A process for the synthesis of posaconazole halocyclic intermediates

Abstract

The application provides a synthesis method of posaconazole halogenated cyclic intermediate, which comprises the following steps: carrying out halogenation reaction on a raw material intermediate shown in formula (1) and a halogenating reagent in an organic solvent in the presence of an acidic substance, so as to obtain a posaconazole halogenated cyclic intermediate shown in formula (2). The application also provides a synthesis method of posaconazole. The synthesis method provided by the application activates the halogenating reagent by using a cheap acidic substance and carries out the halogenation reaction under low-temperature conditions, so that the target product has the advantages of high yield, high diastereoselectivity and the like, the process is simple and convenient to operate, post-treatment is simple, the synthesis efficiency is obviously improved, the synthesis cost is reduced, the synthesis method provided by the application has great potential for industrialized production, has strong industrial practicability, and has important significance for expanding the production and application of posaconazole.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis, specifically to a method for synthesizing a posaconazole halogenated intermediate and a method for synthesizing posaconazole. Background Technology

[0002] Posaconazole, a derivative of itraconazole, is a second-generation triazole antifungal drug approved by the FDA in 2006, marketed under the brand name NOXAFIL, and originally developed by Schering-Plough. Posaconazole possesses broad-spectrum antifungal activity and strong antibacterial efficacy, exhibiting good bactericidal activity against Aspergillus and other fungi, particularly effective against polyene-resistant and other triazole-resistant or invasive fungal infections. In addition, posaconazole is clinically used to treat mycoplasmal infections and can also be used for salvage therapy against invasive Aspergillus and Coccidioides. Since its market launch, posaconazole's sales have increased annually, exceeding $1 billion globally in 2021, demonstrating strong economic impact and promising application prospects.

[0003] In 2012, MSN Laboratories Limited of India disclosed a synthetic route for posaconazole in patent US 2014343285A1. The route uses m-difluorobenzene as a starting material and proceeds through Friedel-Crafts acylation, Wittig, condensation amide, hydroxymethylation, halogenation, reduction, and substitution to obtain the target product. However, this route easily generates intramolecular ring-closing impurities, which, although removable, severely affect the yield. The synthetic route is as follows:

[0004]

[0005] Existing patents and literature disclose synthetic methods that suffer from poor diastereoselectivity, low yields, and high feedstock consumption for the key halogenation step. Considering the high cost of posaconazole synthesis, it is essential to develop a high-yield, high-diastereoselectivity halogenation method to improve intermediate yields and reduce synthesis costs. Summary of the Invention

[0006] To overcome the shortcomings of the prior art, one object of the present invention is to provide a method for synthesizing posaconazole halogenated intermediates, which can significantly improve the yield and diastereoselectivity of posaconazole halogenated intermediates, thereby significantly improving the synthesis efficiency of posaconazole halogenated intermediates and reducing synthesis costs.

[0007] Another object of the present invention is to provide a method for synthesizing posaconazole.

[0008] The first aspect of the present invention provides a method for synthesizing a posaconazole halogenated intermediate, wherein a raw material intermediate as shown in formula (1) is subjected to a halogenation reaction with a halogenating agent in an organic solvent in the presence of an acidic substance to obtain the posaconazole halogenated intermediate as shown in formula (2).

[0009]

[0010] Among them, R 1 It indicates substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted C7-C18 alkylene aryl;

[0011] R 2 and R 3 Each can independently represent hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, or substituted or unsubstituted C7-C18 alkylene aryl;

[0012] When R 1 R 2 and R 3 When each substituent is represented independently, the substituent is selected from C1-C4 alkyl, C1-C4 alkoxy, or C6-C12 aryl;

[0013] X represents halogen.

[0014] The method for synthesizing the posaconazole halogenation intermediate provided by this invention involves a reaction in the presence of an acidic substance. The halogenating reagent is activated in situ by the acidic substance to generate a hydrohalic acid, which then reacts with the starting intermediate. The activation of the halogenating reagent and the halogenation reaction are completed in a single process, thereby yielding the target product. Compared to halogenation reactions under neutral or alkaline conditions, the synthesis method provided by this invention can significantly improve the yield and diastereoselectivity of the target product, thereby increasing the synthesis efficiency, reducing synthesis costs, and alleviating the pressure of subsequent purification.

[0015] In the synthesis method provided by this invention, the R 1 It can further represent substituted or unsubstituted C1-C4 alkyl groups (e.g., substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.), substituted or unsubstituted phenyl groups, or substituted or unsubstituted benzyl groups; the R 2 and R 3 Each can independently represent hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl; when R 1 R 2 and R 3 When each substituent is represented independently, the substituent can be selected from C1 to C4 alkyl groups.

[0016] In some preferred embodiments, the R 1 It can further represent C2-C4 alkyl (e.g., isopropyl), phenyl, or benzyl. In some other preferred embodiments, the R... 2 and R 3 Each can be further represented independently as hydrogen or phenyl.

[0017] In the synthesis method provided by this invention, X may further represent Br or I.

[0018] In the synthesis method provided by this invention, the acidic substance can be selected from common inorganic acids, organic acids, or acid salts (e.g., inorganic acid salts of alkali metals), as long as it can activate the halogenating reagent to generate hydrohalic acid. In some preferred embodiments, the acidic substance can be selected from one or more of hydrochloric acid (e.g., concentrated hydrochloric acid with a concentration of 10-12N), sulfuric acid (e.g., concentrated sulfuric acid with a concentration of 5-8N), nitric acid, carbonic acid, boric acid, orthophosphoric acid, p-toluenesulfonic acid (TsOH), camphorsulfonic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, potassium hydrogen sulfate, and sodium hydrogen sulfate. In some more preferred embodiments, the acidic substance can be selected from hydrochloric acid (e.g., concentrated hydrochloric acid with a concentration of 12N).

