阅读说明：本技术 一种甲维盐类似物粗品以及合成方法 (Emamectin benzoate analogue crude product and synthetic method thereof ) 是由 任勇 徐淑芬 于 2019-09-20 设计创作，主要内容包括：本发明涉及一种甲维盐类似物粗品以及合成方法,该甲维盐类似物粗品以阿维菌素B2a为初始原料,经氧化反应、氨化反应、还原反应和成盐反应后得到甲维盐类似物粗品,其中上述反应均是在以二甲基甲酰胺、四氢呋喃或四氢吡喃为反应溶剂的反应体系中进行。本发明采用四步法代替六步法合成甲维盐类似物,简化了合成工艺步骤,缩短了生产周期,工艺流程易控制,合成收率和有效成分较高,生产成本较低,进一步提高了阿维菌素B2a的利用率,为甲维盐类似物产业化提供了技术保障。(The invention relates to a crude emamectin benzoate analogue product and a synthesis method thereof, wherein the crude emamectin benzoate analogue product takes avermectin B2a as an initial raw material and is subjected to oxidation reaction, ammoniation reaction, reduction reaction and salt forming reaction to obtain the crude emamectin benzoate analogue product, wherein the reactions are carried out in a reaction system taking dimethylformamide, tetrahydrofuran or tetrahydropyran as a reaction solvent. The invention adopts a four-step method to replace a six-step method to synthesize the emamectin benzoate analogue, simplifies the synthesis process steps, shortens the production period, has easily controlled process flow, higher synthesis yield and effective components and lower production cost, further improves the utilization rate of the abamectin B2a and provides technical support for the industrialization of the emamectin benzoate analogue.)

1. An emamectin benzoate analog, characterized in that the molecular structural formula is:

。

2. the method for synthesizing the crude emamectin benzoate analog as claimed in claim 1, which is characterized by comprising the following steps of: the method comprises the steps of taking avermectin B2a as an initial raw material, and carrying out oxidation reaction, ammoniation reaction, reduction reaction and salt forming reaction to obtain a crude emamectin benzoate analogue product, wherein the reactions are carried out in a reaction system taking dimethylformamide, tetrahydrofuran or tetrahydropyran as a reaction solvent.

3. The method for synthesizing the crude emamectin benzoate analog according to claim 2, wherein the reaction solvent, namely dimethylformamide, tetrahydrofuran or tetrahydropyran, is added according to the following proportion:

W_{abamectin B2a}:L_{Reaction solvent}=1kg:10～12L。

4. The method for synthesizing the crude emamectin benzoate analog as claimed in claim 2, wherein the oxidation reaction process comprises the following steps: dissolving avermectin B2a in a reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran, adding a catalyst A and a dilute hydrochloric acid solution, stirring for 5-10 min, adding an oxidant at the solution temperature of 0-5 ℃, reacting for 40-60 min, adding a sodium bicarbonate solution and a sodium sulfite solution after the reaction is finished, stirring for 20-40 min, filtering, concentrating under reduced pressure and drying to obtain a solid compound A.

5. The method for synthesizing crude emamectin benzoate analogues according to claim 4, wherein the step of preparing the crude emamectin benzoate analogues,

the mass concentration of the dilute hydrochloric acid is controlled to be 5-10%, the dosage of the dilute hydrochloric acid is 6-10% of that of reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran, and the dilute hydrochloric acid is calculated by volume ratio;

the oxidant is dess-martin high-valence iodine, and the dosage of the oxidant is abamectin B2a, dess-martin high-valence iodine =1: 1.2-1.6 in terms of mole number;

the catalyst A is tetrabutylammonium bromide, and the dosage of the catalyst A is 2-6% of the oxidant by mass percent;

the mass concentration of the sodium bicarbonate solution is 10-20%, and the using amount of the sodium bicarbonate solution is 4-8% of the volume of the reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran;

the mass concentration of the sodium sulfite solution is 20-40%, and the using amount of the sodium sulfite solution is 3-7% of the volume of the oxidant.

