A process for the preparation of ivermectin

Abstract

The application relates to a preparation method of ivermectin, which comprises the following steps: carrying out a hydrogenation reaction on abamectin and hydrogen under the action of catalyst A and catalyst B, and using anhydrous ethanol and toluene as reaction solvents to generate ivermectin; wherein the catalyst A is a copper-cobalt complex catalyst, and the catalyst B is phosphotungstic acid. The catalyst does not contain noble metal, the catalyst cost is reduced, and the separation and purification process is simplified.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical synthesis, in particular to a preparation method of ivermectin. BACKGROUND

[0002] Ivermectin is a new type of broad-spectrum, high-efficiency, low-toxicity antibiotic anti-parasitic drug, which has good killing effect on endo- and ecto-parasites, especially nematodes and arthropods. It is usually prepared by hydrogenating the double bond at positions 22 and 23 of avermectin under the action of a catalyst. Since avermectin molecules contain not only double bonds at positions 22 and 23, but also double bonds at positions 3 and 4, different catalysts have selectivity for hydrogenation positions. For example, PPh3 Cu / C preferentially hydrogenates the double bond at positions 3 and 4, while catalysts containing rhodium preferentially hydrogenate the double bond at positions 22 and 23, and cobalt catalysts are beneficial to the synthesis of 3,4,22,23-tetrahydroavermectin. In addition, under the action of a Cu2+ catalyst, avermectin is prone to degradation to form degradation products. Therefore, in order to improve the yield of ivermectin and reduce the generation of by-products such as 3,4,22,23-tetrahydroavermectin and 3,4-dihydroavermectin, a catalyst containing noble metal elements such as triphenylphosphine rhodium chloride and ruthenium trichloride is usually used for the hydrogenation synthesis of avermectin. However, there are problems: 1) the catalyst triphenylphosphine rhodium chloride contains noble metal elements, which is relatively expensive, increasing the production cost of ivermectin; 2) it is necessary to use thiourea reflux for at least 8 hours to form a complex for removing the catalyst triphenylphosphine rhodium chloride, which prolongs the catalyst removal time and increases the energy consumption, further increasing the production cost. SUMMARY

[0003] The present application aims to overcome the defects of the prior art and provides a preparation method of ivermectin, which does not contain noble metal elements in the catalyst, thereby reducing the catalyst cost and simplifying the separation and purification process.

[0004] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0005] A preparation method of ivermectin, which uses anhydrous ethanol and toluene as reaction solvents, and generates ivermectin by hydrogenation reaction of avermectin and hydrogen under the action of catalyst A and catalyst B; wherein the catalyst A is a copper-cobalt complex catalyst, and the catalyst B is phosphotungstic acid.

[0006] As a further technical scheme, the preparation method of the copper-cobalt complex catalyst comprises the following steps:

[0007] Step 1, at 50-55℃, dissolve 0.1 mol of anhydrous CuCl2 and 0.05 mol of cobalt nitrate in 200 mL of purified water to prepare solution A;

[0008] Step 2, and 0.5 mol of dibenzo-18-crown-6 is dispersed in 200 mL of methanol to prepare solution B;

[0009] Step 3, solution A and solution B are uniformly mixed, and the precipitate is precipitated. After the precipitate is no longer precipitated, the reaction solvent is removed by distillation under reduced pressure, and the precipitate is obtained after drying;

[0010] Step 4, 0.5 mol of 1,5-bis(diphenylphosphine)pentane is added to 500 mL of DMF, then the precipitate is added, stirred, and incubated at 60°C for 4 hours. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure, and the solid material is dried at 80°C to constant weight to obtain a copper-cobalt complex catalyst.

[0011] As a further technical solution, the abamectin adopts abamectin wet crystals, which need to be activated before the reaction.

[0012] As a further technical solution, the activation of the abamectin wet crystals includes the following steps: first, add the reaction solvents anhydrous ethanol and toluene to the abamectin wet crystals, then heat to 65 degrees Celsius and remove the ethanol by distillation under reduced pressure to obtain an abamectin toluene solution;

[0013] As a further technical solution, the volume ratio of methanol to toluene is 1:3;

[0014] The weight-volume ratio of abamectin to reaction solvent is 1g:5mL;

[0015] The amount of catalyst A is 0.12-0.18% of the weight of abamectin;

[0016] The amount of catalyst B is 0.05-0.10% of the weight of abamectin.

[0017] As a further technical solution, step 1, hydrogenation reaction: add ethanol and toluene to the abamectin toluene solution, then heat to 60-70 degrees Celsius, add catalyst A and catalyst B under nitrogen conditions, then pass in hydrogen, control the reaction kettle pressure at 0.8-1.2 MPa, the temperature at 63-73 degrees Celsius, and the stirring frequency at 50 Hz, and stir for 1.5-2.5 h to generate ivermectin;

[0018] As a further technical solution, a method for preparing ivermectin also includes the following steps:

[0019] Step 2, extraction and purification: water is added to the reaction solution containing ivermectin, stirred for 30 min, and then separated into layers. The water layer is discharged, and the organic layer is distilled under reduced pressure to remove the reaction solvent. Then, ethanol is added, and the temperature is raised to 60 degrees Celsius. After filtration with activated carbon, formamide and purified water are added dropwise to the filtrate. After the dropwise addition is completed, the temperature is lowered to 20-25 degrees Celsius, and ivermectin crystals are precipitated. Filtration is performed to obtain primary wet crystals and a crystallization mother liquor.

