CN107226830B - Chemical synthesis method of spinetoram - Google Patents

Abstract

The invention provides a chemical synthesis method of spinosyn. That is, spinosyn A is hydrolyzed to obtain a macrolide, which is selectively protected and deprotected, and gradually reacted with 3-ethoxy-2,4-dimethoxyrhamnose and fulosamine , and then undergo selective reduction to finally obtain spinosyn, which is of great significance for the future research on the production method of spinosyn.

Description

A kind of chemical synthesis method of spinosad

(1) Technical field

The invention relates to a chemical synthesis method of spinosyn, which belongs to the technical field of chemical synthesis.

(2) Background technology

Spinetoram (Spinetoram, whose structural formula is shown below) was developed by Dow AgroSynthes in the 1990s and is the second generation product of spinosyn. Spinosad belongs to macrolide insecticides, its molecular structure contains a unique four-nuclear ring skeleton, 9-, 17-positions are respectively connected with 3-ethoxy-2,4-dimethoxyratidine Lisose and forosamine.

Spinosyn has the advantages of wide insecticidal spectrum, high efficiency, low toxicity, low residue, safe for humans and non-target animals, and non-toxic to the environment. It has not only been used in rice, wheat, corn, cotton, vegetables, fruit trees, tobacco, etc. It is applied on multiple crops such as flowers and flowers, and it also shows its superiority in applications such as poultry, pet ectoparasite control, and grain storage (GreenChemistry and Engineering Conference.2008). In addition, spinosyn can be rapidly degraded through a combination of multiple pathways, and finally degraded into carbon dioxide, water and nitrogen oxides (Advancing Sustainability Through Green Chemistry and Engineering, 2002, 823:61-73), without adversely affecting the environment . Compared with the first-generation product - spinosad (Spinosad), spinosad not only has obvious insecticidal effect on vegetable crops, but also can effectively control pests on fruits and nuts, especially on pears. A kind of thorny pest on fruit trees-the apple moth has special effects (J.Comput.Aided.Mol.Des., 2008,22:393-401), and won the US President's Green Chemistry Challenge Award in 2008.

Currently, spinosyn is obtained by chemically modifying spinosyn J (Spinosyn J) and spinosyn L (Spinosyn L) (US 2008/0108800A1). However, in this method, the raw materials spinosyn J and spinosyn L have low fermentation yield, difficult separation and high product cost, which restrict the development and application of spinosyn. Therefore, it is of great significance to study new production methods of spinosyn. The invention provides a chemical synthesis method for preparing spinosyn, which provides technical support for further research in the future.

(3) Contents of the invention

The present invention provides a chemical synthesis method of spinosyn, that is, to hydrolyze spinosyn A (Spinosyn A) under acidic conditions (Journal of Antibiotics, 1998, 51 (8): 795-799) to obtain ester (Aglycone) and fultosamine; then the macrolide is selectively protected and deprotected, and gradually reacted with 3-ethoxy-2,4-dimethoxyrhamnose and fultosamine, The spinosyn analogue is obtained; and then through Pd/C catalytic reduction, the spinosyn is finally obtained. Starting from the macrolide, the total yield of the seven-step synthesis of spinosyn is 14%, and the synthetic route is as follows:

The chemical method of the synthetic spinosyn provided by the invention comprises the steps:

(1) Add macrocyclic lactone (Aglycone), tert-butyldimethylsilyl chloride (TBDMSCl) and 4-dimethylaminopyridine (4-DMAP) in sequence in ultra-dry dichloromethane solvent, and the mixture is heated to Reflux to prepare the 9-position glycosidation derivative 1 which selectively protects the 9-position hydroxyl group with TBDMS;

(2) Add compound 1, triisopropylsilyl trifluoromethanesulfonate (TIPSOTf) and 2,6-lutidine in sequence in dichloromethane solvent at -30°C to 5°C, and the mixture React at low temperature for 3 hours to obtain derivative 2 whose 17-hydroxyl group is protected by TIPS;

(3) In tetrahydrofuran, the 9-hydroxyl protecting group TBDMS of compound 2 was selectively removed with aqueous acetic acid to prepare the macrolide derivative 3 with the 9-hydroxyl exposed.

