Method for removing isomer impurities of epoxy intermediate through selective hydrolysis

Abstract

The invention provides a method for removing isomer impurities of an epoxy intermediate through selective hydrolysis, which comprises the following step: in the atmosphere of air or oxygen, reacting a compound shown in a formula II under the action of acid, a Co or Cr metal catalyst and water to obtain a compound shown in a formula I, according to the method, the isomer impurity III can be reduced by 0.2% or below, the synthesis route is high in reaction repeatability and simple in post-treatment, the production cost of purification, preparation, separation and the like in the subsequent production process is reduced, and the method is suitable for industrial production. Wherein R1 and R2 in the imgabs0 # are both independently selected from H; a hydroxyl protecting group; # imgabs1 # R3 is selected from H or a hydroxyl protecting group, and n is equal to 1-5; or R1, R2 together form a vicinal diol protecting group # imgabs2 # wherein R4 and R5 independently represent H, a C1-5 linear or branched alkyl group, or phenyl or a substituted phenyl group wherein the substituted phenyl group is preferably a phenyl group substituted by a methoxy group, a halogen, a cyano group, a nitro group, a C1-5 linear or branched alkyl group.

Description

Technical Field

[0001] The invention relates to a method for selectively hydrolyzing epoxy intermediate isomer impurities, and more specifically provides a method for selectively hydrolyzing and removing idecalcitol epoxy intermediate isomer impurities, belonging to the field of organic synthesis. Background Art

[0002] Idecalcitol ((1R,2R,3R,5Z,7E)-2-(3-hydroxypropoxy)-9,10-openocholesterol-5,7,10(19)-triene-1,3,25-triol) is the active pharmaceutical ingredient (API) of Edirol, an osteoporosis treatment agent. It is a vitamin D drug jointly developed by Chugai Pharmaceutical and Zhengda Pharmaceutical for the treatment of osteoporosis. It was first launched in Japan in 2011 under the trade name Edirol. The structural formula is as follows:

[0003]

[0004] Patent WO2018093223A discloses a method for preparing the A ring of idecalcitol, and its synthesis route is as follows:

[0005]

[0006] This route uses D-mannitol as the chiral source, has a short route, short cycle, and low cost. Although it greatly improves the stereoselectivity of the product, the intermediate epoxide compound has about 5% racemic isomers. As shown in the figure below, the isomer impurity will extend to the API of idecalcitol through subsequent reactions and then needs to be purified by preparative chromatography to remove the impurity. However, the removal of the impurity is extremely difficult and the purification cost is high. At the same time, in other routes for synthesizing idecalcitol API, this site will also produce isomers.

[0007]

[0008] In summary, the removal of isomeric impurities in the synthesis of idecalcitol in the prior art is extremely difficult and the purification cost is high, and a simple method is needed in the art to remove the isomeric impurities. Based on this, the present invention provides a new method to remove the isomeric impurities, further reducing the production costs of purification, preparation and separation in the subsequent production process. Summary of the invention

[0009] The present invention relates to a method for selectively hydrolyzing isomeric impurities of an epoxy intermediate, and more specifically provides a method for selectively hydrolyzing and removing isomeric impurities of an idecalciferol epoxy intermediate, which can effectively remove isomeric impurities at the site and is suitable for industrial production. Based on this, we selectively hydrolyze and split epoxy compounds by chemical methods, effectively removing isomeric impurities at the site.

[0010] The present invention provides a method for selectively hydrolyzing and removing isomer impurities of an epoxy intermediate, and more specifically relates to a method for preparing high-purity epoxy resin of formula I.

[0011] The first aspect of the present invention provides a method for preparing a high-purity compound of formula I, comprising the following steps: reacting a compound of formula II in the presence of an acid, a Co or Cr metal catalyst and water in air or in an oxygen atmosphere to obtain a compound of formula I, wherein the reaction formula is as follows:

[0012]

[0013] wherein R1 and R2 are independently selected from H; a hydroxyl protecting group; R3 is selected from H or a hydroxyl protecting group, n = 1-5; or R1 and R2 together form a vicinal diol protecting group Wherein R4 and R5 independently represent H, C1-5 straight chain or branched alkyl, or phenyl or substituted phenyl, wherein the substituted phenyl is preferably phenyl substituted by methoxy, halogen, cyano, nitro, C1-5 straight chain or branched alkyl;