[0020] Ethanol is added to the primary wet crystals, and the temperature is raised to 60 degrees Celsius to dissolve the crystals. Then, formamide and water are added dropwise. After the dropwise addition is completed, the temperature is lowered to 20-25 degrees Celsius, and ivermectin crystals are precipitated. Filtration is performed to obtain secondary wet crystals and a secondary crystallization mother liquor. The secondary wet crystals are dried to obtain ivermectin products.

[0021] Compared with the prior art, the beneficial effects achieved by the present application are as follows:

[0022] In the present application, ivermectin is synthesized by catalytic hydrogenation using abamectin as raw material and under the action of copper-cobalt complex catalyst and phosphotungstic acid catalyst. Compared with the traditional triphenylphosphine rhodium chloride catalyst, the catalyst does not contain noble metal elements, is inexpensive, and has good selectivity for the double bond at positions 22 and 23, high abamectin conversion rate, and good product purity.

[0023] In the present application, abamectin wet crystals are directly used as raw material for catalytic hydrogenation reaction without drying, which reduces the pressure, catalyst dosage, and reaction temperature of the catalytic hydrogenation reaction, and reduces the production cost compared with the traditional technology of drying abamectin wet crystals before catalytic hydrogenation reaction.

[0024] In the present application, the separation and purification of ivermectin is carried out by adding water to separate the layers, removing the water layer, replacing the reaction solvent, filtering with activated carbon, and crystallizing. Compared with the traditional technology, the separation and purification process is simplified, the separation and purification time is short, the energy consumption is low, and the production cost is reduced. DETAILED DESCRIPTION

[0025] The present application will be further described in detail below in conjunction with examples.

[0026] In the present application,

[0027] 1. The preparation process of abamectin wet crystals, comprising the following steps:

[0028] After the abamectin mycelium is extracted with ethanol and filtered, the filtrate is evaporated and concentrated into a paste. After desugaring, the paste is crystallized 2-3 times with ethanol solvent to obtain abamectin wet crystals. The obtained abamectin wet crystals are stored in a sealed container and used within 7 days while wet.

[0029] 2. Dry abamectin powder: prepared by hot air drying the wet abamectin crystal prepared above.

[0030] 3. Other raw materials used in the present application are commercially available unless otherwise specified.

[0031] Example 1

[0032] I. Preparation of copper-cobalt complex catalyst:

[0033] Step a, 0.1 mol of anhydrous CuCl2 and 0.05 mol of cobalt nitrate were dissolved in 200 mL of purified water at 50-55°C to prepare solution A;

[0034] Step b, 0.5 mol of dibenzo-18-crown-6 was dispersed in 200 mL of methanol to prepare solution B;

[0035] Step c, solution A and solution B were uniformly mixed and stirred vigorously, and a precipitate was separated out. After the precipitate no longer separated out, the reaction solvent was removed by distillation under reduced pressure, and the precipitate was dried to obtain a solid material;

[0036] Step d, 0.5 mol of 1,5-bis(diphenylphosphino)pentane was added to 500 mL of DMF, and then the precipitate was added. After stirring, the mixture was incubated at 60°C for 4 hours. After cooling to room temperature, the reaction solvent was removed by distillation under reduced pressure. The solid material was dried at 80°C to a constant weight to obtain a copper-cobalt complex catalyst.

[0037] II. Preparation of ivermectin, specifically including the following steps,

[0038] Step 1, activation of abamectin

[0039] According to the mass-volume ratio of abamectin (dry weight) to reaction solvent 1g:5mL, 100g of abamectin wet crystal (dry weight) was added to 500mL of reaction solvent, and then the ethanol was removed by distillation under reduced pressure after heating to 65°C to obtain an abamectin toluene solution; the reaction solvent was prepared by mixing anhydrous ethanol and toluene in a volume ratio of 1:3;

[0040] Step 2, hydrogenation reaction: to the abamectin toluene solution, add ethanol and toluene to make the volume ratio of ethanol to toluene 1:3, and the weight-volume ratio of abamectin to reaction solvent 1g:5mL. Then heat to 65°C, and under nitrogen conditions, add 2.0g of catalyst A and 1.0g of catalyst B to the reaction solution according to the mass ratio of abamectin, catalyst A and catalyst B 100:2.0:1.0. Then introduce hydrogen gas, control the pressure of the reaction kettle at 1.0MPa, the temperature at 70°C, and the stirring frequency at 50Hz. Stir for 2h to generate ivermectin. Control the reaction liquid, measure the conversion rate of abamectin and the yield of ivermectin, and calculate the selectivity of ivermectin product.

[0041] Step 3, extraction and purification: add alkali (20% sodium hydroxide) to the reaction solution containing ivermectin to adjust pH to 7.2-8.0, terminate the reaction, stand and separate the layers, discharge the water layer, and remove the reaction solvent from the organic layer by distillation under reduced pressure. Then, take 250 mL of anhydrous ethanol according to the mass volume ratio of ivermectin to anhydrous ethanol 1 g:2.5 mL, add the 250 mL of ethanol to the reaction solution from which the solvent has been removed, dissolve at 60 degrees Celsius, filter using 2 g of activated carbon, then add 10 g of formamide and 200 mL of purified water to the filtrate according to the mass volume ratio of ivermectin, formamide, and purified water 1 g:0.12 g:2 mL, cool to 20-25 degrees Celsius, precipitate ivermectin crystals, filter, and obtain the first wet crystals and the first crystallization mother liquor;

[0042] Take 250 mL of anhydrous ethanol according to the mass volume ratio of ivermectin 1 g:2.5 mL, add to the first wet crystals, dissolve at 60 degrees Celsius, add 10 g of formamide and 200 mL of water according to the mass volume ratio of ivermectin, formamide, and purified water 1 g:0.12 g:2 mL, cool to 20-25 degrees Celsius, precipitate ivermectin crystals, filter, obtain the second crystallization mother liquor and the second wet crystals, and dry the second wet crystals to obtain ivermectin products.

