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

[0047] In some embodiments of the present application, the reaction solvent of 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 the present application, the reaction temperature of step (1) is -10-10°C, and the reaction time of step (1) is 1-6 hours.

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

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

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

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

[0053] A) mixing N,O-dimethylhydroxylamine hydrochloride with an organic solvent, then adding a metal aluminum reagent at -78-0°C, heating to 20-30°C for a first reaction; after the reaction, cooling to 0-10°C, adding compound Ia for a second reaction, and obtaining compound II-a;

[0054]

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

[0056] B) reacting the compound II-a with a hydroxyl protecting agent in the presence of a first alkaline substance to obtain a compound III;

[0057]

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

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

[0060] In some embodiments of the present 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 the present application, in step A), the molar ratio of the metal aluminum reagent to the N,O-dimethylhydroxylamine hydrochloride is (0.5-1.5):1.

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

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

[0064] In some embodiments of the present 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 the present application, in step A), the metal aluminum reagent is added dropwise, and the time of the addition is 0.5-1.5 hours.

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

[0067] In some embodiments of the present application, in step B), the hydroxyl protecting agent is selected from at least one of tert-butyldiphenylsilyl chloride, tert-butyldimethylsilyl methanesulfonate, tert-butyldimethylsilyl chloride, 3,4-dihydro-2H-pyran, chloromethyl methyl ether, 1-(chloromethoxy)-2-methoxyethane, triphenylmethane, trimethylsilyl chloride, and triisopropylsilyl chloride.

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

[0069] In some embodiments of the present 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 the present application provides a method for preparing compound III, comprising the following steps:

[0071] A') reacting a diol with tert-butyldiphenylsilyl chloride in the presence of a second alkaline substance to obtain compound Ib;

[0072]

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

[0074] B') the compound Ib is subjected to oxidation reaction using Jones reagent to obtain compound II-b;

[0075]

[0076] C') activating the compound II-b with a condensing agent, and then reacting with N,O-dimethylhydroxylamine hydrochloride in the presence of a third alkaline substance to obtain compound III;

[0077]

[0078] In some embodiments of the present 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 the present 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 the present application, the reaction solvent of step A') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform and toluene.

[0081] In some embodiments of the present 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 the present application, in step B'), the molar volume ratio of the compound Ib and the Jones reagent is (1-2) mol:1L.

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

[0084] In some embodiments of the present 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 the present application, in step C'), the molar ratio of the compound II-b, the N,O-dimethylhydroxylamine hydrochloride, the condensing agent and the third alkaline substance is 1:(1-1.5):(1.2-2):(2-3).

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

[0087] In some embodiments of the present 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 the present application, the reaction solvent of step C') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, toluene and DMF.

[0089] In some embodiments of the present 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 the present application provides a compound as shown in formula VIII:

[0091]

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

[0093] The eighth aspect of the present application provides a compound as shown in formula VII:

[0094]

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

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

[0097]

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

[0099] The tenth aspect of the present application provides a compound as shown in formula V:

[0100]

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

[0102] Beneficial effects of this application:

[0103] The present application provides a method for preparing an oxaspirocyclic compound, which is simple to operate, highly safe, and can avoid the use of dangerous reagents. The present application can use cheap and readily available compounds as starting materials to prepare oxaspirocyclic compounds, and the total yield of the oxaspirocyclic compound can reach 50% or more, and 100-gram-level synthesis has been achieved.

[0104] Of course, implementing any product or method of the present application does not necessarily require achieving all of the advantages described above at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application, and for ordinary technicians in this field, other embodiments can also be obtained based on these drawings.

[0106] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the compound III prepared in Example 3 (when the hydroxyl protecting group (R) is tert-butyldimethylsilyl);

[0107] Figure 2is the hydrogen nuclear magnetic resonance spectrum of the compound III prepared in Example 11 (when the hydroxyl protecting group (R) is tert-butyldiphenylsilyl);

[0108] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of compound V prepared in Example 16;

[0109] Figure 4 is the hydrogen nuclear magnetic resonance spectrum of compound VI prepared in Example 17;

[0110] Figure 5 is the hydrogen nuclear magnetic resonance spectrum of compound VII prepared in Example 19;

[0111] Figure 6 is the hydrogen nuclear magnetic resonance spectrum of compound VIII prepared in Example 20;

[0112] Figure 7 is the carbon NMR spectrum of compound VIII prepared in Example 20;

[0113] Figure 8 is the hydrogen nuclear magnetic resonance spectrum of compound II'-a prepared in Example 21;

[0114] Fig. 9 is the hydrogen nuclear magnetic resonance spectrum of compound III' prepared in Example 22 (when the hydroxyl protecting group (R) is tert-butyldimethylsilyl);

[0115] Fig.10 is the hydrogen nuclear magnetic resonance spectrum of compound V' prepared in Example 24;

[0116] Fig.11 is the hydrogen nuclear magnetic resonance spectrum of compound VI' prepared in Example 25;

[0117] Fig.12 is the hydrogen nuclear magnetic resonance spectrum of compound VII' prepared in Example 26;

[0118] Fig.13 is the hydrogen nuclear magnetic resonance spectrum of compound VIII' prepared in Example 27;

[0119] Fig.14 This is the carbon NMR spectrum of compound VIII' prepared in Example 27. DETAILED DESCRIPTION

[0120] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by those skilled in the art based on the present application belong to the scope of protection of the present application.

