Preparation method of starting material SM3 of posaconazole

Abstract

The invention relates to the technical field of synthesis of drug intermediates, in particular to a preparation method of a posaconazole starting material SM3. CeCl3. 7H2O and sodium borohydride are added into a compound POS-1 for an asymmetric reduction reaction to obtain a compound POS-2, the compound POS-2 reacts with 3, 5-bis (trifluoromethyl) benzene sulfonyl chloride to obtain a compound POS-3, hydrazine hydrate attacks from the back side of the compound POS-3 with large steric hindrance, an SN2 reaction is carried out to obtain a compound POS-4 with specific stereoselectivity, the compound POS-4 reacts with ethyl formate, and the compound POS-4 reacts with ethyl formate to obtain a compound POS-3 with specific stereoselectivity. And salifying with oxalic acid to obtain the initial raw material SM3 of the product posaconazole. According to the method, the chiral resolution step is effectively avoided in the modes of asymmetric carbonyl reduction and selective nucleophilic substitution, so that the content of isomer impurities is reduced, the prepared product is high in ee value, the yield is also remarkably improved, and the production cost is greatly reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of drug intermediate synthesis, and particularly relates to a preparation method of posaconazole starting material SM3. Background Art

[0002] Posaconazole is a triazole antifungal drug developed by the former Schering-Plough Corporation (acquired by Merck & Co., Inc. in 2009), and was officially approved by the US FDA and launched in the US in 2016. It is an antibacterial drug used to prevent lesions caused by invasive aspergillus, and belongs to the highly lipophilic second-generation broad-spectrum triazole antifungal drugs. Posaconazole is a new chemical molecular entity with four chiral centers in its molecular structure. The synthesis steps are long and complex, with a certain degree of difficulty. The structure of posaconazole is as follows: ; The Chinese chemical name is: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one.

[0003] Among them, the construction of the chiral centers 1S,2S of posaconazole is mainly introduced through a key starting material. The structure of this raw material (named SM3) is as follows: .

[0004] Through literature research, the preparation methods of compound SM3 mainly include the following several: (1) Patent US5625064A discloses a preparation method of compound SM3. The specific synthesis route is as follows: ; This route was reported in the relevant patents of Schering-Plough Corporation. Through the aminolysis of ethyl L-lactate, hydroxyl protection, Grignard reagent ethylation, reduction, hydroxyl activation, hydrazine substitution, resolution, and formylation, compound SM3 was obtained. This reaction route is long, the operation is cumbersome, it is not suitable for industrial production, and the resolution step is adopted, resulting in a low yield of compound SM3.

[0005] (2) Patent WO2013042138A2 discloses a preparation method of compound SM3. The specific synthesis route is as follows: ; This route starts from racemic methyl lactate and involves hydroxyl protection, ester hydrolysis, resolution, esterification, reduction with DIBAL (diisobutylaluminum hydride), aminolysis, and reduction and ethylation with a Grignard reagent. This route uses S-1-phenylethylamine to form a salt for resolution to obtain the first chiral center first. Compared with the route of Schering-Plough Corporation, the cost may be reduced. However, in the subsequent step, reducing the ester group to an aldehyde group with DIBAL at -75 °C requires ultra-low temperature equipment for production, and DIBAL is very reactive, posing safety hazards in production operations. The yield of the last ethylation step is low, and controlling isomeric impurities is a challenge.

[0006] (3) Chinese Patent CN106986787A discloses a method for synthesizing an intermediate of posaconazole, and the specific synthesis route is as follows: ; This route combines the methods of the above two patents, introducing an ethyl group first, then performing aminolysis with formylhydrazine, and finally reducing with sodium borohydride in the presence of a catalyst to construct a chiral center. The catalyst used in this patent is Rh-[(I)-(R,R)-BDPCH] 24 , and this catalyst is difficult to prepare, expensive, and does not fundamentally solve the problems of low yield and large isomeric impurities.

[0007] (4) Chinese Patent CN108586280A discloses a method for synthesizing N′-[(2S,3S)-2-(benzyloxy)pentan-3-yl]formylhydrazine, and the specific synthesis route is as follows: ; This route uses metallic sodium, posing safety hazards in production operations. The last reduction and ethylation step also has problems of low yield and large isomeric impurities.