[0043] Example 2

[0044] I. Preparation of copper-cobalt complex catalyst: same as Example 1;

[0045] II. Preparation of ivermectin, specifically including the following steps:

[0046] Step 1, activation of ivermectin

[0047] Take 100 g of ivermectin wet crystals (dry weight) and add to 600 mL of reaction solvent according to the mass volume ratio of ivermectin (dry weight) to reaction solvent 1 g:6 mL, then heat to 65 degrees Celsius and remove ethanol under reduced pressure to obtain ivermectin toluene solution; the reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3;

[0048] Step 2, hydrogenation reaction: to the avermectin toluene solution, add ethanol and toluene to make the volume ratio of ethanol to toluene 1:3, and the weight volume ratio of avermectin to reaction solvent 1g:6mL, then heat to 70 degrees Celsius, under the condition of nitrogen, add 2.2g of catalyst A and 1.2g of catalyst B to the reaction solution according to the mass ratio of avermectin, catalyst A and catalyst B 100:2.2:1.2, then introduce hydrogen, control the pressure of the reaction kettle at 1.2MPa, the temperature at 75 degrees Celsius, and the stirring frequency at 50Hz, stir for 1.9h to generate ivermectin; control the reaction liquid, determine the conversion rate of avermectin and the yield of ivermectin, and calculate the selectivity of ivermectin product.

[0049] Step 3, extraction and purification: add alkali (20% sodium hydroxide) to the reaction liquid containing ivermectin to adjust the pH to 7.2-8.0 to terminate the reaction, stand and separate the layers, discharge the water layer, and remove the reaction solvent from the organic layer by distillation under reduced pressure; then take 250mL of anhydrous ethanol according to the mass volume ratio of avermectin to anhydrous ethanol 1g:2.5mL, add the 250mL of ethanol to the reaction mixture after removing the solvent, heat to 60 degrees Celsius to dissolve, filter with 2g of activated carbon, then add 10g of formamide and 200mL of purified water to the filtrate according to the mass volume ratio of avermectin, formamide and purified water 1g:0.12g:2mL, after the addition is complete, cool to 20-25 degrees Celsius to precipitate ivermectin crystals, filter to obtain primary wet crystals and a crystallization mother liquor;

[0050] Take 250mL of anhydrous ethanol according to the mass volume ratio of avermectin 1g:2.5mL, add it to the primary wet crystals, heat to 60 degrees Celsius to dissolve, then add 10g of formamide and 200mL of water according to the mass volume ratio of avermectin, formamide and purified water 1g:0.12g:2mL, after the addition is complete, cool to 20-25 degrees Celsius to precipitate ivermectin crystals, filter to obtain secondary crystallization mother liquor and secondary wet crystals, dry the secondary wet crystals to obtain ivermectin product.

[0051] Example 3

[0052] I. Preparation of copper-cobalt complex catalyst: same as example 1;

[0053] II. Preparation of ivermectin, specifically including the following steps:

[0054] Step 1, activation of avermectin

[0055] Take 100g of avermectin wet crystals (dry weight) and add 400mL of reaction solvent to it according to the mass volume ratio of avermectin (dry weight) to reaction solvent 1g:4mL, then heat to 65 degrees Celsius to remove ethanol by distillation under reduced pressure to obtain an avermectin toluene solution; the reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3;

[0056] Step 2, hydrogenation reaction: supplementing ethanol and toluene to the avermectin toluene solution, so that the volume ratio of ethanol to toluene is 1:3, and the weight volume ratio of avermectin to reaction solvent is 1g:4mL, then heating to 60 degrees Celsius, under the condition of nitrogen, adding 1.8g of catalyst A and 0.8g of catalyst B to the reaction solution according to the mass ratio of avermectin, catalyst A and catalyst B of 100:1.8:0.8, then introducing hydrogen, controlling the pressure of the reaction kettle at 0.8MPa, the temperature at 65 degrees Celsius, and the stirring frequency at 50Hz, stirring for 2.1h to generate ivermectin; controlling the reaction liquid, determining the conversion rate of avermectin and the yield of ivermectin, and calculating the selectivity of ivermectin product.

[0057] Step 3, extraction and purification: adding alkali (20% sodium hydroxide) to the reaction liquid containing ivermectin to adjust the pH to 7.2-8.0 to terminate the reaction, standing and separating the layers, discharging the water layer, and then removing the reaction solvent from the organic layer by distillation under reduced pressure; taking 250mL of anhydrous ethanol according to the mass volume ratio of avermectin to anhydrous ethanol of 1g:2.5mL, adding the 250mL of ethanol to the reaction solvent removed from which the solvent is removed, heating to 60 degrees Celsius to dissolve, then filtering with 2g of activated carbon, and then adding 10g of formamide and 200mL of purified water to the filtrate according to the mass volume ratio of avermectin, formamide and purified water of 1g:0.12g:2mL; after the addition is completed, cooling to 20-25 degrees Celsius to precipitate ivermectin crystals, filtering to obtain primary wet crystals and a crystallization mother liquor;

[0058] Taking 250mL of anhydrous ethanol according to the mass volume ratio of avermectin to anhydrous ethanol of 1g:2.5mL, adding the 250mL of ethanol to the primary wet crystals, heating to 60 degrees Celsius to dissolve, then adding 10g of formamide and 200mL of water according to the mass volume ratio of avermectin, formamide and purified water of 1g:0.12g:2mL, and cooling to 20-25 degrees Celsius to precipitate ivermectin crystals, filtering to obtain secondary crystallization mother liquor and secondary wet crystals, and drying the secondary wet crystals to obtain ivermectin product.