[0121] The first aspect of the present 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), trityl (Trt), trimethylsilyl (TMS) or triisopropylsilyl (TIPS).

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

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

[0126] In some embodiments of the present 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 the present application, the reaction solvent of step (1) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, ethyl ether, and dipropyl ether; the present application has no particular limitation on the amount of the reaction solvent added in step (1), as long as the purpose of the present application can be achieved.

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

[0129] In some embodiments of the present 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°C, 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] The present application has no particular limitation on the method for isolating the product obtained in step (1), as long as the purpose of the present application can be achieved. For example, the product obtained by the reaction can be extracted with dichloromethane for multiple times, such as three times, and the organic phase can be washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate 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 a compound of formula IV.

[0131] In step (2), compound IV undergoes an addition reaction with a second organometallic reagent to obtain compound V; wherein the second organometallic reagent is selected from CH2CHCH2MgX 2 or CH2CHCH2CH2Li, the X 2 is selected from Cl, Br or I.

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

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

[0134] In some embodiments of the present application, the reaction solvent of step (2) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, ethyl ether, and dipropyl ether; the present application has no particular limitation on the amount of the reaction solvent added in step (2), as long as the purpose of the present application can be achieved.

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

[0136] In some embodiments of the present 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°C, 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] The present application has no particular limitation on the method for isolating the product obtained in step (2), as long as the purpose of the present application can be achieved. For example, the product obtained by the reaction can be extracted with dichloromethane for multiple times, such as three times, and the organic phase can be washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate 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 a compound of formula V.

[0138] The inventors of the present application have found in their research that, in the synthesis of compound V, if the order of the reaction reagents is changed, for example, first using a second organometallic reagent such as allylmagnesium bromide to react with compound III and then reacting with a first organometallic reagent such as 3-butenylmagnesium bromide, the reaction effect is poor and the yield of compound V is very low; whereas, if a first organometallic reagent such as 3-butenylmagnesium bromide is first used to react with compound III and then reacting with a second organometallic reagent such as allylmagnesium bromide, the yield of the prepared compound V is higher.

[0139] The second aspect of the present application provides a compound as shown in formula V:

[0140]

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

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

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

[0144]

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

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

[0147] In some embodiments of the present 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 has a high yield and is easy to separate and remove from the product. Preferably, the concentration of hydrochloric acid is 1-3 mol / L.

[0148] In some embodiments of the present application, the reaction solvent of step (3) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, dioxane, chloroform, and toluene; the present application has no particular limitation on the amount of the reaction solvent added in step (3), as long as the purpose of the present application can be achieved.

[0149] In some embodiments of the present 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 the present 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] The present application has no particular limitation on the method for isolating the product obtained in step (3), as long as the purpose of the present application can be achieved. For example, the product obtained by the reaction can be extracted with dichloromethane for multiple times, such as three times, and the organic phase can be washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate 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 a compound of formula VI.

[0152] In a fourth aspect, the present application provides a compound as shown in formula VI:

[0153]

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

[0155] In a fifth aspect, the present application provides a method for preparing compound VII, comprising the following steps:

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

[0157]

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

[0159] In some embodiments of the present application, in step (4), the condensing agent is Y-SO2Cl, and 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; 18When the aryl group is selected from phenyl, the hydrogen atoms on the phenyl group can be independently substituted by halogen, nitro, cyano, hydroxyl or C1-C3 alkyl, and 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 the present 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 the present application, the reaction solvent of step (4) is selected from at least one of 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, and toluene; the present application has no particular limitation on the amount of the reaction solvent added in step (4), as long as the purpose of the present application can be achieved.

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

[0163] In some embodiments of the present 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°C, and stirring for 10-30 hours; then separating the product to obtain compound VII.

[0164] The present application has no particular limitation on the method for isolating the product obtained in step (4), as long as the purpose of the present application can be achieved. For example, the product obtained by the reaction can be extracted with dichloromethane for multiple times, such as three times, and the organic phase can be washed with a 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 a compound of formula VII.

[0165] In a sixth aspect, the present application provides a compound as shown in formula VII:

[0166]

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

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

[0169] (5) Compound VII undergoes olefin metathesis reaction in the presence of a catalyst to obtain an oxaspirocyclic compound represented by formula VIII;

[0170]

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

[0172] When n is 2, the oxaspiro compound represented by formula VIII is 1-oxaspiro[4,5]dec-7-ene.

[0173] In some embodiments of the present application, in step (5), the catalyst is selected from Grubbs catalyst, Grubbs catalyst includes first generation Grubbs catalyst (Grubbs first generation catalyst) and second generation Grubbs catalyst (Grubbs second generation catalyst), preferably selected from first generation Grubbs catalyst (Grubbs first generation catalyst).

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

[0175] In some embodiments of the present application, the reaction solvent of step (5) is selected from at least one of dichloromethane, chloroform, dichloroethane, and toluene; the present application has no particular limitation on the amount of the reaction solvent added in step (5), as long as the purpose of the present application can be achieved.

