CN107226830B - Chemical synthesis method of spinetoram - Google Patents
Chemical synthesis method of spinetoram Download PDFInfo
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Abstract
The invention provides a chemical synthesis method of spinetoram. Namely, spinosad A is hydrolyzed to obtain macrolide, the macrolide is subjected to selective protection and deprotection, and reacts with 3-ethoxy-2, 4-dimethoxy rhamnose and fulcosamine gradually, and then is subjected to selective reduction to finally obtain spinetoram, and the method has important significance for researching the production method of spinetoram in the future.
Description
(I) technical field
The invention relates to a chemical synthesis method of spinetoram, belonging to the technical field of chemical synthesis.
(II) background of the invention
spinetoram (structural formula shown below) was developed by the united states of america, the benefin company in the last 90 th century and is the second generation product of spinosad. Spinetoram belongs to macrolide insecticides, and the molecular structure of spinetoram contains a unique four-nucleus ring framework, and 3-ethoxy-2, 4-dimethoxy rhamnose and fulesamine are respectively connected at the 9-position and the 17-position.
Spinetoram has the advantages of wide insecticidal spectrum, high efficiency, low toxicity, low residue, safety to human and non-target animals, no toxicity to the environment and the like, is applied to various crops such as rice, wheat, corn, cotton, vegetables, fruit trees, tobacco, flowers and the like, and also shows superiority in the application of prevention and treatment of ectoparasites of poultry and pets, grain storage and the like (Greenchemistry and Engineering conference Conference.2008). In addition, spinetoram can be rapidly degraded through a combination of pathways, ultimately to carbon dioxide, water and nitrogen oxides (Advancing Sustainability ThroughGreen Chemistry and Engineering,2002,823:61-73), without adversely affecting the environment. Compared with the first-generation product, namely spinetoram (Spinosad), spinetoram not only has obvious insecticidal effect on vegetable crops, but also can effectively control pests on crops such as fruits, nuts and the like, and particularly has special effect on a troublesome pest, namely codling moth, on pome fruit trees (J.Comut.Aided.mol.Des., 2008,22:393 and 401), and the American president green chemical challenge prize is obtained in 2008.
Currently, spinetoram is obtained by chemically modifying spinosad j (spinosyn j) and spinosyn l (spinosyn l) (US 2008/0108800a 1). However, the raw materials spinosyn J and spinosyn L in the method have low fermentation yield, difficult separation and high product cost, and restrict the development and application of spinetoram, so that the research on a novel production method of spinetoram is of great significance. The invention provides a chemical synthesis method for preparing spinetoram, and provides technical support for further research in the future.
Disclosure of the invention
The invention provides a chemical synthesis method of spinetoram, namely spinosyn A (spinosyn A) is hydrolyzed under acidic conditions (Journal of Antibiotics,1998,51(8):795-799) to obtain macrolide (Aglycone) and fulesamine; then, the macrolide is subjected to selective protection and deprotection and reacts with 3-ethoxy-2, 4-dimethoxy rhamnose and the fulcosamine gradually to obtain the spinetoram analogue; and then the spinetoram is finally obtained through Pd/C catalytic reduction. Starting from macrolide, the total yield of the ethyl Spinosad synthesized in seven steps is 14%, and the synthetic route is as follows:
the chemical method for synthesizing spinetoram provided by the invention comprises the following steps:
(1) Sequentially adding macrolide (Aglycone), tert-butyldimethylsilyl chloride (TBDMSCl) and 4-dimethylaminopyridine (4-DMAP) into an ultra-dry dichloromethane solvent, heating the mixed solution to reflux, and preparing a 9-glycosidation derivative 1 with 9-hydroxyl selectively protected by TBDMS;
(2) Sequentially adding a compound 1, triisopropylsilyl trifluoromethanesulfonate (TIPSOTf) and 2, 6-dimethylpyridine into a dichloromethane solvent at the temperature of-30-5 ℃, and reacting the mixed solution at low temperature for 3 hours to obtain a derivative 2 with 17-hydroxyl protected by TIPS;
(3) In tetrahydrofuran, acetic acid aqueous solution is used for selectively removing a 9-hydroxyl protecting group TBDMS of the compound 2 to prepare the macrolide derivative 3 with naked 9-hydroxyl.