[0059] Comparative Example 1

[0060] I. Preparation of ivermectin, specifically including the following steps:

[0061] Step 1, activation of avermectin

[0062] According to the mass volume ratio of avermectin (dry weight) to reaction solvent of 1g:5mL, 100g of avermectin wet crystals (dry weight) is added to 500mL of reaction solvent, then heated to 65 degrees Celsius to remove ethanol by distillation under reduced pressure to obtain an avermectin toluene solution; the reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3;

[0063] Step 2, hydrogenation reaction: to the avermectin toluene solution, add ethanol and toluene to make the volume ratio of ethanol to toluene 1:3, and the weight volume ratio of avermectin to reaction solvent 1g:5mL, then heat to 65 degrees Celsius, under the condition of nitrogen, according to the mass ratio of avermectin to catalyst B 100:1.0, 2.0g of catalyst B (phosphotungstic acid) is added to the reaction solution, then hydrogen is introduced, the pressure of the reaction kettle is controlled at 1.0MPa, the temperature is at 70 degrees Celsius, the stirring frequency is 50Hz, and the stirring reaction is carried out for 2h to generate ivermectin; the reaction solution is controlled, the conversion rate of avermectin and the yield of ivermectin are determined, and the selectivity of ivermectin product is calculated.

[0064] Comparative Example 2

[0065] I. Preparation of copper-cobalt complex catalyst: same as Example 1;

[0066] II. Preparation of ivermectin, specifically including the following steps: same as Example 1, except that catalyst B is not added.

[0067] Step 1, activation of avermectin

[0068] According to the mass volume ratio of avermectin (dry weight) to reaction solvent 1g:5mL, 100g of avermectin wet crystal (dry weight) is added to 500mL of reaction solvent, then heated to 65 degrees Celsius to remove ethanol under reduced pressure to obtain an avermectin toluene solution; the reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3;

[0069] Step 2, hydrogenation reaction: to the avermectin toluene solution, add ethanol and toluene to make the volume ratio of ethanol to toluene 1:3, and the weight volume ratio of avermectin to reaction solvent 1g:5mL, then heat to 65 degrees Celsius, under the condition of nitrogen, according to the mass ratio of avermectin to catalyst A 100:2.0, 2.0g of catalyst A (copper-cobalt complex catalyst) is added to the reaction solution, then hydrogen is introduced, the pressure of the reaction kettle is controlled at 1.0MPa, the temperature is at 70 degrees Celsius, the stirring frequency is 50Hz, and the stirring reaction is carried out for 2h to generate ivermectin; the reaction solution is controlled, the conversion rate of avermectin and the yield of ivermectin are determined, and the selectivity of ivermectin product is calculated.

[0070] Comparative Example 3

[0071] I. Preparation of copper complex catalyst: same as Example 1;

[0072] Step a, 0.1 mol of anhydrous CuCl2 is dissolved in 200mL of purified water at 50-55 degrees Celsius to prepare solution A;

[0073] Step b, and 0.5 mol of dibenzo-18-crown-6 is dispersed in 200 mL of methanol to prepare solution B;

[0074] Step c, solution A and solution B are uniformly mixed, and the precipitate is precipitated by vigorous stirring. After the precipitate is no longer precipitated, the reaction solvent is removed by distillation under reduced pressure, and dried to obtain the precipitate;

[0075] Step d, 0.5 mol of 1,5-bis(diphenylphosphino)pentane is added to 500 mL of DMF, and then the precipitate is added. Stirring is performed, and the temperature is maintained at 60°C for 4 hours. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The solid material is dried at 80°C until the weight is constant, to obtain a copper-cobalt complex catalyst.

[0076] II. Preparation of ivermectin, specifically comprising the following steps:

[0077] Step 1, activation of abamectin: same as Example 1;

[0078] Step 2, hydrogenation reaction: same as Example 1; the difference is that a copper complex catalyst is used as catalyst A

[0079] Comparative Example 4

[0080] I. Preparation of a cobalt complex catalyst: same as Example 1;

[0081] Step a, 0.05 mol of cobalt nitrate is dissolved in 200 mL of purified water at 50-55°C to prepare solution A;

[0082] Step b, and 0.5 mol of dibenzo-18-crown-6 is dispersed in 200 mL of methanol to prepare solution B;

[0083] Step c, solution A and solution B are uniformly mixed, and the precipitate is precipitated by vigorous stirring. After the precipitate is no longer precipitated, the reaction solvent is removed by distillation under reduced pressure, and dried to obtain the precipitate;

[0084] Step d, 0.5 mol of 1,5-bis(diphenylphosphino)pentane is added to 500 mL of DMF, and then the precipitate is added. Stirring is performed, and the temperature is maintained at 60°C for 4 hours. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The solid material is dried at 80°C until the weight is constant, to obtain a copper-cobalt complex catalyst.