(4) Under acetone and room temperature conditions, using potassium carbonate as an acid-binding agent, the self-made 3-ethoxy-2,4- The 1-hydroxyl group of dimethoxyrhamnose to obtain glycoside ligand 4;

(5) In dry dichloromethane at -78°C, use trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a catalyst to glycoside the ligand 4 with the 9-position hydroxyl of compound 3 to obtain the 9-position Glycosidation product 5;

(6) At -10°C to 0°C in acetonitrile medium, the 17-hydroxyl protecting group TIPS of compound 5 was selectively removed with hydrofluoric acid to prepare the macrolide derivative 6 with the 17-position hydroxyl exposed.

(7) Under the condition of room temperature and argon protection, in an ultra-dry dichloromethane solvent, boron trifluoride ether is used to catalyze the connection of the follosamine ligand 7 with the 17-hydroxyl of the macrolide derivative 6, Construct the glycosidic bond to obtain the analog 8 of spinosyn;

(8) At room temperature, in ethyl acetate solvent, 10% Pd/C and hydrogen were used to catalytically reduce the 5,6-position carbon-carbon double bond of compound 8 to finally prepare spinosyn.

The invention has the advantages of using spinosyn A with higher fermentation yield as raw material, each step reaction has higher yield, and the post-treatment is convenient, which provides technical support for the chemical synthesis research of spinosyn in the future .

(4) Specific implementation methods:

The following examples further illustrate the present invention, and its purpose is to better understand the contents of the present invention, but the examples do not limit the scope of rights of the present invention in any way. Improvements and adjustments made by those skilled in the technical field within the scope of the claims of the present invention shall also belong to the protection scope of the present invention.

Example 1

Dissolve 3.11g (7.71mmol) of Aglycone in 60ml of CH ₂ Cl ₂ , stir the resulting solution at room temperature, and quickly add 1.83g (14.98mmol) of 4-dimethylaminopyridine (4-DMAP) and 1.39g (9.22mmol) of tert-butyl Dimethylchlorosilane. After the resulting solution was heated to reflux for 5 h, the reaction was stopped. The reaction solution was diluted with 120 ml of dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. Separation by silica gel column chromatography (petroleum ether:ethyl acetate=5:1, R _f =0.36) gave 2.88g of compound 1 with a yield of 73%. ¹ H NMR (400MHz, CDCl ₃ )δ:0.03(6H,Si(CH ₃ ) ₂ ),0.81(3H,t,C ₂₃ -H),0.87(9H,s,CH ₃ ),1.20(3H,d ,C ₂₄ -H),1.25(1H,m,C ₁₁ -H),(1.38-1.79,2.25)(2H×6,C ₈ -HC ₁₀ -H,C18-H,C19-H,C20-H ,C22-H),2.22(H,m,C ₇ -H).2.39(H,d,J＝13.4,C ₂ -H),2.87(1H,m,C ₁₂ -H),2.99(1H, C ₁₆ -H), 3.12(1H,d,J＝13.4Hz,C ₂ -H), 3.19(1H,m,C ₃ -H), 3.43(1H,m,C ₄ -H), 3.67(1H , m, C17-H), 4.34 (1H, m, C ₉ -H), 4.69 (1H, s, C ₂₁ -H), 5.77 and 5.85 (2H, dd, J=30.4Hz, C ₅ -H , C ₆ -H), 6.79 (1H, s, C ₁₃ -H); ¹³ C NMR (100MHz, CDCl ₃ ) δ: -4.51, 9.16, 15.9, 21.8, 26.1, 28.6, 30.2, 33.0, 34.2, 35.0 ,40.8,40.8,41.4,41.7,46.4,47.8,48.2,49.7,72.7,72.8,77.1,128.5,130.1,144.3,148.2,172.8,202.7; IR(KBr)ν:3467.9(s),2955.5(s) ,2930.6(s),2857.3(s),1724.2(s),1660.4(s),1614.4(s),1462.8(m),1375.1(m)cm ^-1 ; MS(ESI) cal for C ₃₀ H ₄₉ O ₅ Si[M+Na] ⁺ 517.33428, found[M+Na] ⁺ 517.33417.

