A method for synthesizing bicyclic [3.1.0]hexane and its derivatives

Abstract

This invention relates to a method for preparing compounds, and more particularly to a method for synthesizing bicyclo[3.1.0]hexane and its derivatives. The synthetic route is as follows: Compound I undergoes a cyclization reaction with a dihalomethane in the presence of a cobalt salt catalyst, zinc, and a catalytic amount of iodine to obtain compound II; wherein the cobalt salt catalyst in step 1 is shown in Formula IV, with the following structure: R is selected from methyl, ethyl, n-propyl, isopropyl, or n-butyl; X is selected from halogens, such as Cl, Br, or I. Compared with the prior art, this application reduces the amount of materials required and the material prices are lower, while significantly increasing the yield, thereby greatly reducing production costs.

Description

Technical Field

[0001] This invention relates to a method for preparing a compound, and more particularly to a method for preparing bicyclo[3.1.0]hexane and its derivatives. Background Technology

[0002] Bicyclo[3.1.0]hexane and its derivatives, such as bicyclo[3.1.0]hexane-3-one, are key fragments in many drugs and are commonly used in drug development processes, possessing broad market prospects. Their specific structures are as follows: Compound III:

[0003]

[0004] All currently disclosed routes are two-step synthesis methods: first, bicyclo[3.1.0]hex-3-ol is synthesized, and then bis[3.1.0]-3-hexanone is synthesized by oxidation.

[0005] The literature JMC(2023),66(3),1941-1954 discloses a method for synthesizing bicyclic [3.1.0]hex-3-ol, using 3-cyclopenten-1-ol as a raw material, which undergoes ring closure with CH2I2 under the action of Et2Zn. However, Et2Zn is flammable, CH2I2 is expensive, and the yield is only 62% after two consecutive additions, which places high demands on large-scale mass production. The chemical reaction formula is as follows:

[0006]

[0007] Currently, the existing literature discloses three main methods for synthesizing bicyclo[3.1.0]-3-hexanone from bicyclo[3.1.0]hex-3-ol:

[0008] The first method is Dess-Martin oxidation, which is currently the mainstream method.

[0009]

[0010] The DMP oxidant used in this scheme is relatively expensive, and the amount of solvent used in this step is very large, which greatly limits the production capacity.

[0011] The second method (WO2014145095 A1, WO2017103611 A1) uses PCC, K2Cr2O7, etc. as oxidants. This method has complex post-treatment and generates a large amount of environmentally harmful waste.

[0012] The third method (WO2013006738 A1) uses TPAP and NMO as the oxidant, but the literature does not provide the specific yield.

[0013] In summary, existing technologies suffer from problems such as high cost, low yield, significant pollution, and the use of hazardous reagents. Therefore, there is a need to find a new method for synthesizing bicyclo[3.1.0]-3-hexanone. Summary of the Invention

[0014] The technical problem to be solved by this invention relates to a method for preparing bicyclo[3.1.0]hexane and its derivatives. This route is low in cost, high in yield, and short in reaction time, and does not require the use of hazardous reagents, thus meeting the requirements for industrial-scale production.

[0015] The first aspect of this invention provides a method for preparing compound II, the synthetic route of which is as follows:

[0016]

[0017] It includes the following steps:

[0018] Step 1: In the presence of a cobalt salt catalyst, zinc, and a catalytic amount of iodine, compound I undergoes a cyclization reaction with a dihalomethane to give compound II;

[0019] in,

[0020] R2 is selected from OP1 or -COOP2, where P1 is H, any substituted alkyl group, or a hydroxyl protecting group; P2 is H, C1-C6 alkyl group, or C6-C6 alkyl group. 10 Aryl, C6-C 10 Aryl-C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6-alkyl, heterocyclic or heterocyclic-C1-C6 alkyl, wherein each aryl or heterocyclic ring may optionally be substituted with a substituent selected from the following: halogen (e.g., F, Cl, Br or I), C1-C7 alkyl, C1-C7 alkyl substituted with F, Cl, Br or I halogen, C1-C7 alkoxy, C1-C7 alkoxy and C1-C7 alkoxy-C1-C7 alkyl substituted with F, Cl, Br or I halogen; for example, P2 is selected from methyl, ethyl, isopropyl, tert-butyl, tert-amyl, p-pentyl, phenyl or benzyl;

[0021] The hydroxyl protecting group is selected from benzyl, substituted benzyl, and -COR3, wherein R3 is selected from C1-C5 alkyl, C1-C5 substituted alkyl, phenyl, and substituted phenyl; for example, the hydroxyl protecting group is selected from benzyl, p-methoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, formyl, benzyloxycarbonyl, trifluoroacetyl, and chloroacetyl. In some specific embodiments, the hydroxyl protecting group is benzyl or acetyl.