[0014] R1, R2, and R3 are all independently selected from hydroxyl protecting groups; the hydroxyl protecting groups described in the present invention can refer to Greene TW, Wuts PGM, East China University of Science and Technology. Protective Groups in Organic Synthesis [M]. East China University of Science and Technology Press, 2004. For those skilled in the art, the role of "protecting groups" is to temporarily protect certain groups from reaction in certain circumstances and can be deprotected under certain conditions;

[0015] The present invention further preferably selects the hydroxy protecting group to be selected from silyl ether protecting group, pivaloyl, benzoyl, acetyl, tetrahydropyranyl, methoxymethyl ether, trityl, benzyloxycarbonyl, allyl, benzyl or benzyl whose benzene ring is substituted by methoxy, halogen, cyano, nitro, C1-5 straight chain or branched alkyl at will; wherein the silyl ether protecting group is preferably selected from silyl ether protecting group substituted by alkyl or aryl such as tert-butyldimethylsilyl (TBS), triethylsilyl (TES), triisopropylsilyl (TIPS), trimethylsilyl (TMS), tert-butyldiisopropylsilyl, diphenylmethylsilyl, dimethylphenylsilyl and the like.

[0016] Further, the hydroxy protecting group of the present invention is preferably any one of tert-butyldimethylsilyl (TBS), triethylsilyl (TES), triisopropylsilyl (TIPS), trimethylsilyl (TMS), tert-butyldiisopropylsilyl, diphenylmethylsilyl, dimethylphenylsilyl, pivaloyl, benzoyl, acetyl, benzyl, tetrahydropyranyl, methoxymethyl ether, trityl, benzyloxycarbonyl, allyl, and p-methoxybenzyl.

[0017] Preferably, the content of the isomer impurity of formula III in the obtained compound of formula I is less than or equal to 0.5%, more preferably less than or equal to 0.3% or 0.2%.

[0018] The second aspect of the present invention provides a method for preparing a high-purity compound of formula I1, and the reaction formula is as follows:

[0019]

[0020] wherein R2 is selected from a hydroxyl protecting group; the hydroxyl protecting group is preferably pivaloyl, benzoyl, acetyl, tetrahydropyranyl, methoxymethyl ether, trityl, benzyloxycarbonyl, allyl, benzyl or a benzyl group in which the benzene ring is arbitrarily substituted by methoxy, halogen, cyano, nitro, C1-5 straight chain or branched alkyl, preferably p-methoxybenzyl, benzyl or a benzene ring group;

[0021] The steps include:

[0022] In air or in an oxygen atmosphere, the compound of formula II1 reacts with an acid, a Co or Cr metal catalyst and water to obtain a compound of formula I1;

[0023] Preferably, the content of the isomer impurity of formula III1 in the obtained compound of formula I1 is less than or equal to 0.5%, more preferably less than or equal to 0.3% or 0.2%.

[0024] The third aspect of the present invention provides a method for preparing a high-purity compound of formula I2, and the reaction formula is as follows:

[0025]

[0026] Wherein R2, R3 are H or hydroxyl protecting groups;

[0027] When R2 is a hydroxy protecting group, it is preferably pivaloyl, benzoyl, acetyl, tetrahydropyranyl, methoxymethyl ether, trityl, benzyloxycarbonyl, allyl, benzyl or a benzyl group in which the benzene ring is arbitrarily substituted by methoxy, halogen, cyano, nitro, or a C1-5 straight or branched alkyl group, preferably p-methoxybenzyl;

[0028] When R3 is a hydroxy protecting group, a silyl ether protecting group is preferred; wherein the silyl ether protecting group is preferably selected from alkyl or aryl substituted silyl ether protecting groups such as tert-butyldimethylsilyl (TBS), triethylsilyl (TES), triisopropylsilyl (TIPS), trimethylsilyl (TMS), tert-butyldiisopropylsilyl, diphenylmethylsilyl, dimethylphenylsilyl, etc.; tert-butyldimethylsilyl (TBS) is further preferred;

[0029] The steps include:

[0030] In air or in an atmosphere of oxygen, the compound of formula II2 reacts under the action of an acid, a Co or Cr metal catalyst and water to obtain a compound of formula I2;

[0031] Preferably, the content of the isomer impurity of formula III2 in the obtained compound of formula I2 is less than or equal to 0.5%, more preferably less than or equal to 0.3% or 0.2%.

