A method for preparing nematode dimer ascaroside pheromone

Abstract

The invention discloses a preparation method for preparing nematode dimer ascaroside pheromone. The preparation method of the dimer ascaroside pheromone of the invention is to use (2S, 3R, 5R, 6R)-2-methyl-6-hydroxytetrahydro-2H-pyran-3,5-diyl dibenzoate and (R)-oct-7-ene-2-ol as raw materials, and use boron trifluoride ether complex (BF3.Et2O), sodium periodate (NaIO4), ruthenium chloride (RuCl3), tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP) and trifluoroacetic acid (TFA) as catalysts to catalyze the reaction, and synthesize the target nematode dimer ascaroside pheromone dasc#1 through 9 steps of reaction. The synthesis method of the nematode dimer ascaroside pheromone dasc#1 of the invention is simple and easy to operate, and the synthesis can be completed in only 9 steps, and the conditions are mild, the yield is high, and it is easy to expand production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for preparing nematode dimer ascaroside pheromone. Background Art

[0002] The nematode dimeric ascaroside pheromone dasc#1 was originally isolated in extracts of Caenorhabditis elegans ( Caenorhabditis elegans ) was discovered in 1975 and is a type of biological pheromone synthesized by nematodes themselves. It mainly mediates the entry of nematodes into the stress-resistant larval stage, namely the Dauer larval stage (Cassada & Russell, 1975; Golden & Riddle, 1984). In addition, it can also regulate social behaviors such as foraging, avoidance, aggregation and mating (Simon & Sternberg, 2002) in nematodes (von Reuss et al., 2012). Nematodes use nematode dasc#1 as an important signal molecule for the development of nematode stylets, which plays an important physiological role in the life activities of nematodes. At the same time, nematode dasc#1 molecules are also commonly found in parasitic nematodes. Various parasitic nematode damage can cause significant agricultural economic losses and global human diseases. Nematode dasc#1 is expected to develop into a new type of drug that specifically interferes with the reproduction and survival of nematodes. In-depth research on the regulation of nematode dasc#1 on nematode behavior and development is of great significance for controlling major agricultural economic losses and human diseases.

[0003] Currently, the synthesis of nematode dasc#1 has complicated steps, harsh conditions and low yield, so it is of great value to develop a mild and efficient method for synthesizing nematode dasc#1. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing nematode dimer ascaroside pheromone.

[0005] The object of the present invention is achieved by a method for preparing a nematode dimer ascaroside pheromone, which is to use (2S, 3R, 5R, 6R)-2-methyl-6-hydroxytetrahydro-2H-pyran-3,5-diyl dibenzoate and (R)-oct-7-ene-2-ol as raw materials, and to use boron trifluoride ether complex and sodium periodate as raw materials. 、 Ruthenium chloride 、 Tetrabutylammonium fluoride, 4-dimethylaminopyridine and trifluoroacetic acid were used as catalysts to catalyze the reaction, and the target nematode dimer ascaroside pheromone dasc#1 was synthesized through 9 steps. The synthesis route is shown in formula (I):

[0006] (I)

[0007] Wherein, the operation of step a is as follows: Compound A1, i.e. (2S, 3R, 5R, 6R)-2-methyl-6-hydroxytetrahydro-2H-pyran-3,5-diyl dibenzoate and (R)-oct-7-ene-2-ol are dissolved in dichloromethane, oxygen is removed with nitrogen, and then BF3.Et2O is slowly added dropwise at 0°C and stirred for 0.5-2h, and then stirred at room temperature under nitrogen atmosphere to react to obtain intermediate compound A2; the molar ratio of compound A1, (R)-oct-7-ene-2-ol and BF3.Et2O is 1:3:1-3:2-4;

[0008] The operation of step d is as follows: NaIO4 and RuCl3.H2O are added to a mixture of deionized water, acetonitrile and chloroform containing compound A4, and the mixture is stirred at room temperature to react to obtain an intermediate compound A5;

[0009] The operation of step g is as follows: 1,3-dicyclohexylcarbodiimide and compound A5 are added to a dichloromethane solution of compound C2, i.e., 4-methoxybenzyl (R)-6-[((2R,3R,5R,6S)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]heptanoate, and the mixture is stirred at room temperature for 8-12 h to obtain intermediate compound A6.