[0019] In the synthesis method provided by this invention, the amount of the acidic substance can be 1-50 mol% of the raw material intermediate, including but not limited to about 1 mol%, about 5 mol%, about 8 mol%, about 10 mol%, about 12 mol%, about 15 mol%, about 18 mol%, about 20 mol%, about 25 mol%, about 30 mol%, about 35 mol%, about 40 mol%, about 45 mol%, about 50 mol%, or any molar percentage range. In some preferred embodiments, the amount of the acidic substance can be 5-15 mol% of the raw material intermediate.

[0020] In the synthesis method provided by this invention, the halogenating reagent can be selected from common halogenating reagents, as long as it can be activated by acidic substances to generate hydrohalic acid. In some preferred embodiments, the halogenating reagent can be selected from one or more of iodine (I2), N-iodosuccinimide (NIS), N-iodophthalimide, liquid bromine (Br2), dibromohydantoin (DBDMH), diiodohydantoin, N-bromosuccinimide (NBS), and N-bromophthalimide. In some more preferred embodiments, the halogenating reagent can be selected from I2 or NBS.

[0021] In the synthesis method provided by this invention, the amount of the halogenating reagent can be 1.0 to 5.0 equivalents of the raw material intermediate, including but not limited to equivalent values ​​such as about 1.0 equivalents, about 1.2 equivalents, about 1.5 equivalents, about 1.8 equivalents, about 2.0 equivalents, about 2.2 equivalents, about 2.5 equivalents, about 2.8 equivalents, about 3.0 equivalents, about 3.5 equivalents, about 4.0 equivalents, about 4.5 equivalents, and about 5.0 equivalents, or any equivalent range. In some preferred embodiments, the amount of the halogenating reagent can be 1.2 to 2.5 equivalents of the raw material intermediate.

[0022] In the synthesis method provided by this invention, the organic solvent can be selected from common organic solvents such as acetates and nitriles. In some preferred embodiments, the organic solvent can be selected from organic solvents such as CH3COOR', where R' can represent C1-C6 alkyl, preferably C1-C4 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.). In some more preferred embodiments, the organic solvent can be selected from one or more of acetonitrile, butyronitrile, methyl acetate, ethyl acetate, isopropyl acetate, and n-butyl acetate.

[0023] In the synthesis method provided by this invention, the reaction temperature of the halogenation reaction can be -10 to -78°C, including but not limited to temperatures such as approximately -10°C, approximately -20°C, approximately -25°C, approximately -30°C, approximately -35°C, approximately -40°C, approximately -45°C, approximately -50°C, approximately -55°C, approximately -60°C, approximately -65°C, approximately -70°C, approximately -75°C, and approximately -78°C, or any temperature range. Lower reaction temperatures are beneficial for improving diastereoselectivity. Considering factors such as production costs, in some preferred embodiments, the reaction temperature of the halogenation reaction can be -10 to -40°C.

[0024] In the synthesis method provided by this invention, the reaction time of the halogenation reaction can be 1 to 10 hours. In some preferred embodiments, the reaction time of the halogenation reaction can be 2 to 5 hours.

[0025] A second aspect of the present invention provides a method for synthesizing posaconazole, comprising a step of synthesizing a posaconazole halogenated intermediate, wherein the synthesis step employs the method for synthesizing a posaconazole halogenated intermediate described in any of the above-described technical solutions.

[0026] The method for synthesizing the posaconazole halogenation intermediate provided by this invention uses inexpensive acidic substances to activate the halogenating reagent and carries out the halogenation reaction under low temperature conditions. The prepared target product has advantages such as high yield and high diastereoselectivity. The process is simple, easy to operate, and the post-processing is simple, which significantly improves the synthesis efficiency and reduces the synthesis cost. The synthesis method provided by this invention can also realize gram-scale reaction (as shown in Example 69), thus having great potential for industrial-scale production. It has strong industrial applicability and is of great significance for expanding the production and application of posaconazole. Detailed Implementation

[0027] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0028] Unless otherwise specified, the raw materials or reagents used in the embodiments and comparative examples of this invention are all commercially available products, and the operating methods and testing methods used are all conventional methods in the art.

[0029] In the embodiments and comparative examples of the present invention, the hydrochloric acid used is 12N concentrated hydrochloric acid, and the sulfuric acid used is 6N concentrated sulfuric acid.

[0030] Unless otherwise specified, all percentages used in the embodiments and comparative examples of this invention are mass percentages.

[0031] Example 1 Synthesis of (R)-4-phenyl-3-((3S,5R)-5-(2,4))-difluorophenyl-5-iodomethyltetrahydrofuran-3-carbonyl-oxazolidin-2-one (2a)

[0032]

[0033] In a dry Schlenk tube, 1a (387 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and I2 (381 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2a was given in 462 mg, yield 90%, dr = 18:1.

[0034] 1H NMR (400MHz, CDCl3) δ7.43–7.28(m,4H),7.20(d,J=6.9Hz,2H),6.85–6.79(m,1H),6.73(ddd,J=11.2,8.6,2.5Hz,1H),5.36(dd,J=8.7,3.8Hz,1H) ,4.64(t,J=8.8Hz,1H),4.25–4.17(m,2H),4.13–4.01(m,2H),3.63–3.55 (m,2H),2.72(dd,J=13.2,7.1Hz,1H),2.61(ddd,J=13.2,8.1,2.0Hz,1H); 13 C NMR (100MHz, CDCl3) δ173.41,163.84,163.62,160.94,160.81,160.13,157.43,157.28,153.52,138.63,129.71,129.56 ,121.65,110.42,104.56,104.38,104.19,87.39,87.21,70.53,69.71,57.49,44.37,39.01,38.95,38.43,38.40,28.91.