[0176] In some embodiments of the present 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 the present application, the specific operation method of step (5) includes: dissolving compound VII and Grubbs first-generation catalyst in a reaction solvent, reacting at 40-60° C. for 10-30 hours under nitrogen protection; then separating the product to obtain the oxaspiro compound represented by formula VIII.

[0178] The present application has no particular limitation on the method for isolating the product obtained in step (5), as long as the purpose of the present application can be achieved. For example, the product obtained by the reaction can be filtered through diatomaceous earth, extracted with dichloromethane for multiple times, such as three times, the organic phase can be washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated, and purified using 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 oxaspiro compound represented by formula VIII.

[0179] In an eighth aspect, the present application provides a compound as shown in formula VIII:

[0180]

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

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

[0183]

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

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

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

[0187] In some embodiments of the present 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 the present application, in step A), the molar ratio of the metal aluminum reagent to N,O-dimethylhydroxylamine hydrochloride is (0.5-1.5):1.

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

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

[0191] In some embodiments of the present 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 the present application, in step A), the metal aluminum reagent is added dropwise for 0.5-1.5 hours.

[0193] In some embodiments of the present application, the specific operation method of step A) includes: dissolving N, O-dimethylhydroxylamine hydrochloride in a reaction solvent under nitrogen protection, slowly adding a metal aluminum reagent at -78-0°C within 0.5-1.5 hours, heating to 20-30°C after the addition is complete and stirring for 3-5 hours to carry out the first reaction. Then the solution is cooled to 0-10°C, compound Ia is added and stirred for 1-2 hours to carry out the second reaction. Maintaining the temperature of the second reaction, add a saturated sodium potassium L-tartrate tetrahydrate solution and carefully quench, and continue stirring for 10-30 hours; then separate the product to obtain compound II-a.

[0194] The present application has no particular limitation on the method for isolating the product obtained in step A), as long as the purpose of the present application can be achieved. For example, the product obtained by the reaction can be filtered through diatomaceous earth, extracted with dichloromethane multiple times, such as three times, and the organic phase can be dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound II-a.

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

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

[0197] In some embodiments of the present application, in step B), the hydroxyl protecting agent is selected from at least one of tert-butyldiphenylsilyl chloride, tert-butyldimethylsilyl methanesulfonate, tert-butyldimethylsilyl chloride, 3,4-dihydro-2H-pyran, chloromethyl methyl ether, 1-(chloromethoxy)-2-methoxyethane, triphenylmethane, trimethylsilyl chloride, and triisopropylsilyl chloride.

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

[0199] In some embodiments of the present 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 the present application, the specific operation method of step B) includes: dissolving compound II in a reaction solvent at -10-10°C, adding a hydroxyl protecting agent and a first alkaline substance in sequence, and stirring at 15-30°C for 2-4 hours; then separating the product to obtain compound III.

[0201] The present application has no particular limitation on the method for isolating the product obtained in step B), as long as the purpose of the present application can be achieved. For example, the product obtained by the reaction can be extracted with dichloromethane for multiple times, such as three times, and the organic phase can be washed with a saturated sodium chloride solution, dried over 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 10:90) to obtain compound III.

[0202] The method provided in the ninth aspect of the present application is used to prepare compound III, and the total yield of compound III can reach about 82%.

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

[0204]

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

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

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

[0208] In some embodiments of the present 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 the present application, in step A'), the reaction solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform and toluene.

[0210] The present application has no particular limitation on the amount of the reaction solvent used in step A'), as long as the purpose of the present application can be achieved. For example, in step A'), the molar volume ratio of 1,4-butanediol to the reaction solvent is (2-3) mol:1L.

[0211] In some embodiments of the present 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 the present application, the specific operation method of step A') includes: dissolving 1,4-butanediol in a reaction solvent, adding a second alkaline substance and tert-butyldiphenylsilyl chloride at 10-30° C., and stirring for 14-18 hours; then separating the product to obtain compound Ib.

[0213] The present application has no particular limitation on the method for isolating the product obtained in step A'), as long as the purpose of the present application can be achieved. For example, the product obtained by 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 is oxidized using Jones reagent to obtain compound II-b.

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

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

[0217] The present application has no particular limitation on the amount of the solvent used in the oxidation reaction of step B'), as long as the purpose of the present application can be achieved. For example, in step B'), the molar volume ratio of compound Ib to the solvent used in the oxidation reaction is (0.3-1) mol:4L.

[0218] In some embodiments of the present 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 the present 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] The present application has no particular limitation on the method for isolating the product obtained in step B'), as long as the purpose of the present application can be achieved. For example, the product obtained by the reaction can be concentrated, ethyl acetate is added, and washed with water for multiple times, such as twice. The organic phase is dried over 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 obtain compound III.

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

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

[0224] In some embodiments of the present application, in step C'), HOBT and EDCI are used together; the present application has no particular limitation on the molar ratio of HOBT and EDCI, as long as the purpose of the present application can be achieved.

[0225] In some embodiments of the present 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 the present application, the reaction solvent of step C') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, toluene, and DMF (N,N-dimethylformamide).

