A method for synthesizing posaconazole mother ring with high chiral purity

Abstract

The application discloses a synthesis method of a high-chirality purity posaconazole mother ring and belongs to the technical field of medicine preparation. In the application, sodium borohydride is used to reduce (R)-3-[(3S,5R)-5-(2,4-difluorobenzene)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone containing isomers to an intermediate alcohol, the hydroxyl group of the intermediate alcohol is protected, then the intermediate alcohol is beaten in acetonitrile and filtered to obtain an intermediate; then the intermediate is reacted with sodium triazole to obtain a triazole substituent; finally, the triazole substituent is deprotected into a hydroxyl group, and then p-toluenesulfonyl chloride is added to react, so that the high-chirality posaconazole mother ring is obtained. Compared with the existing preparation technology, the synthesis method provided by the application is simple in operation, high in product yield, low in by-products and high in purity.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a high-chirality pure posaconazole mother ring, and specifically to a method for preparing a high-purity posaconazole main ring [(3S,5R)-5-[(1H-1,2,4-triazol-1-yl)methyl]-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl]methyl p-toluenesulfonate, belonging to the technical field of pharmaceutical preparation. Background Art

[0002] Posaconazole, chemically named 4-[4-[4-[4-[[(3R, 5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentyl-3-yl]-1,2,4-triazol-3-one, is a triazole antifungal drug and a derivative of itraconazole. It is a second-generation triazole antifungal drug approved by the FDA in 2006 under the trade name NOXAFIL. The original manufacturer is Schering-Plough. Its structure is shown in Formula I:

[0003]

[0004] Ⅰ

[0005] The drug has strong inhibitory activity against Candida species, Histoplasma capsulatum, Sedoni, bipolar fungi, Fusarium, yeasts, including fluconazole-resistant non-albicans Candida strains, Cryptococcus neoformans and Aspergillus; it is especially effective against relatively rare but life-threatening fungal diseases such as zygomycosis, fusariosis and coccidioidomycosis.

[0006] The posaconazole mother ring can be used to further synthesize posaconazole, the structure of which is shown in Formula II:

[0007]

[0008] Ⅱ

[0009] Schering-Plough disclosed a synthetic route for the posaconazole main ring in US Pat. No. 5,661,151A in 1995. This route uses 2'-chloro-2,4-difluoroacetophenone as the starting material and proceeds through 10 steps to synthesize the parent ring. This synthetic route utilizes a Wittig reaction to introduce a marginal double bond, resulting in triphenylphosphine oxide that is difficult to handle and does not meet green chemistry requirements. Furthermore, the Sharpless epoxidation reaction required to generate the epoxide requires the use of the chiral reagent L-DET and several unstable reagents, such as (i-PrO)4Ti and TBHP. Furthermore, the use of NaH as a base in multiple reactions in this route is hazardous and requires high safety and control costs. The use of flammable lithium borohydride in the fifth step is also highly hazardous. Furthermore, the multiple ring-closure and ring-opening reactions result in low steric selectivity, resulting in very low reaction yields. For example, the yield of compound 1-h to compound 1-i via LiBH4 reduction is only 43.53%. The final step, reaction 1-j, undergoes an intramolecular ring-closure reaction under the strong base NaH. The resulting chiral center exhibits poor stereoselectivity, yielding only 35%, and the overall yield of this route is only 7.99%. The patent mentions the multiple steps involved in separating and purifying the intermediate using column chromatography, which is not conducive to industrial production.

[0010] Patent publication number WO2015059716A2 uses the compound 4-(2,4-difluorophenyl)-4-carbonylbutyric acid as the starting material and proceeds through a 10-step reaction to obtain the posaconazole parent ring, but the overall yield is only 6.71%. The route utilizes the expensive chiral auxiliary group (S)-4-phenyl-2-oxazolidinone for substrate induction, and introduces the chiral carbon atom via triformaldehyde and titanium tetrachloride. The reaction conditions are harsh, resulting in a yield of 56.41%. The removal of the chiral auxiliary group utilizes a two-step reaction involving the unstable reagents H₂O₂ and BF₃-Et₂O, making the route cumbersome and increasing the reaction cost. One intermediate contains two reactive centers, an iodine atom and a hydroxyl group, resulting in low selectivity for triazole ring introduction. Additionally, approximately 20% of intramolecular ring-closure impurities present significant purification challenges, necessitating silica gel column purification. Finally, the sulfonyl group is introduced using DMAP instead of an organic base, which hinders the forward reaction. The overall yield across the two steps is only 23.63%. Therefore, it is an urgent technical problem to design a method for preparing the posaconazole parent ring that is simple and convenient to operate, has fewer reaction steps, produces fewer by-products, has a high conversion rate, a high yield, a high purity of the product, a low production cost, and is suitable for industrial production. Summary of the Invention

[0011] The present invention aims to overcome the deficiencies in the prior art and provide a method for synthesizing a posaconazole parent ring with high chiral purity, which has the advantages of simple operation, high preparation yield, few by-products and high product purity.