[0035] Example 2 Synthesis of compound 2a

[0036]

[0037] Except for using NIS (338 mg, 1.5 mmol) instead of I2, the other steps were the same as in Example 1, yielding compound 2a 433 mg in 82% yield, dr = 16:1.

[0038] Example 3 Synthesis of compound 2a

[0039] Except for the use of N-iodophthalimide (410 mg, 1.5 mmol) instead of I2, the other steps were the same as in Example 1, yielding compound 2a 448 mg in 85% yield, dr = 16:1.

[0040] Example 4 Synthesis of compound 2a

[0041] Except for the use of diiodohydantoin (570 mg, 1.5 mmol) instead of I2, the other steps were the same as in Example 1, yielding compound 2a 459 mg in 87% yield, dr = 17:1.

[0042] Example 5 Synthesis of Compound 2a

[0043] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 1, yielding 469 mg of compound 2a with a yield of 89% and dr = 17:1.

[0044] Example 6 Synthesis of Compound 2a

[0045] Except for using L-(-)camphorsulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 1, yielding 465 mg of compound 2a with a yield of 88% and dr = 17:1.

[0046] Example 7 Synthesis of Compound 2a

[0047] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 1, yielding 459 mg of compound 2a with a yield of 87% and dr = 16:1.

[0048] Example 8 Synthesis of Compound 2a

[0049] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 1, yielding 465 mg of compound 2a with a yield of 88% and dr = 17:1.

[0050] Example 9 Synthesis of (R)-4-phenyl-3-((3S,5R)-5-(2,4))-difluorophenyl-5-bromomethyltetrahydrofuran-3-carbonyl-oxazolidin-2-one (2b)

[0051]

[0052] In a dry Schlenk tube, 1a (387 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and NBS (267 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2b was given in 410 mg, yield 88%, dr = 17:1.

[0053] 1H NMR(400MHz, CDCl3)δ7.43(td,J=8.9,6.5Hz,1H),7.35–7.27(m,3H),7.21(d,J=1.8Hz ,1H),7.19(d,J=2.8Hz,1H),6.85–6.79(m,1H),6.74(ddd,J=11.3,8.6,2.5Hz,1H),5.3 6(dd,J=8.7,3.8Hz,1H),4.64(t,J=8.8Hz,1H),4.25–4.18(m,2H),4.11–4.02(m,2H),3 .69(d,J=1.2Hz,2H),2.72(dd,J=13.4,6.8Hz,1H),2.55(ddd,J=13.6,7.8,2.1Hz,1H); 13 CNMR (100MHz, CDCl3) δ171.50,163.99,163.87,161.51,161.39,160.17,157.83,157.71,153.49,138.59,129.42,129.01 ,125.73,111.22,104.76,104.50,104.24,84.21,84.17,70.26,69.90,57.88,44.47,39.27,39.23,38.59,38.55,29.71.

[0054] Example 10 Synthesis of Compound 2b

[0055] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 9, yielding 402 mg of compound 2b in a yield of 86% and dr = 17:1.

[0056] Example 11 Synthesis of Compound 2b

[0057] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 9, yielding 394 mg of compound 2b in a yield of 84% and dr = 17:1.

[0058] Example 12 Synthesis of Compound 2b

[0059] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 9, yielding compound 2b 398 mg in 85% yield, dr = 16:1.

[0060] Example 13 Synthesis of Compound 2b

[0061] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 9, yielding 400 mg of compound 2b in a yield of 85% and dr = 16:1.

[0062] Example 14 Synthesis of Compound 2b

[0063]

[0064] In a dry Schlenk tube, 1a (387 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and dibromohydantoin (429 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2b was given in 405 mg, yield 87%, dr = 17:1.

[0065] Example 15 Synthesis of Compound 2b

[0066] Except for the use of sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 14, yielding 405 mg of compound 2b in 87% yield, dr = 16:1.

[0067] Example 16 Synthesis of Compound 2b

[0068] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 14, yielding 398 mg of compound 2b in 85% yield, dr = 15:1.

[0069] Example 17 Synthesis of Compound 2b

[0070] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 14, yielding compound 2b 398 mg in 85% yield, dr = 15:1.

[0071] Example 18 Synthesis of Compound 2b

[0072] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 14, yielding 393 mg of compound 2b in a yield of 83% and dr = 15:1.

[0073] Example 19 Synthesis of (R)-4-benzyl-3-((3S,5R)-5-(2,4))-difluorophenyl-5-iodomethyltetrahydrofuran-3-carbonyl-oxazolidin-2-one (2c)

[0074]

[0075] In a dry Schlenk tube, 1b (400 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and I2 (381 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2c was given in 480 mg, yield 91%, dr = 18:1.

[0076] 1 H NMR (400MHz, CDCl3) δ7.41 (td, J=8.9, 6.5Hz, 1H), 7.26 (dd, J=8.0, 6.4Hz, 2H), 7.21–7.17 (m, 1H) ,7.15–7.08(m,2H),6.81(td,J=8.3,2.6Hz,1H),6.72(ddd,J=11.2,8.6,2.5Hz,1H),4.67–4.55(m ,1H),4.21–4.11(m,3H),4.06–3.99(m,1H),3.74(d,J=10.7Hz,1H),3.67(d,J=10.7Hz,1H),3.18 (dd,J=13.5,3.4Hz,1H),2.79(ddd,J=27.6,13.4,8.0Hz,2H),2.57(ddd,J=13.4,8.4,2.1Hz,1H). 13C NMR (100MHz, CDCl3) δ174.56,163.33,163.19,160.97,160.85,160.72,158.53,15 8.31,153.23,140.25,140.24,135.29,130.54,130.52,130.47,130.41,129.50,1 28.94,126.39,124.87,124.84,124.80,124.76,115.24,111.24,111.20,111.07,111.01,104.87,104.67,103.99,66.29,63.54,54.73,44.54,37.93,33.58,33.54.

