Synthesis method of ivermectin

Abstract

The invention relates to a synthesis method of ivermectin, which comprises the following steps: by taking absolute ethyl alcohol and methylbenzene as solvents, carrying out reduction reaction on abamectin and sodium borohydride under the action of catalysts cerium chloride and dichlorotris (triphenylphosphine) ruthenium to generate the ivermectin. According to the method, avermectin is taken as a raw material, under the action of a cerium chloride catalyst and a dichlorotris (triphenylphosphine) ruthenium catalyst, sodium borohydride is taken as a reducing agent for selective reduction of 22 and 23 double bonds, ivermectin is synthesized, hydrogen does not need to be introduced, a series of problems caused by introduction of hydrogen are solved, the catalyst can be purchased on the market, and the method is environment-friendly. The selectivity on 22 and 23 double bonds is good, the conversion rate of abamectin is high, and the product purity is good; compared with a triphenylphosphine rhodium chloride catalyst in the traditional technology, the ruthenium catalyst with relatively low price is adopted, and the dosage of a noble metal catalyst is reduced, so that the cost of the catalyst is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing ivermectin. Background Art

[0002] Ivermectin is prepared by hydrogenating the double bonds at positions 22 and 23 of avermectin under high temperature and high pressure conditions using triphenylphosphine rhodium chloride as a catalyst. The disadvantages of ivermectin are as follows: 1) hydrogen must be introduced during the reaction, and hydrogen is flammable and explosive, so there is a high safety hazard; 2) the amount of triphenylphosphine rhodium chloride catalyst used is relatively high, and rhodium, as a precious metal catalyst, is expensive, thereby increasing the synthesis cost of ivermectin.

[0003] In order to reduce the cost of catalysts in the synthesis of ivermectin, our company has submitted a Chinese invention patent with application number CN202311305772.1, which uses a copper-cobalt complex catalyst and a phosphotungstic acid catalyst to catalyze the hydrogenation of the 22,23 double bonds of avermectin to prepare ivermectin. Although the catalyst of this reaction does not use precious metals, the copper-cobalt complex catalyst is not commercially available and can only be made by ourselves. When making it ourselves, the reaction conditions of the synthesis of the copper-cobalt complex catalyst have a great influence on the state of the obtained copper-cobalt complex catalyst. When the control accuracy of the reaction conditions is reduced, it is easy to cause the catalytic effect of the prepared catalyst to be unstable, and the high-precision condition control will undoubtedly increase the equipment cost. In addition, it also uses the method of introducing hydrogen for hydrogenation in the traditional technology, which cannot solve the safety hazards caused by the use of hydrogen.

[0004] Therefore, it is extremely important to develop a method for synthesizing ivermectin with a catalyst that is easily available, stable, and low-priced and that does not require hydrogen. Summary of the invention

[0005] The purpose of the present invention is to overcome the defects of the prior art and provide a method for synthesizing ivermectin, which does not require the introduction of hydrogen, and the catalyst can be commercially available, has a stable catalytic effect, and has a high yield of ivermectin.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] The invention discloses a method for synthesizing ivermectin. With anhydrous ethanol and toluene as solvents, under the action of catalysts cerium chloride and dichlorotri(triphenylphosphine)ruthenium, avermectin and sodium borohydride undergo reduction reaction to generate ivermectin.

[0008] As a further technical solution, the following steps are specifically included:

[0009] Step 1, reduction reaction: first, add avermectin to a solvent, stir to dissolve, then cool to -30°C to -35°C, then add cerium chloride, stir for 30 minutes, add dichlorotri(triphenylphosphine)ruthenium, continue stirring for 30 minutes, slowly add sodium borohydride, after the sodium borohydride is added, heat to 5 to 10 degrees Celsius, keep warm for 8 to 10 hours to generate ivermectin, and obtain a reaction solution containing ivermectin.

[0010] As a further technical solution, the weight ratio of avermectin to solvent, cerium chloride, and dichlorotris(triphenylphosphine)ruthenium is 100:250-300:150-170:37-42;

[0011] As a further technical solution, the borohydride is sodium borohydride or potassium borohydride;

[0012] The molar ratio of avermectin to borohydride is 1.0 to 1.3 (preferably 1.05 to 1.3).

[0013] As a further technical solution, the volume ratio of anhydrous ethanol to toluene is 1:4.