[0010] The beneficial effects of the present invention are as follows: the present invention innovatively uses (2S, 3R, 5R, 6R)-2-methyl-6-hydroxytetrahydro-2H-pyran-3,5-diyl dibenzoate and (R)-oct-7-ene-2-ol as raw materials, uses boron trifluoride ether complex (BF3.Et2O), sodium periodate (NaIO4), ruthenium chloride (RuCl3), tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP) and trifluoroacetic acid (TFA) as catalysts to catalyze the reaction, and synthesizes the target nematode dimer ascaroside pheromone dasc#1 through 9 steps of reaction. The preparation method of the nematode dimer ascaroside pheromone dasc#1 of the present invention is simple and easy to operate, has mild conditions, high yield, and is easy to expand production. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 The synthetic route of the nematode dimer ascaroside pheromone dasc#1 in Example 1 is shown in FIG.

[0012] Figure 2 is the hydrogen spectrum of compound A2 obtained in Example 1;

[0013] Figure 3 is the hydrogen spectrum of compound A4 obtained in Example 1;

[0014] Figure 4 is the HPLC chromatogram of compound A6 obtained in Example 1;

[0015] Figure 5 is the mass spectrum of compound A6 obtained in Example 1;

[0016] Figure 6 This is the hydrogen spectrum of compound dasc#1 obtained in Example 1. DETAILED DESCRIPTION

[0017] The present invention is further described below in conjunction with the embodiments and drawings, but the present invention is not limited in any way. Any changes or substitutions made based on the teachings of the present invention belong to the protection scope of the present invention.

[0018] The invention discloses a method for preparing nematode dimer ascaroside pheromone, which uses (2S, 3R, 5R, 6R)-2-methyl-6-hydroxytetrahydro-2H-pyran-3,5-diyl dibenzoate and (R)-oct-7-ene-2-ol as raw materials, and uses boron trifluoride ether complex and sodium periodate as raw materials. 、 Ruthenium chloride, tetrabutylammonium fluoride, 4-dimethylaminopyridine and trifluoroacetic acid were used as catalysts to catalyze the reaction, and the target nematode dimer ascaroside pheromone dasc#1 was synthesized through 9 steps. The synthesis route is shown in formula (I):

[0019] (I)

[0020] Wherein, the operation of step a is as follows: Compound A1, i.e. (2S, 3R, 5R, 6R)-2-methyl-6-hydroxytetrahydro-2H-pyran-3,5-diyl dibenzoate and (R)-oct-7-ene-2-ol are dissolved in dichloromethane, oxygen is removed with nitrogen, and then BF3.Et2O is slowly added dropwise at 0°C and stirred for 0.5-2h, and then stirred at room temperature under nitrogen atmosphere to react to obtain intermediate compound A2; the molar ratio of compound A1, (R)-oct-7-ene-2-ol and BF3.Et2O is 1:3:1-3:2-4;

[0021] The operation of step d is as follows: NaIO4 and RuCl3.H2O are added to a mixture of deionized water, acetonitrile and chloroform containing compound A4, and the mixture is stirred at room temperature to react to obtain an intermediate compound A5;

[0022] The operation of step g is as follows: 1,3-dicyclohexylcarbodiimide and compound A5 are added to a dichloromethane solution of compound C2, i.e., 4-methoxybenzyl (R)-6-[((2R,3R,5R,6S)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]heptanoate, and the mixture is stirred at room temperature for 8-12 h to obtain intermediate compound A6.

[0023] In step d, the molar ratio of compound A4, NaIO4 and RuCl3·H2O is 1:2-5:0.1-0.3.

[0024] In step g, the molar ratio of compound C2, 1,3-dicyclohexylcarbodiimide, compound A5 and dimethylaminopyridine is 2:1-2:1-2:1.

