A synthetic method of spinosad A

Abstract

The present invention provides an improved synthesis method of spinosad A, which achieves significant improvement in reaction yield and selectivity through adjustment of glycosyl donor raw materials and catalysts, and has good application value.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of spinosyn A, and in particular to preparation of spinosyn A by an improved chemical synthesis method. Background Art

[0002] Spinosad, also known as spinosad and spinosad, is a macrolide non-toxic and highly effective biological insecticide extracted from the fermentation broth of Saccharopolysporaspinosa. However, unlike general macrolide antibiotics, spinosad has no antibacterial activity but has insecticidal activity. Researchers from Dow AgroSciences (now Dow AgroSciences) found that the bacteria can produce compounds with very high insecticidal activity. The pure spinosad is a white or light gray solid crystal with an odor similar to slightly stale soil. It is a mixture of 85% to 88% spinosad A component and 12% to 15% spinosad D component. The density is 1.167 g / cm3, the boiling point is 801.515°C (under 760 mm Hg pressure), and the flash point is 438.541°C.

[0003] The highly complex and unique structure of spinosyn makes it difficult to chemically synthesize. Spinosyn is still produced by aerobic fermentation of Saccharopolyspora spinosa. However, due to the low unit yield of Saccharopolyspora spinosa fermentation, many by-products, complex extraction steps, low product yield and other factors, its production cost is high, which restricts the promotion and application of spinosyn. Yu Bai et al. disclosed a total synthesis method of Spinosyn A in "J.Am.Chem.Soc." Vol. 138, pp. 10838-10841, but the yield and selectivity of Spinosyn A obtained in the last step are still low. At present, the industry is in urgent need of a chemical synthesis method that can obtain spinosyn A with higher yield and selectivity. Summary of the invention

[0004] The object of the present invention is to provide an improved synthesis method of spinosad A to solve the technical problems of fewer chemical synthesis routes or low efficiency in the prior art.

[0005] In order to solve the above technical problems, the present invention provides an improved synthesis method of spinosad A, comprising using compound 2 and compound 3 as reaction raw materials, in (PPh 3 ) 3 In the presence of RhCl and AgOTf catalysts, the mixture is stirred at room temperature in an organic solvent, chlorobenzene, and then heated to 40-55°C for reaction for 12-36 hours. Finally, the target product is obtained by post-treatment. The synthetic route is as follows:

[0006]

[0007] Further, wherein compound 2, compound 3, (PPh 3 ) 3 The molar ratio of RhCl to AgOTf is 1:1.0-2.0:0.5-3.0:0.5-3.0.

[0008] Furthermore, the stirring time at room temperature is 1-3h.

[0009] Furthermore, the temperature of the heating reaction is preferably 45° C., and the reaction time at this temperature is preferably 20 h.

[0010] Further, wherein the post-treatment operation is: cooling the reactant to room temperature, adding triethylamine to quench the reactant, diluting the mixture with dichloromethane saturated with ammonia, filtering through a celite pad, washing the celite pad twice with DCM saturated with ammonia, concentrating the combined organic layer, and purifying the residue by chromatography (MeOH:DCM=1:45-1:15) to obtain a product as a mixture of α and β isomers, and separating the two isomers using preparative HPLC (THF 8%, CHCl 3 91%, ammonium hydroxide solution 1%) to obtain spinosad A.

[0011] By adopting the above technical scheme, the present invention has the following beneficial effects: using existing raw material compounds 2 and 3, in the presence of a preferred catalyst (PPh 3 ) 3 Under the action of RhCl and AgOTf, spinosad A can be obtained with high reaction yield and stereoselectivity. DETAILED DESCRIPTION

[0012] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0013] The present invention is further explained below in conjunction with specific implementation modes.