[0014] As a further technical solution, a method for synthesizing ivermectin further comprises:

[0015] Step 2, removing the catalyst: adding thiourea to the reaction solution containing ivermectin, refluxing for 4 hours, adding water, standing and stratifying, draining the water layer, removing the solvent from the organic layer by vacuum distillation, adding ethanol to dissolve the ivermectin crude product, then adding activated carbon and heating to about 60°C for decolorization for 3 to 4 hours, and filtering to obtain a filtrate;

[0016] Step 3, crystallization: add formamide and purified water to the filtrate, cool to 20-25 degrees Celsius after the addition is complete, precipitate ivermectin crystals, filter, and obtain primary wet crystals and crystallization mother liquor;

[0017] Add ethanol to the primary wet crystals, heat to 60 degrees Celsius to dissolve, then drop formamide and water, and 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, and dry the secondary wet crystals to obtain ivermectin products.

[0018] As a further technical solution, thiourea is added to the reaction solution containing ivermectin at a weight ratio of avermectin to thiourea of ​​100:1.5-1.7.

[0019] Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

[0020] The invention uses avermectin as a raw material, and under the action of a cerium chloride catalyst and a dichlorotri(triphenylphosphine)ruthenium catalyst, sodium borohydride is used as a reducing agent to selectively reduce the double bonds at positions 22 and 23 to synthesize ivermectin. The invention does not need to introduce hydrogen, thus solving a series of problems caused by introducing hydrogen. The catalysts can be commercially available, have good selectivity for the double bonds at positions 22 and 23, have a high avermectin conversion rate, and have good product purity. Compared with the triphenylphosphine rhodium chloride catalyst in the traditional technology, the invention uses a relatively low-priced ruthenium catalyst, reduces the amount of the noble metal catalyst, and thus reduces the catalyst cost. DETAILED DESCRIPTION

[0021] The present invention is further described in detail below with reference to the embodiments.

[0022] Example 1

[0023] A method for synthesizing ivermectin comprises the following steps:

[0024] Step 1, reduction reaction: first, add 100 kg of avermectin to 270 kg of solvent (anhydrous ethanol and toluene volume ratio of 1:4), stir and dissolve, then cool to -30°C to -35°C, then add 160 g of catalyst A cerium chloride, stir for 30 minutes, then add 40 g of dichlorotri(triphenylphosphine)ruthenium, continue stirring for 30 minutes, slowly add 10 kg of sodium borohydride, control the sodium borohydride to be added within 2 hours, then heat the reaction system to 5 to 10 degrees Celsius, keep the temperature for 8 to 10 hours, until the avermectin residual rate is less than 1%; generate ivermectin, and obtain a reaction solution containing ivermectin.

[0025] Step 2, removing the catalyst: add 1.5 kg of thiourea to the reaction solution containing ivermectin, reflux for 4 hours, add water, let stand for stratification, discharge the water layer, remove the solvent from the organic layer by vacuum distillation, add ethanol, then add activated carbon and heat to about 60°C for decolorization for 3.5 hours, filter and obtain a filtrate;

[0026] Step 3, crystallization: add 25 kg of formamide and 130 kg of purified water to the filtrate, cool to 20-25 degrees Celsius after the addition is complete, precipitate ivermectin crystals, filter, and obtain primary wet crystals and crystallization mother liquor;

[0027] Add 200 kg of ethanol to the primary wet crystals, heat to 60 degrees Celsius to dissolve, then drop 8.5 kg of formamide and 210 kg of water. 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, and dry the secondary wet crystals to obtain ivermectin products.

[0028] Example 2

[0029] A method for synthesizing ivermectin comprises the following steps:

[0030] Step 1, reduction reaction: first, add 100 kg of avermectin to 250 kg of solvent (anhydrous ethanol and toluene volume ratio of 1:4), stir and dissolve, then cool to -30°C to -35°C, then add 165 g of catalyst A cerium chloride, stir for 30 minutes, then add 40 g of dichlorotri(triphenylphosphine)ruthenium, continue stirring for 30 minutes, slowly add 11 kg of sodium borohydride, control the sodium borohydride to be added within 2 hours, then heat the reaction system to 5 to 10 degrees Celsius, keep the temperature for 8 to 10 hours, until the avermectin residual rate is less than 1%; generate ivermectin, and obtain a reaction solution containing ivermectin.

[0031] Step 2, removing the catalyst: add 1.6 kg of thiourea to the reaction solution containing ivermectin, reflux for 4 hours, add water, let stand for stratification, discharge the water layer, remove the solvent from the organic layer by vacuum distillation, add ethanol, then add activated carbon and heat to about 60°C for decolorization for 3.5 hours, filter and obtain a filtrate;

[0032] Step 3, crystallization: add formamide and purified water to the filtrate, cool to 20-25 degrees Celsius after the addition is complete, precipitate ivermectin crystals, filter, and obtain primary wet crystals and crystallization mother liquor;

[0033] Add ethanol to the primary wet crystals, heat to 60 degrees Celsius to dissolve, then drop formamide and water, and 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, and dry the secondary wet crystals to obtain ivermectin products.