[0008] (5) Chinese Patent CN115536602A discloses a method for preparing an intermediate of posaconazole. This patent reports two synthesis routes. Route a is as follows: ; This route adopts the Weinreb amide method, simplifying the operation steps. However, it uses Red-Al for reduction, which not only has a large consumption and high price but also generates sodium metaaluminate during the post-treatment process. This substance is extremely difficult to filter, causing difficulties in scale-up production. In the last step, Zn(OTf) 2 is used as a catalyst, resulting in a relatively high ee value of the product, but the yield is still not high.

[0009] Route b is as follows: ; In this route, the Weinreb amide is first ethylated with a Grignard reagent. However, during this process, the carbonyl group may react further with the Grignard reagent, making the reaction process difficult to control. In the last step, with the combined action of copper(I) chloride, ligand, PMHS (polymethylhydrosiloxane), etc., SM3 with a relatively high ee value is obtained, but the yield still needs to be further improved.

[0010] As can be seen from the above disclosed route, during the production of the starting material SM3 of posaconazole, there are generally problems of high isomer impurities or low yield. Given the unique efficacy of posaconazole in the antifungal field, its global usage is constantly expanding. Therefore, the quality and cost of the starting material SM3 have a crucial impact on the overall quality and production cost of posaconazole API. Based on this, there is an urgent need to develop a preparation method for posaconazole starting material SM3 that can reduce isomer impurities and increase the yield, so as to reduce the potential safety hazards of drug use and lower the production cost. Summary of the Invention

[0011] The object of the present invention is to provide a preparation method for posaconazole starting material SM3. This method effectively avoids the chiral resolution step by asymmetric reduction of the carbonyl group and selective nucleophilic substitution, thereby reducing the content of isomer impurities. The prepared product not only has a high ee value but also a significantly increased yield, thus greatly reducing the production cost.

[0012] The technical solution adopted by the present invention to solve its technical problems is as follows: The preparation method for posaconazole starting material SM3 described above includes the following steps: (1) CeCl 3 ·7H 2 O and sodium borohydride are added to compound POS-1 for a reduction reaction to obtain compound POS-2; (2) 4-Dimethylaminopyridine and a dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride are added to compound POS-2 for a heat preservation reaction to obtain compound POS-3; (3) Compound POS-3 is added to ethanol, and hydrazine hydrate is added for a reaction to obtain compound POS-4; (4) Compound POS-4 is added to ethyl formate for a reaction, and after liquid separation, the organic layer is obtained. Oxalic acid is added to the organic layer for a stirring reaction to obtain posaconazole starting material SM3; The reaction formula is as follows: .

[0013] Wherein: Compound POS-1, CeCl 3 ·7H 2The molar ratio of O to sodium borohydride is 1.0:0.01 - 0.05:1.2 - 1.6, preferably 1.0:0.02:1.3.

[0014] The molar ratio of 4 - dimethylaminopyridine, 3,5 - bis(trifluoromethyl)benzenesulfonyl chloride to compound POS - 1 is 1.0 - 2.0:1.0 - 1.5:1.0, preferably 1.2 - 1.5:1.1 - 1.3:1.0.

[0015] The molar ratio of hydrazine hydrate to compound POS - 1 is 4.0 - 10.0:1.0, preferably 5.0 - 8.0:1.0.

[0016] The molar ratio of ethyl formate, oxalic acid to compound POS - 1 is 8.0 - 15.0:1.0 - 1.5:1.0, preferably 8.0 - 10.0:1.1 - 1.2:1.0.

[0017] In step (1), the reduction reaction temperature is 10 - 30 °C, preferably 10 - 15 °C, and the reduction reaction time is 2 - 4 h.

[0018] In step (2), the heat - preservation reaction temperature is 5 - 30 °C, preferably 10 - 15 °C, and the heat - preservation reaction time is 2 - 4 h.

[0019] In step (3), the reaction temperature is 65 - 80 °C, and the reaction time is 4 - 5 h.

[0020] In step (4), the reaction temperature is 45 - 60 °C, the reaction time is 4 - 5 h, the stirring reaction temperature is 20 - 25 °C, and the stirring reaction time is 2 - 3 h.