[0012] In order to achieve the above object, the technical solution adopted by the present invention is:

[0013] The invention provides a method for synthesizing a posaconazole mother ring with high chiral purity. The method comprises the following steps: using sodium borohydride to reduce (R)-3-[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone containing isomers to an intermediate alcohol; using tert-butyldiphenylchlorosilane to protect the intermediate alcohol's hydroxyl group; then beating the intermediate in acetonitrile and hot filtering the intermediate; then reacting the intermediate with sodium triazole to obtain a triazole substituent; finally, desilylation to protect the intermediate to obtain a hydroxyl group; and then adding p-toluenesulfonyl chloride to react to obtain a high chiral posaconazole mother ring.

[0014] Furthermore, the method specifically includes the following steps:

[0015] The isomer-containing (R)-3-[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone was reduced to the intermediate alcohol using sodium borohydride in tetrahydrofuran solution;

[0016] The intermediate alcohol is protected by hydroxyl group, slurried in acetonitrile, and hot filtered to obtain the intermediate;

[0017] The intermediate reacts with sodium triazole to obtain a triazole substituted product;

[0018] The triazole substituent is desilylated to form a hydroxyl group under acidic conditions, and then p-toluenesulfonyl chloride is added to react under alkaline conditions to obtain a highly chiral posaconazole mother ring.

[0019] Furthermore, the molar ratio of the sodium borohydride to the isomer-containing (R)-3-[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone is (2.5-3):1, the volume ratio of tetrahydrofuran to water in the tetrahydrofuran solution is 10:1, and the temperature of the reduction reaction is 20-25 o C.

[0020] Furthermore, tert-butyldiphenylsilyl chloride is used to protect the hydroxyl group of the intermediate alcohol, and the molar ratio of the tert-butyldiphenylsilyl chloride to the intermediate alcohol is (1.1-1.5): 1, 20-25 o C temperature range for at least 3 hours.

[0021] Furthermore, the intermediate alcohol after hydroxyl protection is slurried in acetonitrile at 35-40° C. for at least 2 hours.

[0022] Furthermore, the temperature range of the hot filtration is 35-40° C., and the filter cake obtained after the hot filtration is washed with acetonitrile and vacuum dried to obtain an intermediate.

[0023] Furthermore, the molar ratio of the sodium triazole to the intermediate is 3-5:1, the solvent is dimethyl sulfoxide, and the reaction is carried out at a temperature range of 90-95° C. for at least 12 hours.

[0024] Furthermore, the acidic condition is a sulfuric acid solution, an acetone solvent is added, the volume ratio of the acetone to the sulfuric acid solution is 1:(5-10), and the reaction temperature is 40-45°C.

[0025] Furthermore, the molar ratio of p-toluenesulfonyl chloride to the hydroxyl-containing triazole substituent is (1.2-1.5):1, and the reaction temperature is 20-25°C.

[0026] Furthermore, the highly chiral posaconazole mother ring is purified by recrystallization in isopropanol and water to obtain a posaconazole mother ring with a chiral purity greater than 99.90%.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. Use tert-butyldiphenylsilyl chloride to protect the intermediate alcohol, and then slurry it in acetonitrile to remove the trans isomer and improve the chiral purity of the product;

[0029] 2. The product after hydroxyl protection reacts with sodium triazole to effectively avoid intramolecular ring-closure by-products and improve product conversion rate and yield;

[0030] 3. The crude posaconazole mother ring was recrystallized in isopropanol and water to obtain high-purity posaconazole mother ring with a chiral purity greater than 99.90%. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a flow chart of a method for synthesizing a high chiral purity posaconazole mother ring provided by an embodiment of the present invention;

[0032] Figure 2 is a hydrogen nuclear magnetic resonance spectrum of the posaconazole parent ring prepared by the method of the present invention;

[0033] Figure 3 is a liquid chromatogram of the posaconazole parent ring prepared by the method of the present invention;

[0034] Figure 4 is a chiral liquid chromatogram of the posaconazole mother ring prepared by the method of the present invention;

[0035] Figure 5 It is the mass spectrum of the posaconazole mother ring prepared by the method of the present invention. DETAILED DESCRIPTION

[0036] The present invention will be further described below in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention.