[0022] X2 is selected from C or N:

[0023] When X2 is a C atom, R1 is H, halogen, C1-C6 alkyl or alkoxy, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, and the alkoxy can be methoxy or ethoxy.

[0024] When X2 is an N atom, R1 may be selected from an amino protecting group, such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, benzyloxycarbonyl, tert-butyloxycarbonyl, 9-fluorenmethoxycarbonyl, p-toluenesulfonyl, methanesulfonyl, acetyl or benzoyl, preferably tert-butyloxycarbonyl.

[0025] Compound I and Compound II can be racemic or any isomer thereof; for example:

[0026]

[0027] The cobalt salt catalyst described in step 1 is shown in Formula IV and has the following structure:

[0028]

[0029] Wherein, R is selected from methyl, ethyl, n-propyl, isopropyl, or n-butyl;

[0030] X is selected from halogens, such as Cl, Br, or I;

[0031] The preparation method of the cobalt salt catalyst can be referred to the catalyst preparation example in patent CN114671798B.

[0032] Preferably, the solvent used in the cyclization reaction of step 1 is selected from one or any combination of ether solvents, alcohol solvents, haloalkanes, aromatic alkanes, alkanes or substituted alkanes; preferably diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, methanol, isopropanol, dichloromethane, dichloroethane, toluene, n-heptane, 1,2-dimethoxyethane; more preferably tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, dichloromethane, dichloroethane, toluene, 1,2-dimethoxyethane.

[0033] Preferably, the halogens in the dihalomethanes described in step 1 are each independently selected from F, Cl, Br, or I.

[0034] Preferably, the molar ratio of the compound of formula I and the cobalt salt catalyst in step 1 is 1:(0.01-0.1), more preferably 1:(0.02-0.08), and even more preferably 1:(0.02-0.05).

[0035] Preferably, the molar ratio of the compound of formula I and the dihalomethane described in step 1 is 1:(1-3); more preferably 1:(1-2).

[0036] Preferably, the molar ratio of the compound of formula I and zinc in step 1 is 1:(1-5); more preferably 1:(1.5-4).

[0037] Preferably, the molar ratio of the compound of formula I and iodine in step 1 is 1:(0.01-0.2); more preferably 1:(0.01-0.1); more preferably 1:(0.01-0.05).

[0038] Preferably, the cyclization reaction in step 1 is carried out at a temperature of 10-40°C, and more preferably at a temperature of 15-35°C.

[0039] Preferably, the cyclization reaction in step 1 takes 0.5-5 hours, and more preferably 1-5 hours.

[0040] In some embodiments of this application, a reaction solution is obtained by stirring a cobalt salt catalyst, the solvent used, zinc powder, and iodine. Then, the compound of formula I is added to the reaction solution in one go, and finally, the desired dihalomethane is added dropwise. The dihalomethane can be selectively diluted with an organic solvent.

[0041] In some embodiments of this application, after the reaction in step 1 is completed, selectively, the reaction solution is directly filtered, the filter cake is washed with dichloromethane, the filtrate is concentrated to dryness to obtain the crude product, and the product is purified by silica gel column chromatography with 0-30% hexane / ethyl acetate to obtain the product.

[0042] A second aspect of this invention provides a method for preparing compound III, the synthetic route of which is as follows:

[0043]

[0044] The R1 and X2 substituents are defined as described in the first aspect above.

[0045] The specific steps are as follows:

[0046] Step 1: In the presence of a cobalt salt catalyst, zinc, and a catalytic amount of iodine, compound I-1 undergoes a cyclization reaction with dihalomethane to give compound II-1;

[0047] Step 2: Compound II-1 is oxidized in the presence of an oxidant, a base, and a co-catalyst to obtain compound III.

[0048] Preferably, in step 1, compound I-1 completely adopts all the technical solutions of the preparation method of compound II in the first aspect of the present invention.

[0049] Preferably, the oxidant in step 2 is a combination of TEMPO and sodium hypochlorite.

