Process for the preparation of a modified ascaridole pheromone

Abstract

This invention discloses a method for preparing aromatic amidated ascaroside pheromones, belonging to the field of chemical synthesis technology. The aromatic amidated ascaroside pheromone prepared by this invention is pasc#1. Using (R)-2-methylethylene oxide, (2R,3R,5R,6S)-2-hydroxy-6-methyltetrahydro-2H-pyran-3,5-dimethyldibenzoate, and (R)-2-amino-1-phenylethanol as raw materials, and ruthenium chloride monohydrate (RuCl3·H2O), 4-dimethylaminopyridine (DMAP), and triethylamine (TEA) as catalysts, pasc#1 is synthesized through three synthetic routes in nine steps. The synthesis method of the aromatic amidated ascaroside pheromone pasc#1 of this invention is simple and easy to operate, completing the synthesis in just nine steps under mild conditions and with high yield, making it easy to scale up production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing aromatic amidated ascaroside pheromones. Background Technology

[0002] Aromatic amidated ascaroside pheromone PASC#1 was initially discovered in extracts of the southern root-knot nematode and is a biopheromone synthesized by the nematode itself. It primarily mediates the nematode's entry into the stress-resistant larval stage; low concentrations can inhibit development and prolong lifespan. Furthermore, it can regulate nematode aggregation, interactions with microorganisms and plants, and plays a crucial physiological role in nematode life activities. Simultaneously, nematode PASC#1 molecules are also commonly found in parasitic nematodes such as *Ascaris suis*. Various parasitic nematodes can cause significant agricultural economic losses and global human diseases. Nematode PASC#1 holds promise for development into novel drugs that specifically interfere with nematode reproduction and survival. In-depth research on the regulation of nematode behavior and development by nematode PASC#1 is of paramount importance for controlling significant agricultural economic losses and human diseases. Currently, the synthesis of nematode PASC#1 involves complex steps, demanding conditions, and low yields; therefore, developing a mild and efficient method for synthesizing PASC#1 is of great value. Summary of the Invention

[0003] The purpose of this invention is to provide a method for preparing aromatic amidated ascaroside pheromones.

[0004] The objective of this invention is achieved as follows: A method for preparing the aromatic amidated ascaroside pheromone, wherein the aromatic amidated ascaroside pheromone is pasc#1, is used as starting materials with compounds A1, E1, and C1, and ruthenium chloride monohydrate, 4-dimethylaminopyridine, and triethylamine as catalysts. Pasc#1 is synthesized through three synthetic routes in nine steps, as shown in formula (I):

[0005] (I);

[0006] Synthetic route one, synthesis of compound B1

[0007] Step 1: Remove oxygen from compound A1 with nitrogen, then slowly add it dropwise to allyl magnesium bromide at -70°C, and then stir and react at 25°C for 2 hours under nitrogen protection to obtain intermediate compound B1;

[0008] Synthetic route two, synthesizing compound J1

[0009] Step 2: Add 4AMS, 2,2,2-trichloroacetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene to a dichloromethane solution of compound E1, and stir the reaction at 0°C for 1 h to obtain compound F1;

[0010] Step 3: Add compound B1 to a dichloromethane suspension in 4AMS and stir at 0°C for 30 min under nitrogen protection. Then add a dichloromethane solution of compound F1 in one go and stir at 0°C for 10 min. Add TMSOTf dropwise to the reaction solution at 0°C and continue stirring at 0°C for 1 h to obtain compound G1.

[0011] Step 4: Dissolve compound G1 in a mixed solvent of methanol, water and tetrahydrofuran, then add lithium hydroxide hydrate, and stir at 25°C for 2 hours to obtain compound H1;

[0012] Step 5: Add TBSOTf and triethylamine to a dichloromethane solution of compound H1, and stir the reaction at 0°C for 2 hours to obtain compound I1;

[0013] Step 6: Dissolve compound I1 in a mixed solvent of water, acetonitrile and chloroform, then add sodium iodate and ruthenium chloride monohydrate, and stir at 25°C for 2 hours to obtain intermediate compound J1;

[0014] Synthesis Route 3, Synthesize pasc#1

[0015] Step 7: Add 70 mL of tetrahydrofuran-2,5-dione dichloromethane solution to the dichloromethane solution of compound C1, and stir the reaction at 25 °C for 16 h to obtain compound D1;

[0016] Step 8: Add dicyclohexylcarbodiimide and 4-dimethylaminopyridine to a dichloromethane solution of compound J1, then add a dichloromethane solution of compound D1 to the mixture, and stir the mixture at 25°C for 2 hours to obtain intermediate compound K1.

