CN110590884A - Emamectin benzoate analogue crude product and synthetic method thereof - Google Patents
Emamectin benzoate analogue crude product and synthetic method thereof Download PDFInfo
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Abstract
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.
Description
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:
Wabamectin B2a:LReaction 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;
Lreaction solvent:WSolid 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.
Example 1
Avermectin B2a 1.12mol (lkg) dissolved in 10L dimethylformamide.
Then, 0.0114kg of tetrabutylammonium bromide serving as a catalyst and 600ml of 5% diluted hydrochloric acid are added, and the mixture is stirred for 5 min. Controlling the temperature of the organic solution of the abamectin B2a at 0 ℃, adding an oxidant DMP1.344mol (0.57 kg), stirring for 40min, and standing for 20 min. 400ml of 10% sodium bicarbonate and 17ml of 20% sodium sulfite solution were added, followed by stirring for 20 minutes and filtration to obtain a solution of Compound A. After concentrating and drying under reduced pressure to obtain solid compound A0.941kg, purified water 9.4L was added, and the mixture was washed with water 1 time, and after drying, the yield of solid compound A1.06mol (0.94 kg) was 94.5%.
Adding 1.06mol (0.94 kg) of solid compound A and 1.27mol (0.22 kg) of amination agent heptamethyldisilazane into 10L of dimethylformamide reaction solvent, controlling the temperature at 20 ℃ after dissolution, adding 0.1mol (5.7 g) of catalyst sodium methoxide, stirring and reflecting for 40min, filtering and concentrating under reduced pressure to obtain solid compound B, adding 2.2L of 5% diluted hydrochloric acid, and stirring for 20 min. Filtered and washed 1 time with 9.3L of purified water. After drying, 1.03mol (0.928 kg) of solid compound B was obtained in a yield of 96.8%.
10L of dimethylformamide was added to the solid compound B and dissolved. Under the protection of nitrogen, 1.13lmol (43 g) of lithium aluminum hydride and 0.2mol (75 g) of titanium-zirconium composite solid catalyst are respectively added into the solution for reduction reaction, the reaction temperature is controlled at 20 ℃, the stirring speed is controlled at 40r/min, and the reaction time is controlled at 20 min. After the reaction, the mixture was concentrated under reduced pressure to obtain a solution of compound C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain 0.9122kg of a solid compound C, which was washed with 9.1L of purified water 1 time and dried. The yield of the solid compound C was 98.3%.
Dissolving the solid compound C in 5.5L of dimethylformamide, adding 1.11mol (135 g) of benzoic acid, stirring for 100min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the crude emamectin benzoate analogue product is detected to be 0.988kg, the effective content of the crude product is 90.3%, and the total yield is 87.5%.
Example 2
Avermectin B2a 1.12mol (lkg) dissolved in 11L dimethylformamide.
Then, 0.026kg of tetrabutylammonium bromide as a catalyst was added thereto, 880ml of 8% diluted hydrochloric acid was added thereto, and the mixture was stirred for 7 min. Controlling the temperature of the abamectin B2a organic solution at 3 ℃, adding 1.6mol (0.66 kg) of oxidant DMP1, stirring for 50min, and standing for 30 min. 660ml of 15% sodium bicarbonate and 33ml of 30% sodium sulfite solution were added, and stirring was continued for 30min, followed by filtration to obtain a compound A solution. The resulting mixture was concentrated under reduced pressure and dried to give solid compound A0.951kg, which was washed with 14.3L of purified water 1 time and dried to give compound A1.07mol (0.95 kg) in a yield of 95.3%.
1.07mol (0.95 kg) of solid compound A and 1.50mol (0.26 kg) of aminating agent heptamethyldisilazane are added into 11L of dimethylformamide reaction solvent, the temperature is controlled at 25 ℃ after dissolution, 0.1mol (8.7 g) of catalyst sodium methoxide is added, stirring is carried out for 50min, and filtration and reduced pressure concentration are carried out to obtain 0.948kg of solid compound B. 3.9L of 8% diluted hydrochloric acid was added, stirred for 30min, filtered, and washed with 14.2L of purified water for 1 time. After drying, solid compound B1.03mol (0.947 kg) was obtained in 97.9% yield.