[0021] The preparation method of the starting material SM3 of posaconazole according to the present invention specifically includes the following steps: (1) Add compound POS - 1 into absolute ethanol, add CeCl 3 ·7H 2 O and sodium borohydride for reduction reaction; after the reaction is completed, add water and dichloromethane, stir and separate layers, dry the organic phase, filter, and obtain the dichloromethane solution of compound POS - 2; (2) Add 4 - dimethylaminopyridine (DMAP) to the dichloromethane solution of compound POS - 2, then add the dichloromethane solution of 3,5 - bis(trifluoromethyl)benzenesulfonyl chloride for heat - preservation reaction, quench with water, separate layers, distill, and obtain compound POS - 3; (3) Add compound POS - 3 into ethanol, add hydrazine hydrate for reaction, cool down, add water and methyl tert - butyl ether (MTBE), stir, extract and separate layers, distill, and obtain compound POS - 4; (4) Add compound POS-4 to ethyl formate, carry out the reaction, cool down the temperature, add water and methyl tert-butyl ether (MTBE), stir, extract and separate the layers. Add oxalic acid to the organic layer and stir for reaction, filter, and dry to obtain the starting material SM3 of posaconazole.

[0022] Among them: In step (1), first add CeCl 3 ·7H 2 O, after cooling down to 0 - 5 °C, then add sodium borohydride for reduction reaction.

[0023] In step (1), the dosage ratio of absolute ethanol to compound POS-1 is 0.5 - 0.6:1.0, and the dosage ratio of water, dichloromethane to compound POS-1 is 1.0 - 1.1:1.5 - 1.6:1.0, where compound POS-1 is in mol, and absolute ethanol, water, dichloromethane are in L.

[0024] In step (2), after cooling the dichloromethane solution of compound POS-2 to 5 - 15 °C, add 4-dimethylaminopyridine, control the temperature at 5 - 15 °C, and then add the dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride for heat preservation reaction.

[0025] In step (2), in the dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride, the dosage ratio of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride to dichloromethane is 1.0 - 1.5:1000, where 3,5-bis(trifluoromethyl)benzenesulfonyl chloride is in mol and dichloromethane is in ml.

[0026] In step (3), the hydrazine hydrate is 80% hydrazine hydrate; cool down to 20 - 30 °C.

[0027] In step (4), cool down to 20 - 30 °C.

[0028] The isomer impurity structure in the present invention is as follows: .

[0029] In compound POS-1 of the present invention, the α-position of the carbonyl group is a carbon atom with a chiral center. Under the catalysis of CeCl 3 ·7H 2 O and sodium borohydride, the carbonyl group is asymmetrically reduced to obtain a stereoselectively specific chiral alcohol compound POS-2. The chiral alcohol compound POS-2 reacts with 3,5-bis(trifluoromethyl)benzenesulfonyl chloride to obtain a sulfonic acid ester compound POS-3 with a large steric hindrance at the chiral carbon. Hydrazine hydrate undergoes an SN2 reaction with the sulfonic acid ester compound POS-3 to obtain a stereoselectively specific compound POS-4. The compound POS-4 reacts with ethyl formate and oxalic acid to obtain the final product, the starting material SM3 of posaconazole.

[0030] The beneficial effects of the present invention are as follows: The present invention uses compound POS-1 as the starting material. The α-position of the carbonyl group in compound POS-1 is a chiral carbon atom. By using a mixed reduction system of CeCl 3 ·7H 2 O and sodium borohydride, the carbonyl group can be asymmetrically reduced to obtain a chiral alcohol compound POS-2 with high stereoselectivity. Then, the hydroxyl group is activated by 3,5-bis(trifluoromethyl)benzenesulfonyl chloride with a large steric hindrance, and hydrazine hydrate selectively attacks the sulfonate ester from the back of the compound POS-3 with a large steric hindrance to undergo an SN2 reaction to obtain a stereoselective and specific compound POS-4. The compound POS-4 then reacts with ethyl formate and forms a salt with oxalic acid. Finally, the ee value of the starting material SM3 of posaconazole obtained reaches more than 99.5%, avoiding the chiral resolution step, and the product yield is increased by more than 40%. On the premise of ensuring the product quality, the yield is increased significantly.