[0017] Step 9: Add triethylamine hydrofluoric acid to the acetonitrile solution of compound K1, and stir the mixture at 25°C for 16 hours to obtain the final product pasc#1.

[0018] The beneficial effects of this invention are as follows: This invention innovatively uses (R)-2-methylethylene oxide (compound A1), 5-benzoyloxy-1-hydroxypyranose (compound E1), and (R)-2-amino-1-phenylethanol (compound C1) as starting materials, and ruthenium chloride monohydrate, 4-dimethylaminopyridine (DMAP), and triethylamine (TEA) as catalysts to synthesize aromatic amidated ascaroside pheromone pasc#1 through three synthetic routes in 9 steps; the aromatic amidated ascaroside pheromone pasc#1 preparation method provided by this invention is simple and easy to operate, with mild conditions, high yield, and easy to scale up production. Attached Figure Description

[0019] Figure 1This is the synthetic route diagram for the aromatic amidated ascaroside pheromone pasc#1 in Example 1;

[0020] Figure 2 The hydrogen spectrum of compound B1 obtained in step 1 of Example 1;

[0021] Figure 3 The hydrogen spectrum of compound I1 obtained in step 5 of Example 1;

[0022] Figure 4 The hydrogen spectrum of compound J1 obtained in step 6 of Example 1;

[0023] Figure 5 The HPLC chromatogram of compound D1 obtained in step 7 of Example 1;

[0024] Figure 6 The HPLC chromatogram of compound K1 obtained in step 8 of Example 1;

[0025] Figure 7 The hydrogen spectrum of compound pasc#1 obtained in step 9 of Example 1 is shown. Detailed Implementation

[0026] The present invention will be further described below with reference to embodiments and accompanying drawings, but this does not limit the present invention in any way. Any modifications or substitutions based on the teachings of the present invention shall fall within the protection scope of the present invention.

[0027] The method for preparing the aromatic amidated ascaroside pheromone of the present invention, wherein the aromatic amidated ascaroside pheromone is pasc#1, is as follows: the preparation method uses compounds A1, E1, and C1 as starting materials, and ruthenium chloride monohydrate, 4-dimethylaminopyridine, and triethylamine as catalysts, and synthesizes pasc#1 through three synthetic routes in 9 steps, as shown in formula (I):

[0028] (I);

[0029] Synthetic route one, synthesis of compound B1

[0030] Step 1: Remove oxygen from compound A1 with nitrogen, then slowly add it dropwise to allyl magnesium bromide at -70°C, and then stir and react at 25°C for 2 hours under nitrogen protection to obtain intermediate compound B1;

[0031] Synthetic route two, synthesizing compound J1

[0032] Step 2: Add 4AMS, 2,2,2-trichloroacetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene to a dichloromethane solution of compound E1, and stir the reaction at 0°C for 1 h to obtain compound F1;

[0033] Step 3: Add compound B1 to a dichloromethane suspension in 4AMS and stir at 0°C for 30 min under nitrogen protection. Then add a dichloromethane solution of compound F1 in one go and stir at 0°C for 10 min. Add TMSOTf dropwise to the reaction solution at 0°C and continue stirring at 0°C for 1 h to obtain compound G1.