[0037] As Figure 1 shown, a flow chart of a method for synthesizing high chiral purity posaconazole mother ring according to an embodiment of the present application is provided, and the specific steps are as follows:

[0038] Step 1:

[0039] Preparation of ((3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl)methanol.

[0040]

[0041] 4 kg of (R)-3-[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3- carbonyl]-4-phenyl-2-oxazolidinone, 40 liters of tetrahydrofuran, and 4 liters of water were added to a 100 L glass reaction kettle, stirring was started, and the temperature was maintained at 20-25°C.

[0042] Sodium borohydride was added in a molar ratio of (2.5-3):1 to (R)-3-[(3S,5R)-5-(2,4- difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone containing isomers, and 740 grams of sodium borohydride were added in 20 batches in this embodiment, 37 grams per batch, and the addition was completed within 2 hours, the temperature was controlled at 20-25°C, and the reaction was continued for 2 hours.

[0043] The reaction was monitored by HPLC, and after the reaction was completed, the temperature was lowered to 0-10°C, and the reaction system was added to a saturated ammonium chloride solution (7.4 kg of ammonium chloride dissolved in 50 kg of purified water), and stirred for 10-20 min.

[0044] Under a vacuum degree of -0.06 MPa to -0.1 MPa, the temperature was controlled at 40-50°C, and the volume was concentrated to about 60 liters under reduced pressure. The aqueous phase in this embodiment was extracted twice with 40 L of dichloromethane and 20 L of dichloromethane, and the organic phase was washed with brine.

[0045] Under a vacuum degree of -0.06 MPa to -0.1 MPa, the temperature was controlled at 35-40°C, and the volume was concentrated to about 5 L under reduced pressure, 5 liters of MTBE solvent was added to replace it, the system was concentrated to a volume of about 5 L, 5 liters of MTBE solvent was added to replace it for the second time, the system was concentrated to a volume of about 5 L, 5 liters of MTBE solvent was added to replace it for the third time, at this time a large amount of chiral auxiliary (R)-4-phenyl-2-oxazolidinone appeared in the system, filtration was performed, the filter cake was washed with 2 liters of MTBE, and the filtrate was collected.

[0046] The filtrate was concentrated under reduced pressure at a vacuum degree of -0.06 MPa to -0.1 MPa and a temperature of 35-40°C to a volume of about 2 L of a light yellow oil, i.e., 2.5 kg of [(3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol. HPLC analysis showed a purity of 98.5% and a yield of 90%.

[0047] Step 2:

[0048] Preparation of tert-butyl[[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methoxy]diphenylsilane.

[0049]

[0050] 2.5 kg [(3R,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methanol (1.0 equivalent) and 25 L dichloromethane were added to a 60 L glass reactor, stirred, and the temperature was maintained at 20-25 o C;

[0051] Add 1.43 kg of triethylamine (2.0 equivalents) and dropwise add a dichloromethane solution of tert-butyldiphenylsilyl chloride (2.76 kg of tert-butyldiphenylsilyl chloride dissolved in 8.3 L of dichloromethane, 1.4 equivalents). Add the mixture within 2 hours and control the temperature at 20-25 o C and continue the reaction for 2 hours.

[0052] The reaction was monitored by HPLC. After the reaction was completed, the reaction system was added to a saturated ammonium chloride solution (7.4 kg of ammonium chloride was dissolved in 50 kg of purified water), stirred for 10 to 20 minutes, separated, and the organic phase was washed with 15 liters of brine. After the organic phase was separated, the temperature was controlled at 35-40°C under a vacuum degree of -0.06 MPa to -0.1 MPa. o C, and concentrated under reduced pressure to a volume of about 6 liters to precipitate a large amount of solid.

[0053] Add 5 L of acetonitrile to displace the mixture, concentrate to a volume of about 6 L, then add 5 L of acetonitrile to displace the mixture, concentrate to a volume of about 6 L, backpressure with nitrogen, rotate at 90 rpm, continue stirring for 2 hours, maintain the system at 35-40°C, and hot filter to obtain a filter cake (hot filtration, not cooling).

[0054] The filter cake was dried under vacuum at 35-40° C. for 12 hours to obtain a white powder of high-purity compound 3, i.e., tert-butyl[[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methoxy]diphenylsilane, 2.95 kg; HPLC purity: 99.3%, de%:>99%, yield: 70%.

[0055] Step 3:

[0056] Preparation of 1-[[(2R,4S)-4-[[(tert-Butyl-diphenylsilyl)oxy]methyl]-2-(2,4-difluorophenyl)tetrahydrofuran-2-yl]methyl]-1H-1,2,4-triazole.