[0227] The present application has no particular limitation on the amount of the reaction solvent used in step C'), as long as the purpose of the present application can be achieved. For example, in step C'), the molar volume ratio of compound II-b and the reaction solvent is (0.2-1) mol:1L.

[0228] In some embodiments of the present 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 the present application, the specific operation method of step C') includes: dissolving intermediate II-b, N,O-dimethylhydroxylamine hydrochloride, a condensing agent and a third alkaline substance in a reaction solvent, stirring at 10-30°C for 1-3 hours; then separating the product to obtain compound III.

[0230] The present application has no particular limitation on the method for isolating the product obtained in step C'), as long as the purpose of the present application can be achieved. For example, the solvent of the product obtained by 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] The method provided in the tenth aspect of the present application is used to prepare compound III, and the total yield of compound III can reach about 76%.

[0232] Compound III is prepared by the preparation method provided in the ninth aspect of the present application, and then compound III is sequentially prepared by the method provided in the first aspect of the present 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 oxygen-containing spirocyclic compound shown in formula VIII. The total yield of the oxygen-containing spirocyclic compound shown in formula VIII can reach about 55%.

[0233] Compound III is prepared by the preparation method provided in the tenth aspect of the present application, and then compound III is sequentially prepared by the method provided in the first aspect of the present 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 oxaspiro compound shown in formula VIII. The total yield of the oxaspiro compound shown in formula VIII can reach about 52%, which is much higher than the yield of the prior art.

[0234] Example

[0235] Hereinafter, the embodiments of the present application are described in more detail by way of examples and comparative examples. Various tests and evaluations were performed according to the following methods. In addition, unless otherwise specified, "parts" and "%" are weight references. The raw materials and reagents used in the present application are all commercially available AR or CP grade.

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

[0237] The present application uses a nuclear magnetic resonance spectrometer (NMR) for structure confirmation, solution: CDCl3; internal standard: TMS (tetramethylsilane).

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

[0239] Example 1

[0240] Synthesis of compound II-a

[0241]

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

[0243] Example 2

[0244] Except that trimethylaluminum was used instead of diisobutylaluminum hydride, the rest was the same as Example 1. The yield of compound II-a was 90%.

[0245] Example 3

[0246] Synthesis of Compound III

[0247]

[0248] 83.34g of compound II-a (0.567mol) was dissolved in dichloromethane at 0°C, and 102g of tert-butyldimethylsilyl chloride (0.680mol) and 77.2g of imidazole (1.334mol) were added in sequence, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed by thin layer chromatography (TLC), the reaction mixture was poured into water, separated, and the aqueous phase was extracted with dichloromethane 3 times (3×100mL), and the organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated. The gradient elution of the silica gel column chromatography was carried out in the forward direction (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether was 10:90), and 130.2g of compound III was obtained, with a yield of 88%. The H NMR spectrum data of the obtained compound III: 1 H NMR (400MHz, CDCl3) δ3.69 (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 nuclear magnetic resonance hydrogen spectrum is as follows Figure 1 shown.

[0249] Embodiment 4-8

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

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

[0252] Table 1 Related parameters and product yields of Examples 3-8

[0253] Hydroxyl Protective Agent The first alkaline substance Yield Example 3 tert-Butyldimethylsilyl chloride Imidazole 88％ Example 4 Tert-Butyldiphenylsilyl chloride Triethylamine 50％ Example 5 Tert-Butyldiphenylsilyl chloride N,N-Diisopropylethylamine 52％ Example 6 Tert-Butyldimethylsilyl methanesulfonate 2,6-Dimethylpyridine 73％ Example 7 tert-Butyldimethylsilyl chloride Triethylamine 56％ Example 8 tert-Butyldimethylsilyl chloride N,N-Diisopropylethylamine 56％

[0254] Example 9

[0255] Synthesis of compound Ib

[0256]

[0257] In a 3000mL three-necked flask, 1,4-butanediol (196.73g, 2.18mol) was dissolved in 1000mL dichloromethane, N,N-diisopropylethylamine (423.22g, 3.27mol) and tert-butyldiphenylsilyl chloride (500g, 1.82mol) were added at room temperature, and stirred for 16 hours at room temperature. After the reaction was completed by thin layer chromatography (TLC), the reaction mixture was poured into water, separated, and the aqueous phase was extracted with dichloromethane 3 times (3×100mL), and the organic phase was combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated. The gradient elution was performed by normal silica gel column chromatography (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether was 10:1), and 642g of compound Ib was obtained 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 was dissolved in 100 mL of water, then 46 mL of concentrated sulfuric acid was slowly added dropwise, and then diluted to 200 mL with water) was added at room temperature and stirred for 1 hour. After the reaction was completed by thin layer chromatography (TLC), the reaction solution was concentrated, 1000 mL of ethyl acetate was added to the obtained crude product, and washed with water (500 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 g of compound II-b, with a yield of 95%.

[0262] Embodiment 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-mouth bottle and stirred at room temperature for 2 hours. After the reaction was completed by thin layer chromatography (TLC), the solvent was dried, the residue was dissolved in ethyl acetate, and the gradient elution was performed by normal silica gel column chromatography (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether was 1:5) to obtain 100.3 g of compound III with a yield of 89%. The H NMR spectrum data of the obtained compound III: 1 H NMR (400MHz, CDCl3) δ7.70 (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), and its nuclear magnetic resonance hydrogen spectrum is shown as follows Figure 2 shown.