[0032] The fourth aspect of the present invention provides a method for preparing a high-purity compound of formula I3, and the reaction formula is as follows:

[0033]

[0034] Wherein R4 and R5 independently represent H, C1-5 straight chain or branched alkyl, or phenyl or substituted phenyl, wherein the substituted phenyl is preferably substituted by methoxy, halogen, cyano, nitro, C1-5 straight chain or branched alkyl; preferably R4 represents H and R5 represents p-methoxybenzyl.

[0035] The steps include:

[0036] In air or in an atmosphere of oxygen, the compound of formula II3 reacts under the action of an acid, a Co or Cr metal catalyst and water to obtain a compound of formula I3;

[0037] Preferably, the content of the isomer impurity of formula III3 in the obtained compound of formula I3 is less than or equal to 0.5%, more preferably less than or equal to 0.3% or 0.2%.

[0038] Referring to all the above technical solutions, the first aspect, the second aspect, the third aspect or the fourth aspect of the present invention respectively provides a method for preparing a high-purity compound of formula I, formula I1, formula I2 or formula I3;

[0039] Furthermore, a method for preparing a high-purity compound of formula I, formula I1, formula I2 or formula I3 is provided, wherein the preparation method can be carried out in a solvent-free environment or in an organic solvent.

[0040] Further, the organic solvent is selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, ethyl ether, dimethyl sulfoxide or any mixture of the above solvents, preferably one of tetrahydrofuran and dioxane or a combination thereof;

[0041] Further, a method for preparing a high-purity compound of formula I, formula I1, formula I2 or formula I3, wherein the acid in the preparation method is selected from acetic acid, benzoic acid, propionic acid, p-nitrobenzoic acid, p-toluenesulfonic acid, and acetic acid is further preferred;

[0042] Further, a method for preparing a high-purity compound of formula I, formula I1, formula I2 or formula I3, wherein the Co or Cr metal catalyst is represented by the general formula: (R,R)-Salen-M(L);

[0043] wherein the metal atom M is selected from Co or Cr;

[0044] When M is Co, L is selected from, for example, H, OAc, Cl, OTs, SbF6, OPh;

[0045] When M is Cr, L is selected from, for example, chloride ion, iodide ion, azide ion;

[0046] Furthermore, the catalyst is preferably (R,R)-Salen-Co (R,R)-SalenCr(Cl)

[0047]

[0048] Furthermore, the molar feed ratio of the epoxy isomer impurity to the acid in the compound II, II1, II2 or II3 is 1:0.02 to 0.1, for example, 1:0.02 to 0.05;

[0049] Further, the molar feed ratio of the compound II, II1, II2 or II3 epoxy isomer impurity to the catalyst is 1:0.02 to 0.1, for example, 1:0.03 to 0.05;

[0050] Further, the molar feed ratio of the epoxy isomer impurity to H2O in compound II, II1, II2 or II3 is 1:1.0 to 1.15, for example, 1:1 to 1.05;

[0051] Further, the epoxy isomer impurity structure in compound II, II1, II2 or II3 is as follows:

[0052]

[0053] Further, the reaction temperature is 10-60°C, and the reaction time is 10-48 hours; for example, the reaction temperature is 20-40°C, and the reaction time is 15-24 hours.

[0054] The present invention can selectively perform post-treatment on the reaction. In a further preferred technical scheme, after the reaction is completed, the reaction solvent is concentrated to remove the reaction solvent, and after being treated by a post-treatment extraction system, the product I is concentrated.

[0055] Furthermore, the extraction system is selected from alcohol solvent / water / alkane solvent; the alcohol solvent is selected from methanol, ethanol, isopropanol; the alkane solvent is selected from petroleum ether, n-hexane, n-heptane, cyclohexane; preferably methanol / water / n-hexane, ethanol / water / n-hexane, acetonitrile / water / n-hexane.

[0056] The fifth aspect of the present invention provides a method for preparing high-purity idecalcitol, comprising all the technical solutions described above; more specifically, the first aspect, the second aspect, the third aspect or the fourth aspect of the present invention respectively provides a method for preparing a high-purity compound of formula I, formula I1, formula I2 or formula I3.