[0025] Step b is as follows: add LiOH-H2O to a mixture of tetrahydrofuran, methanol and deionized water of compound A2, and stir at room temperature for 8-12 h to obtain an intermediate compound A3;

[0026] The molar ratio of compound A2 to LiOH·H2O is 1:2-5.

[0027] Step c is performed as follows: at 0°C, triethylamine and tert-butyldimethylsilyl trifluoromethanesulfonate are added to a dichloromethane solution of compound A3, and the mixture is stirred at room temperature for 1-2 h to obtain an intermediate compound A4;

[0028] The molar ratio of compound A3, triethylamine and tert-butyldimethylsilyl trifluoromethanesulfonate is 1:5-10:3-6.

[0029] The operation of step e is as follows: at 0°C, PMBOCNHCCl3 is added to a dichloromethane solution of compound A5, and stirred at room temperature for 12-16 h to obtain an intermediate compound C1;

[0030] The molar ratio of compound A5 and PMBOCNHCCl3 is 1:1-3.

[0031] The operation of step f is as follows: add tetrabutylammonium fluoride to a tetrahydrofuran solution of compound C1, and stir at room temperature for 24-48 hours to obtain an intermediate compound C2;

[0032] The molar ratio of compound C1 to tetrabutylammonium fluoride is 1:1.

[0033] The operation of step h is as follows: add tetrabutylammonium fluoride to a tetrahydrofuran solution of compound A6, and stir at room temperature for 12-24 h to obtain an intermediate compound A7;

[0034] The molar ratio of compound A6 to tetrabutylammonium fluoride is 1:1-2.

[0035] The operation of step i is as follows: add trifluoroacetic acid to a dichloromethane solution of compound A7, and stir at room temperature for 12-24 h to obtain the final product dasc#1.

[0036] Example 1

[0037] Step 1: Synthesis of compound A2. A solution of compound A1 (7.50 g, 21.1 mmol, 1.00 eq), compound B, i.e., (R)-oct-7-en-2-ol (8.09 g, 63.1 mmol, 3.00 eq) and sodium A-type molecular sieves (8.00 g, 80.0mmol, 3.80 eq) in dichloromethane (100 mL) was degassed and purged with nitrogen three times, and then BF3.Et2O (12.6 g, 88.4 mmol, 10.9 mL, 4.20 eq) was slowly added dropwise (about 10 min) at 0 °C and stirred for 30 min, and then stirred at 25 °C for 12 h under a nitrogen atmosphere. Dilute with deionized water (200 mL) and extract with ethyl acetate (200 mL). Wash the organic layer with saturated NaCl solution (20 mL), dry with Na2SO4, filter, and concentrate in vacuo to obtain the residue, which is then purified by flash silica gel chromatography (120 g silica gel flash column, eluent 0-60% ethyl acetate / petroleum ether, gradient elution rate 100 mL / min). Finally, a yellow oil compound A2 (9.20 g, 19.7 mmol, yield 93.69%) was obtained. 1 H NMR: (400 MHz, CHLOROFORM- d ). δ 8.18-8.12 (m, 2H), 8.07 (d, J = 7.3 Hz, 2H), 7.65-7.57(m, 2H), 7.49 (dt, J = 4.6, 7.5 Hz, 4H), 5.87 (tdd, J = 6.7, 10.2, 17.0 Hz, 1H),5.25-5.16 (m, 2H), 5.12-4.94 (m, 3H), 4.18-4.10 (m, 1H), 3.95-3.82 (m, 1H),2.45 (td, J = 3.6, 13.4 Hz, 1H), 2.29-2.20 (m, 1H), 2.14 (br d, J = 6.4 Hz, 2H),1.7- 1.64 (m, 1H), 1.59-1.40 (m, 5H), 1.31 (d, J = 6.1 Hz, 3H), 1.22 (d, J = 6.0 Hz, 3H).

[0038]

[0039] Step 2: Synthesis of Compound A3. Add LiOH-H2O (4.81 g, 114.7 mmol, 5.00 eq) to a mixture of tetrahydrofuran (100 mL), methanol (20 mL) and deionized water (20 mL) containing Compound A2 (10.7 g, 22.9 mmol, 1.00 eq), and stir at 25 °C for 12 h. Dilute with deionized water (200 mL) and extract with ethyl acetate (100 mL). Wash the organic layer with saturated NaCl solution (20 mL), dry with MgSO4, filter, and concentrate in vacuo to obtain a yellow oily compound A3 (5.20 g, yield 87.8%).