[0266] Example 12

[0267] Except that HATU was replaced by Carter condensation agent, the rest was the same as Example 11. The yield of compound III was 82%.

[0268] Embodiment 13

[0269] Synthesis of compound IV

[0270]

[0271] 130.2g of compound III (0.499mol) was dissolved in tetrahydrofuran, 600mL of 1mol / L 3-butenylmagnesium bromide (0.598mol) was slowly added at 0°C, and stirred for 5 hours. The reaction was completed by thin layer chromatography (TLC), and quenched with 200mL of saturated zinc chloride solution. It was extracted with dichloromethane (3×500mL), and the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated. The mixture was eluted by normal silica gel column chromatography gradient elution (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate to petroleum ether was 2:8), and 121.3g of compound IV was obtained, with a yield of 95%.

[0272] Embodiment 14

[0273] Except that the amount of 3-butenylmagnesium bromide added was adjusted to 0.998 mol, the rest was the same as Example 13. The yield of compound IV was 87%.

[0274] Embodiment 15

[0275] Except that the amount of 3-butenylmagnesium bromide added was adjusted to 0.748 mol, the rest was the same as Example 13. The yield of compound IV was 90%.

[0276] Example 16

[0277] Synthesis of Compound V

[0278]

[0279] 121.3g of compound IV (0.473mol) was dissolved in tetrahydrofuran, 570mL of 1mol / L allylmagnesium bromide was slowly added at 0°C, and stirred for 2 hours. The reaction was completed by thin layer chromatography (TLC) and quenched with 200mL of saturated zinc chloride solution. It was extracted with dichloromethane (3×500mL), the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated. The compound V was obtained by gradient elution in the forward direction of silica gel column chromatography (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether was 2:8), and 135.56g of compound V was obtained with a yield of 96%. The H NMR spectrum data of the obtained compound V: 1 H NMR (400MHz, CDCl3) δ7.69 (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), and its nuclear magnetic resonance hydrogen spectrum is shown as follows Figure 3 shown.

[0280] Embodiment 17

[0281] Synthesis of Compound VI

[0282]

[0283] 135.56g of compound V (0.455mol) was dissolved in tetrahydrofuran, 300mL of 2mol / L dilute hydrochloric acid was slowly added, and stirred for 3 hours. The reaction was completed by thin layer chromatography (TLC) and quenched with 200mL of saturated sodium bicarbonate solution. It was extracted with dichloromethane (3×500mL), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The gradient elution was performed by forward silica gel column chromatography (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether was 2:8) to obtain 69.6g of compound VI with a yield of 90%. The H NMR spectrum data of the obtained compound VI: 1 H NMR (400MHz, CDCl3) δ6.00-5.70 (m, 2H), 5.37-4.81 (m, 4H), 3.64 (t, J = 6.16Hz, 2H), 2.59 (s, 2H), 2.28 (d, J = 7.44Hz, 2H), 2.13 (q, J = 7.96Hz, 2H), 1.65 (m, 6H). Its nuclear magnetic resonance hydrogen spectrum is shown in Figure 4 shown.

[0284] Embodiment 18

[0285] Except that tetrabutylammonium fluoride was used instead of 2 mol / L dilute hydrochloric acid, it was the same as Example 17. The yield of Compound VI was 90%.

[0286] Embodiment 19

[0287] Synthesis of compound VII

[0288]

[0289] 69.6g of compound VI (0.409mol) was dissolved in dichloromethane, and 117.0g of p-toluenesulfonyl chloride (0.614mol), 342mL of triethylamine (2.45mol) and 7.5g of 4-dimethylaminopyridine (0.061mol) were slowly added at 0°C, stirred overnight, and the reaction was completed by thin layer chromatography (TLC). The reaction mixture was poured into water, separated, and the aqueous phase was extracted with dichloromethane for 3 times (3×100mL), and the organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated. The gradient elution was performed by normal silica gel column chromatography (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether was 2:8), and 62.5g of compound VII was obtained, with a yield of 92%. The H NMR spectrum data of the obtained compound VII: 1H NMR (400MHz, CDCl3) δ5.84 (m, 2H), 5.12 (m, 4H), 3.88 (t, J = 6.6Hz, 2H), 2.34 (m, 2H), 2.13 (m, 2H), 1.96 (m, 2H), 1.73 (m, J = 53.7Hz, 2H), 1.61 (m, 2H). Its nuclear magnetic resonance hydrogen spectrum is shown in Figure 5 shown.

[0290] Embodiment 20

[0291] Synthesis of compound VIII

[0292]

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

[0294] The nuclear magnetic resonance hydrogen spectrum measurement data of compound VIII prepared in Example 20 of the present application: 1 H NMR (400MHz,CDCl3)δ5.82-5.45(m,2H),4.05-3.72(m,2H),2.36-1.50(m,10H); H NMR spectrum is shown in Figure 6 As shown; NMR carbon spectrum measurement data: 13 C NMR (400MHz, CDCl3)δ126.68,125.22,80.63,66.91,37.39,36.07,32.82,25.63,24.17, NMR carbon spectrum as shown Figure 7 The compound of formula VIII was identified as 1-oxaspiro[4,5]dec-7-ene by hydrogen nuclear magnetic resonance spectrum and carbon nuclear magnetic resonance spectrum.