[0085] III. Preparation of ivermectin, specifically comprising the following steps:

[0086] Step 1, activation of abamectin: same as Example 1;

[0087] Step 2, hydrogenation reaction: same as Example 1; the difference is that a copper complex catalyst is used as catalyst A.

[0088] Comparative Example 5

[0089] I. Preparation of copper-cobalt complex catalyst: same as example 1.

[0090] II. Preparation of ivermectin, comprising the following steps:

[0091] Step 1, activation of abamectin

[0092] The abamectin wet crystal 100g (dry weight) was added into 500mL reaction solvent, and then heated to 65 degrees Celsius to remove ethanol by distillation under reduced pressure to obtain abamectin toluene solution; the reaction solvent was mixed by anhydrous ethanol and toluene in a volume ratio of 1:3;

[0093] Step 2, hydrogenation reaction: the abamectin toluene solution was supplemented with ethanol and toluene to make the volume ratio of ethanol to toluene 1:3, and the weight volume ratio of abamectin to reaction solvent 1g:5mL, then heated to 65 degrees Celsius, under the condition of nitrogen, 2.0g of catalyst A (copper-cobalt complex catalyst) and 1.0g of catalyst B (phosphomolybdic acid) were added into the reaction solution according to the mass ratio of abamectin, catalyst A and catalyst B 100:2.0:1.0, then hydrogen was introduced, the pressure of the reaction kettle was controlled at 1.0MPa, the temperature was controlled at 70 degrees Celsius, the stirring frequency was 50Hz, and the stirring reaction was carried out for 2h to generate ivermectin; the reaction solution was controlled, the conversion rate of abamectin and the yield of ivermectin were determined, and the selectivity of ivermectin product was calculated.

[0094] Comparative example 6

[0095] I. Preparation of copper-cobalt catalyst:

[0096] Step a, 0.1mol of anhydrous CuCl2 and 0.05mol of cobalt nitrate were dissolved in 200mL of purified water to prepare solution A;

[0097] Step b, 0.5mol of dibenzo-18-crown-6 was dispersed in 200mL of methanol to prepare solution B;

[0098] Step c, after uniform mixing of solution A and solution B, 0.5mol of 1,5-bis(diphenylphosphine)pentane was added, stirred for 4h, the reaction solvent was removed by distillation under reduced pressure, and dried to obtain the copper-cobalt catalyst.

[0099] II. Preparation of ivermectin, comprising the following steps:

[0100] Step 1, activation of abamectin

[0101] The abamectin wet crystal 100g (dry weight) is added into 500mL reaction solvent, then the temperature is raised to 65 degrees Celsius, and the ethanol is removed by distillation under reduced pressure to obtain the abamectin toluene solution; the reaction solvent is mixed by anhydrous ethanol and toluene in a volume ratio of 1:3;

[0102] Step 2, hydrogenation reaction: the abamectin toluene solution is supplemented with ethanol and toluene to make the volume ratio of ethanol to toluene 1:3, and the weight volume ratio of abamectin to reaction solvent 1g:5mL, then the temperature is raised to 65 degrees Celsius, 2.0g of catalyst A (phosphotungstic acid) and 1.0g of catalyst B are added into the reaction solution under the condition of nitrogen, the pressure of the reaction kettle is controlled at 1.0MPa, the temperature is controlled at 70 degrees Celsius, and the stirring frequency is 50Hz, then hydrogen is introduced, and the stirring reaction is carried out for 2h to generate ivermectin; the reaction solution is controlled, the conversion rate of abamectin and the yield of ivermectin are determined, and the selectivity of ivermectin product is calculated.

[0103] Comparative example 7

[0104] I. Preparation of copper-cobalt catalyst:

[0105] Step a, preparation of Raney Cu catalyst: 0.1mol (in terms of copper element) of Cu-Al alloy powder (80 mesh) is gradually added into 50℃ sodium hydroxide aqueous solution with a mass concentration of 30% under the condition of vigorous stirring at a mass ratio of 1:1, and the stirring reaction is carried out for 30min, then the catalyst is washed with deionized water until it is neutral to obtain the Raney Cu catalyst;

[0106] Step b, preparation of Raney Co catalyst: 0.05mol (in terms of cobalt element) of aluminum-cobalt alloy powder (80 mesh) is slowly added into 70 degrees Celsius sodium hydroxide solution with a mass concentration of 5%, and the stirring activation is carried out for 8h, then the catalyst is washed with deionized water until it is neutral to obtain the Raney Co catalyst;

[0107] Step c, mixing: the Raney Cu catalyst prepared in step a and the Raney Co catalyst prepared in step 2 are mixed, then added into 10mL ethanol solution, and stirred uniformly to obtain the copper-cobalt catalyst, which is stored in the refrigerator for standby use;

[0108] II. Preparation of ivermectin, specifically including the following steps:

[0109] Step 1, activation of abamectin

[0110] The wet crystal of 100g avermectin (dry weight) is added into 500ml reaction solvent, then the temperature is raised to 65 degrees Celsius, and the ethanol is removed by distillation under reduced pressure to obtain the avermectin toluene solution; the reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3;

[0111] Step 2, hydrogenation reaction: the ethanol and toluene are added to the avermectin toluene solution to make the volume ratio of ethanol to toluene 1:3, and the weight volume ratio of avermectin to reaction solvent 1g:5ml, then the temperature is raised to 65 degrees Celsius, and 2.0g of catalyst A (copper-cobalt catalyst prepared in the present comparative example) and 1.0g of catalyst B (phosphotungstic acid) are added to the reaction solution under the condition of nitrogen, with the mass ratio of avermectin, catalyst A: catalyst B being 100:2.0:1.0, then hydrogen is introduced, the pressure in the reaction kettle is controlled at 1.0MPa, the temperature is controlled at 70 degrees Celsius, and the stirring frequency is 50Hz, and the reaction is stirred for 2h to generate ivermectin; the reaction solution is controlled, the conversion rate of avermectin and the yield of ivermectin are determined, and the selectivity of ivermectin product is calculated.