[0077] Example 20 Synthesis of Compound 2c

[0078] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 19, yielding compound 2c 469 mg in 89% yield, dr = 18:1.

[0079] Example 21 Synthesis of compound 2c

[0080] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 19, yielding compound 2c 453 mg in 83% yield, dr = 17:1.

[0081] Example 22 Synthesis of compound 2c

[0082] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 19, yielding compound 2c 447 mg in 82% yield, dr = 17:1.

[0083] Example 23 Synthesis of compound 2c

[0084] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 19, yielding 447 mg of compound 2c in a yield of 82% and dr = 17:1.

[0085] Example 24 Synthesis of compound 2c

[0086]

[0087] In a dry Schlenk tube, 1b (400 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and NIS (338 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2c was given in 473 mg, yield 88%, dr = 17:1.

[0088] Example 25 Synthesis of Compound 2c

[0089] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 24, yielding 455 mg of compound 2c in 85% yield, dr = 16:1.

[0090] Example 26 Synthesis of Compound 2c

[0091] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 24, yielding compound 2c 447 mg in 83% yield, dr = 17:1.

[0092] Example 27 Synthesis of Compound 2c

[0093] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 24, yielding compound 2c 450 mg in 84% yield, dr = 16:1.

[0094] Example 28 Synthesis of (R)-4-benzyl-3-((3S,5R)-5-(2,4))-difluorophenyl-5-bromomethyltetrahydrofuran-3-carbonyl-oxazolidin-2-one (2d)

[0095]

[0096] In a dry Schlenk tube, 1b (400 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and NBS (267 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, then allowed to cool naturally to room temperature and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2d was given in 410 mg, yield 88%, dr = 18:1.

[0097] 1 H NMR (400MHz, CDCl3) δ7.45 (td, J=8.8, 6.4Hz, 1H), 7.27 (dd, J=8.0, 6.4Hz, 2H), 7.18 (s, 1H), 7. 16–7.09(m,2H),6.82(td,J=8.3,2.6Hz,1H),6.74(ddd,J=11.2,8.7,2.5Hz,1H),4.61(ddt,J=9 .2,7.0,3.4Hz,1H),4.20–4.12(m,3H),4.01(tt,J=8.0,5.8Hz,1H),3.87–3.73(m,2H),3.19(d d,J=13.4,3.4Hz,1H),2.78(ddd,J=28.2,13.4,8.0Hz,2H),2.52(ddd,J=13.4,8.5,2.2Hz,1H). 13 C NMR (100MHz, CDCl3) δ174.73,163.62,163.49,161.25,161.13,161.01,158.77,15 8.65,153.43,140.36,140.35,135.15,130.77,130.72,130.68,130.62,129.50,1 28.94,127.37,125.09,125.06,124.95,124.91,118.75,111.34,111.30,111.13,111.09,104.43,104.17,103.91,66.18,63.85,55.49,44.26,37.76,35.32,35.29.

[0098] Example 29 Synthesis of compound 2d

[0099] Except for the use of sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 28, yielding 410 mg of compound 2d with a yield of 88% and dr = 17:1.

[0100] Example 30 Synthesis of compound 2d

[0101] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 28, yielding 408 mg of compound 2d with a yield of 85% and dr = 16:1.

[0102] Example 31 Synthesis of compound 2d

[0103] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 28, yielding 408 mg of compound 2d with a yield of 85% and dr = 17:1.

[0104] Example 32 Synthesis of compound 2d

[0105] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 28, yielding compound 2d 395 mg in 82% yield, dr = 16:1.

[0106] Example 33 Synthesis of (R)-4-isopropyl-3-((3S,5R)-5-(2,4))-difluorophenyl-5-iodomethyltetrahydrofuran-3-carbonyl-oxazolidin-2-one (2e)

[0107]

[0108] In a dry Schlenk tube, 1c (353 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and I2 (381 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and the product was used to give 425 mg of compound 2e in 89% yield (dr = 17:1).

[0109] 1H NMR (400MHz, CDCl3) δ7.41 (td, J=8.9, 6.5Hz, 1H), 6.83 (td, J=8.2, 2.5Hz, 1H), 6.74 (ddd, J=11.2,8.6,2.5Hz,1H),4.38(dt,J=7.4,3.5Hz,1H),4.23(td,J=8.4,6.2Hz,2H),4.19–4. 03(m,4H),3.71(q,J=10.7Hz,2H),2.82(dd,J=13.3,6.5Hz,1H),2.57(ddd,J=13.2,8.1,2. 2Hz, 1H), 2.30 (ddt, J=10.9, 7.0, 3.9Hz, 1H), 0.86 (d, J=7.0Hz, 3H), 0.81 (d, J=6.9Hz, 3H). 13 C NMR (100MHz, CDCl3) δ171.74,163.87,163.74,161.39,161.27,160.53,157.79,157.67,152.85,129.73,125.88,111.11,11 0.97,104.59,104.34,104.18,84.25,84.21,70.62,63.45,58.67,44.29,39.41,39.25,38.21,37.95,27.94,17.57,14.63.

[0110] Example 34 Synthesis of compound 2e

[0111] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 33, yielding 407 mg of compound 2e in 85% yield, dr = 16:1.

