Preparation Method of Posaconazole Starting Material SM3

Abstract

The present invention relates to the technical field of drug intermediate synthesis, and particularly relates to a preparation method of posaconazole starting material SM3. CeCl3·7H2O and sodium borohydride are added to compound POS-1 for an asymmetric reduction reaction to obtain compound POS-2. Compound POS-2 reacts with 3,5-bis(trifluoromethyl)benzenesulfonyl chloride to obtain compound POS-3. Hydrazine hydrate attacks from the back of compound POS-3 with a larger steric hindrance to undergo an SN2 reaction to obtain a stereoselectively specific compound POS-4. Compound POS-4 then reacts with ethyl formate and forms a salt with oxalic acid to obtain the product posaconazole starting material SM3. By means of asymmetric reduction of carbonyl groups and selective nucleophilic substitution, the present invention effectively avoids the chiral resolution step, thereby reducing the content of isomeric impurities. The prepared product not only has a high ee value, but also the yield is significantly improved, thereby greatly reducing the production cost.

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). It was approved by the US FDA in 2016 and officially launched in the US. 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:

[0003] ;

[0004] 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.

[0005] 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:

[0006] .

[0007] Through literature research, the preparation methods of compound SM3 mainly include the following several:

[0008] (1) Patent US5625064A discloses a preparation method of compound SM3. The specific synthesis route is as follows:

[0009] ;

[0010] 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.

[0011] (2) Patent WO2013042138A2 discloses a preparation method of compound SM3. The specific synthesis route is as follows:

[0012] ;

[0013] 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 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, the ester group is reduced to an aldehyde group with DIBAL at -75 °C, which requires ultra-low temperature equipment for production. Moreover, DIBAL is very reactive, and there are safety hazards in the production operation. The yield of the last step of ethylation is low, and it is difficult to control the isomer impurities.

[0014] (3)Chinese Patent CN106986787A discloses a method for synthesizing an intermediate of posaconazole, and the specific synthesis route is as follows:

[0015] ;

[0016] This route combines the methods of the above two patents. First, an ethyl group is introduced, then aminolysis is carried out with formylhydrazine, and finally, reduction is carried out 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 isomer impurities.

[0017] (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:

[0018] ;

[0019] This route uses metallic sodium, and there are safety hazards in the production operation. The last step of reduction and ethylation also has problems of low yield and large isomer impurities.

[0020] (5)Chinese Patent CN115536602A discloses a method for preparing an intermediate of posaconazole. This patent reports two synthesis routes, and route a is as follows:

[0021] ;

[0022] This route adopts the Weinreb amide method, which simplifies the operation steps. However, it uses Red-Al for reduction, which not only has a large usage amount and high price, but also sodium meta-aluminate will be generated in the post-treatment process. This substance is extremely difficult to filter, bringing difficulties to the scale-up production. In the last step, Zn(OTf)2 catalyst is used, making the ee value of the product relatively high, but the yield is still not high.

[0023] Route b is as follows:

[0024] ;

[0025] 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 cuprous chloride, ligand, PMHS (polymethylhydrosiloxane), etc., SM3 with a relatively high ee value is obtained, but the yield still needs to be further improved.

[0026] As can be seen from the above disclosed route, in the production process 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 anti-fungal field, its global usage is continuously 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 the starting material SM3 of posaconazole that can reduce isomer impurities and increase the yield, so as to reduce the potential safety hazards of medication and lower the production cost. Summary of the Invention

[0027] The object of the present invention is to provide a preparation method for the starting material SM3 of posaconazole. This method effectively avoids the chiral resolution step through 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.

[0028] The technical solution adopted by the present invention to solve its technical problems is as follows:

[0029] The preparation method for the starting material SM3 of posaconazole described above includes the following steps:

[0030] (1) CeCl3·7H2O and sodium borohydride are added to compound POS-1 for a reduction reaction to obtain compound POS-2;

[0031] (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;

[0032] (3) Compound POS-3 is added to ethanol, and hydrazine hydrate is added for a reaction to obtain compound POS-4;

[0033] (4) Compound POS-4 is added to ethyl formate for a reaction, and after layering, the organic layer is obtained. Oxalic acid is added to the organic layer for a stirring reaction to obtain the starting material SM3 of posaconazole;

[0034] The reaction formula is as follows:

[0035] .