[0057] Furthermore, the present invention provides a method for preparing compound IIC, and the reaction formula is as follows:

[0058]

[0059] Furthermore, the general preparation method is to dissolve compound B1 in dichloromethane and water, add 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), remove the p-methoxybenzyloxy group at room temperature to obtain compound B2, and compound B2 reacts with p-methoxybenzaldehyde under acidic conditions (p-toluenesulfonic acid) to form an acetal to obtain compound IIC.

[0060] The advantages of the method of the present invention mainly lie in:

[0061] 1. The present invention provides a method for selectively hydrolyzing epoxy intermediate isomer impurities, and more specifically provides a method for selectively hydrolyzing and removing idecalciferol epoxy intermediate isomer impurities; for example, removing the following epoxy isomer impurities:

[0062]

[0063] 2. The synthetic route of the present invention has high reaction repeatability, simple post-processing, reduces the production costs of purification, preparation and separation in the subsequent production process, and is suitable for industrial production; in the preferred technical scheme of the present invention, if the impurity content of the S-epoxy isomer is high, the reaction formula is as follows:

[0064]

[0065] The inventors of the present application have proved through experiments that the S-epoxy isomer impurity will be carried over to subsequent reaction products and cannot be purified by other purification methods such as conventional crystallization or extraction.

[0066] 3. The present invention selectively hydrolyzes and splits the epoxy compound by chemical methods, effectively removing the isomeric impurities at the site, and the isomeric impurities can be reduced to 0.2% or less. The catalyst load and reaction repeatability are high, the post-processing is simple, and the production costs such as purification, preparation and separation in the subsequent production process are reduced, which is more conducive to the commercial production of the product.

[0067] 4. The Co or Cr metal catalyst of the present invention also has the advantages of small dosage, high splitting efficiency, easy recovery and no deactivation in the application of hydrolysis kinetic splitting of various terminal epoxide compounds.

[0068] 5. The process of the present invention has good reproducibility; by preferably using acetic acid as a promoter, isomeric impurities are removed by extraction, and a lower Co or Cr metal catalyst is required to obtain highly enantiomerically enriched epoxides. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 HPLC spectrum of raw material IIA in Example 1;

[0070] Figure 2 is the HPLC spectrum of compound IA in Example 1;

[0071] Figure 3 is the HPLC spectrum of compound IA in Example 2;

[0072] Figure 4 is the HPLC spectrum of compound IA in Example 3;

[0073] Figure 5 It is the HPLC spectrum of compound IA in Example 4. Specific embodiments

[0074] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under normal conditions.

[0075] Unless otherwise specified, the raw materials and reagents used in the examples are commercially available.

[0076] The room temperature in the examples refers to 20-35° C. Unless otherwise specified, the reagents were used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and used without treatment.

[0077] The chromatographic column of the HPLC spectrum in Example 1 is Welch Xtimate C18 150*4.6mm*3.5μm (A-RP-1390), and the instrument is Thermo Vanquish (HPLC-60);

[0078] The chromatographic column of the HPLC spectrum in Example 2 is Welch Xtimate C18 150*4.6mm*3.5μm (A-RP-532), and the instrument is Agilent 1260II (HPLC-24)

[0079] Preparation of compound IA:

[0080]

[0081] Example 1

[0082] Compound IIA (50 g, 0.2 mol, purity 94.68%, isomer 4.57%, HPLC spectrum as shown Figure 1 ), dissolved in 50 mL of tetrahydrofuran, added with catalyst (R,R)-Co-salen (0.24 g, 0.0004 mol) at room temperature; added with acetic acid (0.024 g, 0.0004 mol) at room temperature; protected with oxygen; added with water (0.18 g, 0.01 mol) at room temperature; reacted at room temperature for 16 h; after the reaction, the reaction solution was directly concentrated to remove tetrahydrofuran, methanol and water were added, and the solution was extracted and concentrated with n-hexane to obtain IA as a light yellow oily substance (47 g), with 0.16% isomer and a purity of 99.67%. The HPLC spectrum is shown in 2.