Solid compound B was added to 11L of dimethylformamide and dissolved. Under the protection of nitrogen, 1.13lmol (51 g) of lithium aluminum hydride and 0.256mol (93 g) of titanium-zirconium composite solid catalyst are sequentially added into the solution for reduction reaction, the reaction temperature is controlled at 30 ℃, the stirring speed is controlled at 50r/min, and the reaction time is controlled at 25 min. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 0.938kg of a solid compound C, washed with 14.1L of purified water for 1 time and dried to obtain 0.938kg of a compound C in a yield of 99.1%.
Dissolving the solid compound C in 7.5L of dimethylformamide, adding 1.22mol (149 g) of benzoic acid, stirring for 110min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the crude emamectin benzoate analogue is detected to be 1.007kg in crude product, the effective content of the crude product is 91.5%, and the total yield is 89.2%.
Example 3
Avermectin B2a 1.12mol (lkg) dissolved in 12L dimethylformamide.
0.046kg of tetrabutylammonium bromide as a catalyst was added, 1200ml of 10% diluted hydrochloric acid was added, and the mixture was stirred for 10 min. Controlling the temperature of the abamectin B2a organic solution at 5 ℃, adding an oxidant DMP1.792mol (0.76 kg), stirring for 60min, and standing for 40 min. 960ml of 20% sodium bicarbonate and 53ml of 40% sodium sulfite solution were added, and stirring was continued for 40min, followed by filtration to obtain a compound A solution. Concentrated under reduced pressure, filtered and dried to obtain solid compound A0.941, which was washed with 18.8L of purified water 1 time. After drying, the compound A1.06mol (0.94 kg) was obtained with a yield of 94.9%.
1.06mol (0.94 kg) of solid compound A and 1.7mol (0.30 kg) of amination agent heptamethyldisilazane are respectively added into 12L of dimethylformamide reaction solvent, the temperature is controlled at 30 ℃ after dissolution, 0.1mol (11 g) of catalyst sodium methoxide is added, stirring is carried out for 60min, filtering and reduced pressure concentration are carried out to obtain 0.917kg of solid compound B, 6L of 10% diluted hydrochloric acid is added, stirring is carried out for 40min, filtering is carried out, washing is carried out for 1 time by 18.3L of purified water, drying is carried out to obtain 1.01mol (0.916 kg) of solid compound B, and the yield is 97.4%.
12L of dimethylformamide was added to the solid compound B and dissolved. Under the protection of nitrogen, 1.5mol (58 g) of lithium aluminum hydride and 0.256mol (110 g) of titanium-zirconium composite solid catalyst are added into the solution, the reaction temperature is controlled at 40 ℃, the stirring speed is controlled at 60r/min, and the reaction time is controlled at 30 min. After the reaction, the mixture was filtered to obtain a solution of compound C. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain C0.897kg of a solid compound, and the solid compound was washed with 17.9L of purified water 1 time and dried to obtain C0.896kg of a solid compound with a yield of 97.9%.
Dissolving the solid compound C in 8.9L of dimethylformamide, adding 1.28mol (156 g) of benzoic acid, stirring for 120min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the crude emamectin benzoate analogue product is detected to be 0.998kg, the effective content of the crude product is 90.8%, and the total yield is 88.4%.
Example 4
Avermectin B2a 1.12mol (lkg) dissolved in 10L tetrahydrofuran.
0.011kg of tetrabutylammonium bromide as a catalyst is added, 600ml of 5% diluted hydrochloric acid is added, and the mixture is stirred for 5 min. Controlling the temperature of the organic solution of the abamectin B2a at 0 ℃, adding an oxidant DMP1.344mol (0.57 kg), stirring for 40min, and standing for 20 min. 400ml of 10% sodium bicarbonate and 17.1ml of 20% sodium sulfite solution were added thereto, followed by stirring for 20min and filtration to obtain a solution of Compound A. Vacuum concentrating, filtering, drying to obtain solid compound A0.940 kg, adding 9.4L purified water, and washing with water for 1 time. After filtration and drying, the solid compound A1.06mol (0.939 kg) was obtained in a yield of 94.4%.