[0295] Embodiment 21

[0296] Synthesis of Compound II'-a

[0297]

[0298] Under nitrogen protection, 9.31g N, O-dimethylhydroxylamine hydrochloride (96mmol) was dissolved in dichloromethane, and 1mol / L diisobutylaluminum hydride (95mL, 92mmol) was slowly added to the reaction solution within 1 hour at -30°C. After the addition was complete, it was heated to room temperature and stirred for 4 hours. The solution was then cooled to 5°C, 4g delta-valerolactone (I'-a, 40mmol) was added, and the resulting mixture was stirred for another 1.5 hours. L-sodium potassium tartrate tetrahydrate solution was added at 0°C and carefully quenched, and stirred overnight. The resulting precipitate was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane, separated, and the aqueous phase was extracted with dichloromethane (3×50mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 5.9g of compound II'-a, with a yield of 92%. The H NMR spectrum data of the obtained compound II'-a: 1 H NMR (400MHz, CDCl3) δ3.69 (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), and its nuclear magnetic resonance hydrogen spectrum is as follows Figure 8 shown.

[0299] Embodiment 22

[0300] Synthesis of compound III'

[0301]

[0302] 5.9g of compound II'-a (36.6mmol) was dissolved in dichloromethane at 0°C, and 6.62g of tert-butyldimethylsilyl chloride (43.9mmol) and 5.5g of imidazole (80.8mmol) were added in sequence, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed by thin layer chromatography (TLC), the reaction mixture was poured into water, separated, and the aqueous phase was extracted with dichloromethane 3 times (3×50mL), and the organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated. 9.1g of compound III' was obtained by gradient elution of normal silica gel column chromatography (eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether was 10:90), and the yield was 90%. The H NMR spectrum data of the obtained compound III': 1 H NMR (400MHz, CDCl3) δ3.69 (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 nuclear magnetic resonance hydrogen spectrum is as follows Fig. 9 shown.

[0303] Embodiment 23

[0304] Synthesis of Compound IV'

[0305]

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

[0307] Embodiment 24

[0308] Synthesis of Compound V'

[0309]

[0310] 8.22g of compound IV' (30.4mmol) was dissolved in tetrahydrofuran, 31mL of 1mol / L allylmagnesium bromide was slowly added at 0°C, and stirred for 2 hours. The reaction was completed by thin layer chromatography (TLC) detection, and quenched with 30mL of saturated zinc chloride solution. It was extracted with dichloromethane (3×50mL), the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated. 8.61g of compound V' was obtained by gradient elution in the forward direction of silica gel column chromatography (eluent was ethyl acetate / petroleum ether, the volume ratio of ethyl acetate and petroleum ether was 2:8), and the yield was 91%. The H NMR spectrum data of the obtained compound V': 1 H NMR (400MHz,CDCl3)δ5.82(m,2H),5.30-4.79(m,4H),3.64(t,J=6.4Hz,2H),2.25(d,J=7.3Hz,2H),2.13(m,J=14.9Hz,2H),1.65-1.25(m,11H),0.91(s,9H),0.07(s,6H). Its H NMR spectrum is shown in Fig.10 shown.

[0311] Embodiment 25

[0312] Synthesis of Compound VI'

[0313]

[0314] 3g of compound V' (10.1mmol) was dissolved in tetrahydrofuran, 5mL of 6mol / L dilute hydrochloric acid was slowly added, and stirred for 3 hours. The reaction was completed by thin layer chromatography (TLC), and quenched with 50mL of saturated sodium bicarbonate solution. It was extracted with dichloromethane (3×50mL), and the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated. The gradient elution was performed by forward silica gel column chromatography (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether was 2:8) to obtain 1.82g of compound VI' with a yield of 95%. The H NMR spectrum data of the obtained compound VI': 1 H NMR (400MHz,CDCl3)δ5.99-5.71(m,2H),5.37-4.74(m,4H),3.64(t,J=6.4Hz,2H),2.23(d,J=7.5Hz,4H),2.18-2.01(m,2H),1.64-1.34(m,8H). Its H NMR spectrum is shown in Fig.11 shown.

[0315] Embodiment 26

[0316] Synthesis of Compound VII'

[0317]

[0318] 1.82g of compound VI' (9.2mmol) was dissolved in dichloromethane, and 2.63g of p-toluenesulfonyl chloride (13.8mmol), 8mL of triethylamine (55.1mmol) and 0.17g of 4-dimethylaminopyridine (1.4mmol) were slowly added at 0°C, and stirred overnight. After the reaction was completed by thin layer chromatography (TLC), the reaction mixture was poured into water, separated, and the aqueous phase was extracted with dichloromethane 3 times (3×50mL), and the organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated. The gradient elution was performed by normal silica gel column chromatography (the eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether was 2:8), and 1.21g of compound VII' was obtained, with a yield of 73%. The H NMR spectrum data of the obtained compound VII': 1 H NMR (400MHz, CDCl3) δ5.73-5.89 (m, 2H), 5.23-4.84 (m, 4H), 3.36 (t, J = 6.5Hz, 2H), 2.21 (d, J = 9.9Hz, 2H), 2.03-2.14 (m, 2H), 1.60-1.35 (m, 8H). Its nuclear magnetic resonance hydrogen spectrum is shown in Fig.12 shown.