[0050] Preferably, the co-catalyst in step 2 is a brominated alkali metal or an iodinated alkali metal, wherein the alkali metal is selected from K and Na, and the co-catalyst is preferably potassium bromide.

[0051] Preferably, the molar ratio of the compound of formula II-1 in step 2 to the co-catalyst is 1:(0.01-0.1), more preferably 1:(0.01-0.05).

[0052] Preferably, the alkali in step 2 is selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, and sodium carbonate.

[0053] Preferably, the pH of the reaction system for the oxidation reaction in step 2 is 8-10.

[0054] Preferably, the molar ratio of compound II-1 to TEMPO in step 2 is 1:(0.05-1), more preferably 1:(0.05-0.5), for example 1:0.1.

[0055] In some embodiments of this application, the molar ratio of the compound of formula II-1 to sodium hypochlorite is 1:(0.1-3), preferably 1:(0.1-2).

[0056] In one specific embodiment of this application, the molar ratio of compound II-1 and sodium hypochlorite in step 2 is 1:1.2; the sodium hypochlorite is in equimolar amount with TEMPO or in excess.

[0057] Preferably, the solvent used in the oxidation reaction in step 2 is selected from one or more of alcohols, halogenated hydrocarbons, esters, ethers, ketones, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, or water, preferably acetone, benzene, toluene, xylene, tetrahydrofuran, n-heptane, N,N-dimethylformamide, diethyl ether, dioxane, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, acetonitrile, or water; more preferably tetrahydrofuran, dichloromethane, dichloroethane, chloroform, ethyl acetate, or water.

[0058] In some embodiments of this application, the reaction temperature of the oxidation reaction is 0-10°C.

[0059] In some embodiments of this application, the reaction time is 0.5-2 hours.

[0060] In some embodiments of this application, after the reaction in step 2) is completed, sodium thiosulfate is added to quench the reaction, the reaction solution is extracted with dichloromethane, all organic phases are combined, the product is collected by vacuum distillation at no more than 20°C to remove dichloromethane, and then the product is collected by vacuum distillation.

[0061] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0062] The reagents and raw materials used in this invention are all commercially available.

[0063] The main advantages of the method of the present invention are:

[0064] 1) Compared with the prior art, this application uses a cobalt catalyst with a catalytic amount and does not use flammable diethylzinc; it replaces the more expensive diiodomethane with the cheaper dibromomethane, which is more suitable for large-scale industrial production; and as can be seen from the examples, compared with the ethylzinc or zinc-copper catalytic system used in the prior art, the yield using the cobalt catalyst is as high as 92%, which is a significant increase in yield compared with the prior art.

[0065] 2) Unlike existing technologies, this method specifically incorporates a catalytic amount of elemental iodine. During implementation, the applicant unexpectedly discovered that the addition of elemental iodine significantly increased the reaction yield and greatly improved the preparation efficiency.

[0066] 3) Compared with the Dess-Martin oxidation and PCC, K2Cr2O7 and other oxidants commonly used in the prior art, the oxidation system composed of catalytic TEMPO reagent and sodium hypochlorite in this application greatly shortens the reaction time, simplifies the post-processing operation, and is more suitable for large-scale industrial production.

[0067] 4) Compared with the prior art, this application reduces the amount of materials and the material price is cheaper, while the two-step yield is increased by 20%, which greatly reduces the production cost. Detailed Implementation

[0068] The preparation method of the present invention is described in more detail below. However, it should be understood that the present invention is not limited to the specific reaction conditions given below (such as solvent, amount of compound used, reaction temperature, reaction time, etc.).

[0069] Example 1

[0070]

[0071] Add 75 mL of tetrahydrofuran to the reaction flask, then add 0.05 eq of [2-EtPDI]CoBr2 (R = Et, X = Br) cobalt salt catalyst. Stir and mix under nitrogen protection at 20-30 °C. Add zinc powder (3 eq, 116 g, 1.78 mol) and elemental I2 (0.02 eq, 3.05 g, 0.012 mol) all at once, and stir for 10 min. Dissolve 1-pent-3-enol (1.0 eq, 50 g, 0.594 mol) in 25 mL of tetrahydrofuran and add it to the reaction flask all at once, stirring for 10 min. Dilute dibromomethane (124 g, 0.713 mol) with 125 mL of THF and add it dropwise using a dropping funnel, controlling the temperature at 20-30 °C. After the addition is complete, continue stirring for 1 h. TLC monitoring shows the starting material spot has disappeared. The reaction solution was directly filtered, the filter cake was washed with 50 mL of DCM, the filtrate was concentrated to dryness to obtain the crude product, and purified by silica gel column chromatography with 0-30% hexane / ethyl acetate to obtain 53.6 g of product, with a yield of 92%. 1 H NMR (400MHz, CDCl3): δppm 4.36 (1H,m), 2.10-2.06 (2H,m), 1.75-1.71 (2H,d), 1.30-1.28 (2H,m), 0.56-0.47 (2H,m). GC-MS: m / z=98.1.