[0040] Step 3: Synthesis of compound A4. At 0°C, triethylamine (20.4 g, 201.3 mmol, 28.01 mL, 10.0 eq) and tert-butyldimethylsilyl trifluoromethanesulfonate (31.9 g, 120.8 mmol, 27.7 mL, 6.00 eq) were added to a dichloromethane solution (60 mL) of compound A3 (5.20 g, 20.1 mmol, 1.00 eq) and stirred at 25°C for 2 h. Dilute with deionized water (100 mL) and extract with ethyl acetate (100 mL). Wash the organic layer with saturated NaCl solution (20 mL), dry with MgSO4, filter, and concentrate in vacuo to obtain the residue, which is then purified by flash silica gel chromatography (80 g silica gel flash column, eluent 0-10% ethyl acetate / petroleum ether, gradient elution rate 100 mL / min). Finally, compound A4 (9.00 g, yield 91.8%) was obtained as a yellow oil. 1 H NMR: (400 MHz, CHLOROFORM- d ). δ 5.75(tdd, J = 6.7, 10.2, 17.0 Hz, 1H), 5.02-4.82 (m, 2H), 4.49 (s, 1H), 3.78-3.65(m, 2H), 3.63-3.47 (m, 2H), 2.00 (br d, J = 6.5 Hz, 2H), 1.76-1.69 (m, 2H), 1.57-1.46 (m, 2H), 1.40-1.32 (m, 4H), 1.15-1.10 (m, 3H), 1.03 (d, J= 6.0 Hz, 3H), 0.85-0.81 (m, 18H), 0.02- -0.02 (m, 12H).

[0041]

[0042] Step 4: Synthesis of compound A5. NaIO4 (48.3 g, 225.9 mmol, 12.5 mL, 5.00 eq) and RuCl3.H2O (509.3 mg, 2.26 mmol, 0.05 eq) were added to a mixture of deionized water (120 mL), acetonitrile (60 mL) and chloroform (60 mL) containing compound A4 (22.0 g, 45.2 mmol, 1.00 eq), and stirred at 25 °C for 0.5 h. Ethyl acetate (100 mL) was added to the reaction solution and filtered at 25 °C, and then extracted with saturated citric acid solution (100 mL) and saturated Na2S2SO4 (100 mL) in sequence. The organic layer was washed with saturated NaCl solution (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the residue, which was then purified by flash silica gel chromatography (100 g silica gel flash column, eluent: 0-30% ethyl acetate / petroleum ether, gradient elution rate: 100 mL / min). Finally, a colorless oily compound A5 (18.0 g, yield: 78.9%) was obtained.

[0043]

[0044] Step 5: Synthesis of compound C1. PMBOCNHCCl3 (2.01 g, 7.13 mmol, 3.00 eq) was added to a dichloromethane solution (30 mL) of compound A5 (1.20 g, 2.38 mmol, 1.00 eq) at 0 °C and stirred at 25 °C for 16 h. The residue was concentrated by vacuum filtration and then purified by flash silica gel chromatography (40 g silica gel flash column, eluent: 0-60% ethyl acetate / petroleum ether, gradient elution rate: 100 mL / min). Finally, a colorless oil compound C1 (1.19 g, yield: 79.8%) was obtained.

[0045]

[0046] Step 6: Synthesis of compound C2. Tetrabutylammonium fluoride (1.00 M, 1.60 mL, 1.00 eq) was added to a tetrahydrofuran solution (10 mL) of compound C1 (1.00 g, 1.60 mmol, 1.00 eq) and stirred at 25 °C for 48 h. The mixture was diluted with deionized water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with a saturated NaCl solution (3 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue, which was then purified by flash silica gel chromatography (12 g silica gel flash column, eluent 0-40% ethyl acetate / petroleum ether, gradient elution rate 20 mL / min). Finally, a yellow oil compound C2 (500.0 mg, yield 78.8%) was obtained.