[0112] Comparative Example 8

[0113] I. Preparation of Raney Cu catalyst modified by phosphomolybdic acid:

[0114] Step a, preparation of Raney Cu catalyst: 0.1mol (in terms of copper element) of Cu-Al alloy powder (80 mesh) is gradually added to 50℃ of 30% mass concentration sodium hydroxide aqueous solution under the condition of vigorous stirring with the mass ratio of 1:1, the reaction is stirred for 30min, and then the catalyst is washed with deionized water until it is neutral to obtain the Raney Cu catalyst;

[0115] Step b, modification by phosphomolybdic acid: the Raney Cu catalyst prepared in step a is added to a 20% mass concentration phosphomolybdic acid solution, heated to 70 degrees Celsius in a water bath, stirred until the solvent is evaporated, then calcined at 400 degrees Celsius for 4h under the protection of hydrogen atmosphere, and cooled to room temperature to obtain the Raney Cu catalyst modified by phosphomolybdic acid, the conversion rate of avermectin and the yield of ivermectin are determined, and the selectivity of ivermectin product is calculated.

[0116] II. Preparation of ivermectin, specifically including the following steps:

[0117] Step 1, activation of avermectin

[0118] The wet crystal of 100g (dry weight) is added into 500ml of reaction solvent, and then the ethanol is removed by distillation under reduced pressure at 65 degrees Celsius to obtain the abamectin toluene solution; the reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3;

[0119] Step 2, hydrogenation reaction: the toluene solution of abamectin is supplemented with toluene to make the volume ratio of ethanol to toluene 1:3, and the weight volume ratio of abamectin to reaction solvent 1g:5ml, and then heated to 65 degrees Celsius. Under the condition of nitrogen, 2.0g of molybdenum phosphate modified Raney Cu catalyst is added to the reaction solution according to the mass ratio of abamectin to molybdenum phosphate modified Raney Cu catalyst 200:2.0, and then hydrogen is introduced. The pressure in the reaction kettle is controlled at 1.0MPa, the temperature is controlled at 70 degrees Celsius, the stirring frequency is 50Hz, and the stirring reaction is carried out for 6h to generate ivermectin. The reaction solution is controlled, the conversion rate of abamectin and the yield of ivermectin are determined, and the selectivity of ivermectin product is calculated.

[0120] Comparative Example 9

[0121] I. Preparation of copper-cobalt complex catalyst: same as Example 1.

[0122] II. Preparation of ivermectin, specifically comprising the following steps,

[0123] Step 1, activation of abamectin

[0124] According to the mass volume ratio of abamectin (dry weight) to reaction solvent 1g:5ml, 100g (dry weight) of wet crystal of abamectin is added into 500ml of reaction solvent toluene, and then heated to 110 degrees Celsius to distill under reduced pressure until the volume of the solution is 1 / 3 of the original volume to obtain the abamectin toluene solution;

[0125] Step 2, hydrogenation reaction: toluene is added to the abamectin toluene solution to make the weight volume ratio of abamectin to reaction solvent 1g:5ml, and then heated to 65 degrees Celsius. Under the condition of nitrogen, 2.0g of catalyst A and 1.0g of catalyst B are added to the reaction solution according to the mass ratio of abamectin to catalyst A to catalyst B 100:2.0:1.0, and then hydrogen is introduced. The pressure in the reaction kettle is controlled at 1.0MPa, the temperature is controlled at 70 degrees Celsius, the stirring frequency is 50Hz, and the stirring reaction is carried out for 2h to generate ivermectin. The reaction solution is controlled, the conversion rate of abamectin and the yield of ivermectin are determined, and the selectivity of ivermectin product is calculated.

[0126] Step 3, extraction and purification: add alkali (20% sodium hydroxide) to the reaction solution containing ivermectin to adjust pH to 7.2-8.0, terminate the reaction, stand and separate the layers, discharge the water layer, and remove the reaction solvent from the organic layer by distillation under reduced pressure. Then, take 250 mL of anhydrous ethanol according to the mass-volume ratio of ivermectin to anhydrous ethanol 1 g:2.5 mL, and add the measured 250 mL of ethanol to the reaction solution from which the solvent has been removed. After dissolving at 60 degrees Celsius, filter with 2 g of activated carbon. Then, add 10 g of formamide and 200 mL of purified water to the filtrate according to the mass-volume ratio of ivermectin, formamide, and purified water 1 g:0.12 g:2 mL. After the addition is complete, cool to 20-25 degrees Celsius, and precipitate ivermectin crystals. Filter to obtain the first wet crystals and the first crystallization mother liquor.