(4) activating 1-hydroxyl of self-made 3-ethoxy-2, 4-dimethoxy rhamnose by using 2,2, 2-trifluoro-N-phenyl acetimidoyl chloride under the conditions of acetone and room temperature and taking potassium carbonate as an acid-binding agent to prepare a glucoside ligand 4;
(5) Glycosidating ligand 4and 9-hydroxyl of compound 3 in dry dichloromethane at-78 deg.c with trimethylsilyl trifluoromethanesulfonate (TMSOTf) as catalyst to obtain 9-glycosidation product 5;
(6) in acetonitrile medium at-10 deg.C-0 deg.C, selectively removing the 17-position hydroxyl protecting group TIPS of compound 5 by using hydrofluoric acid to obtain 17-position hydroxyl bare macrolide derivative 6.
(7) Under the conditions of room temperature and argon protection, in an ultra-dry dichloromethane solvent, boron trifluoride diethyl etherate is used for catalyzing the fullerene ligand 7 to be connected with 17-hydroxy of a macrolide derivative 6 to construct a glycosidic bond, and then an analogue 8 of spinetoram is prepared;
(8) and (3) carrying out catalytic reduction on the 5, 6-carbon double bond of the compound 8 by using 10% Pd/C and hydrogen in an ethyl acetate solvent at room temperature to finally prepare the spinetoram.
the invention has the advantages that: spinosad A with high fermentation yield is used as a raw material, the yield of each step of reaction is high, the post-treatment is convenient, and the method provides technical support for the chemical synthesis research of spinetoram in the future.
(IV) specific embodiment:
The following examples are further illustrative of the present invention for the purpose of better understanding of the contents of the present invention, but are not intended to limit the scope of the present invention in any way. Those skilled in the art will recognize that variations and modifications can be made within the scope of the claims and their equivalents.
Example 1
3.11g (7.71mmol) of Aglycone is dissolved in 60ml of CH 2 Cl 2, the obtained solution is stirred at room temperature, 1.83g (14.98mmol) of 4-dimethylaminopyridine (4-DMAP) and 1.39g (9.22mmol) of tert-butyldimethylchlorosilane are rapidly added, the reaction is stopped after the obtained solution is heated to reflux for 5H, 120ml of dichloromethane is added to the reaction solution for dilution, a saturated sodium bicarbonate solution is washed, the organic phase is dried with anhydrous sodium sulfate and concentrated in vacuum to obtain a crude product, silica gel chromatographic column is used for separation (petroleum ether: ethyl acetate: 5:1, R f: 0.36), 2.88g of compound 1, yield 73%, 1 H NMR (400MHz, CDCl 1) delta: 0.03(6H, Si (CH 1) 1),0.81(3H, t, C 1 -H),0.87(9H, s, CH 1),1.20(3H, C3H, 72 d, C (1-72), C (CH 72H), 19H, 19- 1 H), C (1 H), 1 H, 1 -19H, 1 -72H, 1 -72H, 1 H72H, 1 H72H, 1 H72H, 1 H72H, 1 H72H, 1 H72H, 1 H72.
Example 2
2 2 f 1 3 1 3 3 2 23 3 24 11 8 10 18 19 20 22 7 2 12 16 2 3 4 17 9 21 5 6 13 13 3 -1 39 69 5 2 + +0.99g (1.91mmol) of compound 1 is dissolved in 30ml of CH Cl, 0.42g (4.01mmol) of 2,6-Lutidine is added, the mixture is frozen to-20 ℃, then 0.66g (2.16mmol) of triisopropylsilyltrifluoromethanesulfonate is slowly added, reaction is carried out at 0 ℃ for 3H, the mixture is diluted with 50ml of dichloromethane, the organic phase is washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, the crude product is distilled off under reduced pressure, silica gel chromatography is carried out (ethyl acetate: petroleum ether: 1:10, R: 0.68) to give 1.08g of compound 2, yield 85%. H NMR (400MHz, CDCl) δ: (1.04 (18H, CH), 1.25(3H, M, J ═ 8.6Hz, CH),0.03(6H, Si (CH)), 0.81(3H, t, C-H), 0.9H-H, H (9H, 1.8H, 18H, 1H, 18H, 8H, 18H, 18H, 5H, 18H, 5H, 18H, 5H, 18H, 5H, 18H, 5H, 18H, 5H, 18H, 5.