[0047]

[0048] Step 7: Synthesis of compound A6. 1, 3-dicyclohexylcarbodiimide (156.1 mg, 756.7 μmol, 153.1 μL, 1.00 eq), compound A5 (382.0 mg, 756.7 μmol, 1.00 eq) and dimethylaminopyridine (92.4 mg, 756.7 μmol, 1.00 eq) were added to a dichloromethane solution (6 mL) of compound C2 (300.0 mg, 756.7 μmol, 1.00 eq) and stirred at 25 °C for 12 h. The residue was concentrated in vacuo and then purified by flash silica gel chromatography (4 g silica gel flash column, eluent 0-20% ethyl acetate / petroleum ether, gradient elution rate 18 mL / min). Finally, a colorless oil compound A6 (484.82 mg, yield 72.4%) was obtained. MS m / z (ESI): 905.6 [M+Na] + .

[0049]

[0050] Step 8: Synthesis of Compound A7. Add tetrabutylammonium fluoride (1 M , 15.2 mL , 2.00 eq) to a tetrahydrofuran solution (67 mL) of Compound A6 (6.70 g , 7.59 mmol , 1.00 eq) and stir at 25 °C for 24 h. Dilute with deionized water (150 mL) and extract with ethyl acetate (150 mL). Wash the organic layer with saturated NaCl solution (10 mL), dry with Na2SO4, filter, and concentrate in vacuo to obtain a yellow oily compound A7 (4.50 g, yield 90.6%).

[0051]

[0052] Step 9: Synthesis of compound dasc#1. Add trifluoroacetic acid (1.53 mL) to a dichloromethane solution (50 mL) of compound A7 (4.50 g, 6.87 mmol, 1.00 eq) and stir at 25 °C for 12 h. Concentrate in vacuo to obtain the residue, which is then chromatographed by reverse phase high performance liquid chromatography (chromatographic column: Daisogel C18, specification: 250 * 70mm* 10 μm; mobile phase: 0.1% ammonium bicarbonate water: acetonitrile, gradient: 15% ~ 45% in 30 min). Finally, a yellow colloid compound dasc#1 (2.37 g, yield 64.8%) is obtained. 1 H NMR: EC11156-4-P3 (400 MHz, METHANOL- d 4 ). δ 4.68 (d, J = 15.1 Hz, 2H),3.9-3.76 (m, 3H), 3.75-3.71 (m, 2H), 3.67-3.48 (m, 2H), 2.36 (t, J = 7.4 Hz,2H), 2.26 (t, J = 7.4 Hz, 2H), 2.09-1.92 (m, 2H), 1.90-1.72 (m, 2H), 1.72-1.58(m, 6H), 1.55-1.41 (m, 6H), 1.23 (d, J = 6.1 Hz, 4H), 1.15 (dd, J = 4.3, 5.6 Hz,9H).

[0053]

[0054] Example 2

[0055] The conditions of steps 2, 3, 5, 6, 8 and 9 of this embodiment are consistent with those of embodiment 1.

[0056] Step 1: Synthesis of compound A2. A solution of compound A1 (7.50 g, 21.1 mmol, 1.00 eq), compound B (2.7 g, 21 mmol, 1.00 eq) and sodium type A molecular sieve (8.00 g, 80.0 mmol, 3.80 eq) in dichloromethane (100 mL) was degassed and purged with nitrogen three times, and then BF3.Et2O (6.3 g, 45 mmol, 5.5 mL, 2.1 eq) was slowly added dropwise (about 10 min) at 0 °C and stirred for 30 min, followed by stirring at 25 °C for 24 h under a nitrogen atmosphere. Dilute with deionized water (200 mL) and extract with methanol (200 mL), wash the organic layer with saturated NaCl solution (20 mL), dry with Na2SO4, filter, and concentrate in vacuo to obtain the residue, which is then purified by flash silica gel chromatography (120 g silica gel flash column, eluent 0-60% tetrahydrofuran / petroleum ether, gradient elution rate 100 mL / min). Finally, compound A2 (4.28 g, 9.2 mmol, yield 43.59%) was obtained as a yellow oil.