Example 2

0.99 g (1.91 mmol) of compound 1 was dissolved in 30 ml of CH ₂ Cl ₂ , and then 0.42 g (4.01 mmol) of 2,6-lutidine was added. After the mixture was frozen to -20°C, 0.66g (2.16mmol) triisopropylsilyl trifluoromethanesulfonate was slowly added and reacted at 0°C for 3h. Dilute with 50ml of dichloromethane, wash the organic phase with saturated sodium bicarbonate solution, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure. The crude product was subjected to silica gel chromatography (ethyl acetate:petroleum ether=1:10, R _f =0.68) to obtain 1.08 g of compound 2 with a yield of 85%. ¹ H NMR (400MHz, CDCl ₃ ) δ: ¹ H NMR (400 MHz, CDCl ₃ ) δ:; 1.04 (18H, CH3), 1.25 (3H, m, J=8.6Hz, CH), 0.03 (6H, Si( CH ₃ ) ₂ ),0.81(3H,t,C ₂₃ -H),0.87(9H,s,CH ₃ ),1.24(3H,m,C ₂₄ -H),1.19(1H,m,C ₁₁ -H ),(1.37-1.83,2.21)(2H×6,C ₈ -H,C ₁₀ -H,C ₁₈ -H,C ₁₉ -H,C ₂₀ -H,C ₂₂ -H),2.24(H,m ,C ₇ -H).2.42(H,d,J＝10.1,C ₂ -H),2.88(1H,m,C ₁₂ -H),3.02(1H,C ₁₆ -H),3.08(1H,d , J=10.1Hz, C ₂ -H), 3.22(1H, m, C ₃ -H), 3.46(1H, m, C ₄ -H), 4.05(1H, m, C ₁₇ -H), 4.34( 1H, m, C ₉ -H), 4.64 (1H, s, C ₂₁ -H), 5.76 and 5.84 (2H, dd, J＝8.1Hz, J＝33.1Hz, C ₅ -H, C ₆ -H ), 6.87 (1H, s, C ₁₃ -H), 7.71 and 7.52 (2,6-Lutidine); ¹³ C NMR (100MHz, CDCl ₃ ) δ; -4.65, 9.47, 13.0, 18.2, 18.5, 26.0, 19.5 ,28.0,31.3,34.9,36.8,40.9,40.9 41.2 41.6,46.9,47.8,48.8,49.8,72.8,74.7,76.0,128.9,130.0,143.5,148.2,172.7,203.6; IR(KBr)νs:2944.6( ), 2866.3(S), 1725.0(s), 1662.1(s), 1462.4(m), 1369.2(m), 1256.1(m), 1148.5(m), 1097.1(m)cm ^-1 ; MS(ESI)cal for C ₃₉ H ₆₉ O ₅ Si ₂ [M+H] ⁺ 673.46780, found [M+H] ⁺ 673.46775.