[0057]

[0058] The molar ratio of sodium triazole to tert-butyl[[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methoxy]diphenylsilane is (3-5):1. In this embodiment, 2.9 kg of tert-butyl[[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-yl]methoxy]diphenylsilane and 29 liters of dimethyl sulfoxide are added to a 60 L glass reactor, stirring is started, and 1.35 kg of sodium 1,2,4-triazole is added. The system temperature is raised to 90-95 o C, and react at this temperature for 12 hours.

[0059] The reaction was monitored by HPLC. After completion, the reaction system was added with 80 kg of water and extracted twice with 20 L of dichloromethane. The organic phase was washed three times with 15 L of brine. After separation, the organic phase was concentrated under reduced pressure to approximately 4 L under a vacuum of -0.06 MPa to -0.1 MPa and a temperature of 35-40°C, resulting in the precipitation of a large amount of solid.

[0060] First, 5 L of n-heptane was added for displacement, and the system was concentrated to a volume of about 4 L. Then, 5 L of n-heptane was added for displacement, and the system was concentrated to a volume of about 4 L. Nitrogen back pressure was applied at a speed of 90 rpm. Stirring was continued for 2 hours, the system was cooled to 5-10°C, and the filter cake was obtained by filtration.

[0061] The filter cake was dried under vacuum at 35-40° C. for 12 h to obtain a white powder of high-purity compound 4, i.e., 1-[[(2R,4S)-4-[[(tert-butyl-diphenylsilyl)oxy]methyl]-2-(2,4-difluorophenyl)tetrahydrofuran-2-yl]methyl]-1H-1,2,4-triazole, with a mass of 2.2 kg. The measured HPLC purity was 97%, de%:>99%, and the yield was 85%.

[0062] Step 4:

[0063] Preparation of [(3R,5R)-5-[(1H-1,2,4-triazole)methyl]-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl]methanol.

[0064]

[0065] Add 2.2 kg of 1-[[(2R,4S)-4-[[(tert-butyl-diphenylsilyl)oxy]methyl]-2-(2,4-difluorophenyl)tetrahydrofuran-2-yl]methyl]-1H-1,2,4-triazole, 11 liters of acetone, and dilute sulfuric acid (2M, 11 L) into a 50 L glass reactor. Start stirring, raise the system temperature to 30-35°C, and react at this temperature for 2 hours.

[0066] The reaction was monitored by HPLC. The reaction system was diluted with 20 kg of water and concentrated under reduced pressure to a volume of about 35 L under the condition of controlling the temperature at 35-40°C. The mixture was extracted twice with 10 L of methyl tert-butyl ether. The by-products were completely extracted by HPLC.

[0067] The aqueous phase was adjusted to pH 9 with 2 mol / L aqueous sodium hydroxide solution and extracted twice with 10 L of dichloromethane. The organic phase was washed three times with 7 L of brine. After separation, the organic phase was concentrated under reduced pressure to approximately 3 L under a vacuum range of -0.06 MPa to -0.1 MPa and a temperature of 35-40°C, resulting in the precipitation of a large amount of solid.

[0068] 5 L of n-heptane was added to the suspension for replacement, and the system was concentrated to a volume of about 3 L. 5 L of n-heptane was added for replacement, and the system was concentrated to a volume of about 3 L. Nitrogen back pressure was applied at a speed of 90 rpm. Stirring was continued for 2 hours, the system was cooled to 5-10°C, and the filter cake was obtained by filtration.

[0069] The filter cake was dried at 35-40° C. under vacuum for 12 hours to obtain a white powder of high-purity compound, namely [(3R,5R)-5-[(1H-1,2,4-triazole)methyl]-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl]methanol, which weighed 1.1 kg in this example.

[0070] HPLC purity: 97%, de%:>99%, yield: 91%.

[0071] Step 5:

[0072] Preparation of [(3S,5R)-5-[(1H-1,2,4-triazol-1-yl)methyl]-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl]methyl 4-methylbenzenesulfonate.

[0073]

[0074] The molar ratio of toluenesulfonyl chloride to [(3R,5R)-5-[(1H-1,2,4-triazole)methyl]-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl]methanol is (1.2-1.5):1. In this example, 1.2 kg of [(3R,5R)-5-[(1H-1,2,4-triazole)methyl]-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl]methanol and 12 liters of dichloromethane were added to a 50 L glass reactor, stirring was started, 1.64 kg of triethylamine and 124 g of N,N-lutidine were added, stirred for 10 minutes, the temperature was controlled at 20-25°C, 1 kg of 4-methylbenzenesulfonyl chloride was added dropwise, and the reaction was carried out at 20-25°C for 2 hours.