[0057] Step 4: Synthesis of compound A5. NaIO4 (24 g, 113 mmol, 6.4 mL, 2.5 eq) and RuCl3.H2O (255 mg, 1.13 mmol, 0.025 eq) were added to a mixture of deionized water (120 mL), acetonitrile (60 mL) and chloroform (60 mL) containing compound A4 (22.0 g, 45.2 mmol, 1.00 eq) and stirred at 25 °C for 1 h. Methanol (100 mL) was added to the reaction solution and filtered at 25 °C, then extracted with saturated citric acid solution (100 mL) and saturated Na2S2SO4 (100 mL) in sequence. The organic layer was washed with saturated NaCl solution (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the residue, which was then purified by flash silica gel chromatography (100 g silica gel flash column, eluent: 0-30% ethyl acetate / petroleum ether, gradient elution rate: 200 mL / min). Finally, compound A5 (7.56 g, 33.14%) was obtained as a colorless oil.

[0058] Step 7: Synthesis of compound A6. 1, 3-dicyclohexylcarbodiimide (78 mg, 378 μmol, 76.5 μL, 0.5 eq), compound A5 (382.0 mg, 756.7 μmol, 1.00 eq) and dimethylaminopyridine (46.2 mg, 378 μmol, 0.5 eq) were added to a dichloromethane solution (6 mL) of compound C2 (300.0 mg, 756.7 μmol, 1.00 eq) and stirred at 20 °C for 12 h. The residue was concentrated in vacuo and then purified by flash silica gel chromatography (2 g silica gel flash column, eluent 0-20% ethyl acetate / petroleum ether, gradient elution rate 18 mL / min). Finally, a colorless oil compound A6 (215.34 mg, yield 32.16%) was obtained.

[0059] Example 3

[0060] (The conditions of steps 2, 3, 5, 6, 8 and 9 are the same as those in Example 1)

[0061] Step 1: Synthesis of compound A2. A solution of compound A1 (7.50 g, 21.1 mmol, 1.00 eq), compound B (5.4 g, 84.1 mmol, 2 eq) and sodium A-type molecular sieve (8.00 g, 80.0 mmol, 3.80 eq) in dichloromethane (100 mL) was degassed and purged with nitrogen three times, and then BF3.Et2O (12.6 g, 88.4 mmol, 10.9 mL, 4.20 eq) was slowly added dropwise (about 10 min) at 0 °C and stirred for 30 min, followed by stirring at 25 °C for 12 h under a nitrogen atmosphere. Dilute with deionized water (200 mL) and extract with ethyl acetate (200 mL). Wash the organic layer with saturated NaCl solution (20 mL), dry with Na2SO4, filter, and concentrate in vacuo to obtain the residue, which is then purified by flash silica gel chromatography (120 g silica gel flash column, eluent 0-60% ethyl acetate / petroleum ether, gradient elution rate 200 mL / min). Finally, compound A2 (6.83 g, 14.6 mmol, yield 69.55%) was obtained as a yellow oil.

[0062] Step 4: Synthesis of compound A5. NaIO4 (32.2 g, 170.6 mmol, 8.3 mL, 3.3 eq) and RuCl3.H2O (339.5 mg, 1.5 mmol, 0.03 eq) were added to a mixture of deionized water (120 mL), acetonitrile (60 mL) and chloroform (60 mL) containing compound A4 (22.0 g, 45.2 mmol, 1.00 eq) and stirred at 25 °C for 0.5 h. Methanol (100 mL) was added to the reaction solution and filtered at 25 °C, then extracted with saturated citric acid solution (100 mL) and saturated Na2S2SO4 (100 mL) in sequence. The organic layer was washed with saturated NaCl solution (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the residue, which was then purified by flash silica gel chromatography (100 g silica gel flash column, eluent: 0-30% ethyl acetate / petroleum ether, gradient elution rate: 100 mL / min). Finally, a colorless oily compound A5 (11.39 g, 49.90%) was obtained.