Example 3

0.71g (1.04mmol) of compound 2 was dissolved in 30ml of tetrahydrofuran, then 40ml of acetic acid and 20ml of water were added, and the mixture was reacted at 70°C for 24 hours. After the reaction, tetrahydrofuran was distilled off under reduced pressure, then diluted with water, neutralized with sodium bicarbonate, the solution was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel chromatography (ethyl acetate:petroleum ether=1:5, R _f =0.68) to obtain 0.41 g of compound 3 with a yield of 71%. ¹ H NMR (400MHz, CDCl ₃ ) δ: 1.00 (18H, CH ₃ ), 1.25 (3H, t, J=8.6Hz, CH), 0.81 (3H, t, J=7.5Hz, C ₂₃ -H), 0.94(3H,d,C ₂₄ -H),1.23(1H,m,C ₁₁ -H),(1.42-1.88,2.36)(2H×6,C ₈ -H,C ₁₀ -H,C ₁₈ -H ,C ₁₉ -H,C ₂₀ -H,C ₂₂ -H),2.26(H,m,C ₇ -H).2.41(H,d,J＝5.0Hz,C ₂ -H),2.92(1H, m,C ₁₂ -H),3.04(1H,C ₁₆ -H),3.08(1H,d,J＝5.0Hz,C ₂ -H),3.23(1H,m,C ₃ -H),3.50(1H ,m,C ₄ -H),4.03(1H,m,C ₁₇ -H),4.46(1H,m,C ₉ -H),4.65(1H,s,C ₂₁ -H),5.81and 5.87(2H , dd, J=15.2Hz, J=9.8Hz, C ₅ -H, C ₆ -H), 6.88 (1H, s, C ₁₃ -H); ¹³ C NMR (100MHz, CDCl ₃ ) δ: 13.0, 18.4 , 9.6, 18.6, 19.5, 28.1, 31.3, 34.8, 36.8, 40.1, 40.8, 41.2, 41.7, 47.2, 47.8, 48.9, 49.7, 72.5, 74.7, 75.9, 129.3, 129.6, 143.6, 147.8, 172.7, IR 203.6; (KBr)ν: 3303.6(s), 2994.2(m), 2914.1(m), 2856.7(m), 1896.1(w), 1640(s), 1594.4(s), 1563.5(s), 1515.5(s), 1403.8(m),1374.3(m),1308.5(m),1291.0(m),1237.8(m),1205.8(m),1108.2(m)cm ^-1 ; MS(ESI) cal for C ₃₃ H ₅₅ O ₅ Si[M+H] ⁺ 559.38133, found[M+H] ⁺ 559.38164.

Example 4

Add 0.91g (4.09mmol) 3-ethoxy-2,4-dimethoxyrhamnose, 5ml acetone, 0.87g (4.19mmol) 2,2,2-trifluoro-N- Phenyl iminoacetyl chloride and 1.14g (8.26mmol) potassium carbonate were reacted at room temperature for 18h. The solvent was distilled off under reduced pressure, and the crude product was subjected to silica gel chromatography (ethyl acetate:petroleum ether=4:1, R _f =0.51) to obtain 1.35 g of colorless oily liquid 4 with a yield of 87%. ¹ H NMR (400MHz, CDCl ₃ )δ: 1.31(m,3H,CH ₃ ),1.35(m,3H,CH ₃ ),3.15(m,1H,CH),3.22(m,1H,CH),3.50 (s,3H,CH ₃ ),3.59(s,3H,CH ₃ ),3.61(m,2H,CH2),3.69(m,1H,CH),3.75(m,1H,CH),5.25(s, 1H, CH); 6.88 (m, 1H, CH), 7.14 (s, 1H, CH), 7.33 (m, 1H, CH), 7.44 (s, 1H, CH); 7.59 (s, 1H, CH); ¹³ C NMR (100MHz, CDCl ₃ )δ: 15.6, 17.8, 59.2, 61.1, 67.8, 70.7, 79.7, 82.0, 96.2, 117.3, 119.5, 120.4, 125.4, 129.2, 129.4, 133.9, 143.6; IR(KBr)ν :2978.9(m),2932.9(m),2833.3(m),1715.0(s), 1598.5(m),1553.1(m),1489.3(m),1450.9(m),1340.5(m),1286.3(s) ,1208.6(s),1161.4(s),1122.2(s),1102.3(s),1043.9(m)cm ^-1 ; MS(ESI)cal for C ₁₈ H ₃₄ F ₃ NO ₅ [M+Na] ⁺ 414.14988 , found [M+Na] ⁺ 414.15034.