Adding 1.06mol (0.939 kg) of solid compound A and 1.272mol (0.223 kg) of amination agent heptamethyldisilazane into 10L of tetrahydrofuran reaction solvent, controlling the temperature at 20 ℃ after dissolution, adding 0.1mol (5.72 g) of catalyst sodium methoxide, stirring for 40min, filtering and concentrating under reduced pressure to obtain 0.912kg of solid compound B, adding 2.23L of 5% diluted hydrochloric acid, stirring for 20min, filtering, and washing with 9.12L of purified water for 1 time. After drying, the compound B1.01mol (0.910 kg) was obtained in a yield of 96.7%.
10L of tetrahydrofuran was added to the solid compound B and dissolved. Under the protection of nitrogen, 1.111lmol (42.2 g) of lithium aluminum hydride and 0.2mol (73.3 g) of titanium-zirconium composite solid catalyst are added into the solution for reduction reaction, the reaction temperature is controlled at 20 ℃, the stirring speed is controlled at 40r/min, and the reaction time is controlled at 20 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain C0.896kg of a solid compound, and the solid compound was washed with 9L of purified water 1 time and dried to obtain C0.895kg of a compound with a yield of 98.4%.
Dissolving the solid compound C in 5.4L tetrahydrofuran, adding 1.11mol (133.3 g) of benzoic acid, stirring for 100min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the detection shows that the crude emamectin benzoate analogue product is 0.987kg, the effective content of the crude product is 90.3%, and the total yield is 87.4%.
Example 5
Avermectin B2a 1.12mol (lkg) dissolved in 11L tetrahydrofuran.
0.026kg of tetrabutylammonium bromide as a catalyst was added thereto, 880ml of 7% diluted hydrochloric acid was added thereto, and the mixture was stirred for 7 min. Controlling the temperature of the abamectin B2a organic solution at 3 ℃, adding 1.6mol (0.66 kg) of oxidant DMP1, stirring for 50min, and standing for 30 min. 660ml of 15% sodium bicarbonate and 33ml of 30% sodium sulfite solution were added, and stirring was continued for 30min, followed by filtration to obtain a compound A solution. The mixture was concentrated under reduced pressure, filtered and dried to obtain 0.953kg of a solid compound A, which was washed with 14.3L of purified water 1 time. Filtration and drying gave solid compound A1.072mol (0.952 kg) in 95.7% yield.
1.072mol (0.952 kg) of solid compound A and 1.50mol (0.263 kg) of amination agent heptamethyldisilazane are added into 11L of tetrahydrofuran reaction solvent, the temperature is controlled to be 25 ℃ after dissolution, 0.1mol (8.68 g) of catalyst sodium methoxide is added, stirring is carried out for 50min, filtration and reduced pressure concentration are carried out to obtain 0.950kg of solid compound B, 3.9L of 7% diluted hydrochloric acid is added, stirring is carried out for 30min, filtration is carried out, 14.25L of purified water is used for washing for 1 time, filtration and drying are carried out to obtain 1.05mol (0.948 kg) of solid compound B, and the yield is 97.8%.
11L of tetrahydrofuran was added to the solid compound B and dissolved. Under the protection of nitrogen, 1.365mol (52 g) of lithium aluminum hydride and 0.26mol (95.3 g) of titanium-zirconium composite solid catalyst are respectively added into the solution for reduction reaction, the reaction temperature is controlled at 30 ℃, the stirring speed is controlled at 50r/min, and the reaction time is controlled at 25 min. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 0.941kg of a solid compound C, and the solid compound C was washed with 14.1L of purified water 1 time and dried to obtain 0.940kg of a solid compound, which was obtained in a yield of 99.2%.