[0112] Example 35 Synthesis of compound 2e

[0113] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 33, yielding 388 mg of compound 2e in a yield of 81% and dr = 15:1.

[0114] Example 36 Synthesis of compound 2e

[0115] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 33, yielding 396 mg of compound 2e in a yield of 83% and dr = 16:1.

[0116] Example 37 Synthesis of compound 2e

[0117] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 33, yielding 387 mg of compound 2e in a yield of 81% and dr = 15:1.

[0118] Example 38 Synthesis of compound 2e

[0119]

[0120] In a dry Schlenk tube, 1c (353 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and NIS (338 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2e was given in 398 mg, yield 84%, dr = 16:1.

[0121] Example 39 Synthesis of compound 2e

[0122] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 38, yielding 388 mg of compound 2e in a yield of 81% and dr = 15:1.

[0123] Example 40 Synthesis of compound 2e

[0124] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 38, yielding 374 mg of compound 2e in a yield of 79% and dr = 15:1.

[0125] Example 41 Synthesis of compound 2e

[0126] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 38, yielding 369 mg of compound 2e in a yield of 78% and dr = 15:1.

[0127] Example 42 Synthesis of compound 2e

[0128] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 38, yielding 369 mg of compound 2e in a yield of 78% and dr = 15:1.

[0129] Example 43 Synthesis of (R)-4-isopropyl-3-((3S,5R)-5-(2,4))-difluorophenyl-5-bromomethyltetrahydrofuran-3-carbonyl-oxazolidin-2-one (2f)

[0130]

[0131] In a dry Schlenk tube, 1c (353 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and NBS (267 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2f was given as 376 mg, in 87% yield, dr = 16:1.

[0132] 1 H NMR(400MHz, CDCl3)δ7.45(td,J=8.9,6.5Hz,1H),6.86–6.80(m,1H),6.77–6.71(m,1H),4.38(d dd,J=8.2,3.9,3.1Hz,1H),4.23(dt,J=9.3,7.8Hz,2H),4.18–4.11(m,2H),4.05(tt,J=8.1,5.9 Hz,1H),3.84(d,J=10.9Hz,1H),3.78(dd,J=10.9,0.9Hz,1H),2.86–2.77(m,1H),2.50(ddd,J=1 3.4, 8.4, 2.3Hz, 1H), 2.30 (qt, J=7.0, 3.5Hz, 1H), 0.86 (d, J=7.0Hz, 3H), 0.81 (d, J=6.9Hz, 3H). 13 C NMR (100MHz, CDCl3) δ172.06,163.96,163.84,161.49,161.37,160.23,157.89,157.77,153.85,129.23,125.88,111.21,11 1.00,104.77,104.52,104.26,84.25,84.21,70.62,63.69,58.67,44.65,39.53,39.49,38.37,38.33,28.44,17.96,14.74.

[0133] Example 44 Synthesis of compound 2f

[0134] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 43, yielding compound 2f 367 mg in 85% yield, dr = 15:1.

[0135] Example 45 Synthesis of compound 2f

[0136] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 43, yielding compound 2f 358 mg in 82% yield, dr = 15:1.

[0137] Example 46 Synthesis of compound 2f

[0138] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 43, yielding compound 2f 360 mg in 82% yield, dr = 16:1.

[0139] Example 47 Synthesis of compound 2f

[0140] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 43, yielding compound 2f 352 mg in 80% yield, dr = 15:1.

[0141] Example 48 Synthesis of compound 2f

[0142]

[0143] Except for the use of DBDMH (429 mg, 1.5 mmol) instead of NBS, the other steps were the same as in Example 43, yielding compound 2f 358 mg in 83% yield, dr = 16:1.

[0144] Example 49 Synthesis of (R)-4-phenyl-3-((3S,5R)-5-(2,4))-difluorophenyl-5-iodomethyltetrahydrofuran-3-carbonyl-5,5-diphenyloxazolidine-2-one (2g)

[0145]

[0146] In a dry Schlenk tube, 1 d (539 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and I2 (381 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and 2 g (565 mg) of the compound was obtained, with a yield of 85% and dr > 20:1.

[0147] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=7.7Hz,2H),7.34(dt,J=15.7,7.5Hz,4H),7.04(s,3H),6.98–6.90(m,7H),6.80(td,J=8.3,2.5Hz,1H),6.70(dd d,J=11.3,8.6,2.5Hz,1H),4.25–4.16(m,1H),4.07–3.95(m,2H),3.57– 3.47(m,2H),2.88(d,J=26.1Hz,1H),2.54(qd,J=13.4,12.9,7.2Hz,2H). 13 C NMR (100MHz, CDCl3) δ171.11,170.66,152.59,141.51,137.64,134.27,128.89,128.55,128.37,128.15,127.79,127.64,126.67, 126.15,125.99,125.94,125.78,111.15,110.93,104.74,104.48,89.37,83.85,83.81,69.14,65.68,44.98,43.92,38.87,38.29.

[0148] Example 50 Synthesis of Compound 2g

[0149] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 49, yielding 2 g of compound (539 mg), with a yield of 81% and dr > 20:1.

[0150] Example 51 Synthesis of Compound 2g

[0151] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 49, yielding 2 g of compound (545 mg), with a yield of 82% and dr = 19:1.

[0152] Example 52 Synthesis of Compound 2g

[0153] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 49, yielding 2 g of compound (552 mg), with a yield of 83% and dr > 20:1.

[0154] Example 53 Synthesis of Compound 2g

[0155] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 49, yielding 2 g of compound 542 mg, with a yield of 80% and dr = 19:1.