[0072] Example 2

[0073]

[0074] Add 75 mL of tetrahydrofuran to the reaction flask, followed by the cobalt salt catalyst [2-EtPDI]CoBr2 (0.05 eq). Stir and mix under nitrogen protection at 20-30 °C. Add 116 g of zinc powder (3 eq., 1.78 mol) and 30.5 g of elemental I2 (0.2 eq., 0.12 mol) all at once, and stir for 10 min. Dissolve 50 g of 1-pent-3-enol (1.0 eq., 0.594 mol) in 25 mL of tetrahydrofuran and add it to the reaction flask all at once, stirring for 10 min. Dilute dibromomethane (124 g, 0.713 mol) with 125 mL of THF and add it dropwise using a dropping funnel, controlling the temperature at 20-30 °C. After the addition is complete, continue stirring for 1 h. TLC monitoring shows the starting material spot has disappeared. The reaction solution was directly filtered, the filter cake was washed with 50 mL of DCM, the filtrate was concentrated to dryness to obtain the crude product, and purified by silica gel column chromatography with 0-30% hexane / ethyl acetate to obtain 37.9 g of product, with a yield of 65%.

[0075] Example 3

[0076]

[0077] Add 75 mL of methyl tert-butyl ether to the reaction flask, then add the cobalt salt catalyst [2-EtPDI]CoBr2 (0.05 eq) sequentially, and stir under nitrogen protection at 20-30 °C until homogeneous. Add 116 g of zinc powder (3 eq., 1.78 mol) and 30.5 g of elemental I2 (0.2 eq., 0.12 mol) all at once, and stir for 10 min. Dissolve 50 g of 1-pent-3-enol (1.0 eq., 0.594 mol) in 25 mL of methyl tert-butyl ether, and add it to the reaction flask all at once, stirring for 10 min. Dilute dibromomethane (124 g, 0.713 mol) with 125 mL of methyl tert-butyl ether, and add it dropwise using a dropping funnel, controlling the temperature at 20-30 °C. After the addition is complete, continue stirring for 1 h. TLC monitoring shows the starting material spot has disappeared. The reaction solution was directly filtered, and the filter cake was washed with 50 mL of methyl tert-butyl ether. The filtrate was concentrated to dryness to obtain the crude product, which was purified by silica gel column chromatography with 0-30% hexane / ethyl acetate to obtain 46.7 g of product, with a yield of 80%.

[0078] Example 4

[0079]

[0080] 482 g of compound 2 and 2.9 L of dichloromethane were added to a 10 L jacketed reactor. Under mechanical stirring at room temperature, 1440 mL of water, 76.9 g of TEMPO (0.10 eq, 492 mmol), potassium bromide (0.05 eq, 29.2 g, 246 mmol), and sodium bicarbonate (2.3 eq, 951 g, 11.3 mol) were added sequentially. The mixture was stirred for 10 min until clear, and the pH of the reaction system was 8-10. The mixture was cooled to 5-10 °C in an ice-water bath, and 3.6 kg of sodium hypochlorite aqueous solution (12% by mass) was slowly added dropwise. After the addition was complete, stirring was continued for 1 h. The reaction mixture was quenched with 200 g of sodium thiosulfate. The reaction solution was extracted with dichloromethane, all organic phases were combined, and the product was collected by concentrated distillation at 70 °C under reduced pressure, yielding 429 g of bicyclo[3.1.0]-3-hexanone, a pale yellow oily liquid, with a yield of 91%.