Dissolving the solid compound C in 7.5L tetrahydrofuran, adding 1.16mol (152.5 g) of benzoic acid, stirring for 110min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the crude emamectin benzoate analogue product is detected to be 1.010kg, the effective content of the crude product is 90.1%, and the total yield is 89.5%.
Example 6
Avermectin B2a 1.12mol (lkg), dissolved in 12L tetrahydrofuran.
0.046kg of tetrabutylammonium bromide as a catalyst was added, 1200ml of 10% diluted hydrochloric acid was added, and the mixture was stirred for 10 min. Controlling the temperature of the abamectin B2a organic solution at 5 ℃, adding an oxidant DMP1.792mol (0.76 kg), stirring for 60min, and standing for 40 min. 960ml of 20% sodium hydrogencarbonate and 53ml of a 40% sodium sulfite solution were added thereto and filtered to obtain a compound A solution. The resulting mixture was concentrated under reduced pressure, filtered and dried to obtain solid compound A0.948kg, washed with 19L of purified water 1 time, filtered and dried to obtain solid compound A1.065mol (0.946 kg) with a yield of 95.1%.
Adding 1.065mol (0.946 kg) of solid compound A and 1.7mol (0.30 kg) of amination agent heptamethyldisilazane into 12L of tetrahydrofuran reaction solvent, controlling the temperature at 30 ℃ after dissolution, adding 0.213mol (11.5 g) of catalyst sodium methoxide, stirring for 100min, filtering and concentrating under reduced pressure to obtain 0.983kg of solid compound B0.983kg, adding 3L of 10% diluted hydrochloric acid, stirring for 40min, washing for 1 time by 20L of purified water after filtering, and drying to obtain 1.086mol (0.982 kg) of solid compound B1.086mol (90.2% of crude effective content, wherein the yield is 97.0%.
12L of tetrahydrofuran was added to the solid compound B and dissolved. Under the protection of nitrogen, 1.5mol (62 g) of lithium aluminum hydride and 0.256mol (118 g) of titanium-zirconium composite solid catalyst are added into the solution, the reaction temperature is controlled at 40 ℃, the stirring speed is controlled at 60r/min, and the reaction time is controlled at 30 min. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain 0.961kg of a solid compound C, which was washed with 19L of purified water 1 time and dried to obtain 0.959kg of a compound C, and the yield thereof was 97.7%.
Dissolving the solid compound C in 9.6L tetrahydrofuran, adding 1.38mol (168 g) of benzoic acid, stirring for 120min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the crude emamectin benzoate analogue is detected to be 0.994kg, the effective content of the crude emamectin benzoate analogue is 90.1%, and the total yield is 88.1%.
Example 7
Avermectin B2a 1.12mol (lkg), dissolved in 10L tetrahydropyran.
0.011kg of tetrabutylammonium bromide as a catalyst is added, 600ml of 5% diluted hydrochloric acid is added, and the mixture is stirred for 5 min. Controlling the temperature of the organic solution of the abamectin B2a at 0 ℃, adding an oxidant DMP1.344mol (0.57 kg), stirring for 40min, and standing for 20 min. 400ml of 10% sodium bicarbonate and 17ml of 20% sodium sulfite solution were added, followed by stirring for 20 minutes and filtration to obtain a solution of Compound A. The mixture was concentrated under reduced pressure, filtered and dried to obtain 0.941kg of a solid compound A, which was washed with water 1 time by adding 9.4L of purified water, and filtered and dried to obtain 1.066mol (0.940 kg) of a compound A in a yield of 94.5%.
1.066mol (0.940 kg) of the solid compound A and 1.279mol (0.224 kg) of an aminating agent heptamethyldisilazane are added into 10L of tetrahydropyran reaction solvent, the temperature is controlled at 20 ℃ after dissolution, 0.107mol (5.78 g) of sodium methoxide serving as a catalyst is added, stirring is carried out for 40min, filtering and reduced pressure concentration are carried out to obtain a solid compound B, 2.24L of 5% diluted hydrochloric acid is added, stirring is carried out for 20min, filtering is carried out to obtain 0.98kg of the solid compound B, washing is carried out for 1 time by 9.8L of purified water, drying is carried out to obtain 1.08mol (0.978 kg) of the compound B, and the yield is 96.6%.