6. The method for synthesizing the crude emamectin benzoate analogue product as claimed in claim 4, wherein the solid compound A is further washed with purified water, and dried, wherein the amount of the purified water is 10-20 times of the mass of the solid compound A.

7. The method for synthesizing the crude emamectin benzoate analog according to claim 2, wherein the ammoniation reaction process comprises the following steps: dissolving the solid compound A obtained by the oxidation reaction and an aminating agent into a reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran, controlling the temperature of the solution to be 20-30 ℃, adding a catalyst B, fully stirring for reaction for 40-60 min, filtering, and concentrating under reduced pressure to obtain a solid compound B.

8. The method for synthesizing crude emamectin benzoate analogues according to claim 7, wherein the amination agent is heptamethyldisilazane, the catalyst A is sodium methoxide, and the quantities of the heptamethyldisilazane and the catalyst A are added according to the following proportions:

the solid compound A, an aminating agent heptamethyldisilazane and a catalyst A, namely sodium methoxide =1: 1.2-1.6: 0.1-0.2 in terms of mole number.

9. The method for synthesizing the emamectin benzoate crude product as claimed in claim 7, wherein dilute hydrochloric acid is added into the solid compound B, the mixture is stirred for 20-40 min, filtered, washed with purified water and dried.

10. The method for synthesizing the crude emamectin benzoate analogue product as claimed in claim 9, wherein the mass concentration of the dilute hydrochloric acid is controlled to be 5-10%, and the dosage of the dilute hydrochloric acid is 10-20 times of the mass of the aminating agent; the amount of the purified water is 10-20 times of the mass of the solid compound B.

11. The method for synthesizing the crude emamectin benzoate analog as claimed in claim 2, wherein the reduction reaction process comprises the following steps: dissolving a solid compound B obtained by ammoniation reaction in a reaction solvent of dimethylformamide, tetrahydrofuran or tetrahydropyran, adding a lithium aluminum hydride and titanium zirconium composite solid catalyst for reduction reaction under the protection of nitrogen, filtering to obtain a compound C solution, wherein the reduction reaction temperature is controlled at 20-40 ℃, the reaction time is 40-60 min, and after the reaction is finished, carrying out reduced pressure concentration to obtain the solid compound C.

12. The method for synthesizing the crude emamectin benzoate analog according to claim 11, wherein the dosage ratio of the solid compound B, the lithium aluminum hydride and the titanium-zirconium composite solid catalyst is as follows:

the solid compound B is lithium aluminum hydride and titanium zirconium composite solid catalyst =1: 1.1-2.5: 0.2-0.3 in terms of mole number.

13. The method for synthesizing the crude emamectin benzoate analog according to claim 11, wherein the solid compound C is washed with purified water and dried, and the amount of the purified water is 10-20 times of the mass of the solid compound C.

14. The method for synthesizing the crude emamectin benzoate analogue product as claimed in claim 2, wherein the salt forming reaction process comprises the following steps: dissolving the solid compound C in a reaction solvent of dimethylformamide, tetrahydrofuran or tetrahydropyran, adding benzoic acid, fully stirring for reaction, and carrying out reduced pressure concentration and drying to obtain a crude emamectin benzoate.

15. The method for synthesizing the crude emamectin benzoate analog according to claim 14, wherein the solid compound C, the reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran and benzoic acid are used in the following amounts:

the solid compound C is benzoic acid =1: 1.1-1.3 in terms of mole number;

L_{reaction solvent}:W_{Solid Compound C} =6～10L:1kg。

Technical Field

The invention belongs to the technical field of antibiotic synthesis, and particularly relates to a crude emamectin benzoate analogue and a synthesis method thereof.

Background

The emamectin benzoate is a high-efficiency, low-toxicity, low-residue, green and environment-friendly biological source pesticide developed and marketed by Nowa company. The emamectin benzoate is a derivative of abamectin which is a biological fermentation product, and compared with a parent, the biological activity of the emamectin benzoate is higher than that of the abamectin. The emamectin benzoate has a wide insecticidal spectrum, has a good poisoning effect on cotton bollworms, beet armyworms, spodoptera hubner, tobacco armyworms and the like, particularly has a good insecticidal effect on lepidoptera pests, but has a weak poisoning effect on underground nematodes.