[0156] Example 54 Synthesis of Compound 2g

[0157]

[0158] Except for using NIS (338 mg, 1.5 mmol) instead of I2, the other steps were the same as in Example 49, yielding 2 g of compound 525 mg, with a yield of 79% and dr = 18:1.

[0159] Example 55 Synthesis of Compound 2g

[0160] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 54, yielding 2 g of compound (520 mg), with a yield of 78% and dr = 18:1.

[0161] Example 56 Synthesis of Compound 2g

[0162] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 54, yielding 2 g of compound 502 mg, with a yield of 76% and dr = 18:1.

[0163] Synthesis of Compound 2g in Example 57

[0164] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 54, yielding 2 g of compound 542 mg, with a yield of 81% and dr = 19:1.

[0165] Example 58 Synthesis of Compound 2g

[0166] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 54, yielding 2 g of compound 509 mg, with a yield of 73% and dr = 18:1.

[0167] Example 59 Synthesis of (R)-4-phenyl-3-((3S,5R)-5-(2,4))-difluorophenyl-5-bromomethyltetrahydrofuran-3-carbonyl-5,5-diphenyloxazolidine-2-one (2h)

[0168]

[0169] In a dry Schlenk tube, 1 d (539 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature, and hydrochloric acid (0.1 mmol, 0.003 mL) was added. The mixture was cooled to -40 °C, and NBS (267 mg, 1.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and the compound was given. 507 mg of the compound was obtained, with a yield of 82% and dr > 20:1.

[0170] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=7.6Hz,2H),7.40–7.31(m,4H),7.06(dd,J=5.2,1.8Hz,3H),6.97–6.93(m,7H),6.81(td,J=8 .3, 2.6Hz, 1H), 6.71 (ddd, J=11.2, 8.5, 2.5Hz, 1H), 4.23 (t, J=8.1Hz, 1H), 4.08–3.98 (m, 2H), 3.63 (s, 2H), 2.71–2.33 (m, 3H). 13 CNMR (100MHz, CDCl3) δ171.11,170.66,152.59,141.51,137.64,135.33,129.08,129.03,128.52,128.39,127.79,127.64,127.26, 126.15,126.11,125.94,125.78,111.22,111.00,104.74,104.48,89.60,84.15,84.11,69.57,66.28,44.98,44.46,39.16,38.64.

[0171] Example 60 Synthesis of Compound 2h

[0172] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 59, yielding 494 mg of the compound in 2 hours, with a yield of 80% and dr = 19:1.

[0173] Example 61 Synthesis of compound 2h

[0174] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 59, yielding 482 mg of compound in 2 hours, with a yield of 78% and dr = 19:1.

[0175] Example 62 Synthesis of compound 2h

[0176] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 59, yielding 503 mg of compound in 2 hours, with a yield of 81% and dr > 20:1.

[0177] Example 63 Synthesis of compound 2h

[0178] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 59, yielding 493 mg of compound 2 h, with a yield of 79% and dr = 19:1.

[0179] Example 64 Synthesis of compound 2h

[0180]

[0181] Except for using DBDMH (429 mg, 1.5 mmol) instead of I2, the other steps were the same as in Example 59, yielding 488 mg of compound 2 h, with a yield of 79% and dr > 20:1.

[0182] Synthesis of Compound 2h in Example 65

[0183] Except for using sulfuric acid (0.1 mmol, 0.002 mL) instead of HCl, the other steps were the same as in Example 64, yielding 474 mg of compound in 2 hours, with a yield of 76% and dr = 19:1.

[0184] Example 66 Synthesis of Compound 2h

[0185] Except for using TsOH (0.1 mmol, 17 mg) instead of HCl, the other steps were the same as in Example 64, yielding 480 mg of compound 2 h, with a yield of 78% and dr = 19:1.

[0186] Example 67 Synthesis of Compound 2h

[0187] Except for using camphor sulfonic acid (0.1 mmol, 23 mg) instead of HCl, the other steps were the same as in Example 64, yielding 472 mg of compound 2 h, with a yield of 76% and dr = 19:1.

[0188] Synthesis of Compound 2h in Example 68

[0189] Except for the use of potassium bisulfate (0.1 mmol, 13 mg) instead of HCl, the other steps were the same as in Example 64, yielding 457 mg of compound 2 h, with a yield of 73% and dr = 19:1.

[0190] Example 69 Synthesis of Compound 2a

[0191] In a dry Schlenk tube, 1a (1.16 g, 3 mmol) was dissolved in ethyl acetate (24 mL) at room temperature, and hydrochloric acid (0.3 mmol, 0.009 mL) was added. The mixture was cooled to -40 °C, and I2 (1.14 g, 4.5 mmol) was added. The resulting solution was stirred at -40 °C for 3 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. 15 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2a 1.4 g was obtained, with a yield of 91% and dr = 18:1.

[0192] Example 70 Synthesis of Compound 2a

[0193] The solvent for the reaction and washing was replaced with methyl acetate. All other steps were the same as in Example 1, yielding 437 mg of compound 2a in 82% yield, dr = 16:1.

[0194] Example 71 Synthesis of Compound 2a

[0195] The solvent for the reaction and washing was replaced with isopropyl acetate. All other steps were the same as in Example 1, yielding 417 mg of compound 2a in 79% yield, dr = 16:1.

[0196] Example 72 Synthesis of Compound 2a

[0197] The solvent for the reaction and washing was replaced with n-butyl acetate. All other steps were the same as in Example 1, yielding 422 mg of compound 2a in 80% yield, dr = 16:1.

[0198] Synthesis of Compound 2a in Comparative Example 1

[0199] No acid was added to the reaction system and the reaction time was extended to 12 hours. All other steps were the same as in Example 1, and compound 2a 285 mg was obtained with a yield of 54% and dr = 6:1.