[0034] Step 4: Dissolve compound G1 in a mixed solvent of methanol, water and tetrahydrofuran, then add lithium hydroxide hydrate, and stir at 25°C for 2 hours to obtain compound H1;

[0035] Step 5: Add TBSOTf and triethylamine to a dichloromethane solution of compound H1, and stir the reaction at 0°C for 2 hours to obtain compound I1;

[0036] Step 6: Dissolve compound I1 in a mixed solvent of water, acetonitrile and chloroform, then add sodium iodate and ruthenium chloride monohydrate, and stir at 25°C for 2 hours to obtain intermediate compound J1;

[0037] Synthesis Route 3, Synthesize pasc#1

[0038] Step 7: Add 70 mL of tetrahydrofuran-2,5-dione dichloromethane solution to the dichloromethane solution of compound C1, and stir the reaction at 25 °C for 16 h to obtain compound D1;

[0039] Step 8: Add dicyclohexylcarbodiimide and 4-dimethylaminopyridine to a dichloromethane solution of compound J1, then add a dichloromethane solution of compound D1 to the mixture, and stir the mixture at 25°C for 2 hours to obtain intermediate compound K1.

[0040] Step 9: Add triethylamine hydrofluoric acid to the acetonitrile solution of compound K1, and stir the mixture at 25°C for 16 hours to obtain the final product pasc#1.

[0041] Furthermore, in step 1, the molar ratio of compound A1 to allyl magnesium bromide is 1:1.2.

[0042] Furthermore, in step 2, the molar ratio of compound E1, 2,2,2-trichloroacetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene is 1:5:0.1.

[0043] Furthermore, in step 4, the molar ratio of compound G1 to lithium hydroxide hydrate is 1:4.

[0044] Furthermore, in step 5, the molar ratio of compound H1, TBSOTf, and triethylamine is 1:6:10.

[0045] Furthermore, in step 6, the molar ratio of compound I1, sodium iodate, and ruthenium chloride monohydrate is 1:5:0.05.

[0046] Furthermore, in step 7, the molar ratio of compound C1 to tetrahydrofuran-2,5-dione is 1:1.1.

[0047] Furthermore, in step 8, the molar ratio of compound J1, dicyclohexylcarbodiimide, 4-dimethylaminopyridine, and compound D1 is 1:0.9:1:1.5.

[0048] Furthermore, step 1 terminates the reaction with water, steps 3 and 5 terminate the reaction with saturated sodium bicarbonate solution, and step 9 terminates the reaction with ammonia.

[0049] Furthermore, the mixture after the reaction in steps 1 and 5 is extracted with ethyl acetate, and the mixture after the reaction in step 3 is extracted with dichloromethane.

[0050] The compounds involved in the synthesis process of this invention include:

[0051] Compound A1: (R)-2-methylethylene oxide;

[0052] Compound B1: (R)-2-hydroxy-5-hexene;

[0053] Compound C1: (R)-2-amino-1-phenylethanol;

[0054] Compound D1: (R)-4-((2-hydroxy-2-phenylethyl)amino)-4-oxobutyric acid;

[0055] Compound E1: 5-benzoyloxy-1-hydroxypyranose;

[0056] Compound F1: 3-amino-2,4,5-trichloro-6-hydroxybenzoyloxybenzoate;

[0057] Compound G1: 2,5-Dibenzoyloxy-3-(4-enylbutoxy)pyranose;

[0058] Compound H1: (2R,3R,5R,6S)-2-[(R)-5-hexen-2-yloxy]-6-methyltetrahydro-2H-pyran-3,5-diol;

[0059] Compound I1: 2,5-bis(triphenylmethylsiloxy)-3-(4-enylbutoxy)pyranose;

[0060] Compound J1: (R)-4-[(2R,3R,5S,6S)-3,5-bis(tert-butyldimethylsiloxy)-6-methyltetrahydro-2H-pyran-2-oxy]valerate;

[0061] Compound K1: 4-(((R)-2-(((R)-4-(((2R,3R,5R,6S)-3,5-di(tert-butyldimethylsiloxy)-6-methylhexahydropyran-2-yl)oxy)pentanoyl)oxy)-2-phenylethyl)amino)-4-oxobutyric acid;

[0062] pasc#1: 1-hydroxy-2-O-(4-carbamoylphenyl)-3-carboxylic acid propyl pyranose.