[0127] Take anhydrous ethanol according to the mass-volume ratio of ivermectin 1 g:2.5 mL, and add it to the first wet crystals. After dissolving at 60 degrees Celsius, add 10 g of formamide and 200 mL of water according to the mass-volume ratio of ivermectin, formamide, and purified water 1 g:0.12 g:2 mL. After the addition is complete, cool to 20-25 degrees Celsius, and precipitate ivermectin crystals. Filter to obtain the second wet crystals and the second crystallization mother liquor. Dry the second wet crystals to obtain ivermectin products.

[0128] Comparative Example 10

[0129] I. Preparation of copper-cobalt complex catalyst: same as Example 1.

[0130] II. Preparation of ivermectin, specifically including the following steps,

[0131] Step 1, activation of ivermectin

[0132] Take 100 g of dried ivermectin (dry weight) and add it to 500 mL of reaction solvent according to the mass-volume ratio of ivermectin (dry weight) to reaction solvent 1 g:5 mL. Then, remove ethanol by distillation under reduced pressure at 65 degrees Celsius to obtain a toluene solution of ivermectin. The reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3.

[0133] Step 2, hydrogenation reaction: add ethanol and toluene to the toluene solution of ivermectin to make the volume ratio of ethanol to toluene 1:3 and the weight-volume ratio of ivermectin to reaction solvent 1 g:5 mL. Then, heat to 65 degrees Celsius. Under nitrogen conditions, add 2.0 g of catalyst A and 1.0 g of catalyst B to the reaction solution according to the mass ratio of ivermectin, catalyst A, and catalyst B 100:2.0:1.0. Then, introduce hydrogen gas, control the pressure of the reaction kettle at 1.0 MPa, the temperature at 70 degrees Celsius, and the stirring frequency at 50 Hz. Stir for 2 h to generate ivermectin. Control the reaction solution, determine the conversion rate of ivermectin and the yield of ivermectin, and calculate the selectivity of ivermectin products.

[0134] Comparative Example 11

[0135] I. Preparation of the copper-cobalt complex catalyst: same as Example 1.

[0136] II. Preparation of Ivermectin, specifically comprising the following steps,

[0137] Step 1, activation of abamectin

[0138] According to the mass-volume ratio of abamectin (dry weight) to reaction solvent 1g:5mL, 100g of abamectin (dry weight) after drying was added to 500mL of reaction solvent, then heated to 65 degrees Celsius to remove ethanol by distillation under reduced pressure, to obtain an abamectin toluene solution; the reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3;

[0139] Step 2, hydrogenation reaction: to the abamectin toluene solution, add ethanol and toluene to make the volume ratio of ethanol to toluene 1:3, and the weight-volume ratio of abamectin to reaction solvent 1g:5mL, then heat to 65 degrees Celsius, under the condition of nitrogen, according to the mass ratio of abamectin, catalyst A, catalyst B 100:3.0:2.0, add 2.0g of catalyst A and 1.0g of catalyst B to the reaction solution, control the reaction kettle pressure at 3.0MPa, the temperature at 80 degrees Celsius, the stirring frequency at 50Hz, stir for 3h to generate ivermectin; control the reaction liquid, determine the conversion rate of abamectin and the yield of ivermectin, and calculate the selectivity of ivermectin product.

[0140] Comparative Example 12

[0141] I. Preparation of Ivermectin, specifically comprising the following steps,

[0142] Step 1, activation of abamectin

[0143] According to the mass-volume ratio of abamectin (dry weight) to reaction solvent 1g:5mL, 100g of abamectin (dry weight) after drying was added to 500mL of reaction solvent, then heated to 65 degrees Celsius to remove ethanol by distillation under reduced pressure, to obtain an abamectin toluene solution; the reaction solvent is a mixture of anhydrous ethanol and toluene in a volume ratio of 1:3;

[0144] Step 2, hydrogenation reaction: the activated abamectin toluene solution is cooled to 70 degrees Celsius, 2.0 g of catalyst (triphenylphosphine chloride) is added to the reaction solution under nitrogen conditions at a mass ratio of abamectin to catalyst of 100:2.0, then hydrogen is introduced, the pressure in the reaction kettle is controlled at 1.5 MPa, the temperature is controlled at 84 degrees Celsius, and the stirring frequency is 50 Hz, and the reaction is stirred for 2 h until the content of the raw material abamectin no longer changes, and ivermectin is generated; the reaction solution is controlled, the conversion rate of abamectin and the yield of ivermectin are determined, and the selectivity of ivermectin product is calculated.

[0145] Step 3, separation and purification: 1.5 g of thiourea is added to the reaction solution containing ivermectin obtained in step 2, refluxing is carried out for 4 h, the catalyst is removed by suction filtration, and the solvent toluene is removed by distillation under reduced pressure from the filtrate to obtain ivermectin crude product;

[0146] Then 240 kg of ethanol is added to the ivermectin crude product, after stirring and dissolving, activated carbon is added, the temperature is raised to 60 degrees Celsius for decolorization treatment for 3-4 h, after filtration, 12 g of formamide and 200 mL of purified water are added to the filtrate at a mass / volume ratio of abamectin, formamide and purified water of 1 g:0.12 g:2 mL, after the addition is completed, the temperature is lowered to 20-25 degrees Celsius, ivermectin crystals are precipitated, and after filtration, first wet crystals and first crystallization mother liquor are obtained;

[0147] Anhydrous ethanol 250 mL is taken in an amount of 2.5 mL per gram of abamectin, and is added to the first wet crystals, after dissolving at a temperature of 60 degrees Celsius, 10 g of formamide and 200 mL of water are added at a mass / volume ratio of abamectin, formamide and purified water of 1 g:0.12 g:2 mL, after the addition is completed, the temperature is lowered to 20-25 degrees Celsius, ivermectin crystals are precipitated, and after filtration, second crystallization mother liquor and second wet crystals are obtained, and the second wet crystals are dried to obtain ivermectin product.