[0319] Embodiment 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, refluxed at 60°C overnight under nitrogen protection, and the reaction was completed by thin layer chromatography (TLC). The catalyst was filtered off with diatomaceous earth, and the reaction mixture was poured into water, separated, and the aqueous phase was extracted with dichloromethane 3 times (3×50 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated. The normal silica gel column chromatography gradient elution (eluent was ethyl acetate / petroleum ether, and the volume ratio of ethyl acetate and petroleum ether was 2:8) was used to obtain 0.77 g of compound VIII', with a yield of 91%.

[0323] The nuclear magnetic resonance hydrogen spectrum measurement data of compound VIII' prepared in Example 27 of the present application: 1 H NMR (400MHz,CDCl3)δ5.53-5.76(m,2H),3.40(t,J=6.4Hz,2H),2.34-1.94(m,4H),1.72-1.45(m,8H).; H NMR spectrum is shown in Fig.13 As shown; NMR carbon spectrum measurement data: 13 C NMR (101MHz,CDCl3)δ126.61,124.49,72.80,58.54,41.11,37.91,33.04,30.14,22.68,19.72., NMR carbon spectrum is shown in Fig.14 Oxyhexaspiro compounds are important synthetic intermediates in the pharmaceutical field. The preparation methods in the prior art have problems such as poor reproducibility, low yield, and dangerous operation, which directly affect their yield, cost, safety, etc. Therefore, the present application provides a new preparation method of oxyhexaspiro compounds, which has the characteristics of being green, environmentally friendly, cheap, and efficient, overcomes the above-mentioned defects, and is conducive to large-scale industrial production.

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

Claims

1. A method for preparing an oxaspirocyclic compound, comprising the following steps: Compound VII undergoes olefin metathesis reaction in the presence of a catalyst to obtain an oxaspiro compound represented by formula VIII; in, n is selected from 1, 2, 3 or 4.

2. The preparation method according to claim 1, wherein The catalyst is selected from Grubbs catalysts, preferably from first generation Grubbs catalysts; Preferably, the molar ratio of the compound VII to the catalyst is 1:(0.01-0.1); Preferably, the reaction solvent is selected from at least one of dichloromethane, chloroform, dichloroethane and toluene; Preferably, the reaction temperature is 40-60° C. and the reaction time is 10-30 hours.

3. A method for preparing compound VII, comprising the following steps: Compound VI reacts with a condensing agent to obtain compound VII; in, n is selected from 1, 2, 3 or 4.

4. The preparation method according to claim 3, wherein 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; 18 When the aryl group is selected from phenyl, the hydrogen atoms on the phenyl group may be independently substituted by halogen, nitro, cyano, hydroxyl or C1-C3 alkyl, and the halogen is selected from F, Cl, Br or I; preferably, the condensing agent is selected from p-toluenesulfonyl chloride; Preferably, the reaction is carried out under the co-catalysis of triethylamine and 4-dimethylaminopyridine, and the molar ratio of the compound VI, the condensing agent, the triethylamine and the 4-dimethylaminopyridine is 1:(1-2):(5-10):(0.1-0.2); Preferably, the reaction solvent is selected from at least one of 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform and toluene; Preferably, the reaction temperature is -10-10°C, and the reaction time is 10-30 hours.

5. A method for preparing compound VI, comprising the following steps: Compound V reacts with a deprotecting agent to obtain compound VI; in, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, trityl, trimethylsilyl or triisopropylsilyl.

6. The preparation method according to claim 5, wherein: The molar ratio of the compound V to the deprotecting agent is 1:(1-10); Preferably, the deprotecting agent is selected from tetrabutylammonium fluoride or hydrochloric acid; Preferably, the reaction solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dichloroethane, dioxane, chloroform and toluene; Preferably, the reaction temperature is 15-30°C and the reaction time is 2-4 hours.

7. A method for preparing compound V, comprising the following steps: (1) Compound III undergoes an addition reaction with a first organometallic reagent to obtain compound IV; in, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, trityl, trimethylsilyl or triisopropylsilyl; The first organometallic reagent is selected from CH2CHCH2CH2MgX 1 or CH2CHCH2CH2Li, the X 1 is selected from Cl, Br or I; preferably, the first organometallic reagent is selected from 3-butenylmagnesium bromide; (2) Compound IV undergoes an addition reaction with a second organometallic reagent to obtain compound V; Wherein, the second organometallic reagent is selected from CH2CHCH2MgX 2 or CH2CHCH2CH2Li, the X 2 is selected from Cl, Br or I; preferably, the second organometallic reagent is selected from allylmagnesium bromide.