[0031] The route of the present invention is simple to operate. By means of asymmetric reduction of the carbonyl group and selective nucleophilic substitution, the chiral resolution step is effectively avoided, thereby reducing the content of isomeric impurities. The prepared product not only has a high ee value, but also the yield is significantly improved, and further significantly reduces the production cost. Description of the Drawings

[0032] Figure 1 is the 1 1H nuclear magnetic resonance spectrum of the starting material SM3 of posaconazole prepared in Example 1; Figure 2 is the HPLC chromatogram of the starting material SM3 of posaconazole prepared in Example 1. Detailed Embodiments

[0033] The present invention will be further described below in conjunction with examples.

[0034] Example 1 (1) Add 19.23 g (0.1 mol) of compound POS-1 to 50 ml of absolute ethanol, add 0.37 g (0.001 mol) of CeCl 3 ·7H 2 O, cool down to 0-5 °C, divide 4.54 g (0.12 mol) of sodium borohydride into three batches and add them to the reaction system at intervals of 30 min. After the addition, keep the temperature at 10-15 °C and react for 4 h; after the reaction is completed, control the temperature <10 °C, add 100 ml of water and 150 ml of dichloromethane, stir and separate the layers. The organic phase is dried with 5 g of anhydrous magnesium sulfate, control the water content <0.5%, filter to obtain a dichloromethane solution of compound POS-2; (2) Add 34.4 g (0.11 mol) of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride to 100 ml of dichloromethane, stir and dissolve to obtain a dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride; Cool the dichloromethane solution of the compound POS-2 obtained in step (1) to 5 - 10 °C, and add 14.7 g (0.12 mol) of DMAP; control the temperature at 5 - 10 °C and dropwise add the above-mentioned dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride. After the addition is completed, keep the temperature at 5 - 10 °C and react for 4 hours. Add 150 ml of water to the system to quench the reaction, separate the layers, and distill dichloromethane to obtain the compound POS-3; (3) Add the compound POS-3 obtained in step (2) to 200 ml of ethanol, add 31.3 g (0.5 mol) of 80% hydrazine hydrate, react at 70 - 75 °C for 5 h, cool to 20 - 25 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers, and distill the solvent to obtain the compound POS-4; (4) Add the compound POS-4 obtained in step (3) to 74.1 g (1.0 mol) of ethyl formate, react at 50 - 55 °C for 4 h, cool to 20 - 25 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers. Add 10.8 g (0.12 mol) of anhydrous oxalic acid to the organic layer, stir at 20 - 23 °C for 2 h, filter, and dry under vacuum at 50 °C to obtain 28.0 g of the posaconazole starting material SM3. The purity of the posaconazole starting material SM3 is 99.39%, the isomer impurity is 0.16%, the ee value is 99.68%, and the total yield of the posaconazole starting material SM3 is 85.8%. The 1 1H nuclear magnetic resonance spectrum and HPLC chromatogram of the posaconazole starting material SM3 are as Figure 1 、 Figure 2 shown.

[0035] Example 2 (1) Add 19.23 g (0.1 mol) of the compound POS-1 to 55 ml of absolute ethanol, add 1.86 g (0.005 mol) of CeCl 3 ·7H 2 O, cool to 0 - 3 °C, divide 5.67 g (0.15 mol) of sodium borohydride into three batches and add them to the reaction system at intervals of 30 min. After the addition is completed, keep the temperature at 15 - 20 °C and react for 3 h; after the reaction is completed, control the temperature < 10 °C, add 100 ml of water and 150 ml of dichloromethane, stir and separate the layers. Dry the organic phase with 5 g of anhydrous magnesium sulfate, control the water content < 0.5%, filter to obtain a dichloromethane solution of the compound POS-2; (2) Add 46.9 g (0.15 mol) of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride to 100 ml of dichloromethane, stir and dissolve to obtain a dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride; Cool the dichloromethane solution of the compound POS-2 obtained in step (1) to 5-10 °C, and add 24.5 g (0.2 mol) of DMAP; control the temperature at 5-10 °C and dropwise add the above dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride. After the addition is complete, keep the temperature at 20-25 °C and react for 2 hours. Add 150 ml of water to the system to quench the reaction, separate the layers, and distill dichloromethane to obtain the compound POS-3; (3) Add the compound POS-3 obtained in step (2) to 200 ml of ethanol, add 47.0 g (0.75 mol) of 80% hydrazine hydrate, react at 65-70 °C for 4 h, cool to 25-30 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers, and distill the solvent to obtain the compound POS-4; (4) Add the compound POS-4 obtained in step (3) to 111.2 g (1.5 mol) of ethyl formate, react at 55-60 °C for 4 h, cool to 25-30 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers. Add 13.5 g (0.15 mol) of anhydrous oxalic acid to the organic layer, stir at 22-25 °C for 3 h, filter, and dry under vacuum at 50 °C to obtain 27.9 g of the posaconazole starting material SM3. The purity of the posaconazole starting material SM3 is 99.41%, the isomer impurity is 0.15%, the ee value is 99.70%, and the total yield of the posaconazole starting material SM3 is 85.5%.