Example 5

Add 0.16g (0.29mmol) compound 3, 0.12g (0.31mmol) compound 4 and 5ml dichloromethane successively in a 50ml single-necked bottle, add 0.05ml trimethylsilyl trifluoromethanesulfonate at -78°C, mix Liquid reaction 1h. The reaction was quenched with saline, the product was extracted with dichloromethane, the organic phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel chromatography (ethyl acetate:petroleum ether=1:4, R _f =0.60) to obtain 0.14 g of compound 5 with a yield of 76%. ¹ H NMR (400MHz, CDCl ₃ ) δ: 0.83 (3H, t, J = 7.5Hz, C ₂₃ -H), 0.92 (1H, m, C ₁₁ -H), 1.23 (3H, d J = 6.4Hz, C ₂₄ -H),(1.37-1.93,2.27)(2H×6,C ₈ -H,C ₁₀ -H,C ₁₈ -H,C ₁₉ -H,C ₂₀ -H,C ₂₂ -H),2.40 and 3.10(2H,m,C ₂ -H),2.17(H,m,C ₇ -H),2.88(2H,m,C ₁₂ -H),3.03(1H,C ₁₆ -OH),3.22(H ,m C ₁₂ -H),3.45(H,m,C ₄ -H),4.06(H,C ₁₇ -H),4.32(1H,m C _9- H),4.67(1H,m C ₂₁ -H ), 5.84 and 5.86 (2H, dd, J = 22.8Hz, C ₅ -H, C ₆ -H), 6.85 (1H, C ₁₃ -H); 1.28 (3H, d, J = 6.5Hz, C _6' -H),1.30(2H,O-CH ₂ ),3.14(1H,t,C 4' _- H),3.47(1H,t,C _3' -H),3.50(3H,s,C2'-OCH3 ),3.50(3H,s,C5'-OC-CH ₃ ),3.73(1H,t,C _2' -H),3.70(1H,C _5' -H),3.57(3H,s,C _4' -OCH3),4.85(1H,s,C 1' _- H),1.09(18H,3H),1.25(3H,CH); ¹³ CNMR(100MHz,CDCl3)δ:9.6,13.0,15.9,17.9,18.4, 18.6, 19.5, 28.1, 31.4, 34.9, 36.5, 36.8, 37.7, 41.2, 41.6, 46.6, 47.8, 48.4, 49.6, 59.4, 61.2, 66.7, 68.1, 74.7, 76.0, 77.4, 78.4, 82.2, 82.3, 95.8, 129.3, 129.6, 143.6, 147.8, 172.7, 203.6; IR (KBr) ν: 2967.7(s), 2939.7(s), 2867.8(s), 1723.5(s), 1661.7(s), 1459.4(m), 1379.5( m), 1289.6(w), 1258(w), 1215.0(w), 1118.9(s), 1056.1(s), 1030.8(s)cm ^-1 ; MS(ESI) cal for C ₄₃ H ₇₂ O ₉ Si[M+Na] ⁺ 783.48378,found[M+Na] ⁺ 783.48396.