[0063] The synthesis process of this invention involves allyl magnesium bromide, dichloromethane (DCM), tetrahydrofuran-2,5-dione, 2,2,2-trichloroacetonitrile (CCl3CN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 4AMS (4A type molecular sieve), trimethylsilyl trifluoromethanesulfonate (TMSOTf), methanol (MeOH), tetrahydrofuran (THF), lithium hydroxide hydrate (LiOH·H2O), tert-butyldimethylchlorosilane trifluoromethanesulfonate (TBSOTf), triethylamine (TEA), acetonitrile (ACN), chloroform (CHCl3), ruthenium chloride monohydrate (RuCl3·H2O), dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), triethylamine hydrofluoric acid (HF-TEA), ammonia water (NH3-H2O), and sodium thiosulfate solution (Na2S2O3).

[0064] Example 1

[0065] Synthesis Route 1:

[0066] Step 1, Synthesis of compound B1: Compound A1 (24.0 g, 413 mmol, 28.9 mL, 1...) was prepared. eq A 250 mL solution of tetrahydrofuran (THF) was added dropwise to 495 mL of 1 M allyl magnesium bromide solution at -70 °C under nitrogen protection. eq In the reaction, the mixture was stirred at 25°C for 2 h under nitrogen protection; thin-layer chromatography (TLC, petroleum ether / ethyl acetate = 10:1, Rf = 0.36) showed that compound A1 was completely consumed and a new spot was formed; the reaction was terminated with 400 mL of water under nitrogen protection at 0°C, and then extracted with ethyl acetate (500 mL × 3); the combined organic layers were dried with magnesium sulfate, filtered and concentrated under reduced pressure to give a colorless oily compound B1 (39.0 g crude product, yield 94.2%), which can be used directly for subsequent synthesis reactions without further purification; 1H NMR: EC19167-97-P1A1 (400 MHz, CDCl3) δ 5.89 - 5.63 (m, 1H), 5.04 -4.82 (m, 2H), 3.75 (m, J = 6.2 Hz, 1H), 2.17 - 2.01 (m, 2H), 1.58 - 1.38 (m,2H), 1.13 (d, J = 6.3 Hz, 3H);

[0067] .

[0068] Synthesis Route 2:

[0069] Step 2, Synthesis of compound F1: In compound E1 (30.0 g, 84.1 mmol, 1 eq Add 20.0 g of 4 AMS and 60.7 g of 2,2,2-trichloroacetonitrile (420 mmol, 42.2 mL, 5 mmol) to a solution of dichloromethane (DCM, 250 mL). eq ) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.28 g, 8.42 mmol, 1.27 mL, 0.1 eq The mixture was stirred at 0°C for 1 h; thin-layer chromatography (TLC, petroleum ether / ethyl acetate = 10:1, Rf = 0.47) showed that compound E1 was completely consumed and a new spot was formed; the filtrate after filtration of the reaction mixture was purified by rapid silica gel column chromatography (ISCO®; 550 g SepaFlash® silica gel column, eluted with 0-45% ethyl acetate / petroleum ether gradient, flow rate 100 mL / min) to give colorless oily compound F1 (38.95 g, yield 94.8%).

[0070] .

[0071] Step 3, Synthesis of compound G1: Compound B1 (9.60 g, 95.8 mmol, 1.2 g) was synthesized. eq The compound was added to a 4AMS (30.0 g) suspension of dichloromethane (DCM, 400 mL) and stirred at 0 °C for 30 min under nitrogen protection; then compound F1 (40.0 g, 79.8 mmol, 1) was added in one step. eq A dichloromethane solution (20 mL) was added to the above suspension, and the suspension was stirred at 0 °C for 30 min. Then, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 5.33 g, 23.9 mmol, 0.3 g) was added at 0 °C. eqThe compound F1 was added dropwise to the reaction solution, and the reaction was continued to be stirred at 0°C for 1 h. Liquid chromatography-mass spectrometry (LC-MS) showed that compound F1 was completely consumed and the target mass was detected. The reaction was terminated with saturated sodium bicarbonate solution (300 mL), and extracted with dichloromethane (300 mL × 3). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel column chromatography (ISCO®; 550 g SepaFlash® silica gel column, eluted with a gradient of 0-9% tetrahydrofuran / petroleum ether at a flow rate of 100 mL / min) to obtain a colorless oily compound G1 (29.4 g, yield 84.0%).