[0036] Example 3 (1) Add 19.23 g (0.1 mol) of the compound POS-1 to 60 ml of absolute ethanol, add 0.75 g (0.002 mol) of CeCl 3 ·7H 2 O, cool to 3-5 °C, divide 6.05 g (0.16 mol) of sodium borohydride into three batches and add them to the reaction system at intervals of 30 min. After the addition is complete, keep the temperature at 25-30 °C and react for 2 h; after the reaction is completed, control the temperature <10 °C, add 110 ml of water and 160 ml of dichloromethane, stir and separate the layers. Dry the organic phase with 5 g of anhydrous magnesium sulfate, control the water content <0.5%, filter to obtain a dichloromethane solution of the compound POS-2; (2) Add 31.3 g (0.10 mol) of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride to 100 ml of dichloromethane, stir and dissolve to obtain a dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride; Cool the dichloromethane solution of the compound POS-2 obtained in step (1) to 10-15 °C, and add 18.4 g (0.15 mol) of DMAP; control the temperature at 10-15 °C and dropwise add the dichloromethane solution of the above 3,5-bis(trifluoromethyl)benzenesulfonyl chloride. After the addition is complete, keep the temperature at 10-15 °C and react for 3 hours. Add 150 ml of water to the system to quench the reaction, separate the layers, and distill the dichloromethane to obtain the compound POS-3; (3) Add 200 ml of ethanol to the compound POS-3 obtained in step (2), add 62.6 g (1.0 mol) of 80% hydrazine hydrate, react at 75-80 °C for 5 h, cool to 23-26 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers, and distill the solvent to obtain the compound POS-4; (4) Add 59.3 g (0.8 mol) of ethyl formate to the compound POS-4 obtained in step (3), react at 45-50 °C for 5 h, cool to 20-25 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers. Add 9.0 g (0.10 mol) of anhydrous oxalic acid to the organic layer, stir at 20-25 °C for 2 h, filter, and dry under vacuum at 50 °C to obtain 28.3 g of the starting material SM3 of posaconazole. The purity of the starting material SM3 of posaconazole is 99.32%, the isomeric impurity is 0.14%, the ee value is 99.72%, and the total yield of the starting material SM3 of posaconazole is 86.7%.

[0037] Comparative Example 1 CeCl is not added in step (1) 3 ·7H 2 O. The remaining steps are the same as in Example 1 to obtain 27.6 g of the starting material SM3 of posaconazole and isomeric impurities. Among them, the isomeric impurity is 41.5%, the purity of the starting material SM3 of posaconazole is 57.3%, the ee value is 15.99%, and the yield of the starting material of posaconazole is 48.5%.

[0038] Comparative Example 2 Change "CeCl 3 ·7H 2 O" in step (1) to "ZnBr", and the remaining steps are the same as in Example 1 to obtain 25.7 g of the starting material SM3 of posaconazole and isomeric impurities. Among them, the isomeric impurity is 45.2%, the purity of the starting material SM3 of posaconazole is 53.6%, the ee value is 8.50%, and the yield of the starting material SM3 of posaconazole is 42.2%.

[0039] Comparative Example 3 Replace the "dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride" in step (2) with "dichloromethane solution of 4-chlorobenzenesulfonyl chloride", and the remaining steps are the same as in Example 1. 28.1 g of posaconazole starting material SM3 and isomeric impurities are obtained, among which the isomeric impurities are 45.3%, the purity of posaconazole starting material SM3 is 54.3%, the ee value is 9.04%, and the yield of posaconazole starting material SM3 is 46.8%.