[0014] Example 1

[0015] 60 mg of activated molecular sieves were added to a dry reaction tube, followed by compound 1 (10 mg, 0.017 mmol, 1.0 eq.) and compound 3 (12 mg, 0.034 mmol, 2.0 eq.) dissolved in 0.5 mL of PhCl. The resulting solution was stirred for 15 min and (PPh 3 ) 3RhCl (31.5 mg, 0.034 mmol, 2.0 equiv) and AgOTf (8.7 mg, 0.034 mmol, 2.0 equiv) were stirred at room temperature for 1 h, and then heated to 45 ° C for 20 h. The reaction was cooled to room temperature, Et3N (0.2 mL) was added to quench the reaction, the mixture was diluted with dichloromethane saturated with ammonia, passed through a celite pad, and the celite pad was washed twice with dichloromethane saturated with ammonia. The combined organic layer was concentrated, and the residue was purified by chromatography (MeOH: DCM = 1: 45-1: 15) to give the product (11.7 mg, 94% yield) as a mixture (β: α = 1: 0.56), which was separated into two isomers using preparative HPLC (THF 8%, CHCl3 91%, ammonium hydroxide solution 1%) to give 7.5 mg spinosyn A and 4.2 mg α-isomer. The relative elution times of spinosyn A and α-isomer in preparative HPLC are consistent with the prior art; spinosyn A[α] D =-177.0°(c0.2,CHCl3).α-isomer [α] D = -485.0° (c 0.2, CHCl3). It can be confirmed that the above product should be spinosyn A and α-isomer in the prior art.

[0016] Example 2

[0017] The (PPh 3 ) 3 RhCl was replaced by an equal molar amount of PPh 3 AuCl, and the other conditions remained unchanged to obtain the product (9.7 mg, 78% yield) as a mixture (β:α=1:0.90). The two isomers were separated and purified using preparative HPLC (THF 8%, CHCl3 91%, ammonium hydroxide solution 1%) to obtain 5.1 mg spinosyn A and 4.6 mg α-isomer.

[0018] Example 3

[0019] The (PPh 3 ) 3 The molar amounts of RhCl and AgOTf were adjusted to 0.017 mmol, and the other conditions remained unchanged to obtain the product (11.1 mg, 90% yield) as a mixture (β:α=1:0.56). The two isomers were separated and purified using preparative HPLC (THF 8%, CHCl3 91%, ammonium hydroxide solution 1%) to obtain 7.1 mg spinosyn A and 4.0 mg α-isomer.

[0020] Example 4

[0021] The compound 3 in Example 1 was replaced by an equimolar amount of the compound The other conditions remained unchanged to obtain the product (10.5 mg, 87% yield) as a mixture (β:α=1:1.02). The two isomers were separated and purified using preparative HPLC (THF 8%, CHCl3 91%, ammonium hydroxide solution 1%) to obtain 5.3 mg spinosyn A and 5.2 mg α-isomer.

[0022] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An improved synthesis method of spinosad A, characterized in that: Compound 2 and compound 3 are used as the reaction raw materials, in the presence of (PPh3)3RhCl and AgOTf catalysts, they are first stirred at room temperature in an organic solvent chlorobenzene, then heated to 40-55°C for reaction for 12-36h, and finally the target product is obtained by post-treatment. The synthesis route is as follows:

2. The synthesis method according to claim 1, characterized in that The molar ratio of compound 2, compound 3, (PPh3)3RhCl and AgOTf is 1:1.0-2.0:0.5-3.0:0.5-3.

0.

3. The synthesis method according to claim 1, characterized in that The stirring time at room temperature is 1-3h.

4. The synthesis method according to claim 1, characterized in that The temperature of the reaction was 45°C and the reaction time was 20 h.

5. The synthesis method according to claim 1, characterized in that The post-treatment operation is as follows: the reactant is cooled to room temperature, triethylamine is added to quench the reactant, the mixture is diluted with dichloromethane saturated with ammonia, filtered through a celite pad, the celite pad is washed twice with DCM saturated with ammonia, the combined organic layer is concentrated, and the residue is purified by chromatography, MeOH:DCM=1:451:15, to obtain a product as a mixture of α and β isomers, and the product is purified by preparative HPLC, THF 8%, CHCl3 91%, ammonium hydroxide solution 1%, to separate the two isomers and obtain spinosad A.

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