[0072] .

[0073] Step 4, Synthesis of compound H1: Compound G1 (29.0 g, 66.1 mmol, 1 eq The solution was dissolved in a mixed solvent of methanol (MeOH, 100 mL), water (H₂O, 50 mL), and tetrahydrofuran (THF, 100 mL), followed by the addition of lithium hydroxide hydrate (LiOH·H₂O, 11.1 g, 264 mmol, 4...). eq The mixture was stirred at 25°C for 2 hours. Thin-layer chromatography (TLC, petroleum ether / ethyl acetate = 5:1, Rf = 0.47) showed that compound G1 was completely consumed and a new spot was formed. The reaction mixture was filtered and concentrated under reduced pressure to give compound H1 (13.2 g crude product, yield 86.7%), which can be used directly for subsequent synthesis reactions without further purification.

[0074] .

[0075] Step 5, Synthesis of compound I1: In compound H1 (12.5 g, 54.2 mmol, 1 eq tert-butyldimethylchlorosilane trifluoromethanesulfonate (TBSOTf, 86.1 g, 325.6 mmol, 74.8 mL, 6) was added to a solution of dichloromethane (DCM, 150 mL). eq ) and triethylamine (TEA, 54.9g, 542.7mmol, 75.5mL, 10 eqThe mixture was stirred at 0°C for 2 h; thin-layer chromatography (TLC, petroleum ether / ethyl acetate = 10:1, Rf = 0.5) showed that compound H1 was completely consumed and a new spot was formed; the reaction was terminated at 0°C with saturated sodium bicarbonate solution (20 mL), followed by dilution with 100 mL of water and extraction with ethyl acetate (50 mL × 2); the organic layers were combined and washed with saturated brine (50 mL × 2), dried with sodium sulfate, filtered and concentrated under reduced pressure to obtain the residue; the residue was purified by rapid silica gel column chromatography (ISCO®; 120 g SepaFlash® silica gel column, eluted with 0-10% ethyl acetate / petroleum ether gradient, flow rate 100 mL / min) to give compound I1 (22.0 g, yield 88.47%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 5.78 (tdd, J = 6.5, 10.3, 17.0 Hz, 1H), 5.04 - 4.84 (m, 2H), 3.81 - 3.67 (m, 2H), 3.64 - 3.43 (m, 2H), 2.21 - 1.96(m, 2H), 1.80 - 1.68 (m, 2H), 1.66 - 1.55 (m, 1H), 1.49 - 1.40 (m, 1H), 1.12(d, J = 5.8 Hz, 3H), 1.05 (d, J = 6.1 Hz, 3H), 0.83 (d, J = 5.0 Hz, 18H),0.02 --0.03 (m, 12H);

[0076] .

[0077] Step 6, Synthesis of compound J1: Compound I1 (20.0 g, 43.5 mmol, 1 eq Dissolved in a mixed solvent of water (H2O, 100 mL), acetonitrile (ACN, 50 mL), and chloroform (CHCl3, 50 mL), followed by the addition of sodium iodate (NaIO4, 46.6 g, 217.0 mmol, 12.1 mL, 5... T ) and ruthenium chloride monohydrate (RuCl3·H2O, 491 mg, 2.18 mmol, 0.05 eqThe mixture was stirred at 25°C for 2 h; thin-layer chromatography (TLC, petroleum ether / ethyl acetate = 3:1, Rf = 0.45) showed that compound I1 was completely consumed and a new spot was formed; the reaction mixture was first diluted with saturated sodium bicarbonate solution (sat. CA, 300 mL), then diluted with dichloromethane (DCM, 300 mL), and then washed with sodium thiosulfate solution (Na2S2O3, 300 mL); the organic layer was separated and dried with sodium sulfate, and concentrated under vacuum to obtain the residue; the residue was purified by rapid silica gel column chromatography (ISCO®; 12 g SepaFlash® silica gel column, eluted with 0-20% tetrahydrofuran / petroleum ether gradient, flow rate 50 mL / min) to give compound J1 (17.0 g, yield 81.9%), which was yellow and oily. 1 H NMR: EC19167-126-P1A1(400 MHz, CDCl3) δ 4.49 (s, 1H), 3.83 - 3.74 (m, 1H), 3.70 (br s, 1H), 3.59(dt, J = 4.6, 9.5 Hz, 1H), 3.54 - 3.45 (m, 1H), 2.52 - 2.34 (m, 2H), 1.84 -1.64 (m, 4H), 1.17 - 1.04 (m, 6H), 0.83 (d, J = 4.3 Hz, 19H), 0.10 - -0.09(m, 13H);