Example 6

0.21g (0.28mmol) of compound 5, 15ml of acetonitrile and 2.5ml of 40% hydrofluoric acid were added to a 50ml single-necked flask, and the reaction was stirred at 0°C for 12h. Dilute with deionized water, neutralize with sodium bicarbonate, rotary evaporate acetonitrile, extract with ethyl acetate, dry the organic phase, and rotary evaporate under reduced pressure. The crude product was subjected to silica gel chromatography (petroleum ether: ethyl acetate = 1:1, R _f = 0.630) to obtain 0.12 g of compound 6 with a yield of 74%. ¹ H NMR (400MHz, CDCl ₃ ) δ: 0.82(t,3H,C ₂₃ -H),0.92(m,1H,C ₁₁ -H),1.23(d,3H,J＝6.4Hz,C ₂₄ -H ),1.37-2.27(m,12H,C ₈ -H,C ₁₀ -H,C ₁₈ -H,C ₁₉ -H,C ₂₀ -H,C ₂₂ -H),2.41and 3.12(m,2H,C ₂ -H),2.17(m,H,C ₇ -H),2.88(m,2H,C ₁₂ -H),3.03(m,1H,C ₁₆ -H),3.21(m,H,C ₁₂ - H),3.46(m,H,C ₄ -H),3.62(m,H,C ₁₇ -H),4.32(m 1H,C ₉ -H),4.69(m,1H,C ₂₁ -H), 5.81 and 5.87 (m, 2H, C ₅ -H, C ₆ -H), 6.78 (m, 1H, C ₁₃ -H); 1.28 (d, 3H, J=6.5Hz, C _6' -H), 1.31 (m,2H,C _4' -O-CH ₂ -),3.14(t,1H,C _4' -H),3.48(t,1H,C _3' -H),3.50(s,3H,C _{2 '} -OCH ₃ ),3.50(s,3H,C _5' -OC-CH ₃ ),3.73(t,1H,C _2' -H),3.69(m,1H,C _5' -H),3.57( s,3H,C _4' -OCCH ₃ ), 4.83(s,1H,C _1' -H); ¹³ C NMR(100MHz,CDCl3)δ:9.5,15.9,18.0,18.6,21.7,28.5,30.2,34.2 ,35.0,36.4,37.5,41.3,41.6,461,47.7,48.2,49.6,59.4,61.2,66.7,68.2,72.8,76.2,77.1,78.6,79.8,82.3,95.9,128.9,129.5,144.5,147.8,17 ,202.9; IR(KBr)ν: 3348.1(m), 2969.7(s), 2931.0(s), 1720.6(s), 1659.9(s), 1608.2(w), 1457.4(m), 1373.4(m), 1251.4 (m),1115.9(s),1036.7(m)cm ^-1 ; MS(ESI)cal for C ₃₄ H ₅₂ O ₉ [M+Na] ⁺ 627.35035,found[M+Na] ⁺ 627.35058.

Example 7

Dissolve 0.12g (0.19mmol) of compound 6 in 2ml of CH ₂ Cl ₂ , stir, add appropriate amount of molecular sieves and 0.09g (0.30mmol) of compound 7, then add 0.05ml of boron trifluoride ether, and stir the mixture at room temperature for 18h. Molecular sieves were removed, the reaction solution was diluted with 5ml CH ₂ Cl ₂ , washed with sodium bicarbonate solution, the organic phase was dried, and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel chromatography (dichloromethane:methanol=5:1, R _f =0.56) to obtain 0.10 g of compound 8 with a yield of 69%. ; ¹ HNMR (400MHz, CDCl ₃ ) δ: 6.70(s, 1H, C ₁₃ -H), 5.82(m, 1H, C ₆ -H), 5.74(m, 1H, C ₅ -H), 4.78(s ,1H,C _1' -H), 4.60(m,1H,C ₂₁ -H), 4.35(d,J＝3.8Hz,1H,C _1” -H), 4.24(m,1H,C ₉ -H ),3.56(m,1H,C _2' -H),3.48-3.38(m,13H,C ₁₇ -H,C _5' -H,C ₄ -H,C _4' -OCH ₃ ,C _2' - OCH ₃ ,C _3' -OCH ₂ -,C _3' -H,C _5” -H),3.22(m,1H,C ₁₆ -H),3.08-3.02(m,2H,one of C ₂ -H ,C ₃ -H),2.94(m,1H,C 4' _- H),2.80(m,1H,C ₁₂ -H),2.34(m,1H,one of C ₂ -H),2.21-2.09( m,10H,C ₁₀ -H,C ₇ -H,C _4” -H,N(CH ₃ ) ₂ ),1.91-1.66(m,5H,one of C ₈ -H,one of C _2” -H ,one of C _3” -H,one of C ₈ -H,one of C ₁₉ -H),1.47-1.28(m,10H,C ₁₈ -H,one of C ₂₀ -H,C ₂₂ -H,one of C _2” -H,one of C _3” -H,C _3' -OC-CH ₃ ),1.21-1.17(m,11H,one of C ₁₉ -H,one of C ₂₀ -H,C _6' -H,C ₁₆ -CH ₃ ), 0.85(m,1H,C ₁₁ -H), 0.75(t,J=7.2Hz,3H,C ₂₃ -H); ¹³ C NMR(101MHz,CDCl ₃ )δ202. 76,172.43,147.40,144.11,129.26,128.77,103.40,95.43,82.22,81.05,80.53,77.67,76.61,76.03,73.61,67.88,64.84,60.84,60.26,58.94,57.63,49.38,47.62,47.57,46.00,41.47, 41.12, 40.65, 37.34, 36.25, 34.27, 30.92, 30.06, 28.36, 21.59, 20.95, 18.90, 18.33, 17.75, 16.08, 14.15, 9.30; MS (MALDI) calfor C ₄₂ H ₆₇ NO ₁₀ [M+Na] ⁺ 768.465718, found [M+Na] ⁺ 768.465844.