[0081] Example 5

[0082]

[0083] Add 75 mL of tetrahydrofuran to the reaction flask, followed by 0.05 eq of [2-EtPDI]CoBr2 cobalt salt catalyst. Stir and mix under nitrogen protection at 20-30 °C. Add 116 g of zinc powder (3 eq., 1.78 mol) and 3.05 g of elemental I2 (0.02 eq., 0.012 mol) all at once, and stir for 10 min. Dissolve 143.2 g of compound 4 (1.0 eq., 0.594 mol) in 50 mL of tetrahydrofuran and add it to the reaction flask all at once, stirring for 10 min. Dilute dibromomethane (124 g, 0.713 mol) with 125 mL of THF and add it dropwise using a dropping funnel, controlling the temperature at 20-30 °C. After the addition is complete, continue stirring for 2 h. TLC monitoring shows the starting material spot has disappeared. The reaction solution was directly filtered, the filter cake was washed with 50 mL of DCM, the filtrate was concentrated to dryness to obtain the crude product, and purified by silica gel column chromatography with 5-30% hexane / ethyl acetate to obtain 131.8 g of product, with a yield of 87%.

[0084] 1 H NMR (400MHz, CDCl3): δppm: 0.70-0.79(2H,m),1.17-1.19(3H,t),1.36(9H,s),1.49-1.53(1H,m),2.13-2.17 (1H,m),2.26-2.31(1H,m),3.36-3.46(1H,m),3.91-3.93(1H,m),4.08-4.14(2H,q).LC-MS:278.1m / z(M+Na).

[0085] Comparative Example 1

[0086]

[0087] Add 75 mL of tetrahydrofuran to the reaction flask, followed by the cobalt salt catalyst (0.05 eq). Stir and mix under nitrogen protection at 20-30 °C. Add 116 g of zinc powder (3 eq, 1.78 mol) all at once, and stir for 10 min. Dissolve 50 g of 1-pent-3-enol (1.0 eq, 0.594 mol) in 25 mL of tetrahydrofuran and add it to the reaction flask all at once, stirring for 10 min. Dilute dibromomethane (124 g, 0.713 mol) with 125 mL of THF and add it dropwise over 10-12 h, controlling the temperature at 20-30 °C. After the addition is complete, continue stirring for 1 h. TLC monitoring shows the starting material spot has disappeared. Filter the reaction solution directly, wash the filter cake with 50 mL of DCM, concentrate the filtrate to dryness to obtain the crude product, and purify it by silica gel column chromatography with 0-30% hexane / ethyl acetate to obtain 29.1 g of product, yield 50%. 1H NMR (400MHz, CDCl3): δ=2.62-2.55(m,2H), 2.18-2.13(m,2H), 1.53-1.44(m,2H), 0.94-0.88(m,1H), -0.08~-0.06(m,1H); GC-MS: m / z=96.1.

[0088] Comparative Example 2

[0089]

[0090] Add 200 mL of dichloromethane to a reaction flask, followed by zinc-copper reagent (116 g, 3 eq). Stir under nitrogen protection at 20-30 °C. Add 3.05 g of elemental I₂ ​​(0.02 eq., 0.012 mol) all at once, stirring for 10 min. Dissolve 50 g of 1-pent-3-enol (1.0 eq., 0.594 mol) in 25 mL of dichloromethane and add it all at once to the flask. Heat to 40 °C. Slowly add 321 g of diiodomethane (2.0 eq., 1.2 mol) diluted in 50 mL of dichloromethane dropwise at 40 °C. Continue stirring at 40 °C for 10-12 h. Filter the reaction solution directly. Wash the filter cake with 50 mL of DCM. Concentrate the filtrate to dryness to obtain the crude product. Purify by silica gel column chromatography with 0-30% hexane / ethyl acetate to obtain 11.67 g of product, yield 20%.

[0091] Comparative Example 3

[0092]

[0093] Add 200 mL of dry dichloromethane to the reaction flask, cool to 0 °C, and under nitrogen protection, add 1188 mL of 1 mol / L ethyl zinc solution (2.0 eq, 1.188 mol). Slowly add 1-pent-3-enol (1.0 eq, 50 g, 0.594 mol) dissolved in 25 mL of dichloromethane at 0 °C. Slowly add 50 mL of diiodomethane diluted with dichloromethane (2.0 eq, 321 g, 1.2 mol) over 30 min. After the addition is complete, raise the temperature to 20-30 °C and maintain the reaction at this temperature for 10-12 h. Add 100 mL of saturated ammonium chloride aqueous solution to the reaction mixture, extract with dichloromethane (200 mL * 2), concentrate under reduced pressure to obtain the crude product, and purify by silica gel column chromatography with 0-30% hexane / ethyl acetate to obtain 29.2 g of product, yield 50%.