[0063] Step 7: Synthesis of compound A6. 1, 3-dicyclohexylcarbodiimide (104 mg, 504.4 μmol, 102 μL, 0.66 eq), compound A5 (382.0 mg, 756.7 μmol, 1.00 eq) and dimethylaminopyridine (61.6 mg, 504.4 μmol, 0.66 eq) were added to a dichloromethane solution (6 mL) of compound C2 (300.0 mg, 756.7 μmol, 1.00 eq) and stirred at 25 °C for 12 h. The residue was concentrated in vacuo and then purified by flash silica gel chromatography (4 g silica gel flash column, eluent 0 ~ 20% tetrahydrofuran / petroleum ether, gradient elution rate 30 mL / min). Finally, a colorless oil compound A6 (326.14 g, yield 48.70%) was obtained.

[0064] Example 4

[0065] (The conditions of steps 2, 3, 5, 6, 8 and 9 are the same as those in Example 1)

[0066] Step 1: Synthesis of compound A2. A solution of compound A1 (7.50 g, 21.1 mmol, 1.00 eq), compound B (6.5 g, 50.5 mmol, 2.4 eq) and sodium type A molecular sieve (8.00 g, 80.0 mmol, 3.80 eq) in dichloromethane (100 mL) was degassed and purged with nitrogen three times, and then BF3.Et2O (10 g, 70.7 mmol, 8.72 mL, 3.36 eq) was slowly added dropwise (about 10 min) at 0 °C and stirred for 30 min, followed by stirring at 25 °C for 24 h under a nitrogen atmosphere. Dilute with deionized water (200 mL) and extract with ethyl acetate (200 mL), wash the organic layer with saturated NaCl solution (20 mL), dry with Na2SO4, filter, and concentrate in vacuo to obtain the residue, which is then purified by flash silica gel chromatography (120 g silica gel flash column, eluent 0-60% tetrahydrofuran / petroleum ether, gradient elution rate 100 mL / min). Finally, compound A2 (7.31 g, 15.7 mmol, yield 74.44%) was obtained as a yellow oil.

[0067] Step 4: Synthesis of compound A5. NaIO4 (38.64 g, 180.7 mmol, 10 mL, 4.00 eq) and RuCl3.H2O (407.4 mg, 1.8 mmol, 0.05 eq) were added to a mixture of deionized water (120 mL), acetonitrile (60 mL) and chloroform (60 mL) containing compound A4 (22.0 g, 45.2 mmol, 1.00 eq) and stirred at 25°C for 1 h. Ethyl acetate (100 mL) was added to the reaction solution and filtered at 25°C, then extracted with saturated citric acid solution (100 mL) and saturated Na2S2SO4 (100 mL) in sequence. The organic layer was washed with saturated NaCl solution (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the residue, which was then purified by flash silica gel chromatography (100 g silica gel flash column, eluent 0-30% tetrahydrofuran / petroleum ether, gradient elution rate 100 mL / min). Finally, a colorless oil compound A5 (14.25 g, yield 62.46%) was obtained.

[0068] Step 7: Synthesis of compound A6. 1, 3-dicyclohexylcarbodiimide (124.9 mg, 605.4 μmol, 122.5 μL, 0.8 eq), compound A5 (382.0 mg, 756.7 μmol, 1.00 eq) and dimethylaminopyridine (73.92 mg, 605.36 μmol, 0.8 eq) were added to a dichloromethane solution (6 mL) of compound C2 (300.0 mg, 756.7 μmol, 1.00 eq) and stirred at 25°C for 12 h. The residue was concentrated in vacuo and then purified by flash silica gel chromatography (2 g silica gel flash column, eluent 0-20% ethyl acetate / petroleum ether, gradient elution rate 18 mL / min). Finally, a colorless oil compound A6 (374.12 g, yield 55.87%) was obtained.