[0148] Effect example:

[0149] The reaction solution of step two in the preparation process of ivermectin in each example and each comparative example is controlled by liquid chromatography, the content of abamectin and the content of ivermectin in the reaction solution at the end of the reaction are determined, the conversion rate of abamectin and the yield of ivermectin in the hydrogenation reaction are calculated, and the results are shown in Table 1.

[0150] The conversion rate refers to the percentage of the part that has reacted in the reaction to the total amount of the reactant before the reaction.

[0151] The conversion rate of abamectin % = [(total amount of abamectin before reaction - residual amount of abamectin after reaction) / total amount of abamectin before reaction] x 100%

[0152] Ivermectin yield % = (actual amount of ivermectin produced / theoretical maximum amount of ivermectin produced) x 100%

[0153] Ivermectin selectivity % = (ivermectin yield / conversion rate of abamectin) x 100%

[0154]

[0155] Example 2

[0156] The weight of the ivermectin product prepared in Examples 1-3 and Comparative Example 12 was determined, and the content (purity) of the ivermectin product was determined according to the relevant provisions of the Chinese Veterinary Pharmacopoeia 2020 Edition Volume 1, and the total yield of ivermectin in the entire process was calculated, and the results are shown in Table 2.

[0157] Table 2

[0158]

[0159]

[0160] The above-described embodiments are merely preferred embodiments of the present application, and are not exhaustive of the feasible implementations of the present application. Any obvious modifications made by those skilled in the art without departing from the principles and spirit of the present application should be considered to be within the scope of protection of the claims of the present application.

Claims

1. A process for the preparation of ivermectin, characterized in that, The abamectin is reacted with hydrogen under the action of catalyst A and catalyst B to generate ivermectin, wherein the catalyst A is a copper cobalt complex catalyst, and the catalyst B is phosphotungstic acid; the abamectin adopts abamectin wet crystal, and the abamectin wet crystal needs to be activated before being reacted; the activation of the abamectin wet crystal comprises the following steps: firstly, the abamectin wet crystal is added into anhydrous ethanol and toluene as reaction solvents, then the ethanol is removed by distillation under reduced pressure after being heated to 65 DEG C, and the abamectin toluene solution is obtained; the copper cobalt complex catalyst comprises the following steps: 0.1 mol of anhydrous CuCl2 and 0.05 mol of cobalt nitrate are dissolved in 200 mL of purified water to prepare solution A under 50-55 DEG C; 0.5 mol of dibenzo-18-crown-6 is dispersed in 200 mL of methanol to prepare solution B; solution A and solution B are uniformly mixed and stirred intensively, and the precipitate is separated out; after the precipitate is no longer separated out, the reaction solvent is removed by distillation under reduced pressure, and the precipitate is dried to obtain the copper cobalt complex catalyst; 500 mL of DMF is added with 0.5 mol of 1,5-bis (diphenylphosphine) pentane, then the precipitate is added, stirred, and kept at 60 DEG C for 4 hours; after being cooled to room temperature, the reaction solvent is removed by distillation under reduced pressure, and the solid substance is dried at 80 DEG C until the weight is constant to obtain the copper cobalt complex catalyst.

2. The preparation method of ivermectin according to claim 1, wherein the volume ratio of the anhydrous ethanol to toluene is 1:3; the weight volume ratio of the abamectin to the reaction solvent is 1g:5 mL; the amount of the catalyst A is 0.12-0.18% of the weight of the abamectin; and the amount of the catalyst B is 0.05-0.10% of the weight of the abamectin. The specific operation comprises the following steps: step 1, hydrogenation reaction: the abamectin toluene solution is supplemented with ethanol and toluene, then heated to 60-70 DEG C, and the catalyst A and the catalyst B are added under the condition of nitrogen; then hydrogen is introduced, the pressure of the reaction kettle is controlled at 0.8-1.2 MPa, the temperature is controlled at 63-73 DEG C, the stirring frequency is 50 Hz, and the stirring reaction is carried out for 1.5-2.5 h to generate ivermectin. The method further comprises the following steps: step 2, extraction and purification: water is added to the reaction liquid containing ivermectin, stirred for 30 min, and then separated into layers; the water layer is discharged, and the organic layer is distilled under reduced pressure to remove the reaction solvent; then ethanol is added, heated to 60 DEG C, filtered through activated carbon, then formamide and purified water are added dropwise to the filtrate, cooled to 20-25 DEG C, and ivermectin crystals are separated out; the ivermectin crystals are filtered to obtain primary wet crystals and a crystallization mother liquor; the primary wet crystals are added with ethanol, dissolved by heating to 60 DEG C, then formamide and water are added dropwise, and the ivermectin crystals are separated out by cooling to 20-25 DEG C; the ivermectin crystals are filtered to obtain secondary wet crystals and a secondary crystallization mother liquor; and the secondary wet crystals are dried to obtain ivermectin products. ​ ​ ​ ​ ​ ​ ​ ​ ​ 3. A process for the preparation of Ivermectin as claimed in claim 1 wherein, ​ ​ 4. A process for the preparation of Ivermectin as claimed in claim 3 wherein, ​ ​ ​

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