Claims

1. A method for preparing a posaconazole starting material SM3, characterized in that The following steps are involved: (1) Add CeCl3·7H2O and sodium borohydride to compound POS-1 for reduction reaction to obtain compound POS-2; (2) Adding a dichloromethane solution of 4-dimethylaminopyridine and 3,5-bis(trifluoromethylbenzenesulfonyl) chloride to compound POS-2 and carrying out a heat-insulating reaction to obtain compound POS-3; (3) Compound POS-3 is added to ethanol, and hydrazine hydrate is added to react to obtain compound POS-4; (4) adding compound POS-4 to ethyl formate to react, separating the layers to obtain an organic layer, adding oxalic acid to the organic layer to react by stirring, and obtaining posaconazole starting material SM3; The reaction formula is: 。 2. The method for preparing the posaconazole starting material SM3 according to claim 1, characterized in that: The molar ratio of compound POS-1, CeCl3·7H2O and sodium borohydride is 1.0:0.01~0.05:1.2~1.6, and the molar ratio of 4-dimethylaminopyridine, 3,5-bis(trifluoromethyl)benzenesulfonyl chloride and compound POS-1 is 1.0~2.0:1.0~1.5:1.

0.

3. The method for preparing the posaconazole starting material SM3 according to claim 1, characterized in that: The molar ratio of hydrazine hydrate to compound POS-1 is 4.0-10.0:1.0, and the molar ratio of ethyl formate, oxalic acid to compound POS-1 is 8.0-15.0:1.0-1.5:1.

0.

4. The method for preparing the posaconazole starting material SM3 according to claim 1, characterized in that: In step (1), the reduction reaction temperature is 10-30°C, and the reduction reaction time is 2-4 hours; in step (2), the insulation reaction temperature is 5-30°C, and the insulation reaction time is 2-4 hours.

5. The method for preparing the posaconazole starting material SM3 according to claim 1, characterized in that: In step (3), the reaction temperature is 65-80°C and the reaction time is 4-5h; in step (4), the reaction temperature is 45-60°C and the reaction time is 4-5h, the stirring reaction temperature is 20-25°C and the stirring reaction time is 2-3h.

6. The method for preparing the posaconazole starting material SM3 according to any one of claims 1 to 5, characterized in that The following steps are involved: (1) Compound POS-1 is added to anhydrous ethanol, and CeCl3·7H2O and sodium borohydride are added to carry out a reduction reaction; after the reaction is completed, water and dichloromethane are added, the layers are stirred, the organic phase is dried, and filtered to obtain a dichloromethane solution of compound POS-2; (2) Add 4-dimethylaminopyridine to a dichloromethane solution of compound POS-2, and then add a dichloromethane solution of 3,5-bis(trifluoromethylbenzenesulfonyl chloride) to carry out a heat-insulated reaction, add water to quench, separate the layers, and distill to obtain compound POS-3; (3) Compound POS-3 is added to ethanol, hydrazine hydrate is added to react, the temperature is lowered, water and methyl tert-butyl ether are added, stirred, extracted and separated, and distilled to obtain compound POS-4; (4) Compound POS-4 is added to ethyl formate to react, the temperature is lowered, water and methyl tert-butyl ether are added, the mixture is stirred, and the layers are separated by extraction. Oxalic acid is added to the organic layer to react by stirring, the mixture is filtered, and the mixture is dried to obtain posaconazole starting material SM3.

7. The method for preparing the posaconazole starting material SM3 according to claim 6, characterized in that: In step (1), CeCl3·7H2O is first added, the temperature is lowered to 0-5°C, and then sodium borohydride is added to carry out a reduction reaction.

8. The method for preparing the posaconazole starting material SM3 according to claim 6, characterized in that: In step (2), after the dichloromethane solution of compound POS-2 is cooled to 5-15°C, 4-dimethylaminopyridine is added, the temperature is controlled at 5-15°C, and then a dichloromethane solution of 3,5-bistrifluoromethylbenzenesulfonyl chloride is added to carry out a heat-insulating reaction.

9. The method for preparing the posaconazole starting material SM3 according to claim 6, characterized in that: In step (3), the hydrazine hydrate is 80% hydrazine hydrate; the temperature is lowered to 20-30°C.

10. The method for preparing the posaconazole starting material SM3 according to claim 6, characterized in that: In step (4), the temperature is lowered to 20-30°C.

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