[0036] Wherein:

[0037] The molar ratio of compound POS-1, CeCl3·7H2O and sodium borohydride is 1.0:0.01 - 0.05:1.2 - 1.6, preferably 1.0:0.02:1.3.

[0038] 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, preferably 1.2 - 1.5:1.1 - 1.3:1.0.

[0039] The molar ratio of hydrazine hydrate and compound POS-1 is 4.0 - 10.0:1.0, preferably 5.0 - 8.0:1.0.

[0040] The molar ratio of ethyl formate, oxalic acid and 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.

[0041] In step (1), the reduction reaction temperature is 10 - 30°C, preferably 10 - 15°C, and the reduction reaction time is 2 - 4 h.

[0042] 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.

[0043] In step (3), the reaction temperature is 65 - 80°C, and the reaction time is 4 - 5 h.

[0044] 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.

[0045] The preparation method of the starting material SM3 of posaconazole according to the present invention specifically includes the following steps:

[0046] (1) Add compound POS-1 into absolute ethanol, add CeCl3·7H2O 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 a dichloromethane solution of compound POS-2;

[0047] (2) Add 4-dimethylaminopyridine (DMAP) to the dichloromethane solution of compound POS-2, and then add a dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride for heat preservation reaction, quench with water, separate layers, and distill to obtain compound POS-3;

[0048] (3) Add compound POS-3 into ethanol, add hydrazine hydrate for reaction, cool down the temperature, add water and methyl tert-butyl ether (MTBE), stir, extract and separate layers, and distill to obtain compound POS-4;

[0049] (4) Add compound POS-4 into ethyl formate for reaction, cool down the temperature, add water and methyl tert-butyl ether (MTBE), stir, extract and separate layers, add oxalic acid to the organic layer for stirring reaction, filter, and dry to obtain the starting material SM3 of posaconazole.

[0050] Wherein:

[0051] In step (1), first add CeCl3·7H2O, and after cooling down the temperature to 0-5°C, then add sodium borohydride for reduction reaction.

[0052] In step (1), the dosage ratio of absolute ethanol to compound POS-1 is 0.5-0.6:1.0, and the dosage ratios of water, dichloromethane to compound POS-1 are 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.

[0053] In step (2), after cooling down 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.

[0054] 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.

[0055] In step (3), the hydrazine hydrate used is 80% hydrazine hydrate; cool down the temperature to 20-30°C.

[0056] In step (4), cool down the temperature to 20-30°C.

[0057] The isomer impurity structures in the present invention are as follows:

[0058] .

[0059] In the compound POS-1 of the present invention, the α-position of the carbonyl group is a chiral carbon atom. Under the catalysis of CeCl3·7H2O 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 is then reacted with 3,5-bis(trifluoromethyl)benzenesulfonyl chloride to obtain a sulfonate compound POS-3 with a large steric hindrance at the chiral carbon position. Hydrazine hydrate undergoes an SN2 reaction with the sulfonate compound POS-3 to obtain a stereoselectively specific compound POS-4. The compound POS-4 is then reacted with ethyl formate and oxalic acid to obtain the starting material SM3 of posaconazole, the final product.

[0060] The beneficial effects of the present invention are as follows:

[0061] Starting from the compound POS-1, in which the α-position of the carbonyl group is a chiral carbon atom, through the selected CeCl3·7H2O and sodium borohydride mixed reduction system, the carbonyl group can be asymmetrically reduced to obtain a highly stereoselective chiral alcohol compound POS-2. 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 from the back of the compound POS-3 with a large steric hindrance to undergo an SN2 reaction, obtaining a stereoselectively specific compound POS-4. The compound POS-4 is then reacted with ethyl formate and salted 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 increases significantly.