8. The preparation method according to claim 7, wherein: In step (1), the molar ratio of the compound III to the first organometallic reagent is 1:(1.2-2.0); Preferably, the reaction solvent of step (1) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, diethyl ether and dipropyl ether; Preferably, the reaction temperature of step (1) is -10-10°C, and the reaction time of step (1) is 1-6 hours; Preferably, in step (2), the molar ratio of the compound IV to the second organometallic reagent is 1:(1-1.5); Preferably, the reaction solvent of step (2) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl ether, dibutyl ether, diethyl ether and dipropyl ether; Preferably, the reaction temperature of step (2) is -10-10°C, and the reaction time of step (2) is 1-6 hours.

9. A method for preparing compound III, comprising the following steps: A) mixing N,O-dimethylhydroxylamine hydrochloride with an organic solvent, then adding a metal aluminum reagent at -78-0°C, heating to 20-30°C for a first reaction; after the reaction, cooling to 0-10°C, adding compound Ia for a second reaction, and obtaining compound II-a; in, n is selected from 1, 2, 3 or 4; B) reacting the compound II-a with a hydroxyl protecting agent in the presence of a first alkaline substance to obtain a compound III; Wherein, R is selected from tert-butyldiphenylsilyl, tert-butyldimethylsilyl, 2-tetrahydropyranyl, methoxymethyl, 2-methoxyethoxymethyl, trityl, trimethylsilyl or triisopropylsilyl.

10. The preparation method according to claim 9, wherein: In step A), the molar volume ratio of the N,O-dimethylhydroxylamine hydrochloride to the organic solvent is (1-2) mol:0.5L; Preferably, in step A), the organic solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane and toluene; Preferably, in step A), the molar ratio of the metal aluminum reagent to the N,O-dimethylhydroxylamine hydrochloride is (0.5-1.5):1; Preferably, in step A), the metal aluminum reagent is selected from at least one of trimethylaluminum and diisobutylaluminum hydride; Preferably, in step A), the molar ratio of the compound Ia to the N,O-dimethylhydroxylamine hydrochloride is (0.2-0.5):1; Preferably, 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; Preferably, in step A), the metal aluminum reagent is added dropwise for 0.5-1.5 hours; Preferably, in step B), the molar ratio of the compound II-a, the hydroxyl protecting agent and the first alkaline substance is 1:(1-1.5):(1.5-2.5), preferably 1:(1-1.1):(1.5-2.5); Preferably, in step B), the hydroxyl protecting agent is selected from at least one of tert-butyldiphenylsilyl chloride, tert-butyldimethylsilyl methanesulfonate, tert-butyldimethylsilyl chloride, 3,4-dihydro-2H-pyran, chloromethyl methyl ether, 1-(chloromethoxy)-2-methoxyethane, triphenylmethane chloride, trimethylsilyl chloride, and triisopropylsilyl chloride; Preferably, in step B), the first alkaline substance is selected from at least one of triethylamine, N,N-diisopropylethylamine, 2,6-lutidine and imidazole; Preferably, the reaction temperature of step B) is 15-30° C., and the reaction time of step B) is 2-4 hours.

11. A method for preparing compound III, comprising the following steps: A') reacting a diol with tert-butyldiphenylsilyl chloride in the presence of a second alkaline substance to obtain compound Ib; in, n is selected from 1, 2, 3 or 4; R is selected from tert-butyldiphenylsilyl; B') the compound Ib is subjected to oxidation reaction using Jones reagent to obtain compound II-b; C') activating the compound II-b with a condensing agent, and then reacting with N,O-dimethylhydroxylamine hydrochloride in the presence of a third alkaline substance to obtain compound III; 12. The preparation method according to claim 11, wherein In step A'), the molar ratio of the diol, the second alkaline substance and the tert-butyldiphenylchlorosilane is (1-2): (1-2): 1; Preferably, in step A'), the second alkaline substance is selected from at least one of N,N-diisopropylethylamine and triethylamine; Preferably, the reaction solvent in step A') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform and toluene; Preferably, the reaction temperature of step A') is 10-30°C, and the reaction time of step A') is 14-18 hours; Preferably, in step B'), the molar volume ratio of the compound Ib and the Jones reagent is (1-2) mol:1L; Preferably, the solvent for the oxidation reaction in step B') is selected from acetone; Preferably, the oxidation reaction temperature of step B') is 10-30°C, and the oxidation reaction time of step B') is 0.5-2 hours; Preferably, in step C'), the molar ratio of the compound II-b, the N,O-dimethylhydroxylamine hydrochloride, the condensing agent and the third alkaline substance is 1:(1-1.5):(1.2-2):(2-3); Preferably, in step C'), the condensing agent is selected from at least one of HATU, HOBT / EDCI, CDI, DCC and Carter condensing agent; Preferably, in step C'), the third alkaline substance is selected from at least one of N,N-diisopropylethylamine and triethylamine; Preferably, the reaction solvent of step C') is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, dioxane, chloroform, toluene and DMF; Preferably, the reaction temperature of step C') is 10-30°C, and the reaction time of step C') is 1-3 hours.

13. A compound as shown in formula VIII: in, n is selected from 1, 3 or 4.

14. A compound as shown in formula VII: in, n is selected from 1, 2, 3 or 4.

15. A compound as shown in formula VI: in, n is selected from 1, 2, 3 or 4.

16. 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, trityl, trimethylsilyl or triisopropylsilyl.

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