10L of tetrahydropyran was added to the solid compound B to conduct reduction reaction. Under the protection of nitrogen, 1.188lmol (45.1 g) of lithium aluminum hydride and 0.216mol (78.4 g) of titanium-zirconium composite solid catalyst are added into the solution, the reaction temperature is controlled at 20 ℃, the stirring speed is controlled at 40r/min, and the reaction time is controlled at 20 min. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain a solid compound C0.961kg, which was washed with 9.6L of purified water 1 time. After filtration and drying, the yield of the compound C0.96kg was 98.2%.
Dissolving the solid compound C in 5.76L, adding 1.17mol (142.3 g) of benzoic acid, stirring for 100min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the crude emamectin benzoate analogue product is detected to be 0.984kg, the effective content of the crude product is 90.0%, and the total yield is 87.2%.
Example 8
Avermectin B2a 1.12mol (lkg) dissolved in 11L tetrahydrofuran.
0.027kg of tetrabutylammonium bromide as a catalyst was added, 880ml of 7% diluted hydrochloric acid was added, and the mixture was stirred for 7 min. Controlling the temperature of the abamectin B2a organic solution at 3 ℃, adding 1.6mol (0.665 kg) of oxidant DMP1, stirring for 50min, and standing for 30 min. 660ml of 15% sodium bicarbonate and 33ml of 30% sodium sulfite solution were added, and stirring was continued for 30min, followed by filtration to obtain a compound A solution. The mixture was concentrated under reduced pressure, filtered and dried to obtain solid compound A0.955kg, 9.6L of purified water was added thereto, the mixture was washed with water 1 time, and the mixture was filtered and dried to obtain compound A1.074mol (0.954 kg) with a yield of 95.9%.
Adding 1.074mol (0.954 kg) of solid compound A and 1.50mol (0.263 kg) of amination agent heptamethyldisilazane into 11L of tetrahydrofuran reaction solvent, controlling the temperature at 25 ℃ after dissolution, adding 0.16mol (8.70 g) of catalyst sodium methoxide, stirring for 50min, filtering and concentrating under reduced pressure to obtain solid compound B, adding 3.9L of 8% diluted hydrochloric acid, stirring for 30min, filtering to obtain 0.951kg of solid compound B, washing with 14.2L of purified water for 1 time, filtering, drying and collecting to obtain 1.05mol (0.950 kg) of solid compound B, wherein the yield is 97.9%.
11L of tetrahydrofuran was added to the solid compound B and dissolved. Under the protection of nitrogen, 1.365mol (52 g) of lithium aluminum hydride and 0.26mol (95.3 g) of titanium-zirconium composite solid catalyst are added into the solution for reduction reaction, the reaction temperature is controlled at 30 ℃, the stirring speed is controlled at 50r/min, and the reaction time is controlled at 25 min. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain C0.944kg of a solid compound. 14L of purified water was added thereto, and the mixture was washed with water 1 time to obtain 0.943kg of a compound (C0.3%) at a yield of 99.3%.
Dissolving the solid compound C in 7.5 tetrahydrofuran, adding 1.25mol (152.6 g) of benzoic acid, stirring for 110min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the crude emamectin benzoate analogue is detected to be 1.011kg, the effective content of the crude product is 90.4%, and the total yield is 89.6%.
Example 9
Avermectin B2a 1.12mol (lkg), dissolved in 12L tetrahydrofuran.
0.046kg of tetrabutylammonium bromide as a catalyst was added, 1200ml of 10% diluted hydrochloric acid was added, and the mixture was stirred for 10 min. Controlling the temperature of the abamectin B2a organic solution at 5 ℃, adding an oxidant DMP1.792mol (0.76 kg), stirring for 60min, and standing for 40 min. 960ml of 20% sodium bicarbonate and 53ml of 40% sodium sulfite solution were added, and stirring was continued for 40min, followed by filtration to obtain a compound A solution. Vacuum concentrating, filtering, drying to obtain solid compound A0.946kg, adding purified water 19L, washing with water for 1 time, filtering, drying to obtain compound A1.063 (0.944 kg), yield is 94.9%.