[0034] Example 3

[0035] A method for synthesizing ivermectin comprises the following steps:

[0036] Step 1, reduction reaction: first, add 100 kg of avermectin to 3000 kg of solvent (anhydrous ethanol and toluene volume ratio of 1:4), stir and dissolve, cool to -30°C to -35°C, then add 155 g of catalyst A cerium chloride, stir for 30 minutes, add 40 g of dichlorotri(triphenylphosphine)ruthenium, continue stirring for 30 minutes, slowly add 9.5 kg of sodium borohydride, control the sodium borohydride to be added within 2 hours, then heat the reaction system to 5 to 10 degrees Celsius, keep the temperature for 8 to 10 hours, until the avermectin residual rate is less than 1%; generate ivermectin, and obtain a reaction solution containing ivermectin.

[0037] Step 2, removing the catalyst: add 1.5 kg of thiourea to the reaction solution containing ivermectin, reflux for 4 hours, add water, let stand for stratification, discharge the water layer, remove the solvent from the organic layer by vacuum distillation, add ethanol, then add activated carbon and heat to about 60°C for decolorization for 3.5 hours, filter and obtain a filtrate;

[0038] Step 3, crystallization: add formamide and purified water to the filtrate, cool to 20-25 degrees Celsius after the addition is complete, precipitate ivermectin crystals, filter, and obtain primary wet crystals and crystallization mother liquor;

[0039] Add ethanol to the primary wet crystals, heat to 60 degrees Celsius to dissolve, then drop formamide and water, and 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, and dry the secondary wet crystals to obtain ivermectin products.

[0040] Comparative Example 1

[0041] A method for synthesizing ivermectin comprises the following steps: the same as Example 1, except that tetrakis(triphenylphosphine)cerium chloride is used to replace cerium chloride.

[0042] Comparative Example 2

[0043] A method for synthesizing ivermectin comprises the following steps: the same as Example 1, except that tetrakis(triphenylphosphine)ruthenium chloride is used to replace dichlorotris(triphenylphosphine)ruthenium.

[0044] Comparative Example 3

[0045] A method for synthesizing ivermectin comprises the following steps: the same as Example 1, except that only cerium chloride is used as a catalyst, and tris(triphenylphosphine)ruthenium dichloride is not used as a catalyst.

[0046] Comparative Example 4

[0047] A method for synthesizing ivermectin comprises the following steps: the same as Example 1, except that only dichlorotris(triphenylphosphine)ruthenium is used instead of cerium chloride.

[0048] Comparative Example 5

[0049] A method for synthesizing ivermectin comprises the following steps:

[0050] Step 1, reduction reaction: first, add 100 kg of avermectin into 270 kg of solvent (anhydrous ethanol and toluene volume ratio of 1:4), stir and dissolve, then cool to -30°C to -35°C, then add 40 g of ruthenium chloride and 160 g of monosulfonated triphenylphosphine sodium salt, stir for 30 minutes, slowly add 10 kg of sodium borohydride, control the sodium borohydride to be added within 2 hours, then heat the reaction system to 5 to 10 degrees Celsius, keep warm and react until the avermectin residual rate is less than 1%; generate ivermectin, and obtain a reaction solution containing ivermectin.

[0051] Step 2, removing the catalyst: same as in Example 1;

[0052] Step 3, crystallization: same as Example 1.

[0053] Comparative Example 6

[0054] A method for synthesizing ivermectin comprises the following steps:

[0055] Step 1, reduction reaction: first, add 100 kg of avermectin into 270 kg of solvent (anhydrous ethanol and toluene volume ratio of 1:4), stir and dissolve, then cool to -30°C to -35°C, then add 1 kg of triphenylphosphine rhodium chloride, stir for 30 minutes, slowly add 10 kg of sodium borohydride, control the sodium borohydride to be added within 2 hours, then heat the reaction system to 5 to 10 degrees Celsius, keep warm and react until the avermectin residual rate is less than 1%; generate ivermectin, and obtain a reaction solution containing ivermectin.

[0056] Step 2, removing the catalyst: same as in Example 1;

[0057] Step 3, crystallization: same as Example 1.

[0058] Comparative Example 7

[0059] A method for synthesizing ivermectin comprises the following steps:

[0060] Step 1: Preparation of copper-cobalt complex catalyst:

[0061] Step a, dissolving 0.1 mol of anhydrous CuCl2 and 0.05 mol of cobalt nitrate in 200 mL of purified water at 50-55° C. to prepare solution A;

[0062] Step b, dispersing 0.5 mol of dibenzo-18-crown-6 in 200 mL of anhydrous ethanol to prepare solution B;

[0063] Step c, uniformly mixing solution A and solution B, and vigorously stirring to precipitate a precipitate, and after the precipitate no longer precipitates, removing the reaction solvent by reduced pressure distillation, and drying to obtain a precipitate;

[0064] Step d: add 0.5 mol of 1,5-bis(diphenylphosphino)pentane to 500 mL of DMF, then add the precipitate, stir, keep warm at 60° C. for 4 hours, cool to room temperature, remove the reaction solvent by vacuum distillation, and dry the solid at 80° C. to constant weight to obtain a copper-cobalt complex catalyst.