[0078] .

[0079] Synthesis Route 3:

[0080] Step 7, Synthesis of compound D1: In compound C1 (7.40 g, 53.9 mmol, 1 eq 70 mL of tetrahydrofuran-2,5-dione (5.94 g, 59.3 mmol, 1.1 g) was added to a 90 mL solution of dichloromethane (DCM). eq A solution of [M+Na] in dichloromethane was reacted with the mixture at 25 °C for 16 h. Liquid chromatography-mass spectrometry (LC-MS) showed that compound C1 was completely consumed and a major peak was detected with a mass-to-charge ratio (m / z) consistent with the target product. The reaction mixture was concentrated under reduced pressure to give a white solid compound D1 (11.6 g crude product, yield 90.71%), which could be used directly for subsequent synthesis reactions without further purification. MS m / z (ESI): 260.1 [M+Na] + ;

[0081] .

[0082] Step 8, Synthesis of compound K1: In compound J1 (8.70 g, 18.3 mmol, 1 eq Dicyclohexylcarbodiimide (DCC, 3.39 g, 16.4 mmol, 3.32 mL, 0.9 g) was added to a 50 mL solution of dichloromethane (DCM). eq ) and 4-dimethylaminopyridine (DMAP, 2.23 g, 18.25 mmol, 1 eq Then, compound D1 (6.49 g, 27.37 mmol, 1.5 g) was added. eq A dichloromethane solution (50 mL) was added to the mixture, and the mixture was stirred at 25 °C for 2 h. Liquid chromatography-mass spectrometry (LC-MS) showed that compound J1 was completely consumed and the content of the target compound was detected to be 30%. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue, which was purified by preparative high performance liquid chromatography (prep-HPLC, neutral conditions) to give compound K1 (9.00 g, yield 47.2%), which was yellow and oily.

[0083] .

[0084] Step 9, Synthesis of compound pasc#1: In compound K1 (9.00 g, 5.17 mmol, 1 eq eq Triethylamine hydrofluoric acid (HF-TEA, 73.3 g, 1.10 mol, 30% purity) was added to a solution of acetonitrile (ACN, 50 mL, purity 40%). The mixture was stirred at 25 °C for 16 h. Liquid chromatography-mass spectrometry (LC-MS) showed that the content of the target compound was 30%. The reaction was terminated at 0 °C with 10 mL of ammonia water (NH3-H2O). The residue was obtained by filtration and concentration under reduced pressure. The residue was purified by preparative high performance liquid chromatography (prep-HPLC, neutral conditions) to give a yellow solid compound pasc#1 (755.7 mg, yield 31.2%). 1H NMR(400 MHz, METHANOL-d4) δ 7.47 - 7.22 (m, 5H), 5.85 (dd, J = 4.5, 8.3 Hz, 1H),3.88 - 3.77 (m, 1H), 3.73 (br d, J = 1.4 Hz, 1H), 3.66 - 3.46 (m, 4H), 2.63 -2.51 (m, 4H), 2.49 - 2.40 (m, 2H), 1.97 (td, J = 3.5, 13.2 Hz, 1H), 1.90 -1.72 (m, 3H), 1.22 (d, J = 6.0 Hz, 3H), 1.15 (d, J = 6.1 Hz, 3H);