[0094] As can be seen from the above examples and comparative examples, the method for synthesizing bicyclo[3.1.0]-3-hexanone provided in this application, by using a cobalt catalyst, avoids the use of hazardous reagents and achieves a yield of 92%, which is significantly higher than that of the prior art. Furthermore, the reaction time is greatly shortened, and the post-processing operations are simpler. At the same time, the addition of a specific amount of iodine as a catalyst unexpectedly and greatly enhances the reaction yield.

[0095] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for preparing compound II, the synthetic route of which is as follows: It includes the following steps: Step 1: In the presence of a cobalt salt catalyst, zinc, and a catalytic amount of iodine, compound I undergoes a cyclization reaction with a dihalomethane to give compound II; in, R2 is selected from OP1 or -COOP2, where P1 is H or a hydroxyl protecting group; P2 is H, a C1-C6 alkyl group, or a C6-C6 alkyl group. 10 Aryl, C6-C 10 Aryl-C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C6-alkyl, heterocyclic or heterocyclic-C1-C6 alkyl, wherein the ring of each aryl or heterocyclic group is optionally substituted with a substituent selected from the following: halogen, C1-C7 alkyl, C1-C7 alkyl substituted with F, Cl, Br or I halogen, C1-C7 alkoxy, C1-C7 alkoxy and C1-C7 alkoxy-C1-C7 alkyl substituted with F, Cl, Br or I halogen; X2 is selected from C or N: When X2 is a C atom, R1 is H, halogen, C1-C6 alkyl or alkoxy, and C1-C6 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl; When X2 is an N atom, R1 is chosen from any amino protecting group; The cobalt salt catalyst is shown in Formula IV and has the following structure: Wherein, R is selected from methyl, ethyl, n-propyl, isopropyl, or n-butyl; X is selected from halogens; The molar ratio of compound I and iodine in step 1 is 1:(0.01-0.2).

2. The preparation method according to claim 1, characterized in that, The P2 is selected from methyl, ethyl, isopropyl, tert-butyl, tert-amyl, p-pentyl, phenyl, or benzyl. And / or, the hydroxyl protecting group is selected from benzyl, -COR3, wherein the R3 is selected from C1-C5 alkyl, phenyl; And / or, R1 may be selected from an amino protecting group, which is selected from benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenmethoxycarbonyl, p-toluenesulfonyl, methanesulfonyl, acetyl, or benzoyl.

3. The preparation method according to claim 1, characterized in that, The hydroxyl protecting group is selected from one of benzyl, p-methoxybenzyl, p-nitrobenzyl, acetyl, benzoyl, formyl, benzyloxycarbonyl, trifluoroacetyl, and chloroacetyl.

4. A method for preparing compound III, the synthetic route is as follows: in, The definitions of substituents R1 and X2 are the same as those of each substituent in claim 1 or 2; The specific steps are as follows: Step 1: In the presence of a cobalt salt catalyst, zinc, and a catalytic amount of iodine, compound I-1 undergoes a cyclization reaction with dihalomethane to give compound II-1; Step 2: Compound II-1 is oxidized in the presence of an oxidant, a base, and a co-catalyst to obtain compound III; The cobalt salt catalyst is shown in Formula IV and has the following structure: Wherein, R is selected from methyl, ethyl, n-propyl, isopropyl, or n-butyl; X is selected from halogens; The molar ratio of compound I-1 to iodine in step 1 is 1:(0.01-0.2).

5. The preparation method according to claim 1 or 4, characterized in that, The preparation method satisfies one or more of the following conditions: (1) In the cyclization reaction of compound I or compound I-1 with dihalomethane: the molar ratio of compound I or compound I-1 to cobalt salt catalyst is 1:(0.01-0.1). (2) X in the cobalt salt catalyst of formula IV is selected from Cl, Br, and I.

6. The preparation method according to claim 1 or 4, characterized in that, The solvent used in the cyclization reaction of compound I or compound I-1 with dihalomethane is selected from one or any combination of ether solvents, alcohol solvents, haloalkanes, aromatic alkanes or alkane solvents.