Example 9

0.09 g (0.35 mmol) of compound 8 was dissolved in 10 ml of ethyl acetate, and then 0.0186 g (0.0175 mmol) of 10% Pd/C was added. Hydrogen gas was introduced under stirring for 48h. After the reaction, filter. The filtrate was concentrated in vacuo. The crude product was subjected to silica gel chromatography (dichloromethane:methanol=8:1, R _f =0.32) to obtain 0.08 g of white solid, namely spinosad, with a yield of 91%. ¹ HNMR (400MHz, CDCl ₃ )δ: 6.86(s, 1H, C ₁₃ -H), 4.84(s, 1H, C _1' -H), 4.65(m, 1H, C ₂₁ -H), 4.45(m ,1H,C ₉ -H),4.21(m,1H,C _2' -H),3.91(m,2H,C ₆ -H),3.73(m,1H,C ₁₇ -H),3.65(m, 1H,C _5” -H),3.62(m,2H,C ₅ -H),3.54(m,1H,C _5' -H),3.52(m,1H,C ₄ -H),3.52(s, 3H,C _4' -OCH ₃ ),3.50(s,3H,C _2' -OCH ₃ ),3.40(s,3H,C _3' -CH ₂ ),3.44(m,1H,C _3' -H) ,3.28(m,1H,C ₁₆ -H),3.16(dd,J＝14.5,5.0Hz,1H,one of C ₂ -H),3.09(m,1H,C ₃ -H),2.96(m, 1H, C ₁₂ -H), 2.81 (m, 1H, C _4' -H), 2.58 (dd, J=16.3, 3.2Hz, 1H, one of C ₂ -H), 2.39 (m, 2H, C ₁₀ -H),2.35(m,1H,C ₇ -H),2.26(s,6H,C _4” -N(CH ₃ ) ₂ ),1.95(m,1H,one of C ₈ -H),1.87( m,2H,C _2” -H),1.81(m,2H,C _3” -H),1.46-1.55(m,8H,one of C ₈ -H,C ₁₈ -H,one of C ₁₉ -H ,C ₂₀ -H,C ₂₂ -H),1.35(m,2H,one of C ₁₀ -H,C ₁₉ -H),1.27(m,3H,C _6' -CH ₃ ),1.25(dd,J =6.8Hz, 3H, C ₁₆ -CH ₃ ), 1.16(t, 3H, C _3' -C-OCH ₃ ), 1.03(m, 1H, C ₁₁ -H), 0.82(t, J=7.5Hz 3H , C ₂₃ -H); ¹³ C NMR (101MHz, CDCl ₃ ) δ203.28, 172.48, 149.45, 145.07, 103.22, 95.73, 82.11, 80.28, 79.56, 78.48, 75.72, 75.55, 73.35, 68.14, 67.843, 64. 60.84, 59.09, 49.98, 47.79, 46.44, 43.15, _{40.92,40.52,39.47,38.68,37.94,34.21,32.94,30.76,29.91,28.35,26.94,24.43,21.83,18.89,18.69,17.73,15.92,15.64,9.25 . _} [M+Na] ⁺ 770.481368, found [M+Na] ⁺ 770.481264.