Example 3
0.71g (1.04mmol) of compound 2 is dissolved in 30ml tetrahydrofuran, 40ml acetic acid and 20ml water are added, the mixture is reacted at 70 ℃ for 24 hours, after the reaction is finished, tetrahydrofuran is distilled off under reduced pressure, water is then diluted, sodium bicarbonate is neutralized, the solution is extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, solvent is distilled off under reduced pressure, the crude product is subjected to silica gel chromatography (ethyl acetate: petroleum ether: 1:5, R f: 0.68), 0.41g of compound 3, yield 71%. 1 H NMR (400, CDCl 3) δ:1.00(18H, CH 3),1.25(3H, t, J ═ 8.6Hz, CH),0.81(3H, t, J ═ 7.5Hz, C 3 -H),0.94(3H, d, C72-H), 1.23 (361H, esim, C72-H1.72H), C72H (72-72H), C72H, H) 3 H (3 H), 3 H- 3 H (3 H), C19H, 3 H72H, 3 H (3 H) 3 H72H, 3 H72H, 3 H72H (3 H) H72H, 3 H) 3 H, 3 H72H, 3 H72H, 3 H72H, 3 H (3 H72H, 3 H72H, 3.
Example 4
In a 50ml single neck flask were charged 0.91g (4.09mmol) of 3-ethoxy-2, 4-dimethoxyrhamnose, 5ml of acetone, 0.87g (4.19mmol) of 2,2, 2-trifluoro-N-phenylimido acetyl chloride and 1.14g (8.26mmol) of potassium carbonate, reacted at room temperature for 18H, and the solvent was distilled off under reduced pressure, and the crude product was chromatographed on silica gel (ethyl acetate: petroleum ether ═ 4:1, R f ═ 0.51) to give 1.35g of colorless oily liquid 4, yield 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 (esis, 3H, CH 61, 3.72, v, 1H, CH 72, 3H, CH 72H, 3.72H, 3 H.
Example 5
f 1 3 23 11 24 8 10 18 19 20 22 2 7 12 16 12 4 17 9- 21 5 6 13 6’ 2 4’ 3’ 3 2’ 5’ 4’ 1’ 13 -1 43 72 9 + +In a 50ml single vial, 0.16g (0.29mmol) of compound 3, 0.12g (0.31mmol) of compound 4and 5ml of dichloromethane are sequentially added, 0.05ml of trimethylsilyl trifluoromethanesulfonate is added at-78 ℃, the mixture is reacted for 1H, the reaction is quenched with brine, the product is extracted with dichloromethane, the organic phase is dried over anhydrous magnesium sulfate, the solvent is removed by distillation under reduced pressure, the crude product is chromatographed on silica gel (ethyl acetate: petroleum ether: 1:4, R: 0.60) to give 0.14g of compound 5, yield 76%, H NMR (400MHz, CDCl) δ:0.83(3H, t, J ═ 7.5Hz, C-H), 0.92(1H, M, C-H), 1.23(3H,. nu 6.4Hz, C-H), (1.37-1.93,2.27) (2H 6, C-H, C-H, C, H, C, 3-H, C, H, 18, H, 18, H, 18, H, 18H, 18H, 18H, 15, 18H, 18H, 15, 18H, 5H, 18H, 15, 18H, 15, 18H, 5H, 18H, 5H.