Meanwhile, the prior art generally adopts a six-step synthesis method for synthesizing emamectin benzoate, for example, the process disclosed in the chinese patent "a synthesis method of emamectin benzoate based on abamectin B2" (patent number 201811383572.7), has the problems that:

1. abamectin B2 contains two components, abamectin B2a and B2B, respectively. The two components are used as initial products, and are subjected to synthesis process steps of hydroxyl protection, oxidation, ammoniation, hydrogenation reduction, deprotection reaction, salification reaction and the like to obtain a methylamino abamectin benzoate crude product of abamectin B2, and the synthesis route is complex.

2. A plurality of raw materials are involved in the synthesis process, and the price is high, the consumption is high, and finally, the production cost is high, and the economic benefit is low.

3. The production process uses various organic reagents, and byproducts are discharged in the synthesis process, so that the environment is easily polluted.

4. The effective content of the product is lower than 85%, the product yield is lower than 60%, and the yield is lower. The details are given in the following table.

Summary of the yields

Serial number	Process step	Yield of
			1	C5OH protection reaction	95～97%
2	C4"-OH Oxidation reaction	82～85%
			3	C4"= O amination reaction	68～70%
4	C4Reduction reaction of "= NCH3	98～99%
			5	C5Deprotection reaction	97～98%
6	Overall yield of	50～56%

5. The verification proves that the effective content of the emamectin benzoate obtained by the method is lower than 80%.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a crude emamectin benzoate analogue product which has simple synthesis process steps, environmental protection, safety, short production period, high synthesis yield and stronger poisoning effect on underground nematodes;

the invention also aims to provide a synthetic method of the crude emamectin benzoate analogue.

The technical scheme adopted for realizing the purpose is as follows:

an emamectin benzoate analog, characterized in that the molecular structural formula is:

。

the synthetic method of the emamectin benzoate analog crude product is characterized by comprising the following steps: the method comprises the steps of taking avermectin B2a as an initial raw material, and carrying out oxidation reaction, ammoniation reaction, reduction reaction and salt forming reaction to obtain a crude emamectin benzoate analogue product, wherein the reactions are carried out in a reaction system taking dimethylformamide, tetrahydrofuran or tetrahydropyran as a reaction solvent.

The reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran is added according to the following proportion:

W_{abamectin B2a}:L_{Reaction solvent}=1kg:10～12L。

The oxidation reaction process comprises the following steps: dissolving avermectin B2a in a reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran, adding a catalyst A and a dilute hydrochloric acid solution, stirring for 5-10 min, adding an oxidant at the solution temperature of 0-5 ℃, reacting for 40-60 min, adding a sodium bicarbonate solution and a sodium sulfite solution after the reaction is finished, stirring for 20-40 min, filtering, concentrating under reduced pressure and drying to obtain a solid compound A.

The mass concentration of the dilute hydrochloric acid is controlled to be 5-10%, the dosage of the dilute hydrochloric acid is 6-10% of that of reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran, and the dilute hydrochloric acid is calculated by volume ratio;

the oxidant is dess-martin high-valence iodine, and the dosage of the oxidant is abamectin B2a, dess-martin high-valence iodine =1: 1.2-1.6 in terms of mole number;

the catalyst A is tetrabutylammonium bromide, and the dosage of the catalyst A is 2-6% of the oxidant by mass percent;

the mass concentration of the sodium bicarbonate solution is 10-20%, and the using amount of the sodium bicarbonate solution is 4-8% of the volume of the reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran;

the mass concentration of the sodium sulfite solution is 20-40%, and the using amount of the sodium sulfite solution is 3-7% of the volume of the oxidant.

And the solid compound A is washed by purified water and dried, wherein the amount of the purified water is 10-20 times of the mass of the solid compound A.

The ammoniation reaction process comprises the following steps: dissolving the solid compound A obtained by the oxidation reaction and an aminating agent into a reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran, controlling the temperature of the solution to be 20-30 ℃, adding a catalyst B, fully stirring for reaction for 40-60 min, filtering, and concentrating under reduced pressure to obtain a solid compound B.