[0200] Synthesis of Compound 2a in Comparative Example 2

[0201]

[0202] In a dry Schlenk tube, 1a (387 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. The mixture was cooled to -40 °C, and I₂ (381 mg, 1.5 mmol) and sodium carbonate (159 mg, 1.5 mmol) were added. The resulting solution was stirred at -40 °C for 12 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, then allowed to cool naturally to room temperature and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, and dried to give compound 2a 370 mg, yield 72%, dr = 9:1.

[0203] Synthesis of Compound 2a in Comparative Example 3

[0204] The solvent for the reaction and washing was replaced with dichloromethane. All other steps were the same as in Example 1, yielding 243 mg of compound 2a in a yield of 46% and dr = 4:1.

[0205] Synthesis of Compound 2a in Comparative Example 4

[0206] The solvent for the reaction and washing was replaced with tetrahydrofuran. All other steps were the same as in Example 1, yielding 332 mg of compound 2a in 63% yield, dr = 1:2.

[0207] Synthesis of Compound 2a in Comparative Example 5

[0208] The solvent for the reaction and washing was replaced with toluene. All other steps were the same as in Example 1, yielding 332 mg of compound 2a in 54% yield, dr = 2:1.

[0209] Synthesis of Compound 2a in Comparative Example 6

[0210] No acid was added to the reaction system and the reaction time was extended to 12 hours. All other steps were the same as in Example 2, and 290 mg of compound 2a was obtained with a yield of 55% and dr = 5:1.

[0211] Synthesis of Compound 2b in Comparative Example 7

[0212] No acid was added to the reaction system and the reaction time was extended to 12 hours. All other steps were the same as in Example 9, and compound 2b 335 mg was obtained with a yield of 72% and dr = 5:1.

[0213] Synthesis of Compound 2b in Comparative Example 8

[0214]

[0215] In a dry Schlenk tube, 1a (387 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. The mixture was cooled to -40 °C, and NBS (267 mg, 1.5 mmol) and sodium carbonate (159 mg, 3 mmol) were added. The resulting solution was stirred at -40 °C for 12 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, then allowed to cool naturally to room temperature and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, and dried to give compound 2b 350 mg, yield 75%, dr = 8:1.

[0216] Synthesis of Compound 2c in Comparative Example 9

[0217] No acid was added to the reaction system and the reaction time was extended to 12 hours. All other steps were the same as in Example 19, and compound 2c 416 mg was obtained with a yield of 79% and dr = 7:1.

[0218] Synthesis of Compound 2c in Comparative Example 10

[0219]

[0220] In a dry Schlenk tube, 1b (400 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. The mixture was cooled to -40 °C, and I2 (381 mg, 1.5 mmol) and sodium carbonate (159 mg, 1.5 mmol) were added. The resulting solution was stirred at -40 °C for 12 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2c was given in 427 mg, yield 81%, dr = 10:1.

[0221] Synthesis of Compound 2d in Comparative Example 11

[0222] No acid was added to the reaction system and the reaction time was extended to 12 hours. All other steps were the same as in Example 28, and compound 2d 342 mg was obtained with a yield of 65% and dr = 5:1.

[0223] Synthesis of Compound 2d in Comparative Example 12

[0224]

[0225] In a dry Schlenk tube, 1b (400 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. The mixture was cooled to -40 °C, and NBS (267 mg, 1.5 mmol) and sodium carbonate (159 mg, 1.5 mmol) were added. The resulting solution was stirred at -40 °C for 12 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, then allowed to cool naturally to room temperature and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2d was given in 360 mg, yield 75%, dr = 8:1.

[0226] Synthesis of Compound 2e in Comparative Example 13

[0227] No acid was added to the reaction system and the reaction time was extended to 12 hours. All other steps were the same as in Example 33, and 359 mg of compound 2e was obtained with a yield of 75% and dr = 6:1.

[0228] Synthesis of Compound 2e in Comparative Example 14

[0229]

[0230] In a dry Schlenk tube, 1c (353 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. The mixture was cooled to -40 °C, and I2 (381 mg, 1.5 mmol) and sodium carbonate (159 mg, 1.5 mmol) were added. The resulting solution was stirred at -40 °C for 12 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2e was given in 373 mg, yield 79%, dr = 8:1.

[0231] Synthesis of Compound 2f in Comparative Example 15

[0232] No acid was added to the reaction system and the reaction time was extended to 12 hours. All other steps were the same as in Example 43, and compound 2f 272 mg was obtained with a yield of 63% and dr = 5:1.

[0233] Synthesis of Compound 2f in Comparative Example 16

[0234]

[0235] In a dry Schlenk tube, 1c (353 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. The mixture was cooled to -40 °C, and NBS (267 mg, 1.5 mmol) and sodium carbonate (159 mg, 1.5 mmol) were added. The resulting solution was stirred at -40 °C for 12 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, then allowed to cool naturally to room temperature and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and compound 2f was given as 316 mg, in 73% yield, dr = 8:1.

[0236] Synthesis of 2g of compound in Comparative Example 17

[0237] No acid was added to the reaction system and the reaction time was extended to 12 hours. All other steps were the same as in Example 49, and 2 g of compound (472 mg) was obtained with a yield of 71% and dr = 6:1.

[0238] Synthesis of 2g of compound 18 in Comparative Example

[0239]

[0240] In a dry Schlenk tube, 1 d (539 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. The mixture was cooled to -40 °C, and I₂ (381 mg, 1.5 mmol) and sodium carbonate (159 mg, 1.5 mmol) were added. The resulting solution was stirred at -40 °C for 12 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, allowed to cool naturally to room temperature, and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and 2 g (485 mg) of the compound was obtained, with a yield of 73% and dr = 11:1.