7. The preparation method according to claim 1 or 4, characterized in that, In step 1, during the cyclization reaction of compound I or compound I-1 with dihalomethane, one or more of the following conditions are met: 1) The halogens in the dihalomethanes are each independently selected from F, Cl, Br or I; 2) The molar ratio of compound I or compound I-1 in step 1 to dihalomethane is 1:(1-3); 3) The molar ratio of compound I or compound I-1 in step 1 to zinc is 1:(1-5); 4) The molar ratio of compound I or compound I-1 in step 1 to iodine is 1:(0.01-0.1); 5) The reaction temperature for the cyclization reaction described in step 1 is 10-40℃; 6) The cyclization reaction in step 1 takes 0.5-5 hours; 7) In the cyclization reaction of compound I or compound I-1 with dihalomethane: the molar ratio of compound I or compound I-1 to cobalt salt catalyst is 1:(0.02-0.08). 8) The solvent used in the cyclization reaction of compound I or compound I-1 with dihalomethane is selected from diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dioxane, methanol, isopropanol, dichloromethane, dichloroethane, toluene, n-heptane, and 1,2-dimethoxyethane.

8. The preparation method according to claim 7, characterized in that, The preparation method satisfies one or more of the following conditions: 1) The molar ratio of compound I or compound I-1 in step 1 to dihalomethane is 1:(1-2); 2) The molar ratio of compound I or compound I-1 in step 1 to zinc is 1:(1.5-4). 3) The molar ratio of compound I or compound I-1 in step 1 to iodine is 1:(0.01-0.05); 4) The reaction temperature for the cyclization reaction described in step 1 is 15-35℃; 5) The cyclization reaction in step 1 takes 1-5 hours; 6) In the cyclization reaction of compound I or compound I-1 with dihalomethane: the molar ratio of compound I or compound I-1 to cobalt salt catalyst is 1:(0.02-0.05). 7) The solvent used in the cyclization reaction of compound I or compound I-1 with dihalomethane is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, dichloromethane, dichloroethane, toluene, and 1,2-dimethoxyethane.

9. The preparation method according to claim 4, characterized in that, Step 2: The oxidant in step 2 is a combination of TEMPO and sodium hypochlorite; And / or, in step 2, the molar ratio of compound II-1 to TEMPO is 1:(0.05-1). And / or, the molar ratio of the compound of formula II-1 to sodium hypochlorite is 1:(0.1-3).

10. The preparation method according to claim 9, characterized in that, The preparation method satisfies one or more of the following conditions: 1) In step 2, the molar ratio of compound II-1 to TEMPO is 1:(0.05-0.5). 2) The molar ratio of the compound of formula II-1 and sodium hypochlorite is 1:(0.1-2).

11. The preparation method according to claim 9 or 10, characterized in that, In step 2, the molar ratio of compound II-1 and sodium hypochlorite is 1:1.

2.

12. The preparation method according to claim 4, characterized in that, The co-catalyst in step 2 is a brominated alkali metal or an iodinated alkali metal, wherein the alkali metal is selected from K and Na.

13. The preparation method according to claim 4 or 11, characterized in that, Step 2 satisfies one or more of the following conditions: 1) The molar ratio of the compound of formula II-1 in step 2 to the co-catalyst is 1:(0.01-0.1); 2) The alkali used in step 2 is selected from potassium bicarbonate, sodium bicarbonate, potassium carbonate, and sodium carbonate; 3) The pH of the reaction system for the oxidation reaction in step 2 is 8-10; 4) The solvent used in the oxidation reaction in step 2 is selected from one or more of alcohols, halogenated hydrocarbons, esters, ethers, ketones, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, or water; 5) The reaction temperature for the oxidation reaction in step 2 is 0-10℃; 6) The reaction time for the oxidation reaction in step 2 is 0.5-2 hours; 7) The co-catalyst in step 2 is potassium bromide.

14. The preparation method according to claim 13, characterized in that, Step 2 satisfies one or more of the following conditions: 1) The molar ratio of the compound of formula II-1 in step 2 to the co-catalyst is 1:(0.01-0.05); 2) The solvent used in the oxidation reaction in step 2 is selected from one or more of the following: acetone, benzene, toluene, xylene, tetrahydrofuran, n-heptane, N,N-dimethylformamide, diethyl ether, dioxane, dichloromethane, dichloroethane, chloroform, ethyl acetate, methanol, ethanol, isopropanol, propanol, acetonitrile, and water.

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