[0075] The reaction was monitored by HPLC, and the reaction system was added to a saturated aqueous ammonium chloride solution for liquid separation. The organic phase was washed twice with brine, 5 L each time, and the liquids were separated. The organic phase was concentrated under reduced pressure at a vacuum degree of -0.06 MPa to -0.1 MPa, with the temperature controlled in the range of 35-40°C, and concentrated under reduced pressure to a volume of about 3 L, precipitating a large amount of solid.

[0076] 2 L of isopropanol was added for replacement, and the system was concentrated to a volume of about 3 L. 2 L of isopropanol was added for replacement, and the system was concentrated to a volume of about 3 L. Nitrogen back pressure was applied, the speed was 90 rpm, and 6 L of water was added dropwise. The addition time was controlled to about 2 hours, and stirring was continued for 12 hours. The system was cooled to 5-10 ° C and filtered to obtain a filter cake.

[0077] The filter cake was dried at 35-40° C. under vacuum for 12 hours to obtain a white powder of high-purity posaconazole mother ring, namely [(3S,5R)-5-[(1-hydrogen-1,2,4-triazol-1-yl)methyl]-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl]methyl 4-methylbenzenesulfonate, with a mass of 1.65 kg.

[0078] like Figures 2-5 The figures show the proton nuclear magnetic resonance spectrum, liquid chromatography, chiral liquid chromatography, and mass spectrum of the posaconazole parent ring prepared using the method of the present invention, respectively. HPLC purity: 99.9%, de%: >99%, yield: 90%. The posaconazole parent ring prepared using this method features simple operation, fewer reaction steps, fewer byproducts, high conversion rate, and a high-purity product, making it more suitable for industrial production.

[0079] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing a high chiral purity posaconazole mother ring, characterized in that: The isomer-containing (R)-3-[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone was reduced to an intermediate alcohol using sodium borohydride. The hydroxyl group of the intermediate alcohol was protected using tert-butyldiphenylsilyl chloride, and then slurried in acetonitrile and hot filtered to obtain the intermediate. The intermediate was then reacted with sodium triazole to obtain a triazole substituent. Finally, the silylation group was protected to a hydroxyl group, and then p-toluenesulfonyl chloride was added to react to obtain the highly chiral posaconazole mother ring.

2. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 1, characterized in that: The specific steps include: The isomer-containing (R)-3-[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone was reduced with sodium borohydride in tetrahydrofuran solution to give the intermediate alcohol; The intermediate alcohol was protected by hydroxyl group using tert-butyldiphenylsilyl chloride, slurried in acetonitrile, and hot filtered to obtain the intermediate; The intermediate reacts with sodium triazole to obtain a triazole substituted product; The triazole substituent is desilylated to form a hydroxyl group under acidic conditions, and then p-toluenesulfonyl chloride is added to react under alkaline conditions to obtain a highly chiral posaconazole mother ring.

3. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 2, characterized in that: The molar ratio of sodium borohydride to (R)-3-[(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-carbonyl]-4-phenyl-2-oxazolidinone containing isomers is (2.5-3):1, the volume ratio of tetrahydrofuran to water in the tetrahydrofuran solution is 10:1, and the temperature of the reduction reaction is 20-25 o C.

4. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 2, wherein: The molar ratio of the tert-butyldiphenylsilyl chloride to the intermediate alcohol is (1.1-1.5): 1, 20-25 o C temperature range for at least 3 hours.

5. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 2, characterized in that: The hydroxy-protected intermediate alcohol was slurried in acetonitrile at 35-40°C for at least 2 hours.

6. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 2, characterized in that: The temperature range of the hot filtration is 35-40° C. The filter cake obtained after the hot filtration is washed with acetonitrile and vacuum dried to obtain an intermediate.

7. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 2, characterized in that: The molar ratio of the sodium triazole to the intermediate is 3-5:1, the solvent is dimethyl sulfoxide, and the reaction is carried out at a temperature range of 90-95° C. for at least 12 hours.

8. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 2, wherein: The acidic condition is a sulfuric acid solution, acetone solvent is added, the volume ratio of acetone to sulfuric acid solution is 1:(5-10), and the reaction temperature is 40-45°C.

9. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 2, wherein: The molar ratio of p-toluenesulfonyl chloride to the hydroxyl-containing triazole substituent is (1.2-1.5):1, and the reaction temperature is 20-25°C.

10. The method for synthesizing a high chiral purity posaconazole mother ring according to claim 2, characterized in that: The highly chiral posaconazole mother ring is purified by recrystallization in isopropanol and water to obtain a posaconazole mother ring with a chiral purity greater than 99.90%.

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