[0062] 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 a significantly improved yield, thus greatly reducing the production cost. Description of the Drawings

[0063] Figure 1 is the 1H nuclear magnetic resonance spectrum of the starting material SM3 of posaconazole prepared in Example 1 1 1H nuclear magnetic resonance spectrum;

[0064] Figure 2 is the HPLC chromatogram of the starting material SM3 of posaconazole prepared in Example 1. Detailed Embodiments

[0065] The following further describes the present invention in conjunction with examples.

[0066] Example 1

[0067] (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 CeCl3·7H2O, 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 for heat preservation 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 the dichloromethane solution of compound POS-2.

[0068] (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 the dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride.

[0069] Cool down the dichloromethane solution of compound POS-2 obtained in step (1) to 5 - 10 °C, 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 dropwise addition, keep the temperature at 5 - 10 °C for heat preservation and react for 4 hours. Add 150 ml of water to the system to quench the reaction, separate the layers, distill dichloromethane to obtain compound POS-3.

[0070] (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 down to 20 - 25 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers, distill the solvent to obtain compound POS-4.

[0071] (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 down 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 starting material SM3 of posaconazole. The purity of the starting material SM3 of posaconazole is 99.39%, the isomeric impurity is 0.16%, the ee value is 99.68%, and the total yield of the starting material SM3 of posaconazole is 85.8%. The 1H nuclear magnetic resonance spectrum and HPLC chromatogram of the starting material SM3 of posaconazole are as 1 shown in Figure 1 、 Figure 2 Figure.

[0072] Example 2

[0073] (1) Add 19.23 g (0.1 mol) of compound POS-1 to 55 ml of absolute ethanol, add 1.86 g (0.005 mol) of CeCl3·7H2O, cool down 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, 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. 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;

[0074] (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;

[0075] Cool the dichloromethane solution of compound POS-2 obtained in step (1) to 5 - 10 °C, 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, keep the temperature at 20 - 25 °C and react for 2 h. Add 150 ml of water to the system to quench the reaction, separate the layers, distill dichloromethane to obtain compound POS-3;

[0076] (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 down to 25 - 30 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers, distill the solvent to obtain compound POS-4;

[0077] (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 down 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 in vacuum at 50 °C to obtain 27.9 g of the starting material SM3 of posaconazole. The purity of the starting material SM3 of posaconazole is 99.41%, the isomeric impurity is 0.15%, the ee value is 99.70%, and the total yield of the starting material SM3 of posaconazole is 85.5%.

[0078] Example 3

[0079] (1) Add 19.23 g (0.1 mol) of compound POS-1 to 60 ml of absolute ethanol, add 0.75 g (0.002 mol) of CeCl3·7H2O, cool down 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, keep the temperature at 25 - 30 °C for insulation 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. The organic phase is dried with 5 g of anhydrous magnesium sulfate, control the water content < 0.5%, filter to obtain the dichloromethane solution of compound POS-2.

[0080] (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 the dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride.

[0081] Cool the dichloromethane solution of compound POS-2 obtained in step (1) to 10 - 15 °C, add 18.4 g (0.15 mol) of DMAP. Control the temperature at 10 - 15 °C and dropwise add the above dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride. After the addition, keep the temperature at 10 - 15 °C for insulation and react for 3 hours. Add 150 ml of water to the system to quench the reaction, separate the layers, distill dichloromethane to obtain compound POS-3.

[0082] (3) Add the compound POS-3 obtained in step (2) to 200 ml of ethanol, add 62.6 g (1.0 mol) of 80% hydrazine hydrate, react at 75 - 80 °C for 5 h, cool down to 23 - 26 °C, add 200 ml of water and 300 ml of MTBE, stir, extract and separate the layers, distill the solvent to obtain compound POS-4.

[0083] (4) Add the compound POS-4 obtained in step (3) to 59.3 g (0.8 mol) of ethyl formate, react at 45 - 50 °C for 5 h, cool down 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 isomer impurity is 0.14%, the ee value is 99.72%, and the total yield of the starting material SM3 of posaconazole is 86.7%.