Adding 1.063mol (0.944 kg) of solid compound A and 1.7mol (0.30 kg) of amination agent heptamethyldisilazane into 12L of tetrahydrofuran reaction solvent, controlling the temperature at 30 ℃ after dissolution, adding 0.213mol (11.5 g) of catalyst sodium methoxide, stirring for 60min, filtering and concentrating under reduced pressure to obtain 0.984kg of solid compound B, adding 6L of 10% diluted hydrochloric acid, stirring for 40min, filtering, washing 1 time with 20L of purified water, filtering and drying to obtain 1.086mol (0.982 kg) of compound B, wherein the yield is 96.8%.
12L of tetrahydrofuran was added to the solid compound B and dissolved. Under the protection of nitrogen, 1.63mol (62 g) of lithium aluminum hydride and 0.256mol (118 g) of titanium-zirconium composite solid catalyst are added into the solution, the reaction temperature is controlled at 40 ℃, the stirring speed is controlled at 60r/min, and the reaction time is controlled at 30 min. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 0.956kg of a solid compound C0.956 kg. 19L of purified water was added thereto, and the mixture was washed with water 1 time, filtered and dried to obtain 0.955kg of the compound with a yield of 97.3%.
Dissolving the solid compound C in 9.5L tetrahydrofuran, adding 1.38mol (173 g) of benzoic acid, stirring for 120min, concentrating under reduced pressure, and drying to obtain crude emamectin benzoate, wherein the detection shows that the crude emamectin benzoate is 0.991kg, the effective content of the crude emamectin benzoate is 90.2%, and the total yield is 87.8%.
Comparative example 1
Avermectin lkg, dissolved in 12L of dichloromethane. Cooling, and adding a protective agent allyl formate and a deacidification agent tetramethyl ethylenediamine for reaction. Extracting with dichloromethane, and concentrating under reduced pressure to obtain 5-bit protected avermectin.
Dissolving the 5-bit protected abamectin in isopropyl acetate, adding dimethyl sulfoxide and triethylamine, cooling to 20 ℃, and adding phenyl dichlorophosphate to obtain 4-bit oxidized abamectin.
Dissolving 4-site oxidized abamectin in isopropyl acetate, and adding zinc chloride and aminating agent heptamethyldisilazane for ammoniation reaction.
After the reaction is finished, adding ethanol and reducing agent sodium borohydride for reduction reaction.
After the reaction is finished, adding benzoic acid to generate emamectin benzoate.
The detection shows that the effective content of the crude product is 73.4 percent, and the total synthesis yield is 65.4 percent.
Comparative example 2
Abamectin B2 lkg, dissolved in 15L of dichloromethane. Cooling, and adding a protective agent allyl formate and a deacidification agent tetramethyl ethylenediamine for reaction. Extracting with dichloromethane, and concentrating under reduced pressure to obtain 5-bit protected avermectin.
Dissolving the 5-bit protected abamectin in isopropyl acetate, adding dimethyl sulfoxide and triethylamine, cooling to 20 ℃, and adding phenyl dichlorophosphate to obtain 4-bit oxidized abamectin.
Dissolving 4-site oxidized abamectin in isopropyl acetate, and adding zinc chloride and aminating agent heptamethyldisilazane for ammoniation reaction.
After the reaction is finished, adding ethanol and reducing agent sodium borohydride for reduction reaction.
After the reaction is finished, adding benzoic acid to generate the emamectin benzoate analogue.
Through detection, the effective content of the crude product is 80.3%, and the total synthesis yield is 55.3%.
Claims (15)
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:
Wabamectin B2a:LReaction 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;
Lreaction solvent:WSolid Compound C =6～10L:1kg。
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