[0083] Example 2

[0084] Compound IIA (50 g, 0.2 mol, purity 94.68%, isomer 4.57%, HPLC spectrum as shown Figure 1 14.0 g, 0.01 mol) was dissolved in 50 mL of dioxane, and a catalyst (R,R)-Co-salen (0.24 g, 0.0004 mol) was added at room temperature; acetic acid (0.024 g, 0.0004 mol) was added at room temperature; oxygen protection was applied; water (0.18 g, 0.01 mol) was added at room temperature; the mixture was reacted at room temperature for 16 h; after the reaction, the dioxane was directly concentrated, methanol and water were added, and the mixture was extracted and concentrated with n-hexane to obtain IA as a light yellow oil (46.2 g), with an isomer content of 0.28% and a purity of 99.09%. The HPLC spectrum is shown in Figure 3.

[0085] Example 3

[0086] Compound IIA (50 g, 0.2 mol, purity 94.68%, isomer 4.57%, HPLC spectrum as shown Figure 11. The reaction mixture was stirred for 1 h at room temperature for 2 h. After the reaction, the tetrahydrofuran was removed from the reaction mixture, methanol and water were added, and the mixture was extracted and concentrated with n-hexane to obtain IA as a light yellow oily substance (46.4 g), with an isomer content of 0.39% and a purity of 99.5%. The HPLC spectrum is shown in Figure 4.

[0087] Example 4

[0088] Compound IIA (50 g, 0.2 mol, purity 94.68%, isomer 4.57%, HPLC spectrum as shown Figure 1 The mixture was added into a reaction bottle, and a catalyst (R,R)-Co-salen (0.24 g, 0.0004 mol) was added at room temperature. Acetic acid (0.024 g, 0.0004 mol) was added at room temperature. Under oxygen protection, water (0.18 g, 0.01 mol) was added at room temperature. The mixture was reacted at room temperature for 21 hours. After the reaction was completed, the reaction solution was directly concentrated to remove tetrahydrofuran. Ethanol and water were added. The mixture was extracted and concentrated with n-hexane to obtain IA as a light yellow oil (46 g), with an isomer content of 0.35% and a purity of 99.5%. The HPLC spectrum was shown in Figure 5.

[0089] Example 5

[0090] Compound IIA (50 g, 0.2 mol, purity 94.68%, isomer 4.57%, HPLC spectrum as shown Figure 1 The product was dissolved in 50 mL of tetrahydrofuran, and the catalyst (R,R)-Co-salen (0.24 g, 0.0004 mol) was added at room temperature. Acetic acid (0.024 g, 0.0004 mol) was added at room temperature. Under air protection, water (0.18 g, 0.01 mol) was added at room temperature. The reaction was carried out for 21 h at room temperature. After the reaction was completed, the reaction solution was directly concentrated to remove the tetrahydrofuran, methanol and water were added, and the product was extracted and concentrated with n-hexane to obtain IA as a light yellow oily substance (47 g), with an isomer content of 0.2% and a purity of 99.8%.

[0091] Example 6

[0092] Compound IIA (50 g, 0.2 mol, purity 94.68%, isomer 4.57%, HPLC spectrum as shown Figure 1The reaction mixture was stirred for 24 hours at room temperature (as shown in the figure). The reaction mixture was dissolved in 50 mL of tetrahydrofuran. A catalyst (R,R)-Co-salen (0.24 g, 0.0004 mol) was added at room temperature. Acetic acid (0.024 g, 0.0004 mol) was added at room temperature. Under oxygen protection, water (0.18 g, 0.01 mol) was added at room temperature. The mixture was reacted at room temperature for 21 hours. After the reaction was completed, the tetrahydrofuran was directly removed from the reaction mixture. Ethanol and water were added. The mixture was extracted and concentrated with n-hexane to obtain IA as a light yellow oily substance (46 g), with an isomer content of 0.2% and a purity of 99.5%.

[0093] Example 7

[0094] Compound IIA (25 g, 0.1 mol, purity 94.68%, isomer 4.57%, HPLC spectrum as shown Figure 1 1, 2-(4-(4-(4-hydroxy-2-nitropropene)-2-yl)-2-nitropropene (as shown) was dissolved in 25 mL of tetrahydrofuran, and a catalyst (R,R)-SalenCr(Cl) (0.12 g, 0.0002 mol) was added at room temperature; acetic acid (0.012 g, 0.0002 mol) was added at room temperature; oxygen protection was applied; water (0.09 g, 0.005 mol) was added at room temperature; the mixture was reacted at room temperature for 16 h; after the reaction, the tetrahydrofuran was directly removed from the reaction solution, methanol and water were added, and the mixture was extracted and concentrated with n-hexane to obtain IA as a light yellow oily substance (23.5 g), with 0.4% isomer and a purity of 99%.