[0084] Comparative Example 1

[0085] In step (1), CeCl3·7H2O was not added, and the remaining steps were the same as in Example 1. A total of 27.6 g of posaconazole starting material SM3 and isomeric impurities were obtained, among which the isomeric impurities were 41.5%, the purity of posaconazole starting material SM3 was 57.3%, the ee value was 15.99%, and the yield of posaconazole starting material was 48.5%.

[0086] Comparative Example 2

[0087] In step (1), "CeCl3·7H2O" was changed to "ZnBr", and the remaining steps were the same as in Example 1. A total of 25.7 g of posaconazole starting material SM3 and isomeric impurities were obtained, among which the isomeric impurities were 45.2%, the purity of posaconazole starting material SM3 was 53.6%, the ee value was 8.50%, and the yield of posaconazole starting material SM3 was 42.2%.

[0088] Comparative Example 3

[0089] In step (2), the "dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride" was changed to the "dichloromethane solution of p-chlorobenzenesulfonyl chloride", and the remaining steps were the same as in Example 1. A total of 28.1 g of posaconazole starting material SM3 and isomeric impurities were obtained, among which the isomeric impurities were 45.3%, the purity of posaconazole starting material SM3 was 54.3%, the ee value was 9.04%, and the yield of posaconazole starting material SM3 was 46.8%.

Claims

1. A preparation method of posaconazole starting material SM3, characterized in that It includes the following steps: (1) CeCl3·7H2O 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 layering, the organic layer is obtained. Oxalic acid is added to the organic layer for a stirring reaction to obtain the starting material SM3 of posaconazole; The reaction formula is: ； In step (1), the molar ratio of compound POS-1, CeCl3·7H2O to sodium borohydride is 1.0:0.01~0.05:1.2~1.6, and the reduction reaction temperature is 10~30°C.

2. The preparation method of posaconazole starting material SM3 according to claim 1, characterized in that: 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.

3. The preparation method of posaconazole starting material SM3 according to claim 1, wherein: 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 preparation method of posaconazole starting material SM3 according to claim 1, characterized in that: In step (1), the reduction reaction time is 2~4h; in step (2), the heat preservation reaction temperature is 5~30°C, and the heat preservation reaction time is 2~4h.

5. The preparation method of 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, the reaction time is 4~5h, the stirring reaction temperature is 20~25°C, and the stirring reaction time is 2~3h.

6. The preparation method of posaconazole starting material SM3 according to any one of claims 1 to 5, characterized in that It includes the following steps: (1) Compound POS-1 is added to absolute ethanol, and CeCl3·7H2O and sodium borohydride are added for a reduction reaction; after the reaction is completed, water and dichloromethane are added, stirred and layered, and the organic phase is dried and filtered to obtain a dichloromethane solution of compound POS-2; (2) 4-dimethylaminopyridine is added to the dichloromethane solution of compound POS-2, and then a dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride is added for a heat preservation reaction, quenched with water, layered, and distilled to obtain compound POS-3; (3) Compound POS-3 is added to ethanol, and hydrazine hydrate is added for a reaction, cooled, water and methyl tert-butyl ether are added, stirred, extracted and layered, and distilled to obtain compound POS-4; (4) Compound POS-4 is added to ethyl formate for a reaction, cooled, water and methyl tert-butyl ether are added, stirred, extracted and layered, and oxalic acid is added to the organic layer for a stirring reaction, filtered and dried to obtain the starting material SM3 of posaconazole.

7. The preparation method of posaconazole starting material SM3 according to claim 6, characterized in that: In step (1), CeCl3·7H2O is added first, and after cooling to 0~5°C, sodium borohydride is added for a reduction reaction.

8. The preparation method of 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, and the temperature is controlled at 5-15 °C, then the dichloromethane solution of 3,5-bis(trifluoromethyl)benzenesulfonyl chloride is added for a heat-insulated reaction.

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

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

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