[0065] Step 2, reduction reaction:

[0066] First, 100 kg of avermectin is added to 270 kg of solvent (the volume ratio of anhydrous ethanol to toluene is 1:4), stirred and dissolved, and then cooled to -30°C to -35°C, then 2 kg of copper-cobalt complex catalyst and 1 kg of phosphomolybdic acid are added, and after stirring for 30 minutes, 10 kg of sodium borohydride is slowly added, and the sodium borohydride is added within 2 hours, and then the reaction system is heated to 5 to 10 degrees Celsius, and the temperature is kept for reaction until the residual rate of avermectin is less than 1%; ivermectin is generated, and a reaction liquid containing ivermectin is obtained.

[0067] Step 3, removing the catalyst: adding water to the reaction solution containing ivermectin, standing and stratifying, draining the water layer, removing the solvent from the organic layer by vacuum distillation, adding ethanol, and then adding activated carbon and heating to about 60°C for decolorization for 3.5 hours, and filtering to obtain a filtrate;

[0068] Step 3, crystallization: same as Example 1.

[0069] Effect example:

[0070] 1) In the ivermectin preparation process of each embodiment and each comparative example, an organic layer sample obtained after standing and stratifying in the catalyst removal step was taken, and the content of the raw material and the product was analyzed by area normalization method. The results are shown in Table 1;

[0071] 2) Determine the weight of the ivermectin product prepared in Examples 1 to 3, and the content (purity) of the ivermectin product, and calculate the total yield of ivermectin. The results are shown in Table 1;

[0072] 3) The ivermectin products were quality controlled in accordance with the relevant provisions of the first part of the Chinese Veterinary Pharmacopoeia 2020. The results are shown in Table 1;

[0073] Table 1

[0074] Note: - means not carried out.

[0075] The above-described embodiments are only preferred embodiments of the present invention, and are not exhaustive of the feasible implementations of the present invention. For those skilled in the art, any obvious changes made thereto without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing ivermectin, characterized in that: With anhydrous ethanol and toluene as solvents, in the presence of catalysts cerium chloride and dichlorotri(triphenylphosphine)ruthenium, avermectin undergoes a reduction reaction with sodium borohydride to produce ivermectin.

2. The method for synthesizing ivermectin according to claim 1, characterized in that: The specific steps include: Step 1, reduction reaction: first, add avermectin to a solvent, stir to dissolve, then cool to -30°C to -35°C, then add cerium chloride, stir for 30 minutes, add dichlorotri(triphenylphosphine)ruthenium, continue stirring for 30 minutes, slowly add sodium borohydride, after the sodium borohydride is added, heat to 5 to 10 degrees Celsius, keep warm for 8 to 10 hours to generate ivermectin, and obtain a reaction solution containing ivermectin.

3. The method for synthesizing ivermectin according to claim 2, characterized in that: The weight ratio of the avermectin to the solvent, cerium chloride and dichlorotris(triphenylphosphine)ruthenium is 100:250-300:150-170:37-42.

4. The method for synthesizing ivermectin according to claim 2, characterized in that: The borohydride is sodium borohydride or potassium borohydride; The molar ratio of avermectin to borohydride is 1.0-1.

3.

5. The method for synthesizing ivermectin according to claim 2, characterized in that: The volume ratio of the anhydrous ethanol to toluene is 1:

4.

6. The method for synthesizing ivermectin according to claim 2, characterized in that: Also includes: Step 2, removing the catalyst: adding thiourea to the reaction solution containing ivermectin, refluxing for 4 hours, adding water, standing and stratifying, draining the water layer, removing the solvent from the organic layer by vacuum distillation, adding ethanol to dissolve the ivermectin crude product, then adding activated carbon and heating to about 60°C for decolorization for 3 to 4 hours, and filtering to obtain a filtrate; Step 3, crystallization: add formamide and purified water to the filtrate, cool to 20-25 degrees Celsius after the addition is complete, precipitate ivermectin crystals, filter, and obtain primary wet crystals and crystallization mother liquor; Add ethanol to the primary wet crystals, heat to 60 degrees Celsius to dissolve, then drop formamide and water, and 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, and dry the secondary wet crystals to obtain ivermectin products.

7. The method for synthesizing ivermectin according to claim 6, characterized in that: Thiourea is added to the reaction solution containing ivermectin at a weight ratio of avermectin to thiourea of ​​100:1.5-1.7.

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