Example 6
f 1 3 23 11 24 8 10 18 19 20 22 2 7 12 16 12 4 17 9 21 5 6 13 6’ 4’ 2 4’ 3’ 2’ 3 5’ 3 2’ 5’ 4’ 3 1’ 13 -1 34 52 9 + +In a 50ml single vial, 0.21g (0.28mmol) of compound 5,15 ml acetonitrile and 2.5ml 40% hydrofluoric acid are added, the reaction is carried out for 12H with stirring at 0 ℃, sodium bicarbonate is neutralized, acetonitrile is evaporated, ethyl acetate is extracted, organic phase is dried, crude product is evaporated under reduced pressure, silica gel chromatography is carried out (petroleum ether: ethyl acetate: 1, R: 0.630) to give 0.12g of compound 6, yield 74%, H NMR (400MHz, CDCl) δ:0.82(t,3H, C-H), 0.92(M,1H, C-H), 1.23(d,3H, J: 6.4Hz, C-H), 1.37-2.27(M,12H, C-H, 2H, C-H, 2.12 (M,2H, C-H, 3H, C-H, C-H, C, 3H, C, 3-H, C, 3H, C, 3H, C, 3H, C, 3, C.
Example 7
2 2 2 2 f 1 3 13 6 5 1’ 21 1” 9 2’ 17 5’ 4 4’ 3 2’ 3 3’ 2 3’ 5” 16 2 3 4’ 12 2 10 7 4” 3 2 8 2” 3” 8 19 18 20 22 2” 3” 3’ 3 19 20 6’ 16 3 11 23 13 3 42 67 10 + +0.12g (0.19mmol) of compound 6 is dissolved in 2ml of CH Cl, stirred, an appropriate amount of molecular sieve and 0.09g (0.30mmol) of compound 7 are added, 0.05ml of boron trifluoride ether are further added, the mixture is stirred at room temperature for 18H, the molecular sieve is removed, the reaction mixture is diluted with 5ml of CH Cl, then washed with sodium bicarbonate solution, the organic phase is dried, the crude product is distilled off under reduced pressure, and silica gel chromatography is carried out to obtain 0.10g of compound 8, yield 69%,. H (400MHz, CDCl) Δ 6.70(s,1H, C-H), 5.82(M,1H, C-H), 5.74(M,1H, C-H), 4.78(s,1H, C-H), 4.60(M,1H, C-H), 4.35(d, J ═ 3.8, 1H, C-H, C-H, C-H, 4.78 (M, C-H), 20H, C-H, C-H, C-14, C-H, C-H, C-H, C-H, C.
Example 9
f 1 3 13 1’ 21 9 2’ 6 17 5” 5 5’ 4 4’ 3 2’ 3 3’ 2 3’ 16 2 3 12 4’ 2 10 7 4” 3 2 8 2” 3” 8 18 19 20 22 10 19 6’ 3 16 3 3’ 3 11 23 13 3 34 54 9 + +0.09g (0.35mmol) of compound 8 is dissolved in 10ml of ethyl acetate, then 0.0186g (0.0175mmol) of 10% Pd/C is added, with stirring, and hydrogen is passed through 48H, after the reaction is complete, the filtrate is concentrated in vacuo, the crude product is chromatographed on silica gel (dichloromethane: 8:1, R: 0.32) to give 0.08g of a white solid, i.e. spinetoram, yield 91%. H (400MHz, CDCl) δ:6.86(s,1H, C-H), 4.84(s,1H, C-H), 4.65(M,1H, C-H), 4.45(M,1H, C-H), 4.21(M,1H, C-H), 3.91(M,2H, C-H), 3.73(M,1H, C-H), 3.65(M,1H, C-H), 3.62H, 18H, 14H, 18H, 14H, 18H, 14H, 18H, 14H, 18H, 14H, 18H, C-H, 18H, 14H, C-H, 14H, 18H, C-H, 18H, C-H, 18H, 14H, 18H, 14H, C-H, 14H, 18H, 14H, C-H, 14H, 18H, C-H, 14H, 18H, C-H, 14H, C-H, 18H, 14H, C-H, 14H, 18H, 14H, C-H, 14H, C-H, 14H, C-H, 14H, C-H, 14H, C-H, 14H.
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.
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