[0095] Preparation of Compound IB:

[0096]

[0097] Compound IIB (84 g, 0.2 mol, 94.68% purity) was dissolved in 84 mL of tetrahydrofuran, and catalyst (R,R)-Co-salen (0.24 g, 0.0004 mol) was added at room temperature. Acetic acid (0.024 g, 0.0004 mol) was added at room temperature. Under oxygen protection, water (0.18 g, 0.01 mol) was added at room temperature. The mixture was reacted at room temperature for 16 h. After the reaction was completed, the reaction solution was directly concentrated to remove tetrahydrofuran, methanol and water were added, and the mixture was extracted and concentrated with n-hexane to obtain 78.2 g of IB as a light yellow oil, 0.2% isomer, and 99.8% purity.

[0098] Preparation of compound IC:

[0099]

[0100] Compound IIC (49.7 g, 0.2 mol, 94.68% purity) was dissolved in 84 mL of tetrahydrofuran, and catalyst (R,R)-Co-salen (0.24 g, 0.0004 mol) was added at room temperature; acetic acid (0.024 g, 0.0004 mol) was added at room temperature; oxygen protection was applied; water (0.18 g, 0.01 mol) was added at room temperature; the reaction was carried out at room temperature for 16 h; after the reaction, the reaction solution was directly concentrated to remove tetrahydrofuran, methanol and water were added, and the product IC was extracted and concentrated with n-hexane to obtain 46.3 g of light yellow oil, 0.2% isomer, and a purity of 99.8%.

Claims

1. A method for selectively hydrolyzing and removing isomeric impurities of epoxy intermediates, characterized in that: The method comprises the following steps: reacting a compound of formula II in the presence of an acid, a Co or Cr metal catalyst and water in air or in an oxygen atmosphere to obtain a compound of formula I; wherein R1 and R2 are independently selected from H; a hydroxyl protecting group; R3 is selected from H or a hydroxyl protecting group, n = 1-5; or R1 and R2 together form a vicinal diol protecting group Preferably, the hydroxy protecting group is selected from a silyl ether protecting group, a pivaloyl group, a benzoyl group, an acetyl group, a tetrahydropyran group, a methoxymethyl ether, a trityl group, a benzyloxycarbonyl group, an allyl group, a benzyl group or a benzyl group whose benzene ring is arbitrarily substituted with a methoxy group, a halogen group, a cyano group, a nitro group, or a C1-5 straight chain or branched chain alkyl group; wherein the silyl ether protecting group is preferably selected from a silyl ether protecting group substituted with an alkyl group or an aryl group such as tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilyl, tert-butyldiisopropylsilyl, diphenylmethylsilyl, dimethylphenylsilyl or the like; wherein R4 and R5 independently represent H, a C1-5 straight chain or branched chain alkyl group, or a phenyl group or a substituted phenyl group, wherein the substituted phenyl group is preferably a phenyl group substituted with a methoxy group, a halogen group, a cyano group, a nitro group, or a C1-5 straight chain or branched chain alkyl group.