[0085] 。

Claims

1. A method for preparing aromatic amidated ascaroside pheromones, characterized in that, The aromatic amidated ascaroside pheromone, named pasc#1, was prepared using compounds A1, E1, and C1 as starting materials, and ruthenium chloride monohydrate, 4-dimethylaminopyridine, and triethylamine as catalysts. Pasc#1 was synthesized via three synthetic routes in nine steps, as shown in formula (I): （I）； Synthetic route one, synthesis of compound B1 Step 1: Remove oxygen from compound A1 with nitrogen, then slowly add it dropwise to allyl magnesium bromide at -70°C, and then stir and react at 25°C for 2 hours under nitrogen protection to obtain intermediate compound B1; Synthetic route two, synthesizing compound J1 Step 2: Add type 4A molecular sieve, 2,2,2-trichloroacetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene to a dichloromethane solution of compound E1, and stir the reaction at 0°C for 1 h to obtain compound F1; Step 3: Add compound B1 to the dichloromethane suspension of type 4A molecular sieve, stir at 0°C for 30 min under nitrogen protection, then add the dichloromethane solution of compound F1 all at once and stir at 0°C for 10 min; add trimethylsilyltrifluoromethanesulfonate dropwise to the reaction solution at 0°C, and continue stirring at 0°C for 1 h to obtain compound G1; Step 4: Dissolve compound G1 in a mixed solvent of methanol, water and tetrahydrofuran, then add lithium hydroxide hydrate, and stir at 25°C for 2 hours to obtain compound H1; Step 5: Add tert-butyldimethylchlorosilane trifluoromethanesulfonate and triethylamine to a dichloromethane solution of compound H1, and stir the reaction at 0°C for 2 h to obtain compound I1; Step 6: Dissolve compound I1 in a mixed solvent of water, acetonitrile and chloroform, then add sodium iodate and ruthenium chloride monohydrate, and stir at 25°C for 2 hours to obtain intermediate compound J1; Synthesis Route 3, Synthesize pasc#1 Step 7: Add 70 mL of tetrahydrofuran-2,5-dione dichloromethane solution to the dichloromethane solution of compound C1, and stir the reaction at 25 °C for 16 h to obtain compound D1; Step 8: Add dicyclohexylcarbodiimide and 4-dimethylaminopyridine to a dichloromethane solution of compound J1, then add a dichloromethane solution of compound D1 to the mixture, and stir the reaction at 25°C for 2 hours to obtain intermediate compound K1; Step 9: Add triethylamine hydrofluoric acid to the acetonitrile solution of compound K1, and stir the mixture at 25°C for 16 hours to obtain the final product pasc#1.

2. The preparation method according to claim 1, characterized in that, In step 1, the molar ratio of compound A1 to allyl magnesium bromide is 1:1.

2.

3. The preparation method according to claim 1, characterized in that, In step 2, the molar ratio of compound E1, 2,2,2-trichloroacetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene is 1:5:0.

1.

4. The preparation method according to claim 1, characterized in that, In step 4, the molar ratio of compound G1 to lithium hydroxide hydrate is 1:

4.

5. The preparation method according to claim 1, characterized in that, In step 5, the molar ratio of compound H1, tert-butyldimethylchlorosilane trifluoromethanesulfonate, and triethylamine is 1:6:

10.

6. The preparation method according to claim 1, characterized in that, In step 6, the molar ratio of compound I1, sodium iodate, and ruthenium chloride monohydrate is 1:5:0.

05.

7. The preparation method according to claim 1, characterized in that, In step 7, the molar ratio of compound C1 to tetrahydrofuran-2,5-dione is 1:1.

1.

8. The preparation method according to claim 1, characterized in that, In step 8, the molar ratio of compound J1, dicyclohexylcarbodiimide, 4-dimethylaminopyridine, and compound D1 is 1:0.9:1:1.

5.

9. The preparation method according to claim 1, characterized in that, Step 1 terminates the reaction with water; steps 3 and 5 terminate the reaction with saturated sodium bicarbonate solution; and step 9 terminates the reaction with ammonia.

10. The preparation method according to claim 1, characterized in that, The mixture after the reaction in steps 1 and 5 was extracted with ethyl acetate, and the mixture after the reaction in step 3 was extracted with dichloromethane.

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