The amination agent is heptamethyldisilazane, the catalyst A is sodium methoxide, and the catalyst A are added according to the following proportion:

the solid compound A, an aminating agent heptamethyldisilazane and a catalyst A, namely sodium methoxide =1: 1.2-1.6: 0.1-0.2 in terms of mole number.

And adding dilute hydrochloric acid into the solid compound B, stirring for 20-40 min, filtering, washing with purified water, and drying.

The mass concentration of the dilute hydrochloric acid is controlled to be 5-10%, and the dosage of the dilute hydrochloric acid is 10-20 times of the mass of the aminating agent; the amount of the purified water is 10-20 times of the mass of the solid compound B.

The reduction reaction process comprises the following steps: dissolving a solid compound B obtained by ammoniation reaction in a reaction solvent of dimethylformamide, tetrahydrofuran or tetrahydropyran, adding a lithium aluminum hydride and titanium zirconium composite solid catalyst for reduction reaction under the protection of nitrogen, filtering to obtain a compound C solution, wherein the reduction reaction temperature is controlled at 20-40 ℃, the reaction time is 40-60 min, and after the reaction is finished, carrying out reduced pressure concentration to obtain the solid compound C.

The dosage proportion of the solid compound B, the lithium aluminum hydride and the titanium zirconium composite solid catalyst is as follows:

the solid compound B is lithium aluminum hydride and titanium zirconium composite solid catalyst =1: 1.1-2.5: 0.2-0.3 in terms of mole number.

And washing the solid compound C with purified water and drying, wherein the amount of the purified water is 10-20 times of the mass of the solid compound C.

The salifying reaction process comprises the following steps: dissolving the solid compound C in a reaction solvent of dimethylformamide, tetrahydrofuran or tetrahydropyran, adding benzoic acid, fully stirring for reaction, and carrying out reduced pressure concentration and drying to obtain a crude emamectin benzoate.

The dosage of the solid compound C, the reaction solvent dimethylformamide, tetrahydrofuran or tetrahydropyran and benzoic acid is as follows:

the solid compound C is benzoic acid =1: 1.1-1.3 in terms of mole number;

L_{reaction solvent}:W_{Solid Compound C} =6～10L:1kg。

The invention has the following technical advantages:

1. the emamectin benzoate B2 synthesized by the abamectin B2 in China is subjected to C5-OH protection, C4 ' -OH oxidation, C4 ' = O amination and C4 ' = NCH₃Reduction, C5 deprotection, C4' NCH₃Salifying six-step reaction synthesis; meanwhile, the abamectin B2 has two components, so that a large number of byproducts are generated in the synthesis process, the effective content of the abamectin B2 is low, and the content of a crude product is lower than 80%. The core process disclosed by the invention is to directly adopt the abamectin B2a as an initial synthesis raw material, have single component, and synthesize the emamectin benzoate analogue by adopting an oxidation reaction, an ammoniation reaction, a reduction reaction and a salt forming reaction, wherein the content of a crude product of the emamectin benzoate analogue is higher than 90%. In addition, the invention adopts a four-step method to replace a six-step method to synthesize the emamectin benzoate analogue, thereby simplifying the synthesis process steps, shortening the production period and having obvious production cost advantage.

2. In the synthetic reaction process of the emamectin benzoate analogue, a reaction solvent is used, so that the emamectin benzoate analogue is convenient to recycle, the discharge amount of byproducts is low, and the pollution to the environment is not easy to cause.

3. By adopting the synthesis process, the synthetic yield of the emamectin benzoate analogue reaches more than 85 percent, the production cost is lower, and the economic benefit is good.

4. The emamectin benzoate analog has obviously better activity of poisoning underground nematodes than emamectin benzoate, and has lower raw material toxicity and production cost and obvious market advantage.

Detailed description of the invention

The invention is illustrated below by way of examples, which are to be understood as being illustrative and not limiting. The scope and core content of the invention are to be determined by the claims.

In the following examples, the titanium zirconium composite solid catalyst was prepared by pu tian nanfeng new material science and technology limited.