2. The method according to claim 1, characterized in that: It includes the following methods: Method 1: In air or in an oxygen atmosphere, the compound of formula II1 reacts with an acid, a Co or Cr metal catalyst and water to obtain a compound of formula I1; wherein R2 is selected from a hydroxyl protecting group; the hydroxyl protecting group is preferably pivaloyl, benzoyl, acetyl, tetrahydropyranyl, methoxymethyl ether, trityl, benzyloxycarbonyl, allyl, benzyl or a benzyl group in which the benzene ring is arbitrarily substituted by methoxy, halogen, cyano, nitro, C1-5 straight chain or branched alkyl, and further preferably p-methoxybenzyl; Method 2: In air or in an oxygen atmosphere, the compound of formula II2 reacts under the action of an acid, a Co or Cr metal catalyst and water to obtain a compound of formula I2; Wherein R2, R3 are H or hydroxyl protecting groups; When R2 is a hydroxy protecting group, it is preferably pivaloyl, benzoyl, acetyl, tetrahydropyranyl, methoxymethyl ether, trityl, benzyloxycarbonyl, allyl, benzyl or a benzyl group in which the benzene ring is arbitrarily substituted by methoxy, halogen, cyano, nitro, or a C1-5 straight or branched alkyl group, preferably p-methoxybenzyl; When R3 is a hydroxyl protecting group, a silyl ether protecting group is preferred; wherein the silyl ether protecting group is preferably selected from alkyl or aryl substituted silyl ether protecting groups such as tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilyl, tert-butyldiisopropylsilyl, diphenylmethylsilyl, and dimethylphenylsilyl; and tert-butyldimethylsilyl is further preferred; Method 3: In air or in an oxygen atmosphere, the compound of formula II3 reacts under the action of an acid, a Co or Cr metal catalyst and water to obtain a compound of formula I3; Wherein R4 and R5 independently represent H, C1-5 straight chain or branched alkyl, or phenyl or substituted phenyl, wherein the substituted phenyl is preferably substituted by methoxy, halogen, cyano, nitro, C1-5 straight chain or branched alkyl; preferably R4 represents H and R5 represents p-methoxybenzyl.

3. The method according to any one of claims 1 to 2, characterized in that: The acid is selected from acetic acid, benzoic acid, propionic acid, p-nitrobenzoic acid, and p-toluenesulfonic acid.

4. The method according to any one of claims 1 to 2, characterized in that: The Co or Cr metal catalyst is selected from 5. The catalyst according to claim 4, characterized in that When the catalyst metal atom M is selected from Co, L is selected from H, OAc, Cl, OTs, SbF6, OPh, preferably H; when the catalyst metal atom M is selected from Cr, L is selected from chloride ion, iodide ion, azide ion.

6. The method according to any one of claims 1 to 2, characterized in that: The molar feed ratio of the epoxy isomer impurity to the acid in the compound II, II1, II2 or II3 is 1:0.02-0.1, preferably 1:0.02-0.

05. Preferably, the molar feed ratio of the compound II, II1, II2 or II3 epoxy isomer impurity to the catalyst is 1:0.02 to 0.1, preferably 1:0.03 to 0.05; Preferably, the molar feed ratio of epoxy isomer impurities to H2O in compound II, II1, II2 or II3 is 1:1.0 to 1.15, preferably 1:1 to 1.05; The structures of the epoxy isomer impurities in compounds II, II1, II2 or II3 are as follows:

7. The method according to any one of claims 1 to 2, characterized in that: The reaction is preferably carried out in a solvent selected from tetrahydrofuran, dichloromethane, acetonitrile, dioxane, 2-methyltetrahydrofuran, toluene, N,N-dimethylformamide, methyl tert-butyl ether, diethyl ether, dimethyl sulfoxide or any mixture of the above solvents.

8. The method according to any one of claims 1 to 2, characterized in that: The reaction temperature is 10-60°C and the reaction time is 10-48 hours; preferably, the reaction temperature is 20-40°C and the reaction time is 15-24 hours; Or / and, further preferably, after the reaction is completed, the reaction solvent is concentrated to remove the reaction solvent, and after being treated with a post-treatment extraction system, the product is concentrated to obtain the product, and the post-treatment extraction system is selected from methanol / water / n-hexane, ethanol / water / n-hexane, acetonitrile / water / n-hexane.

9. The method according to claim 1, characterized in that The content of the isomer impurity of formula III in the compound of formula I is less than or equal to 0.5%, more preferably less than or equal to 0.3% or 0.2%.

10. The method according to claim 2, characterized in that The content of the isomeric impurity of formula III1 in the compound of formula I1 obtained in the method 1 is less than or equal to 0.5%, more preferably less than or equal to 0.3% or 0.2%; the content of the isomeric impurity of formula III2 in the compound of formula I2 obtained in the method 2 is less than or equal to 0.5%, more preferably less than or equal to 0.3% or 0.2%; the content of the isomeric impurity of formula III3 in the compound of formula I3 obtained in the method 3 is less than or equal to 0.5%, more preferably less than or equal to 0.3% or 0.2%.

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