Claims

1. A method for preparing a nematode dimer ascaroside pheromone, characterized in that: The dimeric ascaroside pheromone is dasc#1, and the preparation method thereof is to use (2S, 3R, 5R, 6R)-2-methyl-6-hydroxytetrahydro-2H-pyran-3,5-diyl dibenzoate and (R)-oct-7-ene-2-ol as raw materials, and to use boron trifluoride ether complex and sodium periodate as raw materials. 、 Ruthenium chloride 、 Tetrabutylammonium fluoride, 4-dimethylaminopyridine and trifluoroacetic acid were used as catalysts to catalyze the reaction, and the target nematode dimer ascaroside pheromone dasc#1 was synthesized through 9 steps. The synthesis route is shown in formula (I): （I） Wherein, the operation of step a is as follows: Compound A1, i.e. (2S, 3R, 5R, 6R)-2-methyl-6-hydroxytetrahydro-2H-pyran-3,5-diyl dibenzoate and (R)-oct-7-ene-2-ol are dissolved in dichloromethane, oxygen is removed with nitrogen, and then BF3.Et2O is slowly added dropwise at 0°C and stirred for 0.5-2h, and then stirred at room temperature under nitrogen atmosphere to react to obtain intermediate compound A2; the molar ratio of compound A1, (R)-oct-7-ene-2-ol and BF3.Et2O is 1:1-3:2-4; The operation of step d is as follows: NaIO4 and RuCl3.H2O are added to a mixture of deionized water, acetonitrile and chloroform containing compound A4, and the mixture is stirred at room temperature to react to obtain intermediate compound A5; The operation of step g is as follows: 1,3-dicyclohexylcarbodiimide, compound A5 and dimethylaminopyridine are added to a dichloromethane solution of compound C2, i.e. 4-methoxybenzyl (R)-6-[((2R,3R,5R,6S)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]heptanoate, and the mixture is stirred at room temperature for 8-12 h to obtain intermediate compound A6.

2. The preparation method according to claim 1, characterized in that: In step d, the molar ratio of compound A4, NaIO4 and RuCl3·H2O is 1:2-5:0.1-0.

3.

3. The preparation method according to claim 1, characterized in that: In step g, the molar ratio of compound C2, 1,3-dicyclohexylcarbodiimide, compound A5 and dimethylaminopyridine is 2:1-2:1-2:

1.

4. The preparation method according to claim 1, characterized in that: Step b is as follows: add LiOH-H2O to a mixture of tetrahydrofuran, methanol and deionized water of compound A2, and stir at room temperature for 8-12 h to obtain an intermediate compound A3; The molar ratio of compound A2 to LiOH·H2O is 1:2-5.

5. The preparation method according to claim 1, characterized in that: Step c is performed as follows: at 0°C, triethylamine and tert-butyldimethylsilyl trifluoromethanesulfonate are added to a dichloromethane solution of compound A3, and the mixture is stirred at room temperature for 1-2 h to obtain an intermediate compound A4; The molar ratio of compound A3, triethylamine and tert-butyldimethylsilyl trifluoromethanesulfonate is 1:5-10:3-6.

6. The preparation method according to claim 1, characterized in that: The operation of step e is as follows: at 0°C, PMBOCNHCCl3 is added to a dichloromethane solution of compound A5, and stirred at room temperature for 12-16 h to obtain an intermediate compound C1; The molar ratio of compound A5 and PMBOCNHCCl3 is 1:1-3.

7. The preparation method according to claim 1, characterized in that: The operation of step f is as follows: add tetrabutylammonium fluoride to a tetrahydrofuran solution of compound C1, and stir at room temperature for 24-48 hours to obtain an intermediate compound C2; The molar ratio of compound C1 to tetrabutylammonium fluoride is 1:

1.

8. The preparation method according to claim 1, characterized in that: The operation of step h is as follows: add tetrabutylammonium fluoride to a tetrahydrofuran solution of compound A6, and stir at room temperature for 12-24 h to obtain an intermediate compound A7; The molar ratio of compound A6 to tetrabutylammonium fluoride is 1:1-2.

9. The preparation method according to claim 1, characterized in that: The operation of step i is as follows: add trifluoroacetic acid to a dichloromethane solution of compound A7, and stir at room temperature for 12-24 h to obtain the final product dasc#1.

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