[0241] Synthesis of Compound 2h in Comparative Example 19

[0242] No acid was added to the reaction system and the reaction time was extended to 12 h. All other steps were the same as in Example 59. The compound was prepared in 2 h 401 mg, with a yield of 65% and dr = 6:1.

[0243] Synthesis of Compound 2h in Comparative Example 20

[0244]

[0245] In a dry Schlenk tube, 1 d (539 mg, 1 mmol) was dissolved in ethyl acetate (8 mL) at room temperature. The mixture was cooled to -40 °C, and NBS (267 mg, 1.5 mmol) and sodium carbonate (159 mg, 1.5 mmol) were added. The resulting solution was stirred at -40 °C for 12 h. The reaction was quenched with saturated sodium thiosulfate solution and washed with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated. 5 mL of isopropanol was added, the mixture was heated to 70 °C and stirred until dissolved, then allowed to cool naturally to room temperature and stirred to crystallize for 3 h. The crystals were filtered, the solid was washed with isopropanol, dried, and the compound was given as 2 h 458 mg, yield 74%, dr = 13:1.

[0246] Synthesis of Compound 2a in Comparative Example 21

[0247] The reaction temperature was replaced with room temperature (25°C), and all other steps were the same as those in Comparative Example 2 (i.e., the conditions in patent US2014343285A1) to obtain compound 2a 343 mg, with a yield of 65% and dr = 5:1.

[0248] Synthesis of Compound 2b in Comparative Example 22

[0249] HBr (1.5 mmol, 0.005 ml) was used directly instead of hydrochloric acid and NBS. All other steps were the same as in Example 9, and no reaction was observed.

[0250] Comparative Examples 1-2 and 6-20 show that, without the addition of an activating agent and with the addition of a basic activating agent (e.g., sodium carbonate), the yield and diastereoselectivity of the posaconazole halogenation intermediate are both very unsatisfactory, and even significantly extending the reaction time (from 3 h to 12 h) does not significantly improve the results. The synthetic method of this invention, which carries out the halogenation reaction in the presence of an acidic substance, achieves significantly improved yield and diastereoselectivity of the target product, and also obtains excellent reaction results without requiring a long reaction time. Comparative Examples 3-5 show that the synthetic method of this invention is suitable for use in acetate-based organic solvents. Comparative Example 21 shows that it is difficult to obtain the ideal yield and diastereoselectivity described in patent US 2014343285A1 under the conditions disclosed therein. Comparative Example 22 shows that the reaction cannot proceed at all when HBr is used directly as the halogenating agent.

[0251] Unless otherwise specified, the terms used in this invention have the meanings commonly understood by those skilled in the art.

[0252] The embodiments described in this invention are for illustrative purposes only and are not intended to limit the scope of protection of this invention. Those skilled in the art can make various other substitutions, changes and improvements within the scope of this invention. Therefore, this invention is not limited to the above embodiments, but is only defined by the claims.

Claims

1. A method for synthesizing a posaconazole halogenated intermediate, characterized in that, In the presence of acidic substances, the raw material intermediate shown in formula (1) is halogenated with a halogenating agent in an organic solvent to obtain the posaconazole halogenated intermediate shown in formula (2). Among them, R 1 Indicates C1-C6 alkyl, phenyl, or benzyl; R 2 and R 3 Each can independently represent hydrogen or phenyl; X represents Br or I; The acidic substance is selected from one or more of hydrochloric acid, sulfuric acid, nitric acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, potassium bisulfate, and sodium bisulfate. The halogenating agent is selected from iodine, N-iodosuccinimide, N-iodophthalimide, liquid bromine, dibromohydantoin, diiodohydantoin, N-bromosuccinimide, or N-bromophthalimide; The organic solvent is selected from acetate-based organic solvents; The reaction temperature for the halogenation reaction is -30 to -50°C.

2. The synthesis method according to claim 1, characterized in that, The R 1 It represents C1 to C4 alkyl, phenyl, or benzyl.

3. The synthesis method according to claim 2, characterized in that, The R 1 It indicates C2-C4 alkyl, phenyl, or benzyl.

4. The synthesis method according to claim 1, characterized in that, The amount of the acidic substance used is 1 to 50 mol of the raw material intermediate.

5. The synthesis method according to claim 4, characterized in that, The amount of the acidic substance used is 5 to 15 mol of the raw material intermediate.

6. The synthesis method according to claim 1, characterized in that, The amount of the halogenating agent used is 1.0 to 5.0 equivalents of the raw material intermediate.

7. The synthesis method according to claim 6, characterized in that, The amount of the halogenating agent used is 1.2 to 2.5 equivalents of the raw material intermediate.

8. The synthesis method according to claim 1, characterized in that, The organic solvent is selected from acetate organic solvents such as CH3COOR', where R' represents C1 to C6 alkyl.

9. The synthesis method according to claim 8, characterized in that, R' represents C1 to C4 alkyl.

10. The synthesis method according to claim 9, characterized in that, The organic solvent is selected from one or more of methyl acetate, ethyl acetate, isopropyl acetate, and n-butyl acetate.

11. The synthesis method according to any one of claims 1-10, characterized in that, The reaction time for the halogenation reaction is 1 to 10 hours.

12. The synthesis method according to claim 11, characterized in that, The halogenation reaction takes 2 to 5 hours.

13. A method for synthesizing posaconazole, comprising a step of synthesizing a posaconazole halogenated intermediate, characterized in that, The synthesis step of the posaconazole halogenated intermediate is performed using the synthesis method of the posaconazole halogenated intermediate as described in any one of claims 1-12.

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