Claims (8)

1. A chemical synthesis method of spinetoram is characterized by comprising the following steps: taking macrolide (Aglycone) obtained by acid hydrolysis of spinosad A as an initial material, selectively protecting and deprotecting 9-and 17-hydroxy of the macrolide by different methods, reacting with 3-ethoxy-2, 4-dimethoxy rhamnose and folosamine in sequence, and finally hydrogenating and reducing to obtain the ethyl spinosad, wherein the synthetic route is shown as follows

。

2. The chemical synthesis method of spinetoram according to claim 1, characterized in that: in the process of synthesizing the compound 1, 4-dimethylaminopyridine (4-DMAP) is both an acid-binding agent and a catalyst, tert-butyldimethylsilyl chloride (TBDMSCl) selectively protects the hydroxyl at the 9-position of macrolide only, and the molar ratio of Aglycone to TBDMSCl and 4-DMAP is 1: 1.2-1.5: 2 to 2.5.

3. The chemical synthesis method of spinetoram according to claim 1, characterized in that: in the process of synthesizing the compound 2,6-lutidine is used as an acid-binding agent, triisopropylsilyl triflate (TIPSOTf) selectively protects 17-hydroxy of macrolide 1, and the molar ratio of the compound 1 to TIPSOTf and 2,6-lutidine is 1: 1.2-1.5: 2 to 2.5.

4. the chemical synthesis method of spinetoram according to claim 1, characterized in that: under the alkaline condition, activating self-made 1-hydroxyl of 3-ethoxy-2, 4-dimethoxy rhamnose by using 2,2, 2-trifluoro-N-phenyl acetimidoyl chloride to prepare a glucoside ligand 4; the base can be pyridine, piperidine, potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate; the mol ratio of the 3-ethoxy-2, 4-dimethoxy rhamnose to the N-phenyl trifluoroacetimide and the alkali is 1: 1.2-1.5: 2 to 2.5.

5. The chemical synthesis method of spinetoram according to claim 1, characterized in that: in the process of synthesizing the 9-glycosylation product 5, trimethylsilyl trifluoromethanesulfonate (TMSOTf) is used as a catalyst, the reaction temperature is-85 to-75 ℃, wherein the molar ratio of a macrolide derivative 3 to a 3-ethoxy-2, 4-dimethoxy rhamnose ligand 4 is 1: 1.2 to 1.5.

6. The chemical synthesis method of spinetoram according to claim 1, characterized in that: at room temperature, the synthesis of spinetoram analogue 8 is carried out under anhydrous and argon protection conditions and with boron trifluoride diethyl etherate as a catalyst, wherein the molar ratio of macrolide derivative 6 to fulcosamine ligand 7 is 1: 1.2 to 1.5.

7. The chemical synthesis method of spinetoram according to claim 1, characterized in that: in the process of reducing the compound 8 at room temperature by using 10% Pd/C as a catalyst, only the carbon-carbon double bond between the 5-position and the 6-position is reduced, and the carbon-carbon double bond between the 13-position and the 14-position and the carbonyl group at the 15-position are not reduced.

8. The chemical synthesis method of spinetoram according to claim 1, characterized in that: the method for separating and purifying the intermediate product comprises the following steps:

(1) The reaction solution is extracted with an organic solvent and water, wherein the organic solvent may be ethyl acetate, dichloromethane, chloroform or diethyl ether.

(2) The combined extracts are dried, and the drying agent can be anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride and molecular sieve.

(3) And (4) carrying out rotary evaporation on the extract liquor to obtain a crude product, and purifying the crude